Hyper-phosphorylation of Sequestosome-1 Distinguishes Resistance to Cisplatin in Patient Derived High Grade Serous Ovarian Cancer Cells.
Platinum-resistance is a major limitation to effective chemotherapy regimens in high-grade serous ovarian cancer (HGSOC). To better understand the mechanisms involved we characterized the proteome and phosphoproteome in cisplatin sensitive and resistant HGSOC primary cells using a mass spectrometry-based proteomic strategy. PCA analysis identified a distinctive phosphoproteomic signature between cisplatin sensitive and resistant cell lines. The most phosphorylated protein in cisplatin resistant cells was sequestosome-1 (p62/SQSTM1). Changes in expression of apoptosis and autophagy related proteins Caspase-3 and SQSTM1, respectively, were validated by Western blot analysis. A significant increase in apoptosis in the presence of cisplatin was observed in only the sensitive cell line while SQSTM1 revealed increased expression in the resistant cell line relative to sensitive cell line. Furthermore, site-specific phosphorylation on 20 amino acid residues of SQSTM1 was detected indicating a hyper-phosphorylation phenotype. This elevated hyper-phosphorylation of SQSTM1 in resistant HGSOC cell lines was validated with Western blot analysis. Immunofluoresence staining of s28-pSQSTM1 showed inducible localization to autophagosomes upon cisplatin treatment in the sensitive cell line while being constitutively expressed to autophagosomes in the resistant cell. Furthermore, SQSTM1 expression was localized in cancer cells of clinical high-grade serous tumors. Here, we propose hyper-phosphorylation of SQSTM1 as a marker and a key proteomic change in cisplatin resistance development in ovarian cancers by activating the autophagy pathway and influencing down-regulation of apoptosis.


[Influence of occupational respiratory diseases on life quality parameters].
The article covers results of life quality studies in patients with occupational respiratory diseases and in workers at risk of diseases due to dust. Findings are that occuupational respiratory diseases negatively influence physical and psycho-social status of the patients. The influence degree is connected to smoking intensity, the disease duration and bronchial obstruction grade. Life quality study is an important indicator of the symptoms control, additional parameter to clinical and functional state monitoring.


The effect of hypermethylation on the functional properties of transfer ribonucleic acid. Ribosome-binding and polypeptide synthesis.
1. Phenylalanyl-tRNA formed after chemical hypermethylation of Escherichia coli B tRNA was able to bind to ribosomes with the same efficiency as normal phenylalanyl-tRNA. 2. Under incubation conditions used in the ribosome-binding assay, hypermethylation of tRNA did not measurably decrease the stability of either inter-nucleotide phosphodiester bonds or the covalent bond between amino acid and tRNA in phenylalanyl-tRNA. 3. The ability of hypermethylated tRNA to take part in polyphenylalanine synthesis was inhibited progressively as the degree of hypermethylation increased. 4. Hypermethylation of tRNA affected polyphenylalanine synthesis at the stage of amino acid recognition and at a further point in the synthesis but not at the level of codon-anticodon recognition. 5. The formation of polylysine was more seriously affected by hypermethylation of tRNA than would be accounted for by inhibition of amino acid acceptance alone. 6. Polyproline formation was completely inhibited by the presence of 7mol% excess of methyl groups in tRNA. 7. The possibility of a link between amino acid acceptance and ribosome-binding was suggested for phenylalanyl-tRNA, but not for lysyl- or prolyl-tRNA.


Multisolvent Models for Solvation Free Energy Predictions Using 3D-RISM Hydration Thermodynamic Descriptors.
The potential to predict solvation free energies (SFEs) in any solvent using a machine learning (ML) model based on thermodynamic output, extracted exclusively from 3D-RISM simulations in water is investigated. The models on multiple solvents take into account both the solute and solvent description and offer the possibility to predict SFEs of any solute in any solvent with root mean squared errors less than 1 kcal/mol. Validations that involve exclusion of fractions or clusters of the solutes or solvents exemplify the model's capability to predict SFEs of novel solutes and solvents with diverse chemical profiles. In addition to being predictive, our models can identify the solute and solvent features that influence SFE predictions. Furthermore, using 3D-RISM hydration thermodynamic output to predict SFEs in any organic solvent reduces the need to run 3D-RISM simulations in all these solvents. Altogether, our multisolvent models for SFE predictions that take advantage of the solvation effects are expected to have an impact in the property prediction space.


Bone impairment in phenylketonuria is characterized by circulating osteoclast precursors and activated T cell increase.
Phenylketonuria (PKU) is a rare inborn error of metabolism often complicated by a progressive bone impairment of uncertain etiology, as documented by both ionizing and non- ionizing techniques. Peripheral blood mononuclear cell (PBMC) cultures were performed to study osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). Flow cytometry was utilized to analyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor α (TNF-α), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA. The effects of RANKFc and anti-TNF-α antibodies were also investigated to determine their ability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKU patients were clinically evaluated. Several in vitro studies in PKU patients' cells identified a potential mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patients disclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated and M-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher in PKU patients compared to healthy controls. The addition of specific antagonist RANKFc caused osteoclastogenesis inhibition, whereas anti-TNF-α failed to have this effect. Among PBMCs isolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL were identified. Confirmatory in vivo studies support this proposed model. These in vivo studies included the analysis of osteoclastogenesis in PKU patients, which demonstrated an inverse relation to bone condition assessed by phalangeal Quantitative Ultrasound (QUS). This was also directly related to non-compliance to therapeutic diet reflected by hyperphenylalaninemia. Our results indicate that PKU spontaneous osteoclastogenesis depends on the circulating OCP increase and the activation of T cells. Osteoclastogenesis correlates with clinical parameters, suggesting its value as a diagnostic tool for an early assessment of an increased bone resorption in PKU patients.


Synthesis of heteroaromatic trifluoromethyl ethers with trifluoromethyl triflate as the source of the trifluoromethoxy group.
A series of nitrogen-heterocycles have been transformed to the corresponding trifluoromethyl or higher perfluoroalkyl ethers by reaction of the corresponding N-oxides with trifluoromethyl or higher perfluoroalkyl triflate. Trifluoromethyl triflate, which has generally been used as a precursor to [OCF3]-, is used here as a bifunctional reagent to render the heteroarene more electrophilic and to deliver the trifluoromethoxy group. This reagent was easily prepared on a large scale (>100 grams) and is stable in either pure form or as a stock solution. Applications and limitations of this method are reported.


Misaligned Versus Straight Placement of Anterior Cervical Plates: A Clinical and Radiologic Outcomes Study.
In anterior cervical diskectomy and fusion (ACDF), misaligned plates are concerning because of the risk of screw-and-plate failure; however, these plates also hypothetically have the potential for asymmetric micromotion on the facet and uncovertebral joint. The aim of this study was to determine whether misaligned plate placement during ACDF had clinical benefits compared with straight plate placement. Postoperative AP radiographs of 128 consecutive patients who underwent ACDF with anterior cervical plate (ACP) fixation were reviewed, and plate alignment was assessed. Patients were separated into control group 1 (straight plates) or group 2 (misaligned plates). The mean age of patients was 51.5 ± 0.9 years, and women represented 51% of the total population. There was no significant difference between groups with regard to the preoperative visual analog scale (VAS) and Neck Disability Index (NDI) scores (P = 0.744 and P = 0.943, respectively). At 6 weeks postoperatively, the VAS scores for group 1 decreased from 7.6 ± 0.2 to 4.0 ± 0.2 compared with the scores in group 2, which decreased from 7.7 ± 0.2 to 2.1 ± 0.1, which demonstrated statistical significance (P = 0.019). At 2-year follow-up, no significant difference was demonstrated between the groups' VAS and NDI scores (P = 0.670 and P = 0.266). Misaligned plates have increased torsional strength and are associated with better clinical outcomes compared with those of straight plates in the early postoperative period. After fusion, no significant difference in clinical outcomes between the groups was noted, which may reduce the concerns regarding misaligned plates. Retrospective comparative study.


Latest aspects of aldosterone actions on the heart muscle.
The genomic action of aldosterone has already been known to the scientific community and is well-documented to a satisfactory degree. However, the existence of rapid, non-genomic aldosterone actions has repeatedly been proven. These actions are apparent to a lot of tissues, among which the cardiac tissue, with the cardiac cells being responsible for the secretion of endogenous aldosterone. In the genomic pathway, the connection between the hormone and its receptor results increased reabsorption of sodium and water and excretion of potassium. Thus, the genomic procedure reacts indirectly on cardiovascular system by altering the blood pressure. New studies have shed light on unknown aspects of the non-genomic mechanism, which is sometimes performed by means of mineralocorticoid receptor (MR), while others through an MR-independent pathway. It is believed that aldosterone exerts its non-genomic action with the help of a different receptor, probably a G protein coupled receptor. A possible target is protein kinase C (PKC), and PKCε is postulated increase the permeability of the membrane of the cardiac cells to sodium, resulting in delayed repolarization and prolongation of action potential. These findings totally agree with and account for the serendipitous finding of our laboratory, that there is a positive correlation between plasma aldosterone levels and left ventricle (LV) contraction duration. Also, aldosterone has been proven to exacerbate the oxidative stress and induce vasoconstriction by acting on the vascular resistance and the cardiac output. Finally, this article deals with the role of aldosterone in cardiac fibrosis and the latest aspects of aldosterone actions on the heart muscle as well as providing a historical overview of the landmarks pertaining aldosterone's research.


Impaired fast axonal transport in neurons of the sciatic nerves from dystonia musculorum mice.
Dystonia musculorum (dt) mice suffer from a severe sensory neuropathy caused by mutations in the gene encoding the cytoskeletal cross-linker protein dystonin/bullous pemphigoid antigen 1 (Bpag1). Loss of function of dystonin/Bpag1 within neurons leads to a loss in the maintenance of cytoskeletal organization and to the development of focal axonal swellings prior to death of the neuron. In the present study, we demonstrate that neurons within the sciatic nerves of dt27J mice undergo axonal degeneration as has been previously reported for the dorsal roots. Furthermore, ultrastructural studies reveal a perturbed organization of the neurofilament and microtubule networks within the axons of sciatic nerves in dt27J mice. The disrupted cytoskeletal organization suggested that axonal transport is affected in dt mice. To address this, we assessed fast axonal transport by measuring the rate of accumulation of acetylcholinesterase (AChE) proximal and distal to a surgically introduced ligature on the sciatic nerves of normal and dt27J mice. Our findings demonstrate that axonal transport of AChE in both orthograde and retrograde directions is markedly affected, and allow us to conclude that axonal transport defects do exist in the sciatic nerves of dt27J mice.


Preeclampsia: Long-term effects on pediatric disability.
Preeclampsia affects up to 10% of pregnancies worldwide and is one of the main causes of fetal morbidity and mortality. Although it has been linked to developmental delay, its long-term effects on neurologic development in children have yet to be sufficiently quantified. To evaluate whether preeclampsia's severity and its obstetric management correlate to the degree of disability in these infants. This is an observational and descriptive study performed on a population of 96 women who were diagnosed with preeclampsia at Hospital General Universitario Gregorio Marañón between 2007 and 2014, and their 111 children. To evaluate the mother, we gathered data pertaining to her medical history, renal function markers, and medical management of the preeclampsia. To assess the children, we collected fetal growth measurements, acute fetal distress markers and main diagnoses at birth. We used the Pediatric Evaluation of Disability Inventory in its computerized adaptive test version (PEDI-CAT) to study performance in the relevant areas, and the TNO-AZL Preschool children Quality of Life (TAPQOL) to estimate health-related quality of life. PEDI-CAT percentiles were consistently lower in the social/cognitive domain than in other areas. Lower social/cognitive percentiles were associated to both lower maternal IgG levels and presence of necrotizing enterocolitis during the neonatal period. A connection between preeclampsia and poor social/cognitive outcomes exists that warrants further research.


Swimming capability and swimming behavior of juvenile acipenser schrenckii.
Acipenser schrenckii, the Amur Sturgeon, was a commercially valuable fish species inhabiting the Amur (Heilongjiang) River but populations have rapidly declined in recent years. Dams impede A. schrenckii spawning migration and wild populations were critically endangered. Building fishways helped maintain fish populations but data on swimming performance and behavior was crucial for fishway design. To obtain such data on A. schrenckii, a laboratory study of juvenile A. schrenckii (n = 18, body mass = 32.7 ± 1.2 g, body length = 18.8 ± 0.3 cm) was conducted using a stepped velocity test carried out in a fish respirometer equipped with a high-speed video camera at 20°C. Results indicate: (1) The counter-current swimming capability of A. schrenckii was low with critical swimming speed of 1.96 ± 0.10 BL/sec. (2) When a linear function was fitted to the data, oxygen consumption, as a function of swimming speed, was determined to be MO2 = 337.29 + 128.10U (R(2) = 0.971, P < 0.001) and the power value (1.0) of U indicated high swimming efficiency. (3) Excess post-exercise oxygen cost was 48.44 mgO2 /kg and indicated excellent fatigue recovery. (4) Cost of transport decreased slowly with increased swimming speed. (5) Increased swimming speed led to increases in the tail beat frequency and stride length. This investigation contributed to the basic science of fish swimming behavior and provided data required for the design of fishways. Innovative methods have allowed cultivation of the species in the Yangtze River and, if effective fishways could be incorporated into the design of future hydropower projects on the Amur River, it would contribute to conservation of wild populations of A. schrenckii. The information provided here contributes to the international effort to save this critically endangered species. J. Exp. Zool. 319A:149-155, 2013. © 2013 Wiley Periodicals, Inc.


Enhanced surveillance of norovirus outbreaks of gastroenteritis in Georgia.
The role of noroviruses in both foodborne and person-to-person outbreaks of acute gastroenteritis (AGE) has been difficult to determine in the U.S. because of lack of routine norovirus testing and of national reporting of person-to-person outbreaks. We conducted a prospective study in one state in which enhanced testing for noroviruses was performed to better understand the relative contribution of all gastroenteric pathogens. During the two-year period, 2000-2001, we took all fecal specimens from AGE outbreaks reported in Georgia that were negative for bacteria and tested these for norovirus. We investigated 78 AGE outbreaks, from which suitable fecal samples were collected from 57 of them. Norovirus was identified in 25 (44%) outbreaks, bacteria in 20 (35%) outbreaks, and parasites in one (2%) outbreak. Forty-three (75%) of the outbreaks tested were foodborne, of which 17 (40%) were attributable to norovirus and 18 (42%) were attributable to bacteria. Adjusting for incomplete testing, we estimated that 53% of all AGE outbreaks were attributable to norovirus. A total of 2,674 people were reported ill in the 57 outbreaks, and norovirus infections accounted for 1,735 (65%) of these cases. Norovirus outbreaks tended to be larger than bacterial outbreaks, with a median number of 30 vs. 16 cases per outbreak, respectively (p = 0.057). This study provides further evidence that noroviruses are, overall, the most common cause of AGE outbreaks in the U.S. Improved specimen collection, reporting person-to-person outbreaks, and access to molecular assays are needed to further understand the role of these viruses and methods for their prevention.


Microsatellite markers from a microdissected swine chromosome 6 genomic library.
To develop additional microsatellite (MS) markers in the region of the porcine skeletal muscle ryanodine receptor gene (RYR1), a microdissected genomic library was generated from the proximal half of the q arm of swine chromosome 6. Purified DNA was restriction enzyme-digested, ligated to oligonucleotide adaptors and amplified by PCR using primers complementary to the adaptor sequences. The purity of the amplified products and boundaries of the microdissected chromosomal region were verified by fluorescence in situ hybridization. (CA)n-containing sequences were then identified in a small insert genomic library generated from the PCR-amplified microdissected DNA. Oligonucleotide primers were developed for the PCR amplification of 30 of the 46 (CA)n repeat-containing clones, which were subsequently used to amplify DNA isolated from unrelated pigs of different breeds to determine the informativeness of these MS markers. Twenty-two of these MS markers were genotyped on the University of Illinois Yorkshire x Meishan swine reference population. These 22 markers were all assigned within a 50.7-CM region of the swine chromosome 6 linkage map, indicating the specificity of the microdissected library.


Delayed tolerance with repetitive transient focal ischemic preconditioning in the mouse.
Transient ischemic attacks have long been regarded as a risk factor for the incidence of stroke but may reduce the severity of stroke by inducing ischemic tolerance. The present objective was to develop an ischemic preconditioning (IPC) model of delayed tolerance in the mouse based on repetitive, transient middle cerebral artery occlusion (MCAO). Mice anesthetized with halothane or isoflurane underwent IPC, which consisted of repetitive MCAO at 45-minute intervals by the intraluminal filament technique. A 90-minute test MCAO was performed 24 to 96 hours later. Using an IPC of 2 5-minute MCAO episodes, the reduction in infarct volume from the test MCAO was maximal with a 72-hour delay in striatum (70%) and cerebral cortex (64%) when halothane was used for surgical anesthesia. With isoflurane anesthesia, the reduction in infarct volume was less prominent in striatum (34%) and not significant in cortex (9%) despite similar levels of arterial pressure and decreases in cortical perfusion. Neuronal cell death was rare 6 days after this IPC stimulus alone with halothane or isoflurane. Increasing the severity of IPC to 3 5-minute bouts or 1 15-minute bout of MCAO in the presence of isoflurane anesthesia augmented the reduction in infarct volume in striatum and cortex, but it also augmented selective neuronal cell death in striatum after the IPC stimulus alone. These data demonstrate that a repetitive focal IPC stimulus can be titrated to induce delayed tolerance in both striatum and cortex of the mouse without inducing neuronal death by itself.


Scintigraphic detection of osteoid osteoma.
Bone scanning with 99mTc-diphosphonate disclosed a solitary focus of intense activity in a cervical vertebra of a 17-year-old youth with persistent unexplained neck pain. Surgery subsequently demonstrated a well-circumscribed osteoid osteoma. This experience is further evidence of the efficacy of radionuclide skeletal scintigraphy in the evaluation of benign bone disease.


Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study.
Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. Mean estimated glomerular filtration rate (eGFR) was 46.5 ± 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 ± 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable-adjusted 1.70 µm increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation.


Fertility in essential tremor. Data from population-based and clinical sources.
The view of essential tremor (ET) as a degenerative disorder, which is now gaining support from postmortem studies, is at odds with traditional views of ET as a 'super-healthy' condition characterized by increased longevity and fertility. Longevity has recently been re-examined in ET, yet fertility, measured by number of offspring, has never been critically assessed in this disease. The objective was to determine whether ET cases and controls differ in terms of number of children. Family history data were collected on ET cases and controls from 2 distinct sources, a population and a clinical (referred) sample. In the population, the number of children was similar in 59 cases vs. 72 controls [mean +/- SD (median) = 2.3 +/- 2.9 (1) vs. 2.2 +/- 1.8 (2); p = 0.26]. In the referred sample, number of children was similar in 184 cases vs. 241 controls [2.0 +/- 1.5 (2) vs. 1.9 +/- 1.7 (2); p = 0.33]. In adjusted analyses, results were similar. Fertility, measured by number of children, was similar in cases and controls. With a newer understanding of the biological substrate of ET emerging from postmortem studies, it is important to critically reassess this and other fundamental biological questions about the disease.


Integrated safety summary of FOCUS 1 and FOCUS 2 trials: Phase III randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with community-acquired pneumonia.
Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is a broad-spectrum, parenteral cephalosporin approved for treatment of moderate to severe bacterial infections, including community-acquired pneumonia (CAP). This report provides an integrated safety summary of the ceFtarOline Community-acquired pneUmonia trial versuS ceftriaxone (FOCUS) 1 and 2 trials (registration numbers: NCT00621504 and NCT00509106). Patients hospitalized with CAP requiring intravenous therapy and having Pneumonia Outcomes Research Team (PORT) risk class scores of III or IV were randomized (1:1) to receive 600 mg of ceftaroline fosamil administered intravenously every 12 h or 1 g of ceftriaxone administered intravenously every 24 h for 5-7 days. All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit; serious adverse events (SAEs) including deaths occurring up to the late follow-up visit or within 30 days after the last dose were additionally recorded. Scheduled laboratory testing was conducted up to the test-of-cure visit; unscheduled testing continued up to the late follow-up visit. A total of 1228 patients (613 in the ceftaroline fosamil group and 615 in the ceftriaxone group) received any amount of drug and were included in the safety analysis. The incidences of TEAEs (47.0% versus 45.7%), SAEs (11.3% versus 11.7%), discontinuations (4.4% versus 4.1%) and deaths (2.4% versus 2.0%) were similar between the ceftaroline fosamil and the ceftriaxone groups, respectively. Diarrhoea (4.2%), headache (3.4%) and insomnia (3.1%) were the most commonly reported TEAEs in patients treated with ceftaroline fosamil. The distribution of TEAEs based on severity was also similar between groups, and the majority of patients in both treatment groups (∼75%) had either no TEAEs or only mild TEAEs. The data from the FOCUS 1 and FOCUS 2 trials presented in this integrated safety summary demonstrate that ceftaroline fosamil is well tolerated, with a tolerability profile similar to ceftriaxone and the cephalosporin class overall, with no unexpected safety concerns being identified.


Changing concepts in the systematics of bacterial nitrogen-fixing legume symbionts.
As of February 2003, bacteria that form nitrogen-fixing symbiotic associations with legumes have been confirmed in 44 species of 12 genera. Phylogenies of these taxa containing legume symbionts based on the comparative analysis of 16S rDNA sequences show that they are not clustered in one lineage but are distributed in the classes Alphaproteobacteria and Betaproteobacteria, and dispersed over the following nine monophyletic groups, being intermingled with other taxa that do not contain legume symbionts (shown in parentheses below): Group 1, which comprises Rhizobium and Allorhizobium species containing legume symbionts (intermingled with Agrobacterium and Blastobacter species, which are nonsymbionts); Group 2, Sinorhizobium and Ensifer species (with unclassified nonsymbionts); Group 3, Mesorhizobium species (with nonsymbiotic Aminobacter and Pseudaminobacter species); Group 4, Bradyrhizobium species and Blastobacter denitrificans (with nonsymbiotic Agromonas, Nitrobacter, Afipia, and Rhodopseudomonas species); Group 5, 'Methylobacterium nodulans" (with nonsymbiotic Methylobacterium species); Group 6, Azorhizobium species (with nonsymbiotic Xanthobacter and Aquabacter species); Group 7, 'Devosia neptuniae" (with nonsymbiotic Devosia species and unclassified nonsymbionts); Group 8, symbiotic Burkholderia strains (with nonsymbiotic Burkholderia species); and Group 9, Ralstonia taiwanensis (with nonsymbiotic Ralstonia species). For Groups 5, 8, and 9, the present classification, in which 'each monophyletic group comprises one genus wherein legume symbionts and nonsymbionts are intermingled with each other, " is considered to be retained as is because they are clearly separated from other genera at high bootstrap values and have already been sufficiently characterized based on polyphasic taxonomy. As for the remaining six monophyletic groups, on the other hand, there are currently three options for emending their current classification (definitions and circumscriptions) at the generic level: A) the current classification shall be retained as is; B) all the genera within each monophyletic group shall be amalgamated into one single genus in conformity with the results of phylogenetic analysis; or C) each subordinate lineage in each monophyletic group shall be proposed as a genus. It is considered that research and discussions will be continuously conducted for emending the classification of these monophyletic groups based chiefly on Options B and C as preferable candidates.


Relationship of Circulating Irisin with Body Composition, Physical Activity, and Cardiovascular and Metabolic Disorders in the Pediatric Population.
Exercise-induced irisin, a recently discovered myokine, has been linked to insulin resistance, obesity, and other diseases in adults; however, information in children is scarce and contradictory. We analyzed the limited evidence of irisin's effects in children and adolescents, and its association with body composition, exercise training, cardiovascular risk factors, and metabolic diseases, as well as the results of dietetic interventions. Both positive and negative correlations between irisin concentrations and body mass index, fat mass, fat-free mass, and other anthropometric parameters were found. Likewise, contradictory evidence was shown associating irisin plasma levels with cardiovascular and metabolic parameters such as glucose, insulin resistance, and cholesterol and other lipid and fatty acid plasma levels in healthy children, as well as in those with obesity and the metabolic syndrome. Gender, puberty, and hormonal differences were also examined. Furthermore, important contradictory findings according to the type and duration of exercise and of dietetic interventions in healthy and unhealthy subjects were demonstrated. In addition, correlations between mother⁻infant relations and circulating irisin were also identified. This review discusses the potential role of irisin in health and disease in the pediatric population.


Nitric oxide in myogenesis and therapeutic muscle repair.
Nitric oxide is a short-lived intracellular and intercellular messenger. The first realisation that nitric oxide is important in physiology occurred in 1987 when its identity with the endothelium-derived relaxing factor was discovered. Subsequent studies have shown that nitric oxide possesses a number of physiological functions that are essential not only to vascular homeostasis but also to neurotransmission, such as in the processes of learning and memory and endocrine gland regulation, as well as inflammation and immune responses. The discovery in 1995 that a splice variant of the neuronal nitric oxide synthase is localised at the sarcolemma via the dystrophin-glycoprotein complex and of its displacement in Duchenne muscular dystrophy has stimulated a host of studies exploring the role of nitric oxide in skeletal muscle physiology. Recently, nitric oxide has emerged as a relevant messenger also of myogenesis that it regulates at several key steps, especially when the process is stimulated for muscle repair following acute and chronic muscle injuries. Here, we will review briefly the mechanisms and functions of nitric oxide in skeletal muscle and discuss its role in myogenesis, with specific attention to the promising nitric oxide-based approaches now being explored at the pre-clinical and clinical level for the therapy of muscular dystrophy.


Chitosan-coated artesunate protects against ulcerative colitis via STAT6-mediated macrophage M2 polarization and intestinal barrier protection.
Oral delivery of chitosan-coated artesunate (CPA) has been proven to be effective at preventing ulcerative colitis (UC) in mice. However, the anti-inflammatory mechanism is not fully understood. STAT6 is a key transcription factor that promotes anti-inflammatory effects by inducing M2 and Th2 dominant phenotypes, therefore we hypothesized STAT6 might play a key role in the process. To prove it, a STAT6 gene knockout macrophage cell line (STAT6-/- RAW264.7, by CRISPR/Cas9 method), and its corresponding Caco-2/RAW264.7 co-culture system combined with the STAT6 inhibitor (AS1517499, AS) in a mouse UC model were established and studied. The results showed that CPA remarkably suppressed the activation of TLR-4/NF-κB pathway and the mRNA levels of proinflammatory cytokines, while increased the IL-10 levels in RAW264.7. This effect of CPA contributed to the protection of the ZO-1 in Caco-2 which was disrupted upon the stimulation to macrophages. Simultaneously, CPA reduced the expression of CD86 but increase the expression of CD206 and p-STAT6 in LPS-stimulated RAW264.7 cells. However, above alterations were not obvious as in STAT6-/- RAW264.7 and its co-culture system, suggesting STAT6 plays a key role. Furthermore, CPA treatment significantly inhibited TLR-4/NF-κB activation, intestinal macrophage M1 polarization and mucosal barrier injury induced by DSS while promoted STAT6 phosphorylation in the UC mouse model, but this effect was also prominently counteracted by AS. Therefore, our data indicate that STAT6 is a major regulator in the balance of M1/M2 polarization, intestinal barrier integrity and then anti-colitis effects of CPA. These findings broaden our understanding of how CPA fights against UC and imply an alternative treatment strategy for UC via this pathway.


Using Enhanced Sampling Simulations to Study the Conformational Space of Chiral Aromatic Peptoid Monomers.
Peptoids, or N-substituted glycines, are peptide-like materials that form a wide variety of secondary structures owing to their enhanced flexibility and a diverse collection of possible side chains. Compared to that of peptides, peptoids have a substantially more complex conformational landscape. This is mainly due to the ability of the peptoid amide bond to exist in both cis- and trans-conformations. This makes conventional molecular dynamics simulations and even some enhanced sampling approaches unable to sample the complete energy landscapes. In this article, we present an extension to the CGenFF-NTOID peptoid atomistic forcefield by adding parameters for four side chains to the previously available collection. We employ explicit solvent well-tempered metadynamics simulations to optimize our forcefield parameters and parallel bias metadynamics to study the cis-trans isomerism for SN1-phenylethyl (s1pe) and SN1-naphthylethyl (s1ne) peptoid monomers, the free energy minima generated from which are validated with available experimental data. In the absence of experimental data, we supported our atomistic simulations with ab initio calculations. This work represents an important step toward the computational design of peptoid-based materials.


Evaluation of preventive, supportive and awareness building measures among international students in China in response to COVID-19: a structural equation modeling approach.
Education institutions promptly implemented a set of steps to prevent the spread of COVID-19 among international Chinese students, such as restrictive physical exercise, mask wear, daily health reporting, etc. Success of such behavioral change campaigns largely depends on awareness building, satisfaction and trust on the authorities. The purpose of this current study is to assess the preventive, supportive and awareness-building steps taken during the COVID-19 pandemic for international students in China, that will be useful for planning such a behavioral change campaign in the potential pandemic situation in other parts of the world. We conducted an online-based e-questionnaire survey among 467 international students in China through WeChat. The data collection duration was from February 20, 2020 to March 10, 2020 and we focused on their level of awareness, satisfaction, and trust in authorities regarding pandemic measures. Simple bivariate statistics was used to describe the background characteristics of the respondents along with adoption of the partial least squares-structural equation modeling (PLS-SEM) as the final model to demonstrate the relationship between the variables. In our study, the leading group of the respondents were within 31 to 35 years' age group (39.82%), male (61.88%), living single (58.24%) and doctoral level students (39.8%). The preventive and supportive measures taken by students and/or provided by the respective institution or authorities were positively related to students' satisfaction and had an acceptable strength (β = 0.611, t = 9.679, p < 0.001). The trust gained in authorities also showed an acceptable strength (β = 0.381, t = 5.653, p < 0.001) with a positive direction. Again, the personnel awareness building related to both students' satisfaction (β = 0.295, t = 2.719, p < 0.001) and trust gain (β = 0.131, t = 1.986, p < 0.05) in authorities had a positive and acceptable intensity. Therefore, our study clearly demonstrates the great impact of preventive and supportive measures in the development of students' satisfaction (R2 = 0.507 indicating moderate relationship). The satisfied students possessed a strong influence which eventually helped in building sufficient trust on their institutions (R2 = 0.797 indicating above substantial relationship). The worldwide student group is one of the most affected and vulnerable communities in this situation. So, there is a profound ground of research on how different states or authorities handle such situation. In this study, we have depicted the types and magnitude of care taken by Chinese government and educational institutions towards international students to relieve the panic of pandemic situation. Further research and such initiatives should be taken in to consideration for future emerging conditions.


Development of an event-by-event based Li-ZnS(Ag) neutron imaging detector with selective neutron detection capability.
High sensitivity and high resolution is desired in such technologies as neutron radiography. However, the contamination of gamma photons in neutron images decreases the accuracy of neutron radiography. To solve this problem, we developed an event-by-event based neutron imaging system that can selectively detect neutrons. The developed neutron imaging system consists of an Li-ZnS(Ag) scintillator plate optically coupled to a flat panel photomultiplier tube (FP-PMT) with a light guide. Scintillation light emitted from the Li-ZnS(Ag) by the interaction with neutron-induced particles is used to calculate the position based on the center of mass calculations. The spatial resolution of the neutron imaging detector is ∼2.3 mm FWHM, and the sensitivity for 252Cf at 2 cm from the source with 2-cm-thick polystyrene is 20 cps/MBq. Background count fraction from 60Co gamma photons was 0.2 %. For various types of neutron absorption phantoms, high-contrast and high-resolution neutron images are obtained with the developed neutron imaging detector using a252Cf neutron source.


The effectiveness of a school-based adolescent depression education program.
In an effort to decrease the suicide rate in adolescents, many interventions have focused on school-based suicide prevention programs. Alternatively, depression education in schools might be effective in decreasing the morbidity, mortality, and stigma associated with adolescent depression. The Adolescent Depression Awareness Program (ADAP) developed a 3-hour curriculum to teach high school students about the illness of depression. The purpose of this study was to assess the effectiveness of the ADAP curriculum in improving high school students' knowledge about depression. From 2001 to 2005, 3,538 students were surveyed on their knowledge about depression before and after exposure to the ADAP curriculum. The number of students scoring 80% or higher on the assessment tool more than tripled from pretest to posttest (701 to 2,180), suggesting the effectiveness of the ADAP curriculum. Further study and replication are required to determine if improved knowledge translates into increased treatment-seeking behavior.


A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome.
The functional complexity of the human transcriptome is not yet fully elucidated. We report a high-throughput sequence of the human transcriptome from a human embryonic kidney and a B cell line. We used shotgun sequencing of transcripts to generate randomly distributed reads. Of these, 50% mapped to unique genomic locations, of which 80% corresponded to known exons. We found that 66% of the polyadenylated transcriptome mapped to known genes and 34% to nonannotated genomic regions. On the basis of known transcripts, RNA-Seq can detect 25% more genes than can microarrays. A global survey of messenger RNA splicing events identified 94,241 splice junctions (4096 of which were previously unidentified) and showed that exon skipping is the most prevalent form of alternative splicing.


Reciprocal diversification in a complex plant-herbivore-parasitoid food web.
Plants, plant-feeding insects, and insect parasitoids form some of the most complex and species-rich food webs. According to the classic escape-and-radiate (EAR) hypothesis, these hyperdiverse communities result from coevolutionary arms races consisting of successive cycles of enemy escape, radiation, and colonization by new enemy lineages. It has also been suggested that "enemy-free space" provided by novel host plants could promote host shifts by herbivores, and that parasitoids could similarly drive diversification of gall form in insects that induce galls on plants. Because these central coevolutionary hypotheses have never been tested in a phylogenetic framework, we combined phylogenetic information on willow-galling sawflies with data on their host plants, gall types, and enemy communities. We found that evolutionary shifts in host plant use and habitat have led to dramatic prunings of parasitoid communities, and that changes in gall phenotype can provide "enemy-free morphospace" for millions of years even in the absence of host plant shifts. Some parasites have nevertheless managed to colonize recently-evolved gall types, and this has apparently led to adaptive speciation in several enemy groups. However, having fewer enemies does not in itself increase speciation probabilities in individual sawfly lineages, partly because the high diversity of the enemy community facilitates compensatory attack by remaining parasite taxa. Taken together, our results indicate that niche-dependent parasitism is a major force promoting ecological divergence in herbivorous insects, and that prey divergence can cause speciation in parasite lineages. However, the results also show that the EAR hypothesis is too simplistic for species-rich food webs: instead, diversification seems to be spurred by a continuous stepwise process, in which ecological and phenotypic shifts in prey lineages are followed by a lagged evolutionary response by some of the associated enemies.


Judging the Past: How History Should Inform Bioethics.
Bioethics has become a common course of study in medical schools, other health professional schools, and graduate and undergraduate programs. An analysis of past ethical scandals, as well as the bioethics apparatus that emerged in response to them, is often central to the discussion of bioethical questions. This historical perspective on bioethics is invaluable and demonstrates how, for example, the infamous Tuskegee syphilis study was inherently racist and how other experiments exploited mentally disabled and other disadvantaged persons. However, such instruction can resemble so-called Whig history, in which a supposedly more enlightened mindset is seen as having replaced the "bad old days" of physicians behaving immorally. Bioethical discourse-both in the classroom and in practice-should be accompanied by efforts to historicize but not minimize past ethical transgressions. That is, bioethics needs to emphasize why and how such events occurred rather than merely condemning them with an air of moral superiority. Such instruction can reveal the complicated historical circumstances that led physician-researchers (some of whom were actually quite progressive in their thinking) to embark on projects that seem so unethical in hindsight. Such an approach is not meant to exonerate past transgressions but rather to explain them. In this manner, students and practitioners of bioethics can better appreciate how modern health professionals may be susceptible to the same types of pressures, misguided thinking, and conflicts of interest that sometimes led their predecessors astray.


Mapping the links between climate change and human health in urban areas: how is research conducted? A Scoping review protocol.
Scientists from a wide variety of fields of knowledge are increasingly interested in climate change issues. The importance given to the phenomenon is explained by the uncertainties surrounding it and its consequences not yet fully known. However, there is wide agreement that human activities are modifying the Earth's climate beyond the natural cyclical changes and that these changes impact human health. This scoping review aimed to understand how research on the links between climate change and human health in urban areas is conducted and how this research is approached holistically or not. This scoping review is mainly guided by the Arskey and O'Malley scoping review framework. A broad range of databases will be used, including PubMed, ScienceDirect, Web of Science Core Collection, GreenFILE and Information Science & Technology Abstracts. Predefined inclusion and exclusion criteria will be used, with a focus on climate change and human health outcome studies published between January 1990 and July 2019. An interdisciplinary team has formulated search strategies and the reviewers will independently screen eligible studies for final study selection. We will apply a thematic analysis to evaluate and categorise the study findings. We expect to map the research according to the scientific research methods, the scientific fields and the determinants of health studied. Along these lines, we will be able to understand how holistic the research is. No primary data will be collected since all data presented in this review are based on published articles and publicly available documents. Therefore, ethics committee approval is not a requirement. The findings will be disseminated through publication in a peer-reviewed journal, presentations at conferences relevant to the field of this research, as well as presentations to relevant stakeholders.


A ricin A chain-containing immunotoxin that kills human T lymphocytes in vitro.
An immunotoxin specific for human T lymphocytes was prepared by coupling an IgG2a anti-CD3 murine monoclonal antibody (64.1) to purified ricin A chain (64.1-A). Treatment of blood mononuclear cells with this immunotoxin at a concentration of 1.7 X 10(-9) mol/L for two hours at 37 degrees C in the presence of 20 mmol/L NH4Cl decreased phytohemagglutinin-stimulated protein synthesis by 95%. In addition, a sensitive culture assay showed that fewer than 0.03% T cells remained after treatment of human bone marrow mononuclear cells with 64.1-A at a concentration of 1.7 X 10(-9) mol/L. The inhibition of protein synthesis could be prevented by preincubating cells with unconjugated 64.1 antibody but not by preincubating cells with a control IgG2a antibody that binds to a different T cell antigen (CD5). At concentrations up to 1 X 10(-8) mol/L, 64.1-A had little effect on blood mononuclear cells from baboons or human myeloid precursors (CFU-GM), which do not express the CD3 antigen recognized by 64.1. Taken together, these results indicate that the toxicity of 64.1-A was specific and that 64.1-A may be a useful reagent for depleting T cells from donor marrow as a means of preventing acute graft-v-host disease after allogeneic bone marrow transplantation.


Identification and Characterization of the ERF Subfamily B3 Group Revealed GhERF13.12 Improves Salt Tolerance in Upland Cotton.
The APETALA2 (AP2)/ethylene response factor plays vital functions in response to environmental stimulus. The ethylene response factor (ERF) subfamily B3 group belongs to the AP2/ERF superfamily and contains a single AP2/ERF domain. Phylogenetic analysis of the ERF subfamily B3 group genes from Arabdiposis thaliana, Gossypium arboreum, Gossypium hirsutum, and Gossypium raimondii made it possible to divide them into three groups and showed that the ERF subfamily B3 group genes are conserved in cotton. Collinearity analysis identified172 orthologous/paralogous gene pairs between G. arboreum and G. hirsutum; 178 between G. hirsutum and G. raimondii; and 1,392 in G. hirsutum. The GhERF subfamily B3 group gene family experienced massive gene family expansion through either segmental or whole genome duplication events, with most genes showing signature compatible with the action of purifying selection during evolution. Most G. hirsutum ERF subfamily B3 group genes are responsive to salt stress. GhERF13.12 transgenic Arabidopsis showed enhanced salt stress tolerance and exhibited regulation of related biochemical parameters and enhanced expression of genes participating in ABA signaling, proline biosynthesis, and ROS scavenging. In addition, the silencing of the GhERF13.12 gene leads to increased sensitivity to salt stress in cotton. These results indicate that the ERF subfamily B3 group had remained conserved during evolution and that GhERF13.12 induces salt stress tolerance in Arabidopsis and cotton.


Experience with PGE1 in patients with postoperative trashfoot.
Within a 16 years observation period a trash phenomenon was seen in 15 patients. In 13 of these patients it occurred as a postoperative complication of a surgical intervention for infrarenal abdominal aortic aneurysm. In 2 cases an aortobifemoral bypass had become necessary because of an underlying AOD. In addition to the standard therapy with heparin 8 patients were intravenously given 2 ampoules of Prostavasin (60 mcg of PGE1) twice daily. All patients survived, and only in 1 case a thigh amputation was unavoidable. Apart from the heparinization, the 7 patients of the control group had received i.v. administrations of vaso-active drugs (naftidrofuryl, pentoxifylline) and hemodilution. 3 patients died within the first three postoperative days, one of them after a thigh amputation. A further patient suffered the loss of both lower legs, but survived and recovered completely as did 3 patients who did not require amputation. Though these results cannot claim the significance of a randomized controlled study they indicate that PGE1 may act favourably in the treatment of the trash syndrome.


Evolutionary avenues for, and constraints on, the transmission of frog lung flukes (Haematoloechus spp.) in dragonfly second intermediate hosts.
Metacercariae survival patterns and their distribution in second intermediate odonate hosts were examined for 4 species of frog lung flukes. Surveys of aquatic larvae and recently emerged teneral dragonflies and damselflies indicated that prevalence and mean abundance of Haematoloechus spp. metacercariae were significantly lower in teneral dragonflies than larval dragonflies, while there was no significant difference in prevalence or mean abundance of Haematoloechus spp. metacercariae among larval and teneral damselflies. Experimental infections of dragonflies indicated that metacercariae of Haematoloechus coloradensis and Haematoloechus complexus were located in the head, thorax, and branchial basket of dragonflies, whereas metacercariae of Haematoloechus longiplexus and Haematoloechus parviplexus were restricted to the branchial basket of these hosts. Metacercariae of H. coloradensis, H. complexus, and H. longiplexus infected the head, thorax, and abdomen of damselflies, but these insects were resistant to infection with H. parviplexus. Subsequent metamorphosis experiments on experimentally infected dragonflies indicated that most metacercariae of H. longiplexus were lost from the branchial basket during metamorphosis, but most metacercariae of H. coloradensis, H. complexus, and H. parviplexus survived dragonfly metamorphosis. These observations suggest that the observed ecological host specificity of H. longiplexus in semiterrestrial leopard frogs may be due to few metacercariae of H. longiplexus reaching these frogs in a terrestrial environment. Because of the uncertain validity of Haematoloechus varioplexus as a distinct species from its synonym H. parviplexus, their morphological characters were reevaluated. The morphological data on H. varioplexus and H. parviplexus indicate that they differ in their acetabulum length and width, ovary shape, testes length, and egg length and width. Experimental infections of plains leopard frogs, northern leopard frogs, and bullfrogs with worms from bullfrogs indicate that the synonymy of H. parviplexus with H. varioplexus is not warranted, and that these flukes are distinct species, i.e., H. parviplexus in bullfrogs and H. varioplexus in plains leopard frogs and northern leopard frogs.


PilZ Domain Protein FlgZ Mediates Cyclic Di-GMP-Dependent Swarming Motility Control in Pseudomonas aeruginosa.
The second messenger cyclic diguanylate (c-di-GMP) is an important regulator of motility in many bacterial species. In Pseudomonas aeruginosa, elevated levels of c-di-GMP promote biofilm formation and repress flagellum-driven swarming motility. The rotation of P. aeruginosa's polar flagellum is controlled by two distinct stator complexes, MotAB, which cannot support swarming motility, and MotCD, which promotes swarming motility. Here we show that when c-di-GMP levels are elevated, swarming motility is repressed by the PilZ domain-containing protein FlgZ and by Pel polysaccharide production. We demonstrate that FlgZ interacts specifically with the motility-promoting stator protein MotC in a c-di-GMP-dependent manner and that a functional green fluorescent protein (GFP)-FlgZ fusion protein shows significantly reduced polar localization in a strain lacking the MotCD stator. Our results establish FlgZ as a c-di-GMP receptor affecting swarming motility by P. aeruginosa and support a model wherein c-di-GMP-bound FlgZ impedes motility via its interaction with the MotCD stator. The regulation of surface-associated motility plays an important role in bacterial surface colonization and biofilm formation. c-di-GMP signaling is a widespread means of controlling bacterial motility, and yet the mechanism whereby this signal controls surface-associated motility in P. aeruginosa remains poorly understood. Here we identify a PilZ domain-containing c-di-GMP effector protein that contributes to c-di-GMP-mediated repression of swarming motility by P. aeruginosa We provide evidence that this effector, FlgZ, impacts swarming motility via its interactions with flagellar stator protein MotC. Thus, we propose a new mechanism for c-di-GMP-mediated regulation of motility for a bacterium with two flagellar stator sets, increasing our understanding of surface-associated behaviors, a key prerequisite to identifying ways to control the formation of biofilm communities.


T cell subpopulations in inflammatory bowel disease: evidence for a defective induction of T8+ suppressor/cytotoxic T lymphocytes.
Abnormal immune responses associated with inflammatory bowel disease may reflect a defect in immunoregulatory functions. To analyse T-T cell cooperation, we examined the influence of polyclonal activation with the mitogen phytohaemagglutinin on the distribution of the T4+ helper/inducer and the T8+ cytotoxic/suppressor T cell subset. Compared to controls, lymphocytes from patients with Crohn's disease displayed a slight reduction in T3+ cells; neither in patients with ulcerative colitis nor in patients with Crohn's disease a significant difference in T4+ and T8+ cells and the T4/T8 ratio was observed. Phytohaemagglutinin stimulation of normal lymphocytes resulted in a decrease of the T4 subset and a clear increase of the T8 subpopulation. In contrast, the subset distribution pattern was not changed by the mitogenic stimulation in any of the patients. This abnormal reaction pattern could not be influenced by the addition of interleukin-2. Small numbers of normal lymphocytes, however, were able to restore the predominant proliferation of T8+ cells. Thus, the reduced response of T8+ lymphocytes cannot be attributed to an altered composition of this subset in patient with inflammatory bowel disease; our results provide evidence for a defective induction of T8+ suppressor/cytotoxic T cells, which is independent from disease activity.


Quantifying the response of free-ranging mammalian herbivores to the interplay between plant defense and nutrient concentrations.
While trying to achieve their nutritional requirements, foraging herbivores face the costs of plant defenses, such as toxins. Teasing apart the costs and benefits of various chemical constituents in plants is difficult because their chemical defenses and nutrient concentrations often co-vary. We used an approach derived from predator-prey studies to quantitatively compare the foraging response of a free-ranging mammalian herbivore, the swamp wallaby (Wallabia bicolor), through three feeding trials with artificial diets that differed in their concentrations of (1) the terpene 1,8-cineole, (2) primary constituents (including nitrogen and fiber), and (3) both the terpene and the primary constituents. Applying the giving-up density (GUD) framework, we demonstrated that the foraging cost of food patches increases with higher dietary cineole concentration and decreases with higher dietary nutrient concentration. The effect of combined differences in nutrients and cineole concentrations on GUD was interactive, and high nutrient food required more cineole to achieve the same patch value as low nutrient food. Our results indicate that swamp wallabies equate low nutrient, poorly defended food with high nutrient, highly defended food, providing two contrasting diets with similar cost-benefit outcomes. This behavior suggests that equal concentrations of chemical defenses provide nutrient-poor plants with relatively greater protection as nutrient-rich plants. Nutrient-rich plants may therefore face the exacerbated problem of being preferred by herbivores and therefore need to produce more defense compounds to achieve the same level of defense as nutrient-poor plants. Our findings help explain the difference in anti-herbivore strategy of nutrient-poor and rich plants, i.e., tolerance versus defense.


Hierarchical and chemical space partitioning in new intermetallic borides MNi21B20 (M = In, Sn).
The compounds MNi21B20 (M = In, Sn) have been synthesized and their cubic crystal structure determined (space group Pm3[combining macron]m, lattice parameters a = 7.1730(1) Å and a = 7.1834(1) Å, respectively). The structure can be described as a hierarchical partitioning of space based on a reo-e net formed by Ni3 species with large cubical, cuboctahedral and rhombicuboctahedral voids being filled according to [Ni1@Ni38], [M@Ni312], and [Ni26@B20@Ni324], respectively. The [Ni6@B20] motif inside the rhombicuboctahedral voids features an empty [Ni6] octahedron surrounded by a [B20] cage recently described in E2Ni21B20 (E = Zn, Ga). Position-space bonding analysis using ELI-D and QTAIM space partitioning as well as 2- and 3-center delocalization indices gives strong support to an alternative chemical description of space partitioning based on face-condensed [B@Ni6] trigonal prisms as basic building blocks. The shortest B-B contacts display locally nested 3-center B-B-Ni bonding inside each trigonal prism. This clearly rules out the notion of [Ni6@B20] clusters and leads to the arrangement of 20 face-condensed [B@Ni23Ni33] trigonal prisms resulting in a triple-shell like situation Ni26@B20@Ni324(reo-e), where the shells display comparable intra- and inter-shell bonding. Both compounds are Pauli paramagnets displaying metallic conductivity.


Hypoxia-Inducible Factor 1 Alpha-Mediated RelB/APOBEC3B Down-regulation Allows Hepatitis B Virus Persistence.
Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.


Pharmacokinetics and pharmacodynamics of a therapeutic dose of unfractionated heparin (200 U/kg) administered subcutaneously or intravenously to healthy dogs.
Heparin treatment has been recommended for dogs in hypercoagulable states such as disseminated intravascular coagulation, however, potential benefits have to be balanced against the bleeding risk if overdosage occurs. A better understanding of the pharmacology of heparin and tests to monitor heparin therapy in dogs may help prevent therapeutic hazards. The purpose of this study was to evaluate the effects of 200 U/kg of sodium unfractionated heparin (UFH) on coagulation times in dogs after intravenous (IV) and subcutaneous (SC) administration and to compare these effects with plasma heparin concentrations assessed by its antifactor Xa (aXa) activity. 200 U/kg of UFH were administered IV and SC to 5 healthy adult Beagle dogs with a washout period of at least 3 days. Activated partial thromboplastin time (APTT), prothrombin time (PT), and plasma aXa activity were determined in serial blood samples. After IV injection, PT remained unchanged except for a slight increase in 1 dog; APTT was not measurable (>60 seconds) for 45-90 minutes, and then decreased gradually to baseline values between 150 and 240 minutes. High plasma heparin concentrations were observed (maximal concentration = 4.64 +/-1.4 aXa U/mL) and decreased according to a slightly concave-convex pattern on a semilogarithmic curve, but returned to baseline slightly more slowly (t240-t300 minutes) than did APTT. After SC administration, APTT was moderately prolonged (by a ratio of 1.55 +/-0.28 APTT t0, range 1.35-2.01) between 1 and 4 hours after administration. Plasma aXa activity reached a maximum of 0.56 +/-0.20 aXa U/mL (range 0.42-0.9 U/mL) after 132 +/-26.8 minutes; this lasted for 102 +/-26.8 minutes. Prolongation of APTTs of 120-160% corresponded to plasma heparin concentrations of 0.3-0.7 aXa U/mL. As in humans, the pharmacokinetics of UFH in dogs was nonlinear. Administration of 200 U/kg of UFH SC in healthy dogs resulted in sustained plasma heparin concentrations in accordance with human recommendations for thrombosis treatment or prevention, without excessively increased bleeding risks. In these conditions, APTT can be used as a surrogate to assess plasma heparin concentrations. These findings need to be confirmed in diseased animals.


Heterogeneity of structural brain changes in subtypes of schizophrenia revealed using magnetic resonance imaging pattern analysis.
Schizophrenia is a multifaceted mental disorder characterized by cognitive, perceptual, and affective symptom dimensions. This heterogeneity at the phenomenological level may be subserved by complex and heterogeneous patterns of structural abnormalities. Thus, delineating such patterns may improve the insight into the variability of disease and facilitate future magnetic resonance imaging-based diagnosis. We aimed to identify structurally complex signatures that directly differentiate patients with predominantly negative (pNEG), positive (pPOS), and disorganized (pDIS) symptoms using Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a new analytical framework for group analysis, which showed to have superior sensitivity and specificity over conventional voxel-based morphometric approaches, thus facilitating the identification of subtle neuroanatomical signatures delineating different subgroups. pPOS were characterized by pronounced gray matter (GM) volume reductions in the ventromedial prefrontal cortex (vmPFC), which herein is defined to include the orbitofrontal cortex, and in occipitotemporal GM and parts of the lingual gyrus. pNEG was found to have vmPFC reduction but to a lesser degree than pPOS and with a relative sparing of the more medial vmPFC regions, compared to pDIS; it also had significantly less cerebellar GM. pDIS showed relatively highest GM volume preservation among three subtypes. Although a common prefronto-perisylvian GM reduction pattern was present at the whole-group level, marked morphometric differences emerged between the three subgroups, including reduced cerebellar GM in pNEG and reduced vmPFC and occipitotemporal GM in pPOS. Besides deepening our insight into the neurobiological underpinnings of clinical heterogeneity, these results also identify important imaging biomarkers that may aid patient stratification.


Impact of Freeze-Thaw Cycles on Die-Off of E. coli and Intestinal Enterococci in Deer and Dairy Faeces: Implications for Landscape Contamination of Watercourses.
Characterising faecal indicator organism (FIO) survival in the environment is important for informing land management and minimising public health risk to downstream water users. However, key gaps in knowledge include understanding how wildlife contribute to catchment-wide FIO sources and how FIO survival is affected by low environmental temperatures. The aim of this study was to quantify E. coli and intestinal enterococci die-off in dairy cow versus red deer faecal sources exposed to repeated freeze-thaw cycles under controlled laboratory conditions. Survival of FIOs in water exposed to freeze-thaw was also investigated to help interpret survival responses. Both E. coli and intestinal enterococci were capable of surviving sub-freezing conditions with the faeces from both animals able to sustain relatively high FIO concentrations, as indicated by modelling, and observations revealing persistence in excess of 11 days and in some cases confirmed beyond 22 days. Die-off responses of deer-derived FIOs in both faeces and water exposed to low temperatures provide much needed information to enable better accounting of the varied catchment sources of faecal pollution and results from this study help constrain the parameterisation of die-off coefficients to better inform more integrated modelling and decision-making for microbial water quality management.


Kineococcus terrestris sp. nov. and Kineococcus aureolus sp. nov., isolated from saline sediment.
Two novel actinobacteria, designated YIM 121936T and YIM 121940T, were isolated from alkaline sediment in Yuanjiang, China. The cells of the novel strains were Gram-stain-positive, aerobic, motile, non-spore-forming and coccus-shaped. The two strains both contained meso-diaminopimelic acid as the diagnostic diamino acid. The whole-cell sugars were arabinose, galactose, glucose, mannose and ribose. The predominant menaquinone was MK-9(H2). The polar lipid profile of both strains comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, one unknown phosphoglycolipid and five unknown phospholipids. The predominant fatty acids of both strains were anteiso-C15 : 0. The genomic DNA G+C contents of strains YIM 121936T and YIM 121940T were 74.7 and 75.2 %, respectively. Strain YIM 121936T was closely related to Kineococcus aurantiacus IFO 15268T (97.19 %), Kineococcus gypseus YIM 121300T (97.00 %) and Kineococcus mangrovi NBRC 110933T (97.00 %). Strain YIM 121940T was closely related to K. aurantiacus IFO 15268T (97.41 %), Kineococcus endophytica KLBMP 1274T (97.18 %), Kineococcus rhizosphaerae RP-B16T (97.09 %), Kineococcus radiotolerans SRS 30216T (97.09 %), K. gypseus YIM 121300T (97.00 %) and K. mangrovi NBRC 110933T (97.00 %). Strain YIM 121936T shared high 16S rRNA gene sequence similarity (99 %) with YIM 121940T. Similarities of two strains with other species of the genus Kineococcus were <97 %. The DNA-DNA hybridization values were below 70 % among all the strains studied. YIM 121936T and YIM 121940T are representatives of two new species in the genus Kineococcus, for which names Kineococcus terreus sp. nov. (type strain YIM 121936T=KCTC 39738T=DSM 102155T) and Kineococcus aureolus sp. nov. (type strain YIM 121940T=KCTC 39739T=DSM 102158T) are proposed, respectively.


Comparison of P300 Cognitive-evoked Potentials and Visual and Auditory Reaction Time in Stage 5 Chronic Kidney Disease Patients on Different Treatment Modalities.
Patients with chronic kidney disease (CKD) are at a higher risk of cognitive impairment. Poor quality of life and decreased compliance are frequently observed with cognitive decline among CKD patients. Cognitive impairment among Stage 5 CKD patients varies with different modalities of treatment, and contradicting results have been reported. Fifty-four medically stable Stage 5 CKD patients undergoing different modalities of treatment were recruited: Patients with Stage 5 CKD on maintenance hemodialysis (HD) (n = 18), continuous ambulatory peritoneal dialysis (CAPD) (n = 18), and conservative management (CM) (n = 18). Eighteen apparently healthy participants were recruited as a control group. The cognitive functions assessed were P300 event- related potential, auditory and visual reaction times (VRTs). Kidney function was assessed by serum creatinine and estimated glomerular filtration rate. Creatinine levels were significantly higher in all three treatment groups compared with the control group. Multivariate analysis revealed a significant association between the CKD groups (n = 54) and the parameters of cognitive function. P300 latency was prolonged in all treatment groups compared with the control group and was significantly prolonged in patients on CM compared with HD and CAPD patients. The VRT of CM patients was found to be significantly higher compared with the control group. The auditory reaction time was significantly prolonged in all treatment groups compared with the control group and in the CM group compared with the CAPD group. Cognitive function was more affected in Stage 5 CKD patients on CM compared with patients undergoing HD or CAPD.


Short-duration-focused ultrasound stimulation of Hsp70 expression in vivo.
The development of transgenic reporter mice and advances in in vivo optical imaging have created unique opportunities to assess and analyze biological responses to thermal therapy directly in living tissues. Reporter mice incorporating the regulatory regions from the genes encoding the 70 kDa heat-shock proteins (Hsp70) and firefly luciferase (luc) as reporter genes can be used to non-invasively reveal gene activation in living tissues in response to thermal stress. High-intensity-focused ultrasound (HIFU) can deliver measured doses of acoustic energy to highly localized regions of tissue at intensities that are sufficient to stimulate Hsp70 expression. We report activation of Hsp70-luc expression using 1 s duration HIFU heating to stimulate gene expression in the skin of the transgenic reporter mouse. Hsp70 expression was tracked for 96 h following the application of 1.5 MHz continuous-wave ultrasound with spatial peak intensities ranging from 53 W cm(-2) up to 352 W cm(-2). The results indicated that peak Hsp70 expression is observed 6-48 h post-heating, with significant activity remaining at 96 h. Exposure durations were simulated using a finite-element model, and the predicted temperatures were found to be consistent with the observed Hsp70 expression patterns. Histological evaluation revealed that the thermal damage starts at the stratum corneum and extends deeper with increasing intensity. These results indicated that short-duration HIFU may be useful for inducing heat-shock expression, and that the period between treatments needs to be greater than 96 h due to the protective properties of Hsp70.


miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer.
Expression levels of estrogen receptor (ER) alpha govern estrogen-dependent growth, response to endocrine therapy, and prognosis in ERalpha-positive breast cancer. Multiple mechanisms involved in altering ERalpha gene expression in breast cancer have been identified, including ERalpha gene amplification as well as transcriptional silencing by DNA methylation of CpG islands within the ERalpha promoter and mutations within the open reading frame of ERalpha. However, expression levels of ERalpha in breast cancer tissues differ widely among patients, and frequently change during disease progression and in response to systemic therapies. Recent evidence has shown that microRNA mutations or misexpression correlate with various human cancers, and miR-206 is reported to decrease endogenous ERalpha mRNA and protein levels in human MCF-7 breast cancer cells via two specific target sites within the 3'-untranslated region of the human ERalpha transcript. In this study, we show for the first time that miR-206 expression is markedly decreased in ERalpha-positive human breast cancer tissues assayed by quantitative reverse transcription-PCR analysis. Moreover, we observe that miR-206 expression is inversely correlated with ERalpha but not ERbeta mRNA expression in breast cancer tissues. Transfection experiments revealed that introduction of miR-206 into estrogen-dependent MCF-7 breast cancer cells inhibits cell growth in a dose- and time-dependent manner. Our results suggest that miR-206 could be a novel candidate for endocrine therapy that targets only ERalpha in breast cancer.


The association between flow-mediated dilation and physical function in older men.
The probability that an individual is able to live independently decreases sharply below the threshold score of 57 units on the physical functional performance (PFP-10) test. To examine the relation between brachial artery flow-mediated dilation (BAFMD) on individual and total scores on the PFP-10. We hypothesized that lower scores on the PFP-10 test would be associated with lower BAFMD. Sixty-four men (age, 84 +/- 11 yr) from the Louisiana Healthy Aging Study were studied. Participants were classified by their performance on the PFP-10 test (Class I, score <26; Class II, score between 26 and 57; and Class III, score > 57). BAFMD was assessed after 5 min of forearm occlusion, using high-resolution ultrasonography. The average total score on the PFP-10 test and BAFMD were 42.9 +/- 22 U and 2.76 +/- 2.13%, respectively. The BAFMD was associated with total PFP-10 score (r = 0.45, P = 0.0001) and age (r = -0.36, P = 0.003). BAFMD was significantly different (P = 0.001) between the PFP-10 classes (Class I, 1.44% [95% CI, 0.49-2.39]; Class II, 2.67% [95% CI, 1.95-3.38]; and Class III, 4.01% [95% CI, 3.16-4.85]). This study reports significant relationships between BAFMD and individual and combined measures of physical function in elderly men. More specifically, when individuals were categorized based on their PFP-10 total score, those in the highest functional class, exhibited the highest BAFMD, compared to those in the middle class, who had greater vasoreactivity than those in the lowest functional class.


Cardiac power output accurately reflects external cardiac work over a wide range of inotropic states in pigs.
Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min- 1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min- 1 under various inotropic states. We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min- 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax). CPO showed the best correlation with LV SW min- 1 (r2 = 0.89; p < 0.05) while LV EF did not correlate at all (r2 = 0.01; p = 0.259). Further parameters correlated moderately with LV SW min- 1 (LVPmax r2 = 0.47, RPP r2 = 0.67; and TP r2 = 0.54). LV dP/dtmax correlated worst with LV SW min- 1 (r2 = 0.28). CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU.


Census based mortality study of pharmaceutical industry workers.
This study was designed to investigate whether the mortality of British pharmaceutical industry workers showed any evidence of occupationally related patterns associated with particular sections of the industry with special emphasis on cancers and respiratory diseases. The data were extracted from census schedules by the Office of Population Censuses and Surveys using occupational categories recorded by pharmaceutical workers at the 1961 and 1971 censuses of England and Wales. Subsequent mortality was ascertained through the National Health Service Central Registry. Both cohorts, followed up to the end of 1981, showed a "healthy worker effect," with overall SMRs ranging from 0.77 to 1.04, though comparison with the employed populations of the longitudinal study reduced this effect by 25%. Evidence of inconsistent excess mortality was noted in small numbers for suicide (SMR 0.91 to 2.79) and cancer of the large intestine (SMR 1.09 to 2.38). There was no clear association between the type of industry and the causes of death investigated. Although the census based study has several methodological shortcomings, there was no evidence, on the basis of this study, to suggest any excess mortality risk from employment in the pharmaceutical industry.


Ecophysiology of dorsal versus ventral cuticle in flattened sawfly larvae.
Platycampus larvae are highly cryptic leaf feeders characterised by a dorso-ventrally flattened body, the dorsal integument resembling a shield. Dorsal and ventral cuticles from Platycampus luridiventris were compared by histology and gel electrophoresis. By Azan-staining, a red and a blue layer were distinguished in the dorsal cuticle, while the ventral cuticle showed one, almost uniform blue layer, as in both cuticles of control species. The two cuticles from P. luridiventris had similar amounts and sodium dodecyl sulphate-polyacrylamide gel electrophoresis profiles of soluble proteins, but not insoluble proteins. One insoluble protein (MW approximately 41 kDa) was visible as a large band in the ventral cuticle only. It is likely that this protein renders the cuticle elastic, and that the dorsal, red layer is the exocuticle, mainly composed of insoluble proteins. We discuss eco-physiological implications of the exocuticle in insects. Further, data from the literature indicate that the defence strategy in P. luridiventris larvae relies on being visually cryptic towards avian predators and tactically cryptic towards arthropod predators and parasitoids. Crypsis in both senses is favoured by the shield effect, itself based on an abnormally thick dorsal exocuticle. Although the larvae are external feeders, they may be considered as hidden from an ecological perspective.


Hepatitis B Virus Genotype H: Epidemiological, Molecular, and Clinical Characteristics in Mexico.
The hepatitis B virus (HBV), comprising of ten genotypes (A-J), has been a silent threat against humanity, constituting a public health problem worldwide. In 2016, the World Health Organization set forth an impressive initiative for the global elimination of viral hepatitis by 2030. As the target date approaches, many nations, particularly in the Latin American region, face challenges in designing and implementing their respective elimination plan. This review aimed to portray the state of knowledge about the epidemiological, molecular, and clinical characteristics of HBV genotype H (HBV/H), endemic to Mexico. PubMed, Scopus, Web of Science, and Google Scholar were searched to compile scientific literature over 50 years (1970-2022). A total of 91 articles were organized into thematic categories, addressing essential aspects such as epidemiological data, risk factors, HBV genotype distribution, HBV mixed infections, clinical characteristics, and vaccination. The prevalence and its associated 95% confidence interval (95% CI) were estimated using the Metafor package in R programming language (version 4.1.2). We provide insights into the strengths and weaknesses in diagnostics and prevention measures that explain the current epidemiological profile of HBV/H. Training, research, and awareness actions are required to control HBV infections in Mexico. These actions should contribute to creating more specific clinical practice guides according to the region's characteristics. Mexico's elimination plan for HBV will require teamwork among the government health administration, researchers, physicians, specialists, and civil society advocates to overcome this task jointly.


Genomic instability and copy-number heterogeneity of chromosome 19q, including the kallikrein locus, in ovarian carcinomas.
Many tissue kallikrein (KLK) genes and proteins are candidate diagnostic, prognostic and predictive biomarkers for ovarian cancer (OCa). We previously demonstrated that the KLK locus (19q13.3/4) is subject to copy-number gains and structural rearrangements in a pilot study of cell lines and ovarian cancer primary tissues, shown to overexpress KLK gene family members. To determine the overall frequency of genomic instability and copy-number changes, a retrospective study was conducted using formalin-fixed paraffin embedded (FFPE) tissues. Eighty-one chemotherapy naïve serous OCas were examined using 3-colour fluorescence in situ hybridization (FISH) to identify structural and numerical changes on 19q, including the KLK locus; in addition to immunohistochemistry (IHC) for KLK6, which has been shown to be overexpressed in OCa. The KLK locus was subject to copy-number changes in ∼83% of cases: net gain in 51%, net loss in 30% and amplified in 2%; and found to be chromosomally unstable (p < 0.001). All cases showed a wide range of immuoreactivity for KLK6 by IHC. Although no strong correlation could be found with copy-number, the latter was contributing factor to the observed KLK6 protein overexpression. Moreover, univariate and multivariate analyses showed an association between the net loss of the KLK locus and longer disease-free survival. Interestingly, FISH analyses indicated that chromosome 19q was subjected to structural rearrangement in 62% of cases and was significantly correlated to tumor grade (p < 0.001). We conclude that numerical and structural aberrations of chromosome 19q, affect genes including the KLK gene members, may contribute to ovarian carcinoma progression and aggressiveness.


Effect of RoseOx on peroxidation of rat mitochondrial lipids.
The effect of the RoseOx drug on rat liver mitochondrial lipids free-radical oxidation in vivo was studied. During the period of 14 days 50 mG/kg per body weight of RoseOx was added to the diet of normal rats each day. Free radical oxidation in liver mitochondrial fraction was determined by the help of a chemiluminescence method. Four kinetic The RoseOx addition to the usual diet led for free radical oxidation braking in mitochondrial fraction of liver as was shown. The RoseOx antioxidizing effect was stipulated by availability of carnosic acid as a supplement. One of the mechanism of the caronosic acid antioxidizing action could be its participation in LFRO reactions breaking by its OH-groups. Carnosic acid contains OH-groups in its molecule as well as a vitamin E for example. So, the mechanism of carnosic acid antioxidizing action is probably similar to vitamin E action in lipid free radical oxidation reactions.


Effect of Yersinia pestis YopM on experimental plague.
YopM of Yersinia pestis has previously been shown to be necessary for full virulence in mice and to be able to bind human alpha-thrombin. This activity prompted the hypothesis that YopM, functioning extracellularly during plague, might be accessible to neutralization by antibody and hence might be a protective antigen. This study tested this hypothesis and found that YopM was not protective, either by passive or active immunization, in inbred or outbred mice. These findings showed that either YopM-specific antibody does not have access to YopM during experimental plague or the function of extracellular YopM is not neutralizable by antibody. Exogenously supplied YopM partially restored virulence to a YopM- strain of Y. pestis while having no effect on lethality of Listeria monocytogenes. These findings indicate that YopM does not significantly alter host defenses important for resistance against heterologous infection (Listeria monocytogenes) but raise the possibility that YopM has a minor extracellular function specific to homologous infection (Y. pestis).


Characterizing the Complexity of Weighted Networks via Graph Embedding and Point Pattern Analysis.
We propose a new metric to characterize the complexity of weighted complex networks. Weighted complex networks represent a highly organized interactive process, for example, co-varying returns between stocks (financial networks) and coordination between brain regions (brain connectivity networks). Although network entropy methods have been developed for binary networks, the measurement of non-randomness and complexity for large weighted networks remains challenging. We develop a new analytical framework to measure the complexity of a weighted network via graph embedding and point pattern analysis techniques in order to address this unmet need. We first perform graph embedding to project all nodes of the weighted adjacency matrix to a low dimensional vector space. Next, we analyze the point distribution pattern in the projected space, and measure its deviation from the complete spatial randomness. We evaluate our method via extensive simulation studies and find that our method can sensitively detect the difference of complexity and is robust to noise. Last, we apply the approach to a functional magnetic resonance imaging study and compare the complexity metrics of functional brain connectivity networks from 124 patients with schizophrenia and 103 healthy controls. The results show that the brain circuitry is more organized in healthy controls than schizophrenic patients for male subjects while the difference is minimal in female subjects. These findings are well aligned with the established sex difference in schizophrenia.


Three-dimensional joint dynamics and energy expenditure during the execution of a judo throwing technique (Morote Seoï Nage).
A new method for analysing judo throwing techniques is proposed. Beyond a solely descriptive analysis of the kinematic parameters, we determined the main active joints and segments in the execution of a judo throwing technique. This was achieved by calculating three-dimensional joint dynamics parameters. The environment of the judoka was manipulated by using a judo-specific ergometer to replace his partner. The ergometer was used together with two force sensors coupled with two force platforms, and six synchronized infrared cameras. Sixteen French athletes competing in senior national events participated in this study and executed the throwing technique Morote Seoï Nage ten times, using the Mayeur ergometer loaded with 20 kg. This load was chosen to cover variations in the athletes and represents the effective mass they have to displace during the movement. Our main aims were to evaluate the forces and moments at the main joints in three dimensions during Morote Seoï Nage, and determine the energy expenditure of the athletes during the movement. Contrary to the teaching of some judo coaches and experts, our results show that the main driving moments are generated by the lower limbs [mean 24% (s = 4) of the total moments at the knees and 29% (s = 3) at the hips] and the trunk (mean 28%, s = 3) and not the upper limbs. Moreover, our results show that most energy expenditure (mean 880 J, s = 160) occurs during the Tsukuri phase, when the Tori (the person who throws) is positioned under the Uke (the person who is thrown).


OPTN/SRTR 2013 Annual Data Report: kidney.
A new kidney allocation system, expected to be implemented in late 2014, will characterize donors on a percent scale (0%-100%) using the kidney donor profile index (KDPI). The 20% of deceased donor kidneys with the greatest expected posttransplant longevity will be allocated first to the 20% of candidates with the best expected posttransplant survival; kidneys that are not accepted will then be offered to remaining 80% of candidates. Waiting time will start at the time of maintenance dialysis initiation (even if before listing) or at the time of listing with an estimated glomerular filtration rate of 20 mL/min/1.73 m(2) or less. Under the current system, the number of candidates on the waiting list continues to increase, as each year more candidates are added than are removed. Median waiting times for adults increased from 3 years in 2003 to more than 4.5 years in 2009. Donation rates have not increased. Short-term outcomes continue to improve; death-censored graft survival at 90 days posttransplant was 97% or higher for deceased donor transplants and over 99% for living donor transplants. In 2013, 883 pediatric candidates were added to the waiting list; 65.8% of pediatric candidates on the list in 2013 underwent deceased donor transplant. Five-year graft survival was highest for living donor recipients aged younger than 11 years (89%) and lowest for deceased donor recipients aged 11 to 17 years (68%).


Daily social interactions related to daily performance on mobile cognitive tests among older adults.
The lack of social contact or good social relationships has been linked with cognitive decline and higher risk for Alzheimer's disease and related dementias. One important but unexamined question is how daily social interactions relate to older adults' cognitive function in daily life. The present study examined how changes in daily social interactions related to fluctuations in older adults' performance on mobile cognitive tests from day to day. Using an ecological momentary assessments approach, 312 older adults (aged 70 to 90 years) completed surveys on social interactions and mobile cognitive tests five times a day for 16 consecutive days using smartphones. Multilevel modeling was used for analyses. Results demonstrated that having more daily social interactions, especially more pleasant social interactions, related to better cognitive performance the same day and over the subsequent two days. Cognitive performance, however, did not predict subsequent changes in social interactions across days. At the between-person level, older adults who had more (vs. less) frequent interactions with close partners on average, especially with their friends, had better cognitive performance. Finally, the average levels of social interactions also moderated the within-person associations between daily social interactions and the same-day cognitive performance. In sum, results from this study highlight the importance of having pleasant social interactions and frequent interactions with friends for older adults' cognitive function in daily life, and have important implications for future behavioral interventions targeting certain features of daily social interactions to reduce risk of cognitive decline and Alzheimer's disease and related dementias.


Postglacial range shift and demographic expansion of the marine intertidal snail Batillaria attramentaria.
To address the impacts of past climate changes, particularly since the last glacial period, on the history of the distribution and demography of marine species, we investigated the evolutionary and demographic responses of the intertidal batillariid gastropod, Batillaria attramentaria, to these changes, using the snail as a model species in the northwest Pacific. We applied phylogeographic and divergence population genetic approaches to mitochondrial COI sequences from B. attramentaria. To cover much of its distributional range, 197 individuals collected throughout Korea and 507 publically available sequences (mostly from Japan) were used. Finally, a Bayesian skyline plot (BSP) method was applied to reconstruct the demographic history of this species. We found four differentiated geographic groups around Korea, confirming the presence of two distinct, geographically subdivided haplogroups on the Japanese coastlines along the bifurcated routes of the warm Tsushima and Kuroshio Currents. These two haplogroups were estimated to have begun to split approximately 400,000 years ago. Population divergence analysis supported the hypothesis that the Yellow Sea was populated by a northward range expansion of a small fraction of founders that split from a southern ancestral population since the last glacial maximum (LGM: 26,000-19,000 years ago), when the southern area became re-submerged. BSP analyses on six geographically and genetically defined groups in Korea and Japan consistently demonstrated that each group has exponentially increased approximately since the LGM. This study resolved the phylogeography of B. attramentaria as a series of events connected over space and time; while paleoceanographic conditions determining the connectivity of neighboring seas in East Asia are responsible for the vicariance of this species, the postglacial sea-level rise and warming temperatures have played a crucial role in rapid range shifts and broad demographic expansions of its populations.


Myocardial lysis in acute rheumatic fever followed by regeneration of cardiac muscle and origin of Aschoff bodies.
In acute rheumatic heart disease, lysis of cardiac muscle fibres with or without retention of sarcolemma is found to be the most damaging feature in many cases. In deeper myocardium the cellular lysis often forms anastomosing clefts or sinus-like spaces between surviving muscle bundles and in the outer portion of myocardium cellular lysis may leave the sarcolemma more or less intact. From lysing cardiac muscle fibres there arise dedifferentiated cells with remarkable potentiality for regeneration. For the origin of these dedifferentiated cells, which are often indistinguishable from lymphocytes, no mitosis is seen in cardiac muscle cells. The successive stages of development of muscle cell from these dedifferentiated cells within the remaining or newly formed sarcolemma have been observed in this study. This study infers that the increased number of fibrous septa, when seen, denotes the tracks of previous muscle degeneration and subsequent replacement of it with incomplete muscle regeneration and fibrous tissue formation. In an area of muscle lysis the origin of Aschoff bodies from these dedifferentiated cells has been followed. Ashoff bodies arising in this was behave as an abortive and atypical growth of muscle fibres in a nodular fashion specific to rheumatic fever.