The Type Ic Hypernova SN 2003dh/GRB 030329

The spectra of SN 2003dh, identified in the afterglow of GRB030329, are modeled using radiation transport codes. It is shown that SN 2003dh had a high explosion kinetic energy ($\sim 4 \times 10^{52}$ erg in spherical symmetry), making it one of the most powerful hypernovae observed so far, and supporting the case for association between hypernovae and Gamma Ray Bursts. However, the light curve derived from fitting the spectra suggests that SN 2003dh was not as bright as SN 1998bw, ejecting only \sim 0.35\Msun of \Nifs. The spectra of SN 2003dh resemble those of SN 1998bw around maximum, but later they look more like those of the less energetic hypernova SN 1997ef. The spectra and the inferred light curve can be modeled adopting a density distribution similar to that used for SN 1998bw at $v > 25,000$\kms but more like that of SN 1997ef at lower velocities. The mass of the ejecta is \sim 8\Msun, somewhat less than in the other two hypernovae. The progenitor must have been a massive star (M \sim 35-40\Msun), as for other hypernovae. The need to combine different one-dimensional explosion models strongly indicates that SN 2003dh was an asymmetric explosion.Comment: 11 pages, 1 table and 5 figures. To appear in the Astrophysical Journal (Letters). Revised version taking referee's comments into account, minor change

Models for the Type Ic Hypernova SN 2003lw associated with GRB 031203

The Gamma-Ray Burst 031203 at a redshift z=0.1055 revealed a highly reddened Type Ic Supernova, SN 2003lw, in its afterglow light. This is the third well established case of a link between a long-duration GRB and a type Ic SN. The SN light curve is obtained subtracting the galaxy contribution and is modelled together with two spectra at near-maximum epochs. A red VLT grism 150I spectrum of the SN near peak is used to extend the spectral coverage, and in particular to constrain the uncertain reddening, the most likely value for which is E_{G+H}(B-V) about 1.07 +/- 0.05. Accounting for reddening, SN 2003lw is about 0.3 mag brighter than the prototypical GRB-SN 1998bw. Light curve models yield a 56Ni mass of about 0.55 solar mass. The optimal explosion model is somewhat more massive (ejecta mass about 13 solar mass) and energetic (kinetic energy about 6 times 10^52 erg) than the model for SN 1998bw, implying a massive progenitor (40 - 50 solar mass). The mass at high velocity is not very large (1.4 solar mass above 30000 km/s, but only 0.1 solar mass above 60000 km/s), but is sufficient to cause the observed broad lines. The similarity of SNe 2003lw and 1998bw and the weakness of their related GRBs, GRB031203 and GRB980425, suggest that both GRBs may be normal events viewed slightly off-axis or a weaker but possibly more frequent type of GRB.Comment: 19 pages, 8 figures, accepted for publication in Ap

Eff ectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study

Background Oral cholera vaccines represent a new eff ective tool to fi ght cholera and are licensed as two-dose regimens with 2–4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the fi rst fi eld deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine eff ectiveness study in conjunction with this large public health intervention. Methods We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the fi rst day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confi rmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). Findings Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classifi ed as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine eff ectiveness was 80·2% (95% CI 61·5–100·0) and after adjusting for potential confounders was 87·3% (70·2–100·0). Interpretation One dose of Shanchol was eff ective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings

Recognition of the Major Histocompatibility Complex (MHC) class Ib molecule H2-Q10 by the natural killer cell receptor Ly49C

Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2Kb/H-2Dd, both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ. To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2Kb. Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2Kb possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review

Purpose: Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer. Methods and Materials: The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathologic complete response (pCR) was conducted. Results: We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I2 = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025). Conclusions: Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer

Multiple-interface tracking of degradation process in organic photovoltaics

The investigation of the stability in organic photovoltaics has been focused on individual components via localized and destructive analysis, which is limited to broken devices, instead of an operational OPV, and unable to obtain correlated information of degrading interfaces. DC biased AC impedance spectroscopy is employed here, to track multi-interface degradation without breaking the device. By varying DC bias, individual interface degradation is revealed via current density and capacitance versus voltage plots. While one of the impedance semicircles is linked to the interface of P3HT:PCBM, the other represented the interface between the mixture and metal electrode, involving metal oxide in an aged device. The results confirm that, more than one degradation process take place simultaneously at individual interfaces