Broadening of Neutralization Activity to Directly Block a Dominant Antibody-Driven SARS-Coronavirus Evolution Pathway

Phylogenetic analyses have provided strong evidence that amino acid changes in spike (S) protein of animal and human SARS coronaviruses (SARS-CoVs) during and between two zoonotic transfers (2002/03 and 2003/04) are the result of positive selection. While several studies support that some amino acid changes between animal and human viruses are the result of inter-species adaptation, the role of neutralizing antibodies (nAbs) in driving SARS-CoV evolution, particularly during intra-species transmission, is unknown. A detailed examination of SARS-CoV infected animal and human convalescent sera could provide evidence of nAb pressure which, if found, may lead to strategies to effectively block virus evolution pathways by broadening the activity of nAbs. Here we show, by focusing on a dominant neutralization epitope, that contemporaneous- and cross-strain nAb responses against SARS-CoV spike protein exist during natural infection. In vitro immune pressure on this epitope using 2002/03 strain-specific nAb 80R recapitulated a dominant escape mutation that was present in all 2003/04 animal and human viruses. Strategies to block this nAb escape/naturally occurring evolution pathway by generating broad nAbs (BnAbs) with activity against 80R escape mutants and both 2002/03 and 2003/04 strains were explored. Structure-based amino acid changes in an activation-induced cytidine deaminase (AID) “hot spot” in a light chain CDR (complementarity determining region) alone, introduced through shuffling of naturally occurring non-immune human VL chain repertoire or by targeted mutagenesis, were successful in generating these BnAbs. These results demonstrate that nAb-mediated immune pressure is likely a driving force for positive selection during intra-species transmission of SARS-CoV. Somatic hypermutation (SHM) of a single VL CDR can markedly broaden the activity of a strain-specific nAb. The strategies investigated in this study, in particular the use of structural information in combination of chain-shuffling as well as hot-spot CDR mutagenesis, can be exploited to broaden neutralization activity, to improve anti-viral nAb therapies, and directly manipulate virus evolution

Climate and Famines: a Historical Reassessment

This study, dealing with the question of the impact of climate and extreme weather events on famines, has two objectives. The first objective is to review recent literature on the topic, distinguishing between economic and political science papers aimed at addressing contemporary famine events in the Third World countries, and historical research dealing with famines of the past. The former category of literature is characterized by a tendency to take the connection between the two variables for granted. The latter category, however, tends to exercise more analytical caution, but it still exhibits a degree of environmental determinism. The second objective of the article is to reassess the role and impact of climate and short-term weather anomalies on famines in pre-Industrial societies, in both European and non-European history. At first, it appears that famines went invariably hand-in-hand with climatic changes and anomalies. A closer analysis, however, reveals that those climatic events created environmental shocks (harvest failures and blights), which implied shortages, rather than famines. Whether those shortages were bound to transform into full-fledged famines was determined by nonenvironmental factors: primarily, human institutions and demographic trends. Climate alone, it is argued, is incapable of creating famines. The often unquestioned connection between the two variables appears to be an imaginary cultural and political construct of our era, when the fear of global warming and the awareness of climate change dominate the public and scholarly discours

From mRNP trafficking to spine dysmorphogenesis: The roots of fragile X syndrome

The mental retardation protein FMRP is involved in the transport of mRNAs and their translation at synapses. Patients with fragile X syndrome, in whom FMRP is absent or mutated, show deficits in learning and memory that might reflect impairments in the translational regulation of a subset of neuronal mRNAs. The study of FMRP provides important insights into the regulation and functions of local protein synthesis in the neuronal periphery, and increases our understanding of how these functions can produce specific effects at individual synapses