Analysis of the Contrasting Pathogenicities Induced by the D222G Mutation in 1918 and 2009 Pandemic Influenza A Viruses.

In 2009, the D222G mutation in the hemagglutinin (HA) glycoprotein of pandemic H1N1 influenza A virus was found to correlate with fatal and severe human infections. Previous static structural analysis suggested that, unlike the H1N1 viruses prevalent in 1918, the mutation did not compromise binding to human α2,6-linked glycan receptors, allowing it to transmit efficiently. Here we investigate the interconversion mechanism between two predicted binding modes in both 2009 and 1918 HAs, introducing a highly parallel intermediate network search scheme to construct kinetically relevant pathways efficiently. Accumulated mutations at positions 183 and 224 that alter the size of the binding pocket are identified with the fitness of the 2009 pandemic virus carrying the D222G mutation. This result suggests that the pandemic H1N1 viruses could gain binding affinity to the α2,3-linked glycan receptors in the lungs, usually associated with highly pathogenic avian influenza, without compromising viability.This work was supported by the ERC and the EPSRC.This is the final version of the article. It first appeared from ACS via http://pubs.acs.org/doi/abs/10.1021/ct5010565

Forecasting species distributions : correlation does not equal causation

This research was funded by the U.S. Department of the Interior Northeast Climate Adaptation Science Center, which is managed by the U.S. Geological Survey National Climate Adaptation Science Center. Additional funding was provided by T-2- 3R grants for Nongame Species Monitoring and Management through the New Hampshire Fish and Game Department and E-1- 25 grants for Investigations and Population Recovery through the Vermont Fish and Wildlife Department.Aim Identifying the mechanisms influencing species' distributions is critical for accurate climate change forecasts. However, current approaches are limited by correlative models that cannot distinguish between direct and indirect effects. Location New Hampshire and Vermont, USA. Methods Using causal and correlational models and new theory on range limits, we compared current (2014?2019) and future (2080s) distributions of ecologically important mammalian carnivores and competitors along range limits in the northeastern US under two global climate models (GCMs) and a high-emission scenario (RCP8.5) of projected snow and forest biomass change. Results Our hypothesis that causal models of climate-mediated competition would result in different distribution predictions than correlational models, both in the current and future periods, was well-supported by our results; however, these patterns were prominent only for species pairs that exhibited strong interactions. The causal model predicted the current distribution of Canada lynx (Lynx canadensis) more accurately, likely because it incorporated the influence of competitive interactions mediated by snow with the closely related bobcat (Lynx rufus). Both modeling frameworks predicted an overall decline in lynx occurrence in the central high-elevation regions and increased occurrence in the northeastern region in the 2080s due to changes in land use that provided optimal habitat. However, these losses and gains were less substantial in the causal model due to the inclusion of an indirect buffering effect of snow on lynx. Main conclusions Our comparative analysis indicates that a causal framework, steeped in ecological theory, can be used to generate spatially explicit predictions of species distributions. This approach can be used to disentangle correlated predictors that have previously hampered understanding of range limits and species' response to climate change.Publisher PDFPeer reviewe

Properties of virion transactivator proteins encoded by primate cytomegaloviruses

Background: Human cytomegalovirus (HCMV) is a betaherpesvirus that causes severe disease in situations where the immune system is immature or compromised. HCMV immediate early (IE) gene expression is stimulated by the virion phosphoprotein pp71, encoded by open reading frame (ORF) UL82, and this transactivation activity is important for the efficient initiation of viral replication. It is currently recognized that pp71 acts to overcome cellular intrinsic defences that otherwise block viral IE gene expression, and that interactions of pp71 with the cell proteins Daxx and ATRX are important for this function. A further property of pp71 is the ability to enable prolonged gene expression from quiescent herpes simplex virus type 1 (HSV-1) genomes. Non-human primate cytomegaloviruses encode homologs of pp71, but there is currently no published information that addresses their effects on gene expression and modes of action. Results: The UL82 homolog encoded by simian cytomegalovirus (SCMV), strain Colburn, was identified and cloned. This ORF, named S82, was cloned into an HSV-1 vector, as were those from baboon, rhesus monkey and chimpanzee cytomegaloviruses. The use of an HSV-1 vector enabled expression of the UL82 homologs in a range of cell types, and permitted investigation of their abilities to direct prolonged gene expression from quiescent genomes. The results show that all UL82 homologs activate gene expression, and that neither host cell type nor promoter target sequence has major effects on these activities. Surprisingly, the UL82 proteins specified by non-human primate cytomegaloviruses, unlike pp71, did not direct long term expression from quiescent HSV-1 genomes. In addition, significant differences were observed in the intranuclear localization of the UL82 homologs, and in their effects on Daxx. Strikingly, S82 mediated the release of Daxx from nuclear domain 10 substructures much more rapidly than pp71 or the other proteins tested. All UL82 homologs stimulated the early release of ATRX from nuclear domain 10. Conclusion: All of the UL82 homolog proteins analysed activated gene expression, but surprising differences in other aspects of their properties were revealed. The results provide new information on early events in infection with cytomegaloviruse

A Great Escape : resource availability and density-dependence shape population dynamics along trailing range edges

This research was funded by the Northeast Climate Adaptation Science Center, which is managed by the USGS National Climate Adaptation Science Center. Additional funding was provided by 1) a CFDA grant (15.678) administered by the USFWS via a Cooperative Agreement Award (no. F16AC00435) to the University of Massachusetts (UMass); 2) a Challenge Cost Share Agreement (no. 14-CS-11092200-019) between the USFS and NHFG; 3) a Dissertation Fieldwork Grant awarded to APKS by the UMass Graduate School, 4) generous support from backers of an Experiment award to APKS and MZ (DOI: 10.18258/10737) and 5) a National Science Foundation grant DEB-1907022 to LSM.Populations along geographical range limits are often exposed to unsuitable climate and low resource availability relative to core populations. As such, there has been a renewed focus on understanding the factors that determine range limits to better predict how species will respond to global change. Using recent theory on range limits and classical understanding of density dependence, we evaluated the influence of resource availability on the snowshoe hare Lepus americanus along its trailing range edge. We estimated variation in population density, habitat use, survival, and parasite loads to test the Great Escape Hypothesis (GEH), i.e. that density dependence determines, in part, a species' persistence along trailing edges. We found that variability in resource availability affected density and population fluctuations and led to trade-offs in survival for snowshoe hare populations in the northeastern USA. Hares living in resource-limited environments had lower and less variable population density, yet higher survival and lower parasitism compared to populations living in resource-rich environments. We suggest that density-dependent dynamics, elicited by resource availability, provide hares a unique survival advantage and partly explain persistence along their trailing edge. We hypothesize that this low-density escape from predation and parasitism occurs for other prey species along trailing edges, but the extent to which it occurs is likely conditional on the quality of matrix habitat. Our work indicates that biotic factors play an important role in shaping species' trailing edges and more detailed examination of non-climatic factors is warranted to better inform conservation and management decisions.Publisher PDFPeer reviewe

Emergence of Undetectable Malaria Parasites: A Threat under the Radar amid the COVID-19 Pandemic?

Rapid diagnostic tests (RDTs) play a critical role in malaria diagnosis and control. The emergence of Plasmodium falciparum parasites that can evade detection by RDTs threatens control and elimination efforts. These parasites lack or have altered genes encoding histidine-rich proteins (HRPs) 2 and 3, the antigens recognized by HRP2-based RDTs. Surveillance of such parasites is dependent on identifying false-negative RDT results among suspected malaria cases, a task made more challenging during the current pandemic because of the overlap of symptoms between malaria and COVID-19, particularly in areas of low malaria transmission. Here, we share our perspective on the emergence of P. falciparum parasites lacking HRP2 and HRP3, and the surveillance needed to identify them amid the COVID-19 pandemic

Autoimmune Chronic Active Hepatitis (Lupoid Hepatitis) and Primary Sclerosing Cholangitis in Two Young Adult Females

Autoimmune chronic active hepatitis (CAH) and primary sclerosing cholangitis (PSC) arc chronic diseases of the hepatobiliary system that have many clinical, immunologic and genetic features in common. Despite these similarities, there are few reports of the two diseases coexisting. Two young women with clinical, biochemical, serologic, radiologic and histologic findings compatible with both autoimmune CAH and PSC are described. The observation that there may be a striking overlap in the features of these two diseases and recent improvements in diagnostic imaging of the biliary tract suggest that the association of these two diseases in the same individual may be more common than is presently appreciated