Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication.
Malfunction of ubiquitin-proteasome system is tightly linked to tumor formation and tumor metastasis. Targeting the ubiquitin-pathway provides a new strategy for anti-cancer therapy. Despite the parts played by ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in governing the multiple steps of the metastatic cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Both deregulated ubiquitination and deubiquitination could lead to dysregulation of various critical events and pathways such as apoptosis and epithelial-mesenchymal transition (EMT). Recent TCGA study has further revealed the connection between mutations of DUBs and various types of tumors. In addition, emerging drug design targeting DUBs provides a new strategy for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and highlight the recent discoveries of DUBs with regards to multiple metastatic events including anti-apoptosis pathway and EMT. We will further discuss the regulation of deubiquitination as a novel strategy for anti-cancer therapy.


MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells.
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.


Exposure to GenX and Its Novel Analogs Disrupts Hepatic Bile Acid Metabolism in Male Mice.
Due to its wide usage and recent detection in environmental matrices, hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name GenX) has attracted considerable attention. Here, we explored and compared the toxicity of GenX and its novel analogs with that of perfluorooctanoic acid (PFOA) to provide guidance on the structural design and optimization of novel alternatives to poly- and perfluoroalkyl substances (PFASs). Adult male BALB/c mice were continuously exposed to PFOA, GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2HpA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. The PFOA, GenX, and PFMO3NA treatment groups showed an increase in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, as shown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/d PFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondary bile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure to GenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas the hepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.


Efficacy of coronary artery bypass surgery with gastroepiploic artery. Assessment with thallium 201 myocardial scintigraphy.
This study describes the efficacy of the right gastroepiploic artery (GEA) as graft material for coronary artery bypass grafting (CABG) as assessed by exercise thallium 201 myocardial scintigraphy in eight patients (age, 59.4 +/- 9.35 years [mean +/- SD]) who underwent CABG with the GEA graft in the past 2 years. Planar and single-photon-emission computed tomographic (SPECT) images were obtained during and 3 hours after exercise. Planar images were evaluated quantitatively with the percentile-washout method, and SPECT images were evaluated qualitatively with a bull's-eye, polar-coordinate map. All patients had triple-vessel disease, and in situ GEAs were anastomosed to the right coronary artery in seven patients and to the left anterior descending coronary artery in one. The internal mammary artery graft was concomitantly used in all patients. The mean number of grafts per patient was 3.0 (range, 2-4). Preoperative exercise testing could not be performed in two patients because of emergency operation. By qualitative assessment with the polar-coordinate map, four patients showed improvement, one did not show any change, and one became worse due to perioperative myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of abnormal repolarization in the mechanism of cardiac arrhythmia.
In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K+ currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca2+ handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na+ channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K+ channel (dofetilide).


A qualitative study adopting a user-centered approach to design and validate a brain computer interface for cognitive rehabilitation for people with brain injury.
Cognitive rehabilitation is established as a core intervention within rehabilitation programs following a traumatic brain injury (TBI). Digitally enabled assistive technologies offer opportunities for clinicians to increase remote access to rehabilitation supporting transition into home. Brain Computer Interface (BCI) systems can harness the residual abilities of individuals with limited function to gain control over computers through their brain waves. This paper presents an online cognitive rehabilitation application developed with therapists, to work remotely with people who have TBI, who will use BCI at home to engage in the therapy. A qualitative research study was completed with people who are community dwellers post brain injury (end users), and a cohort of therapists involved in cognitive rehabilitation. A user-centered approach over three phases in the development, design and feasibility testing of this cognitive rehabilitation application included two tasks (Find-a-Category and a Memory Card task). The therapist could remotely prescribe activity with different levels of difficulty. The service user had a home interface which would present the therapy activities. This novel work was achieved by an international consortium of academics, business partners and service users.


To4, the first Tityus obscurus β-toxin fully electrophysiologically characterized on human sodium channel isoforms.
Many scorpion toxins that act on sodium channels (NaScTxs) have been characterized till date. These toxins may act modulating the inactivation or the activation of sodium channels and are named α- or β-types, respectively. Some venom toxins from Tityus obscurus (Buthidae), a scorpion widely distributed in the Brazilian Amazon, have been partially characterized in previous studies; however, little information about their electrophysiological role on sodium ion channels has been published. In the present study, we describe the purification, identification and electrophysiological characterization of a NaScTx, which was first described as Tc54 and further fully sequenced and renamed To4. This toxin shows a marked β-type effect on different sodium channel subtypes (hNav1.1-hNav1.7) at low concentrations, and has more pronounced activity on hNav1.1, hNav1.2 and hNav1.4. By comparing To4 primary structure with other Tityus β-toxins which have already been electrophysiologically tested, it is possible to establish some key amino acid residues for the sodium channel activity. Thus, To4 is the first toxin from T. obscurus fully electrophysiologically characterized on different human sodium channel isoforms.


Mitochondrial depletion syndrome type 3: the Lebanese variant.
Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1 year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.


The quest for load-independent left ventricular chamber properties: exploring the normalized pressure-volume loop.
Left ventricular (LV) pressure-volume (P-V) loop analysis is the gold standard for chamber function assessment. To advance beyond traditional P-V and pressure phase plane (dP/dt-P) analysis in the quest for novel load-independent chamber properties, we introduce the normalized P-V loop. High-fidelity LV pressure and volume data (161 P-V loops) from 13 normal control subjects were analyzed. Normalized LV pressure (PN) was defined by 0 ≤ P(t) ≤ 1. Normalized LV volume (VN) was defined as VN=V(t)/Vdiastasis, since the LV volume at diastasis (Vdiastasis) is the in-vivo equilibrium volume relative to which the LV volume oscillates. Plotting PN versus VN for each cardiac cycle generates normalized P-V loops. LV volume at the peak LV ejection rate and at the peak LV filling rate (peak -dV/dt and peak +dV/dt, respectively) were determined for conventional and normalized loops. VN at peak +dV/dt was inscribed at 64 ± 5% of normalized equilibrium (diastatic) volume with an inter-subject variation of 8%, and had a reduced intra-subject (beat-to-beat) variation compared to conventional P-V loops (9% vs. 13%, respectively; P < 0.005), thereby demonstrating load-independent attributes. In contrast, VN at peak -dV/dt was inscribed at 81 ± 9% with an inter-subject variation of 11%, and had no significant change in intra-subject (beat-to-beat) variation compared to conventional P-V loops (17% vs. 17%, respectively; P = 0.56), therefore failing to demonstrate load-independent tendencies. Thus, the normalized P-V loop advances the quest for load-independent LV chamber properties. VN at the peak LV filling rate (≈sarcomere length at the peak sarcomere lengthening rate) manifests load-independent properties. This novel method may help to elucidate and quantify new attributes of cardiac and cellular function. It merits further application in additional human and animal physiologic and pathophysiologic datasets.


Comparison of the outcome in men and women with chronic heart failure.
Recent studies have suggested some gender-related differences in the incidence, quality of care, response to therapy, and outcome in heart failure patients. The majority of studies have proposed a better survival for women compared to men. However, the under-representation of women in clinical trials leads to some uncertainty regarding the survival benefit. Some data suggest the possibility that ACE-inhibitors may be less beneficial in women as compared to men. Beta-blockers seem to be effective both in women and men. Further studies are needed to clarify whether these differences may have a pathophysiological basis.


The Resin-Bonded Fixed Partial Denture as the First Treatment Consideration to Replace a Missing Tooth.
The resin-bonded fixed partial denture (RB-FPD) is the first restorative treatment option to be considered in cases where one or more teeth are missing. The indications for implants, conventional FPDs, and adhesive FPDs, considering the general and dental conditions of the patient, are discussed in this article. When the RB-FPD is the chosen option, a direct or indirect technique, a cantilever-type or fixed-fixed design, and materials to be used need to be selected. The choice will depend on a variety of factors, such as interproximal space at the connector area, anterior or posterior location, the skills of the dentist, esthetics, and the patient's wishes. The RB-FPD can be made using various techniques and materials.


Single dose, oral antibiotic cover for transurethral prostatectomy.
A double-blind, randomised, placebo-controlled study was carried out to determine the incidence and significance of bacteriuria in 110 patients undergoing transurethral resection of the prostate (TURP) and to assess the effect of a single pre-operative dose of Ciprofloxacin, a 4-quinolone antibiotic. Fifteen (68%) of the 22 patients in the placebo group with a positive post-operative urine culture subsequently developed a clinically apparent urinary tract infection (UTI) or received antibiotics in view of a positive urine culture. Adequate prostatic concentrations of Ciprofloxacin were achieved in all who received the drug. A significant reduction in the number of positive post-operative urine cultures and urinary tract infections requiring antibiotic therapy was achieved in this group. Six patients (5.5%) developed clinical evidence of septicaemia, 5 of whom were in the placebo group. No organisms resistant to Ciprofloxacin were encountered. Prior to surgery, 19% of all patients were found to have previously unsuspected bacteriuria. Ciprofloxacin tended to reduce the chances of this group developing a UTI or requiring antibiotics. Further, there was a highly significant reduction in post-operative infective complications in those with sterile urine at the time of resection who had received the drug. This study suggests that antibiotic cover for TURP is of clinical benefit. Ciprofloxacin may prove suited to this purpose, although further experience with the drug is still required.


Deep caries lesions after incomplete dentine caries removal: 40-month follow-up study.
Radiographic changes after indirect pulp capping (32 teeth in 27 patients) were studied for up to 36-45 months. Radiolucent zone (RZ) depth and tertiary dentine formation were assessed qualitatively and changes in radiographic density (by image subtraction) in RZ and control areas (CA) were estimated. During follow-up there were 1 pulp necrosis, 1 pulp exposure, 3 fractures and 3 withdrawals. Twelve cases showed decreased RZ depth and 4 displayed tertiary dentine. No changes with time in density of CA or RZ, or in the difference between them, were observed. It is concluded that indirect pulp capping arrests lesion progression, suggesting that complete dentine caries removal is not essential for caries control.


Memory impairment and schizophrenia: the role of processing speed.
A link between slowing of processing speed and cognitive disorders, including memory, has repeatedly been found in research on aging, and suggested in other cognitively impaired populations. We tested the hypothesis that a link between memory impairment and slowing of processing speed would also be observed in schizophrenia. Forty-four schizophrenic patients and 40 normal controls were administered a memory task involving free recall and recognition. Processing speed was assessed by the Digit Symbol Substitution Test. Working memory span was assessed as well. The measure of processing speed was consistently correlated with the various memory measures in patients, including efficiency of encoding. These correlations remained significant, or tended to be significant, when working memory span was partialled out. Memory deficits observed in schizophrenia may thus be partly accounted for by a slowing of processing speed. It is suggested that research on cognitive deficits in this and other mental diseases focus more on processing speed.


[Psychosis as an evolutionary adaptive mechanism to environmental changes; A plea for a functional explanatory model].
From an evolutionary perspective it is remarkable that psychotic disorders, mostly occurring during fertile age and decreasing fecundity, maintain in the human population.
 AIM: To argue the hypothesis that psychotic symptoms may not be viewed as an illness but as an adaptation phenomenon.
 METHOD: Philosophical consideration and literature study.
 RESULTS: Until now, biomedical research has not unraveled the definitive etiology of psychotic disorders. Findings are inconsistent and show non-specific brain anomalies and genetic variation with small effect sizes. However, compelling evidence was found for a relation between psychosis and stressful environmental factors, particularly those influencing social interaction. Psychotic symptoms may be explained as a natural defense mechanism or protective response to stressful environments. This is in line with the fact that psychotic symptoms most often develop during adolescence. In this phase of life, it is important for an individual's development to leave the familiar and safe home environment, and to build new social networks. This could cause symptoms of 'hyperconsciousness' and calls on the capacity for social adaptation. This mechanism can become out of control due to different underlying brain vulnerabilities and external stressors, leading to social exclusion. CONCLUSIONS There is theoretical ground to consider psychotic symptoms as an evolutionary maintained phenomenon. Research investigating psychotic disorders may benefit from a focus on underlying general brain vulnerabilities or prevention of social exclusion, instead of regarding psychotic symptoms as abnormal phenomena.


Peculiarities of herpes simplex virus (HSV) transcription: an overview.
The herpes simplex virus (HSV) has a 152 kbp dsDNA encoding probably 84 proteins. The approximate number of ORFs is 94, from which seven are doubled. The most probable number of single copy ORFs is 84 after omitting the two latency associated transcripts (LAT)/ORFs and the putative UL27.5 ORF. The high gene number creates a "crowded" genome with several overlapping transcripts. The unique long (U(L)) segment has at least 10 interposed ORFs, the existence of which was not obvious at first sequence analysis, while the unique short (U(S)) segment has two such genes. The surplus of ORFs causes complex transcription patterns: (1) Transcripts with common initiation signals but different termination; (2) Transcripts with different initiation sites but co-terminal ends; (3) "Nested" transcripts differing at both, the initiation as well as termination signals, having partially collinear sequences. At least three or possibly four ORF (gene) pairs (UL9.5/UL10; UL27/UL27.5; UL43/UL43.5; ICP34.5/ORF P and O) occupy both DNA strands at complementary positions rising anti-sense transcripts expressed by an antagonistic mechanism of mutual exclusion. The anti-sense mRNA mechanism might also operate when either LAT or ICP0 ORFs are expressed during latency assuring the absence of lytic virus replication. In contrast, during productive replication the cascade regulation of gene expression predominates, based on stepwise activation of immediate early (IE), early (E), early late (EL) and late (L) promoters. The promoters of different expression kinetic classes (alpha, beta, gamma-1 and gamma-2) are equipped with different number of cellular transcription factor binding and/or enhancer motifs. Surprisingly, only a few HSV mRNAs are being spliced (ICP0, UL15, US1, US12/ICP47). As reviewed here, the transcription pattern of the great majority of overlapping ORFs within the HSV-1 was quite convincingly elucidated, with exception of the putative UL27.5 gene. The UL27.5 transcript was not identified yet. Since the existence of the UL27.5 gene was based on indirect rather than direct evidence, it needs final confirmation.


Nucleocytoplasmic shuttling and the biological activity of mouse survivin are regulated by an active nuclear export signal.
Survivin appears to function as a regulator of cell division and as an apoptosis inhibitor in many species. Here, we characterized the nucleocytoplasmic transport of mouse survivin(140), and its splice variants survivin(121) and survivin(40). We show that the dynamic intracellular localization of survivin(140) is mediated by a Crm1-dependent nuclear export signal (NES) present also in survivin(121), but absent in survivin(40). In contrast, neither survivin nor survivin splice variants contain an active nuclear import signal and seem to enter the nucleus by passive diffusion. The activity of the NES is required for survivin-mediated protection against cell death inducing stimuli and influences protein degradation. During mitosis, NES-deficient survivin variants fail to correctly localize to the mitotic machinery and promote proper cell division. In vivo and in vitro protein interaction assays show that survivin(140) and survivin(121) as well as their export-deficient mutants are able to form homo- as well as heterodimers. The trans-dominant negative phenotype observed upon expression of export-deficient survivin appears, therefore, to be mediated by the formation of inactive survivin heterodimers. The survivin-Crm1 axis is essential for the biological activities of murine survivin, and mouse models will allow investigating its functional implications during development and tumorigenesis.


Adsorption of beta blockers to environmental surfaces.
Beta-adrenergic blocking agents (beta blockers) are widely used pharmaceuticals which have been detected in the environment. Predicting the transport and ultimate fate of beta blockers in the environment requires understanding their adsorption to soils and sediments, something for which little information is currently available. The objective of this work was to examine the adsorption of three beta blockers, propranolol, metoprolol and nadolol, to a natural alluvial material, as well as to six minerals present as components of the alluvial material. Batch adsorption experiments indicate that, for most of the minerals studied, compound hydrophobicity is an important predictor of adsorption, with propranolol,the most hydrophobic compound studied, adsorbing to the greatest extent. Results further suggest that, for the minerals studied, electrostatic effects are not a good predictor of adsorption; adsorption extent was not well-predicted by either surface zeta potential or by the difference between experiment pH and point of zero charge, despite the cationic nature af the three beta blockers at experiment pH values. Experiments were conducted to examine the effect of an anionic surfactant, sodium dodecyl benzene sulfonate (SDBS), on adsorption. Results indicate that SDBS significantly increases the adsorption of propranolol to two different sorbents. This result is potentially important because surfactants such as SDBS are likely to be present in wastewater effluents with beta blockers and could influence their mobility in the environment.


The effect of acupuncture on the clinical state of patients suffering from chronic spastic bronchitis and undergoing long-term treatment with corticosteroids.
51 patients suffering from chronic spastic bronchitis were treated with acupuncture over a period of three years. The patient group consisted of 15 men and 36 women varying in age from 19 to 75 years, with an average age of 45.7 years. The therapy program consisted of 2 or 3 months of acupuncture treatment in alternation with an equal period (2 or 3 months) of recess during which no treatment was administered. Before acupuncture, patients had taken corticosteroids either orally and/or intramuscularly for a period of 2 to 24 years. For those taking corticosteroids orally the daily dosages ranged from 10 to 40 mg Encorton (Polfa, Poland). The patients took intramuscular injections of 60 to 80 mg Kenalog (Squibb) every two or three weeks. Of the 51 patients, 36 completed 3 years of acupuncture treatment. It was found that 63.8% of the patients were able to eliminate corticosteroids for the last part of this study period, i.e., from 3 to 26 months (average period 10.2 months). In 13.9% of the patients the dose of intramuscular injection of corticosteroids was reduced by over 60% during acupuncture treatment. In 16.7% of the patients, the oral administration of corticosteroids was only during lung infections with dyspnoea. In 7 patients (i.e., in 19.5% of the 36 patients) administration of all previously required drugs (i.e., corticosteroids, mucolytic drugs, appropriate antibiotics, aminoxanthines, sympathomimetic beta-agonists, sedation drugs, aerosolized drugs with corticosteroids, and nebulized drugs) during the last 3 to 15 months of this study period (average of 9.8 months) were no longer required.


Stepwise propagation of the ATP-induced conformational change of the F1-ATPase beta subunit revealed by NMR.
The rotation of F1-ATPase (F1) is driven by the open/close bending motion of the beta subunit. The mechanism underlying the bending motion was investigated for the F1beta monomer from thermophilic Bacillus PS3 (TF1beta) in solution, using mutagenesis and NMR. The hydrogen bond networks involving the side chains of Lys-164 (numbering for TF1beta; 162 for mitochondrial F1beta in parentheses), Thr-165(163), Arg-191(189), Asp-252(256), Asp-311(315), and Arg-333(337) in the catalytic region are significantly different for the ligand-bound and freebeta subunits in the crystal structures of mitochondrial F1. The role of each amino acid residue was examined by Ala substitution. beta(K164A) reduced the affinity constant for 5'-adenyl-beta,gamma-imidodiphosphate by 20-fold and abolished the conformational change associated with nucleotide binding and the ATPase activity of alpha3beta(K164A)3gamma.beta(T165A) and beta(D252A) exhibited no effect on the binding affinity but abolished the conformational change and the ATPase activity. The chemical shift perturbation of backbone amide signals of the segmentally labeled beta(mutant)s indicated stepwise propagation of the open/close conversion on ligand binding. The key action in the conversion is the switching of the hydrogen-bonding partner of Asp-252 from Lys-164 to Thr-165. Residual dipolar coupling analysis revealed that the closed conformation of the beta monomer was more closed than that in the crystal structure and was different for MgATP- and MgADP-bound beta subunits. Actually, MgATP induced a conformational change around Tyr-307 (311 for MF1beta), whereas MgADP did not. The significance of these findings is discussed in connection with the catalytic rotation of F1-ATPase.


DECT evaluation of noncalcified coronary artery plaque.
Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (ρ(e)) and the effective atomic number (Z(eff)) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (ρ(e), Z(eff)) lie in the range of (2.65 × 10(23) ≤ ρ(e) ≤ 3.64 × 10(23)/cm(3)) and (6.80 ≤ Z(eff) ≤ 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V1) and HU(V2), with V1,V2 = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (ρ(e), Z(eff)) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (ρ(e), Z(eff)) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. The authors find that the calibration gives ρ(e) with an accuracy of ±3.5% while Z(eff) is found within ±1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques are practically nonexistent, and microcalcification, as observed in histopathology, has to be taken into account to explain the nature of the observed (ρ(e), Z(eff)) data. This also enables us to judge the composition of the plaque in terms of basic model which considers the plaque to be composed of fibres, lipids, and microcalcification. This simple and reliable method has the potential as an effective modality to investigate the composition of noncalcified coronary artery plaques and thus help in their characterization. In this inversion method, (ρ(e), Z(eff)) of the scanned sample can be found by eliminating the effects of the CT machine and also by ensuring that the determination of the two unknowns (ρ(e), Ze(ff)) does not interfere with each other and the nature of the plaque can be identified in terms of a three component model.


Visual Process Monitoring by Data-Dependent Kernel Discriminant Analysis with t-Distributed Similarities.
Visual process monitoring would provide more directly appreciable and more easily comprehensible information about the process operating status as well as clear depictions of the occurrence path of faults; however, as a more challenging task, it has been sporadically discussed in the research literature on conventional process monitoring. In this paper, the Data-Dependent Kernel Discriminant Analysis (D2K-DA) model is proposed. A special data-dependent kernel function is constructed and learned from the measured data, so that the low-dimensional visualizations are guaranteed, combined with intraclass compactness, interclass separability, local geometry preservation, and global geometry preservation. The new optimization is innovatively designed by exploiting both discriminative information and t-distributed geometric similarities. On the construction of novel indexes for visualization, experiments of visual monitoring tasks on simulated and real-life industrial processes illustrate the merits of the proposed method.


Adductor spasmodic dysphonia and botulinum toxin treatment: the effect on well-being.
Adductor spasmodic dysphonia (AdSD) is a controversial and enigmatic voice disorder. It is generally accepted that it has a neurologic, although undetermined, cause, and it is accompanied by much psychological and physical distress. In this prospective study, standardized psychometric tests were used to assess the personality characteristics and psychological and somatic well-being of 46 patients with AdSD. Moreover, the effect of botulinum toxin (Botox) treatment on their well-being was evaluated. No significant differences could be detected between patients and a representative norm group concerning 7 personality characteristics. Nevertheless, before treatment, there were significantly more psychological and somatic complaints. After establishment of a normal to near-normal voice with Botox injections, these complaints were reduced to normal levels--a finding suggesting these phenomena to be secondary to the voice disorder. These findings, and the normal personality characteristics, do not support a psychogenic cause of AdSD.


New method for the preparation of nonuniform distributed Co/SiO2 catalysts.
Egg-shell, egg-yolk and egg-white types of Co/SiO2 catalysts were prepared by utilizing entrapped air to inhibit the entrance of impregnation or leaching solution into the cores of catalyst pellets during the preparation procedure; the entrapped air played the important role because the capillary pressure was reduced to a suitable range by adjusting the concentration of ethanol in the impregnation or leaching solution for a hydrophobized silica surface.


Can digital examination substitute anorectal manometry for the evaluation of anal canal pressures?
Anorectal manometry provides objective information on the sphincter function of the anal canal. However, in many centers sphincter function is evaluated by digital examination, due to the unavailability of manometry. A study is made to correlate the sensitivity and specificity of a quantitative digital examination in the analysis of sphincter tone with the pressures recorded by manometry, and to examine the capacity of both techniques to discriminate continent subjects and incontinent patients. A total of 191 patients were divided into three groups: control (C), obstructive defecation (OD) and fecal incontinence (FI). Subjective quantitative digital evaluation of anal tone was performed on a scale of 0 to 5 points at rest, and 0 to 10 points at squeeze. A correlation analysis was performed, and the sensitivity and specificity of each fecal incontinence diagnostic test was determined. Digital examination found rectal tone to be diminished in elderly patients. A significant correlation was established between the digital and manometric tone readings, both at rest and at squeeze. Both techniques showed a low anal sphincter pressure in the FI group versus the C and OD groups. Differences in tone were recorded between the C and OD groups with manometry, but not with digital examination. The latter was in turn found to be more sensitive but less specific than manometry in differentiating between fecal continence and incontinence. Although digital examination does not substitute anorectal manometry, a good correlation exists between the two techniques. In this sense, digital examination may afford an approximate clinical evaluation of some fecal continence mechanisms in those centers where manometry is not available.


Angiotensin II type 1 receptor blockers favorably affect renal angiotensin II and MAS receptor expression in patients with diabetic nephropathy.
The aims of this study were to assess the renal expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor in human type 2 diabetic nephropathy (DN). In total, 115 patients diagnosed with DN by renal biopsy were enrolled in this study. The protein expression levels of the AT1R, AT2R, and MAS receptors were assessed by immunohistochemistry. The protein expression levels of AT1R, AT2R, and MAS receptor in the renal biopsy tissue were correlated with the pathologic classification of DN. Tubulointerstitial AT1R expression in patients of class IIb was significantly stronger than control samples (p < 0.05). Expression of AT2R and MAS receptors were highest with class IIb DN patients. When DN patients were treated with AT1R blocker (ARB), the expression of AT1R was downregulated (p < 0.05), and the MAS receptor was upregulated in tubular interstitial (p < 0.05). Our results directly observed that renal expression levels of AT1R increase during the early stages of DN, ARB reducing AT1R while increasing MAS receptor. Therefore, ARB should be used as soon as possible in patients with DN.


Abdominal circumference vs abdominal area--which is better?
The efficacies of ultrasonic abdominal circumference (AC) and abdominal area (AA) measurements in the evaluation of intrauterine fetal growth were compared. The intraobserver random and technical errors were found to be significantly higher with AA measurements. The correlation with intrauterine fetal weight was observed to be better with AC as compared with AA measurements, the fetal weights being expressed as either linear regressions or multiple regressions involving the two parameters. Between 32 and 38 weeks, a single AC measurement detects 74 per cent of small-for-date fetuses, while a single AA measurement detects only 58 per cent of such fetuses. The false-positive rates were similar for the two parameters. It is concluded that AA measurements are no more useful than AC measurements in the routine assessment of intrauterine fetal growth.


Crystallographic study of the complex between sulfite and bakers' yeast flavocytochrome b2.
The complex between Saccharomyces cerevisiae flavocytochrome b2 and the sulfite anion has been analyzed by x-ray diffraction. A map of the difference in electron density between the complex and the native protein has been computed. One positive peak of electron density is visible at the active site of each of the two subunits in the asymmetric unit, very close to the N-5 of the flavin. The molecular fragment SO3(2-) can account for the shape of this difference in electron density. A third peak is visible in the subunit containing pyruvate, the reaction product. It is a peak of negative electron density localized at the position where the pyruvate usually is in the native form. These results are interpreted on the basis of the mechanism defined in solution for the reaction between flavins and sulfite.


Maternal hepatic immunology during pregnancy.
The liver plays pivotal roles in immunologic responses, and correct hepatic adaptations in maternal immunology are required during pregnancy. In this review, we focus on anatomical and immunological maternal hepatic adaptations during pregnancy, including our recent reports in this area. Moreover, we summarize maternal pregnancy-associated liver diseases, including hyperemesis gravidarum; intrahepatic cholestasis of pregnancy; preeclampsia, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute fatty liver of pregnancy. In addition, the latest information about the factors that regulate hepatic immunology during pregnancy are reviewed for the first time, including human chorionic gonadotropin, estrogen, progesterone, growth hormone, insulin like growth factor 1, oxytocin, adrenocorticotropic hormone, adrenal hormone, prolactin, melatonin and prostaglandins. In summary, the latest progress on maternal hepatic anatomy and immunological adaptations, maternal pregnancy-associated diseases and the factors that regulate hepatic immunology during pregnancy are discussed, which may be used to prevent embryo loss and abortion, as well as pregnancy-associated liver diseases.


History of the Exotic Ambrosia Beetles Euwallacea interjectus and Euwallacea validus (Coleoptera: Curculionidae: Xyleborini) in the United States.
Exotic insects are constantly intercepted at U.S. ports-of-entry. Of these, wood-boring beetles, particularly xyleborine ambrosia beetles, are sometimes missed during port inspections and become established in the United States. Euwallacea validus (Eichhoff) and Euwallacea interjectus (Blandford) are morphologically similar Asian ambrosia beetle species that vary by their fungal associates and their potential to cause economic damage. Euwallacea validus and E. interjectus were first discovered in New York (1975) and Hawaii (1976), respectively. Euwallacea validus was collected multiple times from widely separated localities and is assumed to have spread throughout the eastern United States. The discovery of E. interjectus in Florida (2011) and Texas (2011) prompted our review of the E. validus specimens because of the potential misidentification of the species. In addition, using mitochondrial cytochrome oxidase I (COI) DNA data and phylogenetic analysis, we tested the hypothesis that multiple introductions account for the U.S. populations of E. interjectus and E. validus. Our review of 7,184 specimens revealed an earlier introduction to the mainland for E. interjectus, which was first collected from Louisiana in 1984. This species is distributed in the South while E. validus occurs in the North with a known area of syntopy in northeastern Georgia. The extent of the syntopy within the United States is unknown and further investigation is required. Phylogenetic analysis of 24 E. interjectus and 20 E. validus individuals resolved clades that associated with each species and gross geographic provenance. Four well-supported clades represented E. interjectus which included the following localities: 1) Hawaii and Thailand; 2) Vietnam, Taiwan, and Texas; 3) Okinawa (Japan); and 4) Japan and several southern U.S. states. One clade comprised all E. validus specimens from Japan and the mainland United States. Four and two haplotypes were found for the E. interjectus and E. validus specimens, respectively, in mainland United States. Except for the Texas specimen, the haplotypes differed by one nucleotide. The relationship of the haplotypes and their sequence similarity suggested that the provenance of E. validus and the majority of E. interjectus haplotypes was Japan while the Texas haplotype originated later and from a location near Taiwan. Given the high nucleotide sequence difference between the Hawaiian and Thai haplotypes, the exact origin of the Hawaiian E. interjectus is unknown but likely Southeast Asia. A broader investigation including more SE Asian individuals will help to further explain the introduction of E. interjectus into Hawaii and Texas.


1H Nuclear Magnetic Resonance Metabolomics of Plasma Unveils Liver Dysfunction in Dengue Patients.
Dengue, due to its global burden, is the most important arthropod-borne flavivirus disease, and early detection lowers fatality rates to below 1%. Since the metabolic resources crucial for viral replication are provided by host cells, detection of changes in the metabolic profile associated with disease pathogenesis could help with the identification of markers of prognostic and diagnostic importance. We applied (1)H nuclear magnetic resonance exploratory metabolomics to study longitudinal changes in plasma metabolites in a cohort in Recife, Brazil. To gain statistical power, we used innovative paired multivariate analyses to discriminate individuals with primary and secondary infection presenting as dengue fever (DF; mild) and dengue hemorrhagic fever (DHF; severe) and subjects with a nonspecific nondengue (ND) illness (ND subjects). Our results showed that a decrease in plasma low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) discriminated dengue virus (DENV)-infected subjects from ND subjects, and also, subjects with severe infection even presented a decrease in lipoprotein concentrations compared to the concentrations in subjects with mild infection. These results add to the ongoing discussion that the manipulation of lipid metabolism is crucial for DENV replication and infection. In addition, a decrease in plasma glutamine content was characteristic of DENV infection and disease severity, and an increase in plasma acetate levels discriminated subjects with DF and DHF from ND subjects. Several other metabolites shown to be altered in DENV infection and the implications of these alterations are discussed. We hypothesize that these changes in the plasma metabolome are suggestive of liver dysfunction, could provide insights into the underlying molecular mechanisms of dengue virus pathogenesis, and could help to discriminate individuals at risk of the development of severe infection and predict disease outcome. Dengue, due to its global burden, is the most important mosquito-borne viral disease. There is no specific treatment for dengue disease, and early detection lowers fatality rates to below 1%. In this study, we observed the effects of dengue virus infection on the profile of small molecules in the blood of patients with mild and severe infection. Variations in the profiles of these small molecules reflected the replication of dengue virus in different tissues and the extent of tissue damage during infection. The results of this study showed that the molecules that changed the most were VLDL, LDL, and amino acids. We propose that these changes reflect liver dysfunction and also that they can be used to discriminate subjects with mild dengue from those with severe dengue.


Undissociated versus dissociated structures for water clusters and ammonia-water clusters: (H2O)n and NH3(H2O)n-1 (n = 5, 8, 9, 21). Theoretical study.
To understand the autoionization of pure water and the solvation of ammonia in water, we investigated the undissociated and dissociated (ion-pair) structures of (H2O) n and NH3(H2O)n-1 (n = 5, 8, 9, 21) using density functional theory (DFT) and second order Moller-Plesset perturbation theory (MP2). The stability, thermodynamic properties, and infrared spectra were also studied. The dissociated (ion-pair) form of the clusters tends to favor the solvent-separated ion-pair of H3O+/NH4+ and OH-. As for the NH3(H2O)20 cluster, the undissociated structure has the internal conformation, in contrast to the surface conformation for the (H2O)21 cluster, whereas the dissociated structure of NH3(H2O)20 has the surface conformation. As the cluster size of (H2O)n/NH3(H2O)n-1 increases, the difference in standard free energy between undissociated and dissociated (ion-pair) clusters is asymptotically well corroborated with the experimental free energy change at infinite dilution of H3O+/NH4+ and OH-. The predicted NH and OH stretching frequencies of the undissociated and dissociated (ion-pair) clusters are discussed.


Remodeling of brain lipidome in methamphetamine-sensitized mice.
Lipids are predominant components of the brain and key regulators for neural structure and function. The effect of methamphetamine (METH) on behavior, cognition as well as memory has been intensively investigated; however, the impact of METH on brain lipid profiles is largely unknown. Here, we used a global lipidomic approach to investigate brain lipidome of METH-sensitized mice. We found that repeated METH significantly modified the lipidome in the hippocampus, prefrontal cortex (PFC) and striatum. Interestingly, nucleus accumbens showed no obvious alteration in lipidomic profiling. Phospholipid and sphingolipid metabolisms were profoundly modified in the hippocampus of METH-sensitized mice, exhibiting increased phosphatidic acid and ether phosphatidylcholine but decreased lysophosphatidylethanolamine, lactosylceramide and triglycerides. The fatty acyl length of phospholipids and diacylglycerol longer than 40 carbon were clearly decreased in the hippocampus, and that 36 carbon was decreased in the PFC. These results indicate METH can profoundly affect the metabolism of phospholipids, sphingolipids and glycerolipids in the brain. Our findings reveal a link between remodeled brain lipidome and neurobehavior induced by METH.


The effect of atomic substitution on electron-phonon interactions in negatively charged B, N-substituted acenes.
Electron-phonon interactions in the monoanions of B, N-substituted acenes such as B(3)N(3)F(6) (1f) and B(5)N(5)F(8) (2f) are studied, and compared with those in the monoanions of B(3)N(3)H(6) (1h) and B(5)N(5)H(8) (2h), and B(3)N(3)D(6) (1d) and B(5)N(5)D(8) (2d). The low frequency modes around 500 cm(-1) as well as the frequency modes higher than 1000 cm(-1) strongly couple to the lowest unoccupied molecular orbitals (LUMO) in 1f and 2f. The total electron-phonon coupling constants (l(LUMO)) are estimated to be 2.710 and 2.054 eV for 1f and 2f, respectively, and those are estimated to be 0.342 and 0.235 eV for 1d and 2d, respectively, while those were estimated to be 0.340 and 0.237 eV for 1h and 2h, respectively. That is, the l(LUMO) value increases much more significantly by H-F substitution than by H-D substitution in B, N-substituted acenes. The larger displacements of B and N atoms in the vibronic active modes in 1f and 2f than those in 1d and 2d due to larger atomic mass of fluorine than that of deuterium, and the phase patterns difference between the LUMO in 1f and 2f, in which the atomic orbitals between N and its neighboring F atoms form strong sigma-antibonding interactions, and that in 1d and 2d, in which the atomic orbitals between two neighboring B and N atoms form weak pi-bonding and pi-antibonding interactions, are the main reason why the l(LUMO) value increases much more significantly by H-F substitution than by H-D substitution. The reorganization energies between the neutral molecules and the corresponding monoanions are estimated to be 0.122, 0.063, 0.733, and 0.830 eV for 1h, 2h, 1f, and 2f, respectively. Therefore, the estimated reorganization energies between the neutral molecules and the corresponding monoanions for 1f and 2f are much larger than those for 1h and 2h.


Affine Non-Local Means Image Denoising.
This paper presents an extension of the Non-Local Means denoising method, that effectively exploits the affine invariant self-similarities present in the images of real scenes. Our method provides a better image denoising result by grounding on the fact that in many occasions similar patches exist in the image but have undergone a transformation. The proposal uses an affine invariant patch similarity measure that performs an appropriate patch comparison by automatically and intrinsically adapting the size and shape of the patches. As a result, more similar patches are found and appropriately used. We show that this image denoising method achieves top-tier performance in terms of PSNR, outperforming consistently the results of the regular Non-Local Means, and that it provides state-of-the-art qualitative results.


Rabies vaccines: from the past to the 21st century.
Since the first development of a rabies vaccine by Pasteur in the late 19th century, second- and third-generation vaccines with improved efficacy and less reactogenicity have been developed for use in humans and animals. Despite the availability of safe but rather expensive vaccines based on inactivated virus propagated in diploid cell cultures, much of the human vaccinations worldwide are still carried out with nerve tissue-containing vaccines, which have various side effects. A number of experimental vaccines are under development that may provide alternative safe and potent but less expensive vaccine options. These include DNA vaccines, recombinant viral vaccines, and recombinant protein vaccines. Further testing is needed to determine if and which one of these novel vaccines will make their way into mass production and application in the future.


One-pot hydrothermal preparation and defect-enhanced photocatalytic activity of Bi-doped CdWO4 nanostructures.
In the field of photocatalysis, the suppression of electron-hole recombination through various defects has been an emerging trend to enhance photocatalytic activity. The separation efficiency of electron-hole recombination of well-explored wolframite structured monoclinic CdWO4, prepared using the one-pot hydrothermal method, was further improved by Bi3+ doping in CdWO4. Studies using the partial density of states illustrated that Bi 6s and 6p orbitals altered the electronic band structure to the extent of lowering the band gap, resulting in more photon absorption. The positron annihilation lifetime studies unveiled the formation of cluster defects such as oxygen (V0o, Vo1+, Vo2+) along with cadmium vacancies () in Bi-doped CdWO4. The coexistence and synergy of more adsorption sites of V0o, Vo1+, Vo2+, VCd for dye and O2 molecules, suitable oxide/redox band potentials, the modified electronic band structure especially owing to W-O1-Bi-O2-W linkages, together with high surface area endowed Bi-doped CdWO4 to form ˙O2- radicals played a predominant role in the methyl orange degradation. All the experimental findings demonstrated conclusively that Bi3+ doping at Cd2+ facilitated CdWO4 to exhibit superior photocatalytic activity.


In vitro fermentation characteristics of selected oligosaccharides by swine fecal microflora.
The objective of this study was to quantify the fermentation characteristics of oligosaccharides present in feed ingredients or isolated for dietary supplementation. Substrates studied included short-chain fructooligosaccharides, medium-chain fructooligosaccharides, long-chain fructooligosaccharides, raffinose, stachyose, soy solubles, granular and liquid forms of transgalactooligosaccharides, glucooligosaccharides, mannanoligosaccharides, and xylooligosaccharides. Three healthy pigs that had never received antibiotics served as sources of fecal inoculum. Each substrate was fermented in vitro; samples were taken at 0, 2, 4, 8, and 12 h, and pH change and short-chain fatty acid (SCFA) and gas production determined. Gas production at 12 h did not differ (P > 0.05) among all fructooligosaccharides, transgalactooligosaccharides, soy solubles, and xylooligosaccharides. Raffinose, stachyose, and raffinose + stachyose fermentation resulted in the greatest (P < 0.05) gas production at 12 h of all substrates tested. The rate of gas production was greatest (P < 0.05) for stachyose and least (P < 0.05) for glucooligosaccharides and mannanoligosaccharides. Substrate did not affect (P > 0.05) time to attain maximal rate of gas production. The pH at 12 h for all fructooligosaccharides and xylooligosaccharides did not differ (P > 0.05). The pH values at 12 h for raffinose, stachyose, and raffinose + stachyose were highest (P < 0.05) compared with all other substrates. Total SCFA production at 12 h was similar for all fructooligosaccharides and transgalactooligosaccharides, glucooligosaccharides, and soy solubles. Total SCFA production was greatest (P < 0.05) for xylooligosaccharides, stachyose, and raffinose + stachyose, and least (P < 0.05) for mannanoligosaccharides and raffinose. Stachyose fermentation resulted in the greatest (P < 0.05) rate and earliest time to attain maximal rate of SCFA production. All oligosaccharides studied were readily fermentable but varied in amount and type of SCFA produced. Fermentation of the pure forms of oligosaccharides contained in soy solubles resulted in greater gas production and higher pH compared with soy solubles. The oligosaccharides in the soy solubles matrix seemed to behave differently than their pure counterparts. The high rates of fermentation of most oligosaccharides tested indicate that they may serve as fermentable carbohydrate sources in the terminal small intestine or large intestine of swine.


No Observed Effect of Landscape Fragmentation on Pathogen Infection Prevalence in Blacklegged Ticks (Ixodes scapularis) in the Northeastern United States.
Pathogen prevalence within blacklegged ticks (Ixodes scapularis Say, 1821) tends to vary across sites and geographic regions, but the underlying causes of this variation are not well understood. Efforts to understand the ecology of Lyme disease have led to the proposition that sites with higher host diversity will result in lower disease risk due to an increase in the abundance of inefficient reservoir species relative to the abundance of species that are highly competent reservoirs. Although the Lyme disease transmission cycle is often cited as a model for this "dilution effect hypothesis", little empirical evidence exists to support that claim. Here we tested the dilution effect hypothesis for two pathogens transmitted by the blacklegged tick along an urban-to-rural gradient in the northeastern United States using landscape fragmentation as a proxy for host biodiversity. Percent impervious surface and habitat fragment size around each site were determined to assess the effect of landscape fragmentation on nymphal blacklegged tick infection with Borrelia burgdorferi and Anaplasma phagocytophilum. Our results do not support the dilution effect hypothesis for either pathogen and are in agreement with the few studies to date that have tested this idea using either a landscape proxy or direct measures of host biodiversity.


Mechanisms of tissue-iron relaxivity: nuclear magnetic resonance studies of human liver biopsy specimens.
MRI is becoming an increasingly important tool to assess iron overload disorders, but the complex nature of proton-iron interactions has troubled noninvasive iron quantification. Intersite and intersequence variability as well as methodological inaccuracies have been limiting factors to its widespread clinical use. It is important to understand the underlying proton relaxation mechanisms within the (human) tissue environment to address these differences. In this respect, NMR relaxometry was performed on 10 fresh human liver biopsy specimens taken from patients with transfusion-dependent anemia. T1 (1/R1) inversion recovery, T2 (1/R2) single echo, and multiecho T2 CPMG measurements were performed on a 60-MHz Bruker Minispectrometer. NMR parameters were compared to quantitative iron levels and tissue histology. Relaxivities R1 and R2 both increased linearly with hepatic iron content, with R2 being more sensitive to iron. CPMG data were well described by a chemical-exchange model and predicted effective iron center dimensions consistent with hemosiderin-filled lysosomes. Nonexponential relaxation was evident at short refocusing intervals with R2 and amplitude behavior suggestive of magnetic susceptibility-based compartmentalization rather than anatomic subdivisions. NMR relaxometry of human liver biopsy specimens yields unique insights into the mechanisms of tissue-iron relaxivity.


[Ultra-remote robot-assisted laparoscopic surgery for varicocele through 5G network: Report of two cases and review of the literature].
At present, the longest network transmission distance (NTD) for 5G remote endoscopic surgery is reportedly only about 229 km, and the NTD longer than 5 000 km has not yet been reported in clinical application. In this study, we attempted the clinical application of 5G ultra-remote robot-assisted laparoscopic surgery in spermatic vein ligation. This retrospective study included two cases of 5G ultra-remote robot-assisted laparoscopic spermatic vein ligation using the home-made Tumai Surgical Robot System. The operation table was located in Xinjiang Kezhou People's Hospital, with an NTD of about 5 800 km (a linear distance of about 3 800 km) from the surgeon's console in the Telemedical Center of the First Affiliated Hospital of Nanjing Medical University, the apparatuses connected through the public 5G network. We observed the network connection delay, network fluctuation, and data packet loss rate of the devices at both ends of the loop through the feedback value of the Ping command by real-time monitoring. The total operation time of the two cases was 45 and 40 minutes respectively, with a mean blood loss of < 5 ml. The patients resumed a liquid diet and out-of-bed activity on the first day, the abdominal drainage tubes removed on the second, and both discharged from the hospital on the third day. The intraoperative average two-way network delay was 130 ms, and the average continuous data packet loss rate was 1.4%. No adverse network events, such as network interruption, occurred during the operation. Through the public 5G network and home-made Tumai Surgical Robot System, ultra-remote robot-assisted laparoscopic surgery was performed safely and successfully.


Phytoplankton biogeography and community stability in the ocean.
Despite enormous environmental variability linked to glacial/interglacial climates of the Pleistocene, we have recently shown that marine diatom communities evolved slowly through gradual changes over the past 1.5 million years. Identifying the causes of this ecological stability is key for understanding the mechanisms that control the tempo and mode of community evolution. If community assembly were controlled by local environmental selection rather than dispersal, environmental perturbations would change community composition, yet, this could revert once environmental conditions returned to previous-like states. We analyzed phytoplankton community composition across >10(4) km latitudinal transects in the Atlantic Ocean and show that local environmental selection of broadly dispersed species primarily controls community structure. Consistent with these results, three independent fossil records of marine diatoms over the past 250,000 years show cycles of community departure and recovery tightly synchronized with the temporal variations in Earth's climate. Changes in habitat conditions dramatically alter community structure, yet, we conclude that the high dispersal of marine planktonic microbes erases the legacy of past environmental conditions, thereby decreasing the tempo of community evolution.


Notice to Readers: Special Podcast: "Defining Moments in MMWR History - E. coli O157:H7".
MMWR has released a special podcast that highlights the leading role that MMWR played in reporting on the deadly multistate Escherichia coli O157:H7 foodborne outbreak of 1993. "Defining Moments in MMWR History - E. coli O157:H7" features an interview with Dr. Beth Bell conducted by MMWR Editor-in-Chief Dr. Sonja Rasmussen. Dr. Bell, who served as director of the National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) from 2010 to 2017 and as an Epidemic Intelligence Service Officer during 1992-1994, was one of the first public health responders on the scene for this landmark public health emergency.


The effects of coffee on serum lipids and blood pressure in a UK population.
Data on coffee consumption were collected for 1074 adults attending for health checks in the OXCHECK study, to assess associations with serum lipids and blood pressure. Of the sample, 70.5% drank coffee, largely instant. Coffee had no significant effects on total or high-density lipoprotein (HDL) cholesterol or blood pressure, and was negatively correlated with serum triglycerides. The type of coffee drunk in the UK does not adversely effect these cardiovascular risk factors.


3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta.
The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.


PhD programs in nursing in Iran and Canada: A qualitative study.
To compare doctoral programmes of nursing in Iran and Canada. This qualitative study was conducted in Mashhad, Iran, in April 2014. It was based on Beredy's model, including description, interpretation, juxtaposition and comparison. The validity of the related documents was assessed by internal validity, importance and accuracy of documents. Critique on the external validity and core of documents were reviewed. Then, they were interpreted, juxtaposed and compared. Both the countries had significant differences in fundamental elements of their curricula, including mission, vision, aim, objectives, roles and tasks of graduates. Consequently, academic units, final comprehensive exam, and research courses were also different. Doctoral programmes in Canada focussed on competency-based, community-based, task-based and student-centred approaches. These approaches were ignored in the Iranian curriculum.


Defining "adequate" pathogen reduction performance for transfused blood components.
Pathogen reduction of labile blood products offers the opportunity to introduce to the blood banking community the same mechanism of protection that is employed for fractionated or pooled plasma products today--blood components that have been treated with methods to inactivate or reduce the infectivity of a variety of organisms that may contaminate donated blood and thus potentially transmit infection via transfusion. Due to the mechanisms of action, the methods employed in the plasma fractionation environment are not directly applicable to labile blood products. This article examines whether the same criteria of performance required for plasma derivatives (i.e., 6 log/mL reduction by multiple orthogonal methods) should be applied to the treatment of labile components and if not what criteria for performance might be sufficient. In conducting this analysis, we have considered what has been learned in the past several decades regarding the dynamics and infectivity of various pathogens and disease transmission by blood products, the introduction and progressive enhancement of testing methods based on serology and nucleic acid testing, and the performance characteristics for pathogen reduction technologies that are available today.


Application of phototherapy for the healing of the navels of neonatal dairy calves.
The present work evaluated the effects of LED light irradiation on the healing of the navels of neonatal dairy calves. Fifty-seven neonatal calves were divided into two groups. Animals had their umbilical stumps immersed in 10% iodine tincture for 60 s, and this process was repeated every 24 h for three consecutive days. The 29 animals in the first group did not receive LED therapy. The 28 animals in the second group received LED light irradiation at 640 nm with 300 mW power, 46.8 J/cm2 energy density, 60 s irradiation time, and 0.385 cm2 spot size. The animals were irradiated at four points (46.8 J/cm2 per point) evenly distributed around the insertion site of the umbilical stump every 24 h for three consecutive days. Irradiation with LED light was applied before the umbilical stumps were immersed in the iodine solution. The time after birth at which the umbilical stump fell off of each calf was noted. The umbilical stumps of all animals fell off by the 25th day of age. After the umbilical stump fell off, the healing of the remnant wound was followed up to the 30th day after birth. The area of the wound was measured on the 15th, 20th, and 25th day after birth using digital photographs and computer-assisted area measurements. A two-tailed unpaired t test was applied to analyze the falling off the umbilical stump, whereas a Kruskal-Wallis one-way ANOVA test with a Dunn's multiple comparison test was used for the wound size evolution. GraphPad Prisma 5.0® and GraphPad StatMate 2.00® were used for the statistical analysis. The results revealed that phototherapy hastened the falling off the umbilical stump, accelerated navel healing, and reduced the mortality rate in newborn calves. Therefore, this study introduced a preventive and adjuvant after birth treatment that proved to be effective in reducing the incidences of omphalitis and newborn mortality.


[Links between perceptions of cardiovascular disease and participation in cardiac rehabilitation programs: an exploratory study].
Cardiac rehabilitation programs (CRP) entail beneficial changes for the majority of participants with heart problems. However, only 21% to 41% of those patients participate in such programs. The goal of this study was to identify modifable and non-modifiable cardiovascular risk factors, as well as perceptions of illness that affect the participation of patients with cardiovascular problems in CRPs. Thirty individuals with a cardiovascular disease participated in this exploratory, quantitative study. The results suggest that the level of education as well as increases in the level of HDL cholesterol (high-density lipoprotein) and of anxiety predict the participation in CRPs. However, the perception of illness was not associated with participation in CRPs. The implications of these results are discussed.


Endometrial pathology associated with infertility among Nigerian women.
One hundred and forty endometrial specimens of women with infertility were examined with oil immersion at X100 magnification for evidence of secretory activity, presence of any inflammatory cells and characteristic features suggestive of specific pathogens. Twenty-three (16.4%) had evidence of chronic endometritis the majority being non-specific. Only two (1.4%) were granulomatous. There was a significant eosinophilic infiltrate in nine cases (6.4%) some numbering up to 55 eosinophils per 5 high power fields (5 hpf). Sensitive immunohistochemical techniques would be needed to correlate findings with specific pathogens for effective treatment.


The distinction between eye and object motion is reflected by the motion-onset visual evoked potential.
Humans are able to distinguish eye movement-induced retinal image motion and physical object motion during smooth pursuit eye movements. We investigated the neurophysiological basis of this ability by comparing motion-onset visual evoked potentials (VEPs) to onset of: (1) physical object motion during fixation, (2) eye movement-induced retinal image motion, and (3) physical object motion during eye movements. Electro-oculographic (EOG) artifacts were removed and the influence of eye-movement quality was evaluated. Retinal image shift was of similar magnitude in all conditions (9 degrees /s) and elicited typical motion-onset VEPs, with N2 at occipital and P2 at central derivations. During smooth pursuit, physical object motion induced N2 and P2 of higher latencies than during fixation. In the absence of physical object motion, i.e., for exclusively eye movement-induced retinal image motion, the N2 amplitude was reduced. This is taken as evidence that the activity of detectors of physical object motion is reflected by a part of the N2 component. N2 also reflects eye movement-induced retinal image motion. It is concluded that headcentric motion detection and the detection of eye movement-induced retinal image motion is mediated by brain mechanisms with similar latencies and, within the resolution limits of VEPs, at similar locations.


Ion distribution in multilayers of weak polyelectrolytes: A neutron reflectometry study.
Neutron reflectometry was used to determine the distribution of salt ions and water in thin poly(acrylic acid) and poly(allylamine hydrochloride) polyelectrolyte multilayers assembled with and without salt. Increasing salt concentration reverses the exclusion of water from the substrate region, eventually leading to an asymmetric segregation of water near the substrate at high salt concentration. The counterions were found to localize near the substrate in films that were either assembled with salt or were exposed to salt solutions. In addition, the capping layer of the film was found to greatly influence the counterion distribution in the multilayer.


Beep Test Does Not Induce Phosphorylation of Ras/MAPK- or JAK/STAT-Related Proteins in Peripheral Blood T Lymphocytes.
The Th1 cell subset is involved in the immunological response induced by physical exercise. The aim of this work is to evaluate the post-effort activation of Ras/MAPK and JAK/STAT signaling pathways in T cells of young, physically active men. Seventy-six physically active, healthy men between 15 and 21 years old performed a standard physical exercise protocol (Beep test). Phosphorylation levels of Ras/MAPK-(p38 MAPK, ERK1/2) and JAK/STAT-related (STAT1, STAT3, STAT5, and STAT6) proteins were evaluated by flow cytometry in Th and Tc cells post-effort and during the lactate recovery period. The performed physical effort was not a strong enough physiological stimulant to provoke the phosphorylation of ERK1/2, p38 MAPK, STAT1, STAT3, STAT5, and STAT6 in T cells, at least for the duration of our study (the end of the lactate recovery period). We conclude that more observation time-points, including shorter and longer times after the exercise, are required to determine if the Ras/MAPK signaling pathway is involved in modulating the post-effort immunological response.


The importance of external social support for workplace-related stress as we grow older.
For older employees, a mismatch between work and nonwork roles can lead to work-family conflict (WFC) and stress. This paper examines whether the availability of social support from outside the workplace can assist these employees in coping with the stress-related consequences of WFC. This study used data from Waves 16 (Time 1) and 17 (Time 2) of the Household, Income and Labour Dynamics in Australia (HILDA) survey (N = 2867). Sociodemographic characteristics were measured using age, sex and employment tenure. A moderated regression model was applied to the older employees in this sample using stress, WFC with external social support as the moderator. Analysis was additionally undertaken for the different aged employee cohorts, younger than 30 years and middle-aged (30-50). We found that external social support dampened the effect of WFC on employee stress for older employees. This effect was more powerful for older employees than for younger employees. Interestingly, older employees reported the same levels of external social support as employees between 30 and 50, but less than that of employees younger than 30 years. Following our hypothesised relationships based on conservation of resources (COR), selection, optimisation with compensation (SOC) and socio-emotional selectivity theories (SST), this paper demonstrates that older employees benefit significantly from external social support. As external social support increased among older employees, the negative effect of WFC on stress decreased. However, this effect was only significant for employees up to the 68th percentile. Overall, this effect was less powerful for both groups of younger employees. Consistent with SOC and SST, older employees possessed different social motives (less reported external social support). Employer and government strategies assisting employees to develop social networks outside the workplace may provide significant benefits to organisations in addition to employees.


Immunogenicity and contraceptive efficacy of Escherichia coli-expressed recombinant porcine zona pellucida proteins.
To overcome availability of the purified native zona pellucida (ZP) glycoproteins for immunocontraception, porcine ZP3, and ZP4 were expressed in E. coli. Purified recombinant proteins were characterized by SDS-PAGE and Western blot, and immunogenicity and contraceptive efficacy determined in FvB/J female mice. Purified ZP3, ZP3 with promiscuous T-cell epitope of tetanus toxoid, ZP4 and ZP4 incorporating promiscuous T-cell epitope of bovine RNase revealed ~44-, ~49-, ~53-, and ~55-kDa bands by SDS-PAGE and Western blot, respectively. Immunization of female mice with recombinant proteins elicited high antibody titers as well as T-cell responses. Immune sera recognized mouse oocyte ZP and also inhibited in vitro fertilization. Immunized mice showed significant decrease in fertility. Recombinant proteins were able to recall memory antibody response in female mice primed with porcine native ZP. Availability of recombinant porcine proteins will be useful in the development of contraceptive vaccine.


PHYLOGENETIC ANALYSIS OF TRAIT EVOLUTION AND SPECIES DIVERSITY VARIATION AMONG ANGIOSPERM FAMILIES.
Angiosperm families differ greatly from one another in species richness (S). Previous studies have attributed significant components of this variation to the influence of pollination mode (biotic/abiotic) and growth form (herbaceous/woody) on speciation rate, but these results suffer difficulties of interpretation because all the studies ignored the phylogenetic relationships among families. We use a molecular phylogeny of the angiosperm families to reanalyse correlations between S and family-level traits and use reconstructions of trait evolution to interpret the results. We confirm that pollination mode and growth form are correlated with S and show that the majority of changes in pollination mode involved a change from biotic to abiotic pollination with an associated fall in speciation rate. The majority of growth form changes involved the evolution of herbaceousness from woodiness with a correlated rise in speciation rate. We test the hypothesis of Ricklefs and Renner (1994) that "evolutionary flexibility" rather than other trait changes triggered increased speciation rates in some families, but find little support for the hypothesis.


Time-course changes of steroidogenic gene expression and steroidogenesis of rat Leydig cells after acute immobilization stress.
Leydig cells secrete testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid (corticosterone, CORT; in rats), which decreases circulating testosterone levels in part through a direct action by binding to the glucocorticoid receptors (NR3C1) in Leydig cells. The intratesticular CORT level is dependent on oxidative inactivation of glucocorticoid by 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) in Leydig cells. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute immobilization stress in rats. The plasma CORT levels were significantly increased 0.5, 1, 3 and 6 h after immobilization stress, while plasma testosterone levels were significantly reduced 3 and 6 h, after stress and luteinizing hormone (LH) did not change. Immobilization stress caused the down-regulation of Scarb1, Star and Cyp17a1 expression levels in the rat testis starting at the first hour of stress, ahead of the significant decreases of plasma testosterone levels. Other mRNA levels, including Cyp11a1, Hsd3b1 and Hsd17b3, began to decline after 3 h. Hsd11b1 and Nos2 mRNA levels did not change during the course of stress. Administration of glucocorticoid antagonist RU486 significantly restored plasma testosterone levels. In conclusion, Scarb1, Star and Cyp17a1 expression levels are more sensitive to acute stress, and acute immobilization stress causes the decline of the steroidogenic pathway via elevating the levels of glucocorticoid, which binds to NR3C1 in Leydig cells to inhibit steroidogenic gene expression.


Mortality in Patients With Primary Aldosteronism: A Swedish Nationwide Study.
Primary aldosteronism (PA) is associated with increased mortality. The extent to which this phenomenon is affected by sex, age, comorbidities at diagnosis, and different treatment modalities is largely unknown. The objective was to determine all-cause and cause-specific mortality in a population-based cohort of patients with PA and the impact of age at diagnosis, sex, comorbidities, and treatment modalities. We used national registers to identify patients diagnosed with PA between 1997 and 2019 (n=2419) and controls (n=24 187) from the general population, matched for sex, age, and county of residence. We obtained mortality data from the Cause-of-Death Register. We used Cox regression models, adjusted for socioeconomic factors and diabetes, to estimate adjusted hazard ratios (HRs [95% CI]). Overall, 346 (14.3%) patients with PA and 2736 (11.3%) controls died during a median follow-up time of 8.1 years. PA was associated with increased risk from all-cause mortality (HR, 1.23 [95% CI, 1.10-1.38]), death from cardiovascular disease (HR, 1.57 [95% CI, 1.30-1.89]), and stroke (HR, 1.85 [95% CI, 1.16-2.93]). Patients with cardiovascular disease at diagnosis (HR, 1.53 [1.26-1.85]), age >56 years (HR, 1.28 [95% CI, 1.13-1.45]), patients treated with a low dose of a mineralocorticoid receptor antagonist (HR, 1.30 [95% CI, 1.02-1.66]), and untreated patients (HR, 2.51 [95% CI, 1.72-3.67]) had excess mortality. Mortality, mainly due to cardiovascular disease, is increased in patients with PA compared with controls from the general population, particularly in patients aged >56 years, patients with preexisting cardiovascular comorbidities, and patients receiving low dose of a mineralocorticoid receptor antagonist.


Carbamate kinase of Lactobacillus buchneri NCDO110. I. Purification and properties.
Carbamate kinase has been prepared from Lactobacillus buchneri NCDO110. An approximately 91-fold increase in the specific activity of the enzyme was achieved. The purified extract exhibited a single band following polyacrylamide gel electrophoresis. The apparent molecular weight as determined by gel electrophoresis was about 97,000. The enzyme is stable for 2 weeks at -20 degrees C. Maximum enzymatic activity was observed at 30 degrees C and pH 5.4 in 0.1 M acetate buffer. L. buchneri carbamate kinase requires Mg2+ or Mn2+; its activity is higher with Mn2+. The activation energy of the reaction was 4078 cal mol-1 for the reaction with Mn2+ and 3059 cal mol-1 for the reaction with Mg2+. From a Dixon plot a pK value of 4.8 was calculated. The apparent Km values for ADP with Mg2+ or Mn2+ were 0.71 X 10(-3) and 1.17 X 10(-3) M, respectively, and the apparent Km values for carbamyl phosphate with Mg2+ or Mn2+ were 1.63 X 10(-3) and 1.53 X 10(-3) M, respectively. ATP and CTP acted as inhibitors of this reaction and the following values were obtained: Ki (ATP)Mg2+ = 9.4 mM, Ki (ATP)Mn2+ = 6.2 mM, and Ki (CTP)Mg2+ = 4.4 mM.


Transient hypothyroxinemia of prematurity is associated with abnormal cranial ultrasound and illness severity.
Transient hypothyroxinemia without elevated thyroid-stimulating hormone (TSH) levels is common in prematurity, especially in very-low-birth-weight (VLBW) infants. The transient hypothyroxinemia of prematurity (THOP) has been seen as a "benign" condition not requiring medical treatment. However, some recent large observational studies have revealed a relationship between THOP and abnormal neurodevelopment. Furthermore, one study showed THOP had twice the risk of brain echolucency, which was the best predictable neurodevelopmental dysfunction, than the premature infants with normal or higher thyroxine levels. The relationships among THOP, illness severity, and neurodevelopmental dysfunction remain unclear. We propose a hypothesis that THOP is associated with abnormal ultrasound and illness severity. We studied 54 infants who were admitted more than 14 days at our neonatal intensive care unit (NICU) with a birth weight <2000 g from March 1999 to March 2000. The infants received serum thyroxine (T4), free-T4, and TSH measurement during the first weeks of life. Most of them had serum thyroxine levels measured at approximately 2 weeks of age. The infants enrolled in the study were examined by at least 1 of 3 cranial ultrasounds during the first weeks of life, illness severity evaluation according to the neonatal therapeutic intervention scoring system (NTISS) score, as well as NICU hospital stay period. Infant were classified as THOP by T4 value <5.3 microg/dL (68 nmol/L), which is 2.6 SD below the mean for term infants in Massachusetts, without elevated TSH value (<20 microIU/mL). After adjusting for some confounding factors, such as gestational age, birth weight, duration of mechanical ventilation, infants with THOP were associated with abnormal cranial ultrasound, illness severity, and lower 1-minute Apgar score. In our studies, THOP was related with brain ultrasound anomaly, neonatal illness, and lower Apgar score at 1 minute. Does early thyroxine intervention improve the prognosis and neurodevelopmental dysfunction? This question requires further investigation.


[Surgery of brain tumors in childhood].
The Author analyze incidence, localizations and the great variety of hystopathological specimen of brain tumors in infancy and childhood. Clinical and surgical problems expecially derive from growth and development of infant. Medulloblastoma is the most common tumor of posterior fossa. Between supratentorial tumors gliomas and intraventricular neoplasms are the most commonly found at the operation; more rare tumors of the skull and cranial basis. The importance of pre-operative ventricular shunt in case of posterior fossa tumors and the cases of high- dimensioned supratentorial tumors with little symptoms are discussed.


A Comparison of Photocatalytic Activities of Gold Nanoparticles Following Plasmonic and Interband Excitation and a Strategy for Harnessing Interband Hot Carriers for Solution Phase Photocatalysis.
Light driven excitation of gold nanoparticles (GNPs) has emerged as a potential strategy to generate hot carriers for photocatalysis through excitation of localized surface plasmon resonance (LSPR). In contrast, carrier generation through excitation of interband transitions remains a less explored and underestimated pathway for photocatalytic activity. Photoinduced oxidative etching of GNPs with FeCl3 was investigated as a model reaction in order to elucidate the effects of both types of transitions. The quantitative results show that interband transitions more efficiently generate hot carriers and that those carriers exhibit higher reactivity as compared to those generated solely by LSPR. Further, leveraging the strong π-acidic character of the resulting photogenerated Au+ hole, an interband transition induced cyclization reaction of alkynylphenols was developed. Notably, alkyne coordination to the Au+ hole intercepts the classic oxidation event and leads to the formation of the catalytically active gold clusters on subnanometer scale.


Selective potentiation by an A1 adenosine receptor enhancer of the negative dromotropic action of adenosine in the guinea pig heart.
The drug (2-amino-4,5-dimethyl-3-thienyl)-[3(trifluoromethyl)-phenyl]methanone (PD 81,723) has been shown to enhance allosterically A1 adenosine receptor binding in brain membranes. The objective of this study was to determine the specificity and selectivity (A1 versus A2) of PD 81,723 as an enhancer of the negative dromotropic effect of exogenous adenosine in guinea pig isolated and in situ hearts. In isolated hearts, PD 81,723 alone produced only a small stimulus to His bundle (S-H) interval prolongation of 1.5 to 4 msec, which was completely reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase. PD 81,723 (5 microM) significantly decreased the EC50 value of adenosine for prolongation of the S-H interval from 6.7 +/- 0.6 to 4.4 +/- 0.5 microM. The potentiation of the negative dromotropic effect of adenosine by PD 81,723 was dose dependent, i.e., 5 and 10 microM PD 81,723 enhanced the maximal S-H interval prolongation caused by 3 microM adenosine by 207% and 609%, respectively. In contrast, the same concentration of PD 81,723 had no effect on either the S-H interval prolongation caused by carbachol or MgCl2 or the coronary vasodilatory effect of adenosine. In in situ hearts, PD (2 mumol/kg i.v.) alone caused only a small but not significant negative dromotropic effect, increasing the atrium to His interval from 58 +/- 2 to 61 +/- 1 msec. However, the same dose of PD 81,723 caused a significant leftward and upward shift of the adenosine dose-response curve for inducing atrium to His bundle interval prolongation and increased the degree of atrioventricular block caused by adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterizing the landscape of peritoneal exosomal microRNAs in patients with ovarian cancer by high-throughput sequencing.
In the present study, differentially expressed microRNAs (miRNAs) in peritoneal exosomes that were isolated from 10 patients with epithelial ovarian cancer (EOC) with metastasis in the abdominal cavity and 10 participants without cancer (NC) were identified. These differentially expressed miRNAs that were revealed by next-generation sequencing were categorized by Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of their target genes. Notably, two miRNAs that were associated with EOC-miR-149-3p and miR-222-5p-were identified. There were significant differences in expression of miR-149-3p and miR-222-5p between EOC and NC samples, and the effect of the expression level of the two miRNAs on the patient survival was identified using publicly available data from The Cancer Genome Atlas. There is an association between these two miRNAs and EOC, that was further verified by reverse transcription-quantitative polymerase chain reaction in peritoneal exosomes from 10 patients with EOC and NC participants. These results indicated that miR-149-3p and miR-222-5p might be novel biomarkers for evaluating the prognosis of patients with EOC and that these two miRNAs might have potential therapeutic values.


Combination Therapy of LysGH15 and Apigenin as a New Strategy for Treating Pneumonia Caused by Staphylococcus aureus.
Pneumonia is one of the most prevalent Staphylococcus aureus-mediated diseases, and the treatment of this infection is becoming challenging due to the emergence of multidrug-resistant S. aureus, especially methicillin-resistant S. aureus (MRSA) strains. It has been reported that LysGH15, the lysin derived from phage GH15, displays high efficiency and a broad lytic spectrum against MRSA and that apigenin can markedly diminish the alpha-hemolysin of S. aureus. In this study, the combination therapy of LysGH15 and apigenin was evaluated in vitro and in a mouse S. aureus pneumonia model. No mutual adverse influence was detected between LysGH15 and apigenin in vitro. In animal experiments, the combination therapy showed a more effective treatment effect than LysGH15 or apigenin monotherapy (P < 0.05). The bacterial load in the lungs of mice administered the combination therapy was 1.5 log units within 24 h after challenge, whereas the loads in unprotected mice or mice treated with apigenin or LysGH15 alone were 10.2, 4.7, and 2.6 log units, respectively. The combination therapy group showed the best health status, the lowest ratio of wet tissue to dry tissue of the lungs, the smallest amount of total protein and cells in the lung, the fewest pathological manifestations, and the lowest cytokine level compared with the other groups (P < 0.05). With regard to its better protective efficacy, the combination therapy of LysGH15 and apigenin exhibits therapeutic potential for treating pneumonia caused by MRSA. This paper reports the combination therapy of lysin and natural products derived from traditional Chinese medicine.


Pulseq: A rapid and hardware-independent pulse sequence prototyping framework.
Implementing new magnetic resonance experiments, or sequences, often involves extensive programming on vendor-specific platforms, which can be time consuming and costly. This situation is exacerbated when research sequences need to be implemented on several platforms simultaneously, for example, at different field strengths. This work presents an alternative programming environment that is hardware-independent, open-source, and promotes rapid sequence prototyping. A novel file format is described to efficiently store the hardware events and timing information required for an MR pulse sequence. Platform-dependent interpreter modules convert the file to appropriate instructions to run the sequence on MR hardware. Sequences can be designed in high-level languages, such as MATLAB, or with a graphical interface. Spin physics simulation tools are incorporated into the framework, allowing for comparison between real and virtual experiments. Minimal effort is required to implement relatively advanced sequences using the tools provided. Sequences are executed on three different MR platforms, demonstrating the flexibility of the approach. A high-level, flexible and hardware-independent approach to sequence programming is ideal for the rapid development of new sequences. The framework is currently not suitable for large patient studies or routine scanning although this would be possible with deeper integration into existing workflows. Magn Reson Med 77:1544-1552, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


The Association of Serum Carotenoids, Tocopherols, and Ascorbic Acid With Rapid Kidney Function Decline: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Nutritional intervention targeting dietary intake modification is a major component of treatment for chronic kidney disease; however, little is known about the relationship between dietary intake and kidney function decline in individuals with preserved kidney function. In this prospective cohort study we examined the association of biomarkers of dietary intake with kidney function decline over a 5-year interval in 2,152 men and women with cystatin-C-based estimated glomerular filtration rate > 60 mL/minute/1.73 m2 from the Coronary Artery Risk Development in Young Adults study. The biomarkers of interest included carotenoids, tocopherols, and ascorbic acid. Multivariable logistic regression was used to explore the relationship between serum concentrations of the sum of 4 carotenoids (α-carotene, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin), lycopene, α-tocopherol, γ-tocopherol, and ascorbic acid and rapid kidney function decline, defined as .15% decline in cystatin-C-based estimated glomerular filtration rate over 5 years. During the 5-year follow-up, 290 participants (13.5%) experienced rapid kidney function decline. Relative to individuals in the lowest quartile of serum carotenoids, those in the highest quartile had significantly lower odds of rapid kidney function decline in the fully adjusted model (odds ratio, 0.51; 95% confidence interval [CI], 0.32-0.80; P trend, .02). No association of levels of serum tocopherols, ascorbic acid, or lycopene with kidney function decline was found. There was no evidence that results differed for individuals with hypertension or diabetes. These results demonstrate that higher serum carotenoid levels, reflective of a fruit- and vegetable-rich dietary pattern, inversely associate with rapid kidney function decline in early middle adulthood and provide insight into how diet might play a role in chronic kidney disease prevention.


Different ability of novobiocin and coumermycin A1 to interact with nucleic acids.
The possibility of two structurally related antibiotics, Coumermycin A1 and Novobiocin, to interact with nucleic acids was investigated. Only Coumermycin A1 was able to form complexes with DNA showing an apparent affinity constant comparable to that of the interaction with ribosomal RNA. A binding specificity for A + T complementary and repeating sequences was also exhibited by Coumermycin A1. In view of the different behaviour of the two compounds some considerations are made on their mode of action; although they are acting on the same target enzymes in Escherichia coli, they may affect the functions of eukaryotic cells through a different mechanism not equally specific and probably distinct for each of the two antibiotics.