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Supplemental Movie 2: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an LS174T colorectal carcinoma tumour xenograft.

Additional data describing the reproducibility of convectionMRI data, and a figure showing the convectionMRI acquisition sequence.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.

Supplemental Movie 4: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an SW1222 colorectal carcinoma tumour xenograft.

Supplemental Movie 1: Schematic movie illustrating the physical principles underpinning the convection-MRI sequence

Supplemental Movie 5: Interstitial convection, measured using EVAC-MRI and animated using a particle simulation (left), compared with MRI signal enhancement with time, following injection with a contrast agent (Gd-DTPA), in an LS174T tumour.

High-resolution copy of Figure 6b. Fluid flow measured in vivo with convectionMRI is shown as grey streamlines and perfusion is shown as a colorscale. The location of blood vessels is represented by yellow volume renderings, acquired using ex vivo microvascular casting and imaged with micro-CT.

Supplemental Movie 3: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an LS174T colorectal carcinoma tumour xenograft.

This article collates and synthesizes the discussion results of a collaborative research exercise, known as a ‘co-creation session’, formed of a multi-disciplinary group of extended reality (XR) researchers and practitioners. The session sought to develop and theorize the concept of ‘transformative technologies for good’ in creative, applied and clinical contexts. Notions of ‘cutting-edge’ practice were visited from a critical standpoint; participants established that innovation, when measured in terms of social good, challenges technological and economic paradigms of progress. Conversation between participants centred on four key areas: skills and knowledge for effective XR research, appropriate methods and sites for diffusion of XR research, the future of the field, and the possible contributions of XR and associated research to problems arising from COVID-19. The session offered further insights into research design related to composition of participant groups in terms of disciplinary knowledge, activity design, and remote digital interfaces.

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered baboon hybrid zone in the Kafue River Valley of Zambia, where Kinda baboons (Papio kindae) and grey-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compared ancestry patterns from this genome-wide data set to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signalling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results elucidate the dynamics of introgressive hybridization in a primate system while identifying genes and pathways possibly under selection.

Purpose The purpose of this paper is to demonstrate the possibility for the galleries, libraries, archives and museums sector to employ playful, immersive discovery interfaces for their collections and raise awareness of some of the considerations that go into the decision to use such technology and the creation of the interfaces. Design/methodology/approach This is a case study approach using the methodology of research through design. The paper introduces two examples of immersive interfaces to archival data created by the authors, using these as a springboard for discussing the different kinds of embodied experiences that users have with different kinds of immersion, for example, the exploration of the archive on a flat screen, a data “cave” or arena, or virtual reality. Findings The role of such interfaces in communicating with the audience of an archive is considered, for example, in allowing users to detect structure in data, particularly in understanding the role of geographic or other spatial elements in a collection, and in shifting the locus of knowledge production from individual to community. It is argued that these different experiences draw on different metaphors in terms of users’ prior experience with more well-known technologies, for example, “a performance” vs “a tool” vs “a background to a conversation”. Originality/value The two example interfaces discussed here are original creations by the authors of this paper. They are the first uses of mixed reality for interfacing with the archives in question. One is the first mixed reality interface to an audio archive. The discussion has implications for the future of interfaces to galleries, archives, libraries and museums more generally.

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

This article explores a way of thinking about virtual environments and how they might be used to create new spaces, not as an alternate reality, but as an integrated part of reality ‐ regardless of this reality being physical and/or digital. Virtual environments can be seen as an extension of reality ‐ the physical and the virtual sitting side by side with one, more often than not, bleeding into the other. The virtual is not separable from the physical and vice versa. This position will be formed by directly referring to traditions that stem from processes and ideas around materiality, poetics and philosophy rather than centring on technical or hardware specifics. At the centre of this exploration is an ongoing investigation into the role of memory and imagination in narrative spaces in immersive virtual environments, stemming from the author’s background in interactive Installation art and designing for virtual environments. The article’s subtitle refers to Robert Morris’s 1978 article, ‘The present tense of space’, which informs the article’s overall position.

© 2019 Copyright held by the owner/author(s). In this demo we showcase Layered Horizons, a Virtual Reality (VR) experience we have developed for use in an ARC-funded research project, Waves of Words: Mapping and Modelling Australia's Pacific Past. This platform allows users to connect different geospatial datasets (for our purposes, from the humanities and social sciences) into layers that can then be explored by the use of natural gesture and body movement. This kind of interaction design in VR takes full advantage of the media's affordances, without relying on metaphors from other interactive media, yet being familiar enough as to engender intuitive and meaningful use. We demonstrate how the platform is currently being used to connect linguistic data (word lists) with archaeological data (e.g. on the spread of bananas through the Asia-Pacific region, or canoe styles found in different locations) and anthropological data (e.g. shared cultural features like chieftainship systems or kinship systems). Taking into account what we also know about Pacific navigation and simulated canoe travel, we can therefore build a complex layered map of the region over time that allows us to better discover probable human migration and contact patterns.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers. Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.

In foregut-fermenting mammals (e.g., colobine monkeys, artiodactyl ruminants) the enzymes pancreatic ribonuclease (RNASE1) and lysozyme C (LYZ), originally involved in immune defense, have evolved new digestive functions. Howler monkeys are folivorous non-colobine primates that lack the multi-chambered stomachs of colobines and instead digest leaves using fermentation in the caeco-colic region. We present data on the RNASE1 and LYZ genes of four species of howler monkey (Alouatta spp.). We find that howler monkey LYZ is conserved and does not share the substitutions found in colobine and cow sequences, whereas RNASE1 was duplicated in the common ancestor of A. palliata, A. seniculus, A. sara, and A. pigra. While the parent gene (RNASE1) is conserved, the daughter gene (RNASE1B) has multiple amino acid substitutions that are parallel to those found in RNASE1B genes of colobines. The duplicated RNase in Alouatta has biochemical changes similar to those in colobines, suggesting a novel, possibly digestive function. These findings suggest that pancreatic ribonuclease has, in parallel, evolved a new role for digesting the products of microbial fermentation in both foregut- and hindgut-fermenting folivorous primates. This may be a vital digestive enzyme adaptation allowing howler monkeys to survive on leaves during periods of low fruit availability.

© 2019 IEEE. Glossopticon is a Virtual Reality (VR)-based information visualisation system that presents heritage audio recordings in the archival linguistic data of the Pacific and Regional Archive for Digital Sources in Endangered Cultures (PARADISEC) collection. This paper will outline the project, the way it has used VR to visualise information and how it has been used on multiple levels-from public exhibition piece, to research tool-and in doing so provides an exemplar of the notion of the collaborative, interdisciplinary project as a basic unit of scholarly investigation within the digital humanities.

Kinda and gray-footed chacma baboons occupy opposite extremes of the body size distribution in extant baboons (genusPapio). In order to detect signatures of natural selection in these two species, we genotyped 24,790 genome-wide autosomal SNPs from populations of Zambian baboons using double digest RADseq. We scanned the genome for evidence of selection by identifying regions with extreme differentiation between populations. We find evidence of selection on body size influencing multiple genes in one or both species, includingFGF1, ATXN2, andPRKCE. We also find an enriched signal of selection associated with biological processes involved in multicellular organism growth and development, cell proliferation and cell growth, nutrient metabolism, and chondrocyte differentiation. Finally, we find that selection has impacted components of the CCKR signaling pathway, which regulates food intake and metabolism, and the JAK/STAT signaling pathway, which mediates the effect of cytokine signals on processes including epiphyseal chondrocyte proliferation essential for longitudinal bone growth. Our findings highlight promising avenues for future studies disentangling the genetic architecture of body size in primates including humans.

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered baboon hybrid zone in the Kafue River valley of Zambia, where Kinda baboons (Papio kindae) and gray-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compare ancestry patterns from this genome-wide dataset to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signaling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results elucidate the dynamics of introgressive hybridization in a primate system while highlighting genes and pathways under selection.

Recent studies suggest that closely related species can accumulate substantial genetic and phenotypic differences despite ongoing gene flow, thus challenging traditional ideas regarding the genetics of speciation. Baboons (genus Papio) are Old World monkeys consisting of six readily distinguishable species. Baboon species hybridize in the wild, and prior data imply a complex history of differentiation and introgression. We produced a reference genome assembly for the olive baboon (Papio anubis) and whole-genome sequence data for all six extant species. We document multiple episodes of admixture and introgression during the radiation of Papio baboons, thus demonstrating their value as a model of complex evolutionary divergence, hybridization, and reticulation. These results help inform our understanding of similar cases, including modern humans, Neanderthals, Denisovans, and other ancient hominins., The sequencing and analysis activities at the Human Genome Sequencing Center, Baylor College of Medicine, were supported by NIH (NHGRI) grants U54-HG003273 and U54-HG006484 to R.A.G. and GAC grant 1 S10 RR026605 to J. G. Reid. This research was also supported by NIH grant R01-GM59290 to M.A.B.; grants from the Austrian Science Fund (FWF-P24551 and FWF-W1225) and Vienna Science and Technology Fund (WWTF-MA16-061) to C.K.; grants from the Wellcome Trust (WT108749/Z/15/Z) and EMBL to B.A., F.J.M., and M.M.; grants VEGA 1/0719/14 and APVV-14-0253 to T. Vinar (Consortium Member); MINECO/FEDER grant, NIH U01-MH106874 grant, Howard Hughes International Early Career award, and Obra Social “La Caixa” award to T.M.-B.; NSF grants BNS83-03506 to J.P.-C.; NSF1029302 to J.P.-C., J.R., and C.J.J.; BNS96-15150 to J.P.-C., C.J.J., and T.D.; and National Geographic Society and Leakey Foundation grants to J.P.-C. and C.J.J. E.E.E. is an investigator of the Howard Hughes Medical Institute. This work was supported, in part, by U.S. NIH grant HG002385 to E.E.E.

Purpose To examine the effect of breast shielding on blood lymphocyte deoxyribonucleic acid (DNA) double-strand-break levels resulting from in vivo radiation and ex vivo radiation at breast-tissue level, and the effect of breast shielding on image quality. Materials and Methods The study was approved by institutional review and commpliant with HIPAA guidelines. Adult women who underwent 64-section coronary computed tomographic (CT) angiography and who provided informed consent were prospectively randomized to the use (n = 50) or absence (n = 51) of bismuth breast shields. Peripheral blood samples were obtained before and 30 minutes after in vivo radiation during CT angiography to compare DNA double-strand-break levels by γ-H2AX immunofluorescence in blood lymphocytes. To estimate DNA double-strand-break induction at breast-tissue level, a blood sample was taped to the sternum for ex vivo radiation with or without shielding. Data were analyzed by linear regression and independent sample t tests. Results Breast shielding had no effect on DNA double-strand-break levels from ex vivo radiation of blood samples under shields at breast-tissue level (unadjusted regression: β = .08; P = .43 versus no shielding), or in vivo radiation of circulating lymphocytes (β = -.07; P = .50). Predictors of increased DNA double-strand-break levels included total radiation dose, increasing tube potential, and tube current (P < .05). With current radiation exposures (median, 3.4 mSv), breast shielding yielded a 33% increase in image noise and 19% decrease in the rate of excellent quality ratings. Conclusion Among women who underwent coronary CT angiography, breast shielding had no effect on DNA double-strand-break levels in blood lymphocytes exposed to in vivo radiation, or ex vivo radiation at breast-tissue level. At present relatively low radiation exposures, breast shielding contributed to an increase in image noise and a decline in image quality. The findings support efforts to minimize radiation by primarily optimizing CT settings. (©) RSNA, 2016 Clinical trial registration no. NCT02617888 Online supplemental material is available for this article.

Landscape connectivity is increasingly emphasized due to its relevance for interpreting effects of environmental change. Yet substantial uncertainty remains regarding the quantification of connectivity and the extent to which connectivity influences biodiversity. We review and synthesize 370 articles published since 2005 on the quantification and effects of landscape connectivity on biodiversity. We find a notable change in the quantification of connectivity from structural to functional approaches, a rise in network approaches, and a decline in approaches based on metapopulation theory. Most studies (54 %) did not test for the effects of connectivity, but of those that did, 91 % found effects on biodiversity, with over five times as many positive as negative effects reported. These effects were largely consistent across levels of biological organization, despite diverse perspectives on movement and connectivity across these domains. Nevertheless, we argue that several outstanding issues need to be addressed to advance our understanding of the effects of connectivity and its importance for conservation. These issues include the need for greater emphasis on estimating connectivity effects, explicitly incorporating the problem of scale, capturing impacts of movement processes relevant to different levels of organization, proper accounting of uncertainty, and isolating connectivity effects relative to other issues influencing biodiversity.

Madagascar's lemurs, now deemed the most endangered group of mammals, represent the highest primate conservation priority in the world. Due to anthropogenic disturbances, an estimated 10% of Malagasy forest cover remains. The endangered Lemur catta is endemic to the southern regions of Madagascar and now occupies primarily fragmented forest habitats. We examined the influence of habitat fragmentation and isolation on the genetic diversity of L. catta across 3 different forest fragments in south-central Madagascar. Our analysis revealed moderate levels of genetic diversity. Genetic differentiation among the sites ranged from 0.05 to 0.11. These data suggest that the L. catta populations within south-central Madagascar have not yet lost significant genetic variation. However, due to ongoing anthropogenic threats faced by ring-tailed lemurs, continued conservation and research initiatives are imperative for long-term viability of the species.

Natural history collections have long been used by morphologists, anatomists, and taxonomists to probe the evolutionary process and describe biological diversity. These biological archives also offer great opportunities for genetic research in taxonomy, conservation, systematics, and population biology. They allow assays of past populations, including those of extinct species, giving context to present patterns of genetic variation and direct measures of evolutionary processes. Despite this potential, museum specimens are difficult to work with because natural postmortem processes and preservation methods fragment and damage DNA. These problems have restricted geneticists’ ability to use natural history collections primarily by limiting how much of the genome can be surveyed. Recent advances in DNA sequencing technology, however, have radically changed this, making truly genomic studies from museum specimens possible. We review the opportunities and drawbacks of the use of museum specimens, and suggest how to best execute projects when incorporating such samples. Several high-throughput (HT) sequencing methodologies, including whole genome shotgun sequencing, sequence capture, and restriction digests (demonstrated here), can be used with archived biomaterials.

Several distinct fluid flow phenemena occur in solid tumours, including intravascular blood flow and interstitial convection. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we have developed a novel magnetic resonance imaging (MRI) technique named convection-MRI. It uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extra-vascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations and tumor xenograft models to investigate the technical feasibility of convection-MRI. We report a good correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma and show that convection-MRI can provide insights into the growth and response to vascular-targeting therapy in colorectal cancers.

Phylogeneticcomparativemethodsplayacriticalroleinourunderstandingof the adaptive origin of primate behaviors. To incorporate evolutionary history directly into comparative behavioral research, behavioral ecologists rely on strong, well- resolved phylogenetic trees. Phylogenies provide the framework on which behaviors can be compared and homologies can be distinguished from similarities due to conver- gent or parallel evolution. Phylogenetic reconstructions are also of critical importance when inferring the ancestral state of behavioral patterns and when suggesting the evolutionary changes that behavior has undergone. Improvements in genome sequenc- ing technologies have increased the amount of data available to researchers. Recently, several primate phylogenetic studies have used multiple loci to produce robust phylo- genetic trees that include hundreds of primate species. These trees are now commonly usedincomparativeanalysesandthereisaperceptionthatwehaveacompletepictureof the primate tree. But how confident can we be in those phylogenies? And how reliable are comparative analyses based on such trees? Herein, we argue that even recent molecular phylogenies should be treated cautiously because they rely on many assump- tions and have many shortcomings. Most phylogenetic studies do not model gene tree diversity and can produce misleading results, such as strong support for an incorrect speciestree,especiallyinthecaseofrapidandrecentradiations.Wediscussimplications thatincorrectphylogeniescanhaveforreconstructingtheevolutionofprimatebehaviors

Adipose metabolism is an essential contributor to the efficiency of milk production, and metabolism is controlled by several mechanisms, including gene expression of critical proteins; therefore, the objective of this study was to determine how lactational state and the genetic merit of dairy cattle affects adipose tissue (AT) metabolism and mRNA expression of genes known to control metabolism. Animals of high (HGM) and low genetic merit (LGM) were fed to requirements, and weekly dry matter intake, milk production, blood glucose, and nonesterified fatty acids were measured. Subcutaneous AT biopsies were collected at -21, 7, 28 and 56 d in milk (DIM). The mRNA expression of genes coding for lipogenic enzymes [phosphoenolpyruvate carboxykinase 1 (soluble) (PCK1), fatty acid synthase (FASN), diacylglycerol O-acyltransferase 2 (DGAT2), and stearoyl-coenzyme A desaturase (SCD)], transcription regulators [peroxisome proliferator-activated receptor γ (PPARG), thyroid hormone responsive (THRSP), wingless-type MMTV integration site family, member 10B (WNT10B), sterol regulatory element binding transcription factor 1 (SREBF1), and adiponectin (ADIPOQ)], lipolytic enzymes [hormone-sensitive lipase (LIPE), patatin-like phospholipase domain containing 2 (PNPLA2), monoglyceride lipase (MGLL), adrenoceptor β-2 (ADRB2), adipose differentiation-related protein (ADFP), and α-β-hydrolase domain containing 5 (ABHD5)], and genes controlling the sensing of intracellular energy [phosphodiesterase 3A (PDE3A); PDE3B; protein kinase, AMP-activated, α-1 catalytic subunit (PRKAA1); PRKAA2; and growth hormone receptor (GHR)] was measured. Dry matter intake, blood glucose, and nonesterified fatty acid concentrations did not differ between genetic merit groups. Milk production was greater for HGM cows from 6 to 8 wk postpartum. As expected, the rates of lipogenesis decreased in early lactation, whereas stimulated lipolysis increased. At 7 DIM, lipogenesis in HGM cows increased as a function of substrate availability (0.5, 1, 2, 3, 4, or 8mM acetic acid), whereas the response in LGM cows was much less pronounced. However, the lipogenic response at 28 DIM reversed and rates were greater in tissue from LGM than HGM cows. Peak lipolytic response, regardless of DIM, was observed at the lowest dose of isoproterenol (10(-8)M), and -21 d tissue had a greater lipolysis rate than tissue at 7, 28, and 56 d. In HGM compared with LGM cows, stimulated lipolysis at 7 and 28 DIM was greater but peaked at 10(-7)M isoproterenol, suggesting differences in tissue responsiveness due to genetic merit. Regardless of genetic merit, the expression of lipogenic genes decreased markedly in early lactation, whereas those controlling lipolysis stayed similar or decreased slightly. Cows of HGM had lower expression of lipogenic genes after parturition and through 56 DIM. In contrast, the expression of most of the lipolytic enzymes, receptors and proteins was similar in all cows pre- and postpartum. These results confirm that gene transcription is a major control mechanism for AT lipogenesis during early lactation, but that control of lipolysis is likely primarily by posttranslational mechanisms.

Over the last two decades primatologists have benefited from the use of numerous molecular markers to study various aspects of primate behavior and evolutionary history. However, most of the studies to date have been based on a single locus, usually mitochondrial DNA, or a few nuclear markers, e.g., microsatellites. Unfortunately, the use of such markers not only is unable to address successfully important questions in primate population genetics and phylogenetics (mainly because of the discordance between gene tree and species tree), but also their development is often a time-consuming and expensive task. The advent of next-generation sequencing allows researchers to generate large amounts of genomic data for nonmodel organisms. However, whole genome sequencing is still cost prohibitive for most primate species. We here introduce a second-generation sequencing technique for genotyping thousands of genome-wide markers for nonmodel organisms. Restriction site–associated DNA sequencing (RAD-seq) reduces the complexity of the genome and allows inexpensive and fast discovery of thousands of markers in many individuals. Here, we describe the principles of this technique and we demonstrate its application in five primates, Microcebus sp., Cebus sp., Theropithecus gelada, Pan troglodytes, and Homo sapiens, representing some of the major lineages within the order. Despite technical and bioinformatic challenges, RAD-seq is a promising method for multilocus phylogenetic and population genetic studies in primates, particularly in young clades in which a high number of orthologous regions are likely to be found across populations or species.

PURPOSE: To investigate the combined use of hyperoxia-induced ?R(2) * and ?R(1) as a noninvasive imaging biomarker of tumor hypoxia. MATERIALS AND METHODS: MRI was performed on rat GH3 prolactinomas (n = 6) and human PC3 prostate xenografts (n = 6) propagated in nude mice. multiple gradient echo and inversion recovery truefisp images were acquired from identical transverse slices to quantify tumor R(2) * and R(1) before and during carbogen (95% O(2) /5% CO(2) ) challenge, and correlates of ?R(2) * and ?R(1) assessed. RESULTS: Mean baseline R(2) * and R(1) were 119 � 7 s(-1) and 0.6 � 0.03 s(-1) for GH3 prolactinomas and 77 � 12 s(-1) and 0.7 � 0.02 s(-1) for PC3 xenografts, respectively. During carbogen breathing, mean ?R(2) * and ?R(1) were -20 � 8 s(-1) and 0.08 � 0.03 s(-1) for GH3 and -0.5 � 1 s(-1) and 0.2 � 0.08 s(-1) for the PC3 tumors, respectively. A pronounced relationship between ?R(2) * and ?R(1) was revealed. CONCLUSION: Considering the blood oxygen-hemoglobin dissociation curve, fast R(2) * suggested that GH3 prolactinomas were more hypoxic at baseline, and their carbogen response dominated by increased hemoglobin oxygenation, evidenced by highly negative ?R(2) *. PC3 tumors were less hypoxic at baseline, and their response to carbogen dominated by increased dissolved oxygen, evidenced by highly positive ?R(1) . Because the two biomarkers are sensitive to different oxygenation ranges, the combination of ?R(2) * and ?R(1) may better characterize tumor hypoxia than each alone. J. Magn. Reson. Imaging 2013;. � 2013 Wiley Periodicals, Inc.

Vessel size index (Rv, μm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non-invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of Rv in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare Rv measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (μCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n = 6), 30 (n = 6) or 200 mg/kg (n = 3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised μCT imaging approach. Vessel diameters were not measurable by μCT in the 200 mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean Rv for the three treatment groups was 24, 23 and 23.5 μm respectively; the corresponding μCT measurements from corrosion casts from the 0 and 30 mg/kg cohorts were 25 and 28 μm. The strong association between the in vivo MRI and post mortem μCT values supports the use of Rv as an imaging biomarker in clinical trials of investigational vascular targeted therapies., Highlights ► Non-invasive quantitation of vessel calibre in tumour xenografts in vivo ► Assessment of tumour vessel calibre response to a vascular disrupting agent ► Generation of vascular corrosion casts from the same tumours imaged by MRI ► Quantitation of vessel calibre from corrosion casts by microCT ► Excellent agreement between the in vivo MRI and post mortem microCT vessel calibres

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R2∗, before and during carbogen (95% O2/5% CO2) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R2∗ were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R2∗ response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P

The recently described combined carbogen USPIO (CUSPIO) magnetic resonance imaging (MRI) method uses spatial correlations in independent imaging biomarkers to assess specific components of tumor vascular structure and function. Our study aimed to evaluate CUSPIO biomarkers for the assessment of tumor response to antiangiogenic therapy. CUSPIO imaging was performed in subcutaneous rat C6 gliomas before and 2 days after treatment with the potent VEGF-signaling inhibitor cediranib (n = 12), or vehicle (n = 12). Histological validation of Hoechst 33342 uptake (perfusion), smooth muscle actin staining (maturation), pimonidazole adduct formation (hypoxia) and necrosis were sought. Following treatment, there was a significant decrease in fractional blood volume (-43%, p < 0.01) and a significant increase in hemodynamic vascular functionality (treatment alteredδ R 2* carbogen from 1.2 to -0.2 s -1, p < 0.05). CUSPIO imaging revealed an overall significant decrease in plasma perfusion (-27%, p < 0.05) following cediranib treatment, that was associated with selective effects on immature blood vessels. The CUSPIO responses were associated with a significant 15% reduction in Hoechst 33342 uptake (p < 0.05), but no significant difference in vascular maturation or necrosis. Additionally, treatment with cediranib resulted in a significant 40% increase in tumor hypoxia (p < 0.05). The CUSPIO imaging method provides novel and more specific biomarkers of tumor vessel maturity and vascular hemodynamics, and their response to VEGF-signaling inhibition, compared to current MR imaging biomarkers utilized in the clinic. Such biomarkers may prove effective in longitudinally monitoring tumor vascular remodeling and/or evasive resistance in response to antiangiogenic therapy. © 2011 UICC.

The epithelial-mesenchymal transition (EMT) is thought to be essential for cancer metastasis. While chromatin remodeling is involved in EMT, which processes contribute to this remodeling remain poorly investigated. Recently, we showed that silencing or removal of the histone variant H2A.X induced mesenchymal-like characteristics, including activation of the EMT transcription factors, Slug and Zeb1 in human colon cancer cells. Here, we provide the evidence that H2A.X loss in human non-tumorigenic breast cell line MCF10A results in a robust EMT activation, as substantiated by a genome-wide expression analysis. Cells deficient for H2A.X exhibit enhanced migration and invasion, along with an activation of a set of mesenchymal genes and a concomitant repression of epithelial genes. In the breast model, the EMT-related transcription factor Twist1 cooperates with Slug to regulate EMT upon H2A.X Loss. Of interest, H2A.X expression level tightly correlates with Twist1, and to a lesser extent with Slug in the panel of human breast cancer cell lines of the NCI-60 datasets. These new findings indicate that H2A.X is involved in the EMT processes in cells of different origins but pairing with transcription factors for EMT may be tissue specific.

It is difficult to predict how current climate change will affect wildlife species adapted to a tropical rainforest environment. Understanding how population dynamics fluctuated in such species throughout periods of past climatic change can provide insight into this issue. The drill (Mandrillus leucophaeus) is a large-bodied rainforest adapted mammal found in West Central Africa. In the middle of this endangered monkey's geographic range is Lake Barombi Mbo, which has a well-documented palynological record of environmental change that dates to the Late Pleistocene. We used a Bayesian coalescent-based framework to analyze 2,076 base pairs of mitochondrial DNA across wild drill populations to infer past changes in female effective population size since the Late Pleistocene. Our results suggest that the drill underwent a nearly 15-fold demographic collapse in female effective population size that was most prominent during the Mid Holocene (approximately 3-5 Ka). This time period coincides with a period of increased dryness and seasonality across Africa and a dramatic reduction in forest coverage at Lake Barombi Mbo. We believe that these changes in climate and forest coverage were the driving forces behind the drill population decline. Furthermore, the warm temperatures and increased aridity of the Mid Holocene are potentially analogous to current and future conditions faced by many tropical rainforest communities. In order to prevent future declines in population size in rainforest-adapted species such as the drill, large tracts of forest should be protected to both preserve habitat and prevent forest loss through aridification.

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ?R(2)*(carbogen) followed by positive ?R(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ?R(2)*(carbogen) but no significant ?R(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ?R(2)*(carbogen) and ?R(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture.

Habitat quality, as indexed by the reproductive success of individuals, can greatly influence population growth, especially for rare species near the limits of their range. Along the Pacific coast, the Snowy Plover (Charadrius alexandrinus nivosus) is a threatened species that, in recent years, has been breeding on both riverine gravel bars and ocean beaches in northern California. From 2001 to 2009, we compared the habitat characteristics, breeding phenology, reproductive success, and abundance of Western Snowy Plovers occupying these two habitats. Similar percentages of yearling and adult plovers returned to gravel bars and beaches, but plovers breeding on gravel bars arrived and initiated first clutches 2-3 weeks later than those breeding on beaches. Despite this delay, however, the mean annual fledging success of plovers on gravel bars (1.4 ± 0.4 (SD)) was double that on beaches (0.7 ± 0.3). Differences in cumulative reproductive success produced a stronger pattern. By their sixth year, males on gravel bars had fledged 14.5 ± 2.1 chicks, more than four times the number of young fledged by males on beaches (3.3 ± 3.1). Over 9 years, local population size decreased by about 75%, coincident with a shift in breeding distribution away from high-quality gravel bars to ocean beaches. This unexpected population decline and shift to poorer quality beaches may have been related to occasional low survival of plovers that over-winter exclusively on beaches in our study area. Consistently low productivity of plovers breeding on ocean beaches suggests the need for intensified management to ameliorate the negative impacts of predation and human activity on the recovery of this population.

The ranges of small kinda (Papio kindae) and much larger grayfooted chacma (P. ursinus griseipes) baboons adjoin in the Kafue National Park, Zambia. In a visual survey of baboons at 48 sites in the Kafue River drainage we found that, contrary to previous reports, groups at the species interface near the town of Ngoma are phenotypically diverse and presumably formed by multigenerational hybridization. Mitochondrial and/or Y-chromosome genetic markers from fecal samples (N=164) collected at 29 sites support this conclusion. Groups with phenotypic signs of a history of hybridization also had taxon-specific mitochondria and Y-haplotypes from both parental species. Although the distribution of mitochondrial haplotypes largely mirrored that of external phenotypes, a significant proportion of male specimens from grayfoot as well as hybrid groups carried kinda Y-chromosomes, and kinda Y-chromosomes were involved in all observed cases of mitochondrial/Y-chromosome discordance. These observations are consistent with, though they do not prove, a population history in which the range of chacmas and the hybrid zone have advanced at the expense of the kinda range. They also suggest that, unexpectedly, kinda male×chacma female matings are much more common than the reciprocal cross in the ancestry of hybrids. We suggest that distinctive male kinda behavior and the "juvenile" appearance of kinda baboons of both sexes, perhaps combined with obstetric difficulties of a small kinda female carrying the large offspring of a chacma male, may account for this bias.

The earliest Neotropical primate fossils complete enough for taxonomic assessment, Dolichocebus , Tremacebus , and Chilecebus , date to approximately 20 Ma. These have been interpreted as either closely related to extant forms or as extinct stem lineages. The former hypothesis of morphological stasis requires most living platyrrhine genera to have diverged before 20 Ma. To test this hypothesis, we collected new complete mitochondrial genomes from Aotus lemurinus , Saimiri sciureus , Saguinus oedipus , Ateles belzebuth , and Callicebus donacophilus. We combined these with published sequences from Cebus albifrons and other primates to infer the mitochondrial phylogeny. We found support for a cebid/atelid clade to the exclusion of the pitheciids. Then, using Bayesian methods and well-supported fossil calibration constraints, we estimated that the platyrrhine most recent common ancestor (MRCA) dates to 19.5 Ma, with all major lineages diverging by 14.3 Ma. Next, we estimated catarrhine divergence dates on the basis of platyrrhine divergence scenarios and found that only a platyrrhine MRCA less than 21 Ma is concordant with the catarrhine fossil record. Finally, we calculated that 33% more change in the rate of evolution is required for platyrrhine divergences consistent with the morphologic stasis hypothesis than for a more recent radiation. We conclude that Dolichocebus , Tremacebus , and Chilecebus are likely too old to be crown platyrrhines, suggesting they were part of an extinct early radiation. We note that the crown platyrrhine radiation was concomitant with the radiation of 2 South American xenarthran lineages and follows a global temperature peak and tectonic activity in the Andes.

Pattern classification for intracranial electroencephalogram (iEEG) and functional magnetic resonance imaging (fMRI) signals has furthered epilepsy research toward understanding the origin of epileptic seizures and localizing dysfunctional brain tissue for treatment. Prior research has demonstrated that implicitly selecting features with a genetic programming (GP) algorithm more effectively determined the proper features to discern biomarker and non-biomarker interictal iEEG and fMRI activity than conventional feature selection approaches. However for each the iEEG and fMRI modalities, it is still uncertain whether the stochastic properties of indirect feature selection with a GP yield (a) consistent results within a patient data set and (b) features that are specific or universal across multiple patient data sets. We examined the reproducibility of implicitly selecting features to classify interictal activity using a GP algorithm by performing several selection trials and subsequent frequent itemset mining (FIM) for separate iEEG and fMRI epilepsy patient data. We observed within-subject consistency and across-subject variability with some small similarity for selected features, indicating a clear need for patient-specific features and possible need for patient-specific feature selection or/and classification. For the fMRI, using nearest-neighbor classification and 30 GP generations, we obtained over 60% median sensitivity and over 60% median selectivity. For the iEEG, using nearest-neighbor classification and 30 GP generations, we obtained over 65% median sensitivity and over 65% median selectivity except one patient.

Numerous field reports of hybrid monkeys and documented cases of persistent hybrid zones suggest that natural hybridization is common among African cercopithecines. Both theoretical considerations and a review of cases lead us to conclude that parapatric hybridization among closely related allotaxa is a widespread, usually natural process whose incidence may be modified by human influence. Sympatric hybridization, between species ecologically distinct enough to have overlapping ranges, is rarer, and in monkeys tends to occur in settings where natural or anthropogenic habitat edges restrict migration and hence access to unrelated conspecific mates. Although sympatric hybridization occurs in the absence of human disturbance, and may even have been a creative force in cercopithecine evolution, anthropogenic habitat fragmentation may increase its incidence. Hybridization with a more abundant form may increase the level of threat faced by a species whose numbers and range have been severely restricted, either naturally or artificially.

Black lion tamarin (BLT) monkeys ( Leontopithecus chrysopygus ) have suffered a severe reduction in their natural range and are consequently critically endangered. Because allozyme data showed very low levels of variation, it was not clear if these monkeys had much genetic diversity. We designed microsatellite primers for BLTs, and from them we identified nine polymorphic loci, seven of which were tested on golden lion tamarins (GLTs) ( Leontopithecus rosalia ). All of the seven polymorphic loci and two other monomorphic BLT loci were polymorphic in GLTs. The microsatellite markers identified here are directly applicable to ongoing lion tamarin population and conservation genetics studies.

The American struggle to capture the Pacific Island of Iwo Jima from the Japanese in 1945 proved to be the bloodiest fight in Marine Corps history. Yet, ironically, the justifications for seizing the island have undergone little critical analysis. A detailed look into the planning for Iwo Jima demonstrates that the service rivalry resulting from the com- peting agendas of the Navy, Army and Army Air Forces in the Pacific negatively influenced the decision to initiate Operation Detachment. The Marine Corps, which paid the heaviest price, remained com- pletely excluded from the decision making process. When fighter escort operations from Iwo Jima, the original reason given for seizing the island, failed to produce the anticipated results, the military sought additional reasons to justify the costly battle. Historians, unfortu- nately, have perpetuated these illusions.

Objective:The loading of bone-anchored hearing system sound processors usually occurs two to three months after surgical implant. This study examined a new bone-anchored hearing system coupling mechanism that permits loading at two weeks post-implantation without compromising osseointegration.Methods:Twenty implants were implanted into 15 patients. The interval between operation and time of processor loading was recorded, along with the cause of any delay and any late complications.Results:Two patients were fitted with implants at seven and nine weeks. The delay was a result of administrative errors; the patients reported no skin problems. Of the remaining 17 implants, 8 processors were fitted at 2 weeks, 1 at 3 weeks, 4 at 4 weeks, 3 at 7 weeks and 1 at 8 weeks. For those nine implants fitted later than two weeks, the delay was because of incomplete skin healing.Conclusion:The Oticon Medical Xpress system allowed processor loading at two weeks post-operatively, providing skin healing was adequate. Early loading occurred in approximately half of the patients. All patients were fitted within the two to three months traditionally allowed. Prolonged skin healing time was the main reason for the delayed fitting of sound processors.

Rodley and Andrew Burrell explore the potential of ‘big data’ writing in their chapter. They offer examples of data-driven literature that search and reconfigure textual information in real time. This recently emerged form of nonlinear or dynamic writing, drawn from massive databases, is presented as a mode of writing highly suited to the internet age, one which may become more timely in the future.

The impact of the pH of precipitation on the physicochemical properties of aluminium phosphate adjuvants was investigated by precipitating aluminium phosphate adjuvants under constant pH conditions at pH values from 3.0 to 7.5 at intervals of 0.5. The pH of precipitation did not affect the morphology, but the point of zero charge (PZC) and rate of acid neutralization varied directly with pH of precipitation. Aggregation and protein adsorption capacity exhibited a parabolic relationship to the pH of precipitation. Minimum protein adsorption and maximum aggregation were observed at pH 5.5. In contrast to adjuvants precipitated from the same reactants but under uncontrolled pH conditions, the pH of all of the adjuvants precipitated under constant pH conditions remained constant for a 3-month aging period at room temperature.