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1.  Niche construction and Dreaming logic: aboriginal patch mosaic burning and varanid lizards (Varanus gouldii) in Australia 
Anthropogenic fire is a form of ecosystem engineering that creates greater landscape patchiness at small spatial scales: such rescaling of patch diversity through mosaic burning has been argued to be a form of niche construction, the loss of which may have precipitated the decline and extinction of many endemic species in the Western Desert of Australia. We find evidence to support this hypothesis relative to one keystone species, the sand monitor lizard (Varanus gouldii). Paradoxically, V. gouldii populations are higher where Aboriginal hunting is most intense. This effect is driven by an increase in V. gouldii densities near successional edges, which is higher in landscapes that experience extensive human burning. Over time, the positive effects of patch mosaic burning while hunting overwhelm the negative effects of predation in recently burned areas to produce overall positive impacts on lizard populations. These results offer critical insights into the maintenance of animal communities in the desert, supporting the hypothesis that the current high rate of endemic species decline among small animals may be linked to the interaction between invasive species and mid-century removal of Aboriginal niche construction through hunting and patch mosaic burning.
doi:10.1098/rspb.2013.2297
PMCID: PMC3813344  PMID: 24266036
anthropogenic fire; ecosystem engineering; hunter–gatherers; trophic interactions; facilitation; coevolution
2.  To kill a kangaroo: understanding the decision to pursue high-risk/high-gain resources 
In this paper, we attempt to understand hunter–gatherer foraging decisions about prey that vary in both the mean and variance of energy return using an expected utility framework. We show that for skewed distributions of energetic returns, the standard linear variance discounting (LVD) model for risk-sensitive foraging can produce quite misleading results. In addition to creating difficulties for the LVD model, the skewed distributions characteristic of hunting returns create challenges for estimating probability distribution functions required for expected utility. We present a solution using a two-component finite mixture model for foraging returns. We then use detailed foraging returns data based on focal follows of individual hunters in Western Australia hunting for high-risk/high-gain (hill kangaroo) and relatively low-risk/low-gain (sand monitor) prey. Using probability densities for the two resources estimated from the mixture models, combined with theoretically sensible utility curves characterized by diminishing marginal utility for the highest returns, we find that the expected utility of the sand monitors greatly exceeds that of kangaroos despite the fact that the mean energy return for kangaroos is nearly twice as large as that for sand monitors. We conclude that the decision to hunt hill kangaroos does not arise simply as part of an energetic utility-maximization strategy and that additional social, political or symbolic benefits must accrue to hunters of this highly variable prey.
doi:10.1098/rspb.2013.1210
PMCID: PMC3735252  PMID: 23884091
behavioural ecology; foraging theory; risk; statistical methods; hunter–gatherers
4.  Provisioning offspring and others: risk–energy trade-offs and gender differences in hunter–gatherer foraging strategies 
Offspring provisioning is commonly referenced as the most important influence on men's and women's foraging decisions. However, the provisioning of other adults may be equally important in determining gender differences in resource choice, particularly when the goals of provisioning offspring versus others cannot be met with the acquisition of the same resources. Here, we examine how resources vary in their expected daily energetic returns and in the variance or risk around those returns. We predict that when available resources impose no trade-off between risk and energy, the targets of men's and women's foraging will converge on high-energy, low-risk resources that allow for the simultaneous provisioning of offspring and others. However, when minimizing risk and maximizing energy trade-off with one another, we expect men's foraging to focus on provisioning others through the unreliable acquisition of large harvests, while women focus on reliably acquiring smaller harvests to feed offspring. We test these predictions with foraging data from three populations (Aché, Martu and Meriam). The results uphold the predictions, suggesting that men's and women's foraging interests converge when high-energy resources can be reliably acquired, but diverge when higher-energy resources are associated with higher levels of risk. Social factors, particularly the availability of alloparental support, may also play a major role.
doi:10.1098/rspb.2010.2403
PMCID: PMC3125624  PMID: 21227967
gender division of labour; central place provisioning; risk; variance; human behavioural ecology; hunter–gatherers
5.  The major human and mouse granzymes are structurally and functionally divergent 
The Journal of Cell Biology  2006;175(4):619-630.
Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural killer cells and CD8+ T cells. There are 5 granzyme genes in humans and 10 in mice, and it is suggested that granzymes evolve to meet species-specific immune challenge through gene duplication and more subtle alterations to substrate specificity. We show that mouse and human granzyme B have distinct structural and functional characteristics. Specifically, mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. We also show that mouse granzyme A is considerably more cytotoxic than human granzyme A. These results demonstrate that even “orthologous” granzymes have species-specific functions, having evolved in distinct environments that pose different challenges.
doi:10.1083/jcb.200606073
PMCID: PMC2064598  PMID: 17116752
6.  Cationic Sites on Granzyme B Contribute to Cytotoxicity by Promoting Its Uptake into Target Cells 
Molecular and Cellular Biology  2005;25(17):7854-7867.
Granzyme B (GrB) is a key effector of cytotoxic lymphocyte-mediated cell death. It is delivered to target cells bound to the proteoglycan serglycin, but how it crosses the plasma membrane and accesses substrates in the cytoplasm is poorly understood. Here we identify two cationic sequences on GrB that facilitate its binding and uptake. Mutation of cationic sequence 1 (cs1) prevents accumulation of GrB in a distinctive intracellular compartment and reduces cytotoxicity 20-fold. Mutation of cs2 reduces accumulation in this intracellular compartment and cytotoxicity two- to threefold. We also show that GrB-mediated cytotoxicity is abrogated by heparin and that target cells deficient in cell surface sulfate or glycosaminoglycans resist GrB. However, heparin does not completely prevent GrB internalization and chondroitin 4-sulfate does not inhibit cytotoxicity, suggesting that glycosaminoglycans are not essential GrB receptors. We propose that GrB enters cells by nonselective adsorptive pinocytosis, exchanging from chondroitin sulfate on serglycin to anionic components of the cell surface. In this electrostatic “exchange-adsorption” model, cs1 and cs2 participate in binding of GrB to the cell surface, thereby promoting its uptake and eventual release into the cytoplasm.
doi:10.1128/MCB.25.17.7854-7867.2005
PMCID: PMC1190293  PMID: 16107729
7.  Targeted Disruption of SPI3/Serpinb6 Does Not Result in Developmental or Growth Defects, Leukocyte Dysfunction, or Susceptibility to Stroke 
Molecular and Cellular Biology  2004;24(9):4075-4082.
Protease inhibitor 6 (PI-6/SERPINB6) is a widely expressed nucleocytoplasmic serpin. It inhibits granulocyte cathepsin G and neuronal neuropsin, and it is thought to protect cells from death caused by ectopic release or internalization of protease during stress such as infection or cerebral ischemia. To probe the biological functions of PI-6, we generated mice lacking its ortholog (SPI3/Serpinb6). SPI3-deficient mice developed normally and were fertile, and no abnormal pathology or increased sensitivity to cerebral ischemia was observed. There were no perturbations in leukocyte development or numbers, and recruitment of leukocytes to the peritoneal cavity was normal. SPI3-deficient mice were equally susceptible as wild-type mice to systemic Candida albicans infection, although there was a slight decrease in the ability of neutrophils from SPI3-deficient mice to kill C. albicans in vitro. Increased levels of a related inhibitor Serpinb1 (monocyte/neutrophil elastase inhibitor) in the tissues of targeted mice suggests that compensation by other serpins reduces the impact of SPI3 deficiency in these animals and may explain the lack of a more obvious phenotype.
doi:10.1128/MCB.24.9.4075-4082.2004
PMCID: PMC387772  PMID: 15082799
8.  Nucleocytoplasmic Distribution of the Ovalbumin Serpin PI-9 Requires a Nonconventional Nuclear Import Pathway and the Export Factor Crm1 
Molecular and Cellular Biology  2001;21(16):5396-5407.
Proteinase inhibitor 9 (PI-9) is a human serpin present in the cytoplasm of cytotoxic lymphocytes and epithelial cells. It inhibits the cytotoxic lymphocyte granule proteinase granzyme B (graB) and is thought to protect cytotoxic lymphocytes and bystander cells from graB-mediated apoptosis. Following uptake into cells, graB promotes DNA degradation, rapidly translocating to the nucleus, where it binds a nuclear component. PI-9 should therefore be found in cytotoxic lymphocyte and bystander cell nuclei to ensure complete protection against graB. Here we demonstrate by microscopy and subcellular fractionation experiments that PI-9 is present in the nuclei of human cytotoxic cells, endothelial cells, and epithelial cells. We also show that the related serpins, PI-6, monocyte neutrophil elastase inhibitor (MNEI), PI-8, plasminogen activator inhibitor 2 (PAI-2), and the viral serpin CrmA exhibit similar nucleocytoplasmic distributions. Because these serpins lack classical nuclear localization signals and are small enough to diffuse through nuclear pores, we investigated whether import occurs actively or passively. Large (∼70 kDa) chimeric proteins comprising PI-9, PI-6, PI-8, MNEI, or PAI-2 fused to green fluorescent protein (GFP) show similar nucleocytoplasmic distributions to the parent proteins, indicating that nuclear import is active. By contrast, CrmA-GFP is excluded from nuclei, indicating that CrmA is not actively imported. In vitro nuclear transport assays show that PI-9 accumulates at a rate above that of passive diffusion, that it requires cytosolic factors but not ATP, and that it does not bind an intranuclear component. Furthermore, PI-9 is exported from nuclei via a leptomycin B-sensitive pathway, implying involvement of the export factor Crm1p. We conclude that the nucleocytoplasmic distribution of PI-9 and related serpins involves a nonconventional nuclear import pathway and Crm1p.
doi:10.1128/MCB.21.16.5396-5407.2001
PMCID: PMC87262  PMID: 11463822
9.  Selective Regulation of Apoptosis: the Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated Apoptosis without Perturbing the Fas Cell Death Pathway 
Molecular and Cellular Biology  1998;18(11):6387-6398.
Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis of target cells either through Fas activation or through release of granule cytotoxins, particularly granzyme B. CLs themselves resist granule-mediated apoptosis but are eventually cleared via Fas-mediated apoptosis. Here we show that the CL cytoplasmic serpin proteinase inhibitor 9 (PI-9) can protect transfected cells against apoptosis induced by either purified granzyme B and perforin or intact CLs. A PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the P1(Asp) mutant is an effective caspase inhibitor that protects against Fas-mediated apoptosis. We propose that PI-9 shields CLs specifically against misdirected granzyme B to prevent autolysis or fratricide, but it does not interfere with homeostatic deletion via Fas-mediated apoptosis.
PMCID: PMC109224  PMID: 9774654
10.  Morphology, Oviposition, and Embryogenesis in an Australian Population of Acrobeloides nanus 
Journal of Nematology  1993;25(4):607-615.
A population of Acrobeloides nanus in Australia is described and illustrated, based on light and scanning electron microscopy. Embryogenesis from egg laying to hatching is followed over a wide range of temperatures. At 15 C, hatching occurs in about 125 hours and at 35 and 37.5 C after about 40 hours. At 40 C, egg development ceases early in cleavage. The capacity of A. nanus to develop over such a range of temperatures, and its anhydrobiotic capabilities, are discussed in relation to its survival and wide distribution in Australia.
PMCID: PMC2619437  PMID: 19279817
Acrobeloides nanus; Cephalobidae; description; egg laying; embryogenesis; hatching; light microscopy; morphology; nematode; oviposition; scanning electron microscopy
11.  Maspin is not required for embryonic development or tumour suppression 
Nature Communications  2014;5:3164.
Maspin (SERPINB5) is accepted as an important tumour suppressor lost in many cancers. Consistent with a critical role in development or differentiation maspin knockout mice die during early embryogenesis, yet clinical data conflict on the prognostic utility of maspin expression. Here to reconcile these findings we made conditional knockout mice. Surprisingly, maspin knockout embryos develop into overtly normal animals. Contrary to original reports, maspin re-expression does not inhibit tumour growth or metastasis in vivo, or influence cell migration, invasion or survival in vitro. Bioinformatic analyses reveal that maspin is not commonly under-expressed in cancer, and that perturbation of genes near maspin may in fact explain poor survival in certain patient cohorts with low maspin expression.
A role for the serpin maspin has been described in both development and cancer. In this study, the authors demonstrate that maspin knockout mice develop normally and that maspin does not function as a tumour suppressor, suggesting that another gene at the maspin locus may be responsible for this activity.
doi:10.1038/ncomms4164
PMCID: PMC3905777  PMID: 24445777
12.  Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress 
Journal of Medicinal Chemistry  2014;57(15):6275-6288.
Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent the lion’s share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biological contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chemical interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such solution, conferring α-helical structure, protease resistance, cellular penetrance, and biological activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.
doi:10.1021/jm4011675
PMCID: PMC4136684  PMID: 24601557
13.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
Importance
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
Objectives
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Results
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
doi:10.1001/jamaneurol.2014.1491
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
14.  Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus 
Palles, Claire | Chegwidden, Laura | Li, Xinzhong | Findlay, John M. | Farnham, Garry | Castro Giner, Francesc | Peppelenbosch, Maikel P. | Kovac, Michal | Adams, Claire L. | Prenen, Hans | Briggs, Sarah | Harrison, Rebecca | Sanders, Scott | MacDonald, David | Haigh, Chris | Tucker, Art | Love, Sharon | Nanji, Manoj | deCaestecker, John | Ferry, David | Rathbone, Barrie | Hapeshi, Julie | Barr, Hugh | Moayyedi, Paul | Watson, Peter | Zietek, Barbara | Maroo, Neera | Gay, Laura | Underwood, Tim | Boulter, Lisa | McMurtry, Hugh | Monk, David | Patel, Praful | Ragunath, Krish | Al Dulaimi, David | Murray, Iain | Koss, Konrad | Veitch, Andrew | Trudgill, Nigel | Nwokolo, Chuka | Rembacken, Bjorn | Atherfold, Paul | Green, Elaine | Ang, Yeng | Kuipers, Ernst J. | Chow, Wu | Paterson, Stuart | Kadri, Sudarshan | Beales, Ian | Grimley, Charles | Mullins, Paul | Beckett, Conrad | Farrant, Mark | Dixon, Andrew | Kelly, Sean | Johnson, Matthew | Wajed, Shahjehan | Dhar, Anjan | Sawyer, Elinor | Roylance, Rebecca | Onstad, Lynn | Gammon, Marilie D. | Corley, Douglas A. | Shaheen, Nicholas J. | Bird, Nigel C. | Hardie, Laura J. | Reid, Brian J. | Ye, Weimin | Liu, Geoffrey | Romero, Yvonne | Bernstein, Leslie | Wu, Anna H. | Casson, Alan G. | Fitzgerald, Rebecca | Whiteman, David C. | Risch, Harvey A. | Levine, David M. | Vaughan, Tom L. | Verhaar, Auke P. | van den Brande, Jan | Toxopeus, Eelke L. | Spaander, Manon C. | Wijnhoven, Bas P.L. | van der Laan, Luc J.W. | Krishnadath, Kausilia | Wijmenga, Cisca | Trynka, Gosia | McManus, Ross | Reynolds, John V. | O’Sullivan, Jacintha | MacMathuna, Padraic | McGarrigle, Sarah A. | Kelleher, Dermot | Vermeire, Severine | Cleynen, Isabelle | Bisschops, Raf | Tomlinson, Ian | Jankowski, Janusz
Gastroenterology  2015;148(2):367-378.
Background & Aims
Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.
Methods
We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.
Results
We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).
Conclusions
We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.
doi:10.1053/j.gastro.2014.10.041
PMCID: PMC4315134  PMID: 25447851
EAC; Intestinal Metaplasia; Susceptibility; Cancer; ASE, allele-specific expression; BE, Barrett’s esophagus; BEACON, Barrett's and Esophageal Adenocarcinoma Consortium; CI, confidence interval; EAC, esophageal adenocarcinoma; eQTL, expression quantitative trait locus; GWAS, genome-wide association study; LD, linkage disequilibrium; OR, odds ratio; PC, principal component; SNP, single nucleotide polymorphism; TCGA, The Cancer Genome Atlas
15.  Community-academic partnerships in HIV-related research: a systematic literature review of theory and practice 
Introduction
Community involvement in HIV research has increased over recent years, enhancing community-academic partnerships. Several terms have been used to describe community participation in research. Clarification is needed to determine whether these terms are synonymous or actually describe different research processes. In addition, it remains unclear if the role that communities play in the actual research process follows the recommendations given in theoretical frameworks of community-academia research.
Objectives
The objective of this study is to review the existing terms and definitions regarding community-academic partnerships and assess how studies are implementing these in relation to conceptual definitions.
Methods
A systematic literature review was conducted in PubMed. Two reviewers independently assessed each article, applying the following inclusion criteria: the article must be published in English before 2013; it must provide an explicit definition and/or defining methodology for a term describing research with a community component; and it has to refer to HIV or AIDS, reproductive health and/or STDs. When disagreements about the relevance of an article emerged, a third reviewer was involved until concordance was reached. Data were extracted by one reviewer and independently verified by a second. Qualitative data were analyzed using MaxQDA for content and thematic analyses while quantitative data were analyzed using descriptive statistics. Community feedback on data analysis and presentation of results was also incorporated.
Results
In total, 246 articles were retrieved, 159 of which fulfilled the inclusion criteria. The number of studies that included community participation in the field of HIV research increased between 1991 and 2012, and the terms used to describe these activities have changed, moving away from action research (AR) to participatory action research (PAR), community-based research (CBR) and community-based participatory research (CBPR), with the latter being the most commonly used term. While definitions of all terms had common characteristics (e.g. participation of community in research process), they varied with regard to the emphasis placed on these characteristics. The nature of community participation in reviewed studies differed considerably from that described in theoretical models.
Conclusions
This study indicates the increase of participatory approaches in HIV research and underlines the need for clarification of terms and a framework providing orientation to community-academia partnerships.
doi:10.7448/IAS.18.1.19354
PMCID: PMC4309828  PMID: 25630823
HIV; action research; participatory action research; community-based research; community-based participatory research; community involvement; literature review
16.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
Objective:
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
Methods:
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
Results:
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Conclusions:
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
doi:10.1212/WNL.0000000000000596
PMCID: PMC4117367  PMID: 24928124
17.  Single-Dose Replication-Defective VSV-based Nipah Virus Vaccines Provide Protection from Lethal Challenge in Syrian Hamsters 
Antiviral research  2013;101:10.1016/j.antiviral.2013.10.012.
Nipah virus (NiV) continues to cause outbreaks of fatal human encephalitis due to spillover from its bat reservoir. We determined that a single dose of replication-defective vesicular stomatitis virus (VSV)-based vaccine vectors expressing either the NiV fusion (F) or attachment (G) glycoproteins protected hamsters from over 1000 times LD50 NiV challenge. This highly effective single-dose protection coupled with an enhanced safety profile makes these candidates ideal for potential use in livestock and humans.
doi:10.1016/j.antiviral.2013.10.012
PMCID: PMC3874889  PMID: 24184127
Henipavirus; Nipah; vaccine; VSV; single-dose; hamster; glycoproteins
18.  Adipose inflammation and macrophage infiltration after binge ethanol and burn injury 
BACKGROUND
Ethanol exposure prior to traumatic injury, such as a burn, elevates systemic and local inflammatory responses and increases morbidity and mortality. Adipose is a large tissue mass that is often inflamed during obesity or other stresses which disturbs metabolic homeostasis. To date, there has been little investigation into the inflammatory response of adipose tissue after combined ethanol exposure and burn injury.
METHODS
Two ethanol exposure regimens were utilized to examine the role of inflammation in adipose tissue after ethanol and burn injury. Mice were either given a single or episodic binge exposure to ethanol or saline followed by scald (burn) or sham injury 30 minutes later. Twenty-four hours post injury, serum and adipose tissue were collected for assessment of inflammatory mediators.
RESULTS
Single binge ethanol alone induced no inflammation in adipose when compared with sham vehicle treated mice. However, single binge ethanol followed by burn injury induced significant elevations in mRNA and protein concentrations of pro-inflammatory mediators interleukin-6 (IL-6), KC, and monocyte chemoattractant protein 1 (MCP-1) compared to either insult alone or sham vehicle group. Additionally, ethanol exposure and burn injury significantly blunted inducible nitric oxide synthase (iNOS), indicating a complex inflammatory response. Episodic binge ethanol exposure followed by burn injury exacerbated the post-burn adipose inflammatory response. The magnitude of the episodic binge-induced inflammatory parameters post-burn were 2- to 5- fold greater than the response detected after a single exposure of ethanol, indicating ethanol-induced potentiation of burn-induced inflammatory response. Finally, inflammatory loci and crown-like structures in adipose were significantly increased by episodic binge ethanol and burn injury.
CONCLUSIONS
This is the first report of binge and burn-induced crown-like structure formation. Evidence presented herein suggests an important role for alcohol and burn as an additional mediator of adipose inflammation in post-burn injury, a common complication in burn patients.
doi:10.1111/acer.12210
PMCID: PMC3823749  PMID: 23909743
alcohol; crown-like structure; trauma; cytokine; chemokine
19.  The marginal valuation of fertility 
Substantial theoretical and empirical evidence demonstrates that fertility entails economic, physiological, and demographic trade-offs. The existence of trade-offs suggests that fitness should be maximized by an intermediate level of fertility, but this hypothesis has not had much support in the human life-history literature. We suggest that the difficulty of finding intermediate optima may be a function of the way fitness is calculated. Evolutionary analyses of human behavior typically use lifetime reproductive success as their fitness criterion. This fitness measure implicitly assumes that women are indifferent to the timing of reproduction and that they are risk-neutral in their reproductive decision-making. In this paper, we offer an alternative, easily-calculated fitness measure that accounts for differences in reproductive timing and yields clear preferences in the face of risky reproductive decision-making. Using historical demographic data from a genealogically-detailed dataset from 19th century Utah, we show that this measure is highly concave with respect to reproductive effort. This result has three major implications: (1) if births are properly timed, a lower-fertility reproductive strategy can have the same fitness as a high-fertility strategy, (2) intermediate optima are far more likely using fitness measures that are strongly concave with respect to effort, (3) we expect mothers to have strong investment preferences with respect to the risk inherent in reproduction.
doi:10.1016/j.evolhumbehav.2013.10.002
PMCID: PMC4000044  PMID: 24778546
Demography; Life history theory; Human evolution; Fertility; Utah; Reproductive effort
20.  The Impact of Diet and Lifestyle on Gut Microbiota and Human Health 
Nutrients  2014;7(1):17-44.
There is growing recognition of the role of diet and other environmental factors in modulating the composition and metabolic activity of the human gut microbiota, which in turn can impact health. This narrative review explores the relevant contemporary scientific literature to provide a general perspective of this broad area. Molecular technologies have greatly advanced our understanding of the complexity and diversity of the gut microbial communities within and between individuals. Diet, particularly macronutrients, has a major role in shaping the composition and activity of these complex populations. Despite the body of knowledge that exists on the effects of carbohydrates there are still many unanswered questions. The impacts of dietary fats and protein on the gut microbiota are less well defined. Both short- and long-term dietary change can influence the microbial profiles, and infant nutrition may have life-long consequences through microbial modulation of the immune system. The impact of environmental factors, including aspects of lifestyle, on the microbiota is particularly poorly understood but some of these factors are described. We also discuss the use and potential benefits of prebiotics and probiotics to modify microbial populations. A description of some areas that should be addressed in future research is also presented.
doi:10.3390/nu7010017
PMCID: PMC4303825  PMID: 25545101
diet; lifestyle; gut; microbiota; health
21.  Assessment of Genetic Diversity of Sweet Potato in Puerto Rico 
PLoS ONE  2014;9(12):e116184.
Sweet potato (Ipomoea batatas L.) is the seventh most important food crop due to its distinct advantages, such as adaptability to different environmental conditions and high nutritional value. Assessing the genetic diversity of this important crop is necessary due to the constant increase of demand for food and the need for conservation of agricultural and genetic resources. In Puerto Rico (PR), the genetic diversity of sweet potato has been poorly understood, although it has been part of the diet since Pre-Columbus time. Thus, 137 landraces from different localities around PR were collected and subjected to a genetic diversity analysis using 23 SSR-markers. In addition, 8 accessions from a collection grown in Gurabo, PR at the Agricultural Experimental Station (GAES), 10 US commercial cultivars and 12 Puerto Rican accessions from the USDA repository collection were included in this assessment. The results of the analysis of the 23 loci showed 255 alleles in the 167 samples. Observed heterozygosity was high across populations (0.71) while measurements of total heterozygosity revealed a large genetic diversity throughout the population and within populations. UPGMA clustering method revealed two main clusters. Cluster 1 contained 12 PR accessions from the USDA repository collection, while cluster 2 consisted of PR landraces, US commercial cultivars and the PR accessions from GAES. Population structure analysis grouped PR landraces in five groups including four US commercial cultivars. Our study shows the presence of a high level of genetic diversity of sweet potato across PR which can be related to the genetic makeup of sweet potato, human intervention and out-crossing nature of the plant. The history of domestication and dispersal of sweet potato in the Caribbean and the high levels of genetic diversity found through this study makes sweet potato an invaluable resource that needs to be protected and further studied.
doi:10.1371/journal.pone.0116184
PMCID: PMC4281141  PMID: 25551388
22.  Interactions between RNA polymerase and the “core recognition element” counteract pausing 
Science (New York, N.Y.)  2014;344(6189):1285-1289.
Transcription elongation is interrupted by sequences that inhibit nucleotide addition and cause RNA polymerase (RNAP) to pause. Here, by use of native-elongating-transcript sequencing (NET-seq) and a variant of NET-seq that enables analysis of mutant RNAP derivatives in merodiploid cells (mNET-seq), we analyze transcriptional pausing genome-wide in vivo in Escherichia coli. We identify a consensus pause-inducing sequence element, G−10Y−1G+1 (where −1 corresponds to the position of the RNA 3′ end). We demonstrate that sequence-specific interactions between RNA polymerase core enzyme and a core recognition element (CRE) that stabilize transcription initiation complexes also occur in transcription elongation complexes and facilitate pause read-through by stabilizing RNAP in a post-translocated register. Our findings identify key sequence determinants of transcriptional pausing and establish that RNAP-CRE interactions modulate pausing.
doi:10.1126/science.1253458
PMCID: PMC4277259  PMID: 24926020
23.  Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival 
Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s–30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14 + 2 T > G and 5825C > T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343–345 and 1398 T > G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.
doi:10.1016/j.jns.2013.09.014
PMCID: PMC4017341  PMID: 24090759
24.  Socially Responsible Science Is More than “Good Science” 
The role of scientist carries an array of responsibilities. The most obvious is accurate and reliable research that can be depended upon by fellow researchers. Scientists also have a responsibility to oppose misuse or abuse in the application of research findings, and to attend to both the limitations and the foreseeable impacts of their work. In addition, as members of society, scientists have a responsibility to participate in discussions and decisions regarding the appropriate use of science in addressing societal issues and concerns, and to bring their specialized knowledge and expertise to activities and discussions that promote the education of students and fellow citizens, thereby enhancing and facilitating informed decision making and democracy.
doi:10.1128/jmbe.v15i2.870
PMCID: PMC4278471  PMID: 25574272
25.  A Natural Genetic Variant of Granzyme B Confers Lethality to a Common Viral Infection 
PLoS Pathogens  2014;10(12):e1004526.
Many immune response genes are highly polymorphic, consistent with the selective pressure imposed by pathogens over evolutionary time, and the need to balance infection control with the risk of auto-immunity. Epidemiological and genomic studies have identified many genetic variants that confer susceptibility or resistance to pathogenic micro-organisms. While extensive polymorphism has been reported for the granzyme B (GzmB) gene, its relevance to pathogen immunity is unexplored. Here, we describe the biochemical and cytotoxic functions of a common allele of GzmB (GzmBW) common in wild mouse. While retaining ‘Asp-ase’ activity, GzmBW has substrate preferences that differ considerably from GzmBP, which is common to all inbred strains. In vitro, GzmBW preferentially cleaves recombinant Bid, whereas GzmBP activates pro-caspases directly. Recombinant GzmBW and GzmBP induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmBW were unable to control murine cytomegalovirus (MCMV) infection, and succumbed as a result of excessive liver damage. Although similar numbers of anti-viral CD8 T cells were generated in both mouse strains, GzmBW-expressing CD8 T cells isolated from infected mice were unable to kill MCMV-infected targets in vitro. Our results suggest that known virally-encoded inhibitors of the intrinsic (mitochondrial) apoptotic pathway account for the increased susceptibility of GzmBW mice to MCMV. We conclude that different natural variants of GzmB have a profound impact on the immune response to a common and authentic viral pathogen.
Author Summary
Granzymes (Gzm) are serine proteases expressed by cytotoxic T cells and natural killer cells, and are important for the destruction of virally infected cells. To date, the function of these molecules has been assessed exclusively in common laboratory mouse strains that express identical granzyme proteins. In wild mouse populations, variants of granzyme B have been identified, but how these function, especially in the context of infections, is unknown. We have generated a novel mouse strain expressing a granzyme B variant found in wild mice (GzmBW), and exposed these mice to viral infections. The substrates cleaved by GzmBW were found to differ significantly from those cleaved by the GzmBP protein, which is normally expressed by laboratory mice. Alterations in substrate specificity resulted in GzmBW mice being significantly more susceptible to infection with murine cytomegalovirus, a common mouse pathogen. Our findings demonstrate that polymorphisms in granzyme B can profoundly affect the outcome of infections with some viral pathogens.
doi:10.1371/journal.ppat.1004526
PMCID: PMC4263754  PMID: 25502180

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