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Παρασκευή, 10 Νοεμβρίου 2017

In Pursuit of Fellowship: Results from a 2016 Survey of US Trainees

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Publication date: Available online 10 November 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Junjian Huang, Suhag Patel, Richard Scruggs, Dayna Levin
PurposeThe purpose of this study was to gauge radiology trainee perceptions regarding the fellowship selection process and survey their perceived level of preparedness and desire for a fellowship-oriented lecture.MethodsA survey, approved by APCR (Association of program coordinators in Radiology) was distributed via email to all APCR members for distribution to their residents.Results98.6%(n=261) of residents plan to pursue a fellowship. The most popular fellowships are IR, Body, MSK, and Neuro. For fellowship information, residents believe that fellowship directors in their field of intent were the most reliable (76%), followed by fellows (65%). Only about 50% of residents felt somewhat strongly that they were preparing for their fellowship application correctly. Lastly 44% of residents (n=94) replied extremely likely to attend a lecture series given by fellowship directors, and 36% (n=77) said somewhat likely.ConclusionThis survey demonstrates that most trainees plan to pursue fellowship training. Residents ranked certain resources as more important in fellowship selection, such as fellowship directors and fellows. Lastly, there is a high interest in a lecture series that would bring together fellowship directors and residents that are interested in that particular fellowship.



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Perioperative Internal Iliac Artery Balloon Occlusion, In the Setting of Placenta Accreta and its Variants: The Role of the Interventional Radiologist

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Publication date: Available online 10 November 2017
Source:Current Problems in Diagnostic Radiology
Author(s): David A. Petrov, Benjamin Karlberg, Kamalpreet Singh, Matthew Hartman, Pardeep K. Mittal
Placenta accreta and its variants (increta and percreta) are conditions of variant placentation that are encountered with increasing frequency. The spectrum of placenta accreta (including placenta increta and percreta) involves abnormal attachment of the placental chorionic villi to the uterine myometrium. This attachment leads to increased adherence of the placenta to the uterus and abnormal placental-uterine separation at the time of delivery. Placental invasion into, or through the myometrium is associated with increased post-partum morbidity and mortality as a result of uterine hemorrhage during and following cesarean section.A multidisciplinary clinical approach to the treatment of patients with placenta accreta is recommended by the American College of Obstetricians and Gynecologists. As potential members of an interdisciplinary team, interventional radiologists can perform prophylactic internal iliac arterial balloon occlusion as an adjunctive therapy for reducing potentially life-threatening postpartum hemorrhage. The procedure involves placement of a balloon catheter into the internal iliac or common iliac arteries bilaterally prior to cesarean section. Following delivery, and prior to placental separation, the catheter balloons are inflated with a pre-determined volume of saline leading to transient occlusion of the internal iliac arteries and reduced uterine blood flow.



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Delineating sites of failure following post-prostatectomy radiation treatment using 68Ga-PSMA-PET

To identify sites of failure with 68Ga-PSMA-PET (PSMA-PET) imaging in patients who have Biochemical Failure (BF) following post-prostatectomy radiotherapy.

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Wenn der Name zur Einheit wird: Rolf Maximilian Sievert



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Radon and NO2 levels and related environmental factors in 100 underground subway platforms over two-year period

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Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): Sung Ho Hwang, Jae Bum Park, Wha Me Park
In this study, the environmental factors that affect radon (Rn) and nitrogen dioxide (NO2) levels in subway-station underground platforms are evaluated, and the outdoor NO2 levels are compared with those obtained for the underground platforms. The Rn and NO2 levels from May 2013 to September 2015 are determined for lines 1–4 of the Seoul Metro, via calculation of the arithmetic means of the Rn and NO2 levels with their standard deviations (SDs). The underground Rn levels in 2013 are found to be significantly higher than those recorded in 2015 for the Seoul Metro. In addition, the Rn levels are related to the station depth and construction year. Further, the underground NO2 levels are shown to be significantly higher than the outdoor levels for all four Seoul Metro subway lines. The Rn levels are also found to vary significantly between months, and are shown to increase gradually with depth from 8 to 20 m. The Rn levels are also higher for stations constructed in the 1980s. Therefore, stricter monitoring of Rn level may be required for stations constructed in the 1980s and/or having platform depths within the 8–20 m range. Island-type platform stations based on granite areas may also require careful attention.



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Psychologische Merkmale verschiedener Formen des Minderwuchses



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Impaired action of thyroid hormone associated with smoking in women with hypothyroidism

BACKGROUND: The effect of smoking on thyroid function is controversial, and its effect on thyroid hormone action is unknown. We investigated the effects of cigarette smoking in women with various grades of hypothyroidism and in normal women. METHODS: We studied 138 normal women and 135 women with primary hypothyroidism, of whom 84 had subclinical hypothyroidism and 51 overt hypothyroidism. Sixty of the women with hypothyroidism were reevaluated during thyroxine therapy. The women were categorized as smokers or nonsmokers according to their responses to a questionnaire. Thyroid function was evaluated by measurements of serum thyrotropin, free thyroxine, and triiodothyronine. Peripheral thyroid hormone action was assessed by a clinical score and measurements of ankle-reflex time and serum lipids and creatine kinase. RESULTS: Among the women with subclinical hypothyroidism, the smokers had a higher mean (+/- SD) serum thyrotropin concentration (21.3 +/- 16.6 vs. 12.7 +/- 7.2 mU per liter, P = 0.004) and a higher ratio of serum triiodothyronine to serum free thyroxine (by 30 percent, P = 0.003) than the nonsmokers. Their serum concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol were higher (by 16 percent, P = 0.013; and 28 percent, P = 0.003, respectively). Among the women with overt hypothyroidism, the serum concentrations of thyrotropin, free thyroxine, and triiodothyronine were similar in the smokers and nonsmokers. As compared with the nonsmokers, the smokers had a clinical score indicating a greater degree of hypothyroidism (P > 0.001), higher serum concentrations of total and LDL cholesterol (by 25 percent, P > 0.001; and 24 percent, P = 0.002, respectively), longer ankle-reflex time (by 25 percent, P > 0.001), and higher serum concentrations of creatine kinase (by 236 percent, P > 0.001). There were dose-response relations between smoking and serum concentrations of total and LDL cholesterol, serum creatine kinase concentrations, and ankle-reflex time in the women with overt hypothyroidism, and between smoking and serum concentrations of total and LDL cholesterol in the women with subclinical hypothyroidism. CONCLUSIONS: Smoking increases the metabolic effects of hypothyroidism in a dose-dependent way. This may be explained by alteration of both thyroid function and hormone action.

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Izuchenie vzaimodeĭstviia DNK s ionami kal'tsiia metodom kolebatel'noĭ spektroskopii

DNA complexes with Ca2+ ions formed in films at various relative humidities were studied by IR-spectroscopy for molar concentration ratio of calcium ions and DNA phosphate groups [Ca2+]/[P] = 0.4-20. It is shown that the transition of DNA complexed with Ca2+ ions into B-form occurs at higher average numbers (n) of water molecules absorbed per nucleotide: n > 18 at the ratio [Ca2+]/[P] = 10, n > 24 at [Ca2+]/[P] = 20 and n > 12 in the absence of Ca2+ ions. This shows stronger binding of water molecules in the hydrate shell of DNA-Ca2+ if compared with free DNA. The results confirm a model proposed earlier. Ca2+ ions interact with phosphate oxygens of DNA and with N(7) nitrogens of guanine forming chelated complexes.

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Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men

The present study tested the hypothesis that some subjects may not readily show habituation of adrenocortical stress responses to repeated psychological stress. Twenty healthy male subjects were each exposed five times to the same, brief psychosocial stressor (public speaking and mental arithmetic in front of an audience) with one stress session per day. Salivary cortisol levels were assessed as an index of adrenocortical stress responses. For the total group, cortisol levels were significantly elevated on each of the 5 days. The mean response decreased from day 1 to day 2; however, no further attenuation could be observed on the remaining days. Cluster analysis revealed two groups of subjects who showed completely different response kinetics. In the first group (N = 13), termed "low responders," cortisol levels were elevated on day 1 only. Day 2 to 5 cortisol levels were unaltered. In contrast, subjects in the second group ("high responders") displayed large increases to each of the five experimental treatments. This group had no significant response decrement from day 1 to day 2 to 4 and only a marginal response difference between day 1 and day 5. Discriminant analysis revealed that a combination of five personality scales plus the scores on a symptoms checklist significantly discriminated between high and low responders. With this discriminant function, all 20 subjects were correctly classified to the two groups. These results are discussed with a focus on the possible impact of adrenocortical response types on health and disease.

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Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men

Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.

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Network of tangential pathways for neuronal migration in adult mammalian brain

Cells in the brains of adult mammals continue to proliferate in the subventricular zone (SVZ) throughout the lateral wall of the lateral ventricle. Here we show, using whole mount dissections of this wall from adult mice, that the SVZ is organized as an extensive network of chains of neuronal precursors. These chains are immunopositive to the polysialylated form of NCAM, a molecule present at sites of plasticity, and TuJ1, an early neuronal marker. The majority of the chains are oriented along the rostrocaudal axis and many join the rostral migratory stream that terminates in the olfactory bulb. Using focal microinjections of DII and transplantation of SVZ cells carrying a neuron-specific reporter gene, we demonstrate that cells originating at different rostrocaudal levels of the SVZ migrate rostrally and reach the olfactory bulb where they differentiate into neurons. Our results reveal an extensive network of pathways for the tangential chain migration of neuronal precursors throughout the lateral wall of the lateral ventricle in the adult mammalian brain.

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Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls

The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol. Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 +/- 2.7 vs. 4.4 +/- 2.2 vs. 3.4 +/- 2.0; P > 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 +/- 1.6 vs. 2.1 +/- 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P > 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P > 0.0004), and that with T3 was r = -0.56 (P > 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P > 0.0001) and TSH (r = 0.35; P > 0.0005). Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.

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Category fluency is also predominantly affected in Swiss Alzheimer's disease patients

OBJECTIVES: To establish the comparative efficacy to differentiate between Swiss patients with dementia of the Alzheimer type (DAT) and elderly normal control subjects (NC) on two different verbal fluency tasks: category fluency and letter fluency. MATERIAL AND METHODS: Fifty Swiss German DAT patients in the early stages of the disease and 50 matched normal control subjects were compared on letter and category fluency tasks. RESULTS: DAT patients exhibited an overproportional impairment on category fluency as compared with letter fluency. Receiver operating characteristic curves (ROC) showed that category fluency correctly classified a significantly higher number of DAT patients and NC subjects (84%) than letter fluency (70%). CONCLUSION: As similar findings have been described for English-speaking DAT patients, we conclude that deficiencies in category fluency are a general phenomenon, reflecting impaired structures of semantic knowledge occurring early in the course of Alzheimer's disease.

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Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts

Although most mutations are deleterious, an interplay between somatic mutation and selection within germinal centers (GC) results in rapid generation of high affinity memory B cells. How high affinity B cells with large numbers of mutations are generated and preserved within GC containing at their peak only a few thousand cells has been puzzling. We have developed a model of somatic mutation and B cell expansion within a GC that resolves this puzzle. We show that the frequent recycling of Ag-selected centrocytes back into centroblasts can lead to efficient affinity maturation. Memory cells are generated in large numbers even when most of the selected centrocytes recycle back into centroblasts. Our model suggests that a germinal center reaction in which the output of cells is low up to the point of GC dissociation, followed by the release of centrocytes into the periphery, is advantageous for generating high affinity memory.

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Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain

The adult mammalian subventricular zone (SVZ) contains stem cells that give rise to neurons and glia. In vivo, SVZ progeny migrate 3-8 mm to the olfactory bulb, where they form neurons. We show here that the SVZ of the lateral wall of the lateral ventricles in adult mice is composed of neuroblasts, glial cells, and a novel putative precursor cell. The topographical organization of these cells suggests how neurogenesis and migration are integrated in this region. Type A cells had the ultrastructure of migrating neuronal precursors. These cells were arranged as chains parallel to the walls of the ventricle and were polysialylated neural adhesion cell molecule- (PSA-NCAM), TuJ1- (beta-tubulin), and nestin-positive but GFAP- and vimentin-negative. Chains of Type A cells were ensheathed by two ultrastructurally distinct astrocytes (Type B1 and B2) that were GFAP-, vimentin-, and nestin-positive but PSA-NCAM- and TuJ1-negative. Type A and B2 (but not B1) cells incorporated [3H]thymidine. The most actively dividing cell in the SVZ corresponded to Type C cells, which had immature ultrastructural characteristics and were nestin-positive but negative to the other markers. Type C cells formed focal clusters closely associated with chains of Type A cells. Whereas Type C cells were present throughout the SVZ, they were not found in the rostral migratory stream that links the SVZ with the olfactory bulb. These results suggest that chains of migrating neuroblasts in the SVZ may be derived from Type C cells. Our results provide a topographical model for the adult SVZ and should serve as a basis for the in vivo identification of stem cells in the adult mammalian brain.

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Kalorimetricheskoe issledovanie vliianiia ionov Ca2+ i Mn2+ na perekhodspiral'-klubok v DNK

Using the method of differential scanning calorimetry, the DNA helix-coil transition studied in solutions containing divalent metal ions (Mn2+ and Ca2+) at relative metal ion concentrations (Me/PDNA) ranging from 0.2 to 20. Dependences of the melting temperature and enthalpy on the ion relative concentration were measured. The fine structure of melting curves in DNA+Me complexes was observed. The resolution degree of this structure was shown to increase in the range of moderate ion concentrations. The data obtained were compared with values determined by UV-spectroscopy. Association constants were defined for Mn2+ and Ca2+ binding to DNA by the ligand theory.

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Viruses, Vol. 9, Pages 337: Combined Proteomics/Genomics Approach Reveals Proteomic Changes of Mature Virions as a Novel Poxvirus Adaptation Mechanism

Viruses, Vol. 9, Pages 337: Combined Proteomics/Genomics Approach Reveals Proteomic Changes of Mature Virions as a Novel Poxvirus Adaptation Mechanism

Viruses doi: 10.3390/v9110337

Authors: Marica Grossegesse Joerg Doellinger Alona Tyshaieva Lars Schaade Andreas Nitsche

DNA viruses, like poxviruses, possess a highly stable genome, suggesting that adaptation of virus particles to specific cell types is not restricted to genomic changes. Cowpox viruses are zoonotic poxviruses with an extraordinarily broad host range, demonstrating their adaptive potential in vivo. To elucidate adaptation mechanisms of poxviruses, we isolated cowpox virus particles from a rat and passaged them five times in a human and a rat cell line. Subsequently, we analyzed the proteome and genome of the non-passaged virions and each passage. While the overall viral genome sequence was stable during passaging, proteomics revealed multiple changes in the virion composition. Interestingly, an increased viral fitness in human cells was observed in the presence of increased immunomodulatory protein amounts. As the only minor variant with increasing frequency during passaging was located in a viral RNA polymerase subunit and, moreover, most minor variants were found in transcription-associated genes, protein amounts were presumably regulated at transcription level. This study is the first comparative proteome analysis of virus particles before and after cell culture propagation, revealing proteomic changes as a novel poxvirus adaptation mechanism.



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Viruses, Vol. 9, Pages 336: Antibody Competition Reveals Surface Location of HPV L2 Minor Capsid Protein Residues 17–36

Viruses, Vol. 9, Pages 336: Antibody Competition Reveals Surface Location of HPV L2 Minor Capsid Protein Residues 17–36

Viruses doi: 10.3390/v9110336

Authors: Stephanie Bywaters Sarah Brendle Kerstin Tossi Jennifer Biryukov Craig Meyers Neil Christensen

The currently available nonavalent human papillomavirus (HPV) vaccine exploits the highly antigenic L1 major capsid protein to promote high-titer neutralizing antibodies, but is limited to the HPV types included in the vaccine since the responses are highly type-specific. The limited cross-protection offered by the L1 virus-like particle (VLP) vaccine warrants further investigation into cross-protective L2 epitopes. The L2 proteins are yet to be fully characterized as to their precise placement in the virion. Adding to the difficulties in localizing L2, studies have suggested that L2 epitopes are not well exposed on the surface of the mature capsid prior to cellular engagement. Using a series of competition assays between previously mapped anti-L1 monoclonal antibodies (mAbs) (H16.V5, H16.U4 and H16.7E) and novel anti-L2 mAbs, we probed the capsid surface for the location of an L2 epitope (aa17–36). The previously characterized L1 epitopes together with our competition data is consistent with a proposed L2 epitope within the canyons of pentavalent capsomers.



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HPV vaccinated women need just three cervical screens in their lifetime

A new study has found that women who have been given the human papillomavirus (HPV) vaccine may only need three cervical screens in their lifetime.1The authors, writing in the International Journal...
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Differentiating between “baby blues,” severe depression, and psychosis

Mayor reports important facts about perinatal psychological distress.1 Postpartum depression is a severe affective disorder and can affect both sexes. Onset is typically between one week and four...
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Edaravone, a Synthetic Free Radical Scavenger, Enhances Alteplase-Mediated Thrombolysis

The combination of alteplase, a recombinant tissue plasminogen activator, and edaravone, an antioxidant, reportedly enhances recanalization after acute ischemic stroke. We examined the influence of edaravone on the thrombolytic efficacy of alteplase by measuring thrombolysis using a newly developed microchip-based flow-chamber assay. Rat models of embolic cerebral ischemia were treated with either alteplase or alteplase-edaravone combination therapy. The combination therapy significantly reduced the infarct volume and improved neurological deficits. Human blood samples from healthy volunteers were exposed to edaravone, alteplase, or a combination of alteplase and edaravone or hydrogen peroxide. Whole blood was perfused over a collagen- and thromboplastin-coated microchip; capillary occlusion was monitored with a video microscope and flow-pressure sensor. The area under the curve (extent of thrombogenesis or thrombolysis) at 30 minutes was 69.9% lower in the edaravone-alteplase- than alteplase-treated group. The thrombolytic effect of alteplase was significantly attenuated in the presence of hydrogen peroxide, suggesting that oxidative stress might hinder thrombolysis. D-dimers were measured to evaluate these effects in human platelet-poor plasma samples. Although hydrogen peroxide significantly decreased the elevation of D-dimers by alteplase, edaravone significantly inhibited the decrease. Edaravone enhances alteplase-mediated thrombolysis, likely by preventing oxidative stress, which inhibits fibrinolysis by alteplase in thrombi.

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Increasing correlations between personality traits and cortisol stress responses obtained by data aggregation

Attempts to link personality traits and cortisol stress responses have often been inconclusive. The aim of this paper was to investigate this association by aggregating cortisol stress responses. Therefore, 20 healthy men were exposed to a task consisting of public speaking and mental arithmetics in front of an audience on five days. Six cortisol levels were measured in relation to the stressful task obtained at 10-min intervals on each day. Psychological assessment included the Questionnaire for Competence and Control (FKK) and the Giessen-Test (G-T). These questionnaires focus on assessing personality traits, i.e. locus of control and self-concept. Areas under the response curve (AUC) of the six cortisol samples were computed to obtain an index of the individual's cortisol stress response on each day. Since novelty is a random situational factor likely to mask individual differences in the stress response, the AUC cortisol stress responses of days two to five were consecutively aggregated, excluding the first day. Scales of the two questionnaires employed did not correlate with the AUC cortisol stress response of the first stress trial. The correlation pattern of the AUC cortisol measures of days two to five with the questionnaire scales was inconclusive. However, significant correlations emerged with an increasing number of cortisol stress responses aggregated. Correlations between the measure of social dominance and aggregated AUC cortisol stress responses rose from r = -.47 on day two of the experimental session to r = -.70 after aggregating days two to five. Similarly, measures of locus of control and cortisol stress responses became increasingly correlated with aggregation of several stress exposures. These data provide preliminary evidence for a relationship between questionnaire scales aiming at assessing personality traits and cortisol stress responses uncovered by repeated stress exposure and data aggregation. While novelty may mask the impact of personality on the cortisol stress response on the first exposure, differences in the ability to cope with the stressful situation may lead to different cortisol stress response patterns on subsequent stress exposures. With data aggregation, an association between the trait component of cortisol stress responses and questionnaire scales might be uncovered. For reliable investigation of correlations between personality variables and cortisol stress responses, repeated stress exposure and data aggregation is suggested.

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DNA interaction with biologically active metal ions. Cooperativity of metal ion binding and compacting of DNA



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Architecture and cell types of the adult subventricular zone: in search of the stem cells

Neural stem cells are maintained in the subventricular zone (SVZ) of the adult mammalian brain. Here, we review the cellular organization of this germinal layer and propose lineage relationships of the three main cell types found in this area. The majority of cells in the adult SVZ are migrating neuroblasts (type A cells) that continue to proliferate. These cells form an extensive network of tangentially oriented pathways throughout the lateral wall of the lateral ventricle. Type A cells move long distances through this network at high speeds by means of chain migration. Cells in the SVZ network enter the rostral migratory stream (RMS) and migrate anteriorly into the olfactory bulb, where they differentiate into interneurons. The chains of type A cells are ensheathed by slowly proliferating astrocytes (type B cells), the second most common cell type in this germinal layer. The most actively proliferating cells in the SVZ, type C, form small clusters dispersed throughout the network. These foci of proliferating type C cells are in close proximity to chains of type A cells. We discuss possible lineage relationships among these cells and hypothesize which are the neural stem cells in the adult SVZ. In addition, we suggest that interactions between type A, B, and C cells may regulate proliferation and initial differentiation within this germinal layer.

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Beta-amyloid (1-42) peptide impairs blood-brain barrier function after intracarotid infusion in rats

The effects of intracarotid infusions of beta-amyloid (1-42) peptide was studied on the permeability of brain vessels. Using a quantitative Evans blue method a dose-dependent increase of brain tissue albumin content was established following intracarotid injections of the peptide. Cerebral vessels of increased permeability were also demonstrated with a vital 'staining' technique. Lectin histochemistry revealed an almost complete abolition of specific lectin binding sites of affected endothelial cells. The findings indicate a significant deterioration by beta-amyloid (1-42) peptide of blood-brain barrier function and suggest that this may result from endothelial damage. It is assumed that altered permeability of cerebral vessels may be involved in the development of brain pathologies associated with Alzheimer's disease.

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Genetic plasticity of V genes under somatic hypermutation: statistical analyses using a new resampling-based methodology

Evidence for somatic hypermutation of immunoglobulin genes has been observed in all of the species in which immunoglobulins have been found. Previous studies have suggested that codon usage in immunoglobulin variable (V) region genes is such that the sequence-specificity of somatic hypermutation results in greater mutability in complementarity-determining regions of the gene than in the framework regions. We have developed a new resampling-based methodology to explore genetic plasticity in individual V genes and in V gene families in a statistically meaningful way. We determine what factors contribute to this mutability difference and characterize the strength of selection for this effect. We find that although the codon usage in immunoglobulin V genes renders them distinct among translationally equivalent sequences with random codon usage, they are nevertheless not optimal in this regard. We find that the mutability patterns in a number of species are similar to those we find for human sequences. Interestingly, sheep sequences show extremely strong mutability differences, consistent with the role of somatic hypermutation in the diversification of primary antibody repertoire in these animals. Human TCR V(beta) sequences resemble immunoglobulin in mutability pattern, suggesting one of several alternatives, that hypermutation is functionally operating in TCR, that it was once operating in TCR or in the common precursor of TCR and immunoglobulin, or that the hypermutation mechanism has evolved to exploit the codon usage in immunoglobulin (and fortuitously, TCR) rather than vice-versa. Our findings provide support to the hypothesis that somatic hypermutation appeared very early in the phylogeny of immune systems, that it is, to a large extent, shared between species, and that it makes an essential contribution to the generation of the antibody repertoire.

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The Cross-Border Freedom of Form Principle Under Reservation: The Role of Articles 12 and 96 CISG in Theory and Practice

The United Nations Convention on Contracts for the International Sale of Goods of 11 April 1980 (CISG) incorporates the freedom of form principle, allowing the conclusion of international sales contracts as well as their later modification to be made without regard to any form. The Convention does provide, however, for the possibility of individual Contracting States declaring a reservation against this principle, the scope and effect of which are described in Articles 12 and 96 CISG. Eleven among the current Contracting States to the Convention have made such a declaration, making the reservation to the freedom of form principle the most popular among the reservations permitted under the CISG. This article addresses a number of questions and difficulties in interpretation that have arisen under Articles 12 and 96 CISG, and proposes answers and solutions. It covers inter alia the reservation's drafting history, the current reservation states including recent signs for upcoming withdrawals of reservations, the prerequisites for making a declaration under Article 96 CISG and the consequences of such prerequisites lacking in certain reservation States. In its central part, it focusses on the effects of an Article 96 CISG reservation for the Convention's practical application, introducing the distinction between the reservation's 'negative' effect (i.e. the removal of Contracting States' public international law obligation to apply the freedom of form principle) and its disputed 'positive' effect (i.e. the question whether the reservation in itself leads to the applicability of the form requirements of the reservation State - a question that should be denied). It furthermore elaborates on the determination of the law governing the formal validity of CISG contracts in accordance with rules of private international law, and on the inadmissibility of the parties excluding the 'negative' effect through party agreement (Article 12 second sentence CISG).

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Das Wahlrecht des Käufers im Rahmen der Nacherfüllung

Das neue Kaufrecht gewährt dem Käufer, dem eine mangelhafte Kaufsache geliefert wurde, als vorrangigen Rechtsbehelf einen Anspruch auf Nacherfüllung. Dieser dient dabei zugleich den Interessen des Verkäufers, der auf diese Weise die Möglichkeit erhält, sich den Kaufpreis im Wege einer „zweiten Andienung” doch noch zu verdienen. Da die Nacherfüllung jedoch zunächst eine Wahl zwischen Ersatzlieferung und Nachbesserung erfordert, die nach § BGB § 439 BGB § 439 Absatz I BGB dem Käufer (und damit dem Anspruchsgläubiger) zusteht, können eine Reihe von Schwierigkeiten auftreten, die in diesem Beitrag untersucht werden.

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The Status of Hong Kong and Macao under the United Nations Convention on Contracts for the International Sale of Goods



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Gegenwart und Zukunft des Einheitskaufrechts

Uniform sales law forms a part of uniform private law that comprises a number of Conventions unifying either conflict-of-laws rules for sales or substantive sales law. The Hague Convention on the Law Applicable to International Sales of Goods (1955) and the Hague Uniform Sales Laws of 1964 achieved a certain legal uniformity for international sales contracts, but both were ratified by only a few Western European States. The UN (Vienna) Sales Convention of 1980 (CISG) has, in turn, developed into one of the greatest successes of uniform law-making in private law. The currently more than 80 Contracting States are proof of the fact that the CISG has been accepted by the global community of States. Its Contracting States include most major international trading nations and at the same time countries from all regions of the world. In the upcoming years, the Sales Convention's ratification by further developing States should be actively encouraged. By contrast, the extent to which the CISG has been accepted in commercial practice is very difficult to assess empirically. Much is to be said for the assumption that its contractual exclusion is significantly less common than sometimes alleged, given that the courts require a clearly expressed intention to exclude and that any exclusion needs to be agreed upon by both parties, which is often not the case. The assessment of the Sales Convention's practical importance is further complicated by its frequent application by arbitral tribunals, because the resulting arbitral awards usually remain confidential and thus inaccessible. In the future, the quest for a uniform interpretation of the Sales Convention is likely to be the most important challenge. Article 7(1) CISG provides some guidance by imposing three interpretative goals that in practice have mostly been observed. They have resulted in a generally uniform interpretation, although limited areas of non-uniformity exist. A general challenge arises from sales contracts' nature as everyday contracts in international trade, resulting in the uniform sales law's frequent application by non-specialised lawyers. It is therefore necessary to enable and assist a uniform interpretation through appropriate organisational arrangements, with a cross-border cooperation among specialised academics as the most suitable solution, designed to evaluate and assess international CISG case law and make it available to uniform law users in every country. The Sales Convention has furthermore contributed to legal uniformity through its use as a model for other international Conventions as well as for domestic and regional law reforms. By contrast, a future revision of the Convention's text seems neither desirable nor realistic, with its further development best being left to courts and legal academia. Finally, the increasing number of uniform law acts for international sales calls for a better coordination between the various law-making organisations. In particular, regional uniform law (notably EU law) should respect the existing uniform sales law by explicitly granting priority to the CISG.

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IJMS, Vol. 18, Pages 2386: Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction

IJMS, Vol. 18, Pages 2386: Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction

International Journal of Molecular Sciences doi: 10.3390/ijms18112386

Authors: Wen-Hsin Chang Philip Thai Jihao Xu David Yang Reen Wu Ching-Hsien Chen

Cigarette smoke has been shown to trigger aberrant signaling pathways and pathophysiological processes; however, the regulatory mechanisms underlying smoke-induced gene expression remain to be established. Herein, we observed that two smoke-responsive genes, HO-1 and CYP1A1, are robustly induced upon smoke by different mechanisms in human bronchial epithelia. CYP1A1 is mediated by aryl hydrocarbon receptor signaling, while induction of HO-1 is regulated by oxidative stress, and suppressed by N-acetylcysteine treatment. In light of a pivotal role of NRF2 and BACH1 in response to oxidative stress and regulation of HO-1, we examined if smoke-induced HO-1 expression is modulated through the NRF2/BACH1 axis. We demonstrated that smoke causes significant nuclear translocation of NRF2, but only a slight decrease in nuclear BACH1. Knockdown of NRF2 attenuated smoke-induced HO-1 expression while down-regulation of BACH1 had stimulatory effects on both basal and smoke-induced HO-1 with trivial influence on NRF2 nuclear translocation. Chromatin immunoprecipitation assays showed that smoke augments promoter-specific DNA binding of NRF2 but suppresses BACH1 binding to the HO-1 promoter ARE sites, two of which at −1.0 kb and −2.6 kb are newly identified. These results suggest that the regulation of NRF2 activator and BACH1 repressor binding to the ARE sites are critical for smoke-mediated HO-1 induction.



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IJERPH, Vol. 14, Pages 1368: Associations of Fasting Blood Glucose with Influencing Factors in Northeast China: A Quantile Regression Analysis

IJERPH, Vol. 14, Pages 1368: Associations of Fasting Blood Glucose with Influencing Factors in Northeast China: A Quantile Regression Analysis

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14111368

Authors: Xin Guo Li Shen Jing Dou Yaogai Lv Anning Zhang Fanchao Shi Zhiqiang Xue Yaqin Yu Lina Jin Yan Yao

Background: Diabetes mellitus (DM) has become a major public health problem in China. Although a number of researchers have investigated DM risk factors, little is known about the associations between values of fasting blood glucose (FBG) and influencing factors. This study aims to explore these associations by the quantile regression (QR) model. Methods: A cross-sectional survey based on a sample of 23,050 adults aged 18 to 79 years was conducted in Jilin in 2012, and some subjects were excluded due to missing values with respect to necessary variables or having glycemic control, in accordance with the purposes of this study. Finally, in total 14,698 people were included in this study. QR was performed to identify the factors influencing the level of FBG in different quantiles of FBG. Results: The distribution of FBG status was different between males and females (χ2 = 175.30, p &lt; 0.001). The QR model provided more detailed views on the associations of FBG with different factors and revealed apparent quantile-related patterns separately for different factors. Body mass index (BMI) was positively associated with the low and middle quantiles of FBG. Waist circumference (WC) had a positive association with the high quantiles of FBG. Conclusions: FBG had a positive association with BMI in normal FBG, and a positive association with WC in high FBG. Diet and alcohol intake were associated with FBG in normal FBG. FBG was more likely to be elevated in the elderly, female workers, and people with family history of DM.



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IJERPH, Vol. 14, Pages 1370: Are Some of the Cigar Warnings Mandated in the U.S. More Believable Than Others?

IJERPH, Vol. 14, Pages 1370: Are Some of the Cigar Warnings Mandated in the U.S. More Believable Than Others?

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14111370

Authors: Kristen Jarman Sarah Kowitt Jennifer Cornacchione Ross Adam Goldstein

Background: Text warnings are mandated on cigars sold in the United States (U.S.), however little published research has examined effectiveness of cigar warnings. This is the first study examining the believability of cigar warnings among adults in the U.S. Methods: Adults in the U.S. (n = 5014) were randomized in a phone survey to receive one of three cigar-specific mandated warning messages (“Cigar smoking can cause cancers of the mouth and throat, even if you do not inhale”, “Cigar smoking can cause lung cancer and heart disease”, and “Cigars are not a safe alternative to cigarettes”) with one of four warning sources (no source, Surgeon General, CDC (Centers for Disease Control and Prevention), FDA (Food and Drug Administration)). Results: Most adults found the cigar warnings very believable (66.9%). Weighted logistic regression results indicate that the message “Cigar smoking can cause lung cancer and heart disease” was associated with higher odds of being very believable (AOR: 2.05, 95% CI: 1.55, 2.70) and the message “Cigars are not a safe alternative to cigarettes” was associated with lower odds of being very believable (AOR: 0.71, 95% CI: 0.55, 0.92) compared to the message “Cigar smoking can cause cancers of the mouth and throat, even if you do not inhale”. Warning source had no impact on believability. Conclusions: We tested three of the currently mandated cigar warnings in the U.S. and found significant differences in believability between them. Further research on cigar warnings may improve communication to the public on cigar health risks, ultimately preventing uptake of cigars and promoting cessation among cigar users.



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IJERPH, Vol. 14, Pages 1371: The Impact of a Multi-Level Multi-Component Childhood Obesity Prevention Intervention on Healthy Food Availability, Sales, and Purchasing in a Low-Income Urban Area

IJERPH, Vol. 14, Pages 1371: The Impact of a Multi-Level Multi-Component Childhood Obesity Prevention Intervention on Healthy Food Availability, Sales, and Purchasing in a Low-Income Urban Area

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14111371

Authors: Joel Gittelsohn Angela Trude Lisa Poirier Alexandra Ross Cara Ruggiero Teresa Schwendler Elizabeth Anderson Steeves

The multifactorial causes of obesity require multilevel and multicomponent solutions, but such combined strategies have not been tested to improve the community food environment. We evaluated the impact of a multilevel (operating at different levels of the food environment) multicomponent (interventions occurring at the same level) community intervention. The B’more Healthy Communities for Kids (BHCK) intervention worked at the wholesaler (n = 3), corner store (n = 50), carryout (n = 30), recreation center (n = 28), household (n = 365) levels to improve availability, purchasing, and consumption of healthier foods and beverages (low-sugar, low-fat) in low-income food desert predominantly African American zones in the city of Baltimore (MD, USA), ultimately intending to lead to decreased weight gain in children (not reported in this manuscript). For this paper, we focus on more proximal impacts on the food environment, and measure change in stocking, sales and purchase of promoted foods at the different levels of the food system in 14 intervention neighborhoods, as compared to 14 comparison neighborhoods. Sales of promoted products increased in wholesalers. Stocking of these products improved in corner stores, but not in carryouts, and we did not find any change in total sales. Children more exposed to the intervention increased their frequency of purchase of promoted products, although improvement was not seen for adult caregivers. A multilevel food environment intervention in a low-income urban setting improved aspects of the food system, leading to increased healthy food purchasing behavior in children.



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The impact of urbanization on CO 2 emissions in China: an empirical study using 1980–2014 provincial data

Abstract

Towns and cities are not only the focus of attention for their consumption of energy and resources; they are also scrutinized closely for their emissions of greenhouse gases. China’s urbanization level now exceeds 50%, but there is still much disparity compared with the level of urbanization in developed countries. This study selects China’s urban population and carbon emissions data for the years 1980–2014 and discusses the timing and cause effect of urbanization and the corresponding carbon emissions using the Granger causality test and an error correction model (ECM) then uses STIRPAT models to extract six indicators to measure the quality of urbanization, namely, the level of urbanization, area of built-up regions, added value of tertiary industries, disposable income per capita, green areas per capita, and energy intensity. These six indicators represent population agglomeration, the expansion of urban areas, industrial agglomeration, quality of life improvements, ecological conservation, and technological improvements, respectively. The study divides 29 provinces in China into three groups based on the quality of urbanization and analyzes the impacts of the six indicators of urbanization quality on carbon emissions. The findings show that the impacts of different factors on carbon emissions vary substantially among the provinces. Finally, the study uses the findings to give suggestions on how to develop low-carbon urbanization.



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Analysis of various effects of abamectin on erythrocyte morphology in Japanese quails ( Coturnix japonica )

Abstract

Although previous studies have already confirmed the toxicological potential of abamectin (ABA) in different experimental models (from invertebrates to vertebrates), almost nothing is known about the impacts the exposure to this pesticide can cause on birds. Thus, the aim of our study is to investigate the cytotoxic effects on the erythrocytes of female Japanese quails (Coturnix japonica) exposed to low abamectin concentrations. In order to do so, three experimental groups were proposed: “control,” composed of quails exposed to abamectin-free drinking water; “ABA 1% median lethal dose (LD50),” comprising birds exposed to water containing 15.5 mg a.i./L of abamectin (via commercial formulation Kraft® 36EC), and “ABA 10% LD50,” composed by birds exposed to water containing 155.0 mg a.i./L of abamectin. The micronucleus test and the tests applied to other nuclear abnormalities in the peripheral blood of birds were conducted 40 days after exposure. Our study revealed significant physical abnormalities in nuclear shapes (erythrocytes with asymmetric constriction nuclei, notched nuclei, indented and moved nucleus) of those birds exposed to higher abamectin levels. When all nuclear abnormalities were tallied, a significant dose-dependent trend was noted. Therefore, our study presents initial imprints on determination of abamectin-mediated cellular toxicity in avifauna which can be instrumental in checking polluted ecosystems.



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Genes, Vol. 8, Pages 317: Sequencing and De Novo Assembly of the Toxicodendron radicans (Poison Ivy) Transcriptome

Genes, Vol. 8, Pages 317: Sequencing and De Novo Assembly of the Toxicodendron radicans (Poison Ivy) Transcriptome

Genes doi: 10.3390/genes8110317

Authors: Alexandra Weisberg Gunjune Kim James Westwood John Jelesko

Contact with poison ivy plants is widely dreaded because they produce a natural product called urushiol that is responsible for allergenic contact delayed-dermatitis symptoms lasting for weeks. For this reason, the catchphrase most associated with poison ivy is “leaves of three, let it be”, which serves the purpose of both identification and an appeal for avoidance. Ironically, despite this notoriety, there is a dearth of specific knowledge about nearly all other aspects of poison ivy physiology and ecology. As a means of gaining a more molecular-oriented understanding of poison ivy physiology and ecology, Next Generation DNA sequencing technology was used to develop poison ivy root and leaf RNA-seq transcriptome resources. De novo assembled transcriptomes were analyzed to generate a core set of high quality expressed transcripts present in poison ivy tissue. The predicted protein sequences were evaluated for similarity to SwissProt homologs and InterProScan domains, as well as assigned both GO terms and KEGG annotations. Over 23,000 simple sequence repeats were identified in the transcriptome, and corresponding oligo nucleotide primer pairs were designed. A pan-transcriptome analysis of existing Anacardiaceae transcriptomes revealed conserved and unique transcripts among these species.



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Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats

Abstract

VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225–45 µg/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 µg/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 µg/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 µg/kg/day.



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Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target

Abstract

Purpose of Review

The cell surface-attached extracellular glycocalyx (GCX) layer is a major contributor to endothelial cell (EC) function and EC-dependent vascular health and is a first line of defense against vascular diseases including atherosclerosis. Here, we highlight our findings regarding three GCX-dependent EC functions, which are altered when GCX is shed and in atherosclerosis. We discuss why the GCX is a viable option for the prevention and treatment of atherosclerosis.

Recent Findings

GCX regulated EC activities such as barrier and filtration function, active cell-to-cell communication, and vascular tone mediation contribute to function of the entire vascular wall. Atheroprone vessel regions, including bifurcation sites, exhibit breakdown in GCX. This GCX degradation allows increased lipid flux and thereby promotes lipid deposition in the vessel walls, a hallmark of atherosclerosis. GCX degradation also alters EC-to-EC communication while increasing EC-to-inflammatory cell interactions that enable inflammatory cells to migrate into the vessel wall. Inflammatory macrophages and foam cells, to be specific, appear in early stages of atherosclerosis. Furthermore, GCX degradation deregulates vascular tone, by causing ECs to reduce their expression of endothelial nitric oxide synthase (eNOS) which produces the vasodilator, nitric oxide. Loss of vasodilation supports vasoconstriction, which promotes the progression of atherosclerosis.

Summary

Common medicinal atherosclerosis therapies include lipid lowering and anti-platelet therapies. None of these treatments specifically target the endothelial GCX, although the GCX is at the front-line in atherosclerosis combat. This review demonstrates the viability of targeting the GCX therapeutically, to support proper EC functionality and prevent and/or treat atherosclerosis.



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Schiedsverfahren im China-Geschäft: Die neue Schiedsordnung der China International Economic and Trade Arbitration Commission (CIETAC)



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Das einheitliche Kaufrecht der afrikanischen OHADA-Staaten im Vergleich zum UN- Kaufrecht



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Contract validity and the CISG

The article discusses the standards that determine the validity of contracts that are governed by the United Nations Convention on Contracts for the International Sale of Goods of 1980 (CISG). While Article 4(a) of the—CISG � the so-called ‘validity exception’—generally excludes the validity of the contract from the Convention's material scope, it does so incompletely by adding a ‘except as otherwise expressly provided in this Convention’ caveat. Against this background, the article sets out to develop a novel validity definition. According to this definition, provisions concerned with the ‘validity of the contract’ in the sense of Article 4(a) of the CISG are legal limits to party autonomy. The article continues by applying this definition to various potential validity issues as discussed in case law and legal writings. In doing so, it distinguishes between validity issues clearly not covered by the CISG (as legal limits on what to sell, legal limits on who to sell to or to purchase from, and legal limits on how to sell) and validity issues clearly covered by the CISG, as the formal validity of contracts, the validity of open-price contracts and the effect of an initial objective impossibility of the agreed performance on the contract. Finally, the article discusses a more complicated group of borderline issues that may or may not be governed by the Sales Convention, as mistakes or misrepresentations by a contracting party, the effect of contract clauses limiting a party's rights under the contract, surprising contract clauses and the effect of legal prohibitions of interest.

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The Withdrawal of Reservations under Uniform Private Law Conventions



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Defining the Borders of Uniform International Contract Law: The CISG and Remedies for Innocent, Negligent or Fraudulent Misrepresentation

The exact definition of the substantive scope of the United Nations Convention on Contracts für the International Sale of Goods (CISG) of 11 April 1980 is a difficult but necessary task: Necessary because the scope determines over which domestic rules of law the Convention prevails, thereby preempting the concurrent domestic law’s application, and difficult because the CISG itself provides limited guidance about the method through which this definition is to be achieved. This article commences by discussing two approaches used in this regard in case law and legal writings on the Convention: (1) the reliance on Article 4 CISG, and (2) the use of dogmatic categories of domestic law such as "contract" and "tort". Both are found wanting, in particular in light of Article 7(1) CISG calling for an internationally uniform interpretation of the Convention’s scope. Against this background, the article develops a novel two-step approach with Article 7(1) CISG in mind. According to this approach, a domestic law rule is displaced by the Convention if (1) it is triggered by a factual situation which the Convention also applies to (the "factual" criterion), and (2) it pertains to a matter that is also regulated by the Convention (the "legal" criterion). Only if both criteria are cumulatively fulfilled, the domestic law rule concerned overlaps with the Convention’s sphere of application in a way that will generally result in its preemption. In third part of the article, the two-step approach is being applied to remedies for misrepresentation known in Common law jurisdictions, in turn dealing with remedies for innocent misrepresentation, negligent misrepresentation and fraudulent misrepresentation and thus defining their relationship towards the uniform law rules of the Sales Convention.

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Prospektpublizität bei Genussrechtsemissionen und aufsichtsbehördliche Altverfahren



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Der Schiedsspruch mit vereinbartem Wortlaut als Formäquivalent zur notariellen Beurkundung

Nach § ZPO § 1053 Abs. ZPO § 1053 Absatz 3 ZPO wird das Formerfordernis der notariellen Beurkundung durch die Aufnahme der entsprechenden Erklärung in einen Schiedsspruch mit vereinbartem Wortlaut ersetzt. Eine neuere Entscheidung des OLG München zeigt, dass die Praxis versucht, sich diese Wirkung zu Eigen zu machen, in dem zur Umgehung einer kostenintensiven notariellen Beurkundung Schiedsverfahren vorgetäuscht und durch Schiedsspruch mit vereinbartem Wortlaut beendet werden. Es stellt sich deshalb die Frage, welche Voraussetzungen an die Formäquivalenz des Schiedsspruchs mit vereinbartem Wortlaut zu knüpfen sind. Der Autor legt dar, dass die Vorgaben des § ZPO § 1053 Abs. ZPO § 1053 Absatz 3 ZPO als Prüfungsmaßstab bei geschicktem Vorgehen der Beteiligten leer laufen. Er empfiehlt stattdessen, die im konkreten Fall einschlägige Formvorschrift, die die notarielle Beurkundung einer Erklärung verlangt, als Prüfungsmaßstab heranzuziehen. Pursuant to Section ZPO § 1053 para ZPO § 1053 Absatz 3 German Civil Code of Procedure (ZPO) the form requirement of notarial certification of a contract may be substituted by including the corresponding declarations in an award on agreed terms. A recent decision of the Higher Regional Court of Munich illustrates that parties who wish to avoid the costly notarial certification of a contract tend to take advantage of this provision by simulating arbitral proceedings resulting in an award on agreed terms. It is therefore necessary to define the conditions under which the form equivalence of an award on agreed terms applies. The author shows that the legal requirements of Sec. ZPO § 1053 para ZPO § 1053 Absatz 3 ZPO can easily be avoided by astute parties. He recommends instead to have regard to the individual statutory form requirement applicable to determine if the form requirements have been met.

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Occult Breast Carcinoma Presenting as Scalp Metastasis

Breast cancer is the most common tumor among women, and approximately 6% of the patients have de novo metastatic breast cancer. Occult breast cancer accounts for only 0.1–0.8% of the cases and most commonly presents with axillary lymphadenopathy. Scalp metastases are rare and have been described as a sign of progression or widespread metastatic disease. Here, we describe a rare case of de novo metastatic breast cancer to the scalp as the single site of spread and without an identifiable primary breast tumor.
Case Rep Oncol 2017;10:992–997

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Vaccines, Vol. 5, Pages 43: A New Whooping Cough Vaccine That May Prevent Colonization and Transmission

Vaccines, Vol. 5, Pages 43: A New Whooping Cough Vaccine That May Prevent Colonization and Transmission

Vaccines doi: 10.3390/vaccines5040043

Authors: Michael Brennan

This article is a Letter to the Editor. The major purpose of this Letter is to highlight the development of a new genetically altered whooping cough vaccine. Recently a baboon model has been used to show that this next generation pertussis vaccine can prevent colonization, as well as disease, and elicit antibodies against major pertussis antigens. Two phase I clinical trials have been performed, showing that this new vaccine is safe in humans, and a phase II trial will be performed in the US in 2018.



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Clinical significance of the serum biomarker index detection in children with Henoch-Schonlein purpura

Publication date: Available online 10 November 2017
Source:Clinical Biochemistry
Author(s): Narangerel Purevdorj, Yun Mu, Yajun Gu, Fang Zheng, Ran Wang, Jinwei Yu, Xuguo Sun
ObjectiveTo explore a panel of serum biomarkers for laboratory diagnosis of pediatric Henoch-Schönlein purpura (HSP).MethodsThe blood white blood cells (WBC) and serum levels of serum amyloid A (SAA), interleukin 6 (IL-6), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin E (IgE), C-reactive protein (CRP), complement component 3 (C3), complement component 4 (C4), and ASO (anti-streptolysin O) were detected in 127 patients with Henoch-Schonlein purpura (HSP), 110 cases of septicemia patients, and 121 healthy volunteers. The diagnostic ability of biomarkers selected from HSP and septicemia patients was analyzed by ROC curve. By designing the calculation model, the biomarker index was calculated for laboratory diagnosis of HSP and differential diagnosis between HSP and septicemia.ResultsThe levels of serum WBC, CRP, IL-6 and SAA in the septicemia patients were significantly higher than those in the control group (p<0.05). Compared with the healthy individuals, serum levels of WBC, CRP, IL-6, SAA, IgA and IgM were significantly increased in patients with HSP (p<0.05). The area under the curve (AUC) of SAA, IgA, IgM, WBC, IL-6, and CRP in the patients with HSP was 0.964, 0.855, 0.849, 0.787, 0.765, and 0.622, respectively. The values of SAA, IgA, IgM, WBC, IL-6, and CRP in septicemia patients were 0.700, 0.428, 0.689, 0.682, 0.891, and 0.853, respectively. Biomarker index=SAA+IgA/4000+IgM/4000×0.4CRPmean valueCRPi. The biomarker index in HSP patients was significantly higher than that of the healthy controls. However, the biomarker index in septicemia patients was significantly lower than the control.ConclusionThe biomarker index of HSP patients is higher than that of the control group. While in the infectious disease represented by septicemia, it is decreased. The detection of biomarker index could exclude the interference of infection as the auxiliary examination to HSP patients.



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Comparison of fasting and non-fasting lipid profiles in a large cohort of patients presenting at a community hospital

Publication date: Available online 9 November 2017
Source:Clinical Biochemistry
Author(s): Louis-Jacques Cartier, Charlene Collins, Mathieu Lagace, Pierre Douville
ObjectiveTo compare the fasting and non-fasting lipid profile including ApoB in a cohort of patients from a community setting. Our purpose was to determine the proportion of results that could be explained by the known biological variation in the fasting state and to examine the additional impact of non-fasting on these same lipid parameters.Methods1093 adult outpatients with fasting lipid requests were recruited from February to September 2016 at the blood collection sites of the Moncton Hospital. Participants were asked to come back in the next 3–4days after having eaten a regular breakfast to have their blood drawn for a non-fasting lipid profile.Results91.6% of patients in this study had a change in total cholesterol that fell within the biological variation expected for this parameter. Similar results were seen for HDL-C (94.3%) non-HDL-C (88.8%) and ApoB (93.0%). A smaller number of patients fell within the biological variation expected for TG (78.8%) and LDL-C (74.6%). An average TG increase of 0.3mmol/L was observed in fed patients no matter the level of fasting TG. A gradual widening in the range of change in TG concentration was observed as fasting TG increased. Similar results were seen in diabetic patients.ConclusionOutside of LDL-C and TG, little changes were seen in lipid parameters in the postprandial state. A large part of these changes could be explained by the biological variation. We observed a gradual widening in the range of increase in TG for patients with higher fasting TG. Non HDL-C and ApoB should be the treatment target of choice for patients in the non-fasting state.



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Serum reference interval of ARCHITECT alpha-fetoprotein in healthy Chinese Han adults: Sub-analysis of a prospective multi-center study

Publication date: Available online 10 November 2017
Source:Clinical Biochemistry
Author(s): Cunling Yan, Jia Yang, Lianhua Wei, Jian Hu, Jiaqi Song, Xiaoqin Wang, Ruilin Han, Ying Huang, Wei Zhang, Andrew Soh, Agim Beshiri, Zhuping Fan, Yijie Zheng, Wei Chen
ObjectivesAlpha-fetoprotein (AFP) has been widely used in clinical practice for decades. However, large-scale survey of serum reference interval for ARCHITECT AFP is still absent in Chinese population. This study aimed to measure serum AFP levels in healthy Chinese Han subjects, which is a sub-analysis of an ongoing prospective, cross-sectional, multi-center study (ClinicalTrials.gov Identifier: NCT03047603).MethodsThis analysis included a total of 530 participants (41.43±12.14years of age on average, 48.49% males), enrolled from 5 regional centers. Serum AFP level was measured by ARCHITECT immunoassay. Statistical analysis was performed using SAS 9.4 and R software.ResultsAFP distribution did not show significant correlation with age or sex. The overall median and interquartile range of AFP was 2.87 (2.09, 3.83) ng/mL. AFP level did not show a trend of increasing with age. The new reference interval was 2.0–7.07ng/mL (LOQ– 97.5th percentiles).ConclusionsThe reference interval for ARCHITECT AFP is updated with the data of adequate number of healthy Han adults. This new reference interval is more practical and applicable in Chinese adults.



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Der Antrag auf Feststellung der Zulässigkeit eines schiedsrichterlichen Verfahrens gemäß § 1032 Abs. 2 ZPO

Eine Partei, die Zweifel am Bestehen einer wirksamen Schiedsvereinbarung hat, kann in einem Verfahren vor dem zuständigen Oberlandesgericht die Zulässigkeit oder Unzulässigkeit eines schiedsrichterlichen Verfahrens feststellen lassen. Der Antrag auf Einleitung eines entsprechenden Verfahrens nach § ZPO § 1032 Abs. ZPO § 1032 Absatz 2 ZPO kann vor oder bis zur Bildung des Schiedsgerichts neben einem bereits eingeleiteten Schiedsverfahren gestellt werden. Besondere Erwähnung verdient in diesem Zusammenhang die Tatsache, dass dieses Verfahren den Parteien selbst dann zur Verfügung steht, wenn der Ort des schiedsrichterlichen Verfahrens im Ausland liegt und nicht einmal ein geringster Bezug der Angelegenheit zu Deutschland vorliegt. Nachfolgend werden die Auswirkungen eines anhängigen Feststellungsantrags auf parallel geführte Schiedsverfahren sowie in verjährungsrechtlicher Hinsicht dargestellt. Anschließend wird erörtert, inwieweit die Feststellung der Zulässigkeit bzw. Unzulässigkeit eines schiedsrichterlichen Verfahrens Bindungswirkung im Hinblick auf Gerichts- oder Schiedsverfahren, die denselben streitbehafteten Anspruch zum Gegenstand haben, entfaltet. A party who is in two minds as to whether an arbitration agreement is valid or not may make an application to a Higher Regional Court to determine whether or not arbitration is admissible. Such an application pursuant to section 1032 para 2 CCP can be made before or in the course of an already pending arbitration until the arbitral tribunal has been constituted. It is noteworthy that the parties are able to make such an application to a German Higher Regional Court even if the place of arbitration is located in a foreign state and even if there is no established link of the matter to Germany. Below the effects of a pending application to determine whether or not arbitration is admissible on simultaneous pending arbitral proceedings are discussed as well as its effects on the statute of limitation. Furthermore the author discusses how and to which extent a court decision on the admissibility or inadmissibility of arbitration has binding effect on a court or arbitral proceedings dealing with the same matter in dispute.

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Verständlichkeit und Publizität im Recht der Schuldverschreibungen: Das Transparenzgebot für Anleihebedingungen (§ 3 SchVG)



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Der digitale Binnenmarkt für Europa und das UN-Kaufrecht



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A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy

We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib.

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Effects of replacing soybean meal with canola meal or treated canola meal on ruminal digestion, omasal nutrient flow, and performance in lactating dairy cows

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Publication date: Available online 10 November 2017
Source:Journal of Dairy Science
Author(s): E.M. Paula, G.A. Broderick, M.A.C. Danes, N.E. Lobos, G.I. Zanton, A.P. Faciola
Extrusion treated canola meal (TCM) was produced in an attempt to increase the rumen-undegraded protein fraction of canola meal (CM). The objective of this study was to evaluate the effects of replacing soybean meal (SBM) with CM or TCM on ruminal digestion, omasal nutrient flow, and performance in lactating dairy cows. To assess performance, 30 multiparous Holstein cows averaging (mean ± SD) 119 ± 23 d in milk and 44 ± 7 kg of milk/d and 15 primiparous cows averaging 121 ± 19 d in milk and 34 ± 6 kg of milk/d were blocked in a randomized complete block design with a 2-wk covariate period and 12-wk experimental period (experiment 1). Dietary ingredients differed only in protein supplements, which were SBM, CM, or TCM. All diets were formulated to contain (dry matter basis) 30% alfalfa silage, 30% corn silage, 4% soy hulls, 2.4% mineral-vitamin premix, and 16% CP. The SBM diet contained 25% high-moisture shelled corn and 8.6% SBM; the canola diets contained 22% high-moisture shelled corn and either 11.2% CM or 11.4% TCM. To assess ruminal digestion and omasal nutrient flow, 6 rumen-cannulated cows were blocked into 2 squares of 3 cows and randomly assigned within blocks to the same 3 dietary treatments as in experiment 1 in a replicated 3 × 3 Latin square design (experiment 2). Data were analyzed using the MIXED procedure of SAS (SAS Institute, Cary, NC). Orthogonal contrasts were used to compare effects of different protein supplements: SBM versus CM + TCM and CM versus TCM. In experiment 1, compared with SBM, apparent total-tract digestibilities of dry matter and nutrients were greater in cows fed both CM diets, and there was a tendency for nutrient digestibilities to be higher in cows fed CM compared with TCM. Diets did not affect milk yield and milk components; however, both canola diets decreased urinary urea N (% of total urinary N), fecal N (% of total N intake), and milk urea N concentration. In experiment 2, compared with SBM, both canola diets increased N intake and tended to increase rumen-degraded protein supply (kg/d) and N truly digested in the rumen (kg/d). Diets did not affect ruminal digestibility, efficiency of microbial protein synthesis, and rumen-undegraded protein flow among diets. Results from this experiment indicate that replacing SBM with CM or TCM in diets of lactating cows improved digestibility and may reduce environmental impact. Moreover, under the conditions of the present study, treating CM by extrusion did not improve CM utilization.



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Limited proteolysis as a tool to probe the tertiary conformation of dysferlin and structural consequences of patient missense variant L344P [Molecular Biophysics]

Dysferlin is a large transmembrane protein that plays a key role in cell membrane repair and underlies a recessive form of inherited muscular dystrophy. Dysferlinopathy is characterized by absence or marked reduction of dysferlin protein with 43% of reported pathogenic variants being missense variants that span the length of the dysferlin protein. The unique structure of dysferlin, with seven tandem C2 domains separated by linkers, suggests dysferlin may dynamically associate with phospholipid membranes in response to Ca2+ signaling. However, the overall conformation of the dysferlin protein is uncharacterized. To dissect the structural architecture of dysferlin, we have applied the method of limited proteolysis, which allows nonspecific digestion of unfolded peptides by trypsin. Using five antibodies spanning the dysferlin protein, we identified a highly reproducible jigsaw map of dysferlin fragments protected from digestion. Our data infer a modular architecture of four tertiary domains: 1) C2A, which is readily removed as a solo domain; 2) midregion C2B-C2C-Fer-DysF, commonly excised as an intact module, with subdigestion to different fragments suggesting several dynamic folding options; 3) C-terminal four-C2 domain module; and 4) calpain-cleaved mini-dysferlinC72, which is particularly resistant to proteolysis. Importantly, we reveal a patient missense variant, L344P, that largely escapes proteasomal surveillance and shows subtle but clear changes in tertiary conformation. Accompanying evidence from immunohistochemistry and flow cytometry using antibodies with conformationally sensitive epitopes supports proteolysis data. Collectively, we provide insight into the structural topology of dysferlin and show how a single missense mutation within dysferlin can exert local changes in tertiary conformation.

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Interaction between the AAA+ ATPase p97 and its cofactor ataxin3 in health and disease: Nucleotide-induced conformational changes regulate cofactor binding [Protein Structure and Folding]

p97 is an essential ATPase associated with various cellular activities (AAA+) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum-associated degradation. However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer. We mapped the binding determinants on each protein, demonstrating that ataxin3's p97/VCP-binding motif interacts with the inter-lobe cleft in the N-domain of p97. We also probed the nucleotide dependence of this interaction, confirming that ataxin3 and p97 associate in the presence of ATP and in the absence of nucleotide, but not in the presence of ADP. Our experiments suggest that an ADP-driven downward movement of the p97 N-terminal domain dislodges ataxin3 by inducing a steric clash between the D1-domain and ataxin3's C terminus. In contrast, MSP1 mutants of p97 bind ataxin3 irrespective of their nucleotide state, indicating a failure by these mutants to translate ADP binding into a movement of the N-terminal domain. Our model provides a mechanistic explanation for how nucleotides regulate the p97–ataxin3 interaction and why atypical cofactor binding is observed with MSP1 mutants.

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Translesion synthesis DNA polymerases promote error-free replication through the minor-groove DNA adduct 3-deaza-3-methyladenine [DNA and Chromosomes]

N3-Methyladenine (3-MeA) is formed in DNA by reaction with S-adenosylmethionine, the reactive methyl donor, and by reaction with alkylating agents. 3-MeA protrudes into the DNA minor groove and strongly blocks synthesis by replicative DNA polymerases (Pols). However, the mechanisms for replicating through this lesion in human cells remain unidentified. Here we analyzed the roles of translesion synthesis (TLS) Pols in the replication of 3-MeA-damaged DNA in human cells. Because 3-MeA has a short half-life in vitro, we used the stable 3-deaza analog, 3-deaza-3-methyladenine (3-dMeA), which blocks the DNA minor groove similarly to 3-MeA. We found that replication through the 3-dMeA adduct is mediated via three different pathways, dependent upon Polι/Polκ, Polθ, and Polζ. As inferred from biochemical studies, in the Polι/Polκ pathway, Polι inserts a nucleotide (nt) opposite 3-dMeA and Polκ extends synthesis from the inserted nt. In the Polθ pathway, Polθ carries out both the insertion and extension steps of TLS opposite 3-dMeA, and in the Polζ pathway, Polζ extends synthesis following nt insertion by an as yet unidentified Pol. Steady-state kinetic analyses indicated that Polι and Polθ insert the correct nt T opposite 3-dMeA with a much reduced catalytic efficiency and that both Pols exhibit a high propensity for inserting a wrong nt opposite this adduct. However, despite their low fidelity of synthesis opposite 3-dMeA, TLS opposite this lesion replicates DNA in a highly error-free manner in human cells. We discuss the implications of these observations for TLS mechanisms in human cells.

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Mutual synergy between catalase and peroxidase activities of the bifunctional enzyme KatG is facilitated by electron hole-hopping within the enzyme [Protein Structure and Folding]

KatG is a bifunctional, heme-dependent enzyme in the front-line defense of numerous bacterial and fungal pathogens against H2O2-induced oxidative damage from host immune responses. Contrary to the expectation that catalase and peroxidase activities should be mutually antagonistic, peroxidatic electron donors (PxEDs) enhance KatG catalase activity. Here, we establish the mechanism of synergistic cooperation between these activities. We show that at low pH values KatG can fully convert H2O2 to O2 and H2O only if a PxED is present in the reaction mixture. Stopped-flow spectroscopy results indicated rapid initial rates of H2O2 disproportionation slowing concomitantly with the accumulation of ferryl-like heme states. These states very slowly returned to resting (i.e. ferric) enzyme, indicating that they represented catalase-inactive intermediates. We also show that an active-site tryptophan, Trp-321, participates in off-pathway electron transfer. A W321F variant in which the proximal tryptophan was replaced with a non-oxidizable phenylalanine exhibited higher catalase activity and less accumulation of off-pathway heme intermediates. Finally, rapid freeze-quench EPR experiments indicated that both WT and W321F KatG produce the same methionine–tyrosine–tryptophan (MYW) cofactor radical intermediate at the earliest reaction time points and that Trp-321 is the preferred site of off-catalase protein oxidation in the native enzyme. Of note, PxEDs did not affect the formation of the MYW cofactor radical but could reduce non-productive protein-based radical species that accumulate during reaction with H2O2. Our results suggest that catalase-inactive intermediates accumulate because of off-mechanism oxidation, primarily of Trp-321, and PxEDs stimulate KatG catalase activity by preventing the accumulation of inactive intermediates.

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The stress-regulatory transcription factors Msn2 and Msn4 regulate fatty acid oxidation in budding yeast [Gene Regulation]

The transcription factors Msn2 and Msn4 (multicopy suppressor of SNF1 mutation proteins 2 and 4) bind the stress-response element in gene promoters in the yeast Saccharomyces cerevisiae. However, the roles of Msn2/4 in primary metabolic pathways such as fatty acid β-oxidation are unclear. Here, in silico analysis revealed that the promoters of most genes involved in the biogenesis, function, and regulation of the peroxisome contain Msn2/4-binding sites. We also found that transcript levels of MSN2/MSN4 are increased in glucose-depletion conditions and that during growth in nonpreferred carbon sources, Msn2 is constantly localized to the nucleus in wild-type cells. Of note, the double mutant msn2Δmsn4Δ exhibited a severe growth defect when grown with oleic acid as the sole carbon source and had reduced transcript levels of major β-oxidation genes. ChIP indicated that Msn2 has increased occupancy on the promoters of β-oxidation genes in glucose-depleted conditions, and in vivo reporter gene analysis indicated reduced expression of these genes in msn2Δmsn4Δ cells. Moreover, mobility shift assays revealed that Msn4 binds β-oxidation gene promoters. Immunofluorescence microscopy with anti-peroxisome membrane protein antibodies disclosed that the msn2Δmsn4Δ strain had fewer peroxisomes than the wild type, and lipid analysis indicated that the msn2Δmsn4Δ strain had increased triacylglycerol and steryl ester levels. Collectively, our data suggest that Msn2/Msn4 transcription factors activate expression of the genes involved in fatty acid oxidation. Because glucose sensing, signaling, and fatty acid β-oxidation pathways are evolutionarily conserved throughout eukaryotes, the msn2Δmsn4Δ strain could therefore be a good model system for further study of these critical processes.

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Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice [Molecular Bases of Disease]

Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet–accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo. We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet–accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase–mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat–accelerated tumorigenesis in vivo. Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet–mediated prostate tumor progression.

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Orchestrating phospholipid biosynthesis: Phosphatidic acid conducts and Opi1p performs [Gene Regulation]

Phosphatidic acid (PA) and the conserved integral ER membrane protein Scs2p regulate localization of the transcriptional repressor Opi1p, which controls expression of phospholipid biosynthesis genes, but the mechanisms conducting Opi1p localization are not fully understood. A new study suggests the existence of a distinct pool of PA in the ER that is required for regulation of Opi1p localization and thus phospholipid metabolism in yeast.

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Understanding DNA replication by the bacteriophage T4 replisome [DNA and Chromosomes]

The T4 replisome has provided a unique opportunity to investigate the intricacies of DNA replication. We present a comprehensive review of this system focusing on the following: its 8-protein composition, their individual and synergistic activities, and assembly in vitro and in vivo into a replisome capable of coordinated leading/lagging strand DNA synthesis. We conclude with a brief comparison with other replisomes with emphasis on how coordinated DNA replication is achieved.

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Specific electrostatic interactions between charged amino acid residues regulate binding of von Willebrand factor to blood platelets [Molecular Biophysics]

The plasma protein von Willebrand factor (VWF) is essential for hemostasis initiation at sites of vascular injury. The platelet-binding A1 domain of VWF is connected to the VWF N-terminally located D′D3 domain through a relatively unstructured amino acid sequence, called here the N-terminal linker. This region has previously been shown to inhibit the binding of VWF to the platelet surface receptor glycoprotein Ibα (GpIbα). However, the molecular mechanism underlying the inhibitory function of the N-terminal linker has not been elucidated. Here, we show that an aspartate at position 1261 is the most critical residue of the N-terminal linker for inhibiting binding of the VWF A1 domain to GpIbα on platelets in blood flow. Through a combination of molecular dynamics simulations, mutagenesis, and A1–GpIbα binding experiments, we identified a network of salt bridges between Asp1261 and the rest of A1 that lock the N-terminal linker in place such that it reduces binding to GpIbα. Mutations aimed at disrupting any of these salt bridges activated binding unless the mutated residue also formed a salt bridge with GpIbα, in which case the mutations inhibited the binding. These results show that interactions between charged amino acid residues are important both to directly stabilize the A1–GpIbα complex and to indirectly destabilize the complex through the N-terminal linker.

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Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy [Metabolism]

Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M−/−) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M−/− mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60–90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M−/− hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M−/− mice. Lysine acetylation was reduced by ∼50% in Cpt2M−/− hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M−/− hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M−/− hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.

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The periplasmic transaminase PtaA of Pseudomonas fluorescens converts the glutamic acid residue at the pyoverdine fluorophore to {alpha}-ketoglutaric acid [Microbiology]

The periplasmic conversion of ferribactin to pyoverdine is essential for siderophore biogenesis in fluorescent pseudomonads, such as pathogenic Pseudomonas aeruginosa or plant growth-promoting Pseudomonas fluorescens. The non-ribosomal peptide ferribactin undergoes cyclizations and oxidations that result in the fluorophore, and a strictly conserved fluorophore-bound glutamic acid residue is converted to a range of variants, including succinamide, succinic acid, and α-ketoglutaric acid residues. We recently discovered that the pyridoxal phosphate-containing enzyme PvdN is responsible for the generation of the succinamide, which can be hydrolyzed to succinic acid. Based on this, a distinct unknown enzyme was postulated to be responsible for the conversion of the glutamic acid to α-ketoglutaric acid. Here we report the identification and characterization of this enzyme in P. fluorescens strain A506. In silico analyses indicated a periplasmic transaminase in fluorescent pseudomonads and other proteobacteria that we termed PtaA for “periplasmic transaminase A.” An in-frame-deleted ptaA mutant selectively lacked the α-ketoglutaric acid form of pyoverdine, and recombinant PtaA complemented this phenotype. The ptaA/pvdN double mutant produced exclusively the glutamic acid form of pyoverdine. PtaA is homodimeric and contains a pyridoxal phosphate cofactor. Mutation of the active-site lysine abolished PtaA activity and affected folding as well as Tat-dependent transport of the enzyme. In pseudomonads, the occurrence of ptaA correlates with the occurrence of α-ketoglutaric acid forms of pyoverdines. As this enzyme is not restricted to pyoverdine-producing bacteria, its catalysis of periplasmic transaminations is most likely a general tool for specific biosynthetic pathways.

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Dynamic regulation of Cdr1 kinase localization and phosphorylation during osmotic stress [Signal Transduction]

Environmental conditions modulate cell cycle progression in many cell types. A key component of the eukaryotic cell cycle is the protein kinase Wee1, which inhibits the cyclin-dependent kinase Cdk1 in yeast through human cells. In the fission yeast Schizosaccharomyces pombe, the protein kinase Cdr1 is a mitotic inducer that promotes mitotic entry by phosphorylating and inhibiting Wee1. Cdr1 and Wee1 both localize to punctate structures, termed nodes, on the medial cortex, but it has been unknown whether node localization can be altered by physiological signals. Here we investigated how environmental conditions regulate Cdr1 signaling for cell division. Osmotic stress induced hyperphosphorylation of the mitotic inducer Cdr1 for several hours, and cells delayed division for the same time period. This stress-induced hyperphosphorylation required both Cdr1 autophosphorylation and the stress-activated protein kinase Sty1. During osmotic stress, Cdr1 exited cortical nodes and localized in the cytoplasm. Using a series of truncation mutants, we mapped a C-terminal domain that is necessary and sufficient for Cdr1 node localization and found that Sty1 directly phosphorylates this domain in vitro. Sty1 was not required for Cdr1 exit from nodes, indicating the existence of additional regulatory signals. Both Cdr1 phosphorylation and node localization returned to basal levels when cells adapted to osmotic conditions and resumed cell cycle progression. In summary, we identified a mechanism that prevents Cdr1 colocalization with its inhibitory target Wee1 during osmotic stress. Dynamic regulation of protein localization to cortical nodes might represent a strategy to modulate entry into mitosis under differing environmental conditions.

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