Publications by authors named "Natasha Arora"

41 Publications

Comparison of target enrichment strategies for ancient pathogen DNA.

Biotechniques 2020 12 2;69(6):455-459. Epub 2020 Nov 2.

Institute for Archaeological Sciences, Archaeo- & Palaeogenetics, University of Tübingen, 72070 Tübingen, Germany.

In ancient DNA research, the degraded nature of the samples generally results in poor yields of highly fragmented DNA; targeted DNA enrichment is thus required to maximize research outcomes. The three commonly used methods - array-based hybridization capture and in-solution capture using either RNA or DNA baits - have different characteristics that may influence the capture efficiency, specificity and reproducibility. Here we compare their performance in enriching pathogen DNA of and from 11 ancient and 19 modern samples. We find that in-solution approaches are the most effective method in ancient and modern samples of both pathogens and that RNA baits usually perform better than DNA baits.
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http://dx.doi.org/10.2144/btn-2020-0100DOI Listing
December 2020

Ancient Bacterial Genomes Reveal a High Diversity of Treponema pallidum Strains in Early Modern Europe.

Curr Biol 2020 Oct 13;30(19):3788-3803.e10. Epub 2020 Aug 13.

Institute of Evolutionary Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Institute for Archaeological Sciences, University of Tübingen, Rümelinstrasse 19-23, 72070 Tübingen, Germany; Senckenberg Centre for Human Evolution and Palaeoenvironment (S-HEP), University of Tübingen, Tübingen, Germany. Electronic address:

Syphilis is a globally re-emerging disease, which has marked European history with a devastating epidemic at the end of the 15 century. Together with non-venereal treponemal diseases, like bejel and yaws, which are found today in subtropical and tropical regions, it currently poses a substantial health threat worldwide. The origins and spread of treponemal diseases remain unresolved, including syphilis' potential introduction into Europe from the Americas. Here, we present the first genetic data from archaeological human remains reflecting a high diversity of Treponema pallidum in early modern Europe. Our study demonstrates that a variety of strains related to both venereal syphilis and yaws-causing T. pallidum subspecies were already present in Northern Europe in the early modern period. We also discovered a previously unknown T. pallidum lineage recovered as a sister group to yaws- and bejel-causing lineages. These findings imply a more complex pattern of geographical distribution and etiology of early treponemal epidemics than previously understood.
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http://dx.doi.org/10.1016/j.cub.2020.07.058DOI Listing
October 2020

Fostering Partnerships with the Safety Net: An Evaluation of Kaiser Permanente's Community Ambassador Program in the Mid-Atlantic States.

Perm J 2020 13;24. Epub 2020 Mar 13.

Community Health Evaluation and Research, Kaiser Permanente Mid-Atlantic States, Rockville, MD.

Introduction: Kaiser Permanente (KP) Mid-Atlantic States has partnered with communities in its service area since 2011 to provide health services to underserved individuals. As part of KP's Community Benefit investment, the Community Ambassador Program places KP advanced-practice clinicians in safety-net clinics to share best practices and to improve access and quality of care.

Objective: To report program outcomes and disseminate lessons learned.

Methods: Using data from participating clinics, we retrospectively evaluated the program and estimated Community Ambassadors' contributions to clinic capacity, patient access, evidence-based care, and clinical quality measures. Furthermore, we conducted 29 semistructured phone interviews with stakeholders. Questions focused on program benefits, challenges, learning, and sustainability.

Results: From 2013 to 2017, Community Ambassadors filled up to 32.8 full-time equivalent positions and conducted 294,436 patient encounters in 19 clinics. In certain years and for subsets of clinics, Community Ambassadors performed above average on 2 high-priority quality measures: Cervical cancer screening for women aged 21 to 64 years and diabetes (blood glucose) control. Interviews with 15 Community Ambassadors, 15 health centers leaders, and 7 KP Mid-Atlantic States staff members revealed that Community Ambassadors improved patient access, clinic capacity, and care quality. Ambassadors also exported KP best practices and supported KP's community relations. Challenges included patient acuity, clinic resources, staff turnover, and long-term sustainability.

Conclusion: The Community Ambassador Program achieved its goals and had clear benefits, offering a model for large health care systems wanting to collaborate with community-based clinics. Careful planning is needed to ensure that positive results are sustained.
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http://dx.doi.org/10.7812/TPP/19.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089587PMC
March 2020

Directly Sequenced Genomes of Contemporary Strains of Syphilis Reveal Recombination-Driven Diversity in Genes Encoding Predicted Surface-Exposed Antigens.

Front Microbiol 2019 31;10:1691. Epub 2019 Jul 31.

Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.

Syphilis, caused by subsp. (TPA), remains an important public health problem with an increasing worldwide prevalence. Despite recent advances in cultivation, genetic variability of this pathogen during infection is poorly understood. Here, we present contemporary and geographically diverse complete treponemal genome sequences isolated directly from patients using a methyl-directed enrichment prior to sequencing. This approach reveals that approximately 50% of the genetic diversity found in TPA is driven by inter- and/or intra-strain recombination events, particularly in strains belonging to one of the defined genetic groups of syphilis treponemes: Nichols-like strains. Recombinant loci were found to encode putative outer-membrane proteins and the recombination variability was almost exclusively found in regions predicted to be at the host-pathogen interface. Genetic recombination has been considered to be a rare event in treponemes, yet our study unexpectedly showed that it occurs at a significant level and may have important impacts in the biology of this pathogen, especially as these events occur primarily in the outer membrane proteins. This study reveals the existence of strains with different repertoires of surface-exposed antigens circulating in the current human population, which should be taken into account during syphilis vaccine development.
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http://dx.doi.org/10.3389/fmicb.2019.01691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685089PMC
July 2019

Perspective: The promise of multi-cellular engineered living systems.

APL Bioeng 2018 Dec 11;2(4):040901. Epub 2018 Oct 11.

Boston University, Boston, Massachusetts 02215, USA.

Recent technological breakthroughs in our ability to derive and differentiate induced pluripotent stem cells, organoid biology, organ-on-chip assays, and 3-D bioprinting have all contributed to a heightened interest in the design, assembly, and manufacture of living systems with a broad range of potential uses. This white paper summarizes the state of the emerging field of "multi-cellular engineered living systems," which are composed of interacting cell populations. Recent accomplishments are described, focusing on current and potential applications, as well as barriers to future advances, and the outlook for longer term benefits and potential ethical issues that need to be considered.
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http://dx.doi.org/10.1063/1.5038337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481725PMC
December 2018

Microbiome-based body fluid identification of samples exposed to indoor conditions.

Forensic Sci Int Genet 2019 05 11;40:105-113. Epub 2019 Feb 11.

Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, CH-8057, Zurich, Switzerland. Electronic address:

In the forensic reconstruction of crime scene activities, the identification of biological traces and their bodily origin are valuable evidence that can be presented in court. While several presumptive and confirmatory tests are currently available, the limitations in specificity and sensitivity have instigated a search for alternative methods. Bacterial markers have been proposed as a novel approach for forensic body fluid/tissue identification. Bacteria are not only ubiquitous throughout the human body, but also, as shown by recent microbiome sequencing studies of the 16S rRNA gene, bacterial community structures are distinct across body sites. Traces and stains at crime scenes are, however, often exposed to the environment outside the human body for variable periods of time before laboratory processing. Thus, it is not clear whether exposed samples continue to harbor microbial signatures characteristic of their body site of origin. In this proof-of-concept study we collected samples from six different body sites: saliva, skin, peripheral blood, vaginal fluid, menstrual blood and semen. We exposed a subset of these samples to indoor conditions for 30 days while the remaining samples were processed directly after extraction. Our analyses of 16S rRNA gene sequence data for a total of 46 control and exposed samples show that both types of samples group by body site, although a few outliers are observed. Based on our results, vaginal and menstrual samples share their microbial signatures, and cannot be distinguished using bacterial markers. Overall, our findings indicate that bacterial markers are a promising avenue for forensic body fluid/tissue identification.
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http://dx.doi.org/10.1016/j.fsigen.2019.02.010DOI Listing
May 2019

Ecologically informed microbial biomarkers and accurate classification of mixed and unmixed samples in an extensive cross-study of human body sites.

Microbiome 2018 10 24;6(1):192. Epub 2018 Oct 24.

Institute of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.

Background: The identification of body site-specific microbial biomarkers and their use for classification tasks have promising applications in medicine, microbial ecology, and forensics. Previous studies have characterized site-specific microbiota and shown that sample origin can be accurately predicted by microbial content. However, these studies were usually restricted to single datasets with consistent experimental methods and conditions, as well as comparatively small sample numbers. The effects of study-specific biases and statistical power on classification performance and biomarker identification thus remain poorly understood. Furthermore, reliable detection in mixtures of different body sites or with noise from environmental contamination has rarely been investigated thus far. Finally, the impact of ecological associations between microbes on biomarker discovery was usually not considered in previous work.

Results: Here we present the analysis of one of the largest cross-study sequencing datasets of microbial communities from human body sites (15,082 samples from 57 publicly available studies). We show that training a Random Forest Classifier on this aggregated dataset increases prediction performance for body sites by 35% compared to a single-study classifier. Using simulated datasets, we further demonstrate that the source of different microbial contributions in mixtures of different body sites or with soil can be detected starting at 1% of the total microbial community. We apply a biomarker selection method that excludes indirect environmental associations driven by microbe-microbe associations, yielding a parsimonious set of highly predictive taxa including novel biomarkers and excluding many previously reported taxa. We find a considerable fraction of unclassified biomarkers ("microbial dark matter") and observe that negatively associated taxa have a surprisingly high impact on classification performance. We further detect a significant enrichment of rod-shaped, motile, and sporulating taxa for feces biomarkers, consistent with a highly competitive environment.

Conclusions: Our machine learning model shows strong body site classification performance, both in single-source samples and mixtures, making it promising for tasks requiring high accuracy, such as forensic applications. We report a core set of ecologically informed biomarkers, inferred across a wide range of experimental protocols and conditions, providing the most concise, general, and least biased overview of body site-associated microbes to date.
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http://dx.doi.org/10.1186/s40168-018-0565-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201589PMC
October 2018

Molecular characterization of Treponema pallidum subsp. pallidum in Switzerland and France with a new multilocus sequence typing scheme.

PLoS One 2018 30;13(7):e0200773. Epub 2018 Jul 30.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Syphilis is an important public health problem and an increasing incidence has been noted in recent years. Characterization of strain diversity through molecular data plays a critical role in the epidemiological understanding of this re-emergence. We here propose a new high-resolution multilocus sequence typing (MLST) scheme for Treponema pallidum subsp. pallidum (TPA). We analyzed 30 complete and draft TPA genomes obtained directly from clinical samples or from rabbit propagated strains to identify suitable typing loci and tested the new scheme on 120 clinical samples collected in Switzerland and France. Our analyses yielded three loci with high discriminatory power: TP0136, TP0548, and TP0705. Together with analysis of the 23S rRNA gene mutations for macrolide resistance, we propose these loci as MLST for TPA. Among clinical samples, 23 allelic profiles as well as a high percentage (80% samples) of macrolide resistance were revealed. The new MLST has higher discriminatory power compared to previous typing schemes, enabling distinction of TPA from other treponemal bacteria, distinction between the two main TPA clades (Nichols and SS14), and differentiation of strains within these clades.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066202PMC
January 2019

Reanalysis of Chinese Treponema pallidum samples: all Chinese samples cluster with SS14-like group of syphilis-causing treponemes.

BMC Res Notes 2018 Jan 11;11(1):16. Epub 2018 Jan 11.

Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A6, 625 00, Brno, Czech Republic.

Objective: Treponema pallidum subsp. pallidum (TPA) is the causative agent of syphilis. Genetic analyses of TPA reference strains and human clinical isolates have revealed two genetically distinct groups of syphilis-causing treponemes, called Nichols-like and SS14-like groups. So far, no genetic intermediates, i.e. strains containing a mixed pattern of Nichols-like and SS14-like genomic sequences, have been identified. Recently, Sun et al. (Oncotarget 2016. https://doi.org/10.18632/oncotarget.10154 ) described a new "phylogenetic group" (called Lineage 2) among Chinese TPA strains. This lineage exhibited a "mosaic genomic structure" of Nichols-like and SS14-like lineages.

Results: We reanalyzed the primary sequencing data (Project Number PRJNA305961) from the Sun et al. publication with respect to the molecular basis of Lineage 2. While Sun et al. based the analysis on several selected genomic single nucleotide variants (SNVs) and a subset of highly variable but phylogenetically poorly informative genes, which may confound the phylogenetic analysis, our reanalysis primarily focused on a complete set of whole genomic SNVs. Based on our reanalysis, only two separate TPA clusters were identified: one consisted of Nichols-like TPA strains, the other was formed by the SS14-like TPA strains, including all Chinese strains.
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http://dx.doi.org/10.1186/s13104-017-3106-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765698PMC
January 2018

Left Main Coronary Artery Thrombosis With Acute Myocardial Infarction: A Management Dilemma.

Am J Med Sci 2017 06 16;353(6):597-602. Epub 2016 Jun 16.

Division of Cardiology, St. John Hospital & Medical Center, Detroit, Michigan.

Left main coronary artery (LMCA) thrombosis with acute myocardial infarction is a rare condition with very high mortality. The low incidence of this condition and exclusion of patients with LMCA thrombosis from clinical trials prevent the development of optimal management strategy in these patients. Therefore, there are no clear-cut guidelines describing an evidence-based approach for this condition. We describe a patient with LMCA thrombosis presenting with acute myocardial infarction, who was found to have hypercoagulable state related to homocysteinemia on further work-up. This case highlights the challenges faced during the management of this rare condition due to lack of clear-cut guidelines describing an evidence-based approach.
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http://dx.doi.org/10.1016/j.amjms.2016.04.022DOI Listing
June 2017

A process engineering approach to increase organoid yield.

Development 2017 03 7;144(6):1128-1136. Epub 2017 Feb 7.

Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA

Temporal manipulation of the environment and growth factors can direct differentiation of human pluripotent stem cells into organoids - aggregates with multiple tissue-specific cell types and three-dimensional structure mimicking native organs. A mechanistic understanding of early organoid formation is essential for improving the robustness of these methods, which is necessary prior to use in drug development and regenerative medicine. We investigated intestinal organoid emergence, focusing on measurable parameters of hindgut spheroids, the intermediate step between definitive endoderm and mature organoids. We found that 13% of spheroids were pre-organoids that matured into intestinal organoids. Spheroids varied by several structural parameters: cell number, diameter and morphology. Hypothesizing that diameter and the morphological feature of an inner mass were key parameters for spheroid maturation, we sorted spheroids using an automated micropipette aspiration and release system and monitored the cultures for organoid formation. We discovered that populations of spheroids with a diameter greater than 75 μm and an inner mass are enriched 1.5- and 3.8-fold for pre-organoids, respectively, thus providing rational guidelines towards establishing a robust protocol for high quality intestinal organoids.
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http://dx.doi.org/10.1242/dev.142919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358111PMC
March 2017

Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster.

Nat Microbiol 2016 Dec 5;2:16245. Epub 2016 Dec 5.

Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland.

The abrupt onslaught of the syphilis pandemic that started in the late fifteenth century established this devastating infectious disease as one of the most feared in human history. Surprisingly, despite the availability of effective antibiotic treatment since the mid-twentieth century, this bacterial infection, which is caused by Treponema pallidum subsp. pallidum (TPA), has been re-emerging globally in the last few decades with an estimated 10.6 million cases in 2008 (ref. 2). Although resistance to penicillin has not yet been identified, an increasing number of strains fail to respond to the second-line antibiotic azithromycin. Little is known about the genetic patterns in current infections or the evolutionary origins of the disease due to the low quantities of treponemal DNA in clinical samples and difficulties in cultivating the pathogen. Here, we used DNA capture and whole-genome sequencing to successfully interrogate genome-wide variation from syphilis patient specimens, combined with laboratory samples of TPA and two other subspecies. Phylogenetic comparisons based on the sequenced genomes indicate that the TPA strains examined share a common ancestor after the fifteenth century, within the early modern era. Moreover, most contemporary strains are azithromycin-resistant and are members of a globally dominant cluster, named here as SS14-Ω. The cluster diversified from a common ancestor in the mid-twentieth century subsequent to the discovery of antibiotics. Its recent phylogenetic divergence and global presence point to the emergence of a pandemic strain cluster.
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http://dx.doi.org/10.1038/nmicrobiol.2016.245DOI Listing
December 2016

Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis.

J Exp Med 2015 May 13;212(5):665-80. Epub 2015 Apr 13.

Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030 Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030 Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030

Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at embryonic day 9.5, an embryonic stage not previously described to harbor HSCs. Effects on hematopoiesis are mediated in part by a cascade downstream of wall shear stress that involves calcium efflux and stimulation of the prostaglandin E2 (PGE2)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling axis. Blockade of the PGE2-cAMP-PKA pathway in the aorta-gonad-mesonephros (AGM) abolished enhancement in hematopoietic activity. Furthermore, Ncx1 heartbeat mutants, as well as static cultures of AGM, exhibit lower levels of expression of prostaglandin synthases and reduced phosphorylation of the cAMP response element-binding protein (CREB). Similar to flow-exposed cultures, transient treatment of AGM with the synthetic analogue 16,16-dimethyl-PGE2 stimulates more robust engraftment of adult recipients and greater lymphoid reconstitution. These data provide one mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential.
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http://dx.doi.org/10.1084/jem.20142235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419354PMC
May 2015

Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium.

Blood 2015 Feb 13;125(9):1418-26. Epub 2015 Jan 13.

Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;

Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin(+) hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.
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http://dx.doi.org/10.1182/blood-2014-04-568170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342355PMC
February 2015

Reconstructing the demographic history of orang-utans using Approximate Bayesian Computation.

Mol Ecol 2015 Jan 9;24(2):310-27. Epub 2015 Jan 9.

Anthropological Institute & Museum, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Investigating how different evolutionary forces have shaped patterns of DNA variation within and among species requires detailed knowledge of their demographic history. Orang-utans, whose distribution is currently restricted to the South-East Asian islands of Borneo (Pongo pygmaeus) and Sumatra (Pongo abelii), have likely experienced a complex demographic history, influenced by recurrent changes in climate and sea levels, volcanic activities and anthropogenic pressures. Using the most extensive sample set of wild orang-utans to date, we employed an Approximate Bayesian Computation (ABC) approach to test the fit of 12 different demographic scenarios to the observed patterns of variation in autosomal, X-chromosomal, mitochondrial and Y-chromosomal markers. In the best-fitting model, Sumatran orang-utans exhibit a deep split of populations north and south of Lake Toba, probably caused by multiple eruptions of the Toba volcano. In addition, we found signals for a strong decline in all Sumatran populations ~24 ka, probably associated with hunting by human colonizers. In contrast, Bornean orang-utans experienced a severe bottleneck ~135 ka, followed by a population expansion and substructuring starting ~82 ka, which we link to an expansion from a glacial refugium. We showed that orang-utans went through drastic changes in population size and connectedness, caused by recurrent contraction and expansion of rainforest habitat during Pleistocene glaciations and probably hunting by early humans. Our findings emphasize the fact that important aspects of the evolutionary past of species with complex demographic histories might remain obscured when applying overly simplified models.
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http://dx.doi.org/10.1111/mec.13027DOI Listing
January 2015

Effect of developmental stage of HSC and recipient on transplant outcomes.

Dev Cell 2014 Jun;29(5):621-628

Stem Cell Transplantation Program, Howard Hughes Medical Institute, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Boston, MA 02115, USA. Electronic address:

The first hematopoietic stem cells (HSCs) that engraft irradiated adult mice arise in the aorta-gonad-mesonephros (AGM) on embryonic day 11.5 (E11.5). However, at this stage, there is a discrepancy between the apparent frequency of HSCs depicted with imaging and their rarity when measured with limiting dilution transplant. We have attempted to reconcile this difference using neonatal recipients, which are more permissive for embryonic HSC engraftment. We found that embryonic HSCs from E9.5 and E10.5 preferentially engrafted neonates, whereas developmentally mature, definitive HSCs from E14.5 fetal liver or adult bone marrow (BM) more robustly engrafted adults. Neonatal engraftment was enhanced after treating adult BM-derived HSCs with interferon. Adult BM-derived HSCs preferentially homed to the liver in neonatal mice yet showed balanced homing to the liver and spleen in adults. These findings emphasize the functional differences between nascent and mature definitive HSCs.
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http://dx.doi.org/10.1016/j.devcel.2014.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172398PMC
June 2014

Comparison of patients with peripartum heart failure and normal (≥55%) versus low (<45%) left ventricular ejection fractions.

Am J Cardiol 2014 Jul 2;114(2):290-3. Epub 2014 May 2.

Division of Cardiology, Wayne State University, Detroit Medical Center, Detroit, Michigan.

The current definition of peripartum cardiomyopathy (PC) is restricted to patients with left ventricular systolic dysfunction (ejection fraction [EF]<45%). Data on peripartum heart failure (HF) with normal EF are sparse. We describe clinical characteristics of patients with normal (≥55%) and patients with low (<45%) left ventricular ejection fractions (LVEFs). Electronic medical records (2006 to 2013) of our tertiary care center were retrospectively screened to identify peripartum HF with normal EF, defined as an entity meeting Framingham criteria for HF with symptom onset during the last month of pregnancy or up to 5 months after delivery and with an EF of ≥55%. Clinical characteristics, echocardiographic parameters, and outcomes of these patients were compared with age-matched control patients with traditionally defined PC (EF<45%). A total of 25 patients with PC and EF≥55% were identified. Exclusion of hypertension (n=9), preeclampsia (n=1), and diabetes mellitus (n=2) yielded 13 patients with PC and EF≥55%. Age-matched patients with traditional PC (EF<45%) constituted controls (n=16). Compared with patients with PC and low LVEF, patients with PC and normal LVEF had lower B-type natriuretic peptide levels, systolic and diastolic left ventricular dimensions, left atrial size, and incidence of decompensated HF during delivery (p<0.05). Compared with historical age-matched controls, patients with normal LVEF exhibited attenuated E' mitral annular velocities. On follow-up, these patients were associated with a lower New York Heart Association functional class. In conclusion, peripartum HF with normal LVEF appears to be a distinct entity.
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http://dx.doi.org/10.1016/j.amjcard.2014.04.037DOI Listing
July 2014

Anemia and iron deficiency in heart failure.

Heart Fail Clin 2014 Apr;10(2):281-94

Division of Cardiology, School of Medicine, Mercer University, 707 Pine Street, Macon, GA 31201, USA. Electronic address:

Anemia is a common comorbidity in patients with heart failure (HF) and is associated with poor prognosis. Iron deficiency, with or without anemia, confers increased risk of mortality and morbidity. Along with the altered iron metabolism in HF patients, inflammation creates challenges in the interpretation of laboratory parameters used to diagnose anemia in HF. Since the RED-HF trial failed to demonstrate any benefit from the use of erythropoiesis-stimulating agents (ESAs) on mortality or morbidity in HF patients, ESAs are no longer considered a treatment option, although intravenous iron has potential as therapy for anemic and nonanemic HF patients.
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http://dx.doi.org/10.1016/j.hfc.2013.11.002DOI Listing
April 2014

Generation of SNP datasets for orangutan population genomics using improved reduced-representation sequencing and direct comparisons of SNP calling algorithms.

BMC Genomics 2014 Jan 10;15:16. Epub 2014 Jan 10.

Evolutionary Genetics Group, Anthropological Institute and Museum, University of Zurich, Zurich, Switzerland.

Background: High-throughput sequencing has opened up exciting possibilities in population and conservation genetics by enabling the assessment of genetic variation at genome-wide scales. One approach to reduce genome complexity, i.e. investigating only parts of the genome, is reduced-representation library (RRL) sequencing. Like similar approaches, RRL sequencing reduces ascertainment bias due to simultaneous discovery and genotyping of single-nucleotide polymorphisms (SNPs) and does not require reference genomes. Yet, generating such datasets remains challenging due to laboratory and bioinformatical issues. In the laboratory, current protocols require improvements with regards to sequencing homologous fragments to reduce the number of missing genotypes. From the bioinformatical perspective, the reliance of most studies on a single SNP caller disregards the possibility that different algorithms may produce disparate SNP datasets.

Results: We present an improved RRL (iRRL) protocol that maximizes the generation of homologous DNA sequences, thus achieving improved genotyping-by-sequencing efficiency. Our modifications facilitate generation of single-sample libraries, enabling individual genotype assignments instead of pooled-sample analysis. We sequenced ~1% of the orangutan genome with 41-fold median coverage in 31 wild-born individuals from two populations. SNPs and genotypes were called using three different algorithms. We obtained substantially different SNP datasets depending on the SNP caller. Genotype validations revealed that the Unified Genotyper of the Genome Analysis Toolkit and SAMtools performed significantly better than a caller from CLC Genomics Workbench (CLC). Of all conflicting genotype calls, CLC was only correct in 17% of the cases. Furthermore, conflicting genotypes between two algorithms showed a systematic bias in that one caller almost exclusively assigned heterozygotes, while the other one almost exclusively assigned homozygotes.

Conclusions: Our enhanced iRRL approach greatly facilitates genotyping-by-sequencing and thus direct estimates of allele frequencies. Our direct comparison of three commonly used SNP callers emphasizes the need to question the accuracy of SNP and genotype calling, as we obtained considerably different SNP datasets depending on caller algorithms, sequencing depths and filtering criteria. These differences affected scans for signatures of natural selection, but will also exert undue influences on demographic inferences. This study presents the first effort to generate a population genomic dataset for wild-born orangutans with known population provenance.
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http://dx.doi.org/10.1186/1471-2164-15-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897891PMC
January 2014

Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors.

Cell Stem Cell 2013 Oct;13(4):459-70

Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor cells (HSPCs) has limited their characterization to in vitro assays. We report a strategy to respecify lineage-restricted CD34(+)CD45(+) myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engrafted in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34(+)CD38(-) cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, conferred engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription-factor-mediated engraftment of blood progenitors from human pluripotent cells.
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http://dx.doi.org/10.1016/j.stem.2013.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888026PMC
October 2013

Impact of interhospital transport on the physiologic status of very low-birth-weight infants.

Am J Perinatol 2014 Mar 20;31(3):237-44. Epub 2013 May 20.

Division of Neonatal-Perinatal Medicine, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit Medical Center, Children's Hospital of Michigan and Hutzel Women's Hospital, Detroit, Michigan.

Objectives: To evaluate the change in physiologic stability of very low-birth-weight (VLBW) infants following transport using TRIPS (transport risk index of physiologic stability) score as a measure of physiologic stability and compare changes in TRIPS score in groups of VLBW infants who underwent shorter versus longer transport.

Study Design: Retrospective chart review.

Results: Our cohort of 106 infants, 44 (41%) of whom were females, had a mean birth weight of 777 g (standard deviation [SD] 159) and median gestational age of 26 weeks (range 23 to 32 weeks). Mean weight at transfer was 1,610 g (SD 924) and mean postnatal age at transfer was 56 days (SD 45). Median time on transport was 15 minutes (range 10 to 85 minutes). All 106 transports were ground transports. Of the 106 infants, 57 (54%) had deterioration, 20 (19%) had improvement, and 29 (27%) had no change in their physiologic status during transport. Comparison of the two transport duration groups based on median transport time as a cutoff point (i.e., ≤ 15 minutes and > 15 minutes) revealed a higher proportion of infants with deterioration in their physiologic status in the prolonged transport (>15 minutes) group (65% versus 45%; p = 0.03). Temperature change, either alone or in combination with other indices, was responsible for change in TRIPS score (deterioration or improvement) in 79% of these infants.

Conclusions: Interhospital transport of VLBW infants may cause deterioration in their physiologic status, the likelihood of which is increased with longer duration of transport. Better temperature regulation during interhospital transport may decrease the chances of deterioration in physiologic status of VLBW infants.
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http://dx.doi.org/10.1055/s-0033-1345259DOI Listing
March 2014

Variation in developmental arrest among male orangutans: a comparison between a Sumatran and a Bornean population.

Front Zool 2013 Mar 19;10(1):12. Epub 2013 Mar 19.

Anthropological Institute & Museum, University of Zurich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland.

Introduction: The presence of two sexually active male morphs with different reproductive tactics in a single species is rare among mammals. The most striking case of bimaturism among primates is exhibited by the orangutan (Pongo spp), in which one adult morph, the unflanged male, irreversibly develops into another one, the flanged form, but may remain arrested in the unflanged state for many years. However, it has been suggested that such arrest is less common among Bornean orangutans (Pongo pygmaeus) compared to Sumatrans (Pongo abelii). To investigate this possible inter-specific difference we compared both the number of developing males and the ratios of the two male morphs at two long-term study sites, Suaq Balimbing on Sumatra and Tuanan on Borneo.

Results: First, we observed a significantly greater number of flanged than unflanged males per month in the Tuanan study area, whereas the opposite pattern held at Suaq. Second, the same contrast held for the total number of identified individuals over the study, with more flanged than unflanged males at Tuanan and the opposite at Suaq. These differences were mainly due to transient males. For Tuanan, the identification results were confirmed by detailed genetic analyses. Finally, we recorded a higher proportion of unflanged males that became flanged during any given year at Tuanan than at Suaq.

Conclusion: These results show that developmental arrest is far more common at Suaq than at Tuanan. Preliminary comparisons suggest that this is a general contrast between the island taxa of orangutans and should help efforts to identify the function and proximate control of developmental arrest in orangutan males.
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http://dx.doi.org/10.1186/1742-9994-10-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607856PMC
March 2013

Cardiac magnetic resonance imaging in peripartum cardiomyopathy.

Am J Med Sci 2014 Feb;347(2):112-7

Division of Cardiology, Department of Internal Medicine (NPA, NM, TM, AK, LCA), Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan; and Department of Radiology (RD, TL), Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan.

Background: Peripartum cardiomyopathy (PPCM) is a rare life-threatening condition of unclear etiology. Data on the use of cardiac magnetic resonance (CMR) imaging to characterize PPCM are limited. This study was done to assess the role of CMR imaging for the diagnosis and prognostication of patients with PPCM.

Methods: Medical records of a tertiary medical center were screened for PPCM patients with CMR imaging done within the past 5 years (2006-2011). Images were reviewed by 2 expert radiologists (blinded to clinical data) using cine sequences for chamber function and size, T2-weighted images for the determination of edema (T2-ratio), and late gadolinium enhancement (LGE) sequences for myocardial tissue characterization.

Results: Ten PPCM patients (aged 28 ± 6 years, 90% African American) had a total of 15 CMR examinations: 4 in the acute phase (within 7 days of diagnosis) and 11 during follow-up (median, 12 months; range, 1-72 months). Left ventricular ejection fraction was decreased in all 4 initial scans. Elevated T2 ratio (>2) seen in 1 patient decreased on follow-up imaging. LGE was seen in 1 of the 4 acute-phase scans and in 4 of the 11 follow-up phase scans. These 4 patients had multiple readmissions because of heart failure exacerbations and persistently low left ventricular ejection fraction on subsequent echocardiograms.

Conclusions: LGE seems to be associated with a poor prognosis in the setting of PPCM. CMR imaging seems to have promising practical implications in the diagnosis and prognostication of PPCM patients.
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http://dx.doi.org/10.1097/MAJ.0b013e31828155e3DOI Listing
February 2014

Pulmonary fungus ball in a patient with sarcoidosis.

Am J Med Sci 2014 Jul;348(1):87

*Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan (E-mail:

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http://dx.doi.org/10.1097/MAJ.0b013e318278e3d5DOI Listing
July 2014

Cutaneous vasculopathy and neutropenia associated with levamisole-adulterated cocaine.

Am J Med Sci 2013 Jan;345(1):45-51

Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI, USA.

Background: Levamisole has recently been implicated as a cause of cutaneous vasculopathy in cocaine abusers. The objective of this study was to describe this relatively new entity by reviewing published cases identified through a literature search.

Methods: Published reports identified through a search of PubMed database (from 1964 to November 2011) were reviewed to record clinical, serological and pathologic findings.

Results: A cohort of 32 patients had a mean age of 44 ± 9 years with a female predominance (75%). Rash predominately affected lower extremities (87.5%), followed by face (78%) and ears (69%) and typically presented as purpuric plaques, which were seen in a retiform pattern in 16 (50%) and had central necrosis in 11 patients (34%). Leukopenia and neutropenia were found in 20 patients (63%). Antinuclear cytoplasmic antibody (ANCA) was positive in 30 patients (94%); p-ANCA in 28 patients (87.5%), c-ANCA in 19 (59%) and both in 17 patients (53%). Skin biopsy results were available for 29 patients: 14 (48%) had pure thrombotic vasculopathy, 4 (14%) had pure small vessel vasculitis and 11 (38%) had evidence of both. Treatment information was available for 30 patients. Only supportive care was given to 11 patients (37%), steroids to 16 (53%) and surgical treatment for 5 (17%). Clinical course of lesions was available for 24 patients. Rash resolved in 11 patients (46%) and improved in 13 (54%). During median follow-up of 21 days (range, 7-270 days), 10 of 22 patients had recurrences related to cocaine use.

Conclusion: Levamisole-induced cutaneous vasculopathy in cocaine users is characterized by a female predominance, a retiform purpuric rash with a predilection for lower extremities, autoantibody production, leukopenia and/or neutropenia and recurrences with future cocaine use.
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http://dx.doi.org/10.1097/MAJ.0b013e31825b2b50DOI Listing
January 2013

Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition.

Proc Natl Acad Sci U S A 2013 Jan 12;110(2):E141-50. Epub 2012 Dec 12.

Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.

During development, the hematopoietic lineage transits through hemogenic endothelium, but the signaling pathways effecting this transition are incompletely characterized. Although the Hedgehog (Hh) pathway is hypothesized to play a role in patterning blood formation, early embryonic lethality of mice lacking Hh signaling precludes such analysis. To determine a role for Hh signaling in patterning of hemogenic endothelium, we assessed the effect of altered Hh signaling in differentiating mouse ES cells, cultured mouse embryos, and developing zebrafish embryos. In differentiating mouse ES cells and mouse yolk sac cultures, addition of Indian Hh ligand increased hematopoietic progenitors, whereas chemical inhibition of Hh signaling reduced hematopoietic progenitors without affecting primitive streak mesoderm formation. In the setting of Hh inhibition, induction of either Notch signaling or overexpression of Stem cell leukemia (Scl)/T-cell acute lymphocytic leukemia protein 1 rescued hemogenic vascular-endothelial cadherin(+) cells and hematopoietic progenitor formation. Together, our results reveal that Scl overexpression is sufficient to rescue the developmental defects caused by blocking the Hh and Notch pathways, and inform our understanding of the embryonic endothelial-to-hematopoietic transition.
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http://dx.doi.org/10.1073/pnas.1214361110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545793PMC
January 2013

Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose.

Am J Cardiol 2013 Feb 24;111(3):445-7. Epub 2012 Nov 24.

Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Michigan, USA.

The investigators describe the clinical course of a 26-year-old-man who was brought to the emergency department in a comatose state with status epilepticus after smoking a large amount of crack cocaine. In the emergency department, he was intubated because of depressed mental status and respiratory acidosis. His troponin I remained negative, and electrocardiography showed wide-complex tachycardia with a prolonged corrected QT interval. Because of the corrected QT interval prolongation and wide-complex tachycardia, the patient was started on intravenous magnesium sulfate and sodium bicarbonate. Despite these interventions, no improvement in cardiac rhythm was observed, and electrocardiography continued to show wide-complex tachycardia. The patient became more unstable from a cardiovascular standpoint, with a decrease in blood pressure to 85/60 mm Hg. He was then given 100 ml of 20% lipid emulsion (Intralipid). Within 10 minutes of starting the infusion of 20% lipid emulsion, wide-complex tachycardia disappeared, with an improvement in systemic blood pressure to 120/70 mm Hg. Repeat electrocardiography after the infusion of intravenous lipid emulsion showed regular sinus rhythm with normal QRS and corrected QT intervals. The patient was successfully extubated on day 8 of hospitalization and discharged home on day 10. His cardiac rhythm and blood pressure remained stable throughout his further stay in the hospital.
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http://dx.doi.org/10.1016/j.amjcard.2012.10.022DOI Listing
February 2013

Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage.

Addict Sci Clin Pract 2012 Sep 24;7:19. Epub 2012 Sep 24.

Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, 4201 Saint Antoine Street, Detroit, 48201 MI, USA.

Levamisole-induced vasculitis is a relatively new entity in people who use cocaine. We describe a 44-year-old woman with a history of cocaine use who presented with a complaint of a painful rash of 2-3 month's duration on her extremities, cheeks, nose, and earlobes. She had not experienced fever, weight loss, alopecia, dry eyes, oral ulcers, photosensitivity, or arthralgia. Examination revealed tender purpuric eruptions with central necrosis on her nose, cheeks, earlobes, and extremities. Laboratory investigations revealed neutropenia, an elevated erythrocyte sedimentation rate (ESR), presence of lupus anticoagulant, low complement component 3 (C3), and presence of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA). A urine toxicology screen was positive for cocaine, and gas chromatography-mass spectrometry was positive for levamisole. Skin biopsy showed leukocytoclastic vasculitis and small vessel thrombosis. Necrotic lesions of the nose led to its self-amputation. Large bullae on the lower extremities ruptured, leading to wound infection and extensive necrosis that required multiple surgical debridements. When necrosis progressed despite debridement, bilateral above-knee amputation of the legs was performed. Once new lesions stopped appearing, the patient was discharged home. Two months later, she had a recurrence related to cocaine use. To the best of our knowledge, this is only the second reported case of levamisole-induced vasculitis that required above-knee amputation.
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http://dx.doi.org/10.1186/1940-0640-7-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509389PMC
September 2012

Effective population size dynamics and the demographic collapse of Bornean orang-utans.

PLoS One 2012 15;7(11):e49429. Epub 2012 Nov 15.

Population and Conservation Genetics, Instituto Gulbenkian de Ciência, Oeiras, Portugal.

Bornean orang-utans experienced a major demographic decline and local extirpations during the Pleistocene and Holocene due to climate change, the arrival of modern humans, of farmers and recent commercially-driven habitat loss and fragmentation. The recent loss of habitat and its dramatic fragmentation has affected the patterns of genetic variability and differentiation among the remaining populations and increased the extinction risk of the most isolated ones. However, the contribution of recent demographic events to such genetic patterns is still not fully clear. Indeed, it can be difficult to separate the effects of recent anthropogenic fragmentation from the genetic signature of prehistoric demographic events. Here, we investigated the genetic structure and population size dynamics of orang-utans from different sites. Altogether 126 individuals were analyzed and a full-likelihood Bayesian approach was applied. All sites exhibited clear signals of population decline. Population structure is known to generate spurious bottleneck signals and we found that it does indeed contribute to the signals observed. However, population structure alone does not easily explain the observed patterns. The dating of the population decline varied across sites but was always within the 200-2000 years period. This suggests that in some sites at least, orang-utan populations were affected by demographic events that started before the recent anthropogenic effects that occurred in Borneo. These results do not mean that the recent forest exploitation did not leave its genetic mark on orang-utans but suggests that the genetic pool of orang-utans is also impacted by more ancient events. While we cannot identify the main cause for this decline, our results suggests that the decline may be related to the arrival of the first farmers or climatic events, and that more theoretical work is needed to understand how multiple demographic events impact the genome of species and how we can assess their relative contributions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049429PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499548PMC
May 2013

Marked population structure and recent migration in the critically endangered Sumatran orangutan (Pongo abelii).

J Hered 2013 Jan-Feb;104(1):2-13. Epub 2012 Oct 16.

Anthropological Institute & Museum, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

A multitude of factors influence how natural populations are genetically structured, including dispersal barriers, inhomogeneous habitats, and social organization. Such population subdivision is of special concern in endangered species, as it may lead to reduced adaptive potential and inbreeding in local subpopulations, thus increasing the risk of future extinctions. With only 6600 animals left in the wild, Sumatran orangutans (Pongo abelii) are among the most endangered, but also most enigmatic, great ape species. In order to infer the fine-scale population structure and connectivity of Sumatran orangutans, we analyzed the most comprehensive set of samples to date, including mitochondrial hyper-variable region I haplotypes for 123 individuals and genotypes of 27 autosomal microsatellite markers for 109 individuals. For both mitochondrial and autosomal markers, we found a pronounced population structure, caused by major rivers, mountain ridges, and the Toba caldera. We found that genetic diversity and corresponding long-term effective population size estimates vary strongly among sampling regions for mitochondrial DNA, but show remarkable similarity for autosomal markers, hinting at male-driven long-distance gene flow. In support of this, we identified several individuals that were most likely sired by males originating from other genetic clusters. Our results highlight the effect of natural barriers in shaping the genetic structure of great ape populations, but also point toward important dispersal corridors on northern Sumatra that allow for genetic exchange.
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http://dx.doi.org/10.1093/jhered/ess065DOI Listing
June 2013