The effect of prime-site occupancy on the hepatitis C virus NS3 protease structure.

We recently reported a new class of inhibitors of the chymotrypsin-like serine protease NS3 of the hepatitis C virus. These inhibitors exploit the binding potential of the S′ site of the protease, which is not generally used by the natural substrates. The effect of prime-site occupancy was analyzed by circular dichroism spectroscopy and limited proteolysis-mass spectrometry. Generally, nonprime inhibitors cause a structural change in NS3. Binding in the S′ site produces additional conformational changes with different binding modes, even in the case of the NS3/4A cofactor complex. Notably, inhibitor binding either in the S or S′ site also has profound effects on the stabilization of the protease. In addition, the stabilization propagates to regions not in direct contact with the inhibitor. In particular, the N-terminal region, which according to structural studies is endowed with low structural stability and is not stabilized by nonprime inhibitors, was now fully protected from proteolytic degradation. From the perspective of drug design, P-P′ inhibitors take advantage of binding pockets, which are not exploited by the natural HCV substrates; hence, they are an entry point for a novel class of NS3/4A inhibitors. Here we show that binding of each inhibitor is associated with a specific structural rearrangement. The development of a range of inhibitors belonging to different classes and an understanding of their interactions with the protease are required to address the issue of the most likely outcome of viral protease inhibitor therapy, that is, viral resistanc

Biomonitoring of Indoor Air Fungal or Chemical Toxins with Caenorhabditis elegans nematodes

Bad indoor air quality due to toxins and other impurities can have a negative impact on human well-being, working capacity and health. Therefore, reliable methods to monitor the health risks associated with exposure to hazardous indoor air agents are needed. Here, we have used transgenic Caenorhabditis elegans nematode strains carrying stress-responsive fluorescent reporters and evaluated their ability to sense fungal or chemical toxins, especially those that are present in moisture-damaged buildings. Liquid-based or airborne exposure of nematodes to mycotoxins, chemical agents or damaged building materials reproducibly resulted in time- and dose-dependent fluorescent responses, which could be quantitated by either microscopy or spectrometry. Thus, the C. elegans nematodes present an easy, ethically acceptable and comprehensive in vivo model system to monitor the response of multicellular organisms to indoor air toxicity.Peer reviewe

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m2), modulated by MTX (24 h earlier, 200 mg/m2) were alternated with a 3-week continuous infusion of FU (200 mg/m2daily), modulated by LV (20 mg/m2weekly bolus). Mito, 7 mg/m2, was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28–46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III–IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents. © 2001 Cancer Research Campaign http://www.bjcancer.co

Social and cultural origins of motivations to volunteer a comparison of university students in six countries

Although participation in volunteering and motivations to volunteer (MTV) have received substantial attention on the national level, particularly in the US, few studies have compared and explained these issues across cultural and political contexts. This study compares how two theoretical perspectives, social origins theory and signalling theory, explain variations in MTV across different countries. The study analyses responses from a sample of 5794 students from six countries representing distinct institutional contexts. The findings provide strong support for signalling theory but less so for social origins theory. The article concludes that volunteering is a personal decision and thus is influenced more at the individual level but is also impacted to some degree by macro-level societal forces

Broad-emission-line dominated hydrogen-rich luminous supernovae

Hydrogen-rich Type II supernovae (SNe II) are the most frequently observed class of core-collapse SNe (CCSNe). However, most studies that analyse large samples of SNe II lack events with absolute peak magnitudes brighter than -18.5 mag at rest-frame optical wavelengths. Thanks to modern surveys, the detected number of such luminous SNe II (LSNe II) is growing. There exist several mechanisms that could produce luminous SNe II. The most popular propose either the presence of a central engine (a magnetar gradually spinning down or a black hole accreting fallback material) or the interaction of supernova ejecta with circumstellar material (CSM) that turns kinetic energy into radiation energy. In this work, we study the light curves and spectral series of a small sample of six LSNe II that show peculiarities in their H$\alpha$ profile, to attempt to understand the underlying powering mechanism. We favour an interaction scenario with CSM that is not dense enough to be optically thick to electron scattering on large scales -- thus, no narrow emission lines are observed. This conclusion is based on the observed light curve (higher luminosity, fast decline, blue colours) and spectral features (lack of persistent narrow lines, broad H$\alpha$ emission, lack of H$\alpha$ absorption, weak or nonexistent metal lines) together with comparison to other luminous events available in the literature. We add to the growing evidence that transients powered by ejecta-CSM interaction do not necessarily display persistent narrow emission lines.Comment: 27 pages, 16 figures, accepted for publication in MNRA

A characterization of ASAS-SN core-collapse supernova environments with VLT+MUSE: I. Sample selection, analysis of local environments, and correlations with light curve properties

The analysis of core-collapse supernova (CCSN) environments can provide important information on the life cycle of massive stars and constrain the progenitor properties of these powerful explosions. The MUSE instrument at the VLT enables detailed local environment constraints of the progenitors of large samples of CCSNe. Using a homogeneous SN sample from the ASAS-SN survey has enabled us to perform a minimally biased statistical analysis of CCSN environments. We analyze 111 galaxies observed by MUSE that hosted 112 CCSNe detected or discovered by the ASAS-SN survey between 2014 and 2018. The majority of the galaxies were observed by the the AMUSING survey. Here we analyze the immediate environment around the SN locations and compare the properties between the different CCSN types and their light curves. We used stellar population synthesis and spectral fitting techniques to derive physical parameters for all HII regions detected within each galaxy, including the star formation rate (SFR), H$\alpha$ equivalent width (EW), oxygen abundance, and extinction. We found that stripped-envelope (SE) SNe occur in environments with a higher median SFR, H$\alpha$ EW, and oxygen abundances than SNe II and SNe IIn/Ibn. The distributions of SNe II and IIn are very similar, indicating that these events explode in similar environments. For the SESNe, SNe Ic have higher median SFRs, H$\alpha$ EWs, and oxygen abundances than SNe Ib. SNe IIb have environments with similar SFRs and H$\alpha$ EWs to SNe Ib, and similar oxygen abundances to SNe Ic. We also show that the postmaximum decline rate, $s$, of SNe II correlates with the H$\alpha$ EW, and that the luminosity and the $\Delta m_{15}$ parameter of SESNe correlate with the oxygen abundance, H$\alpha$ EW, and SFR at their environments. This suggests a connection between the explosion mechanisms of these events to their environment properties

Carnegie Supernova Project: Kinky i-band light curves of Type Ia supernovae

We present detailed investigation of a specific i-band light-curve feature in Type Ia supernovae (SNe Ia) using the rapid cadence and high signal-to-noise ratio light curves obtained by the Carnegie Supernova Project. The feature is present in most SNe Ia and emerges a few days after the i-band maximum. It is an abrupt change in curvature in the light curve over a few days and appears as a flattening in mild cases and a strong downward concave shape, or a 'kink', in the most extreme cases. We computed the second derivatives of Gaussian Process interpolations to study 54 rapid-cadence light curves. From the second derivatives we measure: (1) the timing of the feature in days relative to i-band maximum; tdm2(i) and (2) the strength and direction of the concavity in mag d-2; dm2(i). 76 per cent of the SNe Ia show a negative dm2(i), representing a downward concavity - either a mild flattening or a strong 'kink'. The tdm2(i) parameter is shown to correlate with the colour-stretch parameter sBV, a SN Ia primary parameter. The dm2(i) parameter shows no correlation with sBV and therefore provides independent information. It is also largely independent of the spectroscopic and environmental properties. Dividing the sample based on the strength of the light-curve feature as measured by dm2(i), SNe Ia with strong features have a Hubble diagram dispersion of 0.107 mag, 0.075 mag smaller than the group with weak features. Although larger samples should be obtained to test this result, it potentially offers a new method for improving SN Ia distance determinations without shifting to more costly near-infrared or spectroscopic observations.Fil: Pessi, Priscila Jael. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Hsiao, E. Y.. Florida State University; Estados UnidosFil: Folatelli, Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Anderson, J. P.. European Southern Observatory Santiago; ChileFil: Burns, C. R.. No especifíca;Fil: Uddin, S.. Texas A&M University; Estados UnidosFil: Galbany, L.. Consejo Superior de Investigaciones Científicas; EspañaFil: Phillips, M. M.. No especifíca;Fil: Morrell, N.. No especifíca;Fil: Ashall, C.. University of Hawaii at Manoa; Estados UnidosFil: Baron, E.. No especifíca;Fil: Contreras, C.. No especifíca;Fil: Hamuy, M.. Texas A&M University; Estados UnidosFil: Hoeflich, P.. Florida State University; Estados UnidosFil: Krisciunas, K.. Texas A&M University; Estados UnidosFil: Kumar, S.. Florida State University; Estados UnidosFil: Lu, J.. Florida State University; Estados UnidosFil: Martinez, Laureano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Piro, A. L.. No especifíca;Fil: Shahbandeh, M.. Florida State University; Estados UnidosFil: Stritzinger, M. D.. University Aarhus; DinamarcaFil: Suntzeff, N. B.. Texas A&M University; Estados Unido