A comprehensive review of tumor proliferative and suppressive role of semaphorins and therapeutic approaches.
Semaphorins have been traditionally known as axon guidance proteins that negatively regulate axonal growth. However, in the past couple of decades, their versatile role in so many other biological processes has come to prominence as well. One such example is their role in cancer. In this review article, the focus was on the tumor proliferative and tumor suppressive role of all 20 semaphorin family members under the 7 semaphorin classes found in vertebrates and invertebrates as well as the ongoing and emerging therapeutic approaches to combat semaphorin-mediated cancers. Except sema6C, 19 of the 20 non-viral semaphorin family members have been discovered to be associated with cancer in one way or another. Eleven semaphorin family members have been discovered to be tumor proliferative and 8 to be tumor suppressive. Six therapeutic avenues and their safety profiles have been discussed which are currently at use or at the various stages of development. Finally, perspectives on which approach is the best for treating cancers associated with semaphorins have been given.


Pheromonal mediation of intraseasonal declines in the attractivity of female red-sided garter snakes, Thamnophis sirtalis parietalis.
During the breeding season, female red-sided garter snakes (Thamnophis sirtalis parietalis) produce and express a sexual attractiveness pheromone that elicits male courtship behavior. Composed of a homologous series of saturated and monounsaturated methyl ketones, this pheromone is expressed in female skin lipids. Recent studies have shown that the sexual attractivity of unmated female garter snakes declines as the breeding season progresses. Here, we investigated whether temporal changes in the quantity and/or quality of the female sexual attractiveness pheromone are responsible for the observed loss of attractivity. Female red-sided garter snakes were collected immediately following spring emergence and held under natural conditions for the duration of the breeding season. Behavioral experiments confirmed that unmated females become significantly less attractive to males within two weeks of emergence from hibernation. Additionally, these females had lower estradiol concentrations at two weeks post-emergence. Subsequent chemical analyses revealed qualitative variation between the pheromone profiles of newly emerged females and those of females at two weeks post-emergence. Together, these results support the hypothesis that changes in the female sexual attractiveness pheromone are responsible for declining post-emergence female attractivity in garter snakes.


Human Mitoribosome Profiling: A Re-engineered Approach Tailored to Study Mitochondrial Translation.
To understand the human mitochondrial translation process, tools are required to dissect this system at a global scale. The mechanisms and regulation of translation in mitochondria are different from those in the cytosol, and mitochondrial ribosomes have distinct biochemical properties. In this chapter, we describe in detail the modifications we have made to the ribosome profiling approach to adapt it to the unique characteristics of the human mitochondrial ribosome. This approach maximizes the fraction of mitochondrial ribosomes recovered, providing a snapshot of the mitochondrial translation landscape with minimal bias. We also describe the use of mouse lysate as an internal spike-in control for normalization, allowing quantification of global changes in translation across samples. Finally, we outline the bioinformatic pipelines to process the raw reads and identify mitoribosome A sites in the absence of untranslated regions flanking open reading frames. This method offers a subcodon-resolution time-sensitive global approach to explore the mitochondrial translation process in human cells.


Co-creation of a sport-specific anterior cruciate ligament injury risk reduction program for women: A concept mapping approach.
To engage physiotherapists experienced in female elite sport and athletes to co-create a sport-specific anterior cruciate ligament (ACL) injury risk reduction program. Concept Mapping. The Concept Systems Global MAX™ web platform was used to collect and analyse data from 27 context and content experts (22 physiotherapists, 5 athletes). Participants brainstormed statements representing the critical elements that should be included in an ACL injury risk reduction program for women playing elite Australian Football (AF). Twenty-two participants brainstormed 56 statements that were synthesised and edited to 62 statements. Statements were sorted into clusters by twenty-three participants and rated on importance and feasibility using six-point scales. Multidimensional scaling and cluster analysis identified a 5-cluster solution as follows: Football-specific preparation (15 statements); Movement skills (17 statements); Strength and conditioning (15 statements); Individual preparation (7 statements); and Education (8 statements). Calculation of mean ratings for each cluster and statement identified the Movement skills cluster as most important (mean=3.61 out of 5) and the Football-specific preparation cluster as most feasible (3.75 out of 5). By contrast, the Individual preparation cluster was rated the least important (mean=2.9 out of 5), and the least feasible (3.12 out of 5), to include in the program. The five clusters of critical elements to include in an ACL injury risk reduction program for women playing elite AF, in order of most to least importance were: movement skills, football-specific preparation, education, strength and conditioning and individual preparation.


Modulatory effects of an NMDAR partial agonist in MK-801-induced memory impairment.
Acute administration of the N-methyl-d-aspartate (NMDA) non-competitive antagonist, MK-801, impairs novel object recognition (NOR), locomotor activity in open field (OF) and conditioned taste aversion (CTA) in rodents. NMDAR partial agonist d-cycloserine (DCS) reverses these effects in NOR and CTA via modulation of glutamatergic, cholinergic and dopaminergic systems. To test this hypothesis, we investigated the effects of DCS, a partial NMDAR agonist, on NOR memory, locomotor activity, and CTA memory in Wistar rats on NMDA-glutamate receptor antagonism by MK-801. The potential involvement of dopaminergic and cholinergic systems in improving cognitive functions was explored. MK-801-induced cognitive deficits were assessed using NOR, OF and CTA paradigms. MK-801-induced dopamine release increase in acetylcholinesterase (AChE), mono amine oxidase (MAO) activity and increase in c-fos expression were also investigated. The effects caused by MK-801 (0.2 mg/kg) were inhibited by administration of the NMDA receptor agonist DCS (15 mg/kg). NOR and CTA paradigms inhibited by MK-801 were attenuated by DCS administration. Moreover, DCS also blocked the MK-801-induced abnormal increase in dopamine content, AChE activity and MAO activity. However, c-fos overexpression was controlled to some extent only. Based on the NMDAR hypo function hypothesis in some neuropsychiatric disorders, our finding suggests that improving NMDAR hypo function by agonist DCS may play a significant role.


Formula with long-chain polyunsaturated fatty acids reduces incidence of allergy in early childhood.
Allergy has sharply increased in affluent Western countries in the last 30 years. N-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) may protect the immune system against development of allergy. We prospectively categorized illnesses by body system in a subset of 91 children from the Kansas City cohort of the DIAMOND (DHA Intake and Measurement of Neural Development) study who had yearly medical records through 4 years of age. As infants, they were fed either a control formula without LCPUFA (n = 19) or one of three formulas with LCPUFA from docosahexaenoic acid (DHA) and arachidonic acid (ARA) (n = 72). Allergic illnesses in the first year were lower in the combined LCPUFA group compared to the control. LCPUFAs significantly delayed time to first allergic illness (p = 0.04) and skin allergic illness (p = 0.03) and resulted in a trend to reduced wheeze/asthma (p = 0.1). If the mother had no allergies, LCPUFAs reduced the risk of any allergic diseases (HR = 0.24, 95% CI = 0.1, 0.56, p = 0.0.001) and skin allergic diseases (HR = 0.35, 95% CI = 0.13, 0.93, p = 0.04). In contrast, if the mother had allergies, LCPUFAs reduced wheezing/asthma (HR = 0.26, 95% CI = 0.07, 0.9, p = 0.02). LCPUFA supplementation during infancy reduced the risk of skin and respiratory allergic diseases in childhood with effects influenced by maternal allergies.


Unusual clinical presentations of plasma cell mucositis involving oral mucosa: Presentation of 2 cases and review of the literature.
Plasma cell mucositis (PCM) is a non-neoplastic plasma cell disorder of the upper aerodigestive tract with a high impact on life quality. Less than 70 cases were reported in the literature. The objective of this study was to report 2 cases of PCM. A concise review of the literature is also presented. Two cases of PCM that presented during the COVID-19 quarantine are reported. The inclusion criteria for the literature review were English-indexed case reports of the last 20 years. Cases were treated with meprednisone. As mechanical trauma was proposed as a triggering factor, its control was also considered. Patients were followed with no relapses. There were 29 studies included. The mean age was 57 years, with a male predominance, different clinical phenotypes, and intensely erythematous mucosa as a classical finding. The most frequent site was the lip, followed by the buccal mucosa. The final diagnosis is clinicopathologic. CD138 expression is a hallmark of plasma cells, frequently aiding PCM diagnosis. Plasma cell mucositis treatment is mostly symptomatic, and several therapeutic modalities have been mostly unsuccessful. Diagnosing plasma cell mucositis becomes challenging as many lesions may mimic other conditions. Consequently, in these cases, the diagnostic process should gather clinical, histopathologic, and immunohistochemical data.


Flotillin-1 mediates PrPc endocytosis in the cultured cells during Cu²⁺ stimulation through molecular interaction.
Flotillins are membrane association proteins consisting of two homologous members, flotillin-1 (Flot-1) and flotillin-2 (Flot-2). They define a clathrin-independent endocytic pathway in mammal cells, which are also distinct from some other endocytosis mechanisms. The implicated cargoes of the flotillin-dependent pathway are mainly some GPI-anchored proteins, such as CD59 and Thy-1, which positionally colocalize with flotillins at the plasma membrane microdomains. To see whether flotillins are involved in the endocytosis of PrP(C), the potential molecular interaction between PrP(C) and flotillins in a neuroblastoma cell line SK-N-SH was analyzed. Co-immunoprecipitation assays did not reveal a detectable complex in the cell lysates of a normal feeding situation. After stimulation of Cu(2+), PrP(C) formed a clear complex with Flot-1, but not with Flot-2. Immunofluorescent assays illustrated that PrP(C) colocalized well with Flot-1, and the complexes of PrP(C)-Flot-1 shifted from the cell membrane to the cytoplasm along with the treatment of Cu(2+). Down-regulating the expression of Flot-1 in SK-N-SH cells by Flot-1-specific RNAi obviously abolished the Cu(2+)-stimulated endocytosis process of PrP(C). Moreover, we also found that in the cell line human embryonic kidney 293 (HEK293) without detectable PrP(C) expression, the distribution of cellular Flot-1 maintained almost unchanged during Cu(2+) treatment. Cu(2+)-induced PrP(C)-Flot-1 molecular interaction and endocytosis in HEK293 cells were obtained when expressing wild-type human PrP (PrP(PG5)), but not in the preparation expressing octarepeat-deleted PrP (PrP(PG0)). Our data here provide direct evidences for the molecular interaction and endocytosis of PrP(C) with Flot-1 in the presence of copper ions, and the octarepeat region of PrP(C) is critical for this process, which strongly indicates that the Flot-1-dependent endocytic pathway seems to mediate the endocytosis process of PrP(C) in the special situation.


Intravitreal conbercept improves outcome of proliferative diabetic retinopathy through inhibiting inflammation and oxidative stress.
Conbercept is a newly-developed anti-vascular endothelial growth factor (VEGF) drug. This study aimed to evaluate the effects of conbercept on inflammation and oxidative response in proliferative diabetic retinopathy (PDR). Morphology changes in retinal microvasculature of PDR patients were determined by optical coherence tomographic angiography (OCTA). The mice were injected with streptozocin (STZ) for 20 weeks to induced PDR, then the changes in inflammatory factors, oxidative response and histological analysis were examined with Elisa assay, real time-PCR and commercial kits analysis. Conbercept treatment significantly alleviated the retinal pathological changes and significantly reduced intercellular cell adhesion molecule-1 (ICAM-1), macrophage inflammatory protein-1 (MIP-1), IL-1β, IL-6 and TNF-α protein levels but not prostaglandin E1 (PGE1), prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) levels, all of which were remarkably elevated in aqueous fluid of PDR patients compared with non-PDR subjects. Meanwhile the inhibitory effects of conbercept on these inflammatory factors were proved by RT-PCR assays in mice experiments. And the inflammatory signal such as p-IKBα and p-p65 was correspondingly inhibited by conbercept in STZ-treated mice. Conbercept treatment significantly elevated the aqueous glutathione level of PDR patients and inhibited NOX-1, NOX-4 and ph22phox mRNA expressions and ROS production of PDR mice. Ki67 immunofluorescence staining showed that conbercept inhibited endothelial cell proliferation in retina of PDR mice. In conclusion, conbercept significantly inhibited the angiogenesis, inflammation and oxidative response in PDR mice, and these findings further reveals the molecular mechanisms of conbercept in treating PDR.


Music, drama, and social development in Portuguese children.
Social competence plays a fundamental role in children's development, and in their functioning at school and in life. Social skills, as learned behaviors that allow children to positively interact with others, are important for success in both academic and peer-group settings. Children's participation in collective music and other arts education has been associated with the development of social skills. However, different measures and diverse programs adopted in various studies make it difficult to contrast study findings. Additionally, research with children from low-income families remains scarce. The aim of this study was to examine the role of music and drama education programs in primary schools on the development of social skills of Portuguese children from disadvantaged communities. Both programs were carefully designed with performing, creating, and listening activities, and were delivered by specialist and experienced teachers/performers, who used active and participatory teaching strategies. In our longitudinal design with pre- and post-evaluations, we used the Social Skills Rating System or SSRS-Teacher Form, adapted for the Portuguese population. Classroom teachers rated their students' social skills on a 3-point scale in three domains: Social skills (Cooperation, Assertion, Self-control), Behavioral problems (Externalizing problems, Internalizing problems, Hyperactivity) and, on a 5-point scale, Academic competence. Our findings suggest that participation in music and drama programs during one school year improved children's assertion and self-control, and cooperation in the drama group. Participation in the music and drama programs also appeared to serve as a protective factor by reducing externalizing, internalizing and behavioral problems. These findings are discussed in light of previous studies along with limitations and directions for future research.


Mesenchymal stem cell-induced 3D displacement field of cell-adhesion matrices with differing elasticities.
Cells maintain homeostasis and perform various functions by interacting mechanically with a cell-adhesive matrix. Regarding cellular differentiation, it has been found that matrix elasticity can determine the differentiation lineage of mesenchymal stem cells (MSCs). Direct quantitative measurements of the mechanical interaction between MSCs and matrix for differentiation, however, have yet to be reported. Herein, the displacement field of the cell-adhesive matrix was observed quantitatively using a digital volume correlation (DVC) method. Maximum displacement and cellular traction stress were analyzed when the MSC differentiated into a neuron-like cell or an osteoblast-like cell on a soft or hard elastic matrix, respectively. The function of non-muscle myosin II (NMM II), which plays an important role in intracellular cytoskeletal dynamics, was investigated during cellular differentiation. The mechanical interaction (maximum displacement and subjected area of the matrix) between the cell and matrix was dependent on matrix elasticity. It has also been shown that the mechanical interaction between the intracellular cytoskeleton and cell-adhesion matrix is indispensable for cellular differentiation. This work provides the first quantitative visualization of the mechanical interaction between MSCs and the cell-adhesion matrix for differentiation.


Agaricus bisporus mushroom as partial fat replacer improves the sensory quality maintaining the instrumental characteristics of beef burger.
The effect of Agaricus bisporus (AB) mushroom as a fat replacer in beef burgers was evaluated. Four treatments were compared: control (0% AB, 20% fat) and 3 treatments with partial fat replacement: AB 5% (5% AB, 15% fat); AB 10% (10% AB, 10% fat); AB 15% (AB 15%, 5% fat). Mushroom addition increased moisture content and yield and decreased cooking loss and diameter reduction of the burgers. Formulations with the highest AB concentrations were lighter and redder than the control. AB incorporation affected texture, resulting in less hard and less chewy products. In general, lipid oxidation increased during the storage time, however the lowest values were observed in AB 15%, i.e. the lowest fat content and the presence of AB increased the oxidative stability. AB 10% and AB 15% had good overall liking and were sensorially characterized as juicy, tender and flavorsome burgers. The partial replacement of animal fat by AB is a promising strategy for developing a low-fat burger.


Laparoscopic long sleeve pancreaticogastrostomy (LPG): a novel pancreatic anastomosis following central pancreatectomy.
Central pancreatectomy (CP) is preferred to distal pancreatectomy (DP) for the excision of benign tumours at the neck or body of the pancreas, in order to preserve pancreatic function and the spleen. However, the pancreaticoenterostomy is technically difficult to perform laparoscopically and the postoperative pancreatic fistula (POPF) rate is high. A novel laparoscopic reconstruction of the pancreatic stump during CP is described, the laparoscopic long sleeve pancreaticogastrostomy (LPG). Two males and two females with a median age of 49 years had a laparoscopic CP with LPG. After a median follow-up of 27.5 months, there was no mortality. One patient had a grade A POPF, managed conservatively. The LPG is a safe and technically less demanding method to reconstruct pancreatic drainage laparoscopically.


Paper Sludge Reuse in Lightweight Aggregates Manufacturing.
The lightweight aggregates used by the civil engineering market are sintered at a high temperature, about 1200 °C. In times of high energy prices and regulation of carbon dioxide emissions, lightweight aggregate products of the high-temperature process in sales marketing are not readily accepted. This study developed a sintered-type paper sludge lightweight aggregate. In order to reduce energy consumption, substitution of some reservoir sediment clay in paper sludge substitutes is to be expected. The study used two types of paper sludge (green clay paper sludge and paper pulp sludge). The sintering temperature was reduced effectively as the green clay paper sludge was substituted for some of the reservoir sediment clay, and the optimum substitute ranges of green clay paper sludge were 10%-50%. The optimum substitute ranges of the paper pulp sludge were 10%-40%. Test results show that the properties of aggregates have a particle density of 0.66-1.69 g/cm³, a water absorption of 5%-30%, and a loss on ignition of 10%-43%. The loss on ignition of aggregate became greater with the increase in paper sludge content. This means that the calorific value provided by the paper sludge will increase as paper sludge content increases. Paper sludge can therefore be considered a good material to provide heat energy for sintering lightweight aggregate.


The Long Noncoding RNA IFNG-AS1 Promotes T Helper Type 1 Cells Response in Patients with Hashimoto's Thyroiditis.
The long noncoding (lnc) RNA-Ifng-AS1 plays an essential role in the transcription of the gene encoding IFN-γ by Th1 cells, and its human ortholog, IFNG-AS1, is expressed in human Th1 cells. However, IFNG-AS1 contributing to Th1 cells' response in Hashimoto's thyroiditis (HT) patients has not been reported. Twenty-eight HT patients and 20 healthy controls were enrolled in the study. The proportion of circulating Th1 cells and the level of T-bet, IFNG mRNA were increased in HT patients, the expression of IFNG-AS1 was upregulated and positively correlated with the proportion of circulating Th1 cells or T-bet, and IFNG expression, or serum level of anti-thyroglobulin antibody/thyroperoxidase antibody in HT patients. IFNG-AS1 regulated the expression of IFNG at both transcriptional and translational level in human CD4(+) T cells. Furthermore, strong positive correlations between the increased transcript level of IFNG-AS1 and the increased transcript level of T-bet or IFNG were revealed in thyroid tissues from HT patients. Our results indicate that enhanced expression of lncRNA-IFNG-AS1 contributes to Th1 cell response in HT patients and may be involved in the pathogenesis of HT.


Biased, Spasmodic, and Ridiculously Incomplete: Sequence Stratigraphy and the Emergence of a New Approach to Stratigraphic Complexity in Paleobiology, 1973-1995.
This paper examines the emergence of a new approach to stratigraphic complexity, first in geology and then, following its creative appropriation, in paleobiology. The approach was associated with a set of models that together transformed stratigraphic geology in the decades following 1970. These included the influential models of depositional sequences developed by Peter Vail and others at Exxon. Transposed into paleobiology, they gave researchers new resources for studying the incompleteness of the fossil record and for removing biases imposed by the processes of sedimentary accumulation. In addition, they helped reconfigure the cultural landscape of paleobiology, consolidating a growing emphasis on fieldwork and eroding the barrier that had been erected in the 1970s between "paleontology" and "paleobiology." This paper traces these developments, paying special attention to the simulation models of stratigraphic paleobiologist Steven Holland. It also considers how the integration of sequence and event stratigraphy and paleobiology has begun to influence long-running discussions of incompleteness and bias in the fossil record.


The Aurora kinase inhibitors in cancer research and therapy.
Compounds that affect enzymatic function of kinases are valuable for the understanding of the complex biochemical processes in cells. Aurora kinases (AURKs) play a key role in the control of the mitosis. These kinases are frequently deregulated in different human cancers: overexpression, amplifications, translocations and deletions were reported in many cancer cell lines as well as patient tissues. These findings steered a rigorous hunt for small-molecule AURK inhibitors not only for research purposes as well as for therapeutic uses. In this review, we describe a number of AURK inhibitors and their use in cancer research and/or therapy. We hope to assist researchers and clinicians in deciding which inhibitor is most appropriate for their specific purpose. The review will also provide a broad overview of the clinical studies performed with some of these inhibitors (if such studies have been performed).


Tumor-infiltrating B cell is associated with the control of progression of gastric cancer.
This study aimed to further explore the clinicopathological correlation of B cell infiltration in gastric cancer (GC) and its impact on prognostic. By immunohistochemical method, CD20+ B cells, CD3+ T cells, CD66b+ tumor-associated neutrophils, CD163+ tumor-associated macrophages, and CD57+ natural killer cells were analyzed in consecutive sections of 584 GC tissues and 69 normal adjacent tissues. Kaplan-Meier and Cox regression analyses determined the relationship between clinical relevance or prognosis and B cell infiltration. The correlation between total B cell infiltration and various T cell subtype infiltration in GC tissues from 407 patients in the TCGA data was also analyzed. Kaplan-Meier and Cox regression analyses determined the effects of total B cell infiltration and various B cell subtype infiltration on the prognosis of patients with GC. The infiltration level of CD20+ B cells was positively correlated with that of T cells (risk ratio [RR] = 0.0930), especially CD4+ T cells and CD8+ T cells (P < 0.05). A high level of CD20+ B cell infiltration was significantly associated with low lymph node involvement and low TNM stage (P < 0.05). High levels of CD20+ B cell infiltration were significantly associated with improvements in overall survival and disease-free survival. Univariate Cox regression and multivariate Cox regression analysis showed that CD20+ B cell infiltration was an independent protective factor of prognosis. Higher levels of class-switched memory B cell and plasma cell also reflected better overall survival, and class-switched memory B cell and plasma cell were independent protective factors for prognosis. The findings indicate that B cell infiltration in GC, especially switched memory B cells and plasma cells, has a significant effect on tumor progression and prognosis.


Mutagenicity of pyrene in Salmonella.
Pyrene was tested for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100 and TA1537. Mutagenicity was seen in all strains when S9 was present.


Leukocyte alkaline phosphatase in malignancies.
The leukocyte alklaine phosphatase (LAP) levels were determined in 183 patients with malignant diseases and 71 normal controls. The median LAP scores were 64 units (range 0 to 290) for the patients and 55 (range 2 to 158) for the controls, respectively, and no significant difference could be established. When analyzed according to primary malignancy, only in patients with Hodgkin's disease (n = 14) was the median value higher than normal (p less than 0.001). In patients with distant metastases (n = 48), higher LAP levels were demonstrated (M = 76, range 21 to 290) as compared to patients with no evidence of metastases (M = 53, range 0 to 229), (p less than 0.01). Thus, LAP activity has very limited value in the diagnosis of malignancies. Its elevation in the presence of malignant disease might, however, indicate metastases.


Proteomic analysis of mouse hypothalamus under simulated microgravity.
Exposure to altered microgravity during space travel induces changes in the brain and these are reflected in many of the physical behavior seen in the astronauts. The vulnerability of the brain to microgravity stress has been reviewed and reported. Identifying microgravity-induced changes in the brain proteome may aid in understanding the impact of the microgravity environment on brain function. In our previous study we have reported changes in specific proteins under simulated microgravity in the hippocampus using proteomics approach. In the present study the profiling of the hypothalamus region in the brain was studied as a step towards exploring the effect of microgravity in this region of the brain. Hypothalamus is the critical region in the brain that strictly controls the pituitary gland that in turn is responsible for the secretion of important hormones. Here we report a 2-dimensional gel electrophoretic analysis of the mouse hypothalamus in response to simulated microgravity. Lowered glutathione and differences in abundance expression of seven proteins were detected in the hypothalamus of mice exposed to microgravity. These changes included decreased superoxide dismutase-2 (SOD-2) and increased malate dehydrogenase and peroxiredoxin-6, reflecting reduction of the antioxidant system in the hypothalamus. Taken together the results reported here indicate that oxidative imbalance occurred in the hypothalamus in response to simulated microgravity.


Vernoguinosterol and vernoguinoside, trypanocidal stigmastane derivatives from Vernonia guineensis (Asteraceae).
Two bitter stigmastane derivatives, vernoguinosterol (1) and vernoguinoside (2), have been isolated from the stem bark of Vernonia guineensis and their structures eludicated using spectroscopic methods. The new compounds exhibit trypanocidal activity.


The genes coding for the cytoskeletal proteins actin and vimentin in warm-blooded vertebrates.
Recombinant plasmids were made containing cDNAs synthesized on hamster mRNAs coding for cytoskeletal (beta- or gamma-) actins and for vimentin. Hybridization of the actin probe on restriction digests of one avian and five mammalian DNAs yielded multiple bands; the vimentin probe revealed only one band (accompanied by 2-3 faint bands in some DNAs). The results obtained with the vimentin probe indicate that the corresponding coding sequences: (a) are highly conserved in warm-blooded vertebrates like the actin sequences; (b) have strongly diverged from those coding for other intermediate filament proteins, since hybridization of the vimentin probe does not lead to a diagnostic multiband pattern; and (c) most likely contribute to single gene, in contrast to the sequences coding for other cytoskeletal proteins. Hybridization of the probes on mRNAs from the different sources used showed that the non-coding sequences of both vimentin and actin genes are conserved in length.


What's new and what's next in diffusion MRI preprocessing.
Diffusion MRI (dMRI) provides invaluable information for the study of tissue microstructure and brain connectivity, but suffers from a range of imaging artifacts that greatly challenge the analysis of results and their interpretability if not appropriately accounted for. This review will cover dMRI artifacts and preprocessing steps, some of which have not typically been considered in existing pipelines or reviews, or have only gained attention in recent years: brain/skull extraction, B-matrix incompatibilities w.r.t the imaging data, signal drift, Gibbs ringing, noise distribution bias, denoising, between- and within-volumes motion, eddy currents, outliers, susceptibility distortions, EPI Nyquist ghosts, gradient deviations, B1 bias fields, and spatial normalization. The focus will be on "what's new" since the notable advances prior to and brought by the Human Connectome Project (HCP), as presented in the predecessing issue on "Mapping the Connectome" in 2013. In addition to the development of novel strategies for dMRI preprocessing, exciting progress has been made in the availability of open source tools and reproducible pipelines, databases and simulation tools for the evaluation of preprocessing steps, and automated quality control frameworks, amongst others. Finally, this review will consider practical considerations and our view on "what's next" in dMRI preprocessing.


Computer aided manual validation of mass spectrometry-based proteomic data.
Advances in mass spectrometry-based proteomic technologies have increased the speed of analysis and the depth provided by a single analysis. Computational tools to evaluate the accuracy of peptide identifications from these high-throughput analyses have not kept pace with technological advances; currently the most common quality evaluation methods are based on statistical analysis of the likelihood of false positive identifications in large-scale data sets. While helpful, these calculations do not consider the accuracy of each identification, thus creating a precarious situation for biologists relying on the data to inform experimental design. Manual validation is the gold standard approach to confirm accuracy of database identifications, but is extremely time-intensive. To palliate the increasing time required to manually validate large proteomic datasets, we provide computer aided manual validation software (CAMV) to expedite the process. Relevant spectra are collected, catalogued, and pre-labeled, allowing users to efficiently judge the quality of each identification and summarize applicable quantitative information. CAMV significantly reduces the burden associated with manual validation and will hopefully encourage broader adoption of manual validation in mass spectrometry-based proteomics.


IgE and IgG-immune mechanisms do not mediate occupation-related respiratory or systemic symptoms in hog farmers.
To determine the frequency and possible immunologic etiology of respiratory and other symptoms after hog barn exposure, we studied 41 hog farmers and their family members. Participants completed questionnaires and provided serum samples for measurement of IgE and IgG antibodies to hog-derived antigens, hog feed, and hog barn dust. Symptoms after hog barn exposure were reported by 85% of participants. Elevated IgE antibody levels to hog pelt, hog urine, and hog serum were found in only one individual; however, skin tests with these materials were negative. By radioimmunoassay, elevated IgG antibody levels to hog barn dust and/or hog feed were found in seven individuals; two of these sera contained precipitating antibodies to hog barn dust and hog feed. In no case could the presence of IgE or IgG antibodies be correlated with symptoms. Thus it appears that neither IgE nor IgG humoral immune mechanisms mediate respiratory or other symptoms in hog barn workers.


Depletion of licensing inhibitor geminin causes centrosome overduplication and mitotic defects.
Metazoans limit origin firing to once per cell cycle by oscillations in cyclin-dependent kinases and the replication licensing inhibitor geminin. Geminin inhibits pre-replication complex assembly by preventing Cdt1 from recruiting the minichromosome maintenance proteins to chromatin. Geminin depletion results in genomic over-replication in Drosophila and human cell lines. Here, we show that loss of geminin affects other cell cycle-dependent events in addition to DNA replication. Geminin inactivation causes centrosome overduplication without passage through mitosis in human normal and cancer cells. Centrosomes are microtubule-organizing centres that are duplicated during S phase and have an important role in the fidelity of chromosome transmission by nucleating the mitotic spindle. Consistent with this, geminin-depleted cells show multiple mitotic defects, including multipolar spindles, when driven into mitosis by checkpoint abrogation. These results show that the consequences of geminin loss exceed its immediate role in DNA replication and extend to promoting chromosome mis-segregation in mitosis.


Denosumab in patients with cancer-a surgical strike against the osteoclast.
Elucidation of the molecular pathways underlying bone turnover has revealed potential therapeutic targets, including receptor activator of nuclear factor-κB ligand (RANKL), which is a mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL. This agent has been developed for use in patients with early-stage and advanced-stage cancer, as well as for the treatment of osteoporosis, and can prevent bone loss and reduce fragility fractures in both types of disease. In the bone metastasis setting, several large phase III studies have shown that denosumab is more effective than bisphosphonates, namely zoledronic acid, in reducing skeletal morbidity arising from a wide range of tumors. In addition, a remarkable activity of denosumab has been demonstrated in giant-cell tumors of the bone. Subsequent studies of denosumab have demonstrated that it can delay bone metastasis in patients with castration-resistant prostate cancer; adjuvant studies in patients with breast cancer are in progress. This Review critically explores the emerging role of denosumab in maintaining bone health in the oncology setting, and discusses the factors that are likely to influence the choice between bisphosphonates and denosumab in clinical practice.


A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders.
Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and may be the principal regulator of plasminogen activation in vivo. Abnormal expression of PAI-1 has been reported in various types of human disorders and in animal models for the diseases in relation to thrombosis. For example, plasma PAI-1 activity was elevated in patients with endotoxemia, and a dramatic induction of PAI-1 mRNA was observed in tissues of endotoxin-treated animals, resulting in tissue microthrombosis. It has also been demonstrated that PAI-1 expression levels are increased in the kidneys of mice with glomerulonephritis, in the adipose tissue of obese subjects or mice, and in human atherosclerotic arteries. This PAI-1 induction may be relevant to pathological processes in these diseases because PAI-1 not only regulated fibrin dissolution in vivo but also inhibited degradation of extracellular matrix by reducing plasmin generation. The responsible cells for abnormal expression of PAI-1 have been identified in each tissue under pathological conditions and PAI-1 synthesis appears to be regulated in a tissue-specific manner. These observations suggest that PAI-1 could play an important role in the progression of tissue pathologies in a variety of human diseases by controlling the rate of plasmin formation.


Induced pluripotent stem cells provide mega insights into kidney disease.
Rare mutations in the LRP2 gene encoding for the endocytic receptor megalin cause developmental abnormalities and kidney disease. However, the mechanisms governing the dysfunction of mutant megalin remain unclear. A new study utilizing patient-derived induced pluripotent stem cells is now putting the endolysosomal system into the spotlight, as it is proposed to play a central role in the regulation of megalin in health and disease.


Synthesis, characterization, and cytotoxicity in human erythrocytes of multifunctional, magnetic, and luminescent nanocrystalline rare earth fluorides.
Multifunctional nanoparticles exhibiting red or green luminescence properties and magnetism were synthesized and thoroughly analyzed. The hydrothermal method was used for the synthesis of Eu3+- or Tb3+-doped GdF3-, NaGdF4-, and BaGdF5-based nanocrystalline materials. The X-ray diffraction patterns of the samples confirmed the desired compositions of the materials. Transmission electron microscope images revealed the different morphologies of the products, including the nanocrystal sizes, which varied from 12 nm in the case of BaGdF5-based nanoparticles to larger structures with dimensions exceeding 300 nm. All of the samples presented luminescence under ultraviolet irradiation, as well as when the samples were in the form of water colloids. The highest luminescence was observed for BaGdF5-based materials. The obtained nanoparticles exhibited paramagnetism along with probable evidence of superparamagnetic behavior at low temperatures. The particles' magnetic characteristics were also preserved for samples in the form of a suspension in distilled water. The cytotoxicity studies against the human erythrocytes indicated that the synthesized nanoparticles are non-toxic because they did not cause the red blood cells shape changes nor did they alter their membrane structure and permeabilization.


[Cell cycle phases: determination of G1, S e G2 by fluorometry (author's transl)].
The G1, S and G2 phases of the cell cycle in Allium cepa root tips were determined in Acriflavin--Feulgen--stained material. Pigeon erythrocyte nuclei were employed as standard for DNA dry mass determinations. Micro-interferometric and fluorometric measurements gave the average of 77,1. 10(-12) g for the G1 nuclei from the root tips.


Downregulation of selenium-binding protein 1 is associated with poor prognosis in lung squamous cell carcinoma.
We found that selenium-binding protein 1 (SBP1) was progressively decreased in the human bronchial epithelial carcinogenic processes. Knockdown of SBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly increased the efficiency of B[a]P-induced cell transformation. However, the relationship between SBP1 expression and clinicopathological factors of patients has not been defined completely. The specific role of SBP1 in prognosis of lung squamous cell carcinoma (LSCC) is still unknown. Tissue samples from 82 patients treated by pulmonary lobectomy for LSCC were used. Immunohistochemistry and western blotting were used to detect the expressions of SBP1 protein. The relationships between the expression level of SBP1 and the clinicopathological features of patients were analyzed. Cox proportional hazard regression analysis and Kaplan-Meier method were used to perform survival analysis. Expressions of SBP1 proteins were significantly lower in LSCC tissues than that in the corresponding normal bronchial epithelium (NBE) tissues (P = 0.000). In LSCC, The expression levels of SBP1 had not correlated with patients' age, gender, smoking state, primary tumor stages (T), TNM clinical stages, and distant metastasis (M) (P > 0.05). However, downregulation of SBP1 was significantly associated with higher lymph node metastasis and lower overall survival rate (P < 0.05). Cox regression analysis indicated low expressions of SBP1 can be an independent prognostic factor for poor overall survival in LSCC patients (P = 0.002). Downregulation of SBP1 may play a key role in the tumorigenic process of LSCC. SBP1 may be a novel potential prognostic factor of LSCC.


Attention modulation of neural tuning through peak and base rate in correlated firing.
The present study investigates the influence of attention modulation on neural tuning functions under a Gaussian correlation structure. Recent experiments have shown that attention modulates the tuning curve via its height and base rate. Inspired by this experimental finding, we previously showed the effective size of attention modulation (i.e. the critical length) on the neural population that enhances encoding accuracy. The previous result, however, was obtained under the assumption of uncorrelated firing, i.e. stimulus-conditional independence of neural responses. A question still remains whether the above findings can be applied to correlated firing. It is important to investigate this issue partly because neural firings are usually correlated but even more so because common attentional inputs may cause correlated firings. The present study first provides the general framework of attention modulation in relation to an attended stimulus and an actual stimulus and then shows the existence of a critical length under a Gaussian correlation structure. In order to improve encoding accuracy, measured by the Fisher information, the height and the base rate should be increased when the attended stimulus is in the critical length from the peak of the tuning curve and decreased otherwise. Furthermore, we confirm that a similar nature of the critical length also holds even when the neural decoder uses an uncorrelated unfaithful model. Thus, the existence of the critical length seems to be a ubiquitous phenomenon in attention modulation, and so its implications are discussed.


Mechanics and control of the cytoskeleton in Amoeba proteus.
Many models of the cytoskeletal motility of Amoeba proteus can be formulated in terms of the theory of reactive interpenetrating flow (Dembo and Harlow, 1986). We have devised numerical methodology for testing such models against the phenomenon of steady axisymmetric fountain flow. The simplest workable scheme revealed by such tests (the minimal model) is the main preoccupation of this study. All parameters of the minimal model are determined from available data. Using these parameters the model quantitatively accounts for the self assembly of the cytoskeleton of A. proteus: for the formation and detailed morphology of the endoplasmic channel, the ectoplasmic tube, the uropod, the plasma gel sheet, and the hyaline cap. The model accounts for the kinematics of the cytoskeleton: the detailed velocity field of the forward flow of the endoplasm, the contraction of the ectoplasmic tube, and the inversion of the flow in the fountain zone. The model also gives a satisfactory account of measurements of pressure gradients, measurements of heat dissipation, and measurements of the output of useful work by amoeba. Finally, the model suggests a very promising (but still hypothetical) continuum formulation of the free boundary problem of amoeboid motion. by balancing normal forces on the plasma membrane as closely as possible, the minimal model is able to predict the turgor pressure and surface tension of A. proteus. Several dynamical factors are crucial to the success of the minimal model and are likely to be general features of cytoskeletal mechanics and control in amoeboid cells. These are: a constitutive law for the viscosity of the contractile network that includes an automatic process of gelation as the network density gets large; a very vigorous cycle of network polymerization and depolymerization (in the case of A. proteus, the time constant for this reaction is approximately 12 s); control of network contractility by a diffusible factor (probably calcium ion); and control of the adhesive interaction between the cytoskeleton and the inner surface of the plasma membrane.


Effects of concentrated drinking water injection on glutathione and glutathione-dependent enzymes in liver of Cyprinus carpio L.
Two drinking water production plants located in North Italy, collecting water from the River Po (Plants 1 and 2) were chosen for this study. Water samples were collected before and after the disinfection process and at two points along the piping system. Water samples were concentrated by the solid-phase extraction system and injected intraperitoneally into specimens of Cyprinus carpio. The concentration of water samples was 3 l/equiv. In order to assess the effects of the water samples on carp liver, total glutathione and glutathione-dependent enzymes, such as glutathione S-transferase, glutathione peroxidase, glutathione reductase and glyoxalase I, were measured following this treatment for 6 days at two experimental times (3 and 6 days). Both water plant-treated carp showed a general increase of the enzymatic activities of glutathione S-transferase, and glutathione reductase which might be employed as potential biomarkers of oxidative stress induced by disinfected river water. Plant 1-treated carp showed higher glyoxalase I and glutathione levels and lower glutathione peroxidase activity. A depleted level of total glutathione and of glyoxalase I for specimens of water plant 2 (for both experimental times), without correlation with the distances in the pipeline, suggests that river plant water can also lead to potentially adverse effects on selected biochemical parameters in C. carpio.


The effect of early cognitive behavior therapy for first-episode treatment-naive major depressive disorder.
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders. Cognitive behavioral therapy (CBT) has been widely applied in MDD treatment, yet mechanistic understanding toward CBT remains limited. Twenty-two MDD patients and twenty-seven matched healthy controls were enrolled. Patients with MDD were given structural early CBT treatment once a week for 6 weeks. Cognitive reconstruction, emotional transformation and behavioral training were included in the treatment process. Local and long-range brain functional connectivity densities (FCD) were obtained to identify abnormal connectivity of MDD by using resting-state functional magnetic resonance imaging (RS-fMRI). After CBT treatment, MDD patients showed increased FCD in the bilateral dorsolateral prefrontal cortex (dlPFC). Functional connectivity (FC) was used to further explore the role of dlPFC in CBT. The results revealed that by the completion of CBT treatment course, the FC between the dlPFC and hippocampus was enhanced. Cognitive behavioral therapy played significant role in alleviating depressive symptoms of MDD patients, evidenced by improved brain connectivity between dlPFC and hippocampus. Further study of dlPFC pathophysiology is needed to better understand these abnormalities in patients with depressive symptoms and the effect of early CBT treatment.


Roles of MT-ND1 in Cancer.
The energy shift toward glycolysis is one of the hallmarks of cancer. Complex I is a vital enzyme complex necessary for oxidative phosphorylation. The mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1 (MT-ND1) is the largest subunit coded by mitochondria of complex I. The present study summarizes the structure and biological function of MT-ND1. From databases and literature, the expressions and mutations of MT-ND1 in a variety of cancers have been reviewed. MT-ND1 may be a biomarker for cancer diagnosis and prognosis. It is also a potential target for cancer therapy.


Emerging drugs for hepatitis C.
Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 200 million carriers worldwide. Current treatment consists of the use of peginterferon (pegIFN)/ribavirin (RBV) for 24 or 48 weeks depending on HCV genotype. Serious side effects and the fact that less than half of patients infected with HCV genotypes 1 and 4 (which are the most common) accomplish sustained virological response with this medication warrant the need for novel anti-HCV therapies. Description of specifically targeted antiviral therapies for hepatitis C (STAT-C) designed to inhibit the serine protease and the RNA-dependent HCV-RNA polymerase. Review of available data reported in peer-reviewed journals and medical conferences. Early preclinical studies using these compounds produced encouraging results, but the initial enthusiasm has been hampered by toxicity issues and rapid selection of resistance. Therefore, combination therapy with a backbone of pegIFN/RBV, or perhaps in the future using several of these small molecules, preferably having distinct modes of action and resistance profiles, will be required.


Cytochrome oxidase activity in the nucleus of the tractus solitarius of the cat.
We studied the cytochrome oxidase (CO) activity in the nucleus of the tractus solitarius (NTS) of normal cats and in animals subjected to unilateral removal of vagal and glossopharyngeal afferents. In normal cats CO activity was higher in the ventrolateral, dorsolateral, interstitial and ventral NTS subnuclei. The dorsal, medial, commissural and gelatinosus subdivisions showed lower levels of CO activity. The peripheral deafferentation up to 47 days did not reduce the CO activity, suggesting an important role for the central inputs in determining the neural activity of the NTS.


Bubbles in a freshwater lake.
WHEN the wind is strong enough to produce whitecaps on Loch Ness, patchy 'clouds' of acoustic reflectors are detected well below the surface, the depth to which they penetrate increasing with wind speed (Fig. 1). No seasonal variation in the occurrence of the reflectors has been detected. A biological explanation is therefore discounted and we suggest here that they are bubbles caused by waves breaking and forming whitecaps in deep water. Similar bubble clouds may occur in other lakes and in the sea.


The role of ductal lavage in the management of women at high risk for breast carcinoma.
Ductal lavage (DL) is a recently introduced technique for nonsurgical breast epithelial sampling of asymptomatic high-risk women. It is based on exfoliative cytology of duct epithelial cells, obtained by cannulation and lavage of ducts that produce nipple fluid after breast massage and nipple aspiration. DL provides information similar to that obtained by cytologic examination of nipple aspiration fluid and random periareolar fine needle aspiration. Women who demonstrate cytologic atypia on these tests can be assumed to be at higher risk for breast cancer and may benefit from prophylactic medication. DL promises to provide more reproducible sampling of the same area of the breast, as opposed to methods of random sampling, such as random fine needle aspiration, but the degree of reproducibility remains to be demonstrated. If reproducibility is greater than with random periareolar fine needle aspiration, DL may represent an important advance in the design of phase II chemoprevention trials, particularly because it also provides another source of material for judging response to prevention agents (ie, the protein component of nipple aspiration fluid), which can be analyzed for levels of hormones, specific proteins, and protein profiles obtained with proteomics. Early data do not suggest that DL is an effective screening tool for breast cancer on the basis of cytologic interpretation of DL samples, although this may change if effective molecular markers are validated for cancer detection in women at high risk.


Pain from renal/ureteral calculosis: evaluation of sensory thresholds in the lumbar area.
Patients with unilateral renal/ureteral calculosis who had suffered a few painful attacks were examined. In the pain-free period, muscular, subcutaneous and cutaneous sensory thresholds to electrical stimulation were measured in the lumbar region (metamer L1) on both sides: (1) pain thresholds were lower on the affected side with respect to both the contralateral side and control thresholds recorded in normal subjects; (2) the greatest decrease in threshold was in the muscle (even the sensation of sustained contraction was no longer detectable), followed by subcutaneous tissue, and the smallest decrease was in the skin.


Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance.
Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal studies suggest that they may impact the microbiome and downstream glycemic responses. We causally assessed NNS impacts in humans and their microbiomes in a randomized-controlled trial encompassing 120 healthy adults, administered saccharin, sucralose, aspartame, and stevia sachets for 2 weeks in doses lower than the acceptable daily intake, compared with controls receiving sachet-contained vehicle glucose or no supplement. As groups, each administered NNS distinctly altered stool and oral microbiome and plasma metabolome, whereas saccharin and sucralose significantly impaired glycemic responses. Importantly, gnotobiotic mice conventionalized with microbiomes from multiple top and bottom responders of each of the four NNS-supplemented groups featured glycemic responses largely reflecting those noted in respective human donors, which were preempted by distinct microbial signals, as exemplified by sucralose. Collectively, human NNS consumption may induce person-specific, microbiome-dependent glycemic alterations, necessitating future assessment of clinical implications.


What is the best way to determine bond-valence parameters?
Two recent systematic determinations of bond-valence parameters addressed the problem of the correlation between R0 and b in different ways raising the question of which is to be preferred.


Unconventional role of RAC1 in MET-driven anchorage-independent tumor growth.
We reported that RAC1 is a master regulator of cell migration and anchorage-independent growth, downstream of the oncogenic Receptor Tyrosine Kinase (RTK) MET. RAC1 growth-promoting role is guanosine triphosphatase (GTPase)- and phosphatidylinositol 3-kinase (PI3K)-independent but promotes mammalian target of rapamycin (mTOR) signaling through triggering its plasma membrane localization.


Impact of non-invasive fetal RhD genotyping on management costs of rhesus-D negative patients: results of a French pilot study.
Fetal rhesus D (RhD) status determination using circulating cell-free fetal DNA from maternal plasma or serum is now recognized in Europe as a reliable and useful tool. A few countries are presently using this test in their management policy of rhesus D negative patients. The objective of this study is to evaluate the impact of this test on the costs of managing RhD-negative pregnant women, whether or not they are allo-immunized. A prospective follow-up of rhesus D negative women during their pregnancy was performed in three French obstetric departments. Non-invasive fetal RhD genotyping was performed in the first trimester and pregnancies were followed The costs of all procedures (biological tests and medication) associated with patient management in relation to their RhD-negative status were calculated according to different management options. A comprehensive follow-up, including medical and biological monitoring, was obtained for 99 of the 101 patients included in the study. Patients were separated into two groups: the "Adverse Event" group (AE, n=23) for which a potentially sensitizing event occurred and the "No Adverse Event" group (NAE, n=76). Fetal RhD status was accurately determined in all cases. The mean cost per patient was estimated at 237€ (range: 115-644) with differences observed depending on the group, notably 331€ (range: 236-644) for the AE group and 208€ (range: 115-366) for the NAE group. Various cost simulations were performed according to various policies of allo-immunization antenatal prophylaxis. Variations ranged from +36.2% to +105.3%. This study demonstrates that fetal RhD genotyping early during pregnancy is not an effective cost-reduction strategy whether or not antenatal prophylaxis is given. The economic issues could, however, be overcome by the fact that there is a major clinical benefit to offering the test systematically to all RhD-negative pregnant women while avoiding unnecessary testing and immunoglobulin injections.


Multiple Non-coding ANRIL Transcripts Are Associated with Risk of Coronary Artery Disease: a Promising Circulating Biomarker.
Multiple ANRIL transcriptional isoforms, such as lncANRIL and circANRIL have been identified. We sought to explore their diagnostic value in patients with coronary artery disease (CAD). First, we selected six target ANRIL isoforms and measured their expression in CAD patients and controls in the peripheral blood. Their diagnostic values were evaluated. circANRIL(exon14-4) was identified as the best potential biomarker. Afterwards, we validated its diagnostic value and evaluated its prognostic value in a larger clinical cohort. Among six tested ANRILs, lncANRIL(exon1) and lncANRIL(exon4-6) in the CAD patients were significantly increased, while circANRIL(exon14-4) was downregulated. circANRIL(exon14-4) had the highest diagnostic value among the three isoforms. The combination of circANRIL(exon14-4) and other factors resulted in a more accurate differentiation of CAD patients. Moreover, lower expression of circANRIL(exon14-4) was associated with higher incidence of MACE. circANRIL(exon14-4) is closely associated with CAD risk and severity, which provides a promising circulating biomarker for CAD diagnosis and prognosis.


Effectiveness of intra-operative topical amiodarone for prevention of postcardiac surgery new-onset atrial fibrillation: A review of current evidence.
Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery and is associated with increased morbidity. Intraoperative topical amiodarone application on epicardial tissue has been shown to reduce systemic concentrations while maintaining therapeutic myocardial concentrations, thereby, lowering the risk of extracardiac adverse effects associated with oral and intravenous amiodarone therapy. However, the efficacy and safety of topical amiodarone in preventing POAF is unclear. This study summarizes the clinical studies to-date that have investigated the efficacy and safety of topical amiodarone administration in preventing POAF following cardiac surgery. A database search was conducted using Medline, Embase, and Cochrane Library to identify relevant studies. Abstracts were screened and data were extracted from relevant full-text articles that met the inclusion and exclusion criteria. The search returned four studies with variable findings on the effect of topical amiodarone therapy on the incidence of POAF, cardiac effects, extracardiac effects, and hospital length of stay. Prophylactic topical application of amiodarone may be effective and safe for preventing post-operative new-onset atrial fibrillation. Further investigation is required to evaluate the efficacy and safety of topical amiodadrone therapy before it can be widely integrated into current practice.


Systematic re-evaluation of SCN5A variants associated with Brugada syndrome.
A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous. We systematically re-evaluated all SCN5A variants reported in BrS using the 2015 American college of medical genetics and genomics and the association for molecular pathology (ACMG-AMP) guidelines. A PubMed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re-analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re-evaluation of frequency in the gnomAD database were performed. Fourteen ACMG-AMP rules were deemed applicable for SCN5A variant analysis. Four hundred and eighty unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. One hundred and fifty-six of 425 (37%) variants were classified as pathogenic/likely pathogenic. Two hundred and fifty-eight (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered "null" variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. In contrast, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly, however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification. Based on contemporary ACMG-AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity.


Alendronate prevents angiotensin II-induced collagen I production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts.
Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, geranylgeraniol- and GGTI-286-treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling.


Release of nucleosides from canine and human hearts as an index of prior ischemia.
During ischemia, myocardial adenosine triphosphate is degraded to adenosine, inosine and hypoxanthine. These nucleosides are released into coronary venous blood and may provide an index of ischemia; adenosine may also participate in the autoregulation of coronary flow. In dogs, the temporal relations between reactive hyperemic flow and nucleoside concentrations in regional venous blood were correlated after brief occlusions of a segmental coronary artery. Reactive hyperemia and adenosine release peaked together in 10 seconds, persisted for 10 to 30 seconds and then decreased in a pattern consistent with the hypothesis that they are related. During initial reflow after 45 seconds of ischemia, mean concentrations of adenosine, inosine and hypoxanthine increased, respectively, to 52, 67 and 114 nmol/100 ml plasma; after 5 minutes of ischemia, the respective levels increased to 58, 1,570 and 1,134 nmol and fell quickly. In nine patients there was a similar release of nucleosides into coronary sinus blood during reperfusion after 59 to 80 minutes of ischemic arrest during cardiac surgery. With initial reflow, adenosine, inosine and hypoxanthine levels reached 65, 655 and 917 nmol/100 ml of blood, respectively. Inosine and hypoxanthine concentrations remained high for 5 to 10 minutes after cardiac beating resumed, often when production of lactate had decreased. The results indicate that postischemic release of nucleosides reaches significant levels in man as well as animals, is parallel with the duration of ischemia, is temporary and may be a useful supplement to measurement of lactate as an index of prior myocardial ischemia.


Interaction of membranous enzymes with membranous lipid substrates. Hydrolysis of diacylglycerol by lipase in rat brain microsomes.
The phospholipids in rat brain microsomes were labeled with tritium by intracerebral administration of radioactive fatty acids and converted to diacylglycerol with phospholipase C. The latter lipid was hydrolyzed in situ at pH 4.8, to monoacylglycerol and fatty acid by the endogenous microsomal lipase. This paper provides an experimental approach to determine whether the lipid was degraded by enzyme molecules residing in its own membrane (intramembrane interaction) or an adjacent membrane (intermembrane interaction). Direct interaction between separate membranes containing enzyme or substrate showed the existence of the inter-membrane route while dilution experiments provided evidence for the presence of the intramembrane interaction as well. A probable difference in the mechanisms of these two interactions is suggested by different shapes of the curves that describe the reaction rate as a function of the endogenous substrate. The curve resulting from the intermembrane interaction was hyperbolic while that representing the intramembrane route was of a parabola-like shape. Competition experiments suggested that when given a choice between the two, the enzyme utilized preferentially the substrate molecules in its own membrane.


Autonomous adaptive data acquisition for scanning hyperspectral imaging.
Non-invasive and label-free spectral microscopy (spectromicroscopy) techniques can provide quantitative biochemical information complementary to genomic sequencing, transcriptomic profiling, and proteomic analyses. However, spectromicroscopy techniques generate high-dimensional data; acquisition of a single spectral image can range from tens of minutes to hours, depending on the desired spatial resolution and the image size. This substantially limits the timescales of observable transient biological processes. To address this challenge and move spectromicroscopy towards efficient real-time spatiochemical imaging, we developed a grid-less autonomous adaptive sampling method. Our method substantially decreases image acquisition time while increasing sampling density in regions of steeper physico-chemical gradients. When implemented with scanning Fourier Transform infrared spectromicroscopy experiments, this grid-less adaptive sampling approach outperformed standard uniform grid sampling in a two-component chemical model system and in a complex biological sample, Caenorhabditis elegans. We quantitatively and qualitatively assess the efficiency of data acquisition using performance metrics and multivariate infrared spectral analysis, respectively.


Pyloricidins, novel anti-helicobacterpylori antibiotics produced by Bacillus sp. I. Taxonomy, fermentation and biological activity.
Novel anti-Helicobacter pylori antibiotics, pyloricidins A, A1, A2, B, C and D, were discovered in the culture broth of two bacilli strains. Pyloricidins selectively inhibited the growth of H. pylori. Pyloricidin B was efficacious in the treatment of gastric infection caused by H. pylori in Mongolian gerbils and may be promising for cure of H. pylori infection as a single agent.


Fundamental principles and mechanisms of the conscious self.
We start by assuming that the self is implemented in the brain as a functional unit, with a definite set of properties. We deduce the fundamental properties of the self from an analysis of neurological disorders and from introspection. We formulate a functionalist concept of the self based on these properties reduced to constraints. We use the formalism of schemas in our functionalist analysis, i.e. a symbolic level description of brain dynamics. We then reformulate the functionalist model at a connectionist level and address the emergent "context shifting" problem. We suggest how the model might be mapped onto the functional neuroanatomy of the brain, and how it could be used to give an account of a range of neurological disorders, including hippocampal amnesia, various forms of schizophrenia, multiple personality, autism, PTSD, hemineglect, and reversible anosognosia. Finally, we briefly discuss future perspectives and possible applications of computer implementations of the model.


Comparison of photon with electron boost in treatment of early stage breast cancer.
In the treatment of early stage breast cancer breast conserving surgery (BCS) followed by whole breast irradiation (WBI) is a standard method. The impact of the tumor bed boost following WBI is well-defined, but there are various delivery methods. In this study the electron and the photon boost techniques were compared. For 78 early stage breast cancer patients both CT based 3D conformal photon boost and electron boost plans were created. For dosimetric comparison coverage index (CI), external volume index (EI) and conformality index (COIN) were studied. Lung volume receiving a dose of 2 Gy was also reviewed. Seventy-eight patients with 156 plans were compared. The mean tumor bed volume was measured as 61.39 cm3 the mean tumor bed-skin distance was 3.13 cm. In the case of CI and COIN significant differences were found in favor of the photon boost. In the comparison of EI no significant difference was detected between the two techniques. The mean lung volume receiving 2 Gy were 42.3 and 168.35 cm3, for photons and electrons respectively. In the adjuvant treatment of early stage breast cancer WBI followed by conformal photon boost showed to be superior to electron boost in focus of the COIN and CI.


Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis.
Accumulating research evidence suggests that individual dietary factors and dietary patterns might be implicated in the risk of development of rheumatoid arthritis (RA). This narrative review aims to present this evidence and provide nutritional recommendations for reducing RA risk in susceptible individuals. Overall, a 'Western' type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in refined carbohydrates and sugar and low in fiber and antioxidants might increase the risk of RA both directly through increasing inflammation and indirectly through increasing insulin resistance and obesity, with the latter being a known risk factor for RA. On the contrary, consumption of long-chain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of RA probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extra-virgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. Based on current research evidence, it is suggested that adherence to the MD enhanced with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Further research on RA susceptibility will allow for more specific dietary recommendations to be made.


Driving simulation can improve insight into impaired driving skills in cirrhosis.
Minimal hepatic encephalopathy (MHE) is associated with poor driving skills and insight. Increasing insight may improve receptiveness for therapy or driving restrictions. To evaluate the change in the self-assessment of driving skills (SADS) using a driving simulator. Cirrhotic patients and age/education-matched controls underwent MHE testing with inhibitory control (ICT) and the psychometric hepatic encephalopathy score (PHES). SADS, a Likert scale from 0 to 10, was administered just before and after a standardized driving simulation comprising testing and navigation tasks. The percentage SADS change from baseline was compared within/between groups. A total of 84 patients (60% men, age 55 years) and 12 controls were included. Controls were significantly better than cirrhotics on cognitive/simulator testing. The baseline SADS was similar between the groups. The baseline patient SADS was only correlated with ICT lures (r = -0.4, P = 0.001). Post-simulation, 60% of patients improved their insight, i.e., reduced SADS (from 8 to 6.5, P = 0.0001) compared to 25% of controls (P = 0.02). The mean percentage SADS reduction was also higher in cirrhotics (18% vs. 8%, P = 0.03). MHE on ICT patients had a significantly higher SADS improvement (P = 0.004) compared to the other patients; no difference was seen in those with/without MHE due to the PHES. The percentage SADS reduction in patients was correlated with getting lost (r = 0.468, P < 0.0001), crashes (P = 0.002), and centerline/road-edge excursions (P = 0.01). There was a significantly higher percentage SADS reduction in cirrhotics who got lost (25%) compared to those who did not get lost (12%) and controls (8%, P = 0.014). Insight into driving skills in cirrhosis improves after driving simulation and is highest in those with navigation errors and MHE on ICT. Driving simulator-associated insight improvement may be the first step towards the cognitive rehabilitation of driving skills in cirrhosis.


Development of a β-glucosidase hyperproducing mutant by combined chemical and UV mutagenesis.
The extracellular β-glucosidase from microorganisms is generally produced in low levels. Therefore, in this study, a β-glucosidase hyperproducing mutant was developed by multiple exposures of ethyl methyl sulfonate (EMS) and ultraviolet (UV) radiation (both individually and jointly) to Bacillus subtilis strain (PS). The developed mutants were screened, selected and characterized. The mutant, PS-UM1 developed after UV exposure alone, indicated a small increase in β-glucosidase production (718 U/l) in comparison to the wild-type strain, PS (675 U/l). The mutant, PS-CM5 developed after EMS exposure alone, displayed a slightly better production (762 U/l) than both the above strains. However, after exposure of the wild-type strain to both UV and EMS mutagens jointly, a better mutant (PS-CM5-UM3) was developed with 1.2-fold increase in production (806 U/l). Further, optimization of culture conditions by classical "one-variable-at-a-time" approach was done to determine the optimum, pH, temperature and nitrogen sources. The selected mutant (PS-CM5-UM3) produced up to 1,797 U/l enzyme and was found to be stable for ten generations. The β-glucosidase from the selected mutant (PS-CM5-UM3) was concentrated and purified using ammonium sulfate, dialysis and size-exclusion chromatography. The enzyme displayed maximal activity at 60 °C and it was found to be fairly stable at temperatures up to 70 °C for 30 min. Its molecular weight was determined to be around 60 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).


Conjugation of 1-naphthol and transport of 1-naphthol-conjugates in the vascularly perfused small intestine of the mouse.
A method is described which allows the simultaneous vascular and luminal perfusion of the murine small intestine. This preparation was used for the investigation of 1-naphthol conjugation in the gut and the sidedness of conjugate release. The viability of this preparation can be maintained for more than 1 hr as indicated by morphological controls, measurement of tissue metabolism and the transport of 3-O-methyl-glucose against a concentration gradient. When 100 microM 1-naphthol was administered on the luminal side, it was conjugated at a constant rate, yielding 1-naphthyl-glucuronide and 1-naphthyl-sulfate in a molar ratio of 1:2. Both metabolites were excreted into the blood at the contraluminal side of the epithelium. The results are discussed with respect to the sidedness of intestinal transport systems for anionic conjugates of xenobiotics and drugs.


Lipid nanoparticles-encapsulated brain-derived neurotrophic factor mRNA delivered through the round window niche in the cochleae of guinea pigs.
The treatment of sensorineural hearing loss (SNHL) may be achieved via the application of a cochlear implant (CI) that allows the electrical stimulation of spiral ganglion neurons (SGNs). Nevertheless, the efficacy of CIs is limited by the degeneration of SGNs following SNHL. Although the application of exogenous neurotrophic factors has been reported to decrease SGN degeneration, non-invasive targeted drug delivery systems are required to achieve effective results. In this study, an SS-cleavable proton-activated lipid-like material [ssPalm; a neutral lipid nanoparticle (LNP)], was loaded with mRNA, and the efficacy of this material as a delivery system was investigated. Our results showed that LNPssPalm carrying brain-derived neurotrophic factor (BDNF) mRNA was suitable for the treatment of inner ear diseases, preventing the degeneration of SGNs. In conclusion, this modern nanotechnology-based bioconjugation system, LNPssPalm, is a potential non-invasive targeted therapy allowing the delivering biomaterials to specific structures within the inner ear for the treatment of SHNL.


Prenatal exposure to perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) and maternally reported developmental milestones in infancy.
Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are fluorinated organic compounds present in the general population at low concentrations. Animal studies have shown that they may affect neuromuscular development at high concentrations. We investigated the association between plasma levels of PFOS and PFOA in pregnant women and motor and mental developmental milestones of their children. We randomly selected 1,400 pairs of pregnant women and their children from the Danish National Birth Cohort. PFOS and PFOA were measured in maternal blood samples taken in early pregnancy. Apgar score was abstracted from the National Hospital Discharge Register in Denmark. Developmental milestones were reported by mothers using highly structured questionnaires when the children were around 6 months and 18 months of age. Mothers who had higher levels of PFOA and PFOS gave birth to children who had similar Apgar scores and reached virtually all of the development milestones at the same time as children born to mothers with lower exposure levels. Children who were born to mothers with higher PFOS levels were slightly more likely to start sitting without support at a later age. We found no convincing associations between developmental milestones in early childhood and levels of PFOA or PFOS as measured in maternal plasma early in pregnancy.


The Cardiac Sodium Channel and Its Protein Partners.
Activation of the electrical signal and its transmission as a depolarizing wave in the whole heart requires highly organized myocyte architecture and cell-cell contacts. In addition, complex trafficking and anchoring intracellular machineries regulate the proper surface expression of channels and their targeting to distinct membrane domains. An increasing list of proteins, lipids, and second messengers can contribute to the normal targeting of ion channels in cardiac myocytes. However, their precise roles in the electrophysiology of the heart are far from been extensively understood. Nowadays, much effort in the field focuses on understanding the mechanisms that regulate ion channel targeting to sarcolemma microdomains and their organization into macromolecular complexes. The purpose of the present section is to provide an overview of the characterized partners of the main cardiac sodium channel, NaV1.5, involved in regulating the functional expression of this channel both in terms of trafficking and targeting into microdomains.


Cross-cultural adaptation and psychometric properties of the Chinese version of the Communication Skills Attitude Scale among medical students in Liaoning province, China: a cross-sectional study.
The aims of this study were to develop the Chinese version of the Communication Skills Attitude Scale (CSAS-Ch) in order to test the psychometric properties of the modified instrument. A cross-sectional study was conducted in September 2016 to evaluate the attitudes of Chinese medical students towards communication skills learning using CSAS at China Medical University. The study recruited 510 fifth-year medical students by cluster sampling. Cronbach's α coefficients were calculated for the entire questionnaire and for the subscales to evaluate the internal consistency of the CSAS-Ch. In order to determine the structure underlying the CSAS, the scale was factor analysed using maximum likelihood extraction and the oblique rotation method. Of the 510 medical students, 492 (96.5%) completed the questionnaire. Cronbach's α coefficient for the CSAS scale was 0.897. Exploratory factor analysis showed that the four-factor structure accounted for 59.8% of the variance and produced an acceptable fit to the data. The modified CSAS-Ch can be used to evaluate attitudes towards communication skills. Further Future research for improving the teaching methods for communication skills should explore the relationship between medical students' attitudes and the demographic characteristics.


Resuscitation from experimental traumatic brain injury by magnolol therapy.
The purpose of the present study was to determine whether magnolol, a free radical scavenger, mitigates the deleterious effects of traumatic brain injury (TBI). Traumatic brain injuries were induced in anesthetized male Sprague-Dawley rats using fluid percussion, and the rats were divided into groups treated with magnolol (2 mg/kg, intravenously) or vehicle. A group of rats that did not undergo TBI induction was also studied as controls. Biomarkers of TBI, including glycerol and 2,3-dihydroxybenzoic acid, were evaluated by microdialysis. Infraction volume, extent of neuronal apoptosis, and antiapoptosis factor transforming growth factor β1 (TGF-β1) were also measured. Functional outcomes were assessed by motor assays. Compared with the rats without TBI, the animals with TBI exhibited higher hippocampal glycerol and 2,3-dihydroxybenzoic acid. Relative to the vehicle-treated group, the magnolol-treated group showed decreased hippocampal levels of glycerol and hydroxyl radical levels. The magnolol-treated rats also exhibited decreased cerebral infarction volume and neuronal apoptosis and increased antiapoptosis-associated factor TGF-β1 expression. These effects were translated into improved motor function post TBI. Our results suggest that intravenous magnolol injection mitigates the deleterious effects of TBI in rats based on its potent free radical scavenging capability, and the mechanism of anti-neuronal apoptosis is partly due to an increase in TGF-β1 expression in the ischemic cortex.


A bioassay for methylated galacturonan on pulp-fiber surfaces.
A colorimetric bioassay has been developed enabling separation of wood pulp qualities based on the quantity of methyl-esterified galacturonan exposed on fiber surfaces. Thermomechanical pulp (TMP) and chemi-TMP (CTMP) had, respectively, 3.1 and 0.7 microg galacturonan on the surface per mg wood pulp. The presence of galacturonan on the surface of TMP and CTMP was further confirmed by immunogold localization.


Effect of pterygium surgery on corneal topography.
To evaluate the effect of successful pterygium surgery on corneal topography. Computerized corneal topography was performed on 20 eyes with pterygium before and 3 months after successful excision and limbo-conjunctival autograft surgery. Corneal shape, corneal spherical power, simulated keratometric astigmatism, surface regularity index (SRI), and surface asymmetry index (SAI) were assessed before and after surgery. Pre- and postoperative uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), and manifest refraction spherical equivalent (MRSE) were also evaluated. Changes in corneal shape were mainly a decrease in midline corneal flattening. Corneal spherical power was 41.65+/-3.29 diopters (D) (mean +/- SD) preoperatively and 44.58+/-1.55 D postoperatively (p=0.04). Simulated keratometric astigmatism was 5.47+/-3.45 D preoperatively and 1.79+/-1.52 D postoperatively (p=0.0005). SRI was 1.39+/-0.93 preoperatively and 1.10+/-0.57 postoperatively (p=0.03). SAI was 1.17+/-1.09 preoperatively and 0.75+/-0.73 postoperatively (p=0.02). UCVA was 0.31+/-0.33 preoperatively and 0.52+/-0.32 postoperatively (p=0.04). BSCVA was 0.73+/-0.20 preoperatively and 0.89+/-0.16 postoperatively (p=0.008). MRSE was -0.54+/-3.29 D preoperatively and -1.30+/-3.05 D postoperatively (p=0.45). Corneal topographic changes caused by the pterygium are almost reversible after surgical treatment. Successful pterygium surgery significantly reduces topographic astigmatism, SRI, SAI, and corneal flattening. However, precise prediction of these refractive changes is not always accurate.


A manometric assessment of anorectal pressures and its significance in the diagnosis of Hirschsprung's disease and idiopathic megacolon.
Anorectal manometric studies were performed on nine patients with Hirschsprung's disease and ten patients with idiopathic megacolon for the purpose of differentiation, comparing with those of the normal subjects. The anorectal reflex was absent in all nine of the patients with Hirschsprung's disease while in all of ten patients with idiopathic megacolon rectal distension produced a relaxation in the anal canal like that of the normal subjects. Manometric studies proved to be a reliable and non-invasive technique for the diagnosis of Hirschsprung's disease and were of particular value as simple screening tests in patients with a clinical suggestion of this disease. The manometric studies of the patients with Hirschsprung's disease or idiopathic megacolon in the present series also demonstrated that the pronounced internal sphincter contraction combined with a total absence of reflex relaxation or an inadequate response of the sphincter to rectal distension might be responsible for the obstructive symptoms in these diseases.


CFTR and lysozyme secretion in human airway epithelial cells.
Lysozyme is secreted in large quantities in human airways (10-20 mg/day), where it helps to defend against bacterial and fungal infection. Lysozyme expression is restricted to the serous cells of the submucosal glands, which also express high levels of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels. It is often assumed that mucus secretion in human airways is coupled to anion secretion through CFTR Cl(-) channels located in the apical membrane. Therefore, a defect in CFTR function could cause abnormal mucus secretion leading to persistent bacterial infection and inflammation of the airways. In this study we measured simultaneous secretion of lysozyme and Cl(-) from human airway epithelial serous cells. Secretion of lysozyme was measured by a turbidimetric assay that relies on the ability of lysozyme to disrupt the wall of the bacterium Micrococcus lysodeikticus, thus causing a fall in the optical density of the sample. Secretion of Cl(-) was measured as short-circuit current in a modified Ussing chamber. Activation of Cl(-) secretion by stimulation of cAMP- or Ca(2+)-dependent pathways caused comparable increases in lysozyme secretion. Similarly, blockers of Cl(-) secretion, such as diphenylamine-2-carboxylate (DPC), also reduced lysozyme secretion. However, while treatment of airway submucosal gland cells with antisense oligonucleotides directed against CFTR reduced Cl(-) secretion, it had no significant effect on the total amount of lysozyme secretion. These results suggest a role for functional CFTR in regulation of lysozyme secretion in human airways.


Central antinociceptive effect of a hydroalcoholic extract of Dioclea grandiflora seeds in rodents.
The acute treatment of rats and mice with a hydroalcoholic extract from the seeds of Dioclea grandiflora (EHDg) at doses of 250 and 500 mg/kg, by intraperitoneal or oral administration, produced a significant antinociceptive effect in the tail flick and hot plate tests, an effect which was inhibited by naloxone. EHDg given to mice daily for 30 days at a dose of 500 mg/kg, did not cause any observable toxic effect nor any alteration in the pattern of antinociceptive response by the tail immersion test during the course of this treatment. These results suggest that EHDg has a central antinociceptive action devoid of tolerance effect typical of opioid drugs.


Structure and dynamics of an archetypal DNA nanoarchitecture revealed via cryo-EM and molecular dynamics simulations.
DNA can be folded into rationally designed, unique, and functional materials. To fully realise the potential of these DNA materials, a fundamental understanding of their structure and dynamics is necessary, both in simple solvents as well as more complex and diverse anisotropic environments. Here we analyse an archetypal six-duplex DNA nanoarchitecture with single-particle cryo-electron microscopy and molecular dynamics simulations in solvents of tunable ionic strength and within the anisotropic environment of biological membranes. Outside lipid bilayers, the six-duplex bundle lacks the designed symmetrical barrel-type architecture. Rather, duplexes are arranged in non-hexagonal fashion and are disorted to form a wider, less elongated structure. Insertion into lipid membranes, however, restores the anticipated barrel shape due to lateral duplex compression by the bilayer. The salt concentration has a drastic impact on the stability of the inserted barrel-shaped DNA nanopore given the tunable electrostatic repulsion between the negatively charged duplexes. By synergistically combining experiments and simulations, we increase fundamental understanding into the environment-dependent structural dynamics of a widely used nanoarchitecture. This insight will pave the way for future engineering and biosensing applications.


Lack of effectiveness of calcium chloride in refractory asystole.
The effectiveness of calcium chloride in asystole has been challenged; retrospective studies have not supported its use. We conducted a prospective, randomized, blinded study comparing the effectiveness of calcium chloride with saline in the prehospital paramedic setting. Seventy-three patients who had received epinephrine, bicarbonate, and atropine and were in refractory asystole were included in the study, which was conducted from October 1982 to October 1983. Traumatic and pediatric arrests were excluded. The successful resuscitation rate was three of 39 in the calcium group versus one of 34 in the saline group (P less than .37). A successful resuscitation was defined as the conveyance of a patient with a pulse and a rhythm to an emergency department. Groups were analyzed for sex, age, and witnessed arrests. There was no statistically significant difference between the groups. No patient who was resuscitated successfully in the field was discharged from the hospital alive. We conclude that calcium chloride is not of value in resuscitating patients from refractory asystole in the prehospital cardiac arrest setting.


Limited neocortical devascularizing lesions causing deficits in memory retention and choline acetyltransferase activity--effects of the monosialoganglioside GM1.
In mature rats with unilateral cortical lesions, choline acetyltransferase activity was found to decrease by 40% in the ipsilateral nucleus basalis magnocellularis, compared with control animals. Intraventricular administration of the monosialoganglioside GM1 (5 mg/kg per day), via minipumps, over a period of 14 days prevented this fall in choline acetyltransferase activity. The activity of this enzyme in the sham operated subjects was not significantly different from that in the unoperated group. This biochemical data is in full agreement with regards to the protective action of monosialoganglioside GM1 on forebrain cholinergic neurons. In this study the behavioral effects of these cortical lesions were investigated for the first time. Results show that these lesions, with their associated retrograde neuronal degenerative effects, altered a variety of sensorimotor and memory-based behaviors. In particular, the limited unilateral devascularization of the neocortex increased baseline locomotor activity above control; affected motor coordination; impaired passive avoidance retention and reacquisition; and decreased the retention of learnt Morris water-maze information. Infusion of the monosialoganglioside into the ventricles, whilst having no effect on the increased motor activity or motor coordination deficit, did enhance the reacquisition of information in both memory-related tasks.


Effect of exposure to diesel exhaust on pulmonary prostaglandin dehydrogenase (PGDH) activity.
There has been evidence that an acute exposure of laboratory animals to nitrogen dioxide (NO2) for a short period of time can cause marked inhibition of pulmonary PGDH activity. Since diesel exhaust contains NO2, this investigation was undertaken to determine the effect of long-term exposure of guinea pigs and rats to diesel exhaust. The study involves measurement of PGDH activity in the lung tissue as obtained from these animals following exposure to 250 and 1500 micrograms m-3 of diesel particles for various time periods in relation to the appropriate time-matched controls. In guinea pigs, exposure for 6 weeks to 250 micrograms m-3 of diesel exhaust seems to stimulate the PGDH activity about two-fold in comparison to the time-matched controls while, paradoxically, the exposure to 1500 micrograms m-3 of diesel exhaust did not show any particular effect. The exposures to diesel exhaust for 12 weeks, as well as 24 weeks, seem to show concentration dependent lowering of PGDH activity as compared to the time-matched controls. This study also documents the well-known species difference in PGDH activity in that the rat shows much lower activity of this enzyme than the guinea pig. Because of undetectable enzyme activity in many samples, it has not been possible to draw any meaningful conclusion as to the effect of diesel exposure on the enzyme in rat.


Reimagining the future of natural history museums with compassionate collection.
Compassionate collection involves minimizing harm while collecting museum data in the field. By adopting this practice, natural history museums could better maintain existing collections, accommodate more nonlethal specimens and data, and foster an inclusive community.


On the metabolic relationships between monogalactosyldiacylglycerol and digalactosyldiacylglycerol molecular species in Dunaliella salina.
Dunaliella salina cells were pulse-labeled for 2 min with [14C]palmitic acid, [14C]oleic acid, or [14C]lauric acid in order to trace the pathway of galactolipid biosynthesis and desaturation. Through the use of high performance liquid chromatography it was possible to follow the movement of radioactivity through many individual molecular species of monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) for periods of 24 h and, in some cases, as much as 120 h. Analysis of the fatty acid fluxes permitted us to refine current views regarding biosynthesis of the predominantly "prokaryotic" galactolipids. The initial D. salina MGDG molecular species, containing paired oleate and palmitate (18:1/16:0), can follow two metabolic routes. If the palmitoyl chain is desaturated to 16:1, the resulting 18:1/16:1 MGDG is subject to rapid further desaturation to varying degrees, and a part of these products is subsequently galactosylated to DGDG. Contrary to widely held opinions, these DGDG molecular species can themselves be further desaturated toward a 18:3/16:4 final product. In a separate series of reactions, a smaller portion of the nascent 18:1/16:0 MGDG is directly galactosylated to 18:1/16:0 DGDG. This molecular species can then be sequentially desaturated to 18:2/16:0 DGDG and 18:3/16:0 DGDG. However, there is only very limited desaturation of the palmitoyl group attached to these molecular species.