Helminth fauna of Rhinella fernandezae (Anura: Bufonidae) from the Rio Grande do Sul coastland, Brazil: analysis of the parasite community.
Ninety specimens of Rhinella fernandezae , collected in Imbé, State of Rio Grande do Sul, Brazil, from August 2006 to April 2007, were examined for presence of helminth parasites; all were infected by at least 1 species. Thirteen species of parasites were found: 4 digeneans, 2 cestodes, 2 acanthocephalans, and 5 nematodes. Rhinella fernandezae represents a new host record, as well as for Gorgoderina festoni , Cylindrotaenia americana , Acanthocephalus lutzi , Aplectana meridionalis , and Strongyloides carinii . The nematodes Cosmocerca parva and A. meridionalis occurred with a prevalence of 79.1%, and, as in other Rhinella species, the nematodes dominated the parasite community. Host gender had no influence on either abundance or prevalence of the helminths, and neither the length nor weight of the hosts influenced the richness of the parasitic helminths of these burrowing toads. Only A. meridionalis and Centrorhynchus sp. (both cystacanths) exhibited a significant correlation between host length and abundance of helminths; only A. meridionalis showed a relationship between host length and prevalence.


123I-ADAM binding to serotonin transporters in patients with major depression and healthy controls: a preliminary study.
The serotonergic system may play an important role in the pathophysiology of major depressive disorder (MDD). Few imaging studies have examined serotonin transporter (SERT) binding in patients with MDD. We hypothesized that SERT binding activity may be altered in patients with MDD. This study compared SERT binding in patients with MDD with that in healthy controls. We studied SERT activity in 7 patients (22-50 y old) with moderate to severe MDD and 6 healthy controls (24-56 y old) using (123)I-labeled 2-((2-((dimethylamino)methyl) phenyl)thio)-5-iodophenylamine (ADAM) and SPECT brain imaging. Subjects underwent SPECT 4 h after intravenous administration of 185 MBq (5 mCi) of (123)I-ADAM. Images were reconstructed in the axial plane, and region-of-interest demarcations were placed on the midbrain, medial temporal region, and basal ganglia region. (123)I-ADAM binding to SERT in the midbrain was significantly lower (P = 0.01) in MDD patients (1.81 +/- 0.07) than in controls (1.95 +/- 0.13). Age-adjusted (123)I-ADAM binding in the midbrain correlated significantly with scores on the Hamilton Depression Rating Scale (r = 0.82; P = 0.02). A significant negative correlation was observed between (123)I-ADAM SERT binding in the midbrain and age in the healthy control group (r = 0.98; P = 0.0002). SERT binding in the basal ganglia or medial temporal regions of interest did not significantly differ between groups. The findings from this preliminary study suggest the possibility of decreased SERT binding in the midbrain region of patients with MDD, with the degree of decrease correlating with the severity of depressive symptoms. There also appears to be an age-related decline in midbrain (123)I-ADAM SERT binding in healthy subjects.


[Cytochrome P-450 in tumors and during carcinogenesis].
The current data concerning regulation of cytochrome P-450 isoforms in tumours and during carcinogenesis are reviewed. These findings can be summarized as follows: (i) the total level of cytochrome P-450 in tumours is generally decreased in comparison with homologous normal tissues; (ii) this decrease is observed during both the transformation and progression of the tumour; (iii) individual isoforms of cytochrome P-450 in tumours and pretumour cell clones are expressed in different ways and can thus be regarded as markers for identifying various stages of carcinogenesis.


No changes in corticospinal excitability, biochemical markers, and working memory after six weeks of high-intensity interval training in sedentary males.
A single bout of aerobic exercise modulates corticospinal excitability, intracortical circuits, and serum biochemical markers such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1). These effects have important implications for the use of exercise in neurorehabilitation. Here, we aimed to determine whether increases in cardiorespiratory fitness (CRF) induced by 18 sessions of high-intensity interval training (HIIT) over 6 weeks were accompanied by changes in corticospinal excitability, intracortical excitatory and inhibitory circuits, serum biochemical markers and working memory (WM) capacity in sedentary, healthy, young males. We assessed motor evoked potential (MEP) recruitment curves for the first dorsal interosseous (FDI) both at rest and during tonic contraction, intracortical facilitation (ICF), and short-interval intracortical inhibition (SICI) using transcranial magnetic stimulation (TMS). We also examined serum levels of BDNF, IGF-1, total and precursor (pro) cathepsin B (CTSB), as well as WM capacity. Compared to pretraining, CRF was increased and ICF reduced after the HIIT intervention, but there were no changes in corticospinal excitability, SICI, BDNF, IGF-1, total and pro-CTSB, and WM capacity. Further, greater CRF gains were associated with larger decreases in total and pro-CTSB and, only in Val/Val carriers, with larger increases in SICI. Our findings confirm that HIIT is efficacious in promoting CRF and show that corticospinal excitability, biochemical markers, and WM are unchanged after 18 HIIT bouts in sedentary males. Understanding how aerobic exercise modulates M1 excitability is important in order to be able to use exercise protocols as an intervention, especially in rehabilitation following brain injuries.


[Pharmacokinetics of the antitumor drug oxoplatinum labeled with 191Pt].
A pharmacokinetic study of the antitumor drug oxoplatinum labeled with 191Pt when administered to control mice and mice with B-16 melanoma have shown that distribution of the drug in organs and tissues in both groups of animals is nonuniform. The drug is more tropic to the kidneys, liver, spleen, adrenals, thymus, skin and tumor. Correlation was established between the values of the coefficient ratios of differential accumulation (CDA) of the organ/blood in the final and initial periods of observation and the period of the drug half-life in the organs. The higher the CDA of the organ/blood the longer the period of the drug half-life. The excretion of the drug from the blood and most other organs is described by a bioexponential curve.


Atypical soluble guanylyl cyclases in Drosophila can function as molecular oxygen sensors.
Conventional soluble guanylyl cyclases are heterodimeric enzymes that synthesize cGMP and are activated by nitric oxide. Recently, a separate class of soluble guanylyl cyclases has been identified that are only slightly activated by or are insensitive to nitric oxide. These atypical guanylyl cyclases include the vertebrate beta2 subunit and examples from the invertebrates Manduca sexta, Caenorhabditis elegans, and Drosophila melanogaster. A member of this family, GCY-35 in C. elegans, was recently shown to be required for a behavioral response to low oxygen levels and may be directly regulated by oxygen (Gray, J. M., Karow, D. S., Lu, H., Chang, A. J., Chang, J. S., Ellis, R. E., Marletta, M. A., and Bargmann, C. I. (2004) Nature 430, 317-322). Drosophila contains three genes that code for atypical soluble guanylyl cyclases: Gyc-88E, Gyc-89Da, and Gyc-89Db. COS-7 cells co-transfected with Gyc-88E and Gyc-89Da or Gyc-89Db accumulate low levels of cGMP under normal atmospheric oxygen concentrations and are potently activated under anoxic conditions. The increase in activity is graded over oxygen concentrations of 0-21%, can be detected within 1 min of exposure to anoxic conditions and is blocked by the soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Gyc-88E and Gyc-89Db are co-expressed in a subset of sensory neurons where they would be ideally situated to act as oxygen sensors. This is the first demonstration of a soluble guanylyl cyclase that is activated in response to changing oxygen concentrations.


The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients. The HEMO Study Group.
Cross sectional studies have established that the serum albumin level is dependent on serum levels of acute-phase proteins (APPs) or cytokine levels in hemodialysis patients. While the acute-phase response is generally associated with acute inflammatory events, a cross sectional analysis relating laboratory values to outcomes assumes these values to be unchanging. The longitudinal relationship among laboratory measurements and how they vary over time in a population of patients are unknown. Patients who were enrolled in the HEMO Study were recruited into an ancillary longitudinal study to establish the predictive effect of temporal variation in the levels of APPs and of temporal variation in normalized protein catabolic rate (nPCR) on the serum albumin concentration. nPCR was measured monthly using a double-pool method. The positive APPs-C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1-AG), and ceruloplasmin-and the negative APP-transferrin (Trf)-were measured in serum obtained before each dialysis session for six weeks and then monthly in 37 hemodialysis patients. A random coefficient regression analysis was used to assess the association of serum albumin with other measured parameters at each time point, as well as fixed patient characteristics. The within-subject coefficients of variation of albumin (median, range of 25th to 75th percentiles; median, 0.0614; range, 0.0485 to 0.0690) were significantly less than that of APPs (CRP, median, 0.878; range, 0.595 to 1.314, P < 0. 05; and alpha1 AG, median, 0.173; range, 0.116 to 0.247, P < 0.05). The levels of APPs and albumin varied considerably over time. The primary predictor of current albumin was the current CRP level (P = 0.0014). nPCR also was a significant predictor for albumin levels (P = 0.0440) after controlling for the effect of APPs, suggesting an effect of nPCR on serum albumin concentration irrespective of the acute-phase response. Age and the presence of an arteriovenous graft were significant predictors that were associated with reduced albumin. The acute-phase response is intermittent and is not a continuous feature in individual dialysis patients. Levels of APPs are the most powerful predictors for the levels of albumin concentration in hemodialysis in a longitudinal setting. Since variations in albumin are small, measurement of variations in APPs may provide greater insight into the dynamics of clinically relevant processes.


Morphing pasta and beyond.
Morphing structures are often engineered with stresses introduced into a flat sheet by leveraging structural anisotropy or compositional heterogeneity. Here, we identify a simple and universal diffusion-based mechanism to enable a transient morphing effect in structures with parametric surface grooves, which can be realized with a single material and fabricated using low-cost manufacturing methods (e.g., stamping, molding, and casting). We demonstrate from quantitative experiments and multiphysics simulations that parametric surface grooving can induce temporary asynchronous swelling or deswelling and can transform flat objects into designed, three-dimensional shapes. By tuning the grooving pattern, we can achieve both zero (e.g., helices) and nonzero (e.g., saddles) Gaussian curvature geometries. This mechanism allows us to demonstrate approaches that could improve the efficiency of certain food manufacturing processes and facilitate the sustainable packaging of food, for instance, by creating morphing pasta that can be flat-packed to reduce the air space in the packaging.


[Evaluation of synthetic peptides for the detection of antibodies against human immunodeficiency virus].
The serologic diagnosis of human immunodeficiency virus (HIV) infection is currently done by detecting the presence of antibodies against the different antigenic viral proteins through immunoassays and later confirmation by Western blot. Several types of antigens can be used in immunoassays, but recombinant proteins and synthetic peptides are the most frequently used. In this paper, peptides mimicking antigenic regions from p24 (region 196-224), gp41 (region 600-614) and gp120 (region 303-338, Loop V3) proteins of HIV-1 have been used as antigens in an enzyme-linked immunosorbent assay and their reactivity was screened against a panel of positive and negative sera. Six antigenic mixtures containing different amounts of each peptide were prepared, and the one consisting of 1 microgram of gp41-15, 0.5 microgram of p24-1 and 0.5 microgram of gp120-1 per well has shown the best performance to differentiate positive and negative serum samples, with sensitivity and specificity values of 99.18% and 100%, respectively. Considering the potential utilization of this system for screening of HIV infection, it would be relevant to evaluate the additional incorporation of sequences derived from Argentine local circulating viral variants to improve the diagnostic sensitivity of the assay, allowing the development of an ELISA based on specific viral sequences.


Post Exposure Prophylaxis for Occupational Exposures to HIV and Hepatitis B: Our Experience of Thirteen Years at a Rural Based Tertiary Care Teaching Hospital of Western India.
Health Care Workers (HCWs) are at risk of occupational transmission of HIV, Hepatitis B and Hepatitis C, which can be minimized by following guidelines for standard precautions as well as taking Post Exposure Prophylaxis (PEP) measures. There are limited studies from India documenting details of PEP for HIV and Hepatitis B. We aimed to study the efficacy, tolerance, details of PEP regimens used among HCWs exposed to HIV and Hepatitis B as well as vaccination status and (Anti-Hepatitis B Surface Antigen) anti-HBS Antibody Titre Level Among HCWs exposed Hepatitis B. This retrospective observational study was done at a rural based tertiary care teaching centre of Western India. Hospital Infection Control Committee of our institute was maintaining a record of all reported incidences of HIV and Hepatitis B positive exposures since 2003. We analysed reported incidences of exposures to HIV and Hepatitis B positive source occurred during the period of January 2003 to December 2015. Of the total 96 exposures, 48 were to HIV and 48 were to Hepatitis B. Of the 48 exposures to HIV, PEP was warranted in 39. Of 39 exposures, only 14 (35.9%) received PEP within two hours. Basic regimen was used in 22 and expanded in 17 exposures. Only 12 (31.6%) reported side effects to PEP. Zidovudine based regimen was less well tolerated. All side effects were reported by female HCWs only. Of the 48 exposed to Hepatitis B, 33 (68.6%) were completely vaccinated. Out of 33, titre result was not available for eight. Three (12.0%) of remaining 25 were having low titre (<10mIU/ml) of anti-HBS antibody. Five of six with incomplete vaccination status demonstrated anti HBS antibody titre > 100mIU/ml. Of the 48, in 17 (35.4%) incidences no action was required; 23 (47.9%) were managed with booster dose of Hepatitis B vaccine and eight (16.7%) with Hepatitis B immunoglobulin. No cases of sero-conversion was reported either for HIV or Hepatitis B from available data. Inspite of high incidences of exposures to HIV or Hepatitis B positive source, good efficacy of PEP was observed with no sero-conversion. PEP for HIV was well tolerated; female HCWs were less tolerant. Study emphasized the need for creating awareness about timely reporting of incidence, achieving maximum vaccination against Hepatitis B for all HCWs and need for anti-HBS antibody titre.


High frequency of Acinetobacter soli among Acinetobacter isolates causing bacteremia at a tertiary hospital in Japan.
Acinetobacter baumannii is generally the most frequently isolated Acinetobacter species. Sequence analysis techniques allow reliable identification of Acinetobacter isolates at the species level. Forty-eight clinical isolates of Acinetobacter spp. were obtained from blood cultures at Tohoku University Hospital. These isolates were identified at the species level by partial sequencing of the RNA polymerase β-subunit (rpoB), 16S rRNA, and gyrB genes. Then further characterization was done by using the PCR for detection of OXA-type β-lactamase gene clusters, metallo-β-lactamases, and carO genes. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing were also performed. The most frequent isolate was Acinetobacter soli (27.1%). Six of the 13 A. soli isolates were carbapenem nonsusceptible, and all of these isolates produced IMP-1. PFGE revealed that the 13 A. soli isolates were divided into 8 clusters. This study demonstrated that A. soli accounted for a high proportion of Acinetobacter isolates causing bacteremia at a Japanese tertiary hospital. Non-A. baumannii species were identified more frequently than A. baumannii and carbapenem-nonsusceptible isolates were found among the non-A. baumannii strains. These results emphasize the importance of performing epidemiological investigations of Acinetobacter species.


Effects of aging on cytochrome b5 expression in the human adrenal gland.
Aging in humans is characterized by a selective decline in circulating levels of adrenal androgens. The results of in vivo studies are suggestive of reduced adrenal 17,20-lyase activity in aging men and women. We sought to determine whether there are changes in the distribution and/or expression of cytochrome B5 (CytB5), an accessory protein important in the regulation of 17,20-lyase activity, in the adrenals of aging humans. Comparison between younger and older adrenal glands. The study was conducted in a University Center. Adrenal glands obtained at autopsy after sudden death as a result of trauma from 46 young (age 20-40 yr) and 26 older (age 50-91 yr) humans were obtained and fixed within 24 h postmortem. Paraffin sections were stained with hematoxylin and eosin and also were subjected to immunohistochemical staining for CytB5. All sections were quantitatively evaluated using an image capture and analysis program and qualitatively evaluated with respect to staining intensity. To determine whether there are any changes in CytB5 distribution in the adult human adrenal cortex during the aging process using qualitative and quantitative analysis with respect to age, gender, race, and postmortem interval. CytB5 immunoreactivity was found in cells that corresponded to those of the zona reticularis. The percentage of the adrenal cortex immunoreactive for CytB5 decreased with aging (38.6 +/- 7.6% for young and 30.1 +/- 5.9% for older, mean +/- sd; P < 0.0001) as did the percentage of adrenocortical tissue comprising the zona reticularis (36.8 +/- 10.8% for young and 27.2 +/- 5.9% for older; P < 0.001). However, there was no apparent change in the staining intensity of CytB5 among those cells that were immunopositive for this factor with aging. There appears to be a reduction in the proportion of the adrenal cortex that expresses CytB5 with aging, and this likely corresponds to a shrinkage of the zona reticularis. The mechanism and cause for this cortical regression are unknown.


Pseudomonas aeruginosa Ethanol Oxidation by AdhA in Low-Oxygen Environments.
Pseudomonas aeruginosa has a broad metabolic repertoire that facilitates its coexistence with different microbes. Many microbes secrete products that P. aeruginosa can then catabolize, including ethanol, a common fermentation product. Here, we show that under oxygen-limiting conditions P. aeruginosa utilizes AdhA, an NAD-linked alcohol dehydrogenase, as a previously undescribed means for ethanol catabolism. In a rich medium containing ethanol, AdhA, but not the previously described PQQ-linked alcohol dehydrogenase, ExaA, oxidizes ethanol and leads to the accumulation of acetate in culture supernatants. AdhA-dependent acetate accumulation and the accompanying decrease in pH promote P. aeruginosa survival in LB-grown stationary-phase cultures. The transcription of adhA is elevated by hypoxia and under anoxic conditions, and we show that it is regulated by the Anr transcription factor. We have shown that lasR mutants, which lack an important quorum sensing regulator, have higher levels of Anr-regulated transcripts under low-oxygen conditions than their wild-type counterparts. Here, we show that a lasR mutant, when grown with ethanol, has an even larger decrease in pH than the wild type (WT) that is dependent on both anr and adhA The large increase in AdhA activity is similar to that of a strain expressing a hyperactive Anr-D149A variant. Ethanol catabolism in P. aeruginosa by AdhA supports growth on ethanol as a sole carbon source and electron donor in oxygen-limited settings and in cells growing by denitrification under anoxic conditions. This is the first demonstration of a physiological role for AdhA in ethanol oxidation in P. aeruginosaIMPORTANCE Ethanol is a common product of microbial fermentation, and the Pseudomonas aeruginosa response to and utilization of ethanol are relevant to our understanding of its role in microbial communities. Here, we report that the putative alcohol dehydrogenase AdhA is responsible for ethanol catabolism and acetate accumulation under low-oxygen conditions and that it is regulated by Anr.


Assessment of Post-Dengue Rheumatic Symptoms Using the WOMAC and DAS-28 Questionnaires in a Honduran Population after a Four-Month Follow-Up.
Introduction: Alphaviruses may cause arthritis, but there is a lack of studies assessing it in flaviviruses such as dengue. Through the 28 Joint Disease Activity Score (DAS-28), incorporating swollen joint counts, and through the Arthritis Index from Western Ontario and McMaster Universities (WOMAC), we assessed pain, stiffness, and dimensions of arthritic function in post-DENV patients. Methods: Prospective study of a cohort of participants who were diagnosed with dengue in centres in Honduras from December 2019 to February 2020, with a follow-up period of 4 months to evaluate post-dengue rheumatological disease through the WOMAC and DAS-28 questionnaires. Results: After a four-month follow-up phase with 281 participants, the final cohort comprised 58.8% women and 41.20% men. After the follow-up, 63.02% persisted with the clinical findings. According to WOMAC, joint involvement was higher in women with (58.76%) (p < 0.0001) these symptoms or functional limitations when performing daily activities were limited to pain when walking (34.81% vs. 5.51%), climbing or descending stairs (36.46% vs. 8.66%), and at night at bedtime (28.73% vs. 7.08%). With the DAS-28, we found at least one alteration with inflammation or pain in 14.91% of the participants, primarily women (p < 0.01). Discussion: Joint involvement was high during the dengue epidemic in 2019. We observed a significant proportion of women with inflammation and joint pain, showing that dengue may lead to the development of chronic rheumatological findings, although lower than in CHIKV, still affecting everyday life and, consequently, their quality of life. Additional long-term evaluation studies after dengue are required.


Thyroid hormone regulates the expression of laminin in the developing rat cerebellum.
In the rat cerebellum, migration of neurons from the external granular layer to the internal granular layer occurs postnatally and is dependent upon the presence of thyroid hormone. In hypothyroidism, many neurons fail to complete their migration and die. Key guidance signals to these migrating neurons are provided by laminin, an extracellular matrix protein that is fixed to the surface of astrocytes. Expression of laminin in the brain is developmentally timed to coincide with neuronal growth spurts. In this study, we examined the role of thyroid hormone on the expression and distribution of laminin in the rat cerebellum. We show that laminin content steadily increased 2- to 3-fold from birth to maximal levels on postnatal day 8-10 then steadily decreased to a plateau by postnatal day 12 in the euthyroid cerebellum. Immunoreactive laminin appeared in the molecular layer of the euthyroid cerebellum by postnatal day 4, reached maximal intensity by postnatal day 8-10, and was gone by postnatal day 14. In contrast, laminin content in the hypothyroid cerebellum remained unchanged from birth until postnatal day 10 and then increased to maximal levels over the next two days; maximal levels were approximately 35% less than those levels in the euthyroid cerebellum. Laminin staining did not appear in the molecular layer of the hypothyroid rat cerebellum until postnatal day 10, reached maximal intensity by postnatal day 15 and disappeared by postnatal day 18, despite the continued presence granular neurons in the external granular layer. These data indicate that the disruption of the timing of the appearance and regional distribution of laminin in the absence of thyroid hormone may play a major role in the profound derangement of neuronal migration observed in the cretinous brain.


Contents, Followers, and Retweets of the Centers for Disease Control and Prevention's Office of Advanced Molecular Detection (@CDC_AMD) Twitter Profile: Cross-Sectional Study.
The Office of Advanced Molecular Detection (OAMD), Centers for Disease Control and Prevention (CDC), manages a Twitter profile (@CDC_AMD). To our knowledge, no prior study has analyzed a CDC Twitter handle's entire contents and all followers. This study aimed to describe the contents and followers of the Twitter profile @CDC_AMD and to assess if attaching photos or videos to tweets posted by @CDC_AMD would increase retweet frequency. Data of @CDC_AMD were retrieved on November 21, 2016. All followers (N=809) were manually categorized. All tweets (N=768) were manually coded for contents and whether photos or videos were attached. Retweet count for each tweet was recorded. Negative binomial regression models were applied to both the original and the retweet corpora. Among the 809 followers, 26.0% (210/809) were individual health professionals, 11.6% (94/809) nongovernmental organizations, 3.3% (27/809) government agencies' accounts, 3.3% (27/809) accounts of media organizations and journalists, and 0.9% (7/809) academic journals, with 54.9% (444/809) categorized as miscellaneous. A total of 46.9% (360/768) of @CDC_AMD's tweets referred to the Office's website and their current research; 17.6% (135/768) referred to their scientists' publications. Moreover, 80% (69/86) of tweets retweeted by @CDC_AMD fell into the miscellaneous category. In addition, 43.4% (333/768) of the tweets contained photos or videos, whereas the remaining 56.6% (435/768) did not. Attaching photos or videos to original @CDC_AMD tweets increases the number of retweets by 37% (probability ratio=1.37, 95% CI 1.13-1.67, P=.002). Content topics did not explain or modify this association. This study confirms CDC health communicators' experience that original tweets created by @CDC_AMD Twitter profile sharing images or videos (or their links) received more retweets. The current policy of attaching images to tweets should be encouraged.


Stable tris(2,2'-bipyridine)ruthenium(III) for chemiluminescence detection.
Two exceedingly stable [Ru(bipy)(3)](3+) reagents were prepared by dissolving either [Ru(bipy)(3)](ClO(4))(2) in acetonitrile (containing 0.05 M HClO(4)) or [Ru(bipy)(3)]Cl(2)·6H(2)O in 95:5 glacial acetic acid-acetic anhydride (containing 0.05 M H(2)SO(4)) followed by oxidation with PbO(2). These conveniently prepared solutions provide highly reproducible chemiluminescence detection over long periods of analysis, avoiding the need for recalibration or preparation of fresh reagent solutions and without the complications associated with online chemical or electrochemical oxidations. The reagent prepared in acetonitrile produced much greater signal intensities with a range of analytes and was deemed most suitable for high-performance liquid chromatography (HPLC) with postcolumn chemiluminescence detection.


Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial.
Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index < 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. Ways to minimise potential problems regarding the execution of this study will be discussed. The Netherlands National Trial Register NTR1972.


Composition of airway surface liquid determined by X-ray microanalysis.
The composition of the airway surface liquid, a thin layer of fluid covering the airway wall, has been debated. Two new techniques to determine the ionic composition of the airway surface liquid are presented. In the first technique, pieces of the airway were shock-frozen and analyzed by X-ray microanalysis in the frozen state in the scanning electron microscope. In the second technique, the airway surface liquid was collected with the help of dextran beads that were allowed to absorb the fluid. The beads were collected in silicon oil, cleaned, dried, and analyzed. Airway surface liquid from pig airways was isotonic to lightly hypertonic, whereas airway surface liquid from mouse and rat airways was hypotonic. The ionic composition of airway surface liquid from rodent airways could be changed by pharmacological stimulation of fluid transport. Transgenic mice with cystic fibrosis (CF) had significantly higher Na and C1 concentrations in the airway surface liquid than normal mice. Nasal fluid was also collected from humans. In CF patients, CF heterozygotes, and rhinitis patients, the levels of Na and C1 in the nasal fluid were significantly higher than in healthy controls. In CF patients K levels were also significantly higher than in healthy controls. The ionic concentrations in fluid collected from patients with primary ciliary dyskinesia (PCD) were not different from normal. Females with CF had significantly higher concentrations of Na, Cl and K in their nasal fluid compared to male patients. The dextran bead technique was also used to determine the ionic composition of the apical fluid in cultures of respiratory epithelial cells from healthy controls and CF patients. In the healthy controls, the fluid was hypotonic. In the CF cell cultures, the apical fluid had a higher Na and Cl concentration than in the controls.


Identification and functions of the plasma membrane receptor for thyroid hormone analogues.
Integrin αvβ3 is a heterodimeric structural protein of the plasma membrane that bears a cell surface receptor for thyroid hormone. The functions of this receptor are distinct from those of the classical nuclear receptor (TR) for thyroid hormone. The integrin is expressed primarily by cancer cells, dividing endothelial and vascular smooth muscle cells, and osteoclasts. The hormone receptor on αvβ3 enables L-thyroxine (T(4)) and 3, 5, 3'-triiodo-L-thyronine (T(3)) to stimulate cancer cell proliferation and angiogenesis and to regulate the activity of certain membrane ion pumps. Bound to the receptor, the hormone ligand also stimulates protein trafficking within the cell. A deaminated derivative of T(4), tetraiodothyroacetic acid (tetrac), blocks binding and actions of T(4) and T(3) at the receptor on αvβ3; tetrac also has anti-proliferative actions at the integrin thyroid hormone receptor beyond the effects of antagonizing actions of agonist thyroid hormone analogues at the receptor. The structure-activity relationships of hormone analogues at the receptor have been computer-modeled and indicate that the receptor includes a site that binds T(3) and a site that binds both T(4) and T(3). Mathematical modeling of the kinetics of hormone-binding also suggests the existence of two sites. Cell proliferation is modulated from the T(4)/T(3) site. Tetrac has been re-formulated as a nanoparticle (nanotetrac) that acts exclusively at the αvβ3 receptor and does not enter cells. Nanotetrac disrupts expression of genes in multiple cancer cell survival pathways. The tetrac formulations block human cancer cell proliferation in vitro and in tumor xenografts. Nanotetrac and tetrac inhibit the pro-angiogenic actions in vitro of vascular endothelial growth factor, basic fibroblast factor, and other growth factors. Thus, the receptor described on integrin αvβ3 for T(4) and T(3), the function of which is materially affected by tetrac and nanotetrac, provides insight into tumor cell biology and vascular biology.


Transplantation of 3D bio-printed cardiac mesh improves cardiac function and vessel formation via ANGPT1/Tie2 pathway in rats with acute myocardial infarction.
A novel tissue engineering strategy using 3D bio-print technology has become a promising therapeutic method for acute myocardial infarction (AMI) in an animal model. However, the application of 3D bio-printed tissue remains limited due to poor graft survival. Therefore, it is a scientific priority to enhance graft survival by precisely adjusting the 3D environment of encapsulated cells. In this study, novel transplantable 3D cardiac mesh (cMesh) tissue with a porous mesh structure was presented using human cardiomyocytes, human cardiac fibroblasts, and gelatin-methacryloyl-collagen hydrogel. Cardiomyocytes and cardiac fibroblasts were well spreaded. The cardiomyocytes were connected with a gap junction channel in bio-printed cMesh and a 3D cardiac patch with an aggregated structure. Porous cMesh demonstrated structural advantages by increased phosphorylation of mTOR, AKT, and ERK signals associated with cell survival. Transplanted cMesh in rats with AMI improved long-term graft survival, vessel formation, and stabilization, reduced fibrosis, increased left ventricle thickness, and enhanced cardiac function. Our results suggest that porous cMesh provides structural advantages and a positive therapeutic effect in an AMI animal model.


Effect of albumin infusion on oxidative albumin modification and albumin binding capacity in chronic liver failure.
Oxidative albumin modification and impaired albumin binding function have been described both in chronic liver failure and for therapeutic albumin solutions. The aim of the present study was to evaluate the effect of albumin infusion on redox state and binding function of circulating albumin. We studied 20 patients with cirrhosis who routinely received albumin infusions for prevention of post-paracentesis circulatory dysfunction or treatment of hepatorenal syndrome. We measured albumin fractions by redox state of cysteine-34 and albumin binding properties using dansylsarcosine as site II ligand. Therapeutic albumin solutions showed high contents of human nonmercaptalbumin-1 and human nonmercaptalbumin-2, exceeding the respective values in our patients with decompensated cirrhosis. An initial protocol for the first 9 patients sampled at baseline, 24h and 48h after albumin infusion revealed no significant changes of oxidized albumin species or albumin binding properties. However, a modified protocol for the remaining 11 patients sampled at baseline, <1h after and 24h after albumin infusion revealed short-lived changes of oxidized albumin species while no changes in albumin binding properties were observed. In conclusion, therapeutic albumin infusion transiently changed albumin redox state but did not improve binding function of circulating albumin in chronic liver failure.


Long-term maintenance treatment of rosacea: experts' opinion.
Rosacea is a chronic inflammatory dermatosis characterized by remissions and flares. Although the rosacea active treatment phase is well established, the long-term maintenance phase is still challenging. To discuss and make recommendations on how to treat patients during the long-term maintenance phase for the main rosacea phenotypes. A panel of six board-certified Brazilian dermatologists and one American dermatologist gathered to compose a consensus based upon an initial statement on how to treat rosacea during the long-term maintenance phase based on the methodology Nominal Group Technique. The experts discussed each factor based upon an initial statement on how to treat rosacea patients in the long-term maintenance phase. A sequence of comprehensive narrative reviews was performed; a questionnaire preparation about the definition of the maintenance phase and its management was presented; an interpersonal discussion and ranking of the ideas were conducted. Recommendations were made if the specialists had 75% agreement. The maintenance treatment phase, which starts by achieving IGA 0 or 1 grades at the active phase, should be considered at least during the 9-month period after remission. The recommendations of all treatments target this period. Daily skincare regimen and sunscreen are crucial. Active treatment phase should be recommended if signs or symptoms reappear or worsen. Maintenance phase success depends on patient's adherence to daily skin care, appropriate treatments, continued follow-up with dermatologist, and self-assessment to identify new signs and symptoms indicating disease relapse.


Differential COVID-19 preventive behaviors among Asian subgroups in the United States.
Given the observed within-Asian disparity in Covid-19 incidence, we aimed to explore the differential preventive behaviors among Asian subgroups in the United States. Based on data from the Asian subsample (N = 982) of the 2020 Health, Ethnicity and Pandemic survey, we estimated the weighted proportion of noncompliance with Center for Disease Control and Prevention (CDC) guidelines on preventive behaviors and Covid-19 testing by Asian subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, Other Asian). We examined these subgroup differences after adjusting for demographic factors and state-level clustering. Filipinos demonstrated the lowest rate of noncompliance for mask-wearing, social distancing and handwashing. As compared with the Filipinos, our logistic models showed that the Chinese and the 'other Asians' subgroup had significantly higher risk of noncompliance with mask-wearing, while the Japanese, the Vietnamese, and other Asians were significantly more likely to report noncompliance with social distancing. The significant variation of preventive behavior across Asian subgroups signals the necessity of data disaggregation when it comes to understanding the health behavior of Asian Americans, which is critical for future pandemic preparedness. The excess behavioral risk among certain Asian subgroups (especially those 'other Asians') warrants further investigation and interventions about the driving forces behind these disparities.


WRKY42 modulates phosphate homeostasis through regulating phosphate translocation and acquisition in Arabidopsis.
The Arabidopsis (Arabidopsis thaliana) WRKY transcription factor family has more than 70 members, and some of them have been reported to play important roles in plant response to biotic and abiotic stresses. This study shows that WRKY42 regulated phosphate homeostasis in Arabidopsis. The WRKY42-overexpressing lines, similar to the phosphate1 (pho1) mutant, were more sensitive to low-inorganic phosphate (Pi) stress and had lower shoot Pi content compared with wild-type plants. The PHO1 expression was repressed in WRKY42-overexpressing lines and enhanced in the wrky42 wrky6 double mutant. The WRKY42 protein bound to the PHO1 promoter under Pi-sufficient condition, and this binding was abrogated during Pi starvation. These data indicate that WRKY42 modulated Pi translocation by regulating PHO1 expression. Furthermore, overexpression of WRKY42 increased root Pi content and Pi uptake, whereas the wrky42 mutant had lower root Pi content and Pi uptake rate compared with wild-type plants. Under Pi-sufficient condition, WRKY42 positively regulated PHOSPHATE TRANSPORTER1;1 (PHT1;1) expression by binding to the PHT1;1 promoter, and this binding was abolished by low-Pi stress. During Pi starvation, the WRKY42 protein was degraded through the 26S proteasome pathway. Our results showed that AtWRKY42 modulated Pi homeostasis by regulating the expression of PHO1 and PHT1;1 to adapt to environmental changes in Pi availability.


Objective and subjective efficacy as well as tolerability of olanzapine in the acute treatment of 120 patients with schizophrenia spectrum disorders.
The aim of the present study was to evaluate the objective and subjective efficacy as well as tolerability of olanzapine in acute treatment of schizophrenia spectrum disorders under naturalistic non-selective conditions. Inpatients with schizophrenia spectrum disorders, consecutively admitted over an 18-month period, treated with olanzapine, were included. Diagnoses were made according to ICD-10 criteria based on repeated clinical assessments. Efficacy and tolerability of olanzapine were assessed at baseline and at the end of inpatient acute treatment including Positive and Negative Symptom Scale (PANSS), Clinical Global Impression, subjective assessments, UKU and biological investigations. One hundred and twenty non-selected patients who met ICD-10 criteria for schizophrenia (73%), schizophreniform disorder (14%) or schizoaffective disorder (13%) were treated with olanzapine 15.3+/-5.2 mg/day. Baseline severity (PANSS total mean score 102.2) was higher compared to various admittance studies (PANSS total mean score 86-90). In 32% of patients (n=38), olanzapine treatment was discontinued, mainly because of inefficacy for positive (89%, n=34) and/or negative (95%, n=36) symptoms and/or because of adverse events (37%, n=14). Response rates as improvement in PANSS total score (after > or =3 weeks of treatment) of > or =20%, 30% or 40% were 68%, 55% and 35%, respectively. Response rates in post-hoc defined treatment resistant patients were not significantly different from non-refractory patients. Sedation (26%) was the most common side-effect, followed by weight gain (22%). With regards to subjective efficacy, 30% of the patients were not satisfied with the efficacy of olanzapine, while only 6% of the patients reported a not satisfying subjective tolerability. According to duration of olanzapine treatment, the results for patients, who remained in hospital, revealed a faster increase of weight compared to admittance studies (7 kg in 14 weeks versus 7 kg in 38 weeks). Olanzapine has been found to be effective and tolerable, also under naturalistic acute treatment conditions. Compared to previous double-blind admittance studies, patients had a higher severity of illness at entry and a lower > or =40% PANSS total score response rate. By contrast to previous results, mean dose of olanzapine was similar for multiple- and first-episode patients, and weight gain was more severe. The results underline the need of Phase IV studies for the assessment of clinical antipsychotic efficacy and tolerability.


Ambient ionisation mass spectrometry for in situ analysis of intact proteins.
Ambient surface mass spectrometry is an emerging field which shows great promise for the analysis of biomolecules directly from their biological substrate. In this article, we describe ambient ionisation mass spectrometry techniques for the in situ analysis of intact proteins. As a broad approach, the analysis of intact proteins offers unique advantages for the determination of primary sequence variations and posttranslational modifications, as well as interrogation of tertiary and quaternary structure and protein-protein/ligand interactions. In situ analysis of intact proteins offers the potential to couple these advantages with information relating to their biological environment, for example, their spatial distributions within healthy and diseased tissues. Here, we describe the techniques most commonly applied to in situ protein analysis (liquid extraction surface analysis, continuous flow liquid microjunction surface sampling, nano desorption electrospray ionisation, and desorption electrospray ionisation), their advantages, and limitations and describe their applications to date. We also discuss the incorporation of ion mobility spectrometry techniques (high field asymmetric waveform ion mobility spectrometry and travelling wave ion mobility spectrometry) into ambient workflows. Finally, future directions for the field are discussed.


Gradient doping of phosphorus in Fe2O3 nanoarray photoanodes for enhanced charge separation.
Hematite (α-Fe2O3) is a promising candidate for solar-to-hydrogen energy conversion. However, the low carrier mobility and extremely high charge recombination rate limit the practical application of hematite in solar water splitting. This paper describes the fabrication of a Fe2O3 photoanode with gradient incorporation of phosphorus (P) employing a facile dipping and annealing method to improve the charge separation for enhanced photoelectrochemical water oxidation. This gradient P incorporation increases the width of band bending over a large region in Fe2O3, which is crucial for promoting the charge separation efficiency in the bulk. Although both gradient and homogeneous P-incorporated Fe2O3 samples exhibit similar electrical conductivity, the Fe2O3 electrode with a gradient P concentration presents an additional charge separation effect. A photocurrent of ∼1.48 mA cm-2 is obtained at 1.23 V vs. reversible hydrogen electrode (vs. RHE) under air mass 1.5G illumination. Additionally, the H2O oxidation kinetics of Fe2O3 with gradient P incorporation was further improved upon loading cobalt phosphate as cocatalyst, reaching a photocurrent of ∼2.0 mA cm-2 at 1.23 V vs. RHE.


A role for the SHP-2 tyrosine phosphatase in nerve growth-induced PC12 cell differentiation.
SHP-1 and SHP-2 are intracellular protein tyrosine phosphatases containing two adjacent src homology 2 domains that target these phosphatases to cell surface receptor signaling complexes and play a role in receptor signal transduction. In this report the PC12 cell system was used to investigate the potential roles of SHP-1 and SHP-2 in the induction of neuronal differentiation by nerve growth factor (NGF). By using neurite outgrowth as a marker for differentiation, the effects of transfected constructs of SHP-1 and SHP-2 were assessed. Overexpression of a catalytically inactive SHP-2, but not a catalytically inactive SHP-1, blocked NGF-stimulated neurite outgrowth. The mitogen-activated protein kinase (MAPK) signaling cascade is important for the morphological differentiation in PC12 cells, and both SHP-1 and SHP-2 have been implicated to act upstream of MAPK in other receptor signaling systems. A positive role for SHP-2 but not SHP-1 in the activation of MAPK by NGF was demonstrated by introduction of the SHP-2 phosphatase mutants along with hemagglutinin-tagged MAPK. Coexpression studies with the SHP-2 mutant along with mutant forms of MAPK kinase suggested that SHP-2 functions upstream of MAPK kinase and MAPK in NGF-induced neurite outgrowth.


Indigenous health: designing a clinical orientation program valued by learners.
Indigenous health programs are seen as a curriculum response to addressing health disparities and social accountability. Several interrelated teaching approaches to cultural competency curricula have been recommended, however evidence of the impact of these on learner outcomes including engagement and self-reported competencies is limited. We aimed to explore undergraduate medical student perspectives of an indigenous health orientation program to inform curriculum strategies that promote learning and development of clinical skills. We analyzed quantitative and qualitative student evaluations (n = 602) of a three-day immersed indigenous health orientation program between 2006 and 2014 based on Likert-scale responses and open-text comments. We conducted a thematic analysis of narrative student experiences (n = 426). Overall, 509 of 551 respondents (92%) rated the indigenous health orientation program as extremely or highly valuable and most (87%) reported that the course strongly increased their interest in indigenous health. The features of the clinical course that enhanced value for learners included situated learning (learning environment; learning context); teaching qualities (enthusiasm and passion for Māori health; role-modelling); curriculum content (re-presenting Māori history; exploring Māori beliefs, values and practices; using a Māori health framework in clinical practice); teaching methodologies (multiple teaching methods; simulated patient interview); and building relationships with peers (getting to know the student cohort; developing professional working relationships). Undergraduate medical students valued an indigenous health program delivered in an authentic indigenous environment and that explicitly reframed historical notions of indigenous health to contextualize learning. Content relevant to clinical practice, faculty knowledge, and strengthened peer interactions combined to build learner confidence and self-reported indigenous health competencies. These findings suggest empirical evidence to support a curriculum approach to indigenous health teaching that enhances clinical learning.


Involvement of the nuclear structural proteins in aging-related responses of human skin to the environmental stress.
Human skin is a stratified endocrine organ with primary roles in protection against detrimental biochemical and biophysical factors in the environment. Environmental stress causes gradual accumulation of the macromolecular damage and clinical manifestations consistent with chronic inflammatory conditions and premature aging of the skin. Structural proteins of cell nucleus, the nuclear lamins and lamina-associated proteins, play an important role in the regulation of a number of signal transduction pathways associated with stress. The nuclear lamina proteins have been implicated in a number of degenerative disorders with frequent clinical manifestations of the skin conditions related to premature aging. Analysis of the molecular signatures in response of the skin to a range of damaging factors not only points at the likely involvement of the nuclear lamina in transmission of the signals between the environment and cell nucleus but also defines skin's sensitivity to stress, and therefore the capacities to counteract external damage in aging.


The immunological properties of Brucella ribosomal preparations.
Ribosomes were isolated from Brucella abortus strains 19 and 45/20 by disruption of the cells followed by differential ultracentrifugation. The ribosome preparations contained 2-3 components reacting in immunodiffusion tests but were free of detectable lipopolysaccharide-protein agglutinogen. They crossreacted with antisera to Br. abortus, Br. melitensis, Br. suis and Br. ovis and elicited intradermal delayed hypersensitivity reactions in animals infected with Br. abortus, Br. melitensis or Br. suis. The ribosomes were antigenic in rabbits, guinea pigs and mice. Those from Br. abortus S19 induced agglutinins reaction with smooth brucella strains whereas those from Br. abortus 45/20 induced agglutinins reacting with rough brucella strains. Cattle vaccinated with S19 or 45/20 vaccines or infected with Br. abortus developed pricipitins to ribosomal components at an early stage in the immune response.


Oxidation-sensitive polymersomes as vaccine nanocarriers enhance humoral responses against Lassa virus envelope glycoprotein.
Lassa virus (LASV) causes severe hemorrhagic fever with high mortality, yet no vaccine currently exists. Antibodies targeting viral attachment proteins are crucial for protection against many viral infections. However, the envelope glycoprotein (GP)-1 of LASV elicits weak antibody responses due to extensive glycan shielding. Here, we explored a novel vaccine strategy to enhance humoral immunity against LASV GP1. Using structural information, we designed a recombinant GP1 immunogen, and then encapsulated it into oxidation-sensitive polymersomes (PS) as nanocarriers that promote intracellular MHCII loading. Mice immunized with adjuvanted PS (LASV GP1) showed superior humoral responses than free LASV GP1, including antibodies with higher binding affinity to virion GP1, increased levels of polyfunctional anti-viral CD4 T cells, and IgG-secreting B cells. PS (LASV GP1) elicited a more diverse epitope repertoire of anti-viral IgG. Together, these data demonstrate the potential of our nanocarrier vaccine platform for generating virus-specific antibodies against weakly immunogenic viral antigens.


An improved method for Southwestern blotting.
We have developed a modified Southwestern blotting technique which utilizes broad-spectrum protease inhibitors during nuclear protein extraction and a procedure for radiolabelling an oligonucleotide probe to a high specific activity. These modifications have resulted in minimal protein degradation during nuclear protein isolation and have permitted room temperature hybridizations, improving both the facility and sensitivity of the standard Southwestern assay. This technique was used in our laboratory to visualize NFAT-1 consensus sequence binding proteins in nuclear extracts of human promyelocytic HL-60 cells.


Dynamically controlled deposition of colloidal nanoparticle suspension in evaporating drops using laser radiation.
Dynamic control of the distribution of polystyrene suspended nanoparticles in evaporating droplets is investigated using a 2.9 μm high power laser. Under laser radiation a droplet is locally heated and fluid flows are induced that overcome the capillary flow, and thus a reversal of the coffee-stain effect is observed. Suspension particles are accumulated in a localised area, one order of magnitude smaller than the original droplet size. By scanning the laser beam over the droplet, particles can be deposited in an arbitrary pattern. This finding raises the possibility for direct laser writing of suspended particles through a liquid layer. Furthermore, a highly uniform coating is possible by manipulating the laser beam diameter and exposure time. The effect is expected to be universally applicable to aqueous solutions independent of solutes (either particles or molecules) and deposited substrates.


Effect of SXWS/WSXWS peptides on chemotaxis and adhesion of the macrophage-like cell line J774.
WSXWS motif is a conserved amino acid sequence that is present in type I cytokine receptors. This motif that can be found both in the ligand binding chains and signal transducer molecule of the receptors with different amino acids at the position "X" plays a role in the receptor folding, ligand binding and signal transduction as well. Structural analysis proved that WSEWS motif of IL-6R is located in a highly accessible location in the protein. Structural properties and chemotaxis of a tetrapeptide library with SXWS sequence, where X was the 19 proteinogenic amino acids except cystein were systematically studied earlier. It has been proved that C-terminal amidation and the identity of amino acid X had a pronounced influence on the chemotactic properties but less of the structure of the peptides. Here, we present our findings on the effect of a tetrapeptide and a pentapeptide library with the sequence of SXWS and WSXWS on the chemotaxis and adhesion of J774 murine macrophage cell line. We studied the effect of the presence/absence of N-terminal tryptophan and the different amino acids at the X position on these physiological responses. Results indicated that amino acid X had a marked influence on chemotaxis, adhesion as well as on proliferation induced by (W)SXWS peptides. Elongation of SXWS sequence with a tryptophan at the N terminus also altered pronouncedly all the physiological responses of the cells studied. A good correlation could be observed between the chemotaxis and the proliferation and physicochemical parameters of the amino acid X.


Efficacy and safety of single versus dual antiplatelet therapy for coiling of unruptured aneurysms.
Although the efficacy of antiplatelet therapy for coiling of unruptured cerebral aneurysms has been reported, regimens for this therapy are not yet well established. The aim of this retrospective study was to analyze correlations among the modes of antiplatelet use, aneurysmal configuration, coiling methods, and complications to elucidate the optimal antiplatelet therapy for coiling. The study population comprised 154 patients with unruptured aneurysms who underwent coiling with antiplatelet therapy at our institution between 2001 and 2009. The patients were categorized by mode of antiplatelet therapy (single [n = 64] or dual [n = 90]), neck size (wide [n = 80] or narrow [n = 74]), and technique used (simple [n = 42] or adjunctive [n = 112]). The incidences of hemorrhagic/ischemic complications and abnormalities on postprocedural diffusion-weighted magnetic resonance imaging (DWI) in each group were statistically assessed. Hemorrhagic complications occurred in 1 case (1.5%) with single antiplatelet therapy and in 2 cases (2.2%) with dual antiplatelet therapy. Symptomatic ischemic complications occurred in 5 cases (7.8%) with single therapy and in 4 cases (4.4%) with dual therapy. Abnormalities were detected by DWI in 27 cases (42%) with single therapy and in 31 cases (34%) with dual therapy. No significant difference was found between modes of antiplatelet therapy even when the technique used was taken into account. In cases of wide neck, however, there were significant differences in the rate of symptomatic ischemic complications (single, 21.7%; dual, 3.5%; P = .014) and DWI abnormalities (single, 37.8%; dual, 20.9%; P = .048). Our data suggest that dual antiplatelet therapy may better prevent ischemic complications from coiling for wide-necked aneurysms compared with single antiplatelet therapy.


ATM-dependent phosphorylation of nibrin in response to radiation exposure.
Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1,2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time. The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.


Tracking the crystallization behavior of high-silica FAU during AEI-type zeolite synthesis using acid treated FAU-type zeolite.
During AEI zeolite synthesis using acid treated FAU (AcT-FAU), we found the recrystallization of high-silica FAU with high crystallinity and Si/Al ratio of 6.1 using N,N-dimethyl-3,5-dimethylpiperidinium hydroxide (DMDMPOH) after 2 h, followed by the crystallization of AEI via FAU-to-AEI interzeolite conversion at a longer synthesis time. In order to understand the formation mechanism of high-silica FAU and generalize its direct synthesis, we have investigated this synthesis process. An analysis of the short-range structure of AcT-FAU revealed that it has an ordered aluminosilicate structure having a large fraction of 4-rings despite its low crystallinity. The changes in the composition of the products obtained at different synthesis times suggested that DMDMP+ plays a certain role in the stabilization of the FAU zeolite framework. Moreover, the results of thermogravimetric analysis showed that the thermal stability of DMDMP+ changed with the zeolite conversion. To the best of our knowledge, this is the first study to clarify the structure-directing effect of DMDMP+ on FAU zeolite formation.


[Study of the monoaminergic mechanisms of the effect of haloperidol in experiments using cats].
Monoaminergic mechanisms of the haloperidol action on the systems "rewards" and "punishments" were studied in 22 cats with nichrome electrodes implanted into the hypothalamus. Haloperidol was introduced against the background of the dopaminomimetic amantadine, precursors of biogenic amines L-DOPA, tryptophan and 5-OTP. The inhibitory influence of haloperidol on the system "rewards" was found to be materialized largely at the expense of its serotonin-negative effect, while in the activating action of haloperidol on the system "punishment" its serotonin- and dopamino-negative effects partook.


Association between airflow limitation and prognosis in patients with chronic pulmonary aspergillosis.
Previous studies have shown that reduced levels of lung function, characterized by forced expiratory volume in 1 second (FEV1), are associated with higher respiratory events and mortality in general population and some chronic lung diseases. Chronic pulmonary aspergillosis (CPA) is a destructive, fatal lung disease caused by Aspergillus infection in non-immunocompromised patients with suboptimal pulmonary function. However, there is limited information on the status and features of CPA according to FEV1. We performed a retrospective observational study to investigate the FEV1 and airflow limitation in patients with CPA between March 2017 and February 2019 at a tertiary hospital in South Korea. Of the 144 CPA patients, 104 underwent spirometry, demonstrating median forced vital capacity (FVC) and FEV1 of 2.35 L (68%) and 1.43 L (62%), respectively. Among them, 56 patients had airflow limitation on PFT, with median FVC, and FEV1 of 2.47 L (73%) and 1.11 L (47%), respectively. Low body mass index (BMI) (20.1 vs. 22.1 kg/m2; P=0.011), breathlessness (60% vs. 20%; P=0.002), and bilateral pulmonary lesions (33.3% vs. 4%; P=0.006) were more common in patients with moderate to very severe airflow limitation than in those with normal to mild airflow limitation. Moderate to very severe airflow limitation was observed in 43.3% of patients with CPA. Additionally, low BMI, breathlessness, and bilateral pulmonary lesions contributing to poor prognosis were more common in patients with moderate to very severe airflow limitation than in those with normal to mild airflow limitation. Our findings suggest that airflow limitation can be associated with the prognosis of CPA. Further investigations are needed to demonstrate the clinical significance of this association.


Where to go: Computational and visual what-if analyses in soccer.
To prepare their teams for upcoming matches, analysts in professional soccer watch and manually annotate up to three matches a day. When annotating matches, domain experts try to identify and improve suboptimal movements based on intuition and professional experience. The high amount of matches needing to be analysed manually result in a tedious and time-consuming process, and results may be subjective. We propose an automatic approach for the realisation of effective region-based what-if analyses in soccer. Our system covers the automatic detection of region-based faulty movement behaviour, as well as the automatic suggestion of possible improved alternative movements. As we show, our approach effectively supports analysts and coaches investigating matches by speeding up previously time-consuming work. We enable domain experts to include their domain knowledge in the analysis process by allowing to interactively adjust suggested improved movement, as well as its implications on region control. We demonstrate the usefulness of our proposed approach via an expert study with three invited domain experts, one being head coach from the first Austrian soccer league. As our results show that experts most often agree with the suggested player movement (83%), our proposed approach enhances the analytical capabilities in soccer and supports a more efficient analysis.


Primary pancreatic lymphoma. Report of five cases.
Primary pancreatic lymphoma (PPL) is a very rare disease. We report five cases of PPL (4 men and 1 woman, mean age 65 years) diagnosed and treated at our Institution from 1987 to 1997. None of these patients had evidence of extrapancreatic disease and they were categorized as PPL involving pancreas only (stage IE, 3 patients) or pancreas and peripancreatic lymph nodes (stage IIE, 2 patients). The most common presenting symptoms were abdominal pain and weight loss. Imaging techniques showed a mass of the pancreatic head in all cases. The histological diagnosis (3 diffuse-large cell non-Hodgkin's lymphoma and 2 lymphoplasmacytic lymphoma/immunocytoma) was made by ultrasound-guided fine needle aspiration biopsy and tissue core fine-needle biopsy in three patients and by surgery in the remaining two patients. The three patients diagnosed by percutaneous biopsy were treated with chemotherapy as front-line therapy and two of them received also local radiotherapy; one of these patients is still alive in complete remission at 69 months, one died of an unrelated disease at 67 months and one died of lymphoma relapse at 88 months. Two patients underwent pancreaticoduodenectomy plus adjuvant chemotherapy; one of them died of recurrent cholangitis 8 months after surgery while the other one is still alive in complete remission after 160 months. This study shows that: 1) imaging techniques can suggest the suspicion of PPL but are unable to distinguish PPL from pancreatic adenocarcinoma; 2) histological diagnosis can be easily obtained by percutaneous US-guided tissue core biopsy; 3) surgery can be avoided both for diagnosis and therapy but the treatment of choice of PPL may only be evaluated on a larger series of patients.


Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.
To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.


Recombinant MDA-7/IL24 Suppresses Prostate Cancer Bone Metastasis through Downregulation of the Akt/Mcl-1 Pathway.
Prostate cancer is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized prostate cancer approaches 100%, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated prostate cancer cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for prostate cancer bone metastasis. Melanoma differentiation associated gene-7 (MDA-7)/IL24 is a well-studied cytokine established as a therapeutic in a wide array of cancers upon delivery as a gene therapy. In this study, we explored the potential anticancer properties of MDA-7/IL24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL24 had significantly less metastatic lesions in their femurs as compared with controls. The inhibitory effects of MDA-7/IL24 on bone metastasis resulted from prostate cancer-selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that prosurvival Akt and Mcl-1 pathways are critically important in the antibone metastatic activity of MDA-7/IL24. Our previous findings showed that MDA-7/IL24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small-molecule inhibitor synergized with MDA-7/IL24 and induced robust antibone metastatic activity. These results expand the potential applications of MDA-7/IL24 as an anticancer molecule and demonstrate that purified recombinant protein is nontoxic in preclinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule. Mol Cancer Ther; 17(9); 1951-60. ©2018 AACR.


The development of corneal astigmatism in contact lens wearers.
In this study of 131 eyes, a comparison of the corneal astigmatism present before wearing hard contact lenses was made with that found after several years of wear (mean length of time: 4.4 years). The eyes were divided into 3 groups according to their ocular rigidity measurements. Statistical analysis of these groups showed that eyes with low ocular rigidity developed a high incidence of with-the-rule astigmatism change and that, furthermore, this change was of significant amount (twice that developed by eyes in the other groups). It was notable that all of the eyes that developed more than 1 1/2 diopters of astigmatism had low ocular rigidity.


Consequences of a changing US strategy in the global HIV investment landscape.
The global fight against HIV/AIDS in Africa has long been a focus of US foreign policy, but this could change if the federal budget for 2018 proposed by the US Office of Management and Budget is adopted. We aim to inform public and Congressional debate around this issue by evaluating the historical and potential future impact of US investment in the African HIV response. We use a previously published mathematical model of HIV transmission to characterize the possible impact of a series of financial scenarios for the historical and future AIDS response across Sub-Saharan Africa. We find that US funding has saved nearly five million adults in Sub-Saharan Africa from AIDS-related deaths. In the coming 15 years, if current numbers on antiretroviral treatment are maintained without further expansion of programs (the proposed US strategy), nearly 26 million new HIV infections and 4.4 million AIDS deaths may occur. A 10% increase in US funding, together with ambitious domestic spending and focused attention on optimizing resources, can avert up to 22 million HIV infections and save 2.3 million lives in Sub-Saharan Africa compared with the proposed strategy. Our synthesis of available evidence shows that the United States has played, and could continue to play, a vital role in the global HIV response. Reduced investment could allow more than two million avoidable AIDS deaths by 2032, whereas continued leadership by the United States and other countries could bring UNAIDS targets for ending the epidemic into reach.


Surface charge of Streptococcus pneumoniae predicts serotype distribution.
Streptococcus pneumoniae (pneumococcus) frequently colonizes the human nasopharynx and is an important cause of pneumonia, meningitis, sinusitis, and otitis media. The outer cell surface of pneumococcus may assume various degrees of negative charge depending on the polysaccharide capsule, of which more than 90 serotypes have been identified. The negative charge of capsular polysaccharides has been proposed to electrostatically repel pneumococci from phagocytic cells, and avoidance of phagocytosis correlates with higher carriage prevalence. We hypothesized that the surface charge of pneumococcus contributes to its success in nasopharyngeal carriage by modulating resistance to phagocyte-mediated killing. Here, we measured the surface charge (zeta potential) of laboratory-constructed strains that share a genetic background but differ in serotype and of clinical strains that differ in serotype and genetic background. A more negative surface charge correlated with higher resistance to nonopsonic killing by human neutrophils in vitro. In addition, a more negative zeta potential was associated with higher carriage prevalence in human populations before and after the widespread use of the pneumococcal conjugate vaccine PCV7. We also confirmed that capsule is the major determinant of net surface charge in clinical isolates with diverse backgrounds. We noted that exceptions exist to the idea that a higher magnitude of negative charge predicts higher prevalence. The results indicated that zeta potential is strongly influenced by pneumococcal capsule type but is unlikely to be the only important mechanism by which capsule interacts with host.


Transient exposure to ethylene stimulates cell division and alters the fate and polarity of hypocotyl epidermal cells.
After transient exposure to the gaseous hormone ethylene, dark-grown cucumber (Cucumis sativus) hypocotyls developed unusual features. Upon ethylene's removal, the developing epidermis showed significant increases in cell division rates, producing an abundance of guard cells and trichomes. These responses to ethylene depended on the stage of development at the time of ethylene exposure. In the upper region of the hypocotyl, where cells were least differentiated at the onset of ethylene treatment, complex, multicellular protuberances formed. Further down the hypocotyl, where stomata and trichomes were beginning to develop at the onset of ethylene exposure, an increase in the number of stomata and trichomes was observed. Stomatal complexes developing after the ethylene treatment had a significant increase in the number of stomatal subsidiary cells and the number of cells per trichome increased. Analysis of division patterns in stomatal complexes indicated that exposure to ethylene either suspended or altered cell fate. Ethylene also altered cell division polarity, resulting in aberrant stomatal complexes and branched trichomes. To our knowledge, the results of this study demonstrate for the first time that transient treatment with physiological concentrations of ethylene can alter cell fate and increase the propensity of cells to divide.


Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase.
Polo-like kinase (Plk) is the mammalian homologue of the Drosophila polo and Saccharomyces cerevisiae CDC5 genes, which are thought to be involved in regulating chromosomal segregation. Previously, we showed that transient ectopic expression of Plk could induce DNA synthesis in quiescent NIH 3T3 cells, suggesting that Plk might also have a function during G1 or S phase. Here we report that microinjection of Plk mRNA is sufficient to drive quiescent cells into mitosis and that constitutive expression of Plk in NIH 3T3 cells causes oncogenic focus formation. These transformed cells grow in soft agar and form tumors in nude mice. Because Plk expression has been shown to be high in various human tumors, we suggest that Plk may contribute to the promotion and/or progression of human cancers.


Roles for menaquinone and the two trimethylamine oxide (TMAO) reductases in TMAO respiration in Salmonella typhimurium: Mu d(Apr lac) insertion mutations in men and tor.
Three groups of mutants defective in trimethylamine oxide (TMAO) reduction were isolated from Salmonella typhimurium LT2 subjected to transposition mutagenesis with Mu d(Apr lac). Mutants were identified by their acidic reaction on a modified MacConkey-TMAO medium. Group I consisted of pleiotropic chlorate-resistant mutants which were devoid of TMAO reductase activity. None expressed the lac operon. Group II mutants were partially defective in TMAO reductase. Electrophoretic studies revealed that they lacked the inducible TMAO reductase, but retained the constitutive activity. The genotypic designation tor was suggested for these mutants. The tor mutation in one was located between 80 and 83 U on the S. typhimurium chromosome. Expression of the lac operon in these mutants was not affected by air, TMAO, or nitrate. Group III mutants reduced little or no TMAO in vivo, but their extracts retained full capacity to reduce it with methyl viologen. These mutants also failed to produce hydrogen sulfide from thiosulfate and could not grow anaerobically on glycerol-fumarate. Two subgroups were distinguished. Vitamin K5 restored wild-type phenotype in subgroup IIIa only; vitamin K1 restored wild-type phenotype in both IIIa and IIIb isolates. The genotypic designation men (menaquinone) was suggested for group III isolates. The mutation in IIIa mutants was cotransducible with glpT, which corresponds to the menBCD site in Escherichia coli. That in IIIb mutants was cotransducible with glpK, which corresponds to the menA site in E. coli. Expression of the lac operon in IIIa, but not IIIb, mutants was repressed by air. An additional mutant group isolated on the same medium consisted of strains defective in formate hydrogenlyase.


TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.
Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm. Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands. Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms. Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.


Analysis of gene sequences indicates that quantity not quality of chloroplast small HSPs improves thermotolerance in C4 and CAM plants.
Chloroplast-localized small heat-shock proteins (Cp-sHSP) protect Photosystem II and thylakoid membranes during heat and other stresses, and Cp-sHSP production levels are related to plant thermotolerance. However, to date, a paucity of Cp-sHSP sequences from C4 or CAM species, or from other extremely heat-tolerant species, has precluded an examination to determine if Cp-sHSP genes or proteins might differ among plants with photosynthetic pathways or between heat-sensitive and heat-tolerant species. To investigate this, we isolated and characterized novel Cp-sHSP genes in four plant species: two moderately heat-tolerant C4 species, Spartina alterniflora (monocot) and Amaranthus retroflexus (eudicot), and two very heat-tolerant CAM species, Agave americana (monocot) and Ferocactus wislizenii (eudicot) (respective genes: SasHSP27.12, ArsHSP26.43, AasHSP26.85 and FwsHSP27.52) by PCR-based genome walking and cDNA RACE. Analysis of these Cp-sHSPs has confirmed the presence of conserved domains common to previously examined species. As expected, the transit peptide was found to be the most variable part of these proteins. Promoter analysis of these genes revealed differences in CAM versus C3 and C4 species that were independent of a general difference between monocots and eudicots observed for the entire protein. Heat-induced gene and protein expression indicated that Cp-sHSP protein levels were correlated with thermotolerance of photosynthetic electron transport, and that in most cases protein and transcript levels were correlated. Thus, available evidence indicates little variation in the amino acid sequence of Cp-sHSP mature proteins between heat-sensitive and -tolerant species, but that variation in Cp-sHSP protein production is related to heat tolerance or photosynthetic pathway (CAM vs. C3 and C4) and is driven by promoter differences. Key message We isolated and characterized four novel Cp-sHSP genes with promoters from wild plants, analysis has shown qualitative and quantitative interspecific variations in Cp-sHSPs of C3, C4, and CAM plant thermotolerance.


Functional safety of health information technology.
In an effort to improve patient safety and reduce adverse events, there has been a rapid growth in the utilisation of health information technology (HIT). However, little work has examined the safety of the HIT systems themselves, the methods used in their development or the potential errors they may introduce into existing systems. This article introduces the conventional safety-related systems development standard IEC 61508 to the medical domain. It is proposed that the techniques used in conventional safety-related systems development should be utilised by regulation bodies, healthcare organisations and HIT developers to provide an assurance of safety for HIT systems. In adopting the IEC 61508 methodology for HIT development and integration, inherent problems in the new systems can be identified and corrected during their development. Also, IEC 61508 should be used to develop a healthcare-specific standard to allow stakeholders to provide an assurance of a system's safety.


ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine.
Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no expression or low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that cells with low ATP11B expression and high PTDSS2 expression (ATP11BloPTDSS2hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11BloPTDSS2hi phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressor cells and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11BloPTDSS2hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11BhiPTDSS2lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11BloPTDSS2hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.


Learned vocalizations in budgerigars (Melopsittacus undulatus): the relationship between contact calls and warble song.
The budgerigar (Melopsittacus undulatus) has an extraordinarily complex, learned, vocal repertoire consisting of both the long rambling warble song of males and a number of short calls produced by both sexes. In warble, the most common elements (>30%) bear a strong resemblance to the highly frequency-modulated, learned contact calls that the birds produce as single utterances. However, aside from this apparent similarity, little else is known about the relationship between contact calls and warble call elements. Here, both types of calls were recorded from four male budgerigars. Signal analysis and psychophysical testing procedures showed that the acoustic features of these two vocalizations were acoustically different and perceived as distinctive vocalizations by birds. This suggests that warble call elements are not simple insertions of contact calls but are most likely different acoustic elements, created de novo, and used solely in warble. Results show that, like contact calls, warble call elements contain information about signaler identity. The fact that contact calls and warble call elements are acoustically and perceptually distinct suggests that they probably represent two phonological systems in the budgerigar vocal repertoire, both of which arise by production learning.


Exudate-based diabetic macular edema detection in fundus images using publicly available datasets.
Diabetic macular edema (DME) is a common vision threatening complication of diabetic retinopathy. In a large scale screening environment DME can be assessed by detecting exudates (a type of bright lesions) in fundus images. In this work, we introduce a new methodology for diagnosis of DME using a novel set of features based on colour, wavelet decomposition and automatic lesion segmentation. These features are employed to train a classifier able to automatically diagnose DME through the presence of exudation. We present a new publicly available dataset with ground-truth data containing 169 patients from various ethnic groups and levels of DME. This and other two publicly available datasets are employed to evaluate our algorithm. We are able to achieve diagnosis performance comparable to retina experts on the MESSIDOR (an independently labelled dataset with 1200 images) with cross-dataset testing (e.g., the classifier was trained on an independent dataset and tested on MESSIDOR). Our algorithm obtained an AUC between 0.88 and 0.94 depending on the dataset/features used. Additionally, it does not need ground truth at lesion level to reject false positives and is computationally efficient, as it generates a diagnosis on an average of 4.4s (9.3s, considering the optic nerve localisation) per image on an 2.6 GHz platform with an unoptimised Matlab implementation.


Healthy memory aging - the benefits of regular daily activities increase with age.
As the number of older adults increases, so does the pressure on health care systems due to age-related disorders. Attempts to reduce cognitive decline have focused on individual interventions such as exercise or diet, with limited success. This study adopted a different approach by investigating the impact of combined daily activities on memory decline. We used data from the National Institute of Aging's Health and Retirement Study to explore two new questions: does combining activities affect memory decline, and if yes, does this impact change across the lifespan? We created a new machine learning model using 33 daily activities and involving 3210 participants. Our results showed that the effect of combined activities on memory decline was stronger than any individual activity's impact. Moreover, this effect increased with age, whereas the importance of historical factors such as education, and baseline memory decreased. The present findings point out the importance of selecting multiple, diverse activities for older adults as they age. These results could have a significant impact on aging health policies promoting new programs such as social prescribing.


Amino acid substitutions in the pore of rat glutamate receptors at sites influencing block by polyamines.
1. The effect on polyamine block of mutations at the Q/R site and the conserved negative charge +4 site in AMPA and kainate receptors was studied using the rat glutamate receptor GluR6 expressed in Xenopus oocytes and human embryonic kidney (HEK) cells. 2. Introduction of negative charge at the Q/R site increased the equilibrium dissociation constant at 0 mV (Kd(0)) for spermine from 1.3 to 4.0 microM (Q590E); the smaller side chains Q590D and Q590N had Kd(0) values of 47 and 20 microM. Reductions in spermine affinity were also obtained for the small hydrophobic residues Q590V and Q590A, with Kd(0) values of 3.6 and 8.8 microM. Positively charged side chains produced outward rectifying responses similar to those recorded for GluR6(Q) with polyamine-free conditions, suggesting a complete absence of voltage-dependent block by spermine. 3. Substitution of tryptophan at the Q/R site produced high-affinity block with a Kd(0) of 190 pM. In Xenopus oocytes no outward current was observed at potentials up to +200 mV. A much smaller increase in affinity was observed for Q590F and Q590Y, which had Kd(0) values of 0.28 and 0.83 microM respectively. 4. The Q590H mutant gave weakly birectifying responses strikingly different from those for other mutants. When ionization of the His group was increased by raising the external hydrogen ion concentration, responses became outward rectifying. The ratios of the conductance at 100 mV over that at -100 mV for Q590H were 0.52 at pH 8.3 and 2.5 at pH 5.3. 5. Neutralization of charge or aromatic residues at the +4 site produced a large reduction of spermine affinity, with Kd(0) values for E594N, E594Q and E594W of 109, 1020 and 2150 microM, respectively. In the absence of polyamines, E594K and E594R produced strongly inward rectifying responses while E594Q, E594A and E594W were birectifying. 6. A model for permeant block allowed quantitative comparisons between mutants. Despite large changes in well depth and barrier heights, there was little change in the voltage dependence of block for both Q/R and +4 site mutants. We propose a model with a distributed binding site for polyamines in which the +4 site is located near the entrance to the channel.


An Efficient Building Extraction Method from High Spatial Resolution Remote Sensing Images Based on Improved Mask R-CNN.
In this paper, we consider building extraction from high spatial resolution remote sensing images. At present, most building extraction methods are based on artificial features. However, the diversity and complexity of buildings mean that building extraction methods still face great challenges, so methods based on deep learning have recently been proposed. In this paper, a building extraction framework based on a convolution neural network and edge detection algorithm is proposed. The method is called Mask R-CNN Fusion Sobel. Because of the outstanding achievement of Mask R-CNN in the field of image segmentation, this paper improves it and then applies it in remote sensing image building extraction. Our method consists of three parts. First, the convolutional neural network is used for rough location and pixel level classification, and the problem of false and missed extraction is solved by automatically discovering semantic features. Second, Sobel edge detection algorithm is used to segment building edges accurately so as to solve the problem of edge extraction and the integrity of the object of deep convolutional neural networks in semantic segmentation. Third, buildings are extracted by the fusion algorithm. We utilize the proposed framework to extract the building in high-resolution remote sensing images from Chinese satellite GF-2, and the experiments show that the average value of IOU (intersection over union) of the proposed method was 88.7% and the average value of Kappa was 87.8%, respectively. Therefore, our method can be applied to the recognition and segmentation of complex buildings and is superior to the classical method in accuracy.


Brief communication: Facial fluctuating asymmetry as a marker of sex differences of the response to phenotypic stresses.
Fluctuating asymmetry (FA) is thought to increase as a result of environmental perturbations during development. A number of studies involving measures of health and developmental stability other than FA have discussed the presumed increased buffering in females relative to males. But, there is little evidence in the literature on FA to support this hypothesis. This research was conducted to determine the level of difference in terms of facial FA between sexes under different environmental conditions. Group 1 included final year students from three high schools in Yenimahalle, a slum district of Ankara (males: N = 163, mean age = 17.55, sd = 0.50; females: N = 141, mean age = 17.48, sd = 0.38). Group 2 included students with higher socioeconomic background and was composed of final year students from three different private schools located in Cankaya (N = 171, mean age = 17.44, sd = 0.26; females: N = 152, mean age = 17.38, sd = 0.31). Digital images were used to assess the degree of facial asymmetry as measured from eight paired traits and calculated as a composite score. The study shows that the male students had higher facial asymmetry than the female students. However, the present difference reaches a significant level in the low-socioeconomic status group. As a result, it could be inferred that differences in developmental stability between sexes might emerge under stressful conditions.


Antimicrobial and Immunomodulatory Activity of PMAP-23 Derived Peptides.
The Porcine Myeloid Antibacterial Peptide (PMAP)-23 is a porcine host defence peptide with strong antibacterial activity against Gram-positive and Gram-negative bacteria, and fungi. PMAP-23 and truncated/mutated derivatives were tested for antibacterial and immunomodulatory activities to determine core elements of the peptide required for functionality. PMAP-23 and truncated and/or mutated derivatives were synthesized. Antibacterial activity against Gram positive and negative bacteria was determined using colony counting assays. Cytotoxicity was measured against red blood cells and epithelial cells. Peptide induced cytokine production of epithelial cells was determined by ELISA. LPS neutralization was measured using isothermal titration calorimetry and inhibition of LPS induced cytokine production by macrophages. The effect of peptides on phagocytosis was performed by measuring uptake of fluorescently labelled beads by porcine macrophages. Truncation of the peptide did not lead to a strong reduction in antibacterial activity, but interestingly, all C-terminal truncated forms were strongly inhibited by salt addition, unlike the full length peptide or the two N-terminally truncated peptides. None of the peptides were hemolytic or toxic in concentrations up to 40 μM. Full length PMAP-23 induced IL-8 production in porcine epithelial cells, however, this activity was lost in all truncated peptides. None of the peptides bound LPS and subsequently did not inhibit LPS-induced cytokine production of monocytes. Finally, all PMAP-23 derived peptides reduced the uptake of beads by freshly isolated monocytes. PMAP-23 is mainly antibacterial with only limited immunomodulating capacity; the full length peptide is required for the full spectrum of activities.