Two Early Cretaceous Fossils Document Transitional Stages in Alvarezsaurian Dinosaur Evolution

1. Download high-res image (201KB)
2. Download full-size image

     

Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance

1. Download high-res image (297KB)
2. Download full-size image

     

Structures of paraoxon‐inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate‐inhibited and oxime‐bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon‐inhibited human acetylcholinesterase in complex with the oximes HI6 and 2‐PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246–1256. © 2016 Wiley Periodicals, Inc.     

Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells

Nef-specific CD8⁺ T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef_165–173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T₁₇₀I, unexpectedly and uniquely degraded Nef''s major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication.     

Intrinsically active variants of Erk oncogenically transform cells and disclose unexpected autophosphorylation capability that is independent of TEY phosphorylation

The receptor-tyrosine kinase (RTK)/Ras/Raf pathway is an essential cascade for mediating growth factor signaling. It is abnormally overactive in almost all human cancers. The downstream targets of the pathway are members of the extracellular regulated kinases (Erk1/2) family, suggesting that this family is a mediator of the oncogenic capability of the cascade. Although all oncogenic mutations in the pathway result in strong activation of Erks, activating mutations in Erks themselves were not reported in cancers. Here we used spontaneously active Erk variants to check whether Erk’s activity per se is sufficient for oncogenic transformation. We show that Erk1(R84S) is an oncoprotein, as NIH3T3 cells that express it form foci in tissue culture plates, colonies in soft agar, and tumors in nude mice. We further show that Erk1(R84S) and Erk2(R65S) are intrinsically active due to an unusual autophosphorylation activity they acquire. They autophosphorylate the activatory TEY motif and also other residues, including the critical residue Thr-207 (in Erk1)/Thr-188 (in Erk2). Strikingly, Erk2(R65S) efficiently autophosphorylates its Thr-188 even when dually mutated in the TEY motif. Thus this study shows that Erk1 can be considered a proto-oncogene and that Erk molecules possess unusual autoregulatory properties, some of them independent of TEY phosphorylation.     

Born to sing! Song development in a singing primate

In animal vocal communication, the development of adult-like vocalization is fundamental to interact appropriately with conspecifics. However, the factors that guide ontogenetic changes in the acoustic features remain poorly understood. In contrast with a historical view of nonhuman primate vocal production as substantially innate, recent research suggests that inheritance and physiological modification can only explain some of the developmental changes in call structure during growth. A particular case of acoustic communication is the indris’ singing behavior, a peculiar case among Strepsirrhine primates. Thanks to a decade of intense data collection, this work provides the first long-term quantitative analysis on song development in a singing primate. To understand the ontogeny of such a complex vocal output, we investigated juvenile and sub-adult indris’ vocal behavior, and we found that young individuals started participating in the chorus years earlier than previously reported. Our results indicated that spectro-temporal song parameters underwent essential changes during growth. In particular, the age and sex of the emitter influenced the indris’ vocal activity. We found that frequency parameters showed consistent changes across the sexes, but the temporal features showed different developmental trajectories for males and females. Given the low level of morphological sexual dimorphism and the marked differences in vocal behavior, we hypothesize that factors like social influences and auditory feedback may affect songs’ features, resulting in high vocal flexibility in juvenile indris. This trait may be pivotal in a species that engages in choruses with rapid vocal turn-taking.     

Local Perspectives on Environmental Insecurity and Its Influence on Illegal Biodiversity Exploitation

Environmental insecurity is a source and outcome of biodiversity declines and social conflict. One challenge to scaling insecurity reduction policies is that empirical evidence about local attitudes is overwhelmingly missing. We set three objectives: determine how local people rank risk associated with different sources of environmental insecurity; assess perceptions of environmental insecurity, biodiversity exploitation, myths of nature and risk management preferences; and explore relationships between perceptions and biodiversity exploitation. We conducted interviews (N = 88) with residents of Madagascar’s Torotorofotsy Protected Area, 2014. Risk perceptions had a moderate effect on perceptions of environmental insecurity. We found no effects of environmental insecurity on biodiversity exploitation. Results offer one if not the first exploration of local perceptions of illegal biodiversity exploitation and environmental security. Local people’s perception of risk seriousness associated with illegal biodiversity exploitation such as lemur hunting (low overall) may not reflect perceptions of policy-makers (considered to be high). Discord is a key entry point for attention.     

Osmostress Induces Autophosphorylation of Hog1 via a C-Terminal Regulatory Region That Is Conserved in p38��

Many protein kinases require phosphorylation at their activation loop for induction of catalysis. Mitogen-activated protein kinases (MAPKs) are activated by a unique mode of phosphorylation, on neighboring Tyrosine and Threonine residues. Whereas many kinases obtain their activation via autophosphorylation, MAPKs are usually phosphorylated by specific, dedicated, MAPK kinases (MAP2Ks). Here we show however, that the yeast MAPK Hog1, known to be activated by the MAP2K Pbs2, is activated in pbs2Δ cells via an autophosphorylation activity that is induced by osmotic pressure. We mapped a novel domain at the Hog1 C-terminal region that inhibits this activity. Removal of this domain provides a Hog1 protein that is partially independent of MAP2K, namely, partially rescues osmostress sensitivity of pbs2Δ cells. We further mapped a short domain (7 amino acid residues long) that is critical for induction of autophosphorylation. Its removal abolishes autophosphorylation, but maintains Pbs2-mediated phosphorylation. This 7 amino acids stretch is conserved in the human p38α. Similar to the case of Hog1, it’s removal from p38α abolishes p38α’s autophosphorylation capability, but maintains, although reduces, its activation by MKK6. This study joins a few recent reports to suggest that, like many protein kinases, MAPKs are also regulated via induced autoactivation.