The clammy grip of parasitic tumors.

An epidemic of leukemia among bivalve molluscs is spreading along the Atlantic coast of North America, with a serious population decline of soft-shelled clams. In this issue of Cell, Metzger et al. use forensic DNA markers to demonstrate that the leukemia cells have a clonal origin and appear to be transmitted through sea water.

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors.

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.

Chalcogen-Bond Catalysis: Telluronium-Catalyzed [4+2]-Cyclocondensation of (in situ Generated) Aryl Imines with Alkenes.

In the chalcogen series, tellurium species exhibit the strongest chalcogen bonding (ChB) interaction with electron-rich atom. This property explains the renewed interested toward tellurium-based derivatives and their use in different applications, such as organocatalysis. In this context, the catalytic activity of telluronium salts in the Povarov reaction is presented herein. Different dienophiles, as well as imines of variable electronic nature, efficiently react in the presence of catalytic amount of either diarylmethyltelluronium or triaryltelluronium salts. Both catalysts could also readily perform the three-component Povarov reaction starting from aldehyde, aniline and dihydrofuran. The reactivity of telluroniums towards imines and aldehydes was confirmed in the solid state by the ability of Te atom to interact through ChB with the oxygen carbonyl of acetone, and in solution with significant shift variations of the imine proton and of the tellurium atom in 1 H and 125 Te NMR spectroscopy. For the most active telluronium catalysts bearing CF3 groups, association constants (K) with N-phenyl phenylmethanimine in the range 22-38 M-1 were measured in dichloromethane.

On viruses, discovery, and recognition.

This year's Nobel Prize in Physiology or Medicine rewards the discoverers of two viruses that cause major afflictions of humankind. Identifying human papilloma virus (HPV) and human immunodeficiency virus (HIV) might now appear to have been simple, but the way forward was far from obvious at the time.

Grafting of Crown Ether and Cryptand Macrocycles on Large Pore Stellate Mesoporous Silica for Sodium Cation Extraction.

Regulation of the sodium cations level in the case of renal failure diseases is a very challenging task for clinicians, and new pollutant extractors based on nanomaterials are emerging as potential treatments. In this work, we report different strategies for the chemical functionalization of biocompatible large pore mesoporous silica, denoted stellate mesoporous silica (STMS), with chelating ligands able to selectively capture sodium. We address efficient methods to covalently graft highly chelating macrocycles onto STMS NPs such as crown ethers (CE) and cryptands (C221) through complementary carbodiimidation reactions. Regarding sodium capture in water, C221 cryptand-grafted STMS showed better capture efficiency than CE-STMS due to higher sodium atom chelation in the cryptand cage (Na+ coverage of 15.5% vs. 3.7%). The sodium selectivity was hence tested with C221 cryptand-grafted STMS in a multi-element aqueous solution (metallic cations with the same concentration) and in a solution mimicking peritoneal dialysis solution. Results obtained indicate that C221 cryptand-grafted STMS are relevant nanomaterials to extract sodium cations in such media and allow us to regulate their levels.

Chalcogen Bonding with Diaryl Ditellurides: Evidence from Solid State and Solution Studies.

The chalcogen bonding (ChB) ability of Te is studied in symmetrical diaryl ditellurides ArTeTeAr. Among the two Te σ-holes, the one along the less polarized Te-Te bond was calculated as the more electropositive. This counter-intuitive situation is due to the hyperconjugation contribution from Te lone pair to the σ* of the adjacent Te which coincides with σ-hole along the more polarized Te-Ar bond. ArTeTeAr showed notable structural features in the solid state as a result of intermolecular Te⋅⋅⋅Te ChB, such as a Te4 rectangle through dimer aggregation or a triangular Te3 motif, where one Te interacts with both Te atoms of a neighboring molecule through both its σ-hole and lone pair, in a slightly frustrated geometry. Lewis acidity of ArTeTeAr was also evaluated by NMR with R3 PO as σ-hole acceptors in different solvents. Thus, 125 Te NMR allowed monitoring Te⋅⋅⋅O interaction and delivering association constants (Ka ) for 1 : 1 adducts. The highest value of Ka =90 M-1 was measured for the adduct between ArTeTeAr bearing CF3 groups and Et3 PO in cyclohexane. Notably, by using nBu3 PO, Te⋅⋅⋅O interaction was revealed by 19 F-1 H HOESY showing spatial proximity between CF3 and CH3 of nBu3 PO.

A perspective on the early days of RAS research.

The name of the oncogene, ras, has its origin in studies of murine leukemia viruses in the 1960s by Jenny Harvey (H-ras) and by Werner Kirsten (K-ras) which, at high doses, produced sarcomas in rats. Transforming retroviruses were isolated, and its oncogene was named ras after rat sarcoma. From 1979, cellular ras sequences with transforming properties were identified by transfection of tumor DNA initially by Robert Weinberg from rodent tumors, and the isolation of homologous oncogenes from human tumors soon followed, including HRAS and KRAS, and a new member of the family named NRAS. I review these discoveries, placing emphasis on the pioneering research of Christopher Marshall and Alan Hall, who subsequently made immense contributions to our understanding of the functions of RAS and related small GTPases to signal transduction pathways, cell structure, and the behavior of normal and malignant cells.

Enantioseparations of polyhalogenated 4,4'-bipyridines on polysaccharide-based chiral stationary phases and molecular dynamics simulations of selector-selectand interactions.

2'-(4-Pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs (TCIBP = 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridyl) are chiral compounds that showed interesting inhibition activity against transthyretin fibrillation in vitro. We became interested in their enantioseparation since we noticed that the M-stereoisomer is more effective than the P-enantiomer. Based thereon, we recently reported the enantioseparation of 2'-substituted TCIBP derivatives with amylose-based chiral columns. Following this study, herein we describe the comparative enantioseparation of both 2'-(4-pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs on four cellulose phenylcarbamate-based chiral columns aiming to explore the effect of the polymer backbone, as well as the nature and position of substituents on the side groups on the enantioseparability of these compounds. In the frame of this project, the impact of subtle variations of analyte and polysaccharide structures, and mobile phase (MP) polarity on retention and selectivity was evaluated. The effect of temperature on retention and selectivity was also considered, and overall thermodynamic parameters associated with the analyte adsorption onto the CSP surface were derived from van 't Hoff plots. Interesting cases of enantiomer elution order (EEO) reversal were observed. In particular, the EEO was shown to be dependent on polysaccharide backbone, the elution sequence of the two analytes being P-M and M-P on cellulose and amylose tris(3,5-dimethylphenylcarbamate), respectively. In this regard, a theoretical investigation based on molecular dynamics (MD) simulations was performed by using amylose and cellulose tris(3,5-dimethylphenylcarbamate) nonamers as virtual models of the polysaccharide-based selectors. This exploration at the molecular level shed light on the origin of the enantiodiscrimination processes.

Enantioseparation of 5,5'-Dibromo-2,2'-Dichloro-3-Selanyl-4,4'-Bipyridines on Polysaccharide-Based Chiral Stationary Phases: Exploring Chalcogen Bonds in Liquid-Phase Chromatography.

The chalcogen bond (ChB) is a noncovalent interaction based on electrophilic features of regions of electron charge density depletion (σ-holes) located on bound atoms of group VI. The σ-holes of sulfur and heavy chalcogen atoms (Se, Te) (donors) can interact through their positive electrostatic potential (V) with nucleophilic partners such as lone pairs, π-clouds, and anions (acceptors). In the last few years, promising applications of ChBs in catalysis, crystal engineering, molecular biology, and supramolecular chemistry have been reported. Recently, we explored the high-performance liquid chromatography (HPLC) enantioseparation of fluorinated 3-arylthio-4,4'-bipyridines containing sulfur atoms as ChB donors. Following this study, herein we describe the comparative enantioseparation of three 5,5'-dibromo-2,2'-dichloro-3-selanyl-4,4'-bipyridines on polysaccharide-based chiral stationary phases (CSPs) aiming to understand function and potentialities of selenium σ-holes in the enantiodiscrimination process. The impact of the chalcogen substituent on enantioseparation was explored by using sulfur and non-chalcogen derivatives as reference substances for comparison. Our investigation also focused on the function of the perfluorinated aromatic ring as a π-hole donor recognition site. Thermodynamic quantities associated with the enantioseparation were derived from van't Hoff plots and local electron charge density of specific molecular regions of the interacting partners were inspected in terms of calculated V. On this basis, by correlating theoretical data and experimental results, the participation of ChBs and π-hole bonds in the enantiodiscrimination process was reasonably confirmed.

Chalcogen-Bonding Catalysis with Telluronium Cations.

Chalcogen bonding results from non-covalent interactions occurring between electrodeficient chalcogen atoms and Lewis bases. Among the chalcogens, tellurium is the strongest Lewis acid, but Te-based compounds are scarcely used as organocatalysts. For the first time, telluronium cations demonstrated impressive catalytic properties at low loadings in three benchmark reactions: the Friedel-Crafts bromination of anisole, the bromolactonization of ω-unsaturated carboxylic acids and the aza-Diels-Alder between Danishefsky's diene and imines. The ability of telluronium cations to interact with a Lewis base through chalcogen bonding was demonstrated on the basis of multi-nuclear (17 O, 31 P, and 125 Te) NMR analysis and DFT calculations.

Factors Impacting σ- and π-Hole Regions as Revealed by the Electrostatic Potential and Its Source Function Reconstruction: The Case of 4,4'-Bipyridine Derivatives.

Positive electrostatic potential (V) values are often associated with σ- and π-holes, regions of lower electron density which can interact with electron-rich sites to form noncovalent interactions. Factors impacting σ- and π-holes may thus be monitored in terms of the shape and values of the resulting V. Further precious insights into such factors are obtained through a rigorous decomposition of the V values in atomic or atomic group contributions, a task here achieved by extending the Bader-Gatti source function (SF) for the electron density to V. In this article, this general methodology is applied to a series of 4,4'-bipyridine derivatives containing atoms from Groups VI (S, Se) and VII (Cl, Br), and the pentafluorophenyl group acting as a π-hole. As these molecules are characterized by a certain degree of conformational freedom due to the possibility of rotation around the two C-Ch bonds, from two to four conformational motifs could be identified for each structure through conformational search. On this basis, the impact of chemical and conformational features on σ- and π-hole regions could be systematically evaluated by computing the V values on electron density isosurfaces (VS) and by comparing and dissecting in atomic/atomic group contributions the VS maxima (VS,max) values calculated for different molecular patterns. The results of this study confirm that both chemical and conformational features may seriously impact σ- and π-hole regions and provide a clear analysis and a rationale of why and how this influence is realized. Hence, the proposed methodology might offer precious clues for designing changes in the σ- and π-hole regions, aimed at affecting their potential involvement in noncovalent interactions in a desired way.

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.

The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3',5,5'-tetrachloro-2-iodo-2'-substituted-4,4'- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2'-substituent. The corresponding racemates, along with other five chiral 4,4'-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4'-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3',5,5'-tetrachloro-2'-(4-hydroxyphenyl)-2-iodo-4,4'-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4'-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4'-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

Open questions: knowing who's who in multicellular animals is not always as simple as we imagine.

The ability of certain tumor cells of mammals and molluscs to spread from the original host to others reopens the question of distinguishing self from non-self. It is part of a wider phenomenon of cellular parasitism and cell chimerism including germ cells.

Chiral Chalcogen Bond Donors Based on the 4,4'-Bipyridine Scaffold.

Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well as the catalytic activity evaluation of the 5,5'-dibromo-2,2'-dichloro-3-((perfluorophenyl)selanyl)-4,4'-bipyridine as organocatalyst. The latter is based on the use of two electron-withdrawing groups, a pentafluorophenyl ring and a tetrahalo-4,4'-bipyridine skeleton, as substituents at the selenium center. Atropisomery of the tetrahalo-4,4'-bipyridine motif provides a chiral environment to these new ChB donors. Their synthesis was achieved through either selective lithium exchange and trapping or a site-selective copper-mediated reaction. Pure enantiomers of the 3-selanyl-4,4'-bipyridine were obtained by high performance liquid chromatography enantioseparation on specific chiral stationary phase, and their absolute configuration was assigned by comparison of the measured and calculated electronic circular dichroism spectra. The capability of the selenium compound to participate in σ-hole-based interactions in solution was studied by 19F NMR. Even if no asymmetric induction has been observed so far, the new selenium motif proved to be catalytically active in the reduction of 2-phenylquinoline by Hantzsch ester.

Exchange of Genetic Sequences Between Viruses and Hosts.

Although genetic transfer between viruses and vertebrate hosts occurs less frequently than gene flow between bacteriophages and prokaryotes, it is extensive and has affected the evolution of both parties. With retroviruses, the integration of proviral DNA into chromosomal DNA can result in the activation of adjacent host gene expression and in the transduction of host transcripts into retroviral genomes as oncogenes. Yet in contrast to lysogenic phage, there is little evidence that viral oncogenes persist in a chain of natural transmission or that retroviral transduction is a significant driver of the horizontal spread of host genes. Conversely, integration of proviruses into the host germ line has generated endogenous retroviral genomes (ERV) in all vertebrate genomes sequenced to date. Some of these genomes retain potential infectivity and upon reactivation may transmit to other host species. During mammalian evolution, sequences of retroviral origin have been repurposed to serve host functions, such as the viral envelope glycoproteins crucial to the development of the placenta. Beyond retroviruses, DNA viruses with complex genomes have acquired numerous genes of host origin which influence replication, pathogenesis and immune evasion, while host species have accumulated germline sequences of both DNA and RNA viruses. A codicil is added on lateral transmission of cancer cells between hosts and on migration of host mitochondria into cancer cells.

Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1.

To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.

Optogenetic stimulation of the cochlea-A review of mechanisms, measurements, and first models.

This review evaluates the potential of optogenetic methods for the stimulation of the auditory nerve and assesses the feasability of optogenetic cochlear implants (CIs). It provides an overview of all critical steps like opsin targeting strategies, how opsins work, how their function can be modeled and included in neuronal models and the properties of light sources available for optical stimulation. From these foundations, quantitative estimates for the number of independent stimulation channels and the temporal precision of optogenetic stimulation of the auditory nerve are derived and compared with state-of-the-art electrical CIs. We conclude that optogenetic CIs have the potential to increase the number of independent stimulation channels by up to one order of magnitude to about 100, but only if light sources are able to deliver confined illumination patterns independently and parallelly. Already now, opsin variants like ChETA and Chronos enable driving of the auditory nerve up to rates of 200 spikes/s, close to the physiological value of their maximum sustained firing rate. Apart from requiring 10 times more energy than electrical stimulation, optical CIs still face major hurdles concerning the safety of gene transfection and optrode array implantation, for example, before becoming an option to replace electrical CIs.

What's the host and what's the microbe? The Marjory Stephenson Prize Lecture 2015.

The interchange between retroviruses and their hosts is an intimate one because retroviruses integrate proviral DNA into host chromosomal DNA as an obligate step in the replication cycle. This has resulted in the occasional transduction of host genes into retroviral genomes as oncogenes, and also led to the integration of viral genomes into the host germ line that gives rise to endogenous retroviruses. I shall reflect on the evolutionary consequences of these events for virus and host. Then, I shall discuss the emergence of non-viral infections of host origin, namely, how malignant cells can give rise to eukaryotic single cell 'parasites' that colonize new hosts and how these in turn have been colonized by host mitochondria.

A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition.

The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.