NMD monitors translational fidelity 24/7.
Nonsense-mediated mRNA decay (NMD) is generally thought to be a eukaryotic mRNA surveillance pathway tasked with the elimination of transcripts harboring an in-frame premature termination codon (PTC). As presently conceived, NMD acting in this manner minimizes the likelihood that potentially toxic polypeptide fragments would accumulate in the cytoplasm. This notion is to be contrasted to the results of systematic RNA-Seq and microarray analyses of NMD substrates in multiple model systems, two different experimental approaches which have shown that many mRNAs identified as NMD substrates fail to contain a PTC. Our recent results provide insight into, as well as a possible solution for, this conundrum. By high-resolution profiling of mRNAs that accumulate in yeast when the principal NMD regulatory genes (UPF1, UPF2, and UPF3) are deleted, we identified approximately 900 NMD substrates, the majority of which are normal-looking mRNAs that lack PTCs. Analyses of ribosomal profiling data revealed that the latter mRNAs tended to manifest elevated rates of out-of-frame translation, a phenomenon that would lead to premature translation termination in alternative reading frames. These results, and related observations of heterogeneity in mRNA isoforms, suggest that NMD should be reconsidered as a probabilistic mRNA quality control pathway that is continually active throughout an mRNA's life cycle.


Effect of Dexamethasone and Fluticasone on Airway Hyperresponsiveness in Horses With Inflammatory Airway Disease.
Airway hyperresponsiveness (AWHR), expressed as hypersensitivity (PC75 RL ) or hyperreactivity (slope of the histamine dose-response curve), is a feature of inflammatory airway disease (IAD) or mild equine asthma in horses. Glucocorticoids are used empirically to treat IAD. To determine whether dexamethasone (DEX) (0.05 mg/kg IM q24h) and inhaled fluticasone (FLUT) (3,000 μg q12h) administered by inhalation are effective in decreasing AWHR, lung inflammation, and clinical signs in horses with IAD. A randomized crossover study design was used. Eight horses with IAD were assigned to a treatment group with either DEX or FLUT. Measured outcomes included lung mechanics during bronchoprovocative challenges, bronchoalveolar lavage fluid (BALF) cytology, and scoring of clinical signs during exercise. Dexamethasone and FLUT abolished the increase in RL by 75% at any histamine bronchoprovocative dose in all horses after the first week of treatment. However, after 2 weeks of FLUT treatment, 1 horse redeveloped hypersensitivity. There was a significant decrease in the number of lymphocytes after treatment with both DEX and FLUT (P = .039 for both) but no significant differences in other BALF cell types or total cell counts (P > .05). There was no difference in the scoring of the clinical signs during each treatment and washout period (P > .05). Both DEX and FLUT treatments significantly inhibit airway hypersensitivity and hyperreactivity in horses with IAD. There are no significant effects on the clinical signs or the number of inflammatory cells (except lymphocytes) in BALF. The treatments have no residual effect 3 weeks after discontinuation.


Reversible immobilization and direct electron transfer of cytochrome c on a pH-sensitive polymer interface.
A pH-sensitive polymer interface has been used as a matrix for reversible immobilization of cytochrome c (Cyt c) on an Au surface through a dip-coating process. The pH-sensitive behavior of the polymer brush interface has been demonstrated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) measurements. The reversible immobilization and electron-transfer properties of Cyt c have been investigated by in situ UV/Vis spectrophotometry and CV. The results have shown that the poly(acrylic acid) (PAA) brush acted as an excellent adsorption matrix and a good accelerant for the direct electron transfer of Cyt c, which gave redox peaks with a formal potential of 40 mV versus Ag/AgCl in pH 7.6 phosphate buffer solution. The average surface coverage of Cyt c on the PAA film was about 1.7 x 10(-10) mol cm(-2), indicating a multilayer of Cyt c. The electron-transfer rate constant was calculated to be around 0.19 s(-1) according to the CV experiments. The interface was subjected to in situ attenuated total internal reflection Fourier-transform infrared (ATR-FTIR) spectroscopic analysis, in order to further confirm the immobilization of Cyt c on the surface. This polymer-protein system may have potential applications in the design of biosensors, protein separation, interfacial engineering, biomimetics, and so on.


A permanent and reversible procedure to block tear drainage for the treatment of dry eye.
To describe a technique of canalicular ligation and report observations on 59 consecutive surgeries. Retrospective, non-comparative case series of canalicular ligation by 3 surgeons over a 7-year period. Fifty-nine eyelids of 29 patients (2 men and 27 women) underwent canalicular ligation for the treatment of severe dry eyes. Patient age ranged from 34 to 90 years. Average length of follow-up was 20 months. There were no complications. Ninety-one percent of patients noted an improvement in their symptoms. Two patients developed symptomatic epiphora more than 1 year postoperatively and both underwent successful reversal. Canalicular ligation is an effective technique for punctal occlusion in patients with severe dry eyes. It combines surgical ease with excellent cosmetic outcomes.


Bedside diagnostic minilaparoscopy in the intensive care patient.
The diagnosis of acute abdominal conditions in the critically ill patient remains difficult. The goal of this study is to demonstrate the use of bedside minilaparoscopy as a diagnostic aid in the intensive care unit (ICU) in patients with possible intra-abdominal catastrophic condition. Between February 1998 and May 1999, intensive care patients with abdominal pain, unexplained acidosis or sepsis, or suspected mesenteric ischemia were eligible for bedside diagnostic minilaparoscopy (3.3-mm laparoscope and instruments). The procedure was performed at bedside in the ICU with the patient under local anesthesia and intravenous sedation. Pneumoperitoneum was established with nitrous oxide (N(2)O) to a pressure of 8 to 10 mm Hg. Hemodynamics and ventilatory parameters were monitored before, during, and after the procedure. Nineteen patients underwent bedside diagnostic minilaparoscopy, including 1 patient who underwent 2 diagnostic laparoscopies. Total procedure time was 9 to 68 minutes (mean, 21 minutes). Three patients were found to have extensive mesenteric ischemia and did not undergo laparotomy. One patient found to have questionably viable bowel at laparoscopy underwent a nontherapeutic formal laparotomy. One patient had a gangrenous gallbladder, and another had a small ischemic segment of bowel; each underwent later open laparotomy and resection. The remaining laparoscopic examinations either showed a nonsurgical cause for the patient's condition or were normal. Nontherapeutic laparotomy was avoided in 19 of 20 patients. One gallbladder perforation occurred during laparoscopy in a patient with a necrotic gallbladder. Bedside minilaparoscopy can be a safe and accurate method to evaluate critically ill patients in whom the possibility of mesenteric ischemia or other intra-abdominal process is entertained. Nontherapeutic laparotomy can be avoided in many critically ill patients. Bedside diagnostic laparoscopy can be a useful replacement for diagnostic laparotomy in the operating room. It should be included in the diagnostic algorithm in the evaluation of the unstable patient in the ICU with a suspected acute intra-abdominal process.


[Mandibular osteoradionecrosis: sword of Damocles of radiotherapy for head and neck cancers?].
Radiotherapy of head and neck cancer is efficient but may have severe late effects. Although unfrequent, mandibular radionecrosis is the most dreadful. A cascade of events leads from hyposialia to bone destruction through extensive caries and trauma linked to tooth removal. Prevention is based on oral hygiene and use of daily topical fluorides. Antibiotics and hyperbaric oxygen can be effective as a conservative management. Progressive osteonecrosis is best treated by mandible resection and reconstruction with microvascular free bone flaps. Patient compliance to prophylaxis is of major importance. The need for periodic follow-up under the supervision of the radiation oncologist is stressed and illustrated by a clinical case having experienced disastrous consequences.


Assessment of quantitative and semi-quantitative biological test methods of artesunate in vitro.
Artesunate is the current most potent antimalarial drug widely used for the treatment of malaria. Considering the emergence of artemisinin resistance, several situations may require a simple method for artesunate quantification. We thus developed a quantitative and a semi-quantitative biological method for the determination of artesunate in liquid samples. The tests are based on the measurement of samples' antimalarial activity on Plasmodium falciparum 3D7 using a modified SYBR Green I drug susceptibility test. For the quantitative test, we established a standard curve that resulted from a dose-response curve and evaluated its performances using controls samples. Whereas the linear regression analysis between artesunate concentration and antimalarial activity showed promising results (linearity range 1.5-24.6 ng/mL, r2 = 0.9373), we found that artesunate content of the controls was significantly overestimated (p = 0.0313). For the semi-quantitative test, we compared the antimalarial activities of samples collected during permeation studies of artesunate to that of a reference (artesunate IC50) by statistical analysis. We demonstrated that antimalarial activities of samples from permeation tests using a powder formulation of artesunate were greater than those of samples from tests using a solution formulation. Bioassays can be simple techniques to assess artesunate in liquid samples, particularly in resource-limited settings. Comparison with reference methods is still recommended when accurate drug quantification is required.


Effect of adaptation process of Pseudomonas aeruginosa to didecyldimethylammonium chloride in 2-propanol on bactericidal efficiency of this active substance.
Microorganisms are characterized by two types of resistance innate and acquired. Innate resistance is associated with the construction of the surface structures. Wide use of active substances as antimicrobial compounds, especially in inhibitory concentrations, may promote the acquisition of bacterial resistance to these substances in the process of adaptation. The aim of the study was to determine changes in efficiency of didecyldimethylammonium chloride in 2-propanol (CMAP) against the Pseudomonas aeruginosa strains, which were adapted to this active substance. Adaptation studies were conducted using two strains: P. aeruginosa ATCC 15442 (PA), which is used in estimation of biocide efficiency and tetracycline-resistant P. aeruginosa ATCC 47085 (PAO-LAC) strain. These strains were adapted to the active substance Bardac22: 50% v/v didecyldimethylammonium chloride in 20% v/v 2-propanol (CMAP) according to the National Institute of Hygiene procedure. After adaptation, obtained isolates were classified to three groups and passaged to solid media: A - strains unadapted passaged onto slant medium without active substance, control group; B - strains with adaptive resistance passaged onto slant medium with 375 mg/l CMAP; C - strains with adaptive resistance passaged onto slant medium without CMAP. Changes in susceptibility of examined strains were determined on the basis of minimum inhibitory concentrations (MICs) by broth dilution method. The minimum bactericidal concentrations (MBCs) were determined by subculture P. aeruginosa strains on solid media without CMAP. The efficiency of CMAP against isolates obtained after adaptation processes was evaluated by using phenol coefficient (PC). There were no differences in the adaptation process between two strains of P. aeruginosa: PA and PAO-LAC. Both isolates obtained after the adaptation process was characterized by approximately 6-8 fold higher MICs compared to the MICs of these strains before the adaptation. Strains passaged to a solid media characterized a variable sensitivity to CMAP. As compared to a control group A, the isolates of PA and PAO-LAC from group B and isolate PA from group C exhibited the highest and stable insensitivity (MIC from > 700 to >1000 mg/l) to 48-49 passages. Isolates from group C of PAO-LAC maintained insusceptibility up to 20th passage (MIC >375 mg/l). There were no statistically significant changes in the CMAP bactericidal efficacy against isolates of reduced sensitivity. Adaptation of P. aeruginosa strains to didecyldimethylammonium chloride in 2-propanol does not significantly change bactericidal efficacy of this active substance against isolates with reduced sensitivity. Antibiotic-resistant strain PAO-LAC showed a similar adaptability and a similar sensitivity to the CMAP as a strain PA used to assess the effectiveness of disinfectants. adaptation process, Pseudomonas aeruginosa, quaternary ammonium compounds, bactericidal efficiency.


IgA nephropathy--human disease and animal model.
IgA nephropathy is one of the most common chronic glomerulonephritides worldwide. Since the first publication on IgA nephropathy, a number of clinical and pathological investigations have revealed that the clinical course of patients with IgA nephropathy is extremely diverse, with approximately 10-20% of the patients developing end-stage chronic renal failure. Glomerular changes similar to IgA nephropathy have also been observed in patients with Schoenlein-Henoch purpura, and with other diseases such as liver cirrhosis and chronic inflammatory diseases of the lung. The broad spectrum of clinical and pathological features of IgA nephropathy encompasses a syndrome which includes both primary and secondary IgA nephropathy. The common etiology and pathogenesis of primary and secondary IgA nephropathy appear to be closely related to immunological abnormalities in the production of IgA induced by antigenic stimulation of the common mucosal immune system. IgA is one of the most important humoral factors of the mucosal immune defense system and functions as an antibody against various extrinsic and intrinsic substances. This review describes the Arthus type of IgA immune complex deposition in the glomeruli which can result from persistent or repeated increases in circulating IgA immune complexes. The latter occurs as a consequence of overproduction of IgA antibodies and/or impairment in clearance of IgA immune complexes by the mononuclear phagocytic system. The present review also focuses on the biology of the IgA-mediated immune system and on the etiology, pathogenesis, and animal models of IgA nephropathy.


Ubiquitination at the mitochondria in neuronal health and disease.
The preservation of mitochondrial function is of particular importance in neurons given the high energy requirements of action potential propagation and synaptic transmission. Indeed, disruptions in mitochondrial dynamics and quality control are linked to cellular pathology in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Here, we will discuss the role of ubiquitination by the E3 ligases: Parkin, MARCH5 and Mul1, and how they regulate mitochondrial homeostasis. Furthermore, given the role of Parkin and Mul1 in the formation of mitochondria-derived vesicles we give an overview of this area of mitochondrial homeostasis. We highlight how through the activity of these enzymes and MDV formation, multiple facets of mitochondrial biology can be regulated, ensuring the functionality of the mitochondrial network thus preserving neuronal health.


A novel role for a glycolytic pathway kinase in regulating autophagy has implications in cancer therapy.
When it comes to cancer initiation and progression, macroautophagy/autophagy seemingly acts in a contradictory fashion, serving either as a suppressive factor that functions to protect against tumor formation or as a support mechanism that sustains the disease itself through its cytoprotective functions. In tumor suppression, autophagy assists by restricting oxidative stress and curbing genomic instability that could possibly cause oncogenic mutations. However, in certain circumstances, autophagy can also promote cancer by providing nourishment and by limiting stress-response pathways, leading to cancer cell survival and rapid proliferation. Thus, autophagy's role in oncogenesis is highly context-dependent and varies from one cancer type to another. As a consequence, identifying the mechanisms that alter and rewire autophagic regulation and flux is extremely crucial to target autophagy as a possible avenue for anticancer treatment. In a recent study, Qian et al. endeavored to identify one such key regulatory pathway in hypoxia- and glutamine deprivation-induced autophagy in tumorigenic cells. In this pathway, phosphatidylinositol 3-phosphate (PtdIns3P) production by the class III phosphatidylinositol 3-kinase (PtdIns3K) complex is greatly improved through a cascade of posttranslational modifications that culminates in the phosphorylation of the scaffolding protein BECN1 by the glycolytic pathway kinase PGK1.


Prenatal diagnosis of four-vessel umbilical cord with supernumerary vein varix: A case report and literature review.
Four-vessel umbilical cord with two arteries and two veins, and fetal intra-abdominal umbilical vein varix are rare fetal vascular pathologies, associated with congenital anomalies and an adverse perinatal outcome, respectively. We report a case of a healthy male neonate born at a gestational age of 38 weeks, five days, after prenatal sonographic diagnosis of a four-vessel umbilical cord with a supernumerary vein varix. To the best of our knowledge, this is the first case with this combination.


Value of a follow-up study of recurrent carcinoma of the colon and rectum.
The results of our programmed follow-up study of patients with carcinoma of the colon and rectum have been disappointing. This is true also for those patients who have undergone resection with the intention of cure. This is mainly because of the discouraging results of our treatment of recurrent lesions. Chemotherapy or roentgen radiation has not regularly been used. The mean survival time has probably been prolonged in some single instances. Only three out of 36 are still alive. Oour negative results show that a follow-up study of this magnitude has been too extensive when the poor outcome is considered. We believe that a follow-up study of patients who have been operated upon for carcinoma of the colon and rectum is necessary but in a simpler form than we have done.


[Nosological classification of headaches].
The problem of headache classification is still open. As a mention of all the attempts to classification is not possible, the Author proposes the scheme of work adopted at Turin Headache Unit (referring himself to the best known classifications). The most important idiopathic headaches are described and it is also suggested that they should be kept separated, one from the other, at least up to now. This criterium makes also easier their differential diagnosis from other head pains. Anyway, is has to be emphasized the actual tendency to group together an ever larger amount of headache types.


From Disappointment to Holistic Ideals: A Qualitative Study on Motives and Experiences of Using Complementary and Alternative Medicine in Sweden.
Recent studies indicate increased use of complementary and alternative medicine (CAM) in western societies, to ameliorate health problems. Even if there is substantial research on general patterns of use, there is limited knowledge on individual motives. This study contributes to a qualitative understanding of experiences of choosing and using CAM. This study consists of in-depth interviews with 10 CAM users in Sweden. The participants represent different backgrounds and experiences of using CAM. The interviews have been analysed in accordance with content analysis. In analysing experiences of choosing and using CAM four main themes were identified: frustration and critique, values and ideology, individual responsibility, and combining treatments. In general, the participants were highly reflexive on issues concerning their health. They highlighted their own role and responsibility, combined a variety of treatments, and continuously dealt with questions on risks, even if they had relatively different approaches to if and when to use CAM. The results also show that motives may change over time. Even if initial choices were closely related to frustration and critique of conventional treatments (for example, by perceiving conventional health care as limited, not receiving proper diagnoses, or being critical to conventional drugs) was long-term use motivated by ideological characteristics of CAM (such as holistic and individualized treatments, and extensive interaction with practitioners). Four main themes, concerning experiences of choosing and using CAM were identified. This study also supports the idea that initial motives for choosing CAM may differ from those explaining long-term use. Significance for public healthRecent studies indicate increased use of complementary and alternative medicine (CAM), both in general western populations and specific patient groups. Well-documented motives for choosing CAM are related to disappointment and failure of conventional health care. In addition, there are findings that demonstrate that certain basic values (such as individualism and holistic orientations) are related to the use of CAM. A better understanding of individual motives behind people's choice of CAM, and how this is related to their perception of the health care system, is important for policy makers and health care professionals alike. This study contributes to a qualitative understanding of experiences of choosing and using CAM and how motives may change over time. It also contributes with knowledge on how users combine CAM with conventional health care and deal with risks.


Towards an optimum colour preference metric for white light sources: a comprehensive investigation based on empirical data.
Colour preference is a critical dimension for describing the colour quality of lighting and numerous metrics have been proposed. However, due to the variation amongst psychophysical studies, consensus has not been reached on the best approach to quantify colour preference. In this study, 25 typical colour quality metrics were comprehensively tested based on 39 groups of psychophysical data from 19 published visual studies. The experimental results showed that two combined metrics: the arithmetic mean of the gamut area index (GAI) and colour rendering index (CRI) and the colour quality index (CQI), a combination of the correlated colour temperature (CCT) and memory colour rendering index (MCRI), exhibit the best performance. Qp in the colour quality scale (CQS) and MCRI also performed well in visual experiments of constant CCT but failed when CCT varied, which highlights the dependence of certain metrics on contextual lighting conditions. In addition, it was found that some weighted combinations of an absolute gamut-based metric and a colour fidelity metric exhibited superior performance in colour preference prediction. Consistent with such a result, a novel metric named MCPI (colour preference index based on meta-analysis) was proposed by fitting the large psychophysical dataset, and this achieved a significantly higher weighted average correlation coefficient between metric predictions and subjective preference ratings.


Scanning-tunneling-spectroscopy-directed design of tailored deep-blue emitters.
Frontier molecular orbitals can be visualized and selectively set to achieve blue phosphorescent metal complexes. For this purpose, the HOMOs and LUMOs of tridentate Pt(II) complexes were measured using scanning tunneling microscopy and spectroscopy. The introduction of electron-accepting or -donating moieties enables independent tuning of the frontier orbital energies, and the measured HOMO-LUMO gaps are reproduced by DFT calculations. The energy gaps correlate with the measured and the calculated energies of the emissive triplet states and the experimental luminescence wavelengths. This synergetic interplay between synthesis, microscopy, and spectroscopy enabled the design and realization of a deep-blue triplet emitter. Finding and tuning the electronic "set screws" at molecular level constitutes a useful experimental method towards an in-depth understanding and rational design of optoelectronic materials with tailored excited state energies and defined frontier-orbital properties.


Medical consultation, time and duration.
This essay is a reflection of the time and duration of the medical consultation, seen as a social process that is determined by macro structures following the productive logic and the demands of modern time. The length of the medical discussion is heterogeneous worldwide; in contrast, what is standard is the perception of the professionals and the patients that the time for interaction is short. Such a perception pervades the doctor-patient relationship, perpetuating a cycle of dissatisfaction-tension-anxiety in these actors. Under the premise of the sociology of time and appealing to the ethical principles of medicine, we propose that the estimation in the length of a medical consultation must be considered. Time is indispensable for an adequate interaction to account for the needs of patients and professionals in a dignified manner since both have rights and obligations to be respected.


[Activity of the enzymes of cerebrospinal fluid and blood serum in patients with the concussion syndrome].
The activity of LDG, ACE and CE was determined in the lumbar CSF and blood serum of patients with sustained mild concussion of the brain. As compared to healthy persons the diseased demonstrated a significant rise of the LDG activity in the CSF while the mounting activity of 2 other enzymes, observed in individual instances in the CSF, lacked statistical significance. It was found that in functional upsets without any marked morphological lesions there may be encountered changes in the enzymatic activity that should be considered as a consequence of deranged metabolism.


Effects of supplementation during late gestation on goat performance and behavior under rangeland conditions.
This study evaluated the effects of peripartum feed supplementation on doe and kid BW and BCS, milk yield and composition, serum metabolites, and maternal-neonatal behavior under rangeland conditions in northern Mexico. Adult does ( = 23) were randomly assigned to 3 nutritional plane groups: 1) goats supplemented (500 g of concentrate [18% CP/kg DM, 2.7 Mcal/kg DM, and 2% salt]) from 15 d prepartum to 7 d postpartum (G15; = 8), 2) the same supplementation as G15 but from 35 d before until 7 d after kidding (G35; = 8), and 3) nonsupplemented does (GC; = 7). Supplemented goats differed from GC goats in BW (48 ± 1.8, 46.1 ± 2.5, and 44.9 ± 2.3 kg; < 0.05), milk yield (1.8 ± 0.1, 1.9 ± 0.2, and 1.2 ± 0.1 kg at d 15 postpartum; < 0.01), kid birth weights (3.8 ± 0.2, 3.6 ± 0.2, and 3.4 ± 0.2 kg; < 0.05), and kid BW at 15 d after birth (6.9 ± 0.2, 6.6 ± 0.2, and 5.6 ± 0.2 kg; < 0.05) for the G35, G15, and GC, respectively. Serum concentrations for total protein, glucose, and cholesterol were not affected ( > 0.05) by treatments. Milk of GC goats showed increased ( < 0.05) percentages for fat, protein, lactose, and nonfat milk solids, whereas total quantities of these variables where higher ( < 0.05) in the G15 and G35 groups. Furthermore, GC dams spent more time seeking their offspring and emitted more low-pitched bleats 4 h postpartum ( < 0.05) in a 2-choice test compared with the G15 and G35 groups. In general, peripartum supplementation promoted a closer dam-kid relationship at 8 h postpartum. Goat performance may be improved in this semiarid region of Mexico with marginal production through supplementation in late gestation.


Molecular Engineering of Photocathodes based on Polythiophene Organic Semiconductors for Photoelectrochemical Hydrogen Generation.
Organic semiconductors provide significant potentials for the construction of photoelectrochemical (PEC) cells for solar hydrogen production because of their highly tunable properties. Herein, on carbon fiber paper (CFP) surface, pyridyl (Py), and 4,4'-bipyridin-1-ium (Py2+) groups were introduced into polythiophene (pTH) semiconductor by electrochemical copolymerization, respectively. After assembly with the Co(dmgBF2)2 type catalyst (CoB, dmgBF2 = difluoroboryldimethylglyoximate), the CoB@Py2+-pTH/CFP photocathode displayed nearly twice the photocurrent enhancement (550 μA cm-2 at 0.15 V vs reversible hydrogen electrode, RHE) comparing to that generated by the CoB@Py-pTH/CFP photocathode (290 μA cm-2 at 0.15 V vs RHE) for light-driven H2 generation under AM 1.5 solar illumination. Investigation of the mechanism revealed that the introduction of the positively charged pyridinium groups could improve the intrinsic Co(dmgBF2)2 catalyst activity for the H2 generation reaction. Meanwhile, the positively charged pyridinium groups serve as p-type dopants to increase the semiconductor bulk charge transfer rate and act as electron transfer mediators to promote the interfacial charge transfer kinetics between the catalyst and the pTH-based organic semiconductor.


Rapid arousal from anaesthesia after reversal of deep rocuronium-induced neuromuscular block with sugammadex in a neuroradiological procedure.
We describe the case of a 42-year-old man undergoing elective embolisation of an arteriovenous malformation at the level of the right posterior cerebral artery under propofol anaesthesia. We used the SedLine Brain Function Monitor (Masimo) to titrate the anaesthetic depth with propofol. At the end of the procedure, the patient aroused from anaesthesia very rapidly after the reversal of deep neuromuscular block with sugammadex, despite still significant calculated doses of propofol at the effect site. This rapid arousal was monitored using the SedLine Brain Function Monitor.


Factors affecting sensitivity and specificity of exercise electrocardiography. Multivariable analysis.
Unlike the predictive value of a diagnostic test, which depends on the prevalence of disease in the population tested, its sensitivity and specificity have been assumed to be constants. This assumption was examined in patients who had both exercise electrocardiography and cardiac catheterization. The effects on sensitivity of factors from clinical history, catheterization, and exercise performance were defined by multivariable logistic regression analysis in 1,401 patients with coronary disease; effects on specificity were defined by a similar analysis in 868 patients without coronary disease. Five factors had significant, independent effects on exercise electrocardiographic sensitivity: maximal exercise heart rate, number of diseased coronary arteries, type of angina, and the patient's age and sex. Only maximal exercise heart rate had a significant, independent effect on exercise electrocardiographic specificity. Thus, the sensitivity and specificity of exercise electrocardiography vary with clinical history, extent of disease, and treadmill performance; the sensitivity and specificity of other diagnostic tests may also vary.


Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells.
A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells.


Novel strains of a pandemic plant virus, tomato spotted wilt orthotospovirus, increase vector fitness and modulate virus transmission in a resistant host.
Tomato spotted wilt orthotospovirus (TSWV) is one of the most successful pandemic agricultural pathogens transmitted by several species of thrips in a persistent propagative manner. Current management strategies for TSWV heavily rely on growing single-gene resistant cultivars of tomato ("Sw-5b" gene) and pepper ("Tsw" gene) deployed worldwide. However, the emergence of resistance-breaking strains (RB) in recent years has compounded the threat of TSWV to agricultural production worldwide. Despite this, an extensive study on the thrips transmission biology of RB strains is currently lacking. It is also unclear whether mutualistic TSWV-thrips interactions vary across different novel strains with disparate geographical origins. To address both critical questions, we studied whether and how four novel RB strains of TSWV (two sympatric and two allopatric), along with a non-RB strain, impact western flower thrips (WFT) fitness and whether this leads to differences in TSWV incidence, symptom severity (virulence), and virus accumulation in two differentially resistant tomato cultivars. Our findings show that all RB strains increased WFT fitness by prolonging the adult period and increasing fecundity compared to non-RB and non-viruliferous controls, regardless of the geographical origin of strains or the TSWV titers in individual thrips, which were substantially low in allopatric strains. TSWV accumulation in thrips varied at different developmental stages and was unrelated to the infected tissues from which thrips acquired the virus. However, it was significantly positively correlated to that in WFT-inoculated susceptible plants, but not the resistant ones. The TSW incidences were high in tomato plants infected with all RB strains, ranging from 80% to 90% and 100% in resistant and susceptible plants, respectively. However, TSW incidence in the non-RB-infected susceptible tomato plants was 80%. Our findings provide new insights into how novel strains of TSWV, by selectively offering substantial fitness benefits to vectors, modulate transmission and gain a potential epidemiological advantage over non-RB strains. This study presents the first direct evidence of how vector-imposed selection pressure, besides the one imposed by resistant cultivars, may contribute to the worldwide emergence of RB strains.


Polynomial-time solution of prime factorization and NP-complete problems with digital memcomputing machines.
We introduce a class of digital machines, we name Digital Memcomputing Machines, (DMMs) able to solve a wide range of problems including Non-deterministic Polynomial (NP) ones with polynomial resources (in time, space, and energy). An abstract DMM with this power must satisfy a set of compatible mathematical constraints underlying its practical realization. We prove this by making a connection with the dynamical systems theory. This leads us to a set of physical constraints for poly-resource resolvability. Once the mathematical requirements have been assessed, we propose a practical scheme to solve the above class of problems based on the novel concept of self-organizing logic gates and circuits (SOLCs). These are logic gates and circuits able to accept input signals from any terminal, without distinction between conventional input and output terminals. They can solve boolean problems by self-organizing into their solution. They can be fabricated either with circuit elements with memory (such as memristors) and/or standard MOS technology. Using tools of functional analysis, we prove mathematically the following constraints for the poly-resource resolvability: (i) SOLCs possess a global attractor; (ii) their only equilibrium points are the solutions of the problems to solve; (iii) the system converges exponentially fast to the solutions; (iv) the equilibrium convergence rate scales at most polynomially with input size. We finally provide arguments that periodic orbits and strange attractors cannot coexist with equilibria. As examples, we show how to solve the prime factorization and the search version of the NP-complete subset-sum problem. Since DMMs map integers into integers, they are robust against noise and hence scalable. We finally discuss the implications of the DMM realization through SOLCs to the NP = P question related to constraints of poly-resources resolvability.


The genotype dependent presence of pyrrolizidine alkaloids as tertiary amine in Jacobaea vulgaris.
Secondary metabolites such as pyrrolizidine alkaloids (PAs) play a crucial part in plant defense. PAs can occur in plants in two forms: tertiary amine (free base) and N-oxide. PA extraction and detection are of great importance for the understanding of the role of PAs as plant defense compounds, as the tertiary PA form is known for its stronger influence on several generalist insects, whereas the N-oxide form is claimed to be less deterrent. We measured PA N-oxides and their reduced tertiary amines by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We show that the occurrence of tertiary PAs is not an artifact of the extraction and detection method. We found up to 50% of tertiary PAs in shoots of Jacobine - chemotype plants of Jacobaea vulgaris. Jacobine and its derivatives (jacoline, jaconine, jacozine and dehydrojaconine) may occur for more than 20% in reduced form in the shoots and more than 10% in the roots. For 22 PAs detected in F(2) hybrids (J. vulgaris × Jacobaea aquatica), we calculate the tertiary amine percentage (TA%=the tertiary amine concentration/(tertiary amine concentration+the corresponding N-oxide concentration) × 100). We found that the TA% for various PAs was genotype-dependent. Furthermore, TA% for the different PAs were correlated and the highest correlations occurred between PAs which share high structural similarity.


The relationship between sandy beach nematodes and environmental characteristics in two Brazilian sandy beaches (Guanabara Bay, Rio de Janeiro).
We investigated if the differences in density and nematode communities of intertidal sediments from two Brazilian sheltered sandy beaches were related to environmental characteristics. The upper tide level (UTL) and the low tide level (LTL) of both beaches were surveyed in January (austral summer) and June 2001 (austral winter) during low-spring tides, by collecting samples of nematodes and sediments. Differences in density between beaches, tidal level and seasons, and nematode community structure were investigated. Sediments from both beaches were composed of medium to very coarse sand. The highest nematode densities were found at the UTL, and significant differences between beaches, tidal levels and months were found. A total of 54 genera were found and the genera composition on both sheltered beaches was similar to other exposed worldwide sandy beaches. The density and structure of the nematode community at both beaches clearly varied along the spatial and temporal scales. Gravel percentage was the most important variable explaining the spatial distribution of the nematodes, determining the four sub-communities; this suggests that the sediment characteristics influence the nematode community, rather than physical hydrodynamic forces. Temperature and salinity were suggested to be important variables affecting the temporal variation.


Epigenetics: Linking Nutrition to Molecular Mechanisms in Aging.
Healthy aging has become a major goal of public health. Many studies have provided evidence and theories to explain molecular mechanisms of the aging process. Recent studies suggest that epigenetic mechanisms are responsible for life span and the progression of aging. Epigenetics is a fascinating field of molecular biology, which studies heritable modifications of DNA and histones that regulate gene expression without altering the DNA sequence. DNA methylation is a major epigenetic mark that shows progressive changes during aging. Recent studies have investigated aging-related DNA methylation as a biomarker that predicts cellular age. Interestingly, growing evidence proposes that nutrients play a crucial role in the regulation of epigenetic modifiers. Because various nutrients and their metabolites function as substrates or cofactors for epigenetic modifiers, nutrition can modulate or reverse epigenetic marks in the genome as well as expression patterns. Here, we will review the results on aging-associated epigenetic modifications and the possible mechanisms by which nutrition, including nutrient availability and bioactive compounds, regulate epigenetic changes and affect aging physiology.


Down-regulation of p27kip1 increases proliferation of progenitor cells in adult rats.
Cyclin-dependent kinases (CDK) mediate the cell division cycle during G1 phase and CDK inhibitors negatively regulate the cell cycle. We investigated expression of the CDK inhibitor p27Kip1 and the effects of PI-3K/Akt on proliferation of progenitors in the subventricular zone of adult rat. Western blots and immunostaining revealed that 4 days after stroke, p27kip1 levels decreased and were absent in nuclei of the ipsilateral subventricular zone cells 7 days after stroke. Reduction in p27kip1 levels was concurrent with significant increases in BrdU immunoreactive cells in the subventricular zone. Treatment of stroke neurospheres with LY294002 significantly (p<0.05) reduced the numbers of neurospheres from 32 +/-5 in the stroke group to 14 +/- 3 in the stroke and LY294002 group. Collectively, our data suggest that stroke induced neural progenitor proliferation is mediated by down-regulation of p27Kip1 and activation of Akt.


The basic science aspect of donor heart preservation: a review.
In cardiac transplantation, the transport time between harvest and recipient is limited by the viability of the donor heart. The problem of viability is a consistent limitation in cardiac transplantation. Since the 1960s, techniques, including hypothermia, perfusion, oxygenation, and hyperbaria, have been used to prolong the preservation of the transplantable heart. Continuing development of cardioplegic solutions has minimized edema and oxygen radical formation, which have resulted in extension of the donor heart viability. New research into the events leading to necrosis, oncosis, and apoptosis may allow further advancement of protective cardioplegic solutions in combination with technology of transporting the heart. With a prolonged preservation time there is potential to increase the donor pool and ultimately improve post-operative outcomes.


Management of Destructive Colon Injuries after Damage Control Surgery.
After the World War II, fecal diversion became the standard of care for colon injuries, although medical, logistic, and technical advancements have challenged this approach. Damage control surgery serves to temporize immediately life-threatening conditions, and definitive management of destructive colon injuries is delayed until after appropriate resuscitation. The bowel can be left in discontinuity for up to 3 days before edema ensues, but the optimal repair window remains within 12 to 48 hours. Delayed anastomosis performed at the take-back operation or stoma formation has been reported with variable results. Studies have revealed good outcomes in those undergoing anastomosis after damage control surgery; however, they point to a subgroup of trauma patients considered to be "high risk" that may benefit from fecal diversion. Risk factors influencing morbidity and mortality rates include hypotension, massive transfusion, the degree of intra-abdominal contamination, associated organ injuries, shock, left-sided colon injury, and multiple comorbid conditions. Patients who are not suitable for anastomosis by 36 hours after damage control may be best managed with a diverting stoma. Failures are more likely related to ongoing instability, and the management strategy of colorectal injury should be based mainly on the patient's overall condition.


Estimation of surfactant lecithin in amniotic fluid and prediction of respiratory distress syndrome.
The quantitative and qualitative analyses of lecithin in the human amniotic fluid in relation to the antenatal prediction of developing respiratory distress syndrome were described. Surfactant lecithin (disaturated and/or dipalmitoyl lecithin) was estimated for the first time in 42 amniotic fluid specimens of 21-42 weeks gestation. Surfactant lecithin was present in considerable amounts in specimens obtained near or at term except in the ones associated with infants who subsequently developed respiratory distress syndrome. One infant developed typical respiratory distress syndrome despite the normal total lecithin concentration of amniotic fluid at birth. The fatty acid analysis, however, revealed that the surfactant lecithin concentration was extremely low, showing a great discrepancy between total lecithin and surfactant lecithin concentrations. Thus the estimation of disaturated and/or dipalmitoyl lecithin in the amniotic fluid seems to be the most precise sign of a potential risk of respiratory distress syndrome.


Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease.
Kawasaki disease (KD) is a self-limited, systemic vasculitis of children for which an infectious trigger is suspected. Recently, an association between KD and human coronavirus (HCoV)-New Haven (NH) was reported, on the basis of polymerase chain reaction (PCR) with primers that also amplified HCoV-NL63. We investigated the possible association between these HCoVs in the respiratory tract and KD by reverse-transcriptase (RT) PCR and viral culture in a geographically and ethnically diverse population. Only 1 (2%) of 48 patients with acute KD was positive by RT-PCR for HCoV-NL63/NH in a nasopharyngeal swab. These data do not support an association between these HCoVs and KD.


Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans.
Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram - and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. Only a subset of AUD patients had increased 51Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis). Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.


Development and physiological characterization of cellobiose-consuming Yarrowia lipolytica.
Yarrowia lipolytica is a promising production host for a wide range of molecules, but limited sugar consumption abilities prevent utilization of an abundant source of renewable feedstocks. In this study we created a Y. lipolytica strain capable of utilizing cellobiose as a sole carbon source by using endogenous promoters to express the cellodextrin transporter cdt-1 and intracellular β-glucosidase gh1-1 from Neurospora crassa. The engineered strain was also capable of simultaneous co-consumption of glucose and cellobiose. Although cellobiose was consumed slower than glucose when engineered strains were cultured with excess nitrogen, culturing with limited nitrogen led to cellobiose consumption rates comparable to those of glucose. Under limited nitrogen conditions, the engineered strain produced citric acid as a major product and we observed greater citric acid yields from cellobiose (0.37 g/g) than glucose (0.28 g/g). Culturing with a sole carbon source of either glucose or cellobiose induced additional differences on cell physiology and metabolism and a link is suggested to evasion of glucose-sensing mechanisms through intracellular creation and consumption of glucose. We ultimately applied this cellobiose-utilization system to produce citric acid from bioconversion of crystalline cellulose through simultaneous saccharification and fermentation (SSF).


Anaesthetic considerations with the metabolic syndrome.
The rising incidence of obesity has led to increased prevalence of a distinct, obesity-related metabolic syndrome. This syndrome is characterized by truncal obesity, insulin resistance, altered lipid levels, and hypertension. Definition of the metabolic syndrome rests on a set of clinical criteria instead of a single diagnostic test. It carries a different risk profile than obesity alone, and poses special challenges for the anaesthesiologist. These include preoperative risk stratification for common comorbidities, identifying reasonable thresholds for implementing preoperative risk reduction, overcoming obesity-related issues in intraoperative management, and delivering safe postoperative care. The metabolic syndrome predisposes to coronary artery disease, congestive heart failure, obstructive sleep apnoea, pulmonary dysfunction, and deep venous thrombosis. Because its different presentations can have different risk profiles, anaesthesiologists should assess the cumulative risk of each component of the metabolic syndrome separately, which significantly complicates preoperative management. Since obesity itself is difficult to treat, preoperative risk reduction can be difficult. Few data exist to inform best practice as to the anaesthetic care of patients with metabolic syndrome. This review evaluates and synthesizes current evidence regarding perioperative care for patients with the metabolic syndrome, including indications for preoperative testing; use of aspirin, β-blockers, statins, heparin, and angiotensin-converting enzyme inhibitors; anaesthetic strategies including regional anaesthesia; and postoperative management including continuous positive pressure ventilation by mask, prevention of pulmonary embolism, and indications for advanced respiratory monitoring.


Helicobacter pylori Reactivates Human Immunodeficiency Virus-1 in Latently Infected Monocytes with Increased Expression of IL-1β and CXCL8.
Helicobacter pylori are gram-negative bacteria, which colonize the human stomach. More than 50% of the world's population is infected by H. pylori. Based on the high prevalence of H. pylori, it is very likely that HIV and H. pylori infection may coexist. However, the molecular events that occur during HIV-H. pylori co-infection remain unclear. Latent HIV reservoirs are the major obstacle in HIV cure despite effective therapy. Here, we explored the effect of H. pylori stimulation on latently HIV-infected monocytic cell line U1. High throughput RNA-Seq using Illumina platform was performed to analyse the change in transcriptome between unstimulated and H. pylori-stimulated latently HIV-infected U1 cells. Transcriptome analysis identified potential genes and pathways involved in the reversal of HIV latency using bioinformatic tools that were validated by real-time PCR. H. pylori stimulation increased the expression of HIV-1 Gag, both at transcription (p<0.001) and protein level. H. pylori stimulation also increased the expression of proinflammatory cytokines IL-1β, CXCL8 and CXCL10 (p<0.0001). Heat-killed H. pylori retained their ability to induce HIV transcription. RNA-Seq analysis revealed 197 significantly upregulated and 101 significantly downregulated genes in H. pylori-stimulated U1 cells. IL-1β and CXCL8 were found to be significantly upregulated using transcriptome analysis, which was consistent with real-time PCR data. H. pylori reactivate HIV-1 in latently infected monocytes with the upregulation of IL-1β and CXCL8, which are prominent cytokines involved in the majority of inflammatory pathways. Our results warrant future in vivo studies elucidating the effect of H. pylori in HIV latency and pathogenesis.


Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations.
Understanding the cellular-molecular substrates of heart disease is key to the development of cardiac specific therapies and to the prevention of off-target effects by non-cardiac targeted drugs. One of the primary targets for therapeutic intervention has been the human ether a go-go (hERG) K+ channel that, together with the KCNQ channel, controls the rate and efficiency of repolarization in human myocardial cells. Neither of these channels plays a major role in adult mouse heart function; however, we show here that the hERG homolog seizure (sei), along with KCNQ, both contribute significantly to adult heart function as they do in humans. In Drosophila, mutations in or cardiac knockdown of sei channels cause arrhythmias that become progressively more severe with age. Intracellular recordings of semi-intact heart preparations revealed that these perturbations also cause electrical remodeling that is reminiscent of the early afterdepolarizations seen in human myocardial cells defective in these channels. In contrast to KCNQ, however, mutations in sei also cause extensive structural remodeling of the myofibrillar organization, which suggests that hERG channel function has a novel link to sarcomeric and myofibrillar integrity. We conclude that deficiency of ion channels with similar electrical functions in cardiomyocytes can lead to different types or extents of electrical and/or structural remodeling impacting cardiac output.


Targeted immunotherapy for colorectal cancer: monoclonal antibodies and immunotoxins.
Colorectal cancer (CRC) is a major health concern worldwide. It is the third most frequently diagnosed cancer and the second leading cause of cancer death. There currently are a number of treatment options for CRC, however many of them have failed to demonstrate desired therapeutic benefit. Therefore, significant efforts are being directed towards the development of new biological therapies with improved efficacy. Immunotherapy is an emerging treatment modality for a variety of cancers. Several promising treatments have already been approved by the US FDA and are being tested in clinical trials. Antibodies have been proved to be useful in cancer therapy due to their ability to recognize tumor-associated antigens expressed at higher density on malignant cells in comparison with those that are normal. Antibodies can be used as a single therapy or in combination with other therapies. A large variety of monoclonal antibodies have been developed. However, only a very few are able to kill a sufficient number of malignant cells and cause tumor regression. Hence, it is often necessary to arm the antibody with a cytotoxic agent to enhance the efficacy of the anti-tumor activity. This review provides a brief overview of some of the current agents being employed in targeted immunotherapy for CRC.


Determination of relative Notch1 and gamma-secretase-related gene expression in puromycin-treated microdissected rat kidneys.
Notch signaling pathways are involved in the regulation of cell differentiation and are highly conserved across species. Notch ligand binding leads to gamma-secretase-mediated proteolytic cleavage of the Notch receptor releasing the Notch intracellular domain, resulting in its subsequent translocation into the nucleus and gene expression regulation. To investigate the level of expression of Notch signaling pathway components in microanatomic regions following renal injury, kidneys from untreated, vehicle control, and puromycin aminonucleoside (PA, 150 mg/kg)-treated rats were evaluated. Frozen tissue sections from rats were microdissected using laser capture microdissection (LCM) to obtain glomeruli, cortical (proximal) tubules, and collecting ducts, and relative gene expression levels of Presenilin1, Notch1 and Hes1 were determined. In untreated rats, the Notch1 expression in glomeruli was higher than in the proximal tubules and similar to that in collecting ducts, whereas Presenilin1 and Hes1 expressions were highest in the collecting ducts, followed by cortical tubules and glomeruli. Following PA-induced renal injury, Hes1 gene expression increased significantly in the glomeruli and tubules compared to the collecting ducts where no injury was observed microscopically. Although these data present some evidence of change in Notch signaling related to injury, the expression of Presenilin1, Notch1, and Hes1 in the microanatomic regions of the kidney following PA treatment were not significantly different when compared to controls. These results demonstrate that there are differences in Notch-related gene expression in the different microanatomic regions of the kidneys in rats and suggest a minimal role for Notch in renal injury induced by PA. In addition, this work shows that LCM coupled with the RT-PCR can be used to determine the relative differences in target gene expression within regions of a complex organ.


Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity.
Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1-(3,4-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor-expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to Gi and Gs by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 μM, strong Ca2+ and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by orexin receptors, as determined utilizing the non-selective orexin receptor antagonist N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing orexin receptors or not. Thus, Yan 7874 is a weak partial agonist of orexin receptors. It also displays strong off-target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as orexin receptor agonist.


Swine management errors.
Management errors can affect all aspects of swine herd health. Inadequate feed, malfunctioning equipment, poor ventilation, low or high environmental temperature, inappropriate groupings, and rough handling all contribute to low productivity. Management errors can contribute to scours and pneumonia outbreaks, reproductive failure, accidental deaths and poor feed conversion.


Human kallikrein 10 expression in surgically removed human pituitary corticotroph adenomas: an immunohistochemical study.
Human kallikrein 10 (hk10), a secreted serine protease, was reported to function as a tumor suppressor. hK10 immunoexpression has been demonstrated in lactrotrophs and corticotrophs of the nontumorous human adenohypophysis. In the present study, for the first time we report hK10 immunoexpression in various surgically removed corticotroph adenoma subtypes. Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed using the streptavidin-biotin-peroxidase complex method with an hK10-specific rabbit polyclonal antibody. Results showed that the endocrinologically active adrenocorticotropic hormone (ACTH)-producing pituitary tumors and the silent subtypes were immunopositve for hK10. Intensity of staining varied between the different subtypes. Intensity was lowest in the silent subtypes (silent corticotroph subtypes 1 and 2) compared with nontumorous human adenohypophysial corticotrophs, whereas the endocrinologically active subtypes (ACTH-secreting adenomas, corticotroph carcinomas, Crooke cell adenomas, Crooke cell carcinomas), showed the highest hK10 immunoexpression. Immunopositivity in the nuclei of the ACTH-secreting adenomas and carcinomas, as well as dual cytoplasmic and nuclear localization of hK10 in some of the secreting tumor types was an intriguing finding. Immunoexpression of hK10 in the ACTH-secreting tumors as well as in the Crooke cell tumors was significantly increased when compared with the nonfunctioning tumors and in the corticotrophs of nontumorous pituitaries.


Thyroid hormones and illness.
To review illness-associated changes in thyroid hormone levels with respect to the alterations in metabolism, regulation, and transport of thyroid hormones present in such a setting. We summarize normal pituitary-thyroid function and categorize the types of changes that have been noted during illness. In addition, we examine studies that have addressed the metabolic status of patients with low thyroid hormone levels and the potential utility of thyroid hormone treatment in severely ill patients. The finding of altered thyroid hormone levels in hospitalized patients confirms the participation of these factors in the adaptive response to illness. Thyroid hormone alterations that occur during illness can be classified into three categories: (1) decreased production of triiodothyronine, (2) decreased serum binding of thyroid hormones, and (3) decreased secretion of thyrotropin. Study of these hormonal changes has provided insight into normal thyroid hormone regulation and metabolism as well as into neuroendocrine adaptations to illness. It seems reasonable to conclude that illness-associated changes in thyroid hormone levels are generally beneficial to the patient as a whole; however, the possibility of concomitant regional or individual tissue hypothyroidism exists. Conclusions about the potential utility of pharmacologic administration of triiodothyronine in selected diseases and clinical settings must await additional clinical trials. Finally, the predictable occurrence of altered thyroid hormone levels in hospitalized patients necessitates caution in both the selection and the interpretation of thyroid hormone tests in this patient population.


Adherence of those at low risk of disease to public health measures during the COVID-19 pandemic: A qualitative study.
Public health measures (PHMs) proactively and reactively reduce the spread of disease. While these measures target individual behaviour, they require broad adherence to be effective. Consequently, the World Health Organization issued a special appeal to young adults, a known non-adherent population, for increased adherence with COVID-19 guidelines. However, little is known about why these low-risk individuals do or do not adhere to PHMs. This study investigates why young adults in a low-risk setting adhered to PHMs implemented during the COVID-19 pandemic. A qualitative research approach was chosen to gain an in-depth understanding of participants' thoughts and experiences related to PHM adherence. Semi-structured interviews were conducted in April-May 2021 with 30 young adults living in Prince Edward Island (PEI), the province with the lowest COVID-19 case rate in Canada at that time. Thematic analysis was used to create a codebook based on the Theoretical Domains Framework, which was then inductively modified. The analysis identified eight themes that explained the adherence of young adults: (1) clear, purpose-driven adherence rationale, (2) developing trust in the local leadership, (3) adapting to novel measures, (4) manageable disruption, (5) adhering to reduce anxiety, (6) collective duty towards one's community, (7) moral culpability and (8) using caution rather than compliance. Together, these themes demonstrate that young adults adhered to PHMs because of their sense of connection to their community, public health leadership, and concerns over stigma. We further argue that clear guidelines and communication from public health officials during both periods of high and low COVID-19 cases facilitate adherence. These findings are important for mitigating future public health emergencies as they explain why young adults, an important segment of the population whose adherence is critical to the success of PHMs, follow PHMs. Further, these findings can inform public health officials and other stakeholders aiming to develop successful adherence strategies.


Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle.
This study was conducted to evaluate the expression of endothelial nitric oxide synthase (eNOS) in ovarian follicles and corpora lutea (CL) throughout the estrous cycle in sheep. Three experiments were conducted to (1) immunolocalize eNOS protein, (2) determine expression of mRNA for eNOS and its receptor guanylate cyclase 1 soluble beta3 (GUCY1B3), and (3) co-localize eNOS and vascular endothelial growth factor (VEGF) proteins in the follicles and/or CL throughout the estrous cycle. In experiment 1, ovaries were collected from ewes treated with FSH, to induce follicular growth or atresia. In experiment 2, ovaries were collected from ewes treated with FSH and hCG to induce follicular growth and ovulation. In experiment 3, ovaries were collected from superovulated ewes to generate multiple CL on days 2, 4, 10, and 15 of the estrous cycle. In experiments 1 and 2, the expression of eNOS protein was detected in the blood vessels of the theca externa and interna of healthy ovarian follicles. However, in early and advanced atretic follicles, eNOS protein expression was absent or reduced. During the immediate postovulatory period, eNOS protein expression was detected in thecal-derived cells that appeared to be invading the granulosa layer. Expression of eNOS mRNA tended to increase in granulosa cells at 12 and 24 h, and in theca cells 48 h after hCG injection. In experiment 3, eNOS protein was located in the blood vessels of the CL during the estrous cycle. Dual localization of eNOS and VEGF proteins in the CL demonstrated that both were found in the blood vessels.


Psychosocial functioning and adjustment to university settings: comparing students with chronic illnesses to healthy peers.
Purpose: College students with chronic illnesses are vulnerable to poor adjustment, but it remains unclear how these students differ from healthy peers. This study compares psychosocial adjustment and risky behavior between students with and without chronic illnesses. Participants: Participants (N = 629, 78% Caucasian, 77% Female) were recruited from universities. Methods: Participants completed measures of illness history, anxiety, depression, stressful life events, social support, and risky behavior. Results: College students with chronic illnesses demonstrated significantly greater symptoms of anxiety F(1,620) = 8.742, p < .003, depression F(1,614) = 26.947, p < .001, more stressful life events F(1,476) = 23.671, p < .001, and lower social support F(1,613) = 15.645, p < .001. No differences in risky behaviors between groups emerged F(1,601) = 3.432, p = .064. An indirect effect of health status on risk-taking behavior was observed [b = .677, 95% CI (.351, 1.072)] partially mediated by depression. Conclusion: College students with chronic illnesses demonstrated worse psychosocial outcomes than healthy students, warranting programs to support these students. Depressive symptoms partially mediated risky behavior.


Locking Plate Fixation for Canine Acetabular Fractures.
The aim of this study was to document application of locking plates for stabilization of acetabular fractures along with complications and clinical outcomes. We hypothesized that complications and clinical outcomes would be comparable to historical reports using non-locking plate and screw constructs. Medical records of dogs presented with acetabular fractures at a single referral centre between 2010 and 2018 were reviewed. Cases surgically managed by open reduction and internal fixation, involving placement of at least one locking plate and screws, were included. Signalment, fracture classification, type of implant used, additional methods of stabilization, along with complications and neurological deficits, were collected. Long-term follow-up was based on Liverpool Osteoarthritis in Dogs questionnaire. Eighteen acetabula were repaired in 17 dogs. Locking implants were VetLOX (4/18), string-of-pearls (7/18) and locking compression plates (7/18). Locking plates and screws were used as the sole method of fixation in 10/18 acetabula, and as adjunctive fixation with other implants in 8/18 acetabula. Two minor complications and one catastrophic complication were reported. Sixteen of seventeen dogs returned to function with radiographic documentation of fracture healing. Complication rate was comparable to historic reports using non-locking implants. Long-term outcomes assessed by Liverpool Osteoarthritis in Dogs questionnaire were positive in most cases. Locking plates are a viable means of stabilizing acetabular fractures in dogs and can provide positive clinical outcomes. Surprisingly, problems including inaccurate fracture reduction and implant loosening were not fully avoided by use of locking implants but incidence was low.


ACE inhibitors in non-diabetic renal disease.
In non-diabetic renal disease ACE inhibitors have brought both benefit and problems. On the one hand, they are undoubtedly effective antihypertensive agents and data suggest that they may have a beneficial role in the prevention of progression of renal disease, although further placebo controlled double blind trials of adequate duration are required. On the other hand, their widespread use in elderly patients and those with generalised atherosclerosis has increased the risk of acute renal failure when occult renovascular disease is present. Awareness among physicians of the high rate of renovascular disease in populations at risk is to be encouraged.


Epigenetic Phosphorylation Control of Mycobacterium tuberculosis Infection and Persistence.
Reversible protein phosphorylation is the most common type of epigenetic posttranslational modification in living cells used as a major regulation mechanism of biological processes. The Mycobacterium tuberculosis genome encodes for 11 serine/threonine protein kinases that are responsible for sensing environmental signals to coordinate a cellular response to ensure the pathogen's infectivity, survival, and growth. To overcome killing mechanisms generated within the host during infection, M. tuberculosis enters a state of nonreplicating persistence that is characterized by arrested growth, limited metabolic activity, and phenotypic resistance to antimycobacterial drugs. In this article we focus our attention on the role of M. tuberculosis serine/threonine protein kinases in sensing the host environment to coordinate the bacilli's physiology, including growth, cell wall components, and central metabolism, to establish a persistent infection.


Serum resistance encoded by colicin V plasmids in Escherichia coli and its relationship to the plasmid transfer system.
Eight colicin V plasmids were conjugated into a plasmidless Escherichia coli (K-12) strain that was susceptible to the bactericidal effects of normal rabbit serum. The resulting colicin V-positive strains were examined for their capacity to resist the lethal effects of serum. Serum resistance was assessed as growth of the bacterial strain in medium containing 5% normal rabbit serum inoculated from a culture in the early exponential phase. Only three of the eight colicin V plasmids were found to confer the serum resistance phenotype on the host strain. Derepression of the transfer system was associated with serum resistance in two of the plasmids. Two other derepressed plasmids did not confer serum resistance on the host bacterium. Therefore, such derepression alone was insufficient to produce serum resistance. The factor(s) encoded by colicin V plasmids and responsible for the serum resistance of the bacterial strains bearing the plasmids was shown to be a property associated with the cell and not an extracellular factor excreted into the growth medium.


Dependence of Xpert MTB/RIF Accuracy for Detecting Rifampin Resistance in Bronchoalveolar Lavage Fluid on Bacterial Load: A Retrospective Study in Beijing, China.
We assessed the effect of Mycobacterium tuberculosis (MTB) bacterial load on Xpert MTB/RIF accuracy for detection of rifampicin (RIF)-resistant MTB in bronchoalveolar lavage fluid (BALF) specimens obtained at a national tuberculosis (TB) specialized hospital in Beijing, China. A retrospective study was conducted at Beijing Chest Hospital. Patients with symptoms suggestive of pulmonary TB who provided BALF specimens for routine MTB detection between June 2019 and July 2020 were enrolled in the study. Chi-square test and Student's t-test were used to compare results across groups stratified according to BALF bacterial load. In total, 1125 patients with positive Xpert results who were enrolled in final analysis, 263 provided BALF specimens that tested positive for RIF-resistant MTB via Xpert MTB/RIF. The RIF-resistance rate of specimens with very low MTB bacterial load was 30.9%, a resistance rate significantly greater than rates obtained for groups with high (25.0%), medium (17.3%) and low (19.2%) MTB loads (P<0.01). Notably, false-positive results obtained for the very low bacterial load group led to markedly reduced positive predictive value of Xpert MTB/RIF to provide correct RIF-resistance predictions for that group (67.1%, 95% CI: 56.1%-78.1%5) relative to the predictive value obtained for all other groups combined (about 90%, P<0.05). Sanger sequencing data obtained for 20 (32.8%) MTB isolates deemed RIF-resistant via Xpert (Probe E) lacked rpoB RRDR mutations. Meanwhile, of another group of 23 isolates deemed RIF-susceptible via DST but RIF-resistant via Xpert MTB/RIF, 20 isolate sequences (87.0%) lacked rpoB RRDR mutations, while sequences of the remaining 3 isolates harbored single rpoB RRDR mutations predicted to cause amino acid substitutions. Xpert MTB/RIF assay performed alarmingly poorly when used to detect RIF-resistant MTB in BALF specimens with very low bacterial loads. A high rate of Xpert probe E hybridization failure was the main driver of false-positive RIF-resistant results.


CDC5L drives FAH expression to promote metabolic reprogramming in melanoma.
Metabolic reprogramming allows tumor cells to thrive in the typically hypoxic tumor microenvironment. Using immunodetection and clinical data analyses, we demonstrate here that fumarylacetoacetate hydrolase (FAH) is highly expressed in melanoma and correlates with poor survival. FAH knockdown inhibits proliferation and migration, while promoting apoptosis in melanoma cells, result in prolonged survival in tumor-bearing mice. Molecular analyses using real time RT-PCR, western blot, and 13C tracing showed that these changes are driven by strong stimulation of anaplerotic reactions through the TCA cycle and the pentose-phosphate pathway, resulting in increased fatty acid and nucleotide synthesis. Using bioinformatic, ChIP-PCR, and gene silencing analyses, we determined that cell division cycle 5-like protein (CDC5L) is an important transcription factor regulating FAH expression in melanoma cells. These findings reveal that FAH induces metabolic reprogramming in melanoma and so emerges as both a potentially useful independent prognostic indicator and an attractive therapeutic target.


Evaluation of patient and doctor perception toward the use of telemedicine in Apollo Tele Health Services, India.
Telemedicine incorporates electronic information and medical technology. It connects healthcare through vast distances which would benefit both patients and doctors. The aim of this questionnaire study was to evaluate the effects of telemedicine on patients and medical specialists. A cross-sectional study was conducted among 122 participants (71 patients and 51 doctors) on satisfaction in quality of service, cost-effectiveness, and problems encountered in healthcare provided by the telemedicine in Apollo Tele Health Services, Hyderabad, Telangana, India. The data for each group were calculated and compared. About 80% patients and all the doctors reported their satisfaction on the quality of treatment given through telemedicine. Approximately, 90% of the participants found telemedicine cost-effective and 61% of the doctors found an increase in patient's inflow apart for their regular practice. Problems encountered in telemedicine were 47% in technical issues and 39% in time scheduling by doctors and 31% of patients were uncomfortable to face the camera, and 24% had technical issues. The results of the present study showed that telemedicine in healthcare could prove to be useful to patients in distant regions and to rural doctors in India. In the near future, telemedicine can be considered as an alternate to face to face patient care.


Bernard-Soulier syndrome Kagoshima: Ser 444-->stop mutation of glycoprotein (GP) Ib alpha resulting in circulating truncated GPIb alpha and surface expression of GPIb beta and GPIX.
The platelet membrane glycoprotein (GP)Ib/IX complex is composed of three polypeptides, GPIb alpha, GPIb beta, and GPIX, and functions as a platelet receptor for von Willebrand factor. All three subunits are reported to be requisite for efficient surface expression of the complex. The absence of the GPIb/IX complex on platelet membrane is the hallmark of a congenital qualitative platelet disorder, termed the Bernard-Soulier syndrome (BSS). We describe here the molecular basis of a novel variant phenotype of BSS in a female patient, designated as BSS Kagoshima. Her platelets completely lacked the surface expression of GPIb alpha, but expressed a residual amount of GPIb beta and GPIX. Unexpectedly, her platelets and plasma contained a truncated GPIb alpha polypeptide with an apparent molecular weight of 116 kD (under nonreducing conditions). The amounts of truncated protein were 23% and 60% of the normal values in platelets and plasma, respectively. The abnormal protein contained a normal amount of sialic acid as demonstrated by digestion with neuraminidase. DNA sequencing analysis showed a homozygous single nucleotide substitution from the serine codon (TCA) to a nonsense codon (TAA) at residue 444 in the GPIb alpha gene. The mutant gene generated a truncated GPIb alpha molecule lacking the transmembrane region and cytoplasmic tail. Her parents were heterozygotes for the mutation. These findings suggest that this type of truncated GPIb alpha was produced, normally glycosylated, and subsequently secreted into the plasma. Furthermore, the truncated GPIb alpha might be associated with the process of the surface expression of incomplete GPIb/IX complex, GPIb beta and GPIX.


Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia.
Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients. From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data. All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (δβ)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient. No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.


EEG Signals Analysis Using Multiscale Entropy for Depth of Anesthesia Monitoring during Surgery through Artificial Neural Networks.
In order to build a reliable index to monitor the depth of anesthesia (DOA), many algorithms have been proposed in recent years, one of which is sample entropy (SampEn), a commonly used and important tool to measure the regularity of data series. However, SampEn only estimates the complexity of signals on one time scale. In this study, a new approach is introduced using multiscale entropy (MSE) considering the structure information over different time scales. The entropy values over different time scales calculated through MSE are applied as the input data to train an artificial neural network (ANN) model using bispectral index (BIS) or expert assessment of conscious level (EACL) as the target. To test the performance of the new index's sensitivity to artifacts, we compared the results before and after filtration by multivariate empirical mode decomposition (MEMD). The new approach via ANN is utilized in real EEG signals collected from 26 patients before and after filtering by MEMD, respectively; the results show that is a higher correlation between index from the proposed approach and the gold standard compared with SampEn. Moreover, the proposed approach is more structurally robust to noise and artifacts which indicates that it can be used for monitoring the DOA more accurately.


Diffusion in a periodically driven damped and undamped pendulum.
We study the diffusion process in a periodically driven damped and undamped pendulum. The effect of angular frequency omega of the external periodic force on the diffusion process is investigated. We show the occurrence of normal and anomalous diffusions in the undamped system. In the presence of damping, normal chaotic diffusion is found. Near certain bifurcation points, the phase velocity is found to be intermittent and the diffusion coefficient is found to exhibit power-law divergence. We argue that the divergence of the diffusion coefficient near the bifurcation points is similar to that of the average laminar lengths near them. The effect of bias on the dynamics is also discussed.


Olfactory detection thresholds using pyridine, thiophene, and phenethyl alcohol.
An objective examination of olfactory function is needed for evaluation and clinical progression of patients with olfactory deficits. Two hundred sixty-eight healthy subjects were studied in order to establish olfactory thresholds for three test odorants. Subjects were required to simply detect the presence of an odor when comparing various log dilutions of test odorant against two "blank flasks. These data have provided a means of quantitating existing olfactory deficits in affected patients. Olfactory function was found to be diminished in elderly subjects and should be considered a factor when evaluating older patients.


Increased adhesion of neutrophils to retinal vascular endothelial cells exposed to hyperosmolarity.
Recent studies suggest that leukocytes may contribute to capillary occlusion and endothelial cell injury in diabetic retinopathy. The present study is an attempt to determine whether high glucose concentration/hyperosmolar conditions would increase neutrophil adhesion to retinal endothelial cell monolayers. Confluent monolayers of bovine retinal endothelial cells were incubated for 24 hr in 96-well microtiter plates in 5.5, 20, 50 or 100 mM glucose using 20, 50 or 100 mM mannitol as osmotic controls. After 24 hr the cells were observed by phase microscopy, washed, and then incubated with isolated human neutrophils for 20 min. Non-adherent neutrophils were washed from the monolayers, and the number of adherent neutrophils was determined using an Elisa assay for neutrophil elastase. Adhesion of neutrophils to confluent monolayers of human umbilical vein and bovine aortic endothelial cells at all levels of glucose were assayed in a similar fashion for comparison. Neutrophil adherence to bovine retinal endothelial cells was significantly increased (P < 0.05, n = 8; paired t-test) at all elevated glucose concentrations compared with adherence at control (5.5 mM) glucose concentration. The effect was also concentration dependent with 20, 50 and 100 mM glucose resulting in 35, 57 and 70% increases respectively over controls. However, mannitol at equal concentrations produced similar increases in neutrophil adherence, indicating that the increases in adhesion caused by elevated glucose concentration were due to hyperosmolarity and not some special effect of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)


Anaphylaxis in the emergency department: a paediatric perspective.
Correct management of anaphylactic manifestations in the emergency department is crucial to prevent mortality and future episodes, in particular for paediatric patients. We make here recommendations based on a critical review of the evidence for the management of anaphylaxis in emergency department with particular emphasis on children. Available information suggests that anaphylaxis must be promptly recognized keeping in mind the airway patency, breathing (ventilation and respiration), circulation and mental status and treated. The first treatment is epinephrine. After successful treatment of an anaphylactic episode, attention must be paid at prevention of early recurrences (biphasic anaphylaxis) and assessment of causes. Patients should not be discharged before prescribing self-injectable epinephrine and explain how and in under what circumstances it must be injected; giving an action plan to be communicated to their communities; inform the school about the possible occurrence of reactions and the appropriate avoidance and rescue measures; and consider the necessity of a Medic-Alert identification. As gross differences have been described in the awareness of the disease and its management between allergists and nonallergists, allergists should interact with emergency doctors to improve education in this area.


Modeling cyclic voltammetry during solid electrolyte interphase formation: Baseline scenario of a dynamically evolving tunneling barrier resulting from a homogeneous single-phase insulating film.
The solid electrolyte interphase (SEI) is an insulating film on anode surfaces in Li-ion batteries, which forms via the reaction of Li ions with reduced electrolyte species. The SEI leads to a reduction in the electrochemical current in heterogeneous electrochemical redox reactions at the electrode/electrolyte interface. Hence, the growth of the SEI is, in principle, self-limited. Toward our ultimate goal of an improved understanding of SEI formation, we develop a baseline quantitative model within Butler-Volmer electrode kinetics, which describes the cyclic voltammetry (CV) of a flat macroelectrode during SEI growth. Here, the SEI building up electrochemically during CV forms a homogeneous single-phase electronically insulating thin film due to the corresponding current. The model is based on a dynamically evolving electron tunneling barrier with increasing film thickness. Our objective is to provide a framework, which allows for both the qualitative, intuitive interpretation of characteristic features of CV measurements and the quantitative extraction of physicochemical parameters via model fitting. We also discuss the limitations of the baseline model and give a brief outlook for improvements. Finally, comparisons to exemplary CVs from the literature relevant to Li-ion battery science are presented.


Longevity and determinants of protective humoral immunity after pandemic influenza infection.
Antibodies to influenza hemagglutinin are the primary correlate of protection against infection. The strength and persistence of this immune response influences viral evolution and consequently the nature of influenza epidemics. However, the durability and immune determinants of induction of humoral immunity after primary influenza infection remain unclear. The spread of a novel H1N1 (A[H1N1]pdm09) virus in 2009 through an unexposed population offered a natural experiment to assess the nature and longevity of humoral immunity after a single primary influenza infection. We followed A(H1N1)pdm09-seronegative adults through two influenza seasons (2009-2011) as they developed A(H1N1)pdm09 influenza infection or were vaccinated. Antibodies to A(H1N1)pdm09 virus were measured by hemagglutination-inhibition assay in individuals with paired serum samples collected preinfection and postinfection or vaccination to assess durability of humoral immunity. Preexisting A(H1N1)pdm09-specific multicytokine-secreting CD4 and CD8 T cells were quantified by multiparameter flow cytometry to test the hypothesis that higher frequencies of CD4(+) T-cell responses predict stronger antibody induction after infection or vaccination. Antibodies induced by natural infection persisted at constant high titer for a minimum of approximately 15 months. Contrary to our initial hypothesis, the fold increase in A(H1N1)pdm09-specific antibody titer after infection was inversely correlated to the frequency of preexisting circulating A(H1N1)pdm09-specific CD4(+)IL-2(+)IFN-γ(-)TNF-α(-) T cells (r = -0.4122; P = 0.03). The longevity of protective humoral immunity after influenza infection has important implications for influenza transmission dynamics and vaccination policy, and identification of its predictive cellular immune correlate could guide vaccine development and evaluation.


A new ferrous iron-uptake transporter, EfeU (YcdN), from Escherichia coli.
Escherichia coli possesses multiple routes for iron uptake. Here we present EfeU (YcdN), a novel iron acquisition system of E. coli strain Nissle 1917. Laboratory strains of E. coli such as K12 lack a functional (efeU) ycdN gene caused by a frameshift mutation. EfeU, a member of the oxidase-dependent iron transporters (OFeT), is a homologue of the iron permease Ftr1p from yeast. The ycdN gene is part of the ycdNOB tricistronic operon which is expressed in response to iron deprivation in a Fur-dependent manner. Expression of efeU resulted in improved growth of an E. coli mutant lacking all known iron-uptake systems and mediated increased iron uptake into cells. Furthermore, the presence of other divalent metal cations did not impair growth of strains expressing efeU. The EfeU protein functioned as ferrous iron permease in proteoliposomes in vitro. Topology analysis indicated that EfeU is an integral cytoplasmic membrane protein exhibiting seven transmembrane helices. Two REXXE motifs within transmembrane helices of OFeT family members are implicated in iron translocation. Site-directed mutagenesis of each REGLE motif of EfeU diminished iron uptake in vivo and growth yield. In vitro the EfeU variant protein with an altered first REGLE motif was impaired in iron permeation, whereas activity of the EfeU variant with a mutation in the second motif was similar to the wild-type protein.


Effect of Paclitaxel-Coated Balloon Angioplasty on Side Branch Lesion and Cardiovascular Outcomes in Patients with De Novo True Coronary Bifurcation Lesions Undergoing Percutaneous Coronary Intervention.
To compare the effects of paclitaxal-coated balloon (PCB) versus conventional balloon (CB) on side branch (SB) lesion and cardiovascular outcomes in patients with de novo true bifurcation lesions. In total, 219 patients with de novo true bifurcation lesions were enrolled and divided into PCB group (102 cases) and CB group (117 cases) according to angioplasty strategy in SB. Drug-eluting stent (DES) was implanted in main vessel (MV) for each subject. All subjects underwent a 12-month follow-up for late lumen loss (LLL), restenosis, and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). MACEs included cardiac death, nonfatal myocardial infarction, and unstable angina requiring admission. There were no differences in diameter, minimum lumen diameter (MLD), and stenosis for bifurcation lesions between the two groups before and immediately after PCI (P > 0.05). After 12-month follow-up, no differences occurred in MV-MLD and MV-LLL between the two groups (P > 0.05); SB-MLD in PCB group was higher than that in CB group (1.97 ± 0.36 mm vs. 1.80 ± 0.43 mm, P = 0.007); SB-LLL in PCB group was lower than that in CB group (0.11 ± 0.18 mm vs. 0.19 ± 0.25 mm, P = 0.024). Multivariate COX analyses indicated that PCB group had lower MACE risk than CB group (HR = 0.480, 95%CI 0.244-0.941, P = 0.033). PCB could decrease SB-LLL and MACE risk in patients with de novo true coronary bifurcation lesion 12 months after single-DES intervention.


Crisis planning to manage risks posed by animal rights extremists.
Among the multitude of crises that US research institutions may face are those caused by animal rights activists. While most activists opposed to animal research use peaceful and lawful means of expressing their opinions, some extremists resort to illegal methods. Arson, break-ins, and theft with significant property damage at US animal research facilities began in the 1980s. The most troubling trend to develop in the past decade is the targeting of individuals associated with animal research, whether directly or indirectly, and the use of violent scare tactics to intimidate researchers and their families. The National Association for Biomedical Research has a 30-year history of monitoring the animal rights movement and assisting member institutions with crisis situations. In this article we discuss attacks on researchers at their homes, cyber crimes, exploitation of new media formats, infiltration of research facilities, and the targeting of external research stakeholders and business partners. We describe the need for a well-conceived crisis management plan and strong leadership to mitigate crisis situations. Institutions with well-informed leaders and crisis management teams ready to take timely action are best equipped to protect staff, laboratory animals, and research programs. They act on early warnings, provide support for targeted staff, seek legal remedies, thoughtfully control access to research facilities, and identify and enlist new research supporters. We underscore the importance of up-to-date crisis planning so that institutions are not only aware of ongoing risks posed by animal rights extremists but also better prepared to take preemptive action and able to manage those risks successfully.


Reflections on telomeres, growth, aging, and essential hypertension.
Here we review the "telomere hypothesis of cellular aging." We propose that this hypothesis is relevant to our understanding of the roles of genetics as well as growth and development in the etiology of essential hypertension and its cardiovascular complications. Elements of this hypothesis and the speculations that we make can be directly tested using tissues (cells) obtained from human beings.


5,5- and 5,6-Membered Spirocyclic Indolinone Hit-Finding Libraries.
The production of two libraries based on spirocyclic indolinones is described. These libraries were selected from numerous spirocyclic indolinone scaffolds with a library evaluation procedure used routinely at Novartis, based on computed physicochemical properties and measured properties of prototype compounds. The library production yielded 176 and 428 compounds that could be isolated in sufficient amounts and purities based on two closely related scaffolds. The novelty and diversity analysis of these libraries shows their complementarity to the chemical space covered by the structures of the PubChem database.