Inelastic helium atom scattering from Sb2Te3(111): phonon dispersion, focusing effects and surfing.

We present an experimental study of inelastic scattering processes on the (111) surface of the topological insulator Sb2Te3 using helium atom scattering. In contrast to other binary topological insulators such as Bi2Se3 and Bi2Te3, Sb2Te3 is much less studied and the as-grown Sb2Te3 sample turns out to be p-doped, with the Fermi-level located below the Dirac-point as confirmed by angle-resolved photoemission spectroscopy. We report the surface phonon dispersion along both high symmetry directions in the energy region below 11 meV, where the Rayleigh mode exhibits the strongest intensity. The experimental data is compared with a study based on density functional perturbation theory calculations, providing good agreement except for a set of additional peculiar inelastic events below the Rayleigh mode. In addition, an analysis of angular scans with respect to a number of additional inelastic events is presented, including resonance enhancement, kinematical focusing, focused inelastic resonance and surfing. In the latter case, phonon-assisted adsorption of the incident helium atom gives rise to a bound state where the helium atom rides the created Rayleigh wave.

Discrimination of differentially inhibited cysteine proteases by activity-based profiling using cystatin variants with tailored specificities.

Recent research has shown the possibility of tailoring the inhibitory specificity of plant cystatins toward cysteine (Cys) proteases by single mutations at positively selected amino acid sites. Here we devised a cystatin activity-based profiling approach to assess the impact of such mutations at the proteome scale using single variants of tomato cystatin SlCYS8 and digestive Cys proteases of the herbivorous insect, Colorado potato beetle, as a model. Biotinylated forms of SlCYS8 and SlCYS8 variants were used to capture susceptible Cys proteases in insect midgut protein extracts by biotin immobilization on avidin-embedded beads. A quantitative LC-MS/MS analysis of the captured proteins was performed to compare the inhibitory profile of different SlCYS8 variants. The approach confirmed the relevance of phylogenetic inferences categorizing the insect digestive Cys proteases into six functionally distinct families. It also revealed significant variation in protease family profiles captured with N-terminal variants of SlCYS8, in line with in silico structural models for Cys protease-SlCYS8 interactions suggesting a functional role for the N-terminal region. Our data confirm overall the usefulness of cystatin activity-based protease profiling for the monitoring of Cys protease-inhibitor interactions in complex biological systems. They also illustrate the potential of biotinylated cystatins to identify recombinant cystatin candidates for the inactivation of specific Cys protease targets.

Association of Prenatal Exposure to Ambient Air Pollution With Circulating Histone Levels in Maternal Cord Blood.

Importance: Exposure to ambient air pollution has been associated with the risk of carcinogenesis in later life. Changes in histone modifications might have long-term adverse health effects. Objective: To investigate the association of prenatal exposure to ambient air pollution with levels of circulating total histone H3 and specific trimethylation marks (ie, H3 lysine 4, H3 lysine 36) in maternal cord blood. Design, Setting, and Participants: The Environmental Influence on Aging (ENVIRONAGE) birth cohort study included 609 mothers and their newborns. Participants were recruited when mothers entered the Hospital East Limburg (Genk, Belgium) for delivery between February 2010 and January 2017. The inclusion criteria were singleton pregnancies and the ability to fill out questionnaires in Dutch. Data analysis was conducted from March to August 2019. Exposures: Exposure to particulate matter with a diameter less than 2.5 µm (PM2.5), black carbon, and nitrogen dioxide during pregnancy was modeled with a high-resolution air pollution model on the basis of maternal address for each trimester of pregnancy as well as for the entire pregnancy. Main Outcomes and Measures: Circulating total histone H3 levels and specific trimethylation marks (ie, trimethylated H3 lysine 4 and trimethylated H3 lysine 36) in cord blood. Results: A total of 609 mother-newborn pairs were included in the study. Mean (SD) maternal age was 29.3 (4.6) years, 391 mothers (64.2%) never smoked, and 314 (51.3%) had a high education level. Overall, 322 newborns (52.4%) were boys, and mean (SD) birth weight was 3414 (485) g. Participants experienced mean (SD) exposure to PM2.5, black carbon, and nitrogen dioxide of 13.4 (2.6) µg/m3, 1.29 (0.31) µg/m3, and 17.98 (4.57) µg/m3, respectively, during their entire pregnancies. Trimethylated H3 lysine 4 and total histone H3 were positively associated with gestational PM2.5 exposure, with a 74.4% increment (95% CI, 26.7% to 140.2%, P < .001) and a 40.2% increment (95% CI, 24.1% to 58.3%, P < .001), respectively, observed for each 5-µg/m3 increase in PM2.5 exposure during the entire pregnancy. For the same exposure window, trimethylated H3 lysine 36 levels were inversely associated with PM2.5 exposure (-34.4%; 95% CI, -50.1% to -13.7%; P = .003). Exposure to black carbon during the entire pregnancy was positively associated with trimethylated H3 lysine 4 (38.4%; 95% CI, 6.2% to 80.3%; P = .003). Conclusions and Relevance: Associations of ambient air pollution with cord plasma histone H3 modifications during early life might indicate that circulating histones are a risk factor in the development of air pollution-associated disease later in life. Additional study is required to correctly estimate the long-term consequences of our findings.

Prenatal particulate air pollution exposure and expression of the miR-17/92 cluster in cord blood: Findings from the ENVIRONAGE birth cohort.

BACKGROUND: Air pollution exposure during pregnancy is an important environmental health issue. Epigenetics mediate the effects of prenatal exposure and could increase disease predisposition in later life. The oncogenic miR-17/92 cluster is involved in normal development and disease. OBJECTIVES: Here, for the first time the potential prenatal effects of particulate matter with a diameter<2.5 µm (PM2.5) exposure on expression of the miR-17/92 cluster in cord blood are explored. METHODS: In 370 mother-newborn pairs from the ENVIRONAGE birth cohort, expression of three members of the miR-17/92 cluster was measured in cord blood by qRT-PCR. Expression of C-MYC and CDKN1A, a cluster activator and a target gene, respectively, was also analyzed. Multivariable linear regression models were used to associate the relative m(i)RNA expression with prenatal PM2.5 exposure. RESULTS: PM2.5 exposure averaged (10th-90th percentile) 11.7 (9.0-14.4) µg/m3 over the entire pregnancy. In cord blood, miR-17 and miR-20a showed a -45.0% (95%CI: -55.9 to -31.4, p < 0.0001) and a -33.7% (95%CI: -46.9 to -17.2, p = 0.0003), decrease in expression in association with first trimester PM2.5 exposure, and a -32.5% (95%CI: -45.6 to -16.3, p = 0.0004) and -23.3% (95%CI: -38.1 to -4.8, p = 0.02), respectively, decrease in expression in association with PM2.5 exposure during the entire pregnancy. In association with third trimester PM2.5 exposure, a reduction of -25.8% (95%CI: -40.2 to -8.0, p = 0.007) and -14.2% (95%CI: -27.7 to 1.9, p = 0.08), for miR-20a and miR-92a expression, respectively, was identified. Only miR-92a expression (-15.7%, 95%CI: -27.3 to -2.4, p = 0.02) was associated with PM2.5 exposure during the last month of pregnancy. C-MYC expression was downregulated in cord blood in association with prenatal PM2.5 exposure during the first trimester and the entire pregnancy, in the adjusted model. DISCUSSION: Lower expression levels of the miR-17/92 cluster in cord blood in association with increased prenatal PM2.5 exposure were observed. Whether this oncogenic microRNA cluster plays a role in trans-placental carcinogenesis remains to be elucidated.

The landscape of cancer cell line metabolism.

Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic features and associated dependencies remain uncommon. To further understand the metabolic diversity of cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography-mass spectrometry (LC-MS). This resource enables unbiased association analysis linking the cancer metabolome to genetic alterations, epigenetic features and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help clarify the landscape of cancer metabolism.

A universal approach for the synthesis of two-dimensional binary compounds.

Only a few of the vast range of potential two-dimensional materials (2D) have been isolated or synthesised to date. Typically, 2D materials are discovered by mechanically exfoliating naturally occurring bulk crystals to produce atomically thin layers, after which a material-specific vapour synthesis method must be developed to grow interesting candidates in a scalable manner. Here we show a general approach for synthesising thin layers of two-dimensional binary compounds. We apply the method to obtain high quality, epitaxial MoS2 films, and extend the principle to the synthesis of a wide range of other materials-both well-known and never-before isolated-including transition metal sulphides, selenides, tellurides, and nitrides. This approach greatly simplifies the synthesis of currently known materials, and provides a general framework for synthesising both predicted and unexpected new 2D compounds.

A randomized trial to determine the duration of analgesia following a 15- and a 30-minute application of acupuncture-like TENS on patients with chronic low back pain.

BACKGROUND: Acupuncture-like TENS (AL-TENS) has been shown to produce prolonged pain relief, but no study has yet investigated its duration on a population suffering from chronic low back pain (CLPB). OBJECTIVE: Our objective was to quantify the duration and magnitude of analgesia induced by a 15- or 30-minute application of AL-TENS. METHODOLOGY: We recruited a sample of 11 participants presenting with CLBP and conducted a randomized, crossover study, where participants were given AL-TENS for 15 and 30 minutes on two separate occasions. The pain intensity of their CLBP was assessed with a visual analogue scale before, during, and after AL-TENS applications. Magnitude and duration of analgesia were determined for each subject and for both AL-TENS application times. RESULTS: The AL-TENS applications induced a clinically and statistically significant (p = 0.003) analgesia in all participants. Median duration of analgesia was 9 hours and 10 hours 30 minutes following the 15- and 30-minute AL-TENS applications, respectively; this 1.5-hour difference was not statistically significant (p = 0.55). Furthermore, we observed no significant difference in the magnitude of analgesia between both applications of AL-TENS (p > 0.56), suggesting that the duration of application of AL-TENS does not influence the magnitude of analgesia. CONCLUSION: Our results suggest that clinicians could use a 15-minute AL-TENS application to provide significant analgesia in patients presenting with low back pain since if provides a comparable analgesia versus a 30-minute application.

Impact of a large deletion in the neuraminidase protein identified in a laninamivir-selected influenza A/Brisbane/10/2007 (H3N2) variant on viral fitness in vitro and in ferrets.

Viral fitness of a laninamivir-selected influenza A/Brisbane/10/2007-like (H3N2) isolate (LRVp9) containing a 237-amino acid neuraminidase deletion and a P194L hemagglutinin mutation was evaluated in vitro and in ferrets. LRVp9 and the wild-type (WT) virus showed comparable replication kinetics in MDCK-ST6GalI cells. Cultured virus was recovered between days 2 and 5 post-infection in nasal washes (NW) from the 4 WT-infected ferrets whereas no virus was recovered from the LRVp9-infected animals. There was a ≥1 log reduction in viral RNA copies/µl of NW for LRVp9 compared to WT at most time points. The large neuraminidase deletion compromises viral infectivity in vivo.

Adjuvanted inactivated influenza A(H3N2) vaccines induce stronger immunogenicity in mice and confer higher protection in ferrets than unadjuvanted inactivated vaccines.

Influenza viruses are major respiratory pathogens and the development of improved vaccines to prevent these infections is of high priority. Here, we evaluated split inactivated A(H3N2) vaccines (A/Uruguay/716/2007) combined or not with adjuvants (AS03, AS25 and Protollin) and administered by three different routes, intramuscular (i.m.), intranasal (i.n.) or intradermal (i.d.), both in BALB/c mice and in ferrets. Ferrets were challenged with the homologous strain A/Uruguay/716/2007 (H3N2) or the heterologous strain A/Perth/16/2009 (H3N2) 4 weeks after the second immunization with A/Uruguay/716/2007 vaccines. Temperature, weight loss and clinical signs were monitored on a daily basis and nasal washes were performed to evaluate viral titers in the upper respiratory tract. All adjuvanted vaccines induced stronger humoral immune responses than unadjuvanted ones in both mice and ferrets. In mice, the AS03- and AS25-adjuvanted i.m. vaccines generated a mixed Th1-Th2 response at 6 and 19 weeks after the last immunization as shown by the production of IgG1 and IgG2a antibodies as well as the production of IL-2, IL-4 and IFN-γ by CD4+ and CD8+ T cells. HAI and MN titers were also higher in those groups when compared to the i.n. Protollin-adjuvanted and unadjuvanted groups. The Protollin-adjuvanted i.n. vaccine induced a more Th1 oriented response with a significant production of IgA in bronchoalveolar lavages. In ferrets, the AS03- and AS25-adjuvanted i.m. vaccines also induced higher HAI and MN titers compared to the other groups. These vaccines also significantly decreased viral titers after challenge with both the homologous A/Uruguay/716/2007 (H3N2) and the heterologous A/Perth/16/2009 (H3N2) strains. In conclusion, adjuvanted influenza vaccines elicited stronger humoral response in mice and conferred greater protection in naive ferrets than unadjuvanted ones. Interestingly, the AS25 adjuvant system containing monophosphoryl-lipid-A appears particularly promising for developing more potent inactivated influenza vaccines.

Molecular and antigenic evolution of human influenza A/H3N2 viruses in Quebec, Canada, 2009-2011.

BACKGROUND: A/H3N2 variability leads to poor vaccine effectiveness when the vaccine strain is not well matched to the circulating virus. OBJECTIVES: We aim to describe the molecular and antigenic evolution of A/H3N2 viruses recovered during the last 3 influenza seasons in Quebec, Canada. STUDY DESIGN: Clinical samples from 33 patients with culture-confirmed A/H3N2 infections were collected over 3 consecutive seasons (March 2009-2011). The isolates' HA gene was amplified and sequenced; phylogenetic analyses of the HA1 region were conducted. To characterize A/H3N2 antigenic properties, standard hemagglutination inhibition (HI) and microneutralization (MN) assays were performed. RESULTS: In 2009, we observed an antigenic drift from A/Brisbane/10/2007 (vaccine strain used in 2008-2009 and 2009-2010) to A/Perth/16/2009 (vaccine strain used in 2010-2011). Antigenic analysis of clinical influenza strains recovered in Quebec during 2009-2010 also illustrated antigenic drift from the previously prevalent A/Brisbane/10/2007-like (March 2009) to A/Perth/16/2009-like (December 2009) strains. In 2010-2011, the emergence of >4 substitutions in 4 different H3 antigenic sites suggested a genetic drift. However, HI and MN results confirmed the emergence of a drift in only 1 strain (8-fold difference in titers), while 19 others remained antigenically similar to A/Perth/16/2009 but exhibited titer differences (2-4-fold) just inferior to the standard definition of a drift. CONCLUSION: Antigenic and molecular characterization of H3N2 viruses over three seasons revealed that not only is the number of HA mutations important, but the nature and location of key mutations may play a significant role in antigenic drift.

Vascular alterations and sexual function in systemic sclerosis.

Sexual dysfunction is common in systemic sclerosis (SSc). Male erectile dysfunction (MED) has been reported in around 80% of subjects and more than half of female patients fulfill criteria for diagnosis as female sexual arousal Disorder (FSAD). While some evidence supports a role for cavernosal fibrosis, abundant data suggest that MED is yet another clinical feature of SSc related to vasculopathy. The contribution of vasculopathy to the more complex issues of female sexual dysfunction is less clear. Inhibitors of Type V phosphodiesterase are effective in men with MED secondary to SSc. Limited study in women suggests inconsistent effects on behavior (frequency) but not on measures related to perfusion. Sexual activity is an important component of quality of life and an important domain for the caregiver to address; it is not clear that it warrants primary consideration as a consistent measure of scleroderma-related vasculopathy.

Influence of target type and RAF rule on the measurement of near point of convergence.

PURPOSE: This study was designed to investigate if the use of different target types or the RAF rule affected the measurement of near point of convergence (NPC). METHODS: The subjects comprised three groups: (1) 20 children aged 6-9 years (2) 17 children aged 11-13 years (3) 14 adults aged 20-30 years. Five targets were used to measure the NPC: (1) pencil tip, (2) fingertip, (3) penlight, (4) N5 letter and (5) vertical line target on the RAF rule. RESULTS: There was no significant difference in NPC measurements between the pencil tip, fingertip and N5 target in free space. The penlight resulted in significantly more remote NPC break and recovery points compared with the fingertip and pencil tip (p < 0.05). The RAF rule influences the NPC obtained (p < 0.001). The greatest difference in NPC measurements was observed when comparing the RAF line target and the finger in free space; the former resulted in NPC values of 1.9 times (95% CI 1.6-2.2 times) as much as those obtained with the finger. CONCLUSIONS: Use of the penlight and RAF rule resulted in a more distant NPC break point compared with other targets. The effect of the RAF rule was more apparent for more receded NPC points.