Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity

TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5α but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations

Quantum folded string and integrability: from finite size effects to Konishi dimension

Using the algebraic curve approach we one-loop quantize the folded string solution for the type IIB superstring in AdS(5)xS(5). We obtain an explicit result valid for arbitrary values of its Lorentz spin S and R-charge J in terms of integrals of elliptic functions. Then we consider the limit S ~ J ~ 1 and derive the leading three coefficients of strong coupling expansion of short operators. Notably, our result evaluated for the anomalous dimension of the Konishi state gives 2\lambda^{1/4}-4+2/\lambda^{1/4}. This reproduces correctly the values predicted numerically in arXiv:0906.4240. Furthermore we compare our result using some new numerical data from the Y-system for another similar state. We also revisited some of the large S computations using our methods. In particular, we derive finite--size corrections to the anomalous dimension of operators with small J in this limit.Comment: 20 pages, 1 figure; v2: references added, typos corrected; v3: major improvement of the references; v4: Discussion of short operators is restricted to the case n=1. This restriction does not affect the main results of the pape

Quantum folded string in S^5 and the Konishi multiplet at strong coupling

The Konishi superconformal multiplet is an important theoretical laboratory where one can test AdS/CFT methods to compute strong coupling corrections to the spectrum of superstrings in AdS_5 x S^5. In particular, one can exploit integrability for finite charge states/operators. The multiplet ground state is a singlet operator with two simple descendants in the rank-1 sectors sl(2) and su(2) of N=4 super Yang-Mills theory. Recently, the next-to-leading quantum correction to the sl(2) state has been computed. Here, we use the algebraic curve approach to determine the correction to the other state recovering universality of the correction inside the multiplet.Comment: 17 pages, 5 eps figure

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Active site remodeling switches HIV specificity of antiretroviral TRIMCyp

TRIMCyps are primate antiretroviral proteins that potently inhibit HIV replication. Here we describe how rhesus macaque TRIMCyp (RhTC) has evolved to target and restrict HIV-2. We show that the ancestral cyclophilin A (CypA) domain of RhTC targets HIV-2 capsid with weak affinity, which is strongly increased in RhTC by two mutations (D66N and R69H) at the expense of HIV-1 binding. These mutations disrupt a constraining intramolecular interaction in CypA, triggering the complete restructuring (>16 A) of an active site loop. This new configuration discriminates between divergent HIV-1 and HIV-2 loop conformations mediated by capsid residue 88. Viral sensitivity to RhTC restriction can be conferred or abolished by mutating position 88. Furthermore, position 88 determines the susceptibility of naturally occurring HIV-1 sequences to restriction. Our results reveal the complex molecular, structural and thermodynamic changes that underlie the ongoing evolutionary race between virus and host