Receptor independent and receptor dependent CoMSA modeling with IVE-PLS: application to CBG benchmark steroids and reductase activators.
Comparative molecular surface analysis (CoMSA) with robust IVE-PLS variable elimination if tested for the benchmark CBG steroid series provides highly predictive RI 3D QSAR models, but failed however to model the activity of sulforaphane (SP) activators of quinone reductase. The application of the SP poses obtained from multipose molecular docking to model the RD IVE-PLS CoMSA resulted in a predictive form. This model indicated lipophilic potential as the activity determinant. The individual molecular surface areas of the highest contribution to the SP activity was identified and visualized by CoMSA contour plots.


Oestrogen receptors, clinical features and prognosis in stage III breast cancer.
One hundred and twenty-four patients with stage III breast cancer who had oestrogen receptor analyses (ER) performed on primary tumour were studied. For operable disease (T3a, N0.1, M0), patients with ER-negative (ER less than 5 fmol/mg cytosol protein) tumours had a shorter duration of symptoms, but no other differences were observed at presentation. In patients with inoperable (T3b,4, N0.1, M0 or any T, N2.3, M0) tumours there were no differences in the clinical characteristics that rendered the primary tumour inoperable between those with ER+ or ER- tumours. The median disease-free interval (DFI) in patients with operable tumours and uninvolved axillary nodes was significantly longer in those with ER+ tumours (P less than 0.05). Median survival was significantly longer in patients with ER+ tumours than in those with ER- tumours (50 vs 27.5 months, P less than 0.05), and when survival was analysed according to various methods of initial treatment, it was significantly prolonged in patients with operable (T3a, N0.1, M0) ER+ tumours compared to those with operable ER- tumours. In patients with inoperable tumours no effect of ER status on prognosis was demonstrated. These results suggest that oestrogen receptor content may be a prognostic variable in patients with operable stage III breast cancer, but further studies of patients with similar methods of initial treatment are needed to confirm this. Patients with operable stage III tumours should be considered separately from those with locally advanced inoperable tumours in view of the significant differences in their survival prospects.


The competition of ecological resonances in the quantum metabolic model of cancer: Potential energetic interventions.
Cancer (a) represents an atavistic reversion to attempted asexual reproduction; (b) metastasizes to absorber "soil" tissues based upon temporal, ontogenetic commonalities; (c) cycles/precesses with competitive immunological surveillance and self-competition within the ecological environment of the body; and (d) is potentially manageable via quantum information qubit phase transitions and universal principles of thermodynamic hysteresis and resonant driving forces . We use retro-recognition of evidence-based cancer anomalies to make these arguments, which in sum position cancer as an ecological quantum information problem. The findings reposition the quantum metabolic model of cancer and presents a research approach aimed at applied treatments: Tertiary Lymphoid Structure ecological competition with cellular transmembrane quantum energy boosting using VDAC and other voltage gated ion channels.


Observations on the chemical structure and cytotoxic activity of marycin, a hematoporphyrin derivative.
This paper describes the preparation, chemical structure and cytotoxic activity of marycin, a hematoporphyrin derivative. Marycin has been prepared by condensing hematoporphyrin dimethyl ester in the presence of p-toluenesulfonic acid and reducing the product with lithium aluminum hydride. The product appeared to be pure by thin-layer chromatography (TLC) and high-performance liquid chormatography (HPLC). The product, analyzed by UV-visible absorbance and fluorescence spectra, appears to be related to the parent hematoporphyrin compound. The product was also analyzed by NMR and Mass spectra: a dimeric structure can be assigned to marycin: this appears to have an oxide bridge between C2-chains of two porphyrin units and hydroxyl groups instead of carboxyls. Marycin was screened for cytotoxic activity against ZR-75, MCF-7, HT-29, K-562, human tumor cell lines and the MRC-9 human embryonic cell line. Marycin decreases the growth index, measured in the radiometric assay, as 14CO2 production. The cytotoxic activity was dose-dependent and is attributable to the pure compound, marycin. Marycin is active at low doses but the activity varies with the cell line studied. The compound had low toxicity versus MRC-9 normal cell line. The compound is active without light activation. How marycin acts is a matter of speculation. Marycin is highly liposoluble and would be expected to have high toxicity for tumors.


European Court of Human Rights Rulings in Home Birth Set to Cause Trouble for the Future: A Review of Two Cases.
The safety of home birth is widely debated. The European Court of Human Rights (ECtHR) recently made two conflicting rulings on home birth, Ternovszky v Hungary and Dubská and Krejzová v the Czech Republic. In Ternovszky v Hungary, the ECtHR essentially forced Hungary to change existing legislation to allow home birth. In contrast, in Dubská and Krejzová v the Czech Republic, the Court found Czech Republic's stringent regulations against home birth acceptable. We describe these cases, the different evidence used and interpreted by the court and examine the ethical conflict between maternal autonomy and the rights of the newborn.


The lipid/protein interface as a target site for general anesthetics: a multiple-site kinetic analysis of synaptosomal Ca2+-ATPase.
There is a long-standing controversy on whether membrane lipids or proteins are the target for general anesthetics. The plasma membrane-associated Ca2+-ATPase of synaptosomes has recently been established as a model system for general anesthesia, the protein interior being the proposed target site (M.M. Lopez, D. Kosk-Kosicka, J. Biol. Chem. 270 (1995) 28239-28245). Multiple-site kinetics is now applied as a mechanistic tool to analyze inhibition by organic solvents and general anesthetics. A close fit to the experimental data points was achieved using the complex equations for a competitive displacement of lipid activators from multiple sites on the protein surface. Inhibitor dissociation constants were about 1. 6x105-fold higher than the microscopic lipid dissociation binding constants that are derived here for the first time. Binding of lipid therefore is by -7.1 kcal/mole favored over that of the tested inhibitors. The latter are nevertheless effective because in the model used displacement of only few of the lipid solvation molecules cause complete inhibition. The lipid/protein interface rather than protein or lipid alone appeared to be the anesthetic target site.


Morphological, physiological and biochemical aspects of salt tolerance of halophyte Petrosimonia triandra grown in natural habitat.
Salt tolerance mechanisms of halophyte Petrosimonia triandra, growing in its natural habitat in Cluj County, Romania, were investigated via biomass, growth parameters, water status, ion content, photosynthetic and antioxidative system efficiency, proline accumulation and lipid degradation. Two sampling sites with different soil electrical conductivities were selected: site 1: 3.14 dS m-1 and site 2: 4.45 dS m-1. Higher salinity proved to have a positive effect on growth. The relative water content did not decline severely, Na+ and K+ content of the roots, stem and leaves was more, and the functions of the photosynthetic apparatus and photosynthetic pigment contents were not altered. The efficiency of the antioxidative defence system was found to be assured by coordination of several reactive oxygen species scavengers. The presence of higher salinity led to accumulation of the osmolyte proline, while degradation of membrane lipids was reduced. As a whole, P. triandra evolved different adaptational strategies to counteract soil salinity, including morphological and physiological adaptations, preservation of photosynthetic activity, development of an efficient antioxidative system and accumulation of the osmotic compound, proline.


The effect of modified Pilates-based positions on pelvic floor electromyographic (EMG) activity; a pilot study.
The evidence regarding the effect of exercise, specifically Modified Pilates (MP), on pelvic floor muscles (PFMs) is limited. We report our pilot study using the MAPLe® device to assess the effect of MP type exercises on PFM electomyographic (EMG) activity and whether PFM contraction could be performed during specific MP exercises. The MAPLe® device was used to measure EMG activity of PFMs in healthy volunteers in different MP positions. Positions were divided into 'neutral', 'core' and 'plank' and EMG readings were taken at rest, during Valsalva and during active contraction. Twenty volunteers were recruited. The median age was 35 (IQR 27-39.5) years. Higher EMG readings were seen in 'core' and 'plank' positions at rest. No position inhibited a conscious contraction and positions which engaged core muscles provoked an augmented contraction. This is the first study to show that when MP positions are held for short periods of time, in asymptomatic women, the changes in PFM EMG are higher. This suggests that a stronger muscle contraction can be achieved when the core is co-contracted. Higher EMG readings were seen during 'core' and 'plank' positions; despite this, further activation with a conscious PFM contraction was still achievable.


Cucurbit[7]uril promoted Fenton oxidation by modulating the redox property of catalysts.
The redox property of a ferrocene derivative, the catalyst of Fenton oxidation, is modulated by the host-guest complexation of cucurbit[7]uril. The supramolecularly modulated catalyst significantly accelerates the catalytic oxidation of dye chromophores, thus providing a way to avoid product inhibition and broadening the range of substrates.


Secukinumab alleviates cognitive impairment by attenuating oxidative stress and neuronal apoptosis via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis.
Septic-associated encephalopathy (SAE) is a critical manifestation of sepsis that leads to long-term cognitive impairment. Interleukin (IL)-17A has been shown to mediate neuronal apoptosis in central nervous system diseases, while oxidative stress has been found to have a detrimental effect in SAE. However, the relationship between IL-17A and oxidative stress in SAE remains unclear. This study aimed to investigate the effects of secukinumab on alleviating cognitive impairment in a rat model of sepsis, as well as examine its underlying molecular mechanism of action. A total of 282 male 8-week-old Sprague-Dawley rats were randomly subjected to cecal ligation and puncture (CLP) or sham treatment followed by volume resuscitation immediately after surgery. Secukinumab was administered intranasally 1 h post-CLP. Rats were given the p-ERK activator ceramide C6 intracerebroventricularly (i.c.v) 24 h before CLP surgery. Recombinant rIL-17A was administered i.c.v. at 0 h in naive rats, followed by intraperitoneal injection of the AKT inhibitor GDC0068 1 h post-rIL-17A injection. Clinical scores, body weight, and survival rate were assessed. In addition, immunofluorescence staining, neurobehavioral tests, Nissl staining, and western blotting were performed. Cognitive function was assessed 15-20 days post-CLP using the Morris water maze test. IL-17A and IL-17RA protein expression levels in the rat hippocampus increased and peaked 24 h post-CLP. Furthermore, IL-17RA was found to be expressed in neurons. The survival rate after CLP was 50%. Following CLP, an increased clinical score and significant decrease in body weight were observed. However, treatment with secukinumab led to a decrease in the clinical score of rats 24 h post-CLP. CLP resulted in spatial and memory impairment and anxiety-like behaviors in rats, while secukinumab treatment significantly alleviated cognitive impairment compared to the CLP group (p < 0.05). In addition, oxidative stress and neuronal apoptosis were found to be increased in the CLP group, while secukinumab significantly reduced oxidative stress and neuronal apoptosis in the hippocampus following CLP. Furthermore, secukinumab treatment led to a significant decrease in the protein expression levels of p-AKT, p-ERK1/2, Romo1, and Bax, together with increased Bcl-2 protein expression. Finally, treatment with ceramide C6 and GDC0068 abolished the neuroprotective effects of secukinumab post-CLP. Our results demonstrated that secukinumab attenuated oxidative stress and neuronal apoptosis and partially ameliorated cognitive impairment via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis. Thus, secukinumab may be a potential therapeutic strategy for septic patients.


Association between serum copper, zinc and their ratio and handgrip strength among adults: a study from National Health and Nutrition Examination Survey (NHANES) 2011-2014.
Evidence for the association between serum copper and zinc status and handgrip strength is very limited only in several observational studies with study participants of specific population or a narrower age range. The aim of this study was to evaluate the association between serum copper, zinc and their ratio and handgrip strength in the general population. This study included adult participants aged 20-80 years with complete data of serum copper and zinc status and handgrip strength from NHANES 2011-2014. Handgrip strength was calculated as the average of the maximum measure obtained in each hand with a grip strength dynamometer and corrected using BMI. Serum copper and zinc levels were measured using inductively coupled plasma dynamic reaction cell mass spectrometry, and their ratios were calculated. The multivariable linear regression and restricted cubic spline models were used. Serum copper level was inversely associated with BMI-corrected handgrip strength, and the beta coefficients (95% confidence intervals) comparing the second, third, and fourth to the lowest quartiles of serum copper level were - 0.17 kg (- 0.26; - 0.08), - 0.22 kg (- 0.32; - 0.13), and - 0.36 kg (- 0.44; - 0.28), respectively (P for trend < 0.001). Non-linear association was detected between serum copper level and BMI-corrected handgrip strength (P < 0.01). Consistent with serum copper, serum copper/zinc ratio was inversely associated with BMI-corrected handgrip strength. However, no significant associations were observed between serum zinc level and BMI-corrected handgrip strength (all P > 0.05). Higher serum copper level and copper/zinc ratios were significantly associated with lower handgrip strength. Further research is needed to address related issues.


Pathogenesis of posthemorrhagic hydrocephalus of prematurity: New horizons.
Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a vexing problem for patients, their families, and the healthcare system. The complexity of the pathogenesis of PHHP also presents a unique challenge within the fields of neonatology, neurology and neurosurgery. Here we focus on pathogenesis of PHHP and its impact on the development of CSF dynamics including choroid plexus, ependymal motile cilia and glymphatic system. PHHP is contrasted with infantile hydrocephalus from other etiologies, and with other types of posthemorrhagic hydrocephalus that occur later in life. The important concept that distinguishing ventricular volume from brain health and function is highlighted. The influence of the pathogenesis of PHHP on current interventions is reviewed, with particular emphasis on how the unique pathogenesis of PHHP contributes to the high rate of failure of current existing interventions. Finally, we discuss emerging interventions. A thorough understanding of the pathogenesis of PHHP is essential to developing effective non-surgical therapeutics to prevent the transformation from severe IVH to PHHP.


Arthroscopy in total knee replacements.
The purpose of this presentation is to relate to the author's experience in treating eight patients for fibroarthrosis following total knee replacements from June 1983 to September 1986. Patients were obtained from referrals by independent orthopedists who had performed total knee replacements and believed that their patients' range of motion (ROM) and pain level were unsatisfactory after trying all standard treatment modalities. Patients evaluated their results through questionnaires and patients were also evaluated by an independent examiner. Improvement in flexion was consistent, yet extension was not generally improved. Postoperative pain level was reduced as compared with preoperative pain level, and there were no major complications. Indications for arthroscopy in total knee arthroplasties are not well defined, but results appear promising for the fibroarthrotic patient with regard to improvement in flexion and subjective pain reduction.


Molecular control of nuclear and subnuclear targeting of the plant CDK inhibitor ICK1 and ICK1-mediated nuclear transport of CDKA.
ICK1 is the first member of a family of plant cyclin-dependent kinase (CDK) inhibitors. It has been shown that ICK1 is localized in the nuclei of transgenic Arabidopsis plants. Since cellular localization is important for the functions of cell cycle regulators, a comprehensive analysis was undertaken to identify specific sequences regulating the cellular localization of ICK1. Deletion and site-specific mutants fused to the green fluorescent protein (GFP) were used in transgenic Arabidopsis plants and transfected tobacco cells. Surprisingly, three separate sequences in the N-terminal, central and C-terminal regions of ICK1 could independently confer nuclear localization of the GFP fusion proteins. The central nuclear localization signal NLS(ICK1) could transport the much larger GUS (beta-glucuronidase)-GFP fusion protein into nuclei, while the other two sequences were unable to. These results suggest that NLS(ICK1) is a strong NLS that actively transports the fusion protein into nuclei, while the other two sequences are either a weaker NLS or confer the nuclear localization of GFP indirectly. It was further observed that the N-terminal sequence specifies a punctate pattern of subnuclear localization, while the C-terminal sequence suppresses it. Furthermore, co-expression of ICK1 and Arabidopsis CDKA, tagged with different GFP variants, showed that ICK1 could mediate the transport of CDKA into nuclei while a mutant ICK1(1-162) that does not interact with CDKA lost this ability. These results illustrate how the nuclear localization of ICK1 is regulated and also suggest a possible role of ICK1 in regulating the cellular distribution of CDKA.


Immunoproteomics of Helicobacter pylori infection in patients with atrophic body gastritis, a predisposing condition for gastric cancer.
Atrophic body gastritis is considered an outcome of H. pylori infection at high risk for gastric cancer. Immunoproteomics has been used to detect H. pylori antigens, which may act as potential markers for neoplastic disease and may be used in specific serological tests. We used immunoproteome technology to identify H. pylori antigens, recognized by sera from patients with atrophic body gastritis. Here, we performed 2DE protein maps of H. pylori strain 10K, probed against single sera from 3 groups of H. pylori-positive patients (atrophic body gastritis; intestinal-type gastric cancer; peptic ulcer) and negative controls. Immunoreactive spots were identified by MALDI-TOF-MS. A total of 155 immunoreactive spots were detected corresponding to 14.1% of total spots detected in our reference map of H. pylori strain 10K. Sera from atrophic body gastritis (40.5±2%) and gastric cancer patients (25.9±1.8%) showed a significantly higher and stronger mean immunoreactivity versus H. pylori antigens compared to peptic ulcer patients (11.2±1.3%). The average intensity of immunoreactivity of sera from atrophic body gastritis and gastric cancer patients was significantly stronger compared to peptic ulcer patients. Sera from atrophic body gastritis and gastric cancer patients differentially recognized 17 H. pylori spots. Immunoproteome technology may discriminate between different H. pylori-related disease phenotypes showing a serological immunorecognition pattern common to patients with gastric cancer and atrophic body gastritis, its precursor condition. This tool may be promising for developing specific serological tests to identify patients with gastritis at high risk for gastric cancer, to be evaluated in prospective investigations.


Comparative cardioprotective effects and mechanisms of vitamin E and lisinopril against ischemic reperfusion induced cardiac toxicity.
The present study was undertaken to scientifically evaluate, validate and compare the cardioprotective effects of lisinopril (Lsp), an angiotensin converting enzyme (ACE) inhibitor and vitamin E (Vit E), an antioxidant in the setting of ischemia and reperfusion (I-R) injury. An open chest left anterior descending coronary artery occlusion and reperfusion induced myocardial injury cardiotoxicity model was used in the present study. Hemodynamic, biochemical and histopathological assessment of myocardial injury was undertaken. Pre-treatment (1 month) with Lsp (50 mg/kg) and Vit E (100 mg/kg) to healthy experimental controls did not adversely affect the histopathological architecture of the myocardium as well as the baseline antioxidant parameters. Subsequent to I-R injury, Lsp demonstrated modest antioxidant effects, superior recovery in left ventricular function as compared to the control IR group. Histopathological and biochemical assessment of injury confirmed the myocardial salvaging effect of this intervention. The cardioprotection afforded by Lsp was found to be superior as compared to Vit E treatment.


[Application of the self-evaluation questionnaire of the WHO multimodal strategy to improve the practice of hand hygiene in a tertiary hospital].
Hand hygiene (HH) is the single most important and effective measure to reduce the risk of healthcare-related infections. However, low compliance with HH indications among healthcare professionals is often low. The objective of this study was to evaluate the implementation of a multimodal strategy to promote HH among healthcare professionals. We used the "Application guide of the multimodal strategy of the World Health Organization for the improvement of hand hygiene", which consists of: changes to the system, education and training, evaluation and feedback, workplace reminders, organizational safety climate and monitoring of compliance with HH. The strategy was designed as an intervention study to promote HH in the Maternal and Child Insular University Hospital Complex in the period 2012-2020. Overall compliance with the HH indications at the end of the study period was 59.2%. The use of alcoholic-based products increased with respect to previous years (p <0.05), reaching 70 liters/1000 hospital admissions in the final year. Healthcare professionals perceived training and accessibility to an alcohol-based preparation at each point of care as the most effective measures for promoting good HH practice. The implementation of a multimodal intervention significantly improved compliance with handwashing and the use of alcohol-based products among healthcare professionals. Despite having previous training on hand hygiene, HH knowledge among professionals remains incomplete. Prior training followed by time worked are the most important determinants of knowledge and perceptions about hand hygiene.


The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis.
The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote steroidogenesis, and PDE5 modulates this process. Finally, PDE mutations may lead to several human diseases characterized by abnormal steroid levels.


Compared analysis of microbial diversity in donkey milk from Xinjiang and Shandong of China through High-throughput sequencing.
Donkey milk has received increasing attention from consumers and dairy industry because of its nutritional value, health benefits, and proximity to human milk. Microbial diversity in donkey milk has a great impact on its quality and safety, however, microbiota in donkey milk from the major donkey-breeding regions of China have not been well documented. In this study, bacterial communities in donkey milk from Yopurga County in Western China (XJ), and Dong'e County in Eastern China (SD) were determined using high-throughput sequencing. Major phyla identified in the two donkey milk groups consistently included Acinetobacter, Proteobacteria, Firmicutes, and Bacteroidetes but with very different abundance for each phylum. Prevelence of genera was found to be diverse between the two groups, with Macrococcus and Acinetobacter dominating in the XJ samples while Streptococcus, Pseudoclavibacter, and Pseudomonas being the most abundant ones in the XJ samples. Alpha diversity analysis showed that there was significant difference in richness between the two sample groups but no difference in bacterial community diversity or coverage. The presence of possible harmful bacteria and lactic acid bacteria in donkey milk in this study provides the microbial profiles of pathogens and spoilage bacteria that need to be controlled and proposes possible utilization of beneficial microbial resources for the future.


An effective management strategy for the control of two lentiviruses in goat breedings.
Caprine Arthritis Encephalitis is an endemic disease in goat breedings, caused by viral strains belonging to the Small Ruminant Lentivirus group and characterized by a progressive chronic course. Its clinical signs are not immediately recognizable and can only be detected via costly serological tests. No vaccine is available. Two main strategies for fighting it are in common use. The "test-and-slaughter" approach, that selects infected goats and directly slaughters them, is expensive, time consuming and often leads to endemic low level persistence of the infection. Alternatively, newborns are removed from their mothers to be raised by healthy goats. After weaning they would rejoin their breeds, but then they could still be subject to horizontal contagion. In this study a mathematical model that considers the cocirculation of two different SRLV viral genotypes (B and E) is devised and analyzed, based on the key assumption of perfect cross-protection between the two genotypes' infections. Two strategic measures arise from its analysis, that are strongly recommended and whose implementation is encouraged: in the presence of both genotypes, the farmer should not isolate the newborns from their mothers but rather raise them with all the other animals. In the case of genotype-B-only affected farm, serological testing and mother-offspring separation should still be considered the best strategy for CAEV control. These strategies completely reverse the current removal policy and, in due conditions, would lead to disease eradication. These represent very reasonable and cheap measures for the eventual control of the epidemics.


Comparison of the differential expression miRNAs in Wistar rats before and 10 days after S.japonicum infection.
When compared to the murine permissive host of Schistosoma japonicum, Wistar rats are less susceptible to Schistosoma japonicum infection, and are considered to provide a less suitable microenvironment for parasite growth and development. MicroRNAs (miRNAs), are a class of endogenous, non-coding small RNAs, that impose an additional, highly significant, level of gene regulation within eukaryotes. To investigate the regulatory mechanisms provided by miRNA in the schistosome-infected rat model, we utilized a miRNA microarray to compare the progression of miRNA expression within different host tissues both before and 10 days after cercarial infection, in order to identify potential miRNAs with roles in responding to a schistosome infection. Among the analysed miRNAs, 16 within the liver, 61 within the spleen and 10 within the lung, were differentially expressed in infected Wistar rats. Further analysis of the differentially expressed miRNAs revealed that many important signal pathways are triggered after infection with S. japonicum in Wistar rats. These include the signal transduction mechanisms associated with the Wnt and MAPK signaling pathways, cellular differentiation, with a particular emphasis on adipocyte and erythroid differentiation. The results presented here include the identification of specific differentially expressed miRNAs within the liver, lungs and spleen of Wistar rats. These results highlighted the function of host miRNA regulation during an active schistosome infection. Our study provides a better understanding of the regulatory role of miRNA in schistosome infection, and host-parasite interactions in a non-permissive host environment.


The adaptiveness of fear (and other emotions) considered more broadly: Missed literature on the nature of emotions and its functions.
We agree with Grossmann that fear often builds cooperative relationships. Yet he neglects much extant literature. Prior researchers have discussed how fear (and other emotions) build cooperative relationships, have questioned whether fear per se evolved to serve this purpose, and have emphasized that human cooperation takes many forms. Grossmann's theory would benefit from a wider consideration of this work.


A comparison of methods to determine maximal accumulated oxygen deficit in running.
The aim of this study was to compare maximal accumulated oxygen deficit (hereafter O2 deficit) estimated from the methods of Whipp et al. (1986), Medbo et al. (1988), and Hill et al. (1998) to determine whether they agree sufficiently to be used interchangeably. Nineteen moderately to highly trained endurance runners first performed an incremental test to exhaustion for the determination of maximal oxygen uptake ([Vdot]O(2max)) and peak treadmill speed, followed by six randomly ordered constant-speed tests at 95, 100, 105, 110, 110, and 120% of peak treadmill speed. All tests were separated by at least 72 h and were performed within 4 weeks. The method of Whipp produced an O(2) deficit estimate that was lower than that derived from the method of Hill or Medbo (bias +/- 95% limits of agreement: -29.6 +/- 36.6 and -26.1 +/- 32.8 ml . kg(-1), respectively; P < 0.001). The O2 deficit did not differ between the methods of Hill and Medbo (bias +/- 95% limits of agreement: 3.5 +/- 41.6 ml . kg(-1); n.s.). However, poor correlations (0.21 < r < 0.33; n.s.) together with wide limits of agreement between O2 deficit estimates (70 - 80% of the mean response) clearly question using these methods interchangeably.


Liming impacts barley yield over a wide concentration range of soil exchangeable cations.
Liming has widespread and significant impacts on soil processes and crop responses. The aim of this study was to describe the relationships between exchangeable cation concentrations in soil and the relative yield of spring barley. The hypothesis was that yield is restricted by the concentration of a single exchangeable cation in the soil. For simplicity, we focused on spring barley which was grown in nine years of a long-term experiment at two sites (Rothamsted and Woburn). Four liming rates were applied and in each year the relative yield (RY) and the concentrations of exchangeable cations were assessed. Liming had highly significant effects on the concentrations of most exchangeable cations, except for Cu and K. There were significant negative relationships (either linear or exponential) between the exchangeable concentrations of Mn, Cd, Cr, Al, Fe, Cu, Co, Zn and Ni in soil and soil pH. The relationships between RY and the concentrations of selected exchangeable cations (Mn, Ca and Al) were described well using log-logistic relationships. For these cations a significant site effect was probably due to fundamental differences in soil properties. At both sites the concentrations of exchangeable soil Al were excessive (> 7.5 mg kg-1) and were most likely responsible for reduced barley yields (where RY ≤ 0.5) with soil acidification. At Rothamsted barley yield was non-limited (where RY ≥ 1) at soil exchangeable Mn concentrations (up to 417 mg kg-1) greater than previously considered toxic, which requires further evaluation of critical Mn concentrations. The online version of this article (10.1007/s10705-020-10117-2) contains supplementary material, which is available to authorized users.


Effect of Gamma Radiation on Zinc Tolerance Efficiency of Aspergillus terreus Thorn.
The present study emphasizes the potential of gamma radiation in enhancing zinc tolerance of Aspergillus terreus. Gamma-exposed A. terreus could tolerate 1.13 times more Zn, reflecting higher growth (in terms of CFU) under Zn stress and enhanced Zn removal efficacies than their unirradiated counterparts. Radiation-induced upregulation of antioxidative system (SOD, CAT, GSH and MT) of A. terreus is responsible for radiation-induced enhancement of Zn tolerance. FTIR spectra reveals the involvement of functional groups in Zn biosorption; SEM study divulges the structural changes due to metal and gamma exposure and SEM-EDX depicts the Zn uptake by A. terreus (both in gamma-exposed and unexposed conditions). This work sheds light toward utilizing low doses of ionizing radiation for making more metal-tolerant fungi and the possible mechanisms adopted by A. terreus for being more metallo-resistant.


Deciphering the physician note.
Objective information about legibility of physician handwriting is scant. This retrospective chart review compared handwritten general medicine clinic chart notes from internal medicine faculty and housestaff with their typed counterparts. The written counterparts took 11 seconds (46%) longer to read and 5 seconds (11%) longer to answer comprehension questions. The authors' comprehension measure (developed specifically for ambulatory clinic notes) was only slightly higher for typed notes. The legibility of physician handwriting is not as dismal as assumed; physicians can effectively communicate on paper.


Protective effect of ebselen against hydrogen peroxide-induced cytotoxicity and DNA damage in HepG2 cells.
The protective effect of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a selenoorganic compound, against hydrogen peroxide (H2O2)-induced cytotoxicity and DNA damage was investigated in a human hepatoma cell line, HepG2. The inhibitory effect of H2O2 on cell growth was determined using the tetrazolium dye colorimetric test (MTT test), and the cytotoxicity and lipid peroxidation were estimated by lactate dehydrogenase (LDH) leakage and malondialdehyde (MDA) formation, respectively. DNA damage was detected using single cell gel electrophoresis (comet assay), and intracellular reactive oxygen species (ROS) formation was measured using a fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA). The results showed that H2O2 suppressed the growth of HepG2 cells and the addition of ebselen significantly reduced the suppression. Furthermore, ebselen also displayed a dose-dependent reduction of LDH leakage and MDA formation in H2O2-treated cells. The results also demonstrate that ebselen was able to reduce the ROS formation and DNA damaging effect caused by H2O2 in a dose-dependent manner. These findings suggest that ebselen has a strong protective ability against the cytotoxicity and DNA damaging effect caused by reactive oxygen species.


Clinical experience with synthetic serum substitute as a protein supplement in IVF culture media: a retrospective study.
Our objective was to evaluate the efficacy of Synthetic Serum Substitute (Irvine Scientific--Materials Section, Santa Ana, CA), a globulin-enriched protein preparation containing human serum albumin for supplementation of IVF culture media. We retrospectively analyzed IVF cycles performed at MacDonald Womens Hospital between January 1992 and November 1994. IVF cycles were reviewed and classified according to the nature of protein supplementation used in the embryo culture medium. Three protein supplements utilized during this time period were compared: Synthetic Serum Substitute (SSS), Plasmanate (PL), and maternal serum (MS). Although clinical pregnancy rates among the three treatment groups were not statistically different, there was a definite trend toward a higher pregnancy rate with SSS supplementation (SSS, 38.2%; MS, 28.0%; and PL, 24.9%). Embryos grown in SSS-supplemented culture media had a significantly higher implantation rate (17.8 vs 10.4 and 10.3%, respectively, for MS and PL). Preliminary data also suggest that human embryo development and blastulation in vitro were enhanced by this protein supplement. The higher implantation rate with SSS suggests that it may be superior to both maternal serum and Plasmanate in supporting human embryo development in vitro. Whether blastocysts derived from PL- and SSS-supplemented media are able to implant and give rise to clinical pregnancies remains to be seen.


[Serology of typhoid fever in children. I. Capillary flocculation- agglutination. Its specificity in an asymptomatic population and its utility at a pediatric emergency service].
Using a capillary flocculation technique we evaluated serum samples of asymptomatic children for typhoid fever serology. Thirty one (5.16%) of the 600 serum samples tested were positive for a specificity of 95%. To evaluate the sensitivity of the test, serum samples from 36 children with proven typhoid fever and a similar number of control patients were evaluated. The sensitivity of the capillary flocculation test in this group was 100%. The test compared favorably with the Ruiz Castañeda serologic test for typhoid fever.


Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register.
von Willebrand factor (VWF) plays a critical role in platelet adhesion and aggregation after vascular injury and at sites of high shear rate. Elevated VWF levels are associated with an increased risk of ischemic cardiovascular events; however, it is unclear whether VWF deficiency is protective against atherosclerosis. We aimed to compare the prevalence of cardiovascular disease (CVD) among patients with and without von Willebrand disease (VWD). A cross-sectional analysis was performed on discharge data for adults from the Nationwide Inpatient Sample (NIS) between the years 2009 and 2011. CVD was defined as ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, or peripheral vascular disease. For prevalence calculations and statistical analyses, we used discharge-level weights provided by the NIS to reflect national estimates. CVD was compared across groups by use of the Rao-Scott chi-square test. Multivariable logistic regression was used to estimate the likelihood of CVD in VWD patients after adjustment for age, gender, and CVD-related risk factors. The prevalence of CVD in VWD patients was less than the prevalence of CVD in non-VWD patients (15.0% versus 26.0%). VWD was associated with a decreased likelihood of CVD after adjustment for age, gender, and CVD-related risk factors (odds ratio 0.85; 95% confidence interval 0.79-0.92). These findings indicate that the risk of CVD is decreased among VWD patients, and that VWF deficiency may be protective against CVD.


Accuracy of a portable electroneurometer for measuring distal motor latency.
A facile electromyographic test in the outpatient clinic is needed to evaluate the outcome of screening for carpal tunnel syndrome. The purpose of the current prospective study was to compare the accuracy of Nervepace digital electroneurometer (Nervepace) and Dantec Neuromatic 2000M (Dantec) measurements of a wide range of distal motor latency (DML) of the median nerve. The DML values for 112 of 126 median nerves examined with Nervepace and conventional electromyography, Dantec were statistically analyzed in this prospective study. The 30 hands of 15 clinically healthy adults 20-24 years old served as the reference group. Sixty consecutive patients (96 hands) with idiopathic carpal tunnel syndrome provided a wider range of DML values. All of the patients had standard clinical tests and standard motor (Dantec and Nervepace) and sensory (Dantec) electrodiagostic tests before endoscopic carpal tunnel release. The DML was measurable in all 30 hands of the reference group, in all 96 hands of the patients by Dantec, but in only 82 hands (52 patients) by Nervepace. Nervepace and Dantec DML values of 6.0 ms or less had high correlation and agreement. Correlation and agreement decreased significantly among values greater than 6.0 ms.


Factors predictive of operative mortality among coronary artery bypass subsets.
As risk-adjusted outcome is increasingly being used to make clinical decisions and to assess and improve quality of care, it is important to develop simple, stable models for predicting outcome. Here we address the hypothesis that a risk factor for increased operative mortality at coronary artery bypass grafting may have differential effects in subgroups of patients defined by the presence or absence of other risk variables. We used a series of univariate and multivariate analyses to identify a group of ten patient-related preoperative characteristics independently predictive of operative death in the total population of 12,712 patients undergoing coronary artery bypass grafting at 43 Department of Veterans Affairs medical centers participating in the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Study. Separate logistic regression models were then developed for each of 14 clinically important subgroups defined by the presence or absence of seven risk variables. Odds ratios for operative death and estimated operative mortality were calculated from these subgroup regression models. Of 65 comparisons of pairs odds ratios of preoperative risk variables between the subgroups with and without a second risk variable, only five were found to be significant (p < 0.05 without adjustment for multiple comparisons); this is only slightly more than would be expected by chance alone. Risk factors for increased operative death appear to have similar odds ratios for subgroups of patients defined by a second risk variable. This finding greatly simplifies the use of predicted operative mortality in clinical decision making and quality assessment and improvement in coronary artery bypass grafting.


A profile of dentists working in the general and community dental services in Scotland in 1987.
A questionnaire was sent to a list of what was considered to be all (1726) practitioners in the General Dental Service (GDS) and Community Dental Service (CDS) in Scotland. The overall response rate was 72%. A comparison of certain characteristics of the respondents with those of the entire group of dentists who were sent questionnaires suggested that the respondents comprised an acceptable cross-section. Proportionally more females worked in the CDS than in the GDS and many of the differences between the general characteristics of practitioners in the two services appeared to reflect differences which are known to exist between the career patterns of male and female dental practitioners. Most respondents (84.7%) claimed to have attended a post-graduate course within the last 5 years, although only 33.4% claimed to have attended more than one course per year. Over three-quarters of the respondents (76.0%) claimed that they belonged to a professional society, whilst 98.5% stated that they regularly read a professional journal or practice newspaper of some description.


The role of virus-induced regulatory T cells in immunopathology.
In recent years, regulatory T cells have received increased attention for their role in immune responses to microbial infections. The list of microbial pathogens associated with regulatory T cell responses is growing rapidly and includes bacteria, viruses, parasites, and fungi. As the biology of regulatory T cells is revealed, we are discovering that their induction during infection is a normal aspect of immunity, necessary to limit collateral damage from inflammatory responses and aggressive immunological effectors. Thus, these cells play a critical role in maintaining the delicate balance between preventing immunopathology and allowing the immune response to clear infections. While generally successful, there are notable exceptions where regulatory T cell-mediated suppression appears to be responsible for allowing certain viruses to establish and maintain a persistent state. In this review, we will discuss our current understanding of what virus-induced regulatory T cells are, how they are induced, and what mechanisms they use to suppress immunity. The complex role of Tregs in regulating immunity to viral infections, and the consequences their activity has on disease is illustrated by a review of specific viral infections including hepatitis C virus and human immunodeficiency virus.


Direct-acting antiviral (DAA) actions in treatment-naïve patients.
The introduction of telaprevir (TVR) and boceprevir (BOC), the first approved protease inhibitors against hepatitis C virus (HCV), into clinical practice represented the start of an exciting new era of HCV treatment. In addition to improving sustained virological response (SVR) rates in HCV genotype-1 treatment-naïve patients, these drugs administered as a triple combination with pegylated interferon (pegIFN) and ribavirin (RBV) provide opportunities for more patients to receive shorter durations of treatment (24-28 weeks) than with pegIFN/RBV alone (48 weeks). Also, the use of TVR and BOC is being enhanced by the acquisition of further data on predictors of SVR, thereby increasing patients'chances of being cured of their HCV infection.


Conceptual and procedural distinctions between fractions and decimals: A cross-national comparison.
Previous work has shown that adults in the United States process fractions and decimals in distinctly different ways, both in tasks requiring magnitude judgments and in tasks requiring mathematical reasoning. In particular, fractions and decimals are preferentially used to model discrete and continuous entities, respectively. The current study tested whether similar alignments between the format of rational numbers and quantitative ontology hold for Korean college students, who differ from American students in educational background, overall mathematical proficiency, language, and measurement conventions. A textbook analysis and the results of five experiments revealed that the alignments found in the United States were replicated in South Korea. The present study provides strong evidence for the existence of a natural alignment between entity type and the format of rational numbers. This alignment, and other processing differences between fractions and decimals, cannot be attributed to the specifics of education, language, and measurement units, which differ greatly between the United States and South Korea.


[Therapeutic options after the accidental application of cyanacrylate into the outer ear canal].
The accidental application of cyanacrylate (superglue) into the outer ear canal requires different treatments depending on location and extent. Two case studies are presented. Treatment included surgical removal, with or without prior conservative treatment, for complete canal obstruction, as well as conservative treatment for partial ear canal obstruction. Because of its unique anatomy, treatment of accidentally applied superglue into the outer ear canal differs from treatment in other locations. Conservative treatment was ineffective for complete obstruction, making secondary surgical removal necessary. Partial obstruction was successfully treated conservatively. No complications were observed after the surgical removal of superglue obstructing the complete outer ear canal. Conservative treatment is adequate for cases of partial obstruction of the outer ear canal with superglue. In cases of complete obstruction or inclusion of the ear drum, surgical treatment is recommended.


Human exposure to respirable manganese in outdoor and indoor air in urban and rural areas.
Methylcyclopentadienyl manganese tricarbonyl (MMT), is an additive in gasoline, and its combustion leads to the emission of Mn particles, which increase atmospheric metal concentrations. The objective of this study was to determine the level of outdoor and indoor respirable Mn (MnR) in Montreal, Canada, where MMT has been used since 1976. Ten women were involved in this study: five living in an urban area, near an expressway with high traffic density, and five residing in a rural area characterized by low traffic density. Outdoor and indoor air samples were collected each week (5 in total) during 3 consecutive days; blood samples were collected at the end of the air sampling period. The average concentration of outdoor MnR in the urban area was 0.025 microg/m3, which is significantly different from the average of 0.005 microg/m3 found in the rural area. The average indoor MnR concentration was also significantly different from teh average MnR indoor concentrations within both areas. The mean blood Mn concentrations were not significantly different between the urban area (0.017 microg/m3) and the rural area (0.007 microg/m3). The average outdoor MnR concentrations within both areas. The mean blood Mn concentrations were not significantly different between the two groups. Data suggest that a high outdoor atmospheric MnR leads to a high indoor MnR, but not to an increase in blood Mn levels.


Prostaglandin E2 receptor EP3alpha subtype: the role of N-glycosylation in ligand binding as revealed by site-directed mutagenesis.
Functional mouse prostaglandin E2 (PGE2) receptor EP3alpha subtype has been expressed in insect cells using a baculovirus system (Huang C. and Tai H.-H. Biochem J 1995; 307: 493-498). EP3alpha receptor has two potential sites (Asn-X-Ser/Thr), Asn 16 and Asn 193, for N-glycosylation. The role of glycosylation in ligand binding of the EP3alpha receptor was investigated by site-directed mutagenesis. Asn was mutated to Gln in each of the two potential glycosylation sites in the EP3alpha receptor. Recombinant wild-type and mutant EP3alpha receptors were expressed in insect cells using baculovirus. Ligand binding assay indicated that the affinity of PGE2 binding was reduced by 50% in the Gln 193 mutant EP3alpha receptor, while the specificity of ligand binding was unaltered. The affinity for PGE2 binding was not affected in the Gln 16 mutant EP3alpha receptor. However, its specificity was partially changed as the EP3-specific agonist became less effective in displacing the [3H]-PGE2 binding to the mutant receptor. These results indicated that N-glycosylation of the EP3alpha receptor could partially affect the affinity and specificity of the ligand binding.


Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production.
Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.


Interaction between mDia1 and ROCK in Rho-induced migration and adhesion of human dental pulp cells.
To investigate the effects of mammalian homologue of Drosophila diaphanous-1(mDia1) and Rho-associated coiled-coil-containing protein kinase (ROCK) on the migration and adhesion of dental pulp cells (DPCs). Lysophosphatidic acid (LPA) was used to activate Rho signalling. mDia1 and ROCK were inhibited by short interfering RNA and the specific inhibitor, Y-27632, respectively. The migration of DPCs was assessed using the transwell migration assay and scratch test. Formation of cytoskeleton and focal adhesions(FAs) was observed by confocal laser scanning microscopy. Cell adhesion and spreading assays were performed. Phosphorylation of focal adhesion kinase (FAK) and paxillin was detected by Western blotting, and the bands were analysed using Adobe Photoshop CS5 software. All experiments were performed at least three times, and data were analysed with one-way anova and a post hoc test. LPA-triggered activation of Rho and inhibition of ROCK significantly increased the cell migration rate. Cell migration was inhibited by silencing mDia1. mDia1 silencing and ROCK inhibition suppressed the LPA-induced formation of the cytoskeleton, FA and phosphorylation of FAK and paxillin. Inhibition of ROCK or mDia1 facilitated early cell adhesion and spreading; by contrast, the combined inhibition of ROCK and mDia1 neutralized these effects. mDia1 promoted RhoA-induced migration of DPCs, but ROCK had an opposite effect. Both mDia1 and ROCK participated in cytoskeleton formation and adhesion of DPCs. The interactions between mDia1 and ROCK might influence dental pulp repair by determining the migration and adhesion of DPCs.


Separation of α-tocotrienol oxidation products and eight tocochromanols by HPLC with DAD and fluorescence detection and identification of unknown peaks by DAD, PBI-EIMS, FTIR, and NMR.
Tocotrienols, like tocopherols, are members of the vitamin E family. While tocopherols (T) have been studied intensively, only recently have tocotrienols (T3) received increased attention due to their special health benefits. However, these positive attributes of T3 are probably lost as a result of degradation during food storage and processing, and there is little information about their oxidation products. Of particular interest are the oxidation products of α-tocotrienol (α-T3) as this is the least thermostable T3 isomer with the highest rate of degradation. The objective of this study was therefore to develop a reliable method for the determination of the most important oxidation products of α-T3 along with other tocochromanol isomers. We developed a high-performance liquid chromatography method with diode array detection, fluorescence detection, and a particle beam interface electron impact mass spectroscopy in order to separate the most important oxidation products of α-T3 (α-T3 spirodimers/spirotrimers, α-tocotrienoldihydroxy dimer, 7-formyl-β-tocotrienol (7-FβT3), 5-formyl-γ-tocotrienol (5-FγT3), α-tocotrienolquinone (α-T3Q), and α-T3Q dimers and α-tocotrienolquinone epoxides (α-T3QE)) from eight tocochromanol isomers. Furthermore, we sought to identify the as yet unknown oxidation products 5-FγT3, 7-FβT3, α-T3Q-dimer, and α-T3QE. Of these, 5-FγT3 was fully characterized by Fourier transform infrared spectroscopy and (1)H and (13)C nuclear magnetic resonance spectroscopy.


Draft genome sequence data of Gordonia hongkongensis strain EUFUS-Z928 isolated from the octocoral Eunicea fusca.
Octocorals are among the most prolific sources of biologically active compounds. A significant part of their specialized metabolites richness is linked to the abundance of their associated microbiota. Consequently, research on the bioprospecting potential of microorganisms associated with these marine invertebrates has gained much interest. Here, we describe the draft genome of Gordonia hongkongensis strain EUFUS-Z928 isolated from the octocoral Eunicea fusca. The genome was assembled de novo from short-read whole-genome sequencing data. Additionally, functional annotation of predicted genes was performed using the RAST tool kit, including genome mining for specialized metabolite biosynthetic gene clusters using the antiSMASH v6.0 tool. The genome sequence data of G. hongkongensis EUFUS-Z928 can provide information for further analysis of the potential biotechnological use of this microorganism and guide the characterization of other related actinobacterial isolates. Likewise, this information increases the analytical capacity for studying the genus Gordonia.


Three hydroxy aurone compounds as chemosensors for cyanide anions.
Three new 4-hydroxy aurone compounds 1-3 with dimethylamino (1), bromine (2) and cyano (3) as terminal group have been synthesized. Their photophysical properties as well as recognition properties for cyanide anions in acetonitrile and aqueous solution have also been examined. These compounds exhibit remarkable response to cyanide anions with obvious color and fluorescence change owing to hydrogen bonding reaction between cyanide anions and the O-H moiety of the sensors, which allows naked eye detection of cyanide anions.


Effectiveness of Wearable Device-based Intervention on Glycemic Control in Patients with Type 2 Diabetes: A System Review and Meta-Analysis.
With the development of flexible electronics and chip technology, the application value of wearable devices in lifelong treatment of chronic diseases is increasing. In view of its rapid development and diversified forms, wearable device-based intervention seems to provide a promising option to solve the problems of long-term glycemic control in type 2 diabetes (T2D). However, to date, it is unclear whether the intervention based on wearable device is effective on glycemic control in patients with T2D. In order to explore whether this choice is effective in glycemic control in patients with T2D, after database search and study screening, 6 studies and 1001 patients were selected from 181studies for this meta-analysis. The results guided that the wearable device-based intervention may be more effective than usual care on glycemic control in patients with T2D. Subgroup analysis showed that when the duration of intervention was equal to or less than 12 weeks, the effect of wearable device-based intervention was significantly different from that of usual care, but when the intervention duration greater than 12 weeks, the effect was not significantly different. The intervention effect of wearable devices with goal-setting or encouragement functions was significantly better than that of usual care, and there was no significant difference between automatic drug delivery wearable devices and usual care. In conclusion, the wearable device-based intervention is effective on glycemic control in patients with T2D. In general, this choice of wearable devices for patients with T2D may be effective to some extent.


The challenge of identifying non-intentionally added substances from food packaging materials: a review.
Packaged food can contain non-intentionally added substances (NIAS) as a result of reaction and degradation processes or the presence of impurities in the raw materials used for the packaging production. This manuscript reviews the evidence of NIAS and their possible origin. One of the most challenging and difficult tasks when a sample of packaging materials arrives at the laboratory is knowing the procedure to apply for identifying the unknown compounds. This work proposes an analytical procedure for sample treatment, applicable to polymers as well as to migration samples, and for NIAS identification. The identification protocol comprises the determination of both volatile and non-volatile compounds. A review is presented of the most novel analytical techniques used for identification purposes, particularly high resolution mass spectrometry (HRMS).


Preoperative detailed evaluation intracranial artery stenosis using three-dimensional visualization analysis reduces the invasiveness of superficial temporal artery-middle cerebral artery bypass.
Superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery is a common treatment for preventing cerebral ischemia in patients with intracranial artery stenosis. The aim of this study was to analyze the surgical outcomes of the STA-MCA bypass procedure, particularly with regard to the invasiveness of targeted bypass (TB) with preoperative planning using Amira® software. Consecutive patients with single STA-MCA bypass performed by a single neurosurgeon from January 2019 to May 2022 were included. The clinical parameters of seven TB patients were compared with those of 11 patients treated with the conventional method (CM). Compared with CM patients, TB using Amira® software patients had a shorter scalp incision (median [interquartile range]=11.2 [9.7-12.7] cm vs. 16.9 [16.0-17.7] cm, respectively; p=0.004], smaller craniotomy size (11.8 [11.5-14.4] cm2 vs. 20.9 [17.1-22.2] cm2, respectively; p=0.01], shorter surgery duration (201 [195-218] min vs. 277 [229-310] min, respectively; p=0.003], and less intraoperative bleeding (10 [10-20] g vs. 23 [20-50] g, respectively; p=0.033]. However, there were no differences in surgical complications between the two groups. Detailed preoperative evaluation using Amira® software can reduce the invasiveness of the STA-MCA bypass procedure.


[Laser photocoagulation and photodynamic therapy (PDT) with verteporfin for retinal angiomatous proliferation (RAP) in age-related macular degeneration (AMD)].
Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (AMD) with particularly bad prognosis. Diverse treatment modalities are performed. This is a retrospective review on the treatment results of 41 consecutive patients from 1/2003 to 12/2005 with RAP stage 1-3 (Yannuzzi classification), who were treated with laser photocoagulation, photodynamic therapy (PDT) and intravitreal injection of triamcinolone acetonide (IVT). Follow-up was 12 months minimally. In RAP stage I complete closure of the vascular lesion in 14 / 22 eyes was achieved by 1.2 +/- 0.5 sessions of laser photocoagulation (4 x combined with IVT) and in 3/14 eyes with photodynamic therapy (2 +/- 0.5 sessions). In RAP stage II closure of the lesion was achieved by 3.2 +/- 0.6 sessions of photodynamic therapy in 6/14 eyes (4 x combined with IVT). In RAP stage III closure of the lesion was achieved by 3.2 +/- 0.4 sessions of photodynamic therapy in 0 / 5 eyes (3 x combined with IVT). A rip of the retinal pigment epithelium was observed in 2/14 eyes of RAP stage II and 2/5 eyes of RAP stage III. Visual acuity improved in 9/17 eyes with occlusion of RAP stage I. Without closure of the vascular lesion all eyes got legally blind (visual acuity 1/50 or less). Early detection and subsequent direct treatment of RAP stage I in AMD is recommended. In advanced stages anatomical closure of the vascular complex is rarely achieved and the risk is improved for development of tears in the retinal pigment epithelium and getting legally blind.


Acute and subacute effects of nicorandil and isosorbide dinitrate on vessel wall properties of large arteries and hemodynamics in healthy volunteers.
Nicorandil (N) and isosorbide dinitrate (ISDN) are vasodilator drugs used in patients with angina. In 24 healthy male volunteers (18-32 years), the acute effect of a single oral dose (20 mg) of N and ISDN on arterial diameter (D), distensibility, and compliance of the elastic common carotid artery (CCA) and the muscular femoral (FA) and brachial (BA) arteries were investigated. The effects on systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and venous hemodynamics were also assessed. In addition, the subacute effects after 8 days of treatment with N (2 x 20 mg/day) and ISDN (3 x 20 mg/day) on these parameters were evaluated. After a 20 mg single oral dose, blood pressure decreased significantly more with ISDN (SBP: 6%; DBP: 14%) than with N (SBP: 2%; DBP: 6%), but after 8 days this decrease in blood pressure was not statistically different between ISDN and N. The diameter of CCA increased more with ISDN (11%) than N (5%) acutely as well as subacutely (ISDN: 12%; N: 9%). Heart rate increased only with ISDN (7% acutely, 3% subacutely). No differences between ISDN and nicorandil were found for acute and subacute effects on SVRI, venous hemodynamics, diameter of muscular arteries (FA, BA), and the distensibility and compliance of elastic (CCA) and muscular (FA, BA) arteries.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of deep tissue massage on respiratory parameters in healthy subjects-A non-randomised pilot study.
Deep tissue massage (DTM), based on deep palpation and elimination of fascia restrictions, can reduce symptoms resulting from fascial disorders. The goal of this study was the analysis of the DTM effect on respiratory parameters in healthy people. The study involved a group of 40 people divided into two subgroups. The experimental group underwent a single DTM session. Classic massage was performed in the control group. Before and after treatment the chest circumference and oxygen saturation were measured and a spirometry test was performed. The chest expandability significantly increased in both groups with greater effect in DTM group. Vital capacity and saturation, significantly increased in the experimental group. No significant changes in dynamic parameters were noticed in the control group, while FVC slightly decreased in the experimental group. In this study, deep tissue massage appeared to improve chest expendability and vital capacity with simultaneous decrease of FVC in healthy subjects. Further studies are needed to specify the effect of DTM on the respiratory system.


Problematic internet use and attachment styles among adolescents in Japan.
Problematic Internet use (PIU) remains a significant social concern in Japan and across the globe. Numerous studies have been conducted to examine the prevalence of PIU, and its association with lifestyle habits and mental health status. To the best of our knowledge, few studies have examined the association between parental attachment and PIU in Japan. Furthermore, preventive measures in Japan have primarily targeted adolescents via education. Therefore, in this study we explored the association between PIU and attachment styles among adolescents to seek a new approach for the development of appropriate, effective measures. A self-administered survey was conducted at one private (in 2018) and two public junior high schools (in 2020) in Kagawa Prefecture, western Japan. We used the Internet Addiction Test (IAT), the Experiences in Close Relationships-Relationship Structures (ECR-RS) questionnaire, and the Birleson Depression Self-Rating Scale for Children (DSRS-C). Multiple regression analysis was performed to examine the association between IAT scores and attachment styles. Of 1,413 participants (grades 7-9; 700 boys and 713 girls), 39% of the students showed possible PIU and 3% showed PIU. Students with PIU tended to sleep for shorter durations, access the Internet for long hours, and have a poor mental health status (p < 0.01). PIU was significantly associated with insecure attachment (p < 0.0001). The findings of our study imply that improving attachment styles and developing secure attachment between the child and parent might help mitigate and/or prevent PIU.


[Time in care of trauma patients in the air rescue service: implications for disposition?].
Time plays a crucial role in treating multiple traumatized patients and delays in management worsen the prognosis. Furthermore, current studies show that trauma patients profit from primary delivery to a trauma center. Therefore, the goal of physician-staffed ground and air rescue services in Germany is to treat these patients as quickly as possible and deliver them to a suitable trauma center. The aim of the present study was to investigate prehospital treatment times for the air rescue team in terms of disposition and efficiency when a ground rescue team was already present at the scene. In a nationwide, multicenter analysis emergency missions carried out for traumatological emergencies in 2006 by 28 air rescue centers (ARC) of the TeamDRF and 6 ARC of the federal police were evaluated using the medical database MEDAT of the German Air Rescue Service. A distinction was made between combined missions with (MEDAT 1 group) and without (MEDAT 2 group) physician-staffed ground emergency medical services already being present at the emergency site and in particular the rescue helicopter treatment times for both groups were investigated. Furthermore, combined missions (MAN 1 group) and solo missions (MAN 2 group) for traumatological emergencies in the period 01.05.2006 to 31.01.2007 were investigated in a complementary prospective regional study at the ARC Heidelberg/Mannheim "Christoph 53". In both groups the total treatment times for all physician-staffed emergency systems involved in treatment at the scene were investigated. Nationwide, 26,010 primary missions could be evaluated and of these, 11,464 missions were traumatological emergencies (44.1%) with 2,229 (19.4%) carried out by the MEDAT 1 group and 9,235 (80.6%) by the MEDAT 2 group. For both groups the helicopter treatment times depended on the severity of the injuries (NACA classification) and were between 17+/-12 min (NACA I) and 34+/-19 min (NACA VII) in MEDAT group 1 versus 21+/-10 and 36+/-19 min in MEDAT group 2 (p<0.05, p<0.001), respectively. In the MEDAT 1 group, the average treatment times were between 2.8 min (NACA VII) and 8.1 min (NACA VI) shorter compared with the MEDAT 2 group. Moreover, when taking the severity of the injury into consideration, a regular and significantly higher treatment effort (e.g. intubation, repositioning and chest tube insertion) and a greater proportion of patients who were transported to the clinic via rescue helicopter were observed for the MEDAT 1 group than for the MEDAT 2 group. In the regional study 670 primary missions were evaluated including 382 traumatological emergencies (57%). From these, 90 multiple trauma patients (NACA V) were not resuscitated or died at the scene, 58 from the MAN 1 group and 32 from the MAN 2 group, and were investigated more closely. The helicopter treatment times were comparable to those observed in the nationwide study and were found to be 26+/-12 min and 35+/-20 min (p<0.05), respectively. In the MAN 1 group the treatment times for the ground rescue services up to the time when the helicopter arrived was 22+/-11 min on average; the total treatment time was 48+/-15 min and 12+/-8 min longer than the time for the MAN 2 group, which was statistically significant. In the MAN 1 group the helicopter was alerted on average 17+/-15 min after the physician-staffed ground rescue services arrived at the emergency site. Treatment by the rescue helicopter teams was significantly more extensive in the MAN 1 group. The treatment times for the helicopter were several minutes shorter when a physician-staffed ground rescue team had already arrived at the emergency site. However, it must be assumed that the total prehospital time is significantly longer for such missions. These results directly affect the disposition at the emergency dispatch center and indicate that when air rescue is required to transport a patient to hospital, the helicopter should be alerted at an early stage. In such settings, it is likely that initiating the operation in this way would improve the prognosis of severely injured patients and save costs.


CMTM6 overexpression is associated with molecular and clinical characteristics of malignancy and predicts poor prognosis in gliomas.
CMTM6, a previously uncharacterized protein, was identified as a critical regulator of PD-L1, which is reported as an immune checkpoint inhibitor, to modulate the T cell activities both in vitro and in vivo of other tumors. However, the role of CMTM6 has so far remained unclear in glioma. To investigate the role of CMTM6 in gliomas, we analyzed the transcriptome level, genomic profiles and its relationship with clinical practice. 1862 glioma samples with transcriptome data were enrolled in this study, including CGGA RNA-seq, TCGA RNA-seq, CGGA-microarray, GSE16011 and IVY GBM databases. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were also obtained. We found that CMTM6 expression was highly correlated with major clinical and molecular characteristics. Cases with high CMTM6 expression were more likely to be predicted as malignant entities and frequent with genomic aberrations of driver oncogenes. Moreover, gene ontology analysis based on significantly correlated genes of CMTM6 expression exhibited that CMTM6 was associated with immune responses and inflammatory activities. CMTM6 was synthetic with other immune checkpoint inhibitors. Additionally, CMTM6 was involved in immune functions via modulating T-lymphocyte-mediated anti-tumor immunity. Finally, high CMTM6 expression was associated with reduced survival time and may serve as a strong indicator of poor prognosis in gliomas. In brief, High level of CMTM6 expression is closely related to high malignant gliomas. Meanwhile, CMTM6 plays an important role in regulating T cell activation and antitumor responses. Therefore, CMTM6 is a promising target for developing immunotherapy of gliomas.


Nail Deformities and Injuries.
A variety of nail deformities commonly presents in the primary care office. An understanding of nail anatomy coupled with inspection of the nails at routine office visits can reveal undetected disorders. Some problems are benign, and treatment should be attempted by the primary care provider, such as onychomycosis, paronychia, or ingrown toenails. For conditions such as benign melanonychia, longitudinal ridges, isolated Beau lines, and onycholysis, clinicians may offer reassurance to patients who are concerned about the change in their nails. For deformities such as early pterygium or clubbing, a thorough evaluation and referral to an appropriate specialist may be warranted.


Plasma S-Adenosylmethionine Is Associated with Lung Injury in COVID-19.
S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are indicators of global transmethylation and may play an important role as markers of severity of COVID-19. The levels of plasma SAM and SAH were determined in patients admitted with COVID-19 (n = 56, mean age = 61). Lung injury was identified by computed tomography (CT) in accordance with the CT0-4 classification. SAM was found to be a potential marker of lung damage risk in COVID-19 patients (SAM > 80 nM; CT3,4 vs. CT 0-2: relative ratio (RR) was 3.0; p = 0.0029). SAM/SAH > 6.0 was also found to be a marker of lung injury (CT2-4 vs. CT0,1: RR = 3.47, p = 0.0004). There was a negative association between SAM and glutathione level (ρ = -0.343, p = 0.011). Interleukin-6 (IL-6) levels were associated with SAM (ρ = 0.44, p = 0.01) and SAH (ρ = 0.534, p = 0.001) levels. A high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19. The association of SAM with IL-6 and glutathione indicates an important role of transmethylation in the development of cytokine imbalance and oxidative stress in patients with COVID-19.


Application of the popliteal lymph node assay in immunotoxicity testing: complementation of the direct popliteal lymph node assay with flow cytometric analyses.
The popliteal lymph node assay (PLNA) has been proposed to measure the immunosensitizing potential of chemicals. The direct PLNA detects an immunomodulating effect but does not give insight into the mode of action of the chemical under test. Modifications of this test have been proposed, but they are difficult to perform in routine toxicity testing and require many animals. In the present investigation the direct PLNA was extended with the flow cytometric determinations of: (a) lymphoblasts; (b) the phenotyping of lymphoid subpopulations; (c) the determination of expression of proliferation/activation markers CD25, CD69 and CD62L/CD44 and (d) the analysis of intracellular cytokines interferon gamma, interleukin 2 and interleukin 4. Streptozotocin, hydrazine, HgCl2 and trinitrobenzene sulfonic acid were used as model chemicals. The different mode of action of these substances was well documented by the techniques applied. As the proposed flow cytometric methods can easily be performed and do not require additional test animals this complementation of the direct PLNA seems a promising approach in immunotoxicity testing.


"High spinal" dysrhaphism. Case report of a complex cervical meningocele.
"High spinal" (cervical and upper thoracic) dysrhaphism usually involves either a meningocele or a dermal sinus tract. These high spinal lesions can have a complex intradural anatomy at the level of the lesion (as this case reports) and are associated with an increased incidence of lower spinal occult dysrhaphic anomalies. It is therefore recommended that patients with "high spinal" dysrhaphism undergo radiological evaluation of the entire spine to identify those patients with intradural anomalies, define the anatomy for surgery, and investigate the lower spine for associated occult anomalies.


Quantitation of 4-hydroxycyclophosphamide/aldophosphamide in whole blood.
There is considerable interest in determining 4-hydroxycylcophosphamide/aldophosphamide (4-HO-CP/AP) blood levels in patients receiving the prodrug, cyclophosphamide (CP). Phosphoramide mustard (PM), the alkylating metabolite of CP, is relatively impermeable to cell membranes and it is generally believed that circulating intermediary metabolites, including aldophosphamide, the immediate precursor of PM, is transported by circulating blood to tumor tissue. Therefore, circulating 4-HO-CP/AP blood levels should more closely reflect the oncostatic and cytotoxic effects of CP than the parent drug. We have developed a gas chromatographic electron-impact mass spectrometric (GC-EIMS) method suitable for routine monitoring of 4-HO-CP/AP levels in whole blood over the range 0.085 microM (25 ng/ml) to 34 microM (10 micrograms/ml). The unstable metabolites were derivatized with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine-HCl to form a stable aldophosphamide oxime derivative (PBOX). [2H4]PBOX was used as an internal standard. For clinical samples, tubes were prepared prior to blood drawing, which contained the derivatizing reagent solution and the internal standard. These solutions were stable for up to 3 months when stored at room temperature. Following addition of blood to the reaction tubes, PBOX formation was rapid and the resulting derivative was stable under these conditions for up to 8 days at room temperature. Application of the method was demonstrated by quantitating 4-HO-CP/AP blood levels in patients receiving 4 g/m2 intravenous infusion of CP over a period of 90 min.


Changes in plasma lipid and glucose levels during the onset of fatty liver and kidney syndrome in chics.
Plasma glucose, free fatty acid and triglyceride levels were measured during the onset of fatty liver and kidney syndrome in chicks. Intial studies indicated that behavioural and clinical changes characteristically associated with the syndrome were observed only during the 24 h preceding death. A more detailed examination of the blood changes was made on fasted birds. Typically, affected birds could be distinguished from healthy fasted birds by a hypoglycaemia which developed within 2.5 h of the removal of food, and a slightly higher and more sustained elevation of free fatty acid levels. Triglyceride values were not generally different from those found in normal birds. Although moderate to large amounts of lipid were occasionally observed in the kidneys of healthy fasted birds, only in affected birds was significant lipid infiltration of the kidneys associated with a similar level of lipid infiltration of the liver. In extreme cases death from fatty liver and kidney syndrome could occur within 4 h of the removal of food.


Replication initiator proteins of Acinetobacter baumannii plasmids: An update note.
The bioinformatic analysis that we made of 492 Acinetobacter baumannii plasmid sequences identified 418 genes encoding Replication Initiator (Rep) proteins that fell into at least fourteen groups according to the protein domains that they contained. The most abundant group of Rep proteins contained a Rep_3 superfamily domain, followed by Rep proteins containing Replicase/PriCT_1 superfamily domains, and then by Reps possessing only an HTH_MerR-SF superfamily domain. The remaining eleven groups contain only a few members. To evaluate the diversity of these Rep proteins, we classify them using the current scheme of GR homology groups, which contains 34 groups. However, we needed to create 22 additional GR homology groups to capture all the Rep protein diversity of the plasmid collection. Finally, our bioinformatic analysis suggests that a large fraction of the plasmids seem to have a restricted host range limited to Acinetobacter species, except for those belonging to GR38 that have a very wide host range. To facilitate the future analysis of the Rep proteins, we included a list of the DNA and protein sequences, in fasta format, of the representatives of each one of the GR homology groups.


Synthesis of phosphine derivatives of [Fe2(CO)6(μ-sdt)] (sdt = SCH2SCH2S) and investigation of their proton reduction capabilities.
The reactions of [Fe2(CO)6(μ-sdt)] (1) (sdt = SCH2SCH2S) with phosphine ligands have been investigated. Treatment of 1 with dppm (bis(diphenylphosphino)methane) or dcpm (bis(dicyclohexylphosphino)methane) affords the diphosphine-bridged products [Fe2(CO)4(μ-sdt)(μ-dppm)] (2) and [Fe2(CO)4(μ-sdt)(μ-dcpm)] (3), respectively. The complex [Fe2(CO)4(μ-sdt)(κ2-dppv)] (4) with a chelating diphosphine was obtained by reacting 1 with dppv (cis-1,2-bis(diphenylphosphino)ethene). Reaction of 1 with dppe (1,2-bis(diphenylphosphino)ethane) produces [{Fe2(CO)4(μ-sdt)}2(μ-κ1-dppe)] (5) in which the diphosphine forms an intermolecular bridge between two diiron cluster fragments. Three products were obtained when dppf (1,1'-bis(diphenylphosphino)ferrocene) was introduced to complex 1; they were [Fe2(CO)5(μ-sdt)(κ1-dppfO)] (6), the previously known [{Fe2(CO)5(μ-sdt)}2(μ-κ1-κ1-dppf)] (7), and [Fe2(CO)4(μ-sdt)(μ-dppf)] (8), with complex 8 being produced in highest yield. Single crystal X-ray diffraction analysis was performed on compounds 2, 3 and 8. All structures reveal the adoption of an anti-arrangement of the dithiolate bridges, while the diphosphines occupy dibasal positions. Infra-red spectroscopy indicates that the mono-substituted complexes 5, 6, and 7 are inert to protonation by HBF4.Et2O, but complexes 2, 3, 4 and [Fe2(CO)5(μ-sdt)(κ1-PPh3)] (9) show shifts of their ν(C-O) resonances that indicate that protons bind to the metal cores of the clusters. Addition of the one-electron oxidant [Cp2Fe]PF6 does not lead to any discernable shift in the IR resonances. The redox chemistry of the complexes was investigated by cyclic voltammetry, and the abilities of complexes to catalyze electrochemical proton reduction were examined.


Sunscreens in the United States: Current Status and Future Outlook.
Incidence rates of nonmelanoma skin cancer and melanoma have been on the rise in the USA for the past 25 years. UV radiation (UVR) exposure remains the most preventable environmental risk factor for these cancers. Aside from sun avoidance, sunscreens continue to provide the best alternative protection. UVR directly damages DNA and causes indirect cellular damage through the creation of reactive oxygen species, the sum of which leads to cutaneous immunosuppression and a tumorigenic milieu. The current generation of sunscreens protect from UVR through two main mechanisms: absorption and deflection. In the USA, the Food and Drug Association (FDA) regulates sunscreen products which are considered over-the-counter drugs. With the release of new FDA testing and labeling requirements in 2011 and the enactment of the Sunscreen Innovation Act in 2014, sunscreen manufacturers are now required to evaluate their products not only on the sun protection factor (SPF) but also on broad-spectrum UVA protection. The American Academy of Dermatology Association and the American Academy of Pediatrics have provided specific recommendations for proper sun protection and sunscreen usage with the continual goal of increasing public awareness and compliance with appropriate sun protective measures. Antioxidants, photolyases, and plant polyphenols remain an interesting avenue of research as additives to sunscreens or stand-alone topical or oral products that appear to modulate the immunosuppressive effects of UVR on the skin. Additionally, although UVR induces endogenous cutaneous production of vitamin D, its damaging effects overshadow this positive benefit, especially in light of the ease of achieving recommended amounts of vitamin D through diet and supplementation.


An origin of the radio jet in M87 at the location of the central black hole.
Powerful radio jets from active galactic nuclei are thought to be powered by the accretion of material onto the supermassive black hole (the 'central engine'). M87 is one of the closest examples of this phenomenon, and the structure of its jet has been probed on a scale of about 100 Schwarzschild radii (R(s), the radius of the event horizon). However, the location of the central black hole relative to the jet base (a bright compact radio 'core') remains elusive. Observations of other jets indicate that the central engines are located about 10(4)-10(6)R(s) upstream from the radio core. Here we report radio observations of M87 at six frequencies that allow us to achieve a positional accuracy of about 20 microarcseconds. As the jet base becomes more transparent at higher frequencies, the multifrequency position measurements of the radio core enable us to determine the upstream end of the jet. The data reveal that the central engine of M87 is located within 14-23R(s) of the radio core at 43 GHz. This implies that the site of material infall onto the black hole and the eventual origin of the jet reside in the bright compact region seen on the image at 43 GHz.


The eQTL colocalization and transcriptome-wide association study identify potentially causal genes responsible for economic traits in Simmental beef cattle.
A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle. To prioritize the putative variants and genes, we ran a comprehensive genome-wide association studies (GWAS) analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle. Then, we applied expression quantitative trait loci (eQTL) mapping between the genotype variants and transcriptome of three tissues (longissimus dorsi muscle, backfat, and liver) in 120 cattle. We identified 1,580 association signals for 21 beef agronomic traits using GWAS. We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits. These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions. We observed an average of 43.5% improvement in cis-eQTL discovery using multi-tissue eQTL mapping. Fine-mapping analysis revealed that 111, 192, and 194 variants were most likely to be causative to regulate gene expression in backfat, liver, and muscle, respectively. The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits. Via the colocalization and Mendelian randomization analyses, we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues, which included genes, such as NADSYN1, NDUFS3, LTF and KIFC2 in liver, GRAMD1C, TMTC2 and ZNF613 in backfat, as well as TIGAR, NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits. The extensive atlas of GWAS, eQTL, fine-mapping, and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.


The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase.
Neuroleukin (NLK) is a protein of relative molecular mass (Mr) 56,000 (56K) secreted by denervated rat muscle and found in large amounts in muscle, brain, heart and kidneys. The protein is a neurotrophic factor for spinal and sensory neurons and a lymphokine product of lectin-stimulated T-cells. It also induces immunoglobulin secretion by human mononuclear cells. Molecular clones of NLK have been expressed in monkey COS cells and the product was shown to have the same biological and biochemical properties as the extracted protein. NLK is abundant in muscle, brain and kidney, but is active at concentrations of 10(-9) to 10(-11) M, similar to those for other polypeptide factors. We have cloned the gene for pig muscle phosphohexose isomerase (PHI) (EC 126.96.36.199) which catalyses the conversion of glucose-6-phosphate to fructose-6-phosphate, an obligatory step in glycolysis, and determined its amino-acid sequence. Surprisingly, it is 90% homologous to the sequence of mouse neuroleukin.


Correction: Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget's disease of the scrotum.
[This corrects the article DOI: 10.1371/journal.pone.0254678.].


Development of a novel platform for recombinant protein production in Corynebacterium glutamicum on ethanol.
Corynebacterium glutamicum represents an emerging recombinant protein expression factory due to its ideal features for protein secretion, but its applicability is harmed by the lack of an autoinduction system with tight regulation and high yield. Here, we propose a new recombinant protein manufacturing platform that leverages ethanol as both a delayed carbon source and an inducer. First, we reanalysed the native inducible promoter PICL from the acetate uptake operon and found that its limited capacity is the result of the inadequate translation initial architecture. The two strategies of bicistronic design and ribozyme-based insulator can ensure the high activity of this promoter. Next, through transcriptional engineering that alters transcription factor binding sites (TFBSs) and the first transcribed sequence, the truncated promoter PA256 with a dramatically higher transcription level was generated. When producing the superfolder green fluorescent protein (sfGFP) under 1% ethanol conditions, PA256 exhibited substantially lower protein accumulation in prophase but an approximately 2.5-fold greater final yield than the strong promoter PH36. This superior expression mode was further validated using two secreted proteins, camelid antibody fragment (VHH) and endoxylanase (XynA). Furthermore, utilizing CRISPRi technology, ethanol utilization blocking strains were created, and PA256 was shown to be impaired in the phosphotransacetylase (PTA) knockdown strains, indicating that ethanol metabolism into the tricarboxylic acid cycle is required for PA256 upregulation. Finally, this platform was applied to produce the "de novo design" protein NEO-2/15, and by introducing the N-propeptide of CspB, NEO-2/15 was effectively secreted with the accumulation 281 mg/L obtained after 24 h of shake-flask fermentation. To the best of our knowledge, this is the first report of NEO-2/15 secretory overexpression.


The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.
It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.


Marker-free registration for intraoperative navigation using the transverse palatal rugae.
Registration is most important in navigation-assisted-surgery including the matching between the coordinates of the actual patient space and the medical image. Marker-based techniques mostly include marker application with subsequent radiography. In the edentulous patient, maker-free methods are generally less accurate and reproducible. This new method of a marker-free registration uses the transverse palatal rugae as registration structures. (1) Segmentation of bone and hard palatal mucosa from initial 3D imaging (DICOM), (2) Maxillary intraoral-scan with transfer to the 3D imaging using an Iterative-Closest-Point-Algorithm (ICP), (3) Marking digital registration points with holes within IOS-stl, (4) Transformation of the spatially aligned IOS-stl to LabelMap and storage in DICOM (IOS-DICOM), (5) Alignment of DICOM and IOS-DICOM, (6) Controlled positioning of digital reg. points and clinical correlation. Fiducial localization error (0.48 mm) and Target registration error (0.65 mm) is comparable to those of tooth-supported registration methods. This approach of marker-free registration for navigation-assisted-surgery could improve the treatment in edentulous patients avoiding additional imaging and invasive marker insertion.


A country-wide malaria survey in Mozambique. I. Plasmodium falciparum infection in children in different epidemiological settings.
Across tropical Africa the bulk of malaria-related morbidity and mortality is particularly high during childhood. Classical malariometric surveys have relied on assessing malaria infection prevalence. The last comprehensive evaluation of the malaria situation in Mozambique was carried out during the 1950s. This study aims to characterize the malaria transmission intensities and to estimate the disease burden that may help guide control programme. Between February 2002 and April 2003, a house-to-house survey, was carried out in 24 districts randomly selected. A total of 8,816 children aged below 10 years old were enrolled. Finger prick and blood collection were performed to prepare thick and thin films for malaria parasite species identification, density and haemoglobin concentration. Axillary temperature was also measured. Prevalence of infection, parasite density and anaemia were estimated for age groups category in each region/stratum. Comparisons between proportions were made using Chi-square test or Fisher exact. Relationship between age groups, region/stratum and parasite prevalence, density was determined using linear regression. All survey mean estimations were adjusted for sampling weights, clustering and stratification. Malaria parasite prevalence was 58.9% (5.190/8.816), the majority of blood smears 52.4% (4,616/8,816) were due to Plasmodium falciparum and geometric mean parasite density was 1,211 parasites/microl (95% CI, 1,141-1.286). Gametocytes prevalence, only for P. falciparum was 5.6% (518/8,816). The burden was highest in the northern regions and in the coastal stratum. Parasite infection and geometric mean parasite density peaked during the second year of life and thereafter decreased with increasing age. Mean haemoglobin concentrations was 9.9 g/dl (95% CI 9.5-10.2). Anaemia prevalence was 69.8% (6.257/8.816) and among anaemic children 11.5% (743/6.257) were severely anaemic. Anaemia rose dramatically during the first year of life to peak among children in the 12-23 months age group. Highest levels of anaemia were recorded in both northern and central-northern regions 77.9% and 79.4% respectively. This survey confirms that malaria especially that caused by P. falciparum, remains endemic throughout the country. The burden of malaria disease and anaemia-related malaria during childhood constitute a major public health problem and warrant integrated and collaborative interventions towards its control.