Canopy Catalysts for Alkyne Metathesis: Investigations into a Bimolecular Decomposition Pathway and the Stability of the Podand Cap

Molybdenum alkylidyne complexes with a trisilanolate podand ligand framework (“canopy catalysts”) are the arguably most selective catalysts for alkyne metathesis known to date. Among them, complex 1a endowed with a fence of lateral methyl substituents on the silicon linkers is most reactive, although fairly high loadings are required in certain applications. It is now shown that this catalyst decomposes readily via a bimolecular pathway, which engages the Mo≡CR entities in a stoichiometric triple bond metathesis event to furnish RC≡CR and the corresponding dinuclear complex 8 with a Mo≡Mo core. In addition to the regular analytical techniques, 95Mo NMR was used to confirm this unusual outcome. This rapid degradation mechanism is largely avoided by increasing the size of the peripheral substituents on silicon, without unduly compromising the activity of the resulting complexes. When chemically challenged, however, canopy catalysts can open the apparently somewhat strained tripodal ligand cages; this reorganization leads to the formation of cyclo-tetrameric arrays composed of four metal alkylidyne units linked together via one silanol arm of the ligand backbone. The analogous tungsten alkylidyne complex 6 endowed with a tripodal tris-alkoxide (rather than siloxide) ligand framework is even more susceptible to such a controlled and reversible cyclo-oligomerization. The structures of the resulting giant macrocyclic ensembles were established by single crystal X-ray diffraction

Epigraph hemagglutinin vaccine induces broad cross-reactive immunity against swine H3 influenza virus

Influenza A virus infection in swine impacts the agricultural industry in addition to its zoonotic potential. Here, we utilize epigraph, a computational algorithm, to design a universal swine H3 influenza vaccine. The epigraph hemagglutinin proteins are delivered using an Adenovirus type 5 vector and are compared to a wild type hemagglutinin and the commercial inactivated vaccine, FluSure. In mice, epigraph vaccination leads to significant cross-reactive antibody and T-cell responses against a diverse panel of swH3 isolates. Epigraph vaccination also reduces weight loss and lung viral titers in mice after challenge with three divergent swH3 viruses. Vaccination studies in swine, the target species for this vaccine, show stronger levels of cross-reactive antibodies and T-cell responses after immunization with the epigraph vaccine compared to the wild type and FluSure vaccines. In both murine and swine models, epigraph vaccination shows superior cross-reactive immunity that should be further investigated as a universal swH3 vaccine

Extreme N-emitters at high-redshift: signatures of supermassive stars and globular cluster or black hole formation in action?

[Abridged] Using the JWST/NIRSpec observations from CEERS we found an extreme N-emitter, CEERS-1019 at z=8.6782 showing intense NIV and NIII emission. From the observed rest-UV and optical lines we conclude that it is compatible with photoionization from stars and we determine accurate abundances for C, N, O, and Ne, relative to H, finding a highly supersolar ratio log(N/O) = -0.18+/-0.11, and normal log(C/O) = -0.75+/-0.11 and log(Ne/O) = -0.63+/-0.07, for its low metallicity, 12+log(O/H)= 7.70+/-0.18. We also analyze other N-emitters from the literature. All show strongly enhanced N/O ratios and two of them normal C/O. Massive star ejecta from WR stars are needed to explain the galaxies with enhanced C/O (Lynx arc and Mrk 996). On the other hand, supermassive stars (>1000 Msun, SMS) in the ``conveyer-belt model'' put forward to explain globular clusters (GCs), predict a high N/O and small changes in C/O, compatible with CEERS-1019, the Sunburst cluster, SMACS2031, and GN-z11. Based on the chemical abundances, possible enrichment scenarios, compactness, and high ISM density, we suggest that CEERS-1019, SMACS2031, and the Sunburst cluster could contain proto-GCs. Finally, we propose that some N-emitters enriched by SMS could also have formed intermediate-mass black holes, and we suggest that this might be the case for GN-z11. Our observations and analysis reinforce the suggested link between some N-emitters and proto-GC formation, which is supported both by empirical evidence and quantitative models. Furthermore, the observations provide possible evidence for the presence of supermassive stars in the early Universe (z>8) and at z~2-3. Our analysis also suggests that the origin and nature of the N-emitters is diverse, including also objects like GN-z11 which possibly host an AGN.Comment: Submitted to A&A, 19 pages, 8 figures, 4 table

HIV Types, Groups, Subtypes and Recombinant Forms: Errors in Replication, Selection Pressure and Quasispecies

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1{*}1303, KIR and PARD3B. Copyright (C) 2012 S. Karger AG, Base

ShoRAH: estimating the genetic diversity of a mixed sample from next-generation sequencing data

<p>Abstract</p> <p>Background</p> <p>With next-generation sequencing technologies, experiments that were considered prohibitive only a few years ago are now possible. However, while these technologies have the ability to produce enormous volumes of data, the sequence reads are prone to error. This poses fundamental hurdles when genetic diversity is investigated.</p> <p>Results</p> <p>We developed ShoRAH, a computational method for quantifying genetic diversity in a mixed sample and for identifying the individual clones in the population, while accounting for sequencing errors. The software was run on simulated data and on real data obtained in wet lab experiments to assess its reliability.</p> <p>Conclusions</p> <p>ShoRAH is implemented in C++, Python, and Perl and has been tested under Linux and Mac OS X. Source code is available under the GNU General Public License at <url>http://www.cbg.ethz.ch/software/shorah</url>.</p

Construction and evaluation of novel rhesus monkey adenovirus vaccine vectors

Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. IMPORTANCE Although there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens

Estimating time since infection in early homogeneous HIV-1 samples using a poisson model

<p>Abstract</p> <p>Background</p> <p>The occurrence of a genetic bottleneck in HIV sexual or mother-to-infant transmission has been well documented. This results in a majority of new infections being homogeneous, <it>i.e</it>., initiated by a single genetic strain. Early after infection, prior to the onset of the host immune response, the viral population grows exponentially. In this simple setting, an approach for estimating evolutionary and demographic parameters based on comparison of diversity measures is a feasible alternative to the existing Bayesian methods (<it>e.g</it>., BEAST), which are instead based on the simulation of genealogies.</p> <p>Results</p> <p>We have devised a web tool that analyzes genetic diversity in acutely infected HIV-1 patients by comparing it to a model of neutral growth. More specifically, we consider a homogeneous infection (<it>i.e</it>., initiated by a unique genetic strain) prior to the onset of host-induced selection, where we can assume a random accumulation of mutations. Previously, we have shown that such a model successfully describes about 80% of sexual HIV-1 transmissions provided the samples are drawn early enough in the infection. Violation of the model is an indicator of either heterogeneous infections or the initiation of selection.</p> <p>Conclusions</p> <p>When the underlying assumptions of our model (homogeneous infection prior to selection and fast exponential growth) are met, we are under a very particular scenario for which we can use a forward approach (instead of backwards in time as provided by coalescent methods). This allows for more computationally efficient methods to derive the time since the most recent common ancestor. Furthermore, the tool performs statistical tests on the Hamming distance frequency distribution, and outputs summary statistics (mean of the best fitting Poisson distribution, goodness of fit p-value, etc). The tool runs within minutes and can readily accommodate the tens of thousands of sequences generated through new ultradeep pyrosequencing technologies. The tool is available on the LANL website.</p