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Abstract: Human kallikrein 5 and 7 (KLK5 and KLK7) are trypsin-like and chymotrypsin-like serine proteases, respectively, and promising targets for the treatment of skin desquamation, inflammation and cancer. In an effort to develop new inhibitors for these enzymes, we carried out enzymatic inhibition assays and docking studies with three isocoumarin compounds. Some promising inhibitors were uncovered, with vioxanthin and 8,8′-paepalantine being the most potent competitive inhibitors of KLK5 (Ki =22.9μM) and KLK7 (Ki =12.2μM), respectively. Our docking studies showed a good correlation with the experimental results, and revealed a distinct binding mode for the inhibitors at the binding sites of KLK5 and KLK7. In addition, the docking results suggested that the formation of hydrogen bonds at the oxyanion hole is essential for a good inhibitor. [Copyright &y& Elsevier]

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cystic Fibrosis (CF) lung disease is characterised by an inexorable decline in lung function, punctuated by periods of symptomatic worsening known as pulmonary exacerbations (referred to here as CFPE). Despite their clinical significance, the cause of CFPE remains undetermined. It has been suggested that an increase in bacterial density may be a trigger, although this has not been shown empirically. Methods: Here, a previously validated quantitative PCR-based approach was used to assess numbers of Pseudomonas aeruginosa and of total bacteria in respiratory secretions from patients during the period leading up to CFPE. Sputum samples collected from 12 adult CF patients were selected retrospectively to fall approximately 21, 14, 7 and 0days prior to CFPE diagnosis. In addition, the relationships between clinical parameters (FEV1, temperature and patient reported outcome measures) and microbiological data were investigated. Results: No significant changes either in total bacterial or P. aeruginosa numbers were identified prior to CFPE. Of all the correlations tested, only temperature showed a significant correlation with total bacterial numbers in the period leading to CFPE. Conclusions: These findings strongly suggest that CFPE do not generally result from increased bacterial density within the airways. Instead, data presented here are consistent with alternative models of pulmonary exacerbation. [Copyright &y& Elsevier]

Summary Background Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes. Objectives To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation. Methods Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing. Results KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype. Conclusions This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation. [ABSTRACT FROM AUTHOR]

The white-light corona (WLC) during the total solar eclipse on 2010 July 11 was observed by several teams in the Moon's shadow stretching across the Pacific Ocean and a number of isolated islands. We present a comparison of the WLC as observed by eclipse teams located on the Tatakoto Atoll in French Polynesia and on Easter Island, 83 minutes later, combined with near-simultaneous space observations. The eclipse was observed at the beginning of the solar cycle, not long after solar minimum. Nevertheless, the solar corona shows a plethora of different features (coronal holes, helmet streamers, polar rays, very faint loops and radial-oriented thin streamers, a coronal mass ejection, and a puzzling "curtain-like" object above the north pole). Comparing the observations from the two sites enables us to detect some dynamic phenomena. The eclipse observations are further compared with a hairy-ball model of the magnetic field and near-simultaneous images from the Atmospheric Imaging Assembly on NASA's Solar Dynamics Observatory, the Extreme Ultraviolet Imager on NASA's Solar Terrestrial Relations Observatory, the Sun Watcher, using Active Pixel System Detector and Image Processing on ESA's PRoject for Onboard Autonomy, and the Naval Research Laboratory's Large Angle and Spectrometric Coronagraph on ESA's Solar and Heliospheric Observatory. The Ludendorff flattening coefficient is 0.156, matching the expected ellipticity of coronal isophotes at 2 R⊙, for this rising phase of the solar-activity cycle. [ABSTRACT FROM AUTHOR]

Killer cell immunoglobulin-like receptors (KIRs), expressed in both natural killer (NK) cells and a subset of T cells, represent a family of both inhibitory and activating receptors that can regulate NK and T cells upon interacting with human leucocyte antigen (HLA) class I molecules on target cells. The number and distribution of KIR genes vary between individuals and populations from different geographical regions and ethnic origins. In this study, we investigated KIR gene frequencies and genotype diversities of 13 KIR genes, 2 pseudogenes, expressed and non-expressed forms of KIR2DL5 and the two subtypes, full-length and deleted forms, of KIR2DS4 in 100 unrelated healthy individuals of the Bai population, living in the Dali Bai autonomous prefecture in the Yunnan province. All individuals were typed positive for the three framework loci KIR3DL3, 2DL4 and 3DL2, as well as for three non-framework genes KIR2DL1, 2DL3 and the pseudogene KIR2DP1. The gene frequencies of the other KIR genes ranged from 7%-95%. The results of tested linkage disequilibrium (LD) among KIR genes demonstrated that they display a wide range of LD. χ2 analysis among non-ubiquitous genes, using the KIR gene frequency data from our study population, as well as from previously published population data, was conducted and revealed significant differences in the KIR2DL1, 2DL2, 3DL1 and KIR2DS1 genes. The results of the present study can be valuable for enriching the Chinese ethnical gene information resources of the KIR gene pool, for anthropological studies, as well as for KIR-related disease research. [ABSTRACT FROM AUTHOR]

Inhibitors of quinone reductase-2 (NQO2; QR-2) can have antimalaiial activity and antitumor activities or can function as chemoprevention agents by preventing the metabolic activation of toxic quinones such as menadione. To expedite the search for new natural product inhibitors of QR-2, we developed a screening assay based on ultrafiltration liquid chromatography-mass spectro- metry that is compatible with complex samples such as bacterial or botanical extracts. Human QR-2 was prepared recombinantly, and the known QR-2 inhibitor, resveratrol, was used as a positive control and as a competitive ligand to eliminate false positives. Ultrafiltration LC-MS screening of extracts of marine sediment bactena resulted in the discovery of tetrangulol methyl ether as an inhibitor of QR-2. When applied to the screening of hop extracts from the botanical, Humulus lupulus L, xanthohumol and xanthohumol D were identified as ligands of QR-2. Inhibition of QR-2 by these ligands was confinned using a functional enzyme assay. Furthermore, binding of xanthohumol and xanthohumol D to the active site of QR-2 was confirmed using X-ray crystallography. Ultrafiltration LCMS was shown to be a useful assay for the discovery of inhibitors of QR-2 in complex matrixes such as extracts of bacteria and botanicals. [ABSTRACT FROM AUTHOR]

Abstract: Cocaine exhibits preferential (~15-fold) affinity for σ1 over σ2 sigma receptors, and previous research has shown an interaction of σ1 receptor-selective ligands and cocaine''s behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine''s locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants. [Copyright &y& Elsevier]

The imprecise status of Psychiatry may be due to Cartesian dualism and the mind / body assumption. We can clarify this status resorting to an alternative ontology. Popper''s Worlds 1, 2 and 3, and the corresponding concepts of matter, energy and information, from Von Bertalanffy and his General Systems Theory, are candidates for a new ontology. Applying them to the history and present structure of Western Medicine, we can assume that General Surgery is the branch of medicine which deals with bodily matter, Internal Medicine deals with energy and Psychiatry is the branch which deals with information. The respective basic disciplines are Anatomy, Physiology and Psychology. None of them is a medical specialty, because specialties, such as Neurology, Urology and Cardiology, deal with a sub-system of the organism and may have a surgical, medical or even psychiatric emphasis. In the same way that the body / mind problem seemed important for Cartesian dualism, this triadic structure of Medicine may also inform a new ontology. The recent history of Philosophy may be interpreted as an attempt of looking for it. [Copyright &y& Elsevier]

To identify HLA-B*15 subtypes distribution in Han population in Beijing, People’s Republic of China, 826 unrelated healthy individuals were typed using the polymerase chain reaction-sequence-based typing method. Within the 246 HLA-B*15 positive individuals, 29 HLA-B*15 alleles were identified, the most predominant of which is B*1501 (40.07%), followed by B*1502 (12.87%), B*1511 (12.87%), B*1518 (9.19%) and B*1532 (3.31%). The distribution of HLA-B*15 subtype frequencies was compared between the Beijing Han, eight other Chinese ethnic minorities and six Chinese populations covering the mainland of China, Taiwan, Hong Kong and Singapore. A neighbor-joining phylogenetic tree was constructed and revealed that the Beijing Han population clustered into the northern populations group and had a closer relationship with northern Han and Hui than with southern Han or other ethnic minorities. These results thus provide useful information that can be used in anthropology, selection for bone marrow transplantation as well as in disease-association study, such as in carbamazepine (CBZ)-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required.Design: Prospective, randomized laboratory investigation.Setting: University-affiliated laboratory.Subjects: Adult female rats.Interventions: Tuberoinfundibular peptide, mimicking the lectin-like domain of tumor necrosis factor, mutant TIP peptide, N,N'-diacetylchitobiose/TIP peptide, and amiloride/TIP peptide were instilled intratracheally in the left lung immediately before the isotransplantation was performed. An additional group received an intravenous TIP peptide treatment, 1.5 mins before transplantation. Studies using isolated rat type II alveolar epithelial cell monolayers and ovine pulmonary endothelial cells were also performed.Measurements and Main Results: Intratracheal pretreatment of the transplantable left lung with the TIP peptide, but not with an inactive mutant TIP peptide, resulted in significantly improved oxygenation 24 hrs after transplantation. This treatment led to a significantly reduced neutrophil content in the lavage fluid. Both the effects on oxygenation and neutrophil infiltration were inhibited by the epithelial sodium channel blocker amiloride. The TIP peptide blunted reactive oxygen species production in pulmonary artery endothelial cells under hypoxia and reoxygenation and reduced reactive oxygen species content in the transplanted rat lungs in vivo. Ussing chamber experiments using monolayers of primary type II rat pneumocytes indicated that the primary site of action of the peptide was on the apical side of these cells.Conclusions: These data demonstrate that the TIP peptide significantly improves lung function after lung transplantation in the rat, in part, by reducing neutrophil content and reactive oxygen species generation. These studies suggest that the TIP peptide is a potential therapeutic agent against the ischemia reperfusion injury associated with lung transplantation. [ABSTRACT FROM AUTHOR]

The odd-odd 88 37Rb51 and 86 35Br51 nuclei have been produced as fission fragments in the fusion reaction 18O$ + $208Pb at 85MeV bombarding energy and studied with the Euroball IV array. Their high-spin level schemes have been built from the triple $ \gamma$ -ray coincidence data and $ \gamma$ - $ \gamma$ angular correlations have been analyzed in order to assign spin and parity values to many observed states. The proposed configurations involve proton excitations from three sub-shells located close to the Fermi levels, $ \pi$ p3/2 , $ \pi$ f5/2 , and $ \pi$ g9/2 , the $ \nu$ d5/2 neutron acting as a spectator. The residual $ \pi$ $ \nu$ interactions are extracted from the multiplets of states resulting from the $ \pi$ p3/2 $ \nu$ d5/2 and $ \pi$ f5/2 $ \nu$ d5/2 configurations. The empirical values of the latter are discussed and compared to those known in two similar configurations having jp = jn with lp = ln + 1 , where the role of the tensor force had been highlighted. [ABSTRACT FROM AUTHOR]

The 81, 82, 83, 85Se nuclei have been produced as fission fragments in the fusion reaction 18O + 208Pb at 85MeV bombarding energy and studied with the Euroball IV array. Their high-spin level schemes have been built from the triple $ \gamma$ -ray coincidence data and $ \gamma$ - $ \gamma$ angular correlations have been analyzed in order to assign spin and parity values to many observed states. The lowest-spin states of the two-neutron and three-neutron configurations are strongly mixed with two-proton excitations among the fp orbits. On the other hand, the highest-spin states of these neutron configurations are found to remain almost pure. Neutron excitation across the N = 50 gap is observed both in 83Se49 and in 85Se51 . [ABSTRACT FROM AUTHOR]

Light-dependent release of dopamine (DA) in the retina is an important component of light-adaptation mechanisms. Melanopsin-containing inner retinal photoreceptors have been shown to make physical contacts with DA amacrine cells, and have been implicated in the regulation of the local retinal environment in both physiological and anatomical studies. Here we determined whether they contribute to photic regulation of DA in the retina as assayed by the ratio of DA with its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and by c-fos induction in tyrosine hydroxylase (TH)-labelled DA amacrine cells. Light treatment (∼0.7 log W/m2 for 90 min) resulted in a substantial increase in DA release (as revealed by an increase in the DOPAC : DA ratio), as well as widespread induction of nuclear c-fos in DA amacrine cells in wild-type mice and in mice lacking melanopsin ( Opn4 −/−). Light-induced DA release was also retained in mice lacking rod phototransduction (Gnat1 −/−), although the magnitude of this response was substantially reduced compared with wild-types, as was the incidence of light-dependent nuclear c-fos in DAergic amacrines. By contrast, the DAergic system of mice lacking both rods and cones ( rd/rd cl) showed no detectable light response. Our data suggest that light regulation of DA, a pivotal retinal neuromodulator, originates primarily with rods and cones, and that melanopsin is neither necessary nor sufficient for this photoresponse. [ABSTRACT FROM AUTHOR]

Abstract: The use of neopentylphosphine ligands in the palladium-catalyzed Suzuki, Sonogashira, Heck, and Hartwig–Buchwald couplings of aryl bromides and chlorides are reported. Di-tert-butylneopentylphosphine (DTBNpP) provided highly active catalysts for the coupling of aryl bromides at mild temperatures. Trineopentylphosphine, an air-stable trialkylphosphine, gave inactive catalysts at room temperature, but showed good activity in the H–B amination of aryl chlorides at elevated temperatures. [Copyright &y& Elsevier]

Abstract: This paper describes an efficient procedure for selective 3′-O- or 3-N-protection of 5′-O-tert-butyldimethylsilylthymidine, depending on the use of aprotic polar solvents with low or high dielectric constant, respectively. These syntheses were activated by either ultrasound or microwaves. Several alkyl bromides offer a convenient route to prepare 3′-O- or 3-N-protected and functionalized thymidine derivatives. [Copyright &y& Elsevier]

High-spin states in the 142Ce and 140Ba nuclei have been populated in the 12C + 238U and 18O + 208Pb fusion-fission reactions at 90MeV and 85MeV bombarding energy, respectively. The emitted γ -radiation was detected using the Euroball III and IV arrays. The high-spin yrast and near-to-yrast structures of 142Ce have been considerably extended. The level scheme of 140Ba has been extended by six new levels. The newly observed structures in these N = 84 isotones are discussed by analogy with the neighbouring nuclei. [ABSTRACT FROM AUTHOR]

Introduction: Choosing surgery as a career is declining among U.S. medical students. The 8-wk third year surgery clerkship at our institution can be an intense learning experience, and we hypothesized that during this clerkship medical student quality-of-life would drop significantly from baseline, and that this drop would be greater among certain subgroups, such as women students not interested in pursuing a surgical career, and those who place a high value on a controllable lifestyle. Methods: At clerkship orientation (baseline), students were asked to complete a survey that measured quality-of-life on an 84-point scale, and depression on a 40-point scale. The quality-of-life scale was composed of select questions from the Medical Outcomes Study, and the Harvard Department of Psychiatry/NDSD brief screening instrument was used to measure depression. Students were also asked the typical number of hours they slept per night. Demographics, attitude toward a controllable lifestyle, and top three specialties of interest were also gathered at baseline. On week 6 of the clerkship, students were surveyed on the same quality-of -life and depression scales, and asked average hours of sleep per night for the previous week. Results: From June 2005 through December 2006, 143 of 177 (81%) students agreed to participate, and after exclusions for missing data, 137 students were included in the analysis. Sixty-nine students were women (51%), and the average age was 25.8 (sd 2.6). Mean quality-of-life at baseline was 57.0 (sd 11.3) and at week 6 was 50.4 (sd 10.1) representing a statistically significant average decline of 6.6 points (P < 0.0001). Mean depression at baseline was 14.4 (sd 3.8) and at week 6 was 15.1 (sd 3.6), representing a small but significant average decline of 0.7 points (P = 0.0155). Mean sleep at baseline was 6.3 h/night (sd 0.9) and at week 6 was 5.7 h/night (sd 1.2), representing a statistically significant average decline of 0.6 h/night (P < 0.0001). Declines were similar on all outcomes between men versus women, those who ranked surgery in their top three career choices versus those who did not, and those who ranked controllable lifestyle as “very important” versus all other categories. Conclusion: Quality-of-life and sleep declines and depression increases significantly in third-year medical students from orientation to week 6 of their surgery clerkship at our institution. We look forward to studying quality-of-life on other clerkships for comparison, assessing whether the magnitude of this decline in quality-of-life predicts students avoiding a future career in surgery, and testing interventions to prevent this decline in quality-of-life during the clerkship. [Copyright &y& Elsevier]

Abstract: A collection of 17 enterococci isolates obtained from fermentations of capers (the fruits of Capparis sp.) were investigated for incidence of known virulence determinants, antibiotic resistance and production of biogenic amines. Molecular identification revealed the presence of Enterococcus faecium (nine isolates), Enterococcus faecalis (4), E. avium (3) and Enterococcus casseliflavus/flavescens (1). Alpha-haemolytic activity was detected in two E. avium and one E. faecalis isolates, and beta-haemolytic activity was detected in E. casseliflavus/flavescens. The haemolytic component cylB was detected by PCR amplification in three non-haemolytic isolates and in E. casseliflavus/flavescens. The collagen adhesin ace gene and the endocarditis associated antigen gene efaA fm were detected in two isolates each. Genes encoding sex pheromone precursors (cpd, cob, ccf) were detected in E. faecalis and E. casseliflavus/flavescens. Other presumed virulence genes (agg, gelE, cylM, cylA and efaA fs ) were not detected. All isolates were resistant to rifampicin, erythromycin and ciprofloxacin, and some were also resistant to quinupristin/dalfopristin, tetracycline, levofloxacin, gentamicin and streptomycin. Vancomycin resistance was not detected. Tyrosine decarboxylation was detected in all E. faecium isolates. Given the high resistance of enterococci to environmental conditions, and their implication in opportunistic infections, the incidence of potential virulent enterococci in foods (especially those of a higher risk-like home-made foods) should be carefully studied. [Copyright &y& Elsevier]

The 84, 85Br nuclei have been produced as fission fragments in the fusion reaction 18O + 208Pb at 85MeV bombarding energy and studied with the Euroball IV array. The high-spin states of the odd-odd 84Br nucleus have been identified for the first time, the observed structure being built on the known 6- isomeric state. High-spin states of 85Br have been observed up to 5.4MeV excitation energy and spin I ∼ 21/2. From angular correlation analysis, spin values have been assigned to most of the 85Br excited states up to 4MeV. None of these excited states has been found to exhibit a delayed decay having T 1/2 > 10ns. All the observed states in 84, 85Br can be described by various proton excitations involving at least the two sub-shells ( π f 5/2 and π p 3/2) located just above the Z = 28 shell closure. [ABSTRACT FROM AUTHOR]

Abstract: In this work, we present the rate constants, with the Wigner and Eckart tunneling corrections and the minimum energy path calculated with our own code for the NF3+N=NF2+NF gas-phase reaction, over the temperature range of 200–4000K. The information about equilibrium geometries, frequencies and the potential energies for reactant, products and saddle point are obtained from accurate electronic structure calculation. The rate constant at the Arrhenius form, using Eckart tunneling correction is . [Copyright &y& Elsevier]

The 87Kr nucleus has been produced as fission fragment in the fusion reaction 18O + 208Pb at 85MeV bombarding energy and studied with the Euroball IV array. High-spin states of this neutron-rich isotope have been identified for the first time. Its level scheme has been obtained up to 6.3MeV excitation energy and spin I ∼ 23/2ℏ. Its structure is interpreted by analogy with those of the heavier isotones. The proposed configurations involve both proton and neutron excitations from several sub-shells located close to the Fermi levels, particularly ν d 5/2, π p 3/2 f 5/2 and π g 9/2. Moreover, a revised spin value of 5/2- for the 87Br ground state is proposed. [ABSTRACT FROM AUTHOR]

A new high-spin level scheme of 149Nd has been identified, which is at variance with the one previously published. The states have been populated in the 12C + 238U fusion-fission reaction at 90MeV bombarding energy and the emitted γ-transitions were detected using the Euroball III array. The yrast band is built on the ν i 13/2 sub-shell as in the neighbouring isotones. Moreover, sign of octupole vibrations has been found in 149Nd, as well as in 147Ce, where several new states decaying to the yrast band have been newly observed. [ABSTRACT FROM AUTHOR]

In many human infections, hosts and pathogens coexist for years or decades. Important examples include HIV, herpes viruses, tuberculosis, leprosy, and malaria. With the exception of intensively studied viral infections such as HIV/AIDs, little is known about the extent to which the clonal expansion that occurs during long-term infection by pathogens involves important genetic adaptations. We report here a detailed, whole-genome analysis of one such infection, that of a cystic fibrosis (CF) patient by the opportunistic bacterial pathogen Pseudomonas aeruginosa. The bacteria underwent numerous genetic adaptations during 8 years of infection, as evidenced by a positive-selection signal across the genome and an overwhelming signal in specific genes, several of which are mutated during the course of most CF infections. Of particular interest is our finding that virulence factors that are required for the initiation of acute infections are often selected against during chronic infections. It is apparent that the genotypes of the P. aeruginosa strains present in advanced CF infections differ systematically from those of ‘wild-type’ Po aeruginosa and that these differences may offer new opportunities for treatment of this chronic disease. [ABSTRACT FROM AUTHOR]

High-spin states of the N = 87 nuclei, 147Nd and 145Ce, have been populated in the 12C + 238U and 18O + 208Pb fusion-fission reactions at 90 MeV and 85 MeV bombarding energy, respectively. The emitted γ-radiation was detected using the Euroball III and IV arrays. High-spin states of the 147Nd isotope have been identified for the first time. The high-spin yrast and near-to-yrast structures of the 145Ce nucleus have been considerably extended. The newly observed structures, discussed by analogy with the neighbouring isotones, show the coupling of an h 9/2 neutron to the quadrupole and octupole excitations of the core. [ABSTRACT FROM AUTHOR]

A small number of mammalian retinal ganglion cells act as photoreceptors for regulating certain non-image forming photoresponses. These intrinsically photosensitive retinal ganglion cells express the putative photopigment melanopsin. Ablation of the melanopsin gene renders these cells insensitive to light; however, the precise role of melanopsin in supporting cellular photosensitivity is unconfirmed. Here we show that heterologous expression of human melanopsin in a mouse paraneuronal cell line (Neuro-2a) is sufficient to render these cells photoreceptive. Under such conditions, melanopsin acts as a sensory photopigment, coupled to a native ion channel via a G-protein signalling cascade, to drive physiological light detection. The melanopsin photoresponse relies on the presence of cis-isoforms of retinaldehyde and is selectively sensitive to short-wavelength light. We also present evidence to show that melanopsin functions as a bistable pigment in this system, having an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths. [ABSTRACT FROM AUTHOR]

The84Se nucleus has been produced as fission fragment in the fusion reaction18O +208Pb at 85MeV bombarding energy and studied with the Euroball IV array. Medium-spin states of this neutron-rich isotope have been identified for the first time. Its level scheme has been obtained up to 4.9MeV excitation energy and spinI~ 7?. Its structure is interpreted by analogy with those of the stable heavier isotones. The evolution of the energy of theN= 50 neutron-core excitation is discussed as a function of the proton number. [ABSTRACT FROM AUTHOR]

Alveolar epithelial type I and type II cells (AEC I and II) are closely aligned in alveolar surface. There is much interest in the precise identification of AEC I and II in order to separate and evaluate functional and other properties of these two cells. This study aims to identify specific AEC I and AEC II cell markers by DNA microarray using the in vitro trans-differentiation of AEC II into AEC I-like cells as a model. Quantitative real-time PCR confirmed five AEC I genes: fibroblast growth factor receptor-activating protein 1, aquaporin 5, purinergic receptor P2X 7 (P2X7), interferon-induced protein, and Bcl2-associated protein, and one AEC II gene: γ-aminobutyric acid receptor pi subunit (GABRP). Immunostaining on cultured cells and rat lung tissue indicated that GABRP and P2X7 proteins were specifically expressed in AEC II and AEC I, respectively. In situ hybridization of rat lung tissue confirmed the localization of GABRP mRNA in type II cells. P2X7 and GABRP identified in this study could be used as potential AEC I and AEC II markers for studying lung epithelial cell biology and monitoring lung injury. [Copyright &y& Elsevier]

The fission probability distributions of 232,233,234Pa and 231Th have been measured up to an excitation energy of 15 MeV, using the transfer reactions 232Th(3He,t)232Pa, 232Th(3He,d)233Pa, 232Th(3He,p)234Pa and 232Th(3He,4He)231Th. From these measurements, the neutron induced fission cross sections of 231Pa, 233Pa and 230Th have been determined from the product of the fission probabilities of 232Pa, 233Pa and 231Th respectively with the calculated compound nucleus formation cross sections in the 231Pa+n, 233Pa+n and 230Th+n reactions. The validity of the applied method has been successfully tested with the existing neutron induced fission cross sections of 230Th and 231Pa. Special emphasis is put on the 233Pa(n,f) reaction which is of importance for thorium fueled nuclear reactors. Based on a statistical model analysis of the neutron induced fission cross section as a function of neutron energy, it has been possible to determine the barrier parameters of the 234Pa fissioning nucleus. Cross sections for the compound nucleus inelastic scatttering 233Pa(n,n′) and radiative capture 233Pa(n,γ) reactions have also been calculated and compared with recent evaluations. [Copyright &y& Elsevier]

High-spin states from the three-quasiparticle (3qp) configuration &paig9/2vh211/2 in the neutronrich 49In isotopes have been studied in the framework of shell model calculation. The two-body residual interactions needed for such calculations have been extracted from the level schemes of neighbouring nuclei. In particular, the evolution of the proton-neutron &paig9/2vh211/2 interaction has been analyzed as a function of the neutron number. When the gradual filling of the vh211/2 sub-shell is taken into account, the results of the 3qp configuration calculations are found to be very close to the experimental positive-parity yrast states located above 2 MeV excitation energy in 113-121In. Moreover, several long-lived isomeric states with positive parity are predicted in 123, 125, 127In. [ABSTRACT FROM AUTHOR]

Objective: The impact of childhood cancer on the patient and family is devastating and results in significant emotional and physical effects on the child and family. An increasing awareness of the role of health care professionals at this time has led to the development of hospital-based bereavement support services. However, many services are not evidence based, and family support varies between institutions. The objective of this study was to determine current practice relating to hospital-based bereavement support programmes.Methods: A survey of all major tertiary paediatric oncology units in Australia and New Zealand (N = 10) was undertaken. The survey instrument consisted of a 19-item questionnaire with open-ended and closed questions.Results: Nine hospitals (90%) participated. Most hospitals provided a multidisciplinary bereavement service for approximately one year after a child's death. Programmes varied, but the most common hospital-based supports provided were counselling and support groups. Important findings were: a significant number of hospitals worked from a limited theoretical basis and understanding, did not screen for high risk of complicated grieving, did not formally evaluate their programme, and identified areas of unmet needs.Conclusion: The majority of paediatric oncology units in Australia and New Zealand provide dedicated multidisciplinary bereavement support services. There is variation in services provided, often due to a lack of resources and staffing. Findings indicate a need to further develop bereavement programmes, improve staff education and support, and increase the availability of resources in this area. Future research should explore the needs of bereaved families, as well as the range of services and evaluation methods that could be implemented as the baseline for 'best practice' hospital-based bereavement programmes. [ABSTRACT FROM AUTHOR]

High-spin states in 108,110Pd isotopes are studied by γ-ray spectroscopy of heavy-ion-induced fission. The Pd isotopes are produced in the fission channel of the 31P + 176Yb reaction at beam energy 152 MeV. The prompt γ-rays are detected with the EUROBALL4 multidetector array. The yrast states of 108,110Pd have been observed above the region of the first backbend. The level scheme of 108Pd was extended with a new negative-parity band. The yrast sequence in 110Pd is observed up to spin I = 14+ and negative-parity bands have also been identified. The back bending in these even-mass Pd isotopes is associated with the alignment of the neutron (h11/2)² pair. The negative-parity states arise from two neutron configurations vh11/2 ⊗ vg7/2 and vh11/2 ⊗ vd5/2 and they are interpreted in the frame of two-quasiparticle + rotor model as semidecoupled bands. The observed experimental staggering in the γ-bands of 108,110Pd supports the theoretical predictions for γ-instability of their shapes. [ABSTRACT FROM AUTHOR]

Abstract Maximum light-saturated photosynthetic rate (Pmax) and stomatal conductance (gs) of field-grown cocksfoot (Dactylis glomerata L.) leaves in a silvopastoral system were measured at different times under moderate (850–950 µmol m-2 s-1 photosynthetic photon flux density, PPFD) and severe shade (85–95 µmol m-2 s-1 PPFD). Also Pmax and gs were measured after 30, 60 and 180 min of severe shade to determine the lag in the rise of photosynthesis rate from low to high irradiance levels (induction state). The highest Pmax and gs values obtained were 26·5 µmol CO2 m-2 s-1 and 0·41 mol H2 O m-2 s-1 in non-limiting conditions with full sunlight (1900 µmol m-2 s-1 PPFD). These values were defined as standardized dimensionless Pmaxs =1 and gss =1 for comparison of treatment effects. The Pmaxs under severe shade decreased by 0·004 units per minute from 1 to 180 min and reached a steady-state of 0·37 units after 140 min. Under moderate shade, Pmaxs decreased by 0·002 units per minute from 1 to 120 min and reached a steady-state of 0·76 units. The time required to reach full induction on return to full sun (Pmaxs =1) was 15 min after 30 min of severe shade and 37 min after 180 min of shade. Mathematical equations were derived to describe the changes in Pmaxs and gss under severe and moderate shade and during induction. The rate of change of gss was slower than for Pmaxs on entering shade and also slower during the subsequent induction process. This indicated other factors in addition to gs were operating in the reduction and increment of Pmax and a two-step model to explain this is proposed. The defined photosynthetic responses of cocksfoot leaves to fluctuating light regimes could... [ABSTRACT FROM AUTHOR]

BACKGROUND: Being overweight or obese has substantial effects on individuals' perceptions of their health and quality of life (QoL). Generic measures often miss important QoL information, and existing obesity-specific instruments have shortcomings with respect to cross-cultural input, application to differing levels of severity, conceptual clarity, and patient burden. OBJECTIVE: This study aimed to develop culturally sensitive measures of QoL and symptoms in overweight or obese persons, both those trying to lose weight and those not trying to lose weight. METHODS: Currently accepted criteria and guidelines for questionnaire development were streamlined and augmented to include cross-cultural input from 5 European countries and the United States. The preliminary pool of items was created based on qualitative interviews conducted in the United States, followed by an early check of item translatability and preharmonization across all languages. Ten additional qualitative in-country interviews were then conducted to produce further culture-specific items. This was followed by 2 forward and 1 backward translation, plus cognitive debriefing interviews in each country. Finally, an expanded international harmonization meeting was held to ensure inclusion of appropriate new items and their acceptability across all 6 cultures. RESULTS: The procedures described resulted in development of the 41-item Obesity and Weight Loss Quality of Life questionnaire and the 20-item Weight-Related Symptom Measure. These questionnaires are subject to further psychometric validation. CONCLUSIONS: Augmentation of the initial item-generation and international harmonization steps of questionnaire development through integration of cross-cultural input allowed greater validity of cross-cultural content while meeting time, budget, and resource constraints. [ABSTRACT FROM AUTHOR]

A simple multiplicative model using temperature, foliage nitrogen (N) concentration and water status was developed to predict the maximum photosynthetic rate (Pmax ) of field-grown cocksfoot (Dactylis glomerata L.) leaves when none, one, two or all the factors were limiting. The highest Pmax was 27·4 μmol CO2 m–2 s-1 in non-limited conditions, which was defined as the standardized Pmax value dimensionless (Pmaxs =1). Pmaxs increased 0·058 units per °C from 10°C to the optimum range (19–23°C) (Pmaxs =1) and then declined 0·077 units of Pmaxs per °C from 23 to 31°C. Pmaxs =1 was also measured from 59 to 52 g N kg-1 dry matter (DM) foliage N. Pmaxs then decreased at the rate of 0·115 units per 10 g N kg-1 DM from 52 to 26 g N kg-1 DM, and 0·409 units of Pmaxs per 10 g N kg-1 DM from 26 to 15 g N kg-1 DM. For predawn leaf water potential (ψlp ), Pmaxs =1 was measured from -0·1 to -1·2 bar but declined linearly at a rate of 0·078 units per bar of ψlp from -1·2 to -14·0 bar because of a linear decrease in stomatal conductance. An interaction between low N content (≤20 g N kg-1 DM) and high temperature (>23°C) was also detected. Together, this multiplicative model accounted for 0·82 of the variation in Pmaxs . [ABSTRACT FROM AUTHOR]

Simple Summary: The usage of forage cactus is essential for the maintenance of livestock activity in semiarid regions as an alternative to conventional crops. Cactaceae have adaptive characteristics that ensure their development progress under drought conditions. Four genotypes of forage cactus (Gigante, Miúda, IPA Sertânia, and Orelha de Elefante Mexicana) were fed to lactating dairy cows and the diets were then evaluated based on animal performance, milk fatty acid profile, and microbial protein synthesis. Miúda forage cactus led to a higher nutrient intake and milk yield, as well as greater microbial protein synthesis. Higher saturated fatty acids were observed when the Gigante and IPA Sertânia forage cactus genotypes were fed to dairy cows. Orelha de Elefante Mexicana forage cactus caused lower milk yield along with protein yields and content; however, it improved the milk fatty acid profile by promoting a higher ratio of unsaturated to saturated fatty acids and desirable fatty acids. It is concluded that the Miúda forage cactus is the genotype most suitable for the diets of lactating dairy cows. This study aimed to investigate the effects on nutrient intake and digestibility, milk yield (MY) and composition, milk fatty acids profile, and microbial protein synthesis caused by feeding lactating dairy cows four different forage cactus genotypes. Eight Girolando cows (5/8 Holstein × 3/8 Gyr), weighing 490 ± 69.0 kg (means ± standard deviation), and producing 15.5 ± 1.0 kg/d of milk during pretrial were distributed to two contemporaneous 4 × 4 Latin squares. The cows were fed a total mixed ration composed of sorghum silage (385 g/kg of dry matter (DM)), concentrated mix (175 g/kg DM), and forage cactus (440 g/kg DM). The experimental treatments consisted of different cactus genotypes, such as Gigante cactus (GC), Miúda cactus (MC), IPA Sertânia cactus (SC), and Orelha de Elefante Mexicana cactus (OEMC). The feeding of MC provided a higher intake of DM, organic matter (OM), and total digestible nutrients, as well as higher MY, energy-corrected milk, and microbial protein synthesis in comparison with those resulting from the other genotypes tested. The GC promoted lower DM and OM, and the apparent digestibility of neutral detergent fiber. The cows fed with OEMC showed lower MY and milk protein yield and content, and higher unsaturated over saturated fatty acid ratio in milk. Miúda forage cactus increased nutrient intake, digestibility of DM and OM, and microbial synthesis without impairing the milk fatty acid profile. [ABSTRACT FROM AUTHOR]

Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

From orbit, the visibility of Titan's surface is limited to a handful of narrow spectral windows in the near-infrared (near-IR), primarily from the absorption of methane gas. This has limited the ability to identify specific compounds on the surface—to date Titan's bulk surface composition remains unknown. Further, understanding of the surface composition would provide insight into geologic processes, photochemical production and evolution, and the biological potential of Titan's surface. One approach to obtain wider spectral coverage with which to study Titan's surface is by decreasing the integrated column of absorbers (primarily methane) and scatterers between the observer and the surface. This is only possible if future missions operate at lower altitudes in Titan's atmosphere. Herein, we use a radiative transfer model to measure in detail the absorption through Titan's atmosphere from different mission altitudes, and consider the impacts this would have for interpreting reflectance measurements of Titan's surface. Over our modeled spectral range of 0.4–10 μ m , we find that increases in the width of the transmission windows as large as 317% can be obtained for missions performing remote observations at the surface. However, any appreciable widening of the windows requires onboard illumination. Further, we make note of possible surface compounds that are not currently observable from orbit, but could be identified using the wider windows at low altitudes. These range from simple nitriles such as cyanoacetylene, to building blocks of amino acids such as urea. Finally, we discuss the implications that the identifications of these compounds would have for Titan science. • Titan's infrared spectral windows broaden considerably in the lower atmosphere. • Onboard illumination is needed to utilize widened windows in the lower atmosphere. • Enhanced spectral coverage improves the understanding of Titan's prebiotic potential. [ABSTRACT FROM AUTHOR]

Reports on a study conducted on Swiss Webster mice which were injected with 10 cysts of Toxoplasma gondii. Role of cytokines in inducing cachexia; Methodology used to conduct the study; Results of the study.

Investigates the metabolic-cytokine responses to a second immunological challenge with lipopolysaccharide in mice with Toxoplasma gondii. Prolonged energy used of infected mice; Elevation of serum levels of tumor necrosis factor-alpha (TNF-alpha); Exacerbation of the hypophagic and hyperresponsiveness in TNF-alpha.

Chronic airways infection with methicillin-resistant Staphylococcus aureus (MRSA) is associated with worse respiratory disease cystic fibrosis (CF) patients. Ceftaroline is a cephalosporin that inhibits the penicillin-binding protein (PBP2a) uniquely produced by MRSA. We analyzed 335 S. aureus isolates from CF sputum samples collected at three US centers between 2015–2018. Molecular relationships demonstrated that high-level resistance of preceding isolates to carbapenems were associated with subsequent isolation of ceftaroline resistant CF MRSA. In vitro evolution experiments showed that pre-exposure of CF MRSA to meropenem with further selection with ceftaroline implied mutations in mecA and additional mutations in pbp1 and pbp2, targets of carbapenems; no effects were achieved by other β-lactams. An in vivo pneumonia mouse model showed the potential therapeutic efficacy of ceftaroline/meropenem combination against ceftaroline-resistant CF MRSA infections. Thus, the present findings highlight risk factors and potential therapeutic strategies offering an opportunity to both prevent and address antibiotic resistance in this patient population. Varela, Roch et al. find that resistance of preceding isolates to carbapenems is associated with the subsequent isolation of methicillin-resistant Staphylococcus aureus (MRSA) resistant to ceftaroline. Addition of meropenem reduces the cystic fibrosis MRSA's resistance to ceftaroline in a pneumonia mouse model, suggesting a strategy to control antibiotics resistance. [ABSTRACT FROM AUTHOR]

The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) regulates cellular motility and the synthesis of organelles and molecules that promote adhesion to a variety of biological and nonbiological surfaces. These properties likely require tight spatial and temporal regulation of c-di-GMP concentration. We have developed genetically encoded fluorescence resonance energy transfer (FRET)-based biosensors to monitor c-di-GMP concentrations within single bacterial cells by microscopy. Fluctuations of c-di-GMP were visualized in diverse Gram-negative bacterial species and observed to be cell cycle dependent. Asymmetrical distribution of c-di-GMP in the progeny correlated with the time of cell division and polarization for Cautobacter crescentus and Pseudomonas aeruginosa. Thus, asymmetrical distribution of c-di-GMP was observed as part of cell division, which may indicate an important regulatory step in extracellular organelle biosynthesis or function. [ABSTRACT FROM AUTHOR]

A letter to the editor on Riga-Fede disease an ulcerative lesion in oral mucosa of children is presented.

Summary: 隐性营养不良性大疱性表皮松解症(RDEB)、Kindler综合征 (KS) 和 C 组着色性干皮病(XPC) 是三种令患者发生癌症风险增加的遗传性皮肤疾病(遗传性皮肤病) 。仍未充分了解在这些疾病中导致癌症的事件, 包括在皮肤水平发生的事件, 尽管已对它们进行了深入调查。为了加深对于这些罕见病的认识,最终发现新的治疗, 西班牙研究小组调查了来自 RDEB、KS 和 XPC 患者的一种称为真皮纤维母细胞的皮肤细胞的基因表达谱 (标签) 。研究者们发现, 来自这三种遗传皮肤病的纤维母细胞都有大量以相同方式异常(错误)表达的基因。它们反过来转化成一种活化表型, 导致真皮 (一层皮肤) 硬度变化和氧化还原 (一种化学反应)状态失衡。这一重叠标签似乎不依赖于导致缺乏缺陷 (即 VII 型胶原、kindlin‐1 或 XPC 的丢失) 的原发疾病,而是尚未充分了解的常见损伤‐反应性事件的结果。总而言之, 该研究为真皮纤维母细胞在 RDEB、XPC 和 KS 中所扮演角色添加了最新认识, 并强调了可能的新治疗靶点。 Linked Article: Chacón‐Solano et al. Br J Dermatol 2019; 181:512–522 [ABSTRACT FROM AUTHOR]