Investigation and kinetic evaluation of the reactions of hydroxymethylfurfural with amino and thiol groups of amino acids.
In this study, reactions of hydroxymethylfurfural (HMF) with selected amino acids (arginine, cysteine and lysine) were investigated in HMF-amino acid (high moisture) and Coffee-amino acid (low moisture) model systems at 5, 25 and 50°C. The results revealed that HMF reacted efficiently and effectively with amino acids in both high and low moisture model systems. High-resolution mass spectrometry (HRMS) analyses of the reaction mixtures confirmed the formations of Michael adduct and Schiff base of HMF with amino acids. Calculated pseudo-first order reaction rate constants were in the following order; kCysteine>kArginine>kLysine for high moisture model systems. Comparing to these rate constants, the kCysteine decreased whereas, kArginine and kLysine increased under the low moisture conditions of Coffee-amino acid model systems. The temperature dependence of the rate constants was found to obey the Arrhenius law in a temperature range of 5-50°C under both low and high moisture conditions.


Predictors for recurrent chest pain and relationship to myocardial ischaemia during long-term follow-up after coronary artery bypass grafting.
To describe the impact of coronary artery bypass grafting on chest pain during 2 years of follow-up after the operation and to identify predictors of chest pain and its relationship to myocardial ischaemia 2 years after the operation. Patients were approached with a questionnaire at the time of coronary angiography (1291) and 3 months (1664), 1 year (1638) and 2 years (1613) after coronary artery bypass grafting. Two years after the operation, a computerised 12-lead electrocardiogram was obtained during a standardised bicycle exercise test (618). Prior to surgery, 37% of the patients were unable to perform physical activity compared with 6% after the operation (P < 0.0001 for change in degree of limitation). Only 3% had no chest pain at all prior to the operation, while 58% of the patients were free from chest pain 2 years after surgery (P < 0.0001). We found no correlation between patients reporting chest pain and signs of ischaemia at exercise test, but there was a highly significant correlation with chest pain during the exercise test (P < 0.0001). Independent predictors of chest pain were severity of preoperative angina (P < 0.0001), younger age (P = 0.0009), previous coronary artery bypass grafting (P = 0.003), duration of symptoms (P = 0.005), the need for prolonged cardiopulmonary bypass (P = 0.04) and the absence of left main stenosis (P = 0.04). Independent predictors of chest pain were identified 2 years after coronary artery bypass grafting. There was a dramatic improvement after coronary artery bypass grafting. However, almost half the patients complained of some kind of chest pain even after the operation. This chest pain correlated well with chest pain during the exercise test but not with signs of myocardial ischaemia.


T-138C polymorphism of matrix gla protein promoter alters its expression but is not directly associated with atherosclerotic vascular calcification.
Matrix Gla protein (MGP) is a crucial inhibitor of vessel and cartilage calcification. We investigated the association of T-138C MGP promoter polymorphism with the degree of atherosclerosis, vascular calcification and patients' clinical background including calcification of the trachea and costal cartilage. Analysis of 108 autopsy cases was carried out by polymorphism-specific PCR on formalin-fixed paraffin-embedded samples. Statistical correlations among eight risk factors and five markers related to atherosclerosis and extra-bone tissue calcification were multivariantly analyzed. We found very high canonical correlations between the factors and the markers, and Pearson's correlation analysis revealed six significant correlations between age and the Gore index; age and costal cartilage calcification; sex and costal cartilage calcification; hypertension and the Gore index; hypertension and the calcification factor of the Gore index; and hyperlipidemia and costal cartilage calcification. The promoter activity of the -138T allele was significantly higher than that of the -138C allele; treatment with 12-O-tetradecanonylphorbol 13-acetate (TPA) significantly activated the former, but had almost no effect on the latter. The C genotype was significantly common among Japanese subjects, (TT 45.5%, TC 37.6% and CC 16.8%) compared with that reported in the Netherlands, Northern Ireland and France. No significant correlation was observed, however, between T-138C MGP promoter polymorphism and the markers. Although the C genotype (TC+CC) tended to show a higher calcification factor than the TT genotype, no significant difference was observed among the genotypes in the Gore index or in the calcification factor. Although MGP promoter activity and the binding of the AP-1 transcription factor were clearly different between T-138 and C-138 MGP promoter polymorphism in vitro, T-138C polymorphism was, statistically, not an independent factor of atherosclerosis or atherosclerotic vascular calcification in the abdominal aorta.


The predictive value of flow-mediated dilation and carotid artery intima-media thickness for occult coronary artery disease.
Multidetector row computed tomography (MDCT) is an attractive noninvasive alternative to assess overall coronary artery disease (CAD) burden and may reveal coronary plaques, which may be underestimated by conventional coronary angiography. The aim of this study was to determine whether brachial artery flow-mediated dilation (FMD) and carotid artery intima-media thickness (CIMT) might accurately predict patients with occult coronary plaques whose conventional coronary angiographies revealed normal coronary arteries (NCA). Thirty-five patients with angiographically NCA were consecutively recruited into the study. They underwent MDCT and were divided into NCA group (18 patients; 8 male; 47 ± 9 years) and occult CAD group (17 patients; 11 male; 50 ± 10 years) according to presence of coronary plaque. Nineteen consecutive patients with evident CAD (16 male; 54 ± 7 years) and 19 healthy subjects (10 male; 50 ± 6 years) were included as control groups. FMD and CIMT were measured by brachial and carotid artery ultrasonography. Occult CAD group had significantly lower FMD and insignificantly higher CIMT than NCA group whereas they had significantly higher FMD and insignificantly lower CIMT than evident CAD group. NCA group had significantly lower CIMT than evident CAD group. Receiver operating characteristic curve analysis demonstrated FMD < 8% (sensitivity: 94.4%; specificity: 73.0%; PPV: 77.3%; NPV: 93.1%) and CIMT ≥ 0.65 cm (sensitivity: 72.2%; specificity: 62.2%; PPV: 65.0%; NPV: 69.7%) could predict patients with CAD. FMD and CIMT were independent predictors of CAD (P < 0.001; OR: 45.630; 95%CI: 5.38-386.983 and P = 0.015; OR: 14.226; 95%CI: 1.666-121.467, respectively). FMD and CIMT might predict patients with occult CAD and be helpful in selecting patients for MDCT.


Trait-anger enhances effects of caffeine on psychomotor vigilance performance.
This study examined the combined effects of caffeine and the personality attribute of trait-anger on the speed of psychomotor vigilance performance during sleep deprivation. 23 young adult soldiers (19 male) were administered the State-Trait Anger Expression Inventory-2 when well-rested. Participants were then sleep deprived for three consecutive nights (77 hours total) during which they completed repeated psychomotor vigilance testing. Half of the participants received four doses of oral caffeine (200 mg every 2 hr.; 800 mg total) each night, while the other half were administered a placebo. For the first night, higher scores on trait-anger, outward anger expression, and intensity of anger expression predicted better sustained overnight vigilance performance, but only for those volunteers receiving caffeine. These correlations were not significant for the subsequent nights. Findings suggest a possible synergistic effect between personality traits associated with arousal of the central nervous system and vigilance-promoting effects of caffeine.


Cardiac spheroids as promising in vitro models to study the human heart microenvironment.
Three-dimensional in vitro cell systems are a promising alternative to animals to study cardiac biology and disease. We have generated three-dimensional in vitro models of the human heart ("cardiac spheroids", CSs) by co-culturing human primary or iPSC-derived cardiomyocytes, endothelial cells and fibroblasts at ratios approximating those present in vivo. The cellular organisation, extracellular matrix and microvascular network mimic human heart tissue. These spheroids have been employed to investigate the dose-limiting cardiotoxicity of the common anti-cancer drug doxorubicin. Viability/cytotoxicity assays indicate dose-dependent cytotoxic effects, which are inhibited by the nitric oxide synthase (NOS) inhibitor L-NIO, and genetic inhibition of endothelial NOS, implicating peroxynitrous acid as a key damaging agent. These data indicate that CSs mimic important features of human heart morphology, biochemistry and pharmacology in vitro, offering a promising alternative to animals and standard cell cultures with regard to mechanistic insights and prediction of toxic effects in human heart tissue.


Assessment of Equine Autoimmune Thrombocytopenia (EAT) by flow cytometry.
RATIONALE: Thrombocytopenia is a platelet associated process that occurs in human and animals as result of i) decreased production; ii) increased utilization; iii) increased destruction coupled to the presence of antibodies, within a process know as immune-mediated thrombocytopenia (IMT); or iv) platelet sequestration. Thus, the differentiation of the origin of IMT and the development of reliable diagnostic approaches and methodologies are important in the clarification of IMT pathogenesis. Therefore, there is a growing need in the field for easy to perform assays for assessing platelet morphological characteristics paired with detection of platelet-bound IgG. OBJECTIVES: This study is aimed to develop and characterize a single color flow cytometric assay for detection of platelet-bound IgG in horses, in combination with flow cytometric assessment of platelet morphological characteristics. FINDINGS: The FSC and SSC evaluation of the platelets obtained from the thrombocytopenic animals shows several distinctive features in comparison to the flow cytometric profile of platelets from healthy animals. The thrombocytopenic animals displayed i) increased number of platelets with high FSC and high SSC, ii) a significant number of those gigantic platelets had strong fluorescent signal (IgG bound), iii) very small platelets or platelet derived microparticles were found significantly enhanced in one of the thrombocytopenic horses, iv) significant numbers of these microplatelet/microparticles/platelet-fragments still carry very high fluorescence. CONCLUSIONS: This study describes the development and characterization of an easy to perform, inexpensive, and noninvasive single color flow cytometric assay for detection of platelet-bound IgG, in combination with flow cytometric assessment of platelet morphological characteristics in horses.


The transseptal approach for ablation of cardiac arrhythmias: experience of 104 procedures.
To report retrospectively on the training and subsequent experience of two operators in transseptal ablation of arrhythmias arising in the left atrium and left atrioventricular annulus, to show whether, with adequate training and careful attention to detail, this is a safe and effective technique. Electrophysiological studies and transseptal procedures were performed in the electrophysiology laboratories of the Moffatt Hospital, University of California at San Francisco (39) and Manchester Royal Infirmary (65) from January 1993 to June 1997. Close supervision by a fully trained operator was provided for at least the first 20 procedures performed by each operator. 94 consecutive patients underwent electrophysiological study and ablation for Wolff-Parkinson-White syndrome with left sided accessory connections (81 patients) or ectopic atrial tachycardia (13 patients); 104 transseptal procedures were done; eight patients required multiple procedures. 92 patients (98%) were initially successfully ablated. Five of 81 with accessory pathways (6%) and three of 13 with atrial tachycardia (23%) required further procedures. One patient with Wolff-Parkinson-White syndrome could not be ablated at a second procedure. Long term success rate for accessory pathway ablation was therefore 99%. Procedures were abandoned in three patients because of minor complications. All were subsequently ablated successfully by a transseptal approach on another day. The transseptal approach is safe and effective for ablation of left sided arrhythmias. The technique has similar success rates to the retrograde transaortic approach but without the risk of inadvertent damage to the coronary arteries or aortic valve.


Escherichia coli σ70 promoters allow expression rate control at the cellular level in genome-integrated expression systems.
The genome-integrated T7 expression system offers significant advantages, in terms of productivity and product quality, even when expressing the gene of interest (GOI) from a single copy. Compared to plasmid-based expression systems, this system does not incur a plasmid-mediated metabolic load, and it does not vary the dosage of the GOI during the production process. However, long-term production with T7 expression system leads to a rapidly growing non-producing population, because the T7 RNA polymerase (RNAP) is prone to mutations. The present study aimed to investigate whether two σ70 promoters, which were recognized by the Escherichia coli host RNAP, might be suitable in genome-integrated expression systems. We applied a promoter engineering strategy that allowed control of expressing the model protein, GFP, by introducing lac operators (lacO) into the constitutive T5 and A1 promoter sequences. We showed that, in genome-integrated E. coli expression systems that used σ70 promoters, the number of lacO sites must be well balanced. Promoters containing three and two lacO sites exhibited low basal expression, but resulted in a complete stop in recombinant protein production in partially induced cultures. In contrast, expression systems regulated by a single lacO site and the lac repressor element, lacIQ, on the same chromosome caused very low basal expression, were highly efficient in recombinant protein production, and enables fine-tuning of gene expression levels on a cellular level. Based on our results, we hypothesized that this phenomenon was associated with the autoregulation of the lac repressor protein, LacI. We reasoned that the affinity of LacI for the lacO sites of the GOI must be lower than the affinity of LacI to the lacO sites of the endogenous lac operon; otherwise, LacI autoregulation could not take place, and the lack of LacI autoregulation would lead to a disturbance in lac repressor-mediated regulation of transcription. By exploiting the mechanism of LacI autoregulation, we created a novel E. coli expression system for use in recombinant protein production, synthetic biology, and metabolic engineering applications.


The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects.
Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named "cerebral insulin resistance", is responsible for overeating and the development of obesity. To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a "cerebral insulin resistance" in obese subjects and might be relevant in the pathogenesis of obesity.


Optimization of the spatial light modulation with twisted nematic liquid crystals by a genetic algorithm.
An optimization technique determining the configuration of optical components in a spatial light modulator is proposed. We study a spatial light modulator composed of a twisted nematic liquid crystal, a polarization state generator, and a polarization state detector. To obtain the desired phase and amplitude modulations, four parameters of the polarization state generator and detector should be optimized. A genetic algorithm is applied in searching the configurations suitable to a given twisted nematic liquid crystal. By embodying the proposed technique, the evolution of the designed cost functions is proved.


Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias.
The diagnosis of idiopathic immune thrombocytopenia remains a clinical diagnosis based on the exclusion of other causes of immune and nonimmune thrombocytopenia. Measurement of platelet-associated Ig (PAIg), while sensitive, is nonspecific for the diagnosis of immune thrombocytopenia. Published experience of antigen capture assays (including monoclonal antibody immobilization of platelet antigens or MAIPA) suggest a high sensitivity and specificity (70% to 80%) in selected groups of patients. In a prospective evaluation of 158 patients with thrombocytopenia from all causes, we report a sensitivity of 51% and specificity of 80% for direct MAIPA assays. MAIPA was considerably better in discriminating immune from nonimmune thrombocytopenia than two assays of PAIgG. Antiplatelet antibodies detected by MAIPA were more frequently directed against the glycoprotein (GP) IIb/IIIa than the GP Ib/IX complex. Our experience suggests that MAIPA assays are useful in the laboratory assessment of thrombocytopenia, should be performed before therapy, and that some patients with 'nonimmune' thrombocytopenia may have genuine antiplatelet antibodies.


Lotus Accessions Possess Multiple Checkpoints Triggered by Different Type III Secretion System Effectors of the Wide-Host-Range Symbiont Bradyrhizobium elkanii USDA61.
Bradyrhizobium elkanii, a rhizobium with a relatively wide host range, possesses a functional type III secretion system (T3SS) that is involved in symbiotic incompatibility against Rj4-genotype soybean (Glycine max) and some accessions of mung bean (Vigna radiata). To expand our knowledge on the T3SS-mediated partner selection mechanism in the symbiotic legume-rhizobia association, we inoculated three Lotus experimental accessions with wild-type and T3SS-mutant strains of B. elkanii USDA61. Different responses were induced by T3SS in a host genotype-dependent manner. Lotus japonicus Gifu inhibited infection; L. burttii allowed infection, but inhibited nodule maturation at the post-infection stage; and L. burttii and L. japonicus MG-20 both displayed a nodule early senescence-like response. By conducting inoculation tests with mutants of previously reported and newly identified effector protein genes of B. elkanii USDA61, we identified NopF as the effector protein triggering the inhibition of infection, and NopM as the effector protein triggering the nodule early senescence-like response. Consistent with these results, the B. elkanii USDA61 gene for NopF introduced into the Lotus symbiont Mesorhizobium japonicum induced infection inhibition in L. japonicus Gifu, but did not induce any response in L. burttii or L. japonicus MG-20. These results suggest that Lotus accessions possess at least three checkpoints to eliminate unfavorable symbionts, including the post-infection stage, by recognizing different T3SS effector proteins at each checkpoint.


Detoxification of azo dyes by bacterial oxidoreductase enzymes.
Azo dyes and their intermediate degradation products are common contaminants of soil and groundwater in developing countries where textile and leather dye products are produced. The toxicity of azo dyes is primarily associated with their molecular structure, substitution groups and reactivity. To avoid contamination of natural resources and to minimize risk to human health, this wastewater requires treatment in an environmentally safe manner. This manuscript critically reviews biological treatment systems and the role of bacterial reductive and oxidative enzymes/processes in the bioremediation of dye-polluted wastewaters. Many studies have shown that a variety of culturable bacteria have efficient enzymatic systems that can carry out complete mineralization of dye chemicals and their metabolites (aromatic compounds) over a wide range of environmental conditions. Complete mineralization of azo dyes generally involves a two-step process requiring initial anaerobic treatment for decolorization, followed by an oxidative process that results in degradation of the toxic intermediates that are formed during the first step. Molecular studies have revealed that the first reductive process can be carried out by two classes of enzymes involving flavin-dependent and flavin-free azoreductases under anaerobic or low oxygen conditions. The second step that is carried out by oxidative enzymes that primarily involves broad specificity peroxidases, laccases and tyrosinases. This review focuses, in particular, on the characterization of these enzymes with respect to their enzyme kinetics and the environmental conditions that are necessary for bioreactor systems to treat azo dyes contained in wastewater.


Computer-based information collection and feedback for Norwegian municipal health and social services.
Norway is governed by a three-tier parliamentary system where each tier is governed by a popularly selected body: the national parliament, the county councils, and the municipality councils. This three-tier system is in many ways also reflected in the organization, management, and financing of health and social services. A large amount of information (e.g.,statistics and annual reports) flows between the three levels of management. In order to have a proper and efficient information flow, The Norwegian Ministry of Health and Social Affairs has, since 1992, been conducting a nation-wide project for information collection from and feedback to municipal health and social services (see Figure 1). In this presentation, we will present the basic idea behind The Wheel. We will also discuss some of the major activities in and experiences from the project of using Information Technology to implement an electronic Wheel. The following are basic issues to consider in implementing such a system, related to the following basic issues in implementing such a system [1]: Obtaining a unified information basis to: increase the data quality, and compile "definition catalogs" that contain commonly agreed-upon definitions of central concepts and data sets that are used in the municipal health and social services [2]. Achieving electronic data collection, both in terms of the automatic selection and aggregation of relevant data from operational systems in the municipalities and in terms of using Electronic Forms. Experiments with various ways of electronically feeding back the statistics and other comparative data to the municipalities. Providing the municipal users with appropriate tools for using the statistics that are fed back.


A role for REV3 in mutagenesis during double-strand break repair in Saccharomyces cerevisiae.
Recombinational repair of double-strand breaks (DSBs), traditionally believed to be an error-free DNA repair pathway, was recently shown to increase the frequency of mutations in a nearby interval. The reversion rate of trp1 alleles (either nonsense or frameshift mutations) near an HO-endonuclease cleavage site is increased at least 100-fold among cells that have experienced an HO-mediated DSB. We report here that in strains deleted for rev3 this DSB-associated reversion of a nonsense mutation was greatly decreased. Thus REV3, which encodes a subunit of the translesion DNA polymerase zeta, was responsible for the majority of these base substitution errors near a DSB. However, rev3 strains showed no decrease in HO-stimulated recombination, implying that another DNA polymerase also functioned in recombinational repair of a DSB. Reversion of trp1 frameshift alleles near a DSB was not reduced in rev3 strains, indicating that another polymerase could act during DSB repair to make these frameshift errors. Analysis of spontaneous reversion in haploid strains suggested that Rev3p had a greater role in making point mutations than in frameshift mutations.


Hepatitis B surface antigenemia (HBsAg) among pregnant women in southern Nigeria.
Hepatitis B virus (HBV) infection is one of the most common public health problems worldwide. Over one million people die annually of HBV- related chronic liver disease. Maternal to fetal transmission from chronic carriers exceeds 90% and accounts for up to 40% of the world's chronic carriers in endemic areas. This was a descriptive study which involved Serial recruitment of 836 women attending the antenatal clinic at a health facility in Cross-River State, Nigeria from 1(st) January to 30(th) June 2010. HBsAg screening was done using an ELISA test. Fifty five (6.6%) of the 836 women screened tested positive for HBsAg. The mean age and parity of sero-positive subjects was 26.9 ±5.0 (range 18-38 years) and 2.2±1.2 (0 to 5) respectively. The prevalence was more in women who were farmers (29.1%) and those with either none or low level of formal education (67.2%). Sero-prevalence of 6.6% among pregnant women is reported. Women education, economic empowerment and public enlightenment programmes focused on modification of risky social lifestyle is recommended. Efforts to promote routine screening of pregnant women, immunization and vaccination of infants should be sustained.


A platelet P-selectin test predicts adverse cardiovascular events in patients with acute coronary syndromes treated with aspirin and clopidogrel.
There is wide variation in response to antiplatelet therapy and high on-treatment platelet reactivity is associated with adverse cardiovascular events. The objective here was to determine whether the results of a novel strategy for assessing platelet reactivity (based on P-selectin measurement) are associated with clinical outcomes in patients with acute coronary syndromes (ACS). This was a prospective cohort study of 100 ACS patients taking aspirin and clopidogrel. P-selectin tests designed to assess response to P2Y12 antagonists or aspirin were performed alongside light transmission aggregometry. For the P2Y12 P-selectin test, an optimal cutoff for high platelet reactivity was determined by receiver operating characteristic (ROC) curve analysis. Patients were divided into two cohorts based on this value: patients with (n = 42) or without (n = 58) high platelet reactivity. The primary endpoint was defined as the composite of cardiovascular death, myocardial infarction and stent thrombosis. After 12 months, the primary endpoint occurred in 12 patients. ROC curve analysis determined that the P2Y12 P-selectin test results were predictive of the primary endpoint (area under curve = 0.69, p = 0.046). The primary endpoint occurred more frequently in patients with high on-treatment platelet reactivity compared to those without (21.4% vs. 5.2%; hazard ratio (HR) 4.14; p = 0.026). The P2Y12 P-selectin test results correlated with light transmission aggregometry (Spearman p < 0.0001). Using the Aspirin P-selectin test, only two patients demonstrated high on-treatment platelet reactivity. This study suggests that a P2Y12 P-selectin test is capable of detecting high on-treatment platelet reactivity, which is associated with subsequent cardiovascular events.


Fast bi-directional prediction selection in H.264/MPEG-4 AVC temporal scalable video coding.
In this paper, we propose a fast algorithm that efficiently selects the temporal prediction type for the dyadic hierarchical-B prediction structure in the H.264/MPEG-4 temporal scalable video coding (SVC). We make use of the strong correlations in prediction type inheritance to eliminate the superfluous computations for the bi-directional (BI) prediction in the finer partitions, 16×8/8×16/8×8 , by referring to the best temporal prediction type of 16 × 16. In addition, we carefully examine the relationship in motion bit-rate costs and distortions between the BI and the uni-directional temporal prediction types. As a result, we construct a set of adaptive thresholds to remove the unnecessary BI calculations. Moreover, for the block partitions smaller than 8 × 8, either the forward prediction (FW) or the backward prediction (BW) is skipped based upon the information of their 8 × 8 partitions. Hence, the proposed schemes can efficiently reduce the extensive computational burden in calculating the BI prediction. As compared to the JSVM 9.11 software, our method saves the encoding time from 48% to 67% for a large variety of test videos over a wide range of coding bit-rates and has only a minor coding performance loss.


Tombusviruses Target a Major Crossroad in the Endocytic and Recycling Pathways via Co-opting Rab7 Small GTPase.
Positive-strand RNA viruses induce the biogenesis of unique membranous organelles called viral replication organelles (VROs), which perform virus replication in infected cells. Tombusviruses have been shown to rewire cellular trafficking and metabolic pathways, remodel host membranes, and recruit multiple host factors to support viral replication. In this work, we demonstrate that tomato bushy stunt virus (TBSV) and the closely related carnation Italian ringspot virus (CIRV) usurp Rab7 small GTPase to facilitate building VROs in the surrogate host yeast and in plants. Depletion of Rab7 small GTPase, which is needed for late endosome and retromer biogenesis, strongly inhibits TBSV and CIRV replication in yeast and in planta. The viral p33 replication protein interacts with Rab7 small GTPase, which results in the relocalization of Rab7 into the large VROs. Similar to the depletion of Rab7, the deletion of either MON1 or CCZ1 heterodimeric GEFs (guanine nucleotide exchange factors) of Rab7 inhibited TBSV RNA replication in yeast. This suggests that the activated Rab7 has proviral functions. We show that the proviral function of Rab7 is to facilitate the recruitment of the retromer complex and the endosomal sorting nexin-BAR proteins into VROs. We demonstrate that TBSV p33-driven retargeting of Rab7 into VROs results in the delivery of several retromer cargos with proviral functions. These proteins include lipid enzymes, such as Vps34 PI3K (phosphatidylinositol 3-kinase), PI4Kα-like Stt4 phosphatidylinositol 4-kinase, and Psd2 phosphatidylserine decarboxylase. In summary, based on these and previous findings, we propose that subversion of Rab7 into VROs allows tombusviruses to reroute endocytic and recycling trafficking to support virus replication. IMPORTANCE The replication of positive-strand RNA viruses depends on the biogenesis of viral replication organelles (VROs). However, the formation of membranous VROs is not well understood yet. Using tombusviruses and the model host yeast, we discovered that the endosomal Rab7 small GTPase is critical for the formation of VROs. Interaction between Rab7 and the TBSV p33 replication protein leads to the recruitment of Rab7 into VROs. TBSV-driven usurping of Rab7 has proviral functions through facilitating the delivery of the co-opted retromer complex, sorting nexin-BAR proteins, and lipid enzymes into VROs to create an optimal milieu for virus replication. These results open up the possibility that controlling cellular Rab7 activities in infected cells could be a target for new antiviral strategies.


Polarity-independent effects of transcranial direct current stimulation over the bilateral opercular somatosensory region: a magnetoencephalography study.
The opercular somatosensory region (OP) plays an indispensable role in pain perception. In the present study, we investigated the neurophysiological effects of transcranial direct current stimulation (tDCS) over the OP. Somatosensory-evoked magnetic fields following noxious intraepidermal electrical stimulation to the left index finger (pain-SEFs) were recorded before and after tDCS with a single-blind, sham-controlled, cross-over trial design. Three tDCS conditions of left anodal/right cathodal tDCS, left cathodal/right anodal tDCS (each, 2 mA, 12 min), and sham tDCS (2 mA, 15 s) were applied. Despite the subjective pain sensation being unaltered, the two anodal (real) interventions significantly decreased OP activity associated with pain-SEFs. In conclusion, tDCS over the OP with the present parameters did not have a significant impact on pain sensation, but modulated its cortical processing.


Protection against Pertussis in Humans Correlates to Elevated Serum Antibodies and Memory B Cells.
Pertussis is a respiratory infection caused by Bordetella pertussis that may be particularly severe and even lethal in the first months of life when infants are still too young to be vaccinated. Adults and adolescents experience mild symptoms and are the source of infection for neonates. Adoptive maternal immunity does not prevent pertussis in the neonate. We compared the specific immune response of mothers of neonates diagnosed with pertussis and mothers of control children. We show that women have pre-existing pertussis-specific antibodies and memory B cells and react against the infection with a recall response increasing the levels specific serum IgG, milk IgA, and the frequency of memory B cells of all isotypes. Thus, the maternal immune system is activated in response to pertussis and effectively prevents the disease indicating that the low levels of pre-formed serum antibodies are insufficient for protection. For this reason, memory B cells play a major role in the adult defense. The results of this study suggest that new strategies for vaccine design should aim at increasing long-lived plasma cells and their antibodies.


Transfer of the conjugal tetracycline resistance transposon Tn916 from Streptococcus faecalis to Staphylococcus aureus and identification of some insertion sites in the staphylococcal chromosome.
The Streptococcus faecalis pheromone-dependent conjugative plasmid pAD1::Tn916 and the membrane filter-dependent conjugative plasmid pPD5::Tn916 were used to introduce Tn916 into Staphylococcus aureus by intergeneric protoplast fusions and intergeneric membrane-filter matings. In recombinants obtained by protoplast fusion where no plasmid DNA could be detected, tetracycline resistance resulted from transposition of Tn916 from pAD1 to the S. aureus chromosome. Transformation analyses showed that S. aureus Tn916 chromosomal insertions occurred near pig, ilv, uraA, tyrB, fus, ala, and the trp operon. DNA hybridization analyses of EcoRI- and HindIII-digested chromosomal DNAs confirmed the diversity of chromosomal sites involved and demonstrated that the inserts were Tn916 insertions rather than integrations of all or part of pAD1::Tn916. Both pAD1::Tn916 and pPD5::Tn916 were transferred to S. aureus by membrane-filter matings. These plasmids remained intact and expressed tetracycline resistance in S. aureus. S. aureus strains carrying pAD1::Tn916, but not a chromosomal insert of Tn916, and any one of several conjugal gentamicin-resistance plasmids lost their ability to serve as conjugal donors of the gentamicin-resistance plasmids.


Rule-based interpretation of aerial imagery.
In this paper, we describe the organization of a rule-based system, SPAM, that uses map and domain-specific knowledge to interpret airport scenes. This research investigates the use of a rule-based system for the control of image processing and interpretation of results with respect to a world model, as well as the representation of the world model within an image/map database. We present results on the interpretation of a high-resolution airport scene wvhere the image segmentation has been performed by a human, and by a region-based image segmentation program. The results of the system's analysis is characterized by the labeling of individual regions in the image and the collection of these regions into consistent interpretations of the major components of an airport model. These interpretations are ranked on the basis of their overall spatial and structural consistency. Some evaluations based on the results from three evolutionary versions of SPAM are presented.


Differential transcriptional profiles induced by amphotericin B formulations on human monocytes during response to hyphae of Aspergillus fumigatus.
Amphotericin B formulations possess diverse immunomodulatory properties that may contribute to the activity of phagocytes against invasive aspergillosis. In this work we provide a novel set of data on different gene transcriptional profiles of monocytes exposed to the combination of Aspergillus fumigatus and amphotericin B formulations. We used pathway-specific microarray analysis, RT-PCR analysis and enzyme-linked immunosorbent assays to compare the effects of amphotericin B deoxycholate (DAMB) at 1 μg/ml and amphotericin B lipid complex (ABLC) at 5 μg/ml to assess gene expression of immune molecules of THP-1 cells exposed to A. fumigatus hyphae (AF) for 4 h. A. fumigatus hyphae at effector/target ratio 10/1 induced mostly chemotactic factors for monocyte recruitment. DAMB at 1 μg/ml in the presence or absence of AF induced the most pronounced changes in pro-inflammatory and chemokine gene expression, while ABLC under the same conditions caused less dramatic effect. There was a reciprocal response of increased expression of the genes encoding IL-1β and IL-20 and decreased expression of IL-10, IL-2 and IL-3 in response of monocytes to both the hyphae and antifungal agents. These results demonstrate that amphotericin B formulations exert differential effects on genes encoding pro-inflammatory molecules, immunoregulatory molecules and chemokines by human monocytes during response to A. fumigatus and that these molecules may affect antifungal activity.


The p.Cys169Tyr variant of connexin 26 is not a polymorphism.
Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26 (Cx26), are the primary cause of hereditary prelingual hearing impairment. Here, the p.Cys169Tyr missense mutation of Cx26 (Cx26C169Y), previously classified as a polymorphism, has been identified as causative of severe hearing loss in two Qatari families. We have analyzed the effect of this mutation using a combination of confocal immunofluorescence microscopy and molecular dynamics simulations. At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT). The lack of the disulfide bridge in the Cx26C169Y protein causes a spatial rearrangement of two important residues, Asn176 and Thr177. In the Cx26WT protein, these residues play a crucial role in the intra-molecular interactions that permit the formation of an intercellular channel by the head-to-head docking of two opposing hemichannels resident in the plasma membrane of adjacent cells. Our results elucidate the molecular pathogenesis of hereditary hearing loss due to the connexin mutation and facilitate the understanding of its role in both healthy and affected individuals.


Sequential combination of karyotyping and RNA-sequencing in the search for cancer-specific fusion genes.
Cancer-specific fusion genes are often caused by cytogenetically visible chromosomal rearrangements such as translocations, inversions, deletions or insertions, they can be the targets of molecular therapy, they play a key role in the accurate diagnosis and classification of neoplasms, and they are of prognostic impact. The identification of novel fusion genes in various neoplasms therefore not only has obvious research importance, but is also potentially of major clinical significance. The "traditional" methodology to detect them began with cytogenetic analysis to find the chromosomal rearrangement, followed by utilization of fluorescence in situ hybridization techniques to find the probe which spans the chromosomal breakpoint, and finally molecular cloning to localize the breakpoint more precisely and identify the genes fused by the chromosomal rearrangement. Although laborious, the above-mentioned sequential approach is robust and reliable and a number of fusion genes have been cloned by such means. Next generation sequencing (NGS), mainly RNA sequencing (RNA-Seq), has opened up new possibilities to detect fusion genes even when cytogenetic aberrations are cryptic or information about them is unknown. However, NGS suffers from the shortcoming of identifying as "fusion genes" also many technical, biological and, perhaps in particular, clinical "false positives," thus making the assessment of which fusions are important and which are noise extremely difficult. The best way to overcome this risk of information overflow is, whenever reliable cytogenetic information is at hand, to compare karyotyping and sequencing data and concentrate exclusively on those suggested fusion genes that are found in chromosomal breakpoints. This article is part of a Directed Issue entitled: Rare Cancers.


An active microwave imaging system for reconstruction of 2-D electrical property distributions.
The goal of this work is to develop a microwave-based imaging system for hyperthermia treatment monitoring and assessment. Toward this end, a four transmit channel and four receive channel hardware device and concomitant image reconstruction algorithm have been realized. The hardware is designed to measure electric fields (i.e., amplitude and phase) at various locations in a phantom tank with and without the presence of various heterogeneities using standard heterodyning principles. Particular attention has been paid to designing a receiver with better than 115 dB of linear dynamic range which is necessary for imaging biological tissue which often has very high conductivity, especially for tissues with high water content. A calibration procedure has been developed to compensate for signal loss due to three-dimensional radiation in the measured data, since the reconstruction process is only two-dimensional at the present time. Results are shown which demonstrate the stability and accuracy of the measurement system, the extent to which the forward computational model agrees with the measured field distribution when the electrical properties are known, and image reconstructions of electrically unknown targets of varying diameter. In the latter case, images of both the reactive and resistive component of the electrical property distribution have been recoverable. Quantitative information on object location, size, and electrical properties results when the target is approximately one-half wavelength in size. Images of smaller objects lack the same level of quantitative information, but remain qualitatively correct.


Complications of skull caliper traction.
During a period of 20 years 88 patients with fracture dislocation of the cervical spine were treated by attaching Crutchfield tongs to the skull. Sixty-seven per cent of all patients had some complications. The different types of complications are reported and discussed in order of frequency.


Physicochemical and bacteriological assessment of Wupa wastewater treatment plant effluent and the effluent-receiving Wupa River in Abuja, Nigeria.
The occurrence of pathogens in discharged wastewater effluent may constitute potential public health risks. This study assessed the physicochemical and bacteriological characteristics of water samples taken from the Wupa River in Abuja, Nigeria, which receives the final effluent of the Wupa Wastewater Treatment Plant. Sixty sewage/water samples were collected over 12 months from five sampling points. Coliform bacteria and Escherichia coli were simultaneously enumerated using the membrane filtration technique and Chromocult Coliform Agar. HANNA multiparameter metre was used to measure the physicochemical parameters including temperature, pH, electrical conductivity (EC), dissolved oxygen (DO) and total dissolved solids (TDS). Results of the bacteriological analysis showed that impermissible high mean counts of E. coli (≥ 1.2 × 104 CFU/100 ml) and total coliforms (≥ 5.4 × 104 CFU/100 ml) were detected in 95% and 100% of the water samples respectively. These values exceed the acceptable standard limits. The mean values of physicochemical parameters ranged from 6.3 to 8.7, 20.9 to 27.3 °C, 116 to 325.0 µS/cm, 1.3 to 11.4 mg/l and 98.0 to 180.0 mg/l for pH, temperature, EC, DO and TDS respectively, with all conforming to international and national standards. Wupa River seems to have a minor negative environmental impact, per the physicochemical data obtained in this study. However, the high counts of faecal indicator bacteria demonstrated in the effluent samples were higher than those of the river at both upstream and downstream sites, implying that the river microbial load may increase to constitute an unchecked environmental hazard. Adequate disinfection of the Wupa plant effluent before discharge into the Wupa River is imperative.


Approaches to Deprescribing Psychotropic Medications for Changed Behaviours in Long-Term Care Residents Living with Dementia.
Psychotropic medications have a high risk of serious adverse events and small effect size for changed behaviours for people with dementia. Non-pharmacological approaches are recommended as first-line treatment for changed behaviours, yet psychotropic medications remain highly prevalent in long-term aged care settings. This narrative review describes the current evidence regarding deprescribing psychotropic medications for people with dementia in long-term care. Deprescribing psychotropic medications can be achieved without harm to the person with dementia, and most people experience no withdrawal symptoms. Interventions to deprescribe psychotropic medications should be multifactorial, including lowering the dose of the medication over time, educational interventions and psychological support. However, implementing this is a significant challenge due to the overreliance on psychotropic medications for behavioural management in long-term aged care. Facilitators to deprescribing psychotropic medications in long-term care include multidisciplinary teams with adequate training, education and managerial support, engaging residents and families and change 'champions'. Deprescribing practices should be person-centred, and an individualised deprescribing protocol should be in place, followed by careful monitoring of the individual. The person with dementia and their family, general practitioner, pharmacist, and allied health and direct care staff should all be involved throughout the deprescribing process. Direct care staff need adequate support, education and training, so they can effectively help the individual and implement person-centred approaches in the absence of psychotropic medications. Effective communication between residents and staff and amongst staff is consistently shown to be an important factor for deciding whether deprescribing of a medication should occur and the successful implementation of deprescribing psychotropic medications.


Monitoring the chronic effects of anticholinesterase pesticides in aerial applicators.
Four pilots were monitored over a six month period for physiological signs of anticholinesterase exposures in this preliminary study. Two pilots were controls and two were aerial applicators whose spraying activities included the application of ethyl parathion on more than 85% of their total acreages. Erythrocytic and plasma cholinesterase assays, plus dark-adapted pupil dilation, and a measure of the amplitude of respiratory sinus arrhythmia (RSA), were measured pre-seasonally and near the end of the spraying season. Comparisons between the controls and the two aerial applicators indicated that one aerial applicator displayed organophosphorus toxicosis symptoms. Dark-adapted pupil dilation and RSA more clearly indicated the chronic exposure than did the blood cholinesterase assays. The alleged exposure was linked by post-study interviews to flight pattern and residue cleaning procedures.


An Increased Level of Aryl Hydrocarbon Receptor in Patients with Pancreatic Cancer.
BACKGROUND Aryl-carbon receptor (AhR), a ligand-activated transcription factor, is best known for its ability to mediate the effects of environmental toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. AhR is expressed in several tumor cells and regulates the expression of genes in the signal transduction pathways. In this study, we examined the soluble levels of AhR in patients with pancreatic cancer. METHODS 123 samples, including 59 (48%) samples of pancreatic ductal adenocarcinoma based on histological evidence and 64 (52%) healthy control samples, were evaluated to determine plasma levels of AhR by Enzyme-linked immunoassay. RESULTS The median of AhR among patients was 0.280 ng/mL, which differed considerably from 0.07 ng/mL in the control group (p < 0.001). Significant differences of the AhR were observed between the plasma samples of the patients compared with the healthy group, with respect to male sex (p < 0.001), age groups (p = 0.001), diabetic status (p < 0.001), body mass index (BMI) categories (p = 0.035), and constantly smokers (p < 0.001). We also observed significant differences between the level of AhR expression between men and women (p = 0.01) and ever to never smokers (p = 0.009) in the case group. In addition, the age of 65 and a BMI of 25 or less were significant factors in plasma AhR levels ([1.61 95%CI 1.08-2.38] and [1.84 95%CI 1.22-2.77], respectively). CONCLUSION The results of this study can add diagnostic information to pancreatic cancer involving AhR and the potential efficacy of this receptor in therapeutic strategies.


Morphology-dependent resonance of the optical forces on Mie particles in an Airy beam.
Morphology-dependent resonance (MDR) of the optical forces for a particle illuminated by Airy beams is investigated with respect to its internal field distribution. We find the ring structures arising from the resonance transform significantly with the parametric evolution of Airy evanescent wave, and the interference of the internal waves have a great impact on the Q factor and the background of the resonant peak, but it's not proper for Airy transmitted wave. The multiple reflections of the evanescent wave between the particle and the interface are also investigated, which show significant impacts on the region where the energy concentrate in.


Emerging innovations and advancements in the treatment of extremity and truncal soft tissue sarcomas.
In this special edition update on soft tissue sarcomas (STS), we cover classifications, emerging technologies, prognostic tools, radiation schemas, and treatment disparities in extremity and truncal STS. We discuss the importance of enhancing local control and reducing complications, including the role of innovative imaging, surgical guidance, and hypofractionated radiation. We review advancements in systemic and immunotherapeutic treatments and introduce disparities seen in this vulnerable population that must be considered to improve overall patient care.


Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent, and impulsive offenders.
Plasma phospholipid essential fatty acids and some of their main metabolites, prostaglandins, were measured among habitually violent and impulsive male offenders, who all had alcohol abuse problems, and nonviolent control persons. Linoleic acid (18:2n-6), the precursor of the n-6 fatty acids, was below normal in intermittent explosive disorder, but the dihomogammalinolenic acid (DGLA) (20:3n-6) and some subsequent n-6 acids were at the same time elevated among all offenders. Also, a monounsaturate, oleic acid (18:1n-9) was elevated. The high DGLA correlated with low cholesterol level in intermittent explosive disorder. The arachidonic acid metabolites PGE2 and TxB2 were elevated in violent antisocial personality. The PGE1/DGLA ratio was low in intermittent explosive disorder. The number of registered violent crimes and violent suicidal attempts correlated with high phospholipid DGLA values. The possibility that the high phospholipid DGLA is connected with low free DGLA pool, and therefore low PGE1 formation, among these offenders is discussed.


SARS-CoV-2 and Nervous System - Neurological Manifestations in Patients With COVID-19: A Systematic Review.
Coronavirus (CoV) is a virus infectious disease with a considerable spectrum of clinical presentations. Symptoms ranged from asymptomatic infection to severe pneumonia that may lead to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and several clinical complications. Neurologic symptoms related to CoV have been described recently in the literature. The relationship between SARS-CoV-2 and the central nervous system (CNS) is still not clear. This review aimed to reveal the current knowledge regarding CNS manifestation in SARS-CoV-2. A systematic literature review was carried out to identify the particularities of coronavirus disease 2019 (COVID-19) in patients with CNS involvement, using the PubMed database between January 1, 2020 and April 30, 2020. Conference papers, reviews, published letters, editorials, studies in pregnant women and children, and studies only reporting on a specific factor were excluded. An initial search included as many as 83 articles. Out of the 83 screened articles, 32 were selected for full-text review. Sixteen studies were excluded because they did not analyze nervous system involvement in SARS-CoV-2 infection. Thus, 16 papers were included in this review. There were three retrospective studies and 13 case reports/series of cases. Data from the current literature reveal that patients who suffer from a severe illness have more CNS involvement, neurological symptoms (i.e., dizziness, headache) and an association with strokes. The severe patients had higher D-dimer and C-reactive protein levels than non-severe patients and presented multiple organ involvement, such as serious liver, kidney and muscle damage.


Occurrence of fibrin and tissue factor antigen in human small cell carcinoma of the lung.
Fibrin was detected by specific immunofluorescence in tissue obtained from five of six cases of small cell carcinoma of the lung. Dense specific fluorescence was observed in the connective tissue stroma surrounding metastatic tumor nodules and frequently in the scant extracellular stroma surrounding individual viable tumor cells and small tumor cell clusters. When observed by electron microscopy, the fibrin hugged tumor cell plasma membranes and, in some areas, seemed to envelop the cells. Fluorescent staining of tumor cells, but not the stroma, was observed with an antibody to tissue factor. These findings suggest that local activation of coagulation occurs in small cell carcinoma of the lung. Deposited fibrin may contribute to the growth and spread of this particular type of cancer.


Spatial speech perception benefits in young children with normal hearing and cochlear implants.
Several studies have demonstrated better speech perception performance in children using two rather than one cochlear implant (CI). The extent to which bilaterally implanted children benefit from binaural cues to segregate speech and noise in a spatial configuration is less clear. Although better-ear effects are expected to be similar to adults, it is unknown whether electrical stimulation allows true binaural processing of speech signals in noise. Moreover, little data are available on the binaural hearing abilities of normal-hearing children. This study aimed at (1) developing and evaluating a speech test based on numbers to determine speech reception thresholds (SRTs) fast and accurately in young children, (2) evaluating a setup for measuring benefits of speech perception in a spatial configuration in young children and determining normative values of normal-hearing children, and (3) measuring spatial speech benefits in cochlear-implanted children with good sound localization abilities. The speech test was conducted using the Leuven Intelligibility Number Test (LINT) data base. The test was limited to the numbers 1 to 10 spoken by one female speaker ("LittleLINT"). The LINT speech-weighted noise was used as a masker. Perception of this speech material was evaluated at fixed signal-to-noise ratios (SNRs) through monaural presentation via headphones in 34 normal-hearing children of 4 and 5 yrs of age and 20 normal-hearing adults. Subsequently, spatial speech perception benefits were measured in 50 normal-hearing children between 4 and 8 yrs of age, 15 normal-hearing adults, and eight children with bilateral CIs. An adaptive procedure was used for estimating unilateral and bilateral SRTs for different spatial configurations of speech and noise. Speech was always presented at 0 degrees azimuth (the front) and noise at the front, 90 degrees to the right, or 90 degrees to the left. Unilateral headphone SRTs for the LittleLINT were higher for children (-9 dB SNR) than for adults (-13 dB SNR) and were lower than those for the LINT (-10 dB SNR for adults). Slopes (12 to 14%/dB) were comparable with that of the LINT (15%/dB), suggesting equal efficiency for the limited set of numbers. Normal-hearing subjects demonstrated several benefits of two-ear listening in spatial configurations (spatial release from masking [SRM], head shadow, summation, and squelch). Only SRM was influenced by age. Implanted children clearly benefited from bilateral implantation, as shown by SRM (3 dB) and head shadow effects (4 to 6 dB) comparable with normal-hearing children, but no summation or binaural squelch was established. The first CI seemed to contribute most to spatial speech perception. The steep slope, the familiarity to children, and the repeatability of lists make the LittleLINT suitable for fast and accurate SRT estimation in children. Spatial speech perception benefits were observed in normal-hearing subjects from the age of 4 yrs. Cochlear-implanted children showed better-ear effects but there was no evidence of true binaural processing.


Personalized protein coronas: a "key" factor at the nanobiointerface.
It is now well known that the primary interactions of biological entities (e.g., tissues and cells) with nanoparticles (NPs) are strongly influenced by the protein composition of the "corona" (i.e., the NP surface attached proteins). The composition of the corona strongly depends on the protein source (e.g., human plasma). Because the protein source determines the NP corona, it is reasonable to hypothesize that humans with specific disease(s) may have specific NP coronas. To test this hypothesis, we incubated two different hydrophobic/hydrophilic types of NPs (polystyrene and silica) with plasma from human subjects with different diseases and medical conditions (e.g., breast cancer, diabetes, hypercholesterolemia, rheumatism, fauvism, smoking, hemodialysis, thalassemia, hemophilia A and B, pregnancy, common cold and hypofibrinogenemia). Our results demonstrate that the type of disease has a crucial role in the protein composition of the NP corona. Based on these results, we introduce the concept of the "personalized protein corona" (PPC) as a determinant factor in nano-biomedical science. This study will help researchers rationally design experiments based on the "personalized protein corona" for clinical and biological applications.


Influenza A Virus NS1 Protein Structural Flexibility Analysis According to Its Structural Polymorphism Using Computational Approaches.
Influenza A viruses are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Their non-structural protein NS1, a homodimer of two 230-residue chains, is the main viral factor in counteracting the antiviral defenses of the host cell. Its RNA-binding domain is an obligate dimer that is connected to each of the two effector domains by a highly flexible unstructured linker region of ten amino acids. The flexibility of NS1 is a key property that allows its effector domains and its RNA binding domain to interact with several protein partners or RNAs. The three-dimensional structures of full-length NS1 dimers revealed that the effector domains could adopt three distinct conformations as regards their mutual interactions and their orientation relative to the RNA binding domain (closed, semi-open and open). The origin of this structural polymorphism is currently being investigated and several hypotheses are proposed, among which one posits that it is a strain-specific property. In the present study, we explored through computational molecular modeling the dynamic and flexibility properties of NS1 from three important influenza virus A strains belonging to three distinct subtypes (H1N1, H6N6, H5N1), for which at least one conformation is available in the Protein Data Bank. In order to verify whether NS1 is stable in three forms for the three strains, we constructed homology models if the corresponding forms were not available in the Protein Data Bank. Molecular dynamics simulations were performed in order to predict the stability over time of the three distinct sequence variants of NS1, in each of their three distinct conformations. Our results favor the co-existence of three stable structural forms, regardless of the strain, but also suggest that the length of the linker, along with the presence of specific amino acids, modulate the dynamic properties and the flexibility of NS1.


Relationship between the Mediterranean dietary pattern and musculoskeletal health in children, adolescents, and adults: systematic review and evidence map.
An understanding of the modifiable effects of diet on bone and skeletal muscle mass and strength over the life course will help inform strategies to reduce age-related fracture risk. The Mediterranean diet is rich in nutrients that may be important for optimal musculoskeletal health. The aim of this systematic review was to investigate the relationship between a Mediterranean diet and musculoskeletal outcomes (fracture, bone density, osteoporosis, sarcopenia) in any age group. Ten electronic databases were searched. Randomized controlled trials and prospective cohort studies that investigated a traditional Mediterranean diet, published in any language, were eligible. Studies using other designs or other definitions of the Mediterranean diet were collated separately in an evidence map. Details on study design, methods, population, dietary intervention or exposure, length of follow-up, and effect on or association with musculoskeletal outcomes were extracted. The search yielded 1738 references. Data from eligible randomized controlled trials (n = 0) and prospective cohort studies (n = 3) were synthesized narratively by outcome for the systematic review. Two of these studies reported on hip fracture incidence, but results were contradictory. A third study found no association between the Mediterranean diet and sarcopenia incidence. Overall, the systematic review and evidence map demonstrate a lack of research to understand the relationship between the Mediterranean diet and musculoskeletal health in all ages. PROSPERO registration number IDCRD42016037038.


Comparison of a MEMS-Based Handheld OCT Scanner With a Commercial Desktop OCT System for Retinal Evaluation.
The goal of this study was to evaluate the ability of our handheld optical coherence tomography (OCT) scanner to image the posterior and anterior structures of the human eye, and especially the individual layers of the retina, and to compare its diagnostic performance with that of a fixed desktop commercial ophthalmic OCT system. We compared the clinical imaging results of our handheld OCT with a leading commercial desktop ophthalmic system (RTVue) used in specialist offices. Six patients exhibiting diabetes-related retinal pathology had both eyes imaged with each OCT system. In both sets of images, the structural irregularities of the retinal layers could be identified such as retinal edema and vitreomacular traction. Our handheld OCT system can be used to identify relevant anatomical structures and pathologies in the eye, potentially enabling earlier screening, disease detection, and treatment. Images can be acquired quickly, with sufficient resolution and negligible motion artifacts that would normally limit its diagnostic use. Following screening and early disease detection in primary care via our optimized handheld OCT system, patients can be referred to a specialist for treatment, preventing further disease progression. While many primary care physicians are adept at using the ophthalmoscope, they can definitely take advantage of more advanced technologies.


Correlates of real-world goal-directed behavior in schizophrenia.
Deficits in goal-directed behavior (i.e. behavior conducted to achieve a specific goal or outcome) are core to schizophrenia, difficult to treat, and associated with poor functional outcomes. Factors such as negative symptoms, effort-cost decision-making, cognition, and functional skills have all been associated with goal-directed behavior in schizophrenia as indexed by clinical interviews or laboratory-based tasks. However, little work has examined whether these factors relate to the real-world pursuit of goal-directed activities in this population. This study aimed to fill this gap by using Ecological Momentary Assessment (four survey prompts per day for 1 week) to test hypotheses about symptom, effort allocation, cognitive, and functional measures associated with planned and completed goal-directed behavior in the daily lives of 63 individuals with schizophrenia. Individuals with schizophrenia completed more goal-directed activities than they planned [t(62) = -4.01, p < 0.001]. Motivation and pleasure (i.e. experiential) negative symptoms, controlling for depressive symptoms, negatively related to planned goal-directed behavior [odds ratio (OR) 0.92, p = 0.005]. Increased effort expenditure for high probability rewards (planned: OR 1.01, p = 0.034, completed: OR 1.01, p = 0.034) along with performance on a daily functional skills task (planned: OR 1.04, p = 0.002, completed: OR 1.03, p = 0.047) negatively related to both planned and completed goal-directed activity. Our results present correlates of real-world goal-directed behavior that largely align with impaired ability to make future estimations in schizophrenia. This insight could help identify targeted treatments for the elusive motivated behavior deficits in this population.


Sugars to control ligand shape in metal complexes: conformationally constrained glycoligands with a predetermination of stereochemistry and a structural control.
In coordination chemistry, ligand shape can be used to tune properties, such as metal selectivity, coordination number, electronic structure, redox potential, and metal center stereochemistry including coordination helicates formation, and also to generate cavities for encapsulation. The results presented in this article indicate that two epimeric glycoligands (3 and 4) based on the conformationally restrained xylo- and ribo-1,2-O-isopropylidenefurano scaffolds are preorganized in water through pi-pi stacking due to hydrophobic interactions, as evidenced from excimer observation. The structure obtained in the solid state for one of the Cu(II) complexes (5) is chiral, with an original helical chirality arising from the coiling of the two ligands around the Cu-Cu axis. It shows an unusual double-deck type structure, with pi-pi interaction between two triazoyl-pyridyl rings and with a small cavity between the two Cu(II) ions able to host a bridging water molecule, as suggested by electron paramagnetic resonance. The Cu(II) complex from the epimeric ligand (6) shows similar properties with a mirror-image CD spectrum in the d-d region of the Cu(II). There is a predetermination of chirality at the metal center by the glycoligand induced by the C3 configuration, 6 and 5 being pseudoenantiomers. Interestingly, the stereochemistry at the metal center is here controlled by the combination of pi-stacking and chiral backbone.


An epidemiological investigation of minimal brain dysfunction in six elementary schools in Beijing.
Six elementary schools from urban, suburban and mountain areas of Beijing (containing 2770 school children) were screened with a standardized questionnaire and each suspected case was interviewed to determine whether diagnostic criteria were met for attention deficit disorder with hyperactivity (DSM-III), with some cultural modification. The MBD prevalence rate was 3.1% in the urban, 7.8% in the suburban and 7.0% in the mountain area. Lower rates were found in the families of scientific and technical professionals or in those with higher education than others. The mean score or the severity of some clinical manifestations of MBD children showed differences in families with different occupations or educational levels. Social environmental factors were considered to play an important role in the development of MBD, which is possibly based on biological factors.


[Seroconversion of anti-aquaporin-4 antibody in a patient with neuromyelitis optica spectrum disorder: a case report].
We report a case of a patient with neuromyelitis optica spectrum disorder (NMOSD) who was originally treated for multiple sclerosis (MS) due to a negative anti-aquaporin-4 (AQP4) antibody test, but later the antibody titer became positive. A 58-year-old woman without prior medical history developed acute left facial pain, vomiting, and hiccups. MRI showed an intraparenchymal lesion extending from the medulla oblongata to cervical cord with high T2-weighted signal intensity. The patient responded to steroid pulse therapy. However, she developed diplopia and gait disturbance after six months, and follow-up MRI revealed a new lesion in the left middle cerebellar peduncle. The patient was diagnosed with MS due to the dissemination in the time and space of her lesions and negative anti-AQP4 antibody status. There was no relapse for three and a half years on fingolimod therapy. However, a severe relapse occurred four years later that involved optic neuritis and multiple new brain lesions. During this episode, the anti-AQP4 antibody test was positive, and the patient was diagnosed with NMOSD. This case highlights the possibility that seroconversion of anti-AQP4 antibody may occur at any time in NMOSD patients. Therefore, this diagnostically paramount antibody should be measured several times during the treatment of relapsing-remitting MS in patients with repeat frequent recurrences and uncommon symptoms of MS.


Portal vein thrombosis after hepatectomy.
Although various complications after hepatectomy have been reported, there have been no large studies on postoperative portal vein thrombosis (PVT) as a complication. This study evaluated the incidence, risk factors, and clinical outcomes of PVT after hepatectomy. The preoperative and postoperative clinical characteristics of patients who underwent hepatectomy were retrospectively analyzed. A total of 208 patients were reviewed. The incidence of PVT after hepatectomy was 9.1 % (n = 19), including main portal vein (MPV) thrombosis (n = 7) and peripheral portal vein (PPV) thrombosis (n = 12). Patients with MPV thrombosis had a significantly higher incidence of right hepatectomy (p < 0.001), larger resection volume (p = 0.003), and longer operation time (p = 0.021) than patients without PVT (n = 189). Multivariate analysis identified right hepatectomy as a significant independent risk factor for MPV thrombosis (odds ratio 108.9; p < 0.001). Patients with PPV thrombosis had a significantly longer duration of Pringle maneuver than patients without PVT (p = 0.002). Among patients who underwent right hepatectomy, those with PVT (n = 6) had a significantly lower early liver regeneration rate than those without PVT (n = 13; p = 0.040), and those with PVT had deterioration of liver function on postoperative day 7. In all patients with MPV thrombosis who received anticoagulation therapy, PVT subsequently resolved. Postoperative PVT after hepatectomy is not rare. It is closely related to delayed recovery of liver function and delayed liver regeneration.


Alternaria toxins in South African sunflower seeds: cooperative study.
Sunflower seed samples (N = 80) from different sunflower cultivars originating from different localities in South Africa were analyzed for 15 toxins produced by fungi of the genus Alternaria by means of a simple one-step extraction dilute-and-shoot HPLC-MS/MS approach. References for valine-tenuazonic acid (Val-TeA), altenusin (ALTS), and altenuisol (ALTSOH) were isolated from fungal culture extracts and spectroscopically characterized. Additionally, valine-tenuazonic acid was tested regarding its cytotoxicity in comparison with tenuazonic acid (TeA) and showed less activity on HT-29 cells. Furthermore, alternariol monomethyl ether-3-O-ß-D-glucoside (AME-3G) was produced by fermentation of alternariol monomethyl ether (AME) with the fungus Rhizopus oryzae. The seed samples were analyzed both with and without hulls. The method covers the AAL toxins TA1 and TA2, altenuene (ALT) and iso-altenuene (iso-ALT), altenuisol, altenusin, altertoxin I (ATX-I) and altertoxin II (ATX-II), alternariol (AOH) and alternariol monomethyl ether, alternariol monomethyl ether-3-O-ß-D-glucoside, tenuazonic acid, allo-tenuazonic acid (allo-TeA) and valine-tenuazonic acid, and tentoxin (TEN). More than 80% of the samples were positive for one or more analytes above the respective limit of detection (0.2-23 μg/kg). Alternariol, its monomethyl ether, tentoxin, tenuazonic acid, altenuisol, and valine-tenuazonic acid were found in quantifiable amounts. The highest prevalences were found for tentoxin (73% positive, mean content 13.2 μg/kg, maximum level 130 ± 0.9 μg/kg) followed by tenuazonic acid (51% positive, mean content 630 μg/kg, maximum level 6300 ± 560 μg/kg). The obtained data were further analyzed statistically to identify quantitative or qualitative relationships between the levels of Alternaria toxin in the samples.


Re-thinking the biology of essential tremor: from models to morphology.
Remarkably little has been written on the biology of essential tremor (ET), despite its high prevalence. The traditional pathophysiological model for ET, the olivary model, states that ET is a primary electrical//electrophysiological entity, the result of pacemaking neurons in the inferior olivary nucleus that begin firing in a coupled and rhythmic manner, and thus, through an abnormal olivo-cerebellar output, produce tremor. Though this model is based on several sound neurophysiological observations, there are major problems as well. Despite its shortcomings, however, the model persists. With the traditional focus in ET on clinical neurophysiology, there has been little research on pathological anatomy, cell biology, and molecular mechanisms, and over the years, there have been few alternatives to the olivary model. However, rigorous tissue-based studies have recently identified a series of structural changes in the ET brain, most of which are centered on the Purkinje cell and connected neuronal populations, and which may involve a partial loss of Purkinje cells. An implication of these newer studies is that ET could be degenerative. This shift in paradigm opens the door for research that aims to identify the primary set of molecular triggers and the cascade of molecular/cellular events that accompany this disease.


Nonabsorbable disaccharides for hepatic encephalopathy: A systematic review and meta-analysis.
Nonabsorbable disaccharides (NADs) have been used to treat hepatic encephalopathy (HE) since 1966. However, a Cochrane Review, published in 2004, found insufficient evidence to recommend their use in this context. This updated systematic review evaluates the effects of the NADs, lactulose and lactitol, for the treatment and prevention of HE in patients with cirrhosis. Thirty-eight randomized controlled trials, involving 1,828 patients, were identified through electronic and manual searches; 31 randomized controlled trials looked at the treatment of HE, while seven looked at its primary/secondary prevention. Random-effects meta-analyses showed that, compared to placebo/no intervention, NADs had a beneficial effect on HE (relative risk [RR] = 0.63, 95% confidence interval [CI] 0.53-0.74, number needed to treat [NNT] = 4) and serious liver-related adverse events such as liver failure, variceal bleeding, serious infections, spontaneous bacterial peritonitis, and hepatorenal syndrome (RR = 0.42, 95% CI 0.26-0.69, NNT = 50). Treatment was also associated with a reduction in mortality in patients with overt HE (RR = 0.36, 95% CI 0.14-0.94, NNT = 20), although not in patients with minimal HE. Meta-analyses of the prevention randomized controlled trials showed that NADs prevented the development of HE (RR = 0.47, 95% CI 0.33-0.68, NNT = 6), the risk of developing serious liver-related adverse events (RR = 0.48, 95% CI 0.33-0.70, NNT = 6), and reduced mortality (RR = 0.63, 95% CI 0.40-0.98, NNT = 20). Use of NADs was associated with nonserious gastrointestinal adverse events. There were no differences in the efficacy or safety of lactulose and lactitol. NADs have beneficial effects in the treatment and prevention of HE; their use, in this context, confers additional benefits including a reduction in serious liver-related morbidities and all-cause mortality. (Hepatology 2016;64:908-922).


Membrane differentiations at sites specialized for cell fusion.
Fusion of plasma membranes between Chlamydomonas reinhardtii gametes has been studied by freeze-fracture electron microscopy of unfixed cells. The putative site of cell fusion developes during gametic differentiation and is recognized in thin sections of unmated gametes as a plaque of dense material subjacent to a sector of the anterior plasma membrane (Goodenough, U.W., and R.L. Weiss. 1975.J. Cell Biol. 67:623-637). The overlying membrane proves to be readily recognized in replicas of unmated gametes as a circular region roughly 500 nm in diameter which is relatively free of "regular" plasma membrane particles on both the P and E fracture faces. The morphology of this region is different for mating-type plus (mt+) and mt- gametes: the few particles present in the center of the mt+ region are distributed asymmetrically and restricted to the P face, while the few particles present in the center of the mt- region are distributed symmetrically in the E face. Each gamete type can be activated for cell fusion by presenting to it isolated flagella of opposite mt. The activated mt+ gamete generates large expanses of particle-cleared membrane as it forms a long fertilization tubule from the mating structure region. In the activated mt- gamete, the E face of the mating structure region is transformed into a central dome of densely clustered particles surrounded by a particle-cleared zone. When mt+ and mt- gametes are mixed together, flagellar agglutination triggeeeds to fuse with an activated mt- region. The fusion lip is seen to develop within the particle-dense central dome. We conclude that these mt- particles play an active role in membrane fusion.


Cloning and characterization of four SIR genes of Saccharomyces cerevisiae.
Mating type in the yeast Saccharomyces cerevisiae is determined by the MAT (a or alpha) locus. HML and HMR, which usually contain copies of alpha and a mating type information, respectively, serve as donors in mating type interconversion and are under negative transcriptional control. Four trans-acting SIR (silent information regulator) loci are required for repression of transcription. A defect in any SIR gene results in expression of both HML and HMR. The four SIR genes were isolated from a genomic library by complementation of sir mutations in vivo. DNA blot analysis suggests that the four SIR genes share no sequence homology. RNA blots indicate that SIR2, SIR3, and SIR4 each encode one transcript and that SIR1 encodes two transcripts. Null mutations, made by replacement of the normal genomic allele with deletion-insertion mutations created in the cloned SIR genes, have a Sir- phenotype and are viable. Using the cloned genes, we showed that SIR3 at a high copy number is able to suppress mutations of SIR4. RNA blot analysis suggests that this suppression is not due to transcriptional regulation of SIR3 by SIR4; nor does any SIR4 gene transcriptionally regulate another SIR gene. Interestingly, a truncated SIR4 gene disrupts regulation of the silent mating type loci. We propose that interaction of at least the SIR3 and SIR4 gene products is involved in regulation of the silent mating type genes.


Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice.
Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.


A high-quality bonobo genome refines the analysis of hominid evolution.
The divergence of chimpanzee and bonobo provides one of the few examples of recent hominid speciation1,2. Here we describe a fully annotated, high-quality bonobo genome assembly, which was constructed without guidance from reference genomes by applying a multiplatform genomics approach. We generate a bonobo genome assembly in which more than 98% of genes are completely annotated and 99% of the gaps are closed, including the resolution of about half of the segmental duplications and almost all of the full-length mobile elements. We compare the bonobo genome to those of other great apes1,3-5 and identify more than 5,569 fixed structural variants that specifically distinguish the bonobo and chimpanzee lineages. We focus on genes that have been lost, changed in structure or expanded in the last few million years of bonobo evolution. We produce a high-resolution map of incomplete lineage sorting and estimate that around 5.1% of the human genome is genetically closer to chimpanzee or bonobo and that more than 36.5% of the genome shows incomplete lineage sorting if we consider a deeper phylogeny including gorilla and orangutan. We also show that 26% of the segments of incomplete lineage sorting between human and chimpanzee or human and bonobo are non-randomly distributed and that genes within these clustered segments show significant excess of amino acid replacement compared to the rest of the genome.


"Proximal-type" epithelioid sarcoma in a young girl.
Epithelioid sarcoma is a rare, malignant soft-tissue neoplasm occurring on the distal extremities of young adults. Its histologic features consist of a proliferation of rounded to plump, spindle-shaped cells with abundant eosinophilic cytoplasm around areas of necrosis, simulating a granulomatous process. Recently a different type of epithelioid sarcoma has been described and named "proximal-type" epithelioid sarcoma. It is found mostly in the pelvic and perineal areas of young to middle-aged adults. On microscopic examination, the tumor is characterized by a proliferation of epithelioid-like cells with rhabdoid features in the absence of a granuloma-like pattern, and immunohistochemically it coexpresses vimentin, cytokeratin, epithelial membrane antigen, and CD34. As we found no report of proximal epithelioid sarcoma in the dermatologic literature, we describe an additional case in a 12-year-old girl. This type of tumor appears to be somewhat more aggressive than the classical, distal type and it should be considered in the differential diagnosis of tumors showing rhabdoid features, in particular extrarenal malignant rhabdoid tumor.


Individual differences in loudness processing and loudness scales.
Parameters of the psychophysical function for loudness (a 1000-Hz tone) were assessed for individual subjects in three experiments: (a) binaural loudness summation, (b) temporal loudness summation, and (c) judgments of loudness intervals. The loudness scales that underlay the additive binaural summation closely approximated S. S. Stevens's (1956) sone scale but were nonlinearly related to the scales that underlay the subtractive interval judgments, the latter approximating Garner's (1954) lambda scale. Interindividual differences in temporal summation were unrelated to differences in scaling performance or in binaural summation. Although the exponents of magnitude-estimation functions and the exponents underlying interval judgments varied considerably from subject to subject, exponents computed on the basis of underlying binaural summation varied less. The results suggest that interindividual variation in the exponent of magnitude-estimation functions largely reflects differences in the ways that subjects use numbers to describe loudnesses and that the sensory representations of loudness are fairly uniform, though probably not wholly uniform, among people with normal hearing. The magnitude of individual variation in at least one measure of auditory intensity processing, namely, temporal summation, seems at least as great as the magnitude of the variation in the underlying loudness scale.


Selective press extinctions, but not random pulse extinctions, cause delayed ecological recovery in communities of digital organisms.
A key issue concerning recovery from mass extinctions is how extinction and diversification mechanisms affect the recovery process. We evolved communities of digital organisms, subjecting them to instantaneous "pulse" extinctions, choosing survivors at random, or to prolonged "pulse" extinctions involving a period of low resource availability. Functional activity at low trophic levels recovered faster than at higher levels, with the most extensive delays seen at the top level. Postpress communities generally did not fully recover functional activity in the allotted time, which equaled that of their original diversification. We measured recovery of phenotypic diversity, observing considerable variation in outcomes. Communities subjected to pulse extinctions recovered functional activity and phenotypic diversity substantially faster than when subjected to press extinctions. Follow-up experiments tested whether organisms with shorter generation times and low functional activity contributed to delayed recovery after press extinctions. The results indicate that adaptation during the press episode degraded the organisms' ability to re-evolve preextinction functionality. There are interesting parallels with patterns from the paleontological record. We suggest that some delayed recoveries from mass extinction may reflect the need to both re-evolve biological functions and reconstruct ecological interactions lost during the extinction. Adaptation to conditions during an extended disturbance may hinder subsequent recovery.


A replication study for association of ITPKC and CASP3 two-locus analysis in IVIG unresponsiveness and coronary artery lesion in Kawasaki disease.
Single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC, rs28493229) and caspase-3 (CASP3, rs113420705) are associated with susceptibility to KD in Japanese and Taiwanese populations. This study was conducted to investigate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Taiwanese population. A total of 340 KD patients were subjected to assess by the identification of 2-locus genes model. A combinatorial association between ITPKC (rs28493229) and CASP3 (rs113420705) was found in CAL formation (P = 0.0227, OR: 3.06). KD patients with high-risk genotype had a trend of overrepresentation in IVIG resistance compared with individual SNPs. Our findings suggest the existence of genetic factors affecting patients' risk for CAL formation and IVIG responsiveness in a Taiwanese population.


Spatial organization of active and inactive genes and noncoding DNA within chromosome territories.
The position of genes within the nucleus has been correlated with their transcriptional activity. The interchromosome domain model of nuclear organization suggests that genes preferentially locate at the surface of chromosome territories. Conversely, high resolution analysis of chromatin fibers suggests that chromosome territories do not present accessibility barriers to transcription machinery. To clarify the relationship between the organization of chromosome territories and gene expression, we have used fluorescence in situ hybridization to analyze the spatial organization of a contiguous approximately 1 Mb stretch of the Wilms' tumor, aniridia, genitourinary anomalies, mental retardation syndrome region of the human genome and the syntenic region in the mouse. These regions contain constitutively expressed genes, genes with tissue-restricted patterns of expression, and substantial regions of intergenic DNA. We find that there is a spatial organization within territories that is conserved between mouse and humans: certain sequences do preferentially locate at the periphery of the chromosome territories in both species. However, we do not detect genes necessarily at the periphery of chromosome territories or at the surface of subchromosomal domains. Intraterritory organization is not different among cell types that express different combinations of the genes under study. Our data demonstrate that transcription of both ubiquitous and tissue-restricted genes is not confined to the periphery of chromosome territories, suggesting that the basal transcription machinery and transcription factors can readily gain access to the chromosome interior.


β-Radiation exposure to fingertips after using a trained routine application method during radiosynovectomy.
There are few, but worrisome, data available on fingertip radiation exposure of medical personnel during radiosynovectomy (RSV). To reduce radiation exposure, we performed a dedicated application procedure. This report summarizes the acquired skin equivalent dose [Hp(0.07)] of the personnel involved in the preparation and administration of the three RSV β-emitters Y, Re and Er. Over a period of 3 years, 547 joints in 368 patients were treated with 52421 MBq of the aforementioned three radionuclides. The Hp(0.07) was recorded with thermoluminescence dosimeters worn on the dominant index fingertip and was analysed monthly. Eight staff members were exposed to an Hp(0.07) of 492 mSv. The cumulative dose was less than 10 μSv/MBq. The dose per person was 1.1 μSv/MBq in physicians and up to 4.5 μSv/MBq in technicians. The accumulated personal Hp(0.07) during RSV was far below the regulatory limit and published data.


Estimating phylogenetic inertia in Tithonia (Asteraceae): a comparative approach.
Phylogenetic inertia is a difficult issue in evolutionary biology because we have yet to reach a consensus about how to measure it. In this study a comparative approach is used to evaluate phylogenetic inertia in 14 demographic and morphological characters in 10 species and one subspecies of the genus Tithonia (Asteraceae). Three different methods, autocorrelational analysis, phylogenetic correlograms, and ancestor-state reconstruction, were used to evaluate phylogenetic inertia in these traits. Results were highly dependent on the method applied. Autoregression and phylogenetic eigenvector regression (PVR) methods found more inertia in morphological traits. In contrast, phylogenetic correlograms and ancestor-state reconstruction suggest that morphological characters exhibit less phylogenetic inertia than demographic ones. The differences between results are discussed and methods are compared in an effort to understand phylogenetic inertia more thoroughly.


A Social Network Analysis of the Financial Links Backing Health and Fitness Apps.
To identify the major stakeholders in mobile health app development and to describe their financial relationships using social network analysis. We conducted a structured content analysis of a purposive sample of prominent health and fitness apps available in November 2015 in the United States, Canada, and Australia. We conducted a social network analysis of apps' developers, investors, other funding sources, and content advisors to describe the financial relationships underpinning health app development. Prominent health and fitness apps are largely developed by private companies based in North America, with an average of 4.7 (SD = 5.5) financial relations, including founders, external investors, acquiring companies, and commercial partnerships. Network analysis revealed a core of 41 sampled apps connected to 415 other entities by 466 financial relations. This core largely comprised apps published by major technology, pharmaceutical, and fashion corporations. About one third of apps named advisors, many of whom had commercial affiliations. Public health needs to extend its scrutiny and advocacy beyond the health messages contained within apps to understanding commercial influences on health and, when necessary, challenging them.


Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive ovarian carcinoma cell lines.
Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies to avoid platinum inefficacy and to exploit platinum sensitivity. TOV-21G devoid of FANCF expression, OV-90 and SKOV-3 were employed as examples of platinum-sensitive, platinum-intermediate and platinum-resistant cell lines, respectively. Antineoplastic agents examined included mitomycin C, doxorubicin, etoposide, gemcitabine, chlorambucil, paclitaxel, triapine and X-rays. Their effectiveness against cell lines was analyzed by clonogenic assays. Cytotoxic profiles of mitomycin C and carboplatin were similar, with mitomycin C exhibiting greater potency and selectivity against TOV-21G than carboplatin. Cytotoxic profiles of doxorubicin, etoposide and X-rays overlapped with that of carboplatin, while OV-90 overexpressing Rad51 was more resistant to chlorambucil than SKOV-3. The efficacy of paclitaxel and triapine was independent of platinum sensitivity or resistance. Consistent with these cytotoxic profiles, cisplatin/mitomycin C, triapine, and paclitaxel differed in the capacity to induce phosphorylation of H2AX, and produced unique inhibitory patterns of DNA/RNA syntheses in HL-60 human leukemia cells. Paclitaxel and triapine in combination produced additive antitumor effects in M109 murine lung carcinoma. In conclusion, mitomycin C is potentially more effective against Fanconi anemia pathway-deficient EOCs than carboplatin. Doxorubicin and etoposide, because of their overlapping cytotoxic properties with carboplatin, are unlikely to be efficacious against platinum-refractory EOCs. Paclitaxel and triapine are effective regardless of platinum sensitivity status, and promising in combination for both platinum-sensitive and platinum-refractory EOCs.