Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding

The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120SU plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this “glycan shield” can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens

Breastfeeding and childhood asthma: a six-year population-based cohort study

<p>Abstract</p> <p>Background</p> <p>The question of the protective effect of breastfeeding on development of asthma has raised substantial interest, but the scientific evidence of the optimal duration of breastfeeding is controversial.</p> <p>Methods</p> <p>The authors elaborated the optimal duration of breastfeeding with respect to the risk of asthma primarily, and secondarily to the risk of persistent wheezing, cough and phlegm in school age in a population-based cohort study with the baseline in 1991 and follow-up in 1997. The study population comprised 1984 children aged 7 to 14 years at the end of the follow-up (follow-up rate 77). Information on breastfeeding was based on the baseline survey and information on the health outcomes at the follow-up.</p> <p>Results</p> <p>There was a U-shaped relation between breastfeeding and the outcomes with the lowest risk with breastfeeding from four to nine months for asthma and seven to nine months for persistent wheezing, cough and phlegm.</p> <p>Conclusion</p> <p>Our results suggest a U shape relation between duration of breastfeeding and risk of asthma with an optimal duration of 4 to 6 months. A true concave relation would explain the inconsistent results from the previous studies.</p

New Human Papilloma Virus E2 Transcription Factor Mimics: A Tripyrrole-Peptide Conjugate with Tight and Specific DNA-Recognition

BACKGROUND: Human papillomavirus (HPV) is the main causative agent of cervical cancer, particularly high risk strains such us HPV-16, -18 and -31. The viral encoded E2 protein acts as a transcriptional modulator and exerts a key role in viral DNA replication. Thus, E2 constitutes an attractive target for developing antiviral agents. E2 is a homodimeric protein that interacts with the DNA target through an α-helix of each monomer. However, a peptide corresponding to the DNA recognition helix of HPV-16 E2 binds DNA with lower affinity than its full-length DNA binding domain. Therefore, in an attempt to promote the DNA binding of the isolated peptide, we have designed a conjugate compound of the E2 α-helix peptide and a derivative of the antibiotic distamycin, which involves simultaneous minor- and major-groove interactions. METHODOLOGY/PRINCIPAL FINDINGS: An E2 α-helix peptide-distamycin conjugate was designed and synthesized. It was characterized by NMR and CD spectroscopy, and its DNA binding properties were investigated by CD, DNA melting and gel shift experiments. The coupling of E2 peptide with distamycin does not affect its structural properties. The conjugate improves significantly the affinity of the peptide for specific DNA. In addition, stoichiometric amounts of specific DNA increase meaningfully the helical population of the peptide. The conjugate enhances the DNA binding constant 50-fold, maintaining its specificity. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that peptide-distamycin conjugates are a promising tool to obtain compounds that bind the E2 target DNA-sequences with remarkable affinity and suggest that a bipartite major/minor groove binding scaffold can be a useful approach for therapeutic treatment of HPV infection

N-glycans of Human Protein C Inhibitor: Tissue-Specific Expression and Function

Protein C inhibitor (PCI) is a serpin type of serine protease inhibitor that is found in many tissues and fluids in human, including blood plasma, seminal plasma and urine. This inhibitor displays an unusually broad protease specificity compared with other serpins. Previous studies have shown that the N-glycan(s) and the NH2-terminus affect some blood-related functions of PCI. In this study, we have for the first time determined the N-glycan profile of seminal plasma PCI, by mass spectrometry. The N-glycan structures differed markedly compared with those of both blood-derived and urinary PCI, providing evidence that the N-glycans of PCI are expressed in a tissue-specific manner. The most abundant structure (m/z 2592.9) had a composition of Fuc3Hex5HexNAc4, consistent with a core fucosylated bi-antennary glycan with terminal Lewisx. A major serine protease in semen, prostate specific antigen (PSA), was used to evaluate the effects of N-glycans and the NH2-terminus on a PCI function related to the reproductive tract. Second-order rate constants for PSA inhibition by PCI were 4.3±0.2 and 4.1±0.5 M−1s−1 for the natural full-length PCI and a form lacking six amino acids at the NH2-terminus, respectively, whereas these constants were 4.8±0.1 and 29±7 M−1s−1 for the corresponding PNGase F-treated forms. The 7–8-fold higher rate constants obtained when both the N-glycans and the NH2-terminus had been removed suggest that these structures jointly affect the rate of PSA inhibition, presumably by together hindering conformational changes of PCI required to bind to the catalytic pocket of PSA

Treatment of diaphyseal non-unions of the ulna and radius

Non-unions of the forearm often cause severe dysfunction of the forearm as they affect the interosseus membrane, elbow and wrist. Treatment of these non-unions can be challenging due to poor bone stock, broken hardware, scarring and stiffness due to long-term immobilisation. We retrospectively reviewed a large cohort of forearm non-unions treated by using a uniform surgical approach during a period of 33 years (1975-2008) in a single trauma centre. All non-unions were managed following the AO-principles of compression plate fixation and autologous bone grafting if needed. The study cohort consisted of 47 patients with 51 non-unions of the radius and/or ulna. The initial injury was a fracture of the diaphyseal radius and ulna in 22 patients, an isolated fracture of the diaphyseal ulna in 13, an isolated fracture of the diaphyseal radius in 5, a Monteggia fracture in 5, and a Galeazzi fracture-dislocation of the forearm in 2 patients. Index surgery for non-union consisted of open reduction and plate fixation in combination with a graft in 30 cases (59%), open reduction and plate fixation alone in 14 cases (27%), and only a graft in 7 cases (14%). The functional result was assessed in accordance to the system used by Anderson and colleagues. Average follow-up time was 75 months (range 12-315 months). All non-unions healed within a median of 7 months. According to the system of Anderson and colleagues, 29 patients (62%) had an excellent result, 8 (17%) had a satisfactory result, and 10 (21%) had an unsatisfactory result. Complications were seen in six patients (13%). Our results show that treatment of diaphyseal forearm non-unions using classic techniques of compression plating osteosynthesis and autologous bone grafting if needed will lead to a high union rate (100% in our series). Despite clinical and radiographic bone healing, however, a substantial subset of patients will have a less than optimal functional outcom

Ocean community warming responses explained by thermal affinities and temperature gradients

As ocean temperatures rise, species distributions are tracking towards historically cooler regions in line with their thermal affinity. However, different responses of species to warming and changed species interactions make predicting biodiversity redistribution and relative abundance a challenge. Here, we use three decades of fish and plankton survey data to assess how warming changes the relative dominance of warm-affinity and cold-affinity species. Regions with stable temperatures (for example, the Northeast Pacific and Gulf of Mexico) show little change in dominance structure, while areas with warming (for example, the North Atlantic) see strong shifts towards warm-water species dominance. Importantly, communities whose species pools had diverse thermal affinities and a narrower range of thermal tolerance showed greater sensitivity, as anticipated from simulations. The composition of fish communities changed less than expected in regions with strong temperature depth gradients. There, species track temperatures by moving deeper, rather than horizontally, analogous to elevation shifts in land plants. Temperature thus emerges as a fundamental driver for change in marine systems, with predictable restructuring of communities in the most rapidly warming areas using metrics based on species thermal affinities. The ready and predictable dominance shifts suggest a strong prognosis of resilience to climate change for these communities

Observation of the diphoton decay of the Higgs boson and measurement of its properties

Peer reviewe

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics