AID and Apobec3G haphazard deamination and mutational diversity

Activation-induced deoxycytidine deaminase (AID) and Apobec 3G (Apo3G) cause mutational diversity by initiating mutations on regions of single-stranded (ss) DNA. Expressed in B cells, AID deaminates C → U in actively transcribed immunoglobulin (Ig) variable and switch regions to initiate the somatic hypermutation (SHM) and class switch recombination (CSR) that are essential for antibody diversity. Apo3G expressed in T cells catalyzes C deaminations on reverse transcribed cDNA causing HIV-1 retroviral inactivation. When operating properly, AID- and Apo3G-initiated mutations boost human fitness. Yet, both enzymes are potentially powerful somatic cell “mutators”. Loss of regulated expression and proper genome targeting can cause human cancer. Here, we review well-established biological roles of AID and Apo3G. We provide a synopsis of AID partnering proteins during SHM and CSR, and describe how an Apo2 crystal structure provides “surrogate” insight for AID and Apo3G biochemical behavior. However, large gaps remain in our understanding of how dC deaminases search ssDNA to identify trinucleotide motifs to deaminate. We discuss two recent methods to analyze ssDNA scanning and deamination. Apo3G scanning and deamination is visualized in real-time using single-molecule FRET, and AID deamination efficiencies are determined with a random walk analysis. AID and Apo3G encounter many candidate deamination sites while scanning ssDNA. Generating mutational diversity is a principal aim of AID and an important ancillary property of Apo3G. Success seems likely to involve hit and miss deamination motif targeting, biased strongly toward miss.     

A new species of the genus Zhangixalus (Amphibia: Rhacophoridae) from Vietnam

ABSTRACT

A new rhacophorid species is described from Vietnam on the basis of nine specimens collected in Quan Ba District, Ha Giang Province, northeastern Vietnam. The new species is morphologically similar to Zhangixalus pinglongensis, Z. dorsoviridis, and Z. nigropunctatus, however, it differs from the latter by having the flank cream with large black blotches on axilla and groin. The genetic distance between the new species and Zhangixalus pinglongensis, Z. dorsoviridis and Z. nigropunctatus is >3.57% (16S mtDNA gene fragment). Zhangixalus jodiae sp. nov. can be distinguished from all other species of Zhangixalus and other small rhacophorid species from Southeast Asia by a combination of the following characters: size small (SVL 36.1–39.8 mm in males); head as long as wide; vomerine teeth present; dorsal surface of head and body green without spots; axilla cream with large black blotches, groin and front-rear parts of the thigh, ventral surface of tibia black with orange blotches; lower jaw region greyish, chest and belly cream.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:89597718-024F-4FFC-B0AE-2005F12CF66C     

Integrative taxonomic analysis reveals a new species of Leptobrachium (Anura: Megophryidae) from north-eastern Cambodia and central Vietnam

ABSTRACT

Species boundaries within the red-eyed Leptobrachium of southern Indochina have been uncertain. Leptobrachium pullum and L. mouhoti from upper and lower elevations, respectively, of the Langbian Plateau of southern Vietnam and eastern Cambodia differ in body size but have relatively low interspecific mitochondrial DNA divergence, leading to speculation that these might represent a single species with an elevational cline in body size. The recent discovery of an allopatric high-elevation population of red-eyed Leptobrachium on the Kon Tum Plateau (= Central Highlands) of north-eastern Cambodia and central Vietnam has been referred to both species, and to a putatively undescribed species. We examine variation in morphology of adults and tadpoles, mitochondrial DNA, 11 nuclear genes and advertisement calls, and show corroborating lines of evidence for the existence of three species of red-eyed Leptobrachium in southern Indochina. Although the three species are reciprocally monophyletic in mitochondrial DNA, their shallow mitochondrial DNA divergences are not mirrored by morphology, advertisement calls, or – in part – nuclear DNA, and probably reflect past mitochondrial introgression rather than recent speciation. The Central Highlands taxon is described herein as a new species.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:CE6650AF-D9FB-40F4-8A2E-9B4E23AAC205     

Structure of the insulin receptor ectodomain reveals a folded-over conformation

The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.     

Broad neutralization coverage of HIV by multiple highly potent antibodies

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.     

Highly active brookite TiO2-assisted photocatalytic degradation of dyes under the simulated solar−UVA radiation

Brookite TiO_2 nanoparticles were synthesized by hydrothermal method and characterized by X-ray powder diffraction(XRD), diffuse reflectance UV–Visible spectroscopy(DRUV), and scanning electron microscopy(SEM). The obtained particles were spherical in shape with the diameter of about ～10 nm under the hydrothermal temperature of 175 °C. The photocatalytic performance of brookite was investigated in the photodegradation of dyes(rhodamine B and rose bengal) under UV-A radiation by low-power lamp. The activity of brookite and the photodegradation efficiency of dyes were estimated using a UV–Visible spectrophotometer and a total organic carbon(TOC) analyzer. Compared to anatase and rutile prepared by the similar synthesis procedure, brookite is highly active in terms of decolourization, aromatic ring opening, and mineralization.     

Selective activation of p53-mediated tumour suppression in high-grade tumours

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.