Publications by authors named "Daniel Bradley"

151 Publications

Herded and hunted goat genomes from the dawn of domestication in the Zagros Mountains.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland;

The Aceramic Neolithic (∼9600 to 7000 cal BC) period in the Zagros Mountains, western Iran, provides some of the earliest archaeological evidence of goat () management and husbandry by circa 8200 cal BC, with detectable morphological change appearing ∼1,000 y later. To examine the genomic imprint of initial management and its implications for the goat domestication process, we analyzed 14 novel nuclear genomes (mean coverage 1.13X) and 32 mitochondrial (mtDNA) genomes (mean coverage 143X) from two such sites, Ganj Dareh and Tepe Abdul Hosein. These genomes show two distinct clusters: those with domestic affinity and a minority group with stronger wild affinity, indicating that managed goats were genetically distinct from wild goats at this early horizon. This genetic duality, the presence of long runs of homozygosity, shared ancestry with later Neolithic populations, a sex bias in archaeozoological remains, and demographic profiles from across all layers of Ganj Dareh support management of genetically domestic goat by circa 8200 cal BC, and represent the oldest to-this-date reported livestock genomes. In these sites a combination of high autosomal and mtDNA diversity, contrasting limited Y chromosomal lineage diversity, an absence of reported selection signatures for pigmentation, and the wild morphology of bone remains illustrates domestication as an extended process lacking a strong initial bottleneck, beginning with spatial control, demographic manipulation via biased male culling, captive breeding, and subsequently phenotypic and genomic selection.
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http://dx.doi.org/10.1073/pnas.2100901118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237664PMC
June 2021

Exploring the phylogeography and population dynamics of the giant deer () using Late Quaternary mitogenomes.

Proc Biol Sci 2021 05 12;288(1950):20201864. Epub 2021 May 12.

Centre for Geogenetics, Natural History Museum Denmark, University of Copenhagen, Østervoldgade 5-7, 1350 Copenhagen, Denmark.

Late Quaternary climatic fluctuations in the Northern Hemisphere had drastic effects on large mammal species, leading to the extinction of a substantial number of them. The giant deer () was one of the species that became extinct in the Holocene, around 7660 calendar years before present. In the Late Pleistocene, the species ranged from western Europe to central Asia. However, during the Holocene, its range contracted to eastern Europe and western Siberia, where the last populations of the species occurred. Here, we generated 35 Late Pleistocene and Holocene giant deer mitogenomes to explore the genetics of the demise of this iconic species. Bayesian phylogenetic analyses of the mitogenomes suggested five main clades for the species: three pre-Last Glacial Maximum clades that did not appear in the post-Last Glacial Maximum genetic pool, and two clades that showed continuity into the Holocene. Our study also identified a decrease in genetic diversity starting in Marine Isotope Stage 3 and accelerating during the Last Glacial Maximum. This reduction in genetic diversity during the Last Glacial Maximum, coupled with a major contraction of fossil occurrences, suggests that climate was a major driver in the dynamics of the giant deer.
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http://dx.doi.org/10.1098/rspb.2020.1864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114472PMC
May 2021

Improving smartphone follow-up after patient discharge from annual short-term head and neck missions in Ethiopia.

J Plast Reconstr Aesthet Surg 2021 Mar 31. Epub 2021 Mar 31.

Department of Head and Neck Surgery, University College London Hospital, London, England, United Kingdom.

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http://dx.doi.org/10.1016/j.bjps.2021.03.037DOI Listing
March 2021

Hyperspectral interference tomography of nacre.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Electrical and Computer Engineering, University of Wisconsin-Madison, Madison, WI 53706;

Structural characterization of biologically formed materials is essential for understanding biological phenomena and their enviro-nment, and for generating new bio-inspired engineering concepts. For example, nacre-the inner lining of some mollusk shells-encodes local environmental conditions throughout its formation and has exceptional strength due to its nanoscale brick-and-mortar structure. This layered structure, comprising alternating transparent aragonite (CaCO) tablets and thinner organic polymer layers, also results in stunning interference colors. Existing methods of structural characterization of nacre rely on some form of cross-sectional analysis, such as scanning or transmission electron microscopy or polarization-dependent imaging contrast (PIC) mapping. However, these techniques are destructive and too time- and resource-intensive to analyze large sample areas. Here, we present an all-optical, rapid, and nondestructive imaging technique-hyperspectral interference tomography (HIT)-to spatially map the structural parameters of nacre and other disordered layered materials. We combined hyperspectral imaging with optical-interference modeling to infer the mean tablet thickness and its disorder in nacre across entire mollusk shells from red and rainbow abalone ( and ) at various stages of development. We observed that in red abalone, unexpectedly, nacre tablet thickness decreases with age of the mollusk, despite roughly similar appearance of nacre at all ages and positions in the shell. Our rapid, inexpensive, and nondestructive method can be readily applied to in-field studies.
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http://dx.doi.org/10.1073/pnas.2023623118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053970PMC
April 2021

Synthetic Derivatives of Ciclopirox are Effective Inhibitors of .

ACS Omega 2021 Mar 15;6(12):8477-8487. Epub 2021 Mar 15.

Edward A. Doisy Department of Biochemistry, Saint Louis University School of Medicine, 1100 South Grand Blvd., St. Louis, Missouri 63104, United States.

Opportunistic fungal infections caused by are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a -hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 -hydroxypyridone derivatives to develop an initial structure-activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against and and counter-screened for specificity in and two species. Eight of the ten show inhibition at 1-3 μM concentration (0.17-0.42 μg per mL) in both species and in , but poor activity in the species. In , the -hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure-activity relationship points to the need for a lipophilic functional group at position six of the -hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.
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http://dx.doi.org/10.1021/acsomega.1c00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015083PMC
March 2021

High Resolution Manometry in a Functioning Fundoplication - Establishing a Standard Profile: Retrospective Chart Review.

Ann Surg 2021 Feb 12. Epub 2021 Feb 12.

*The Foundation for Surgical Innovation & Education, 4805 NE Glisan St., Suite 6N60, Portland, OR 97213, USA †The Oregon Clinic, Department for Gastrointestinal & Minimally Invasive Surgery 4805 NE Glisan St, Suite 6N60, Portland, OR 97213, USA ‡Providence Portland Medical Center 4805 NE Glisan St, Portland, OR 97213, USA §University of Cologne, Department of General, Visceral, Cancer and Transplant Surgery, Kerpener Straße 62, 50937 Köln, Germany ¶IHU Strasbourg 1, place de l'Hôpital, 67091 Strasbourg Cedex, France.

Objective: The aim of this study was to provide a full HRM data set in patients with a normal functioning fundoplication.

Background: The Chicago classification was devised to correlate High Resolution Manometry (HRM) values to the clinical status of patients with swallowing disorder. However, it is unclear whether those values are applicable after fundoplication as the literature is sparse.

Methods: We identified patients with pre- and postoperative HRM who had a normal functioning primary fundoplication as defined by 1) resolution of preoperative symptoms without significant postoperative side effects, 2) no dysphagia reported on a standardized questionnaire given on the day of the postoperative HRM and 3) normal acid exposure determined objectively by esophageal pH-testing.

Results: Fifty patients met inclusion criteria for the study. Thirty-three patients (66%) underwent complete fundoplication and 17 patients (34%) underwent posterior partial fundoplication. Postoperative HRM was performed at a median of 12 months after primary surgery. LES values significantly increased with the addition of a fundoplication. Median IRP was 14mmHg (p = 0.0001), median resting pressure 19.5mmHg (p = 0.0263) and median total length LES was 3.95 cm (p = 0.0098). The 95th percentile for IRP in a complete fundoplication was 29 vs. 23mmHg in a partial fundoplication (p = 0.3667).

Conclusion: We offer a new standard manometric profile for a normally functioning fundoplication which provides a necessary benchmark for analyzing postoperative problems with a fundoplication. The previously accepted upper limit defining esophageal outflow obstruction (IRP > 20mmHg) is not clinically applicable after fundoplication as the majority of patients in this dysphagia-free cohort exceeded this value. Interestingly, there does not appear to be a significant difference in HRM LES values between complete and partial fundoplication.
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http://dx.doi.org/10.1097/SLA.0000000000004813DOI Listing
February 2021

POEM: clinical outcomes beyond 5 years.

Surg Endosc 2021 Jan 4. Epub 2021 Jan 4.

Foundation for Surgical Innovation and Education, Portland, OR, USA.

Background: The short-term success of peroral endoscopic myotomy (POEM) is well documented but the durability of the operation is questioned. The aim of this study was to evaluate the clinical outcomes of the POEM procedure for esophageal motility disorders in a large cohort in which all patients had at least 5 years of follow-up.

Methods: All patients from a single center who underwent a POEM between October 2010 and September 2014 were followed for long-term clinical outcomes. Postoperative Eckardt symptom scores of short term and ≥ 5 years were collected through phone interview. Clinical success was defined as an Eckardt score < 3. Overall success was defined as Eckardt score < 3 and freedom from additional interventions.

Results: Of 138 patients, 100 patients were available for follow-up (mean age 56, 52% male). The indication for operation was achalasia in 94. The mean follow-up duration was 75 months (range: 60-106 months). Dysphagia was improved in 91% of patients. Long-term overall success was achieved in 79% of patients (80% of achalasia patients, 67% of DES patients). Preoperative mean Eckardt score was 6. At 6 months, it was 1, and at 75 months, it was 2 (p = 0.204). Five-year freedom from intervention was 96%. Overall, 7 patients had additional treatments: 1 balloon dilation (35 mm), 4 laparoscopic Heller myotomy, and 2 redo POEM at a mean of 51 months post-POEM. Ninety-three percent expressed complete satisfaction with POEM.

Conclusion: A multitude of studies has shown the early benefits of POEM. Here, we show that nearly 80% of patients report clinical success with no significant decrement in symptom scores between their short- and long-term follow-up. Clearly POEM is an effective option for achalasia with durable long-term treatment efficacy.
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http://dx.doi.org/10.1007/s00464-020-08031-3DOI Listing
January 2021

Adjuvant Alendronic Acid in the Management of Severe Cherubism: A Case Report and Literature Review.

J Oral Maxillofac Surg 2021 Mar 10;79(3):598-607. Epub 2020 Oct 10.

Professor of Oral and Maxillofacial Surgery, Department of Head and Neck Surgery, University College London Hospital, London, United Kingdom. Electronic address:

Cherubism is a rare disease of the jaws characterized by bilateral symmetrical painless expansion of the mandible and maxilla. In extreme cases, larger lesions can become exophytic and have profound functional and esthetic implications. Several pharmacologic agents have been trialed in the treatment of cherubism with variable success reported. Bisphosphonates have not been significantly studied in this setting. We present a case where oral alendronic acid was used as an adjuvant treatment after surgical debulking of the maxilla in a 13-year-old boy with a severe case of cherubism.
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http://dx.doi.org/10.1016/j.joms.2020.10.001DOI Listing
March 2021

Population genomics of the Viking world.

Nature 2020 09 16;585(7825):390-396. Epub 2020 Sep 16.

NTNU University Museum, Department of Archaeology and Cultural History, Trondheim, Norway.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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http://dx.doi.org/10.1038/s41586-020-2688-8DOI Listing
September 2020

Short-term surgical missions to resource-limited settings in the wake of the COVID-19 pandemic.

J Plast Reconstr Aesthet Surg 2021 03 29;74(3):644-710. Epub 2020 Aug 29.

Department of Head and Neck Surgery, University College London Hospital, London, United Kingdom.

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http://dx.doi.org/10.1016/j.bjps.2020.08.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455554PMC
March 2021

The origin of domestication genes in goats.

Sci Adv 2020 May 20;6(21):eaaz5216. Epub 2020 May 20.

Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.

Goat domestication was critical for agriculture and civilization, but its underlying genetic changes and selection regimes remain unclear. Here, we analyze the genomes of worldwide domestic goats, wild caprid species, and historical remains, providing evidence of an ancient introgression event from a West Caucasian tur-like species to the ancestor of domestic goats. One introgressed locus with a strong signature of selection harbors the gene, which encodes a gastrointestinally secreted mucin. Experiments revealed that the nearly fixed introgressed haplotype confers enhanced immune resistance to gastrointestinal pathogens. Another locus with a strong signal of selection may be related to behavior. The selected alleles at these two loci emerged in domestic goats at least 7200 and 8100 years ago, respectively, and increased to high frequencies concurrent with the expansion of the ubiquitous modern mitochondrial haplogroup A. Tracking these archaeologically cryptic evolutionary transformations provides new insights into the mechanisms of animal domestication.
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http://dx.doi.org/10.1126/sciadv.aaz5216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314551PMC
May 2020

Screening archaeological bone for palaeogenetic and palaeoproteomic studies.

PLoS One 2020 25;15(6):e0235146. Epub 2020 Jun 25.

Department of Archaeology, McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, United Kingdom.

The recovery and analysis of ancient DNA and protein from archaeological bone is time-consuming and expensive to carry out, while it involves the partial or complete destruction of valuable or rare specimens. The fields of palaeogenetic and palaeoproteomic research would benefit greatly from techniques that can assess the molecular quality prior to sampling. To be relevant, such screening methods should be effective, minimally-destructive, and rapid. This study reports results based on spectroscopic (Fourier-transform infrared spectroscopy in attenuated total reflectance [FTIR-ATR]; n = 266), palaeoproteomic (collagen content; n = 226), and palaeogenetic (endogenous DNA content; n = 88) techniques. We establish thresholds for three different FTIR indices, a) the infrared splitting factor [IRSF] that assesses relative changes in bioapatite crystals' size and homogeneity; b) the carbonate-to-phosphate [C/P] ratio as a relative measure of carbonate content in bioapatite crystals; and c) the amide-to-phosphate ratio [Am/P] for assessing the relative organic content preserved in bone. These thresholds are both extremely reliable and easy to apply for the successful and rapid distinction between well- and poorly-preserved specimens. This is a milestone for choosing appropriate samples prior to genomic and collagen analyses, with important implications for biomolecular archaeology and palaeontology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235146PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316274PMC
August 2020

A dynastic elite in monumental Neolithic society.

Nature 2020 06 17;582(7812):384-388. Epub 2020 Jun 17.

Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

The nature and distribution of political power in Europe during the Neolithic era remains poorly understood. During this period, many societies began to invest heavily in building monuments, which suggests an increase in social organization. The scale and sophistication of megalithic architecture along the Atlantic seaboard, culminating in the great passage tomb complexes, is particularly impressive. Although co-operative ideology has often been emphasised as a driver of megalith construction, the human expenditure required to erect the largest monuments has led some researchers to emphasize hierarchy-of which the most extreme case is a small elite marshalling the labour of the masses. Here we present evidence that a social stratum of this type was established during the Neolithic period in Ireland. We sampled 44 whole genomes, among which we identify the adult son of a first-degree incestuous union from remains that were discovered within the most elaborate recess of the Newgrange passage tomb. Socially sanctioned matings of this nature are very rare, and are documented almost exclusively among politico-religious elites-specifically within polygynous and patrilineal royal families that are headed by god-kings. We identify relatives of this individual within two other major complexes of passage tombs 150 km to the west of Newgrange, as well as dietary differences and fine-scale haplotypic structure (which is unprecedented in resolution for a prehistoric population) between passage tomb samples and the larger dataset, which together imply hierarchy. This elite emerged against a backdrop of rapid maritime colonization that displaced a unique Mesolithic isolate population, although we also detected rare Irish hunter-gatherer introgression within the Neolithic population.
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http://dx.doi.org/10.1038/s41586-020-2378-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116870PMC
June 2020

Animal domestication in the era of ancient genomics.

Nat Rev Genet 2020 08 7;21(8):449-460. Epub 2020 Apr 7.

Laboratoire d'Anthropobiologie Moléculaire et d'Imagerie de Synthèse, CNRS UMR 5288, Université de Toulouse, Université Paul Sabatier, Toulouse, France.

The domestication of animals led to a major shift in human subsistence patterns, from a hunter-gatherer to a sedentary agricultural lifestyle, which ultimately resulted in the development of complex societies. Over the past 15,000 years, the phenotype and genotype of multiple animal species, such as dogs, pigs, sheep, goats, cattle and horses, have been substantially altered during their adaptation to the human niche. Recent methodological innovations, such as improved ancient DNA extraction methods and next-generation sequencing, have enabled the sequencing of whole ancient genomes. These genomes have helped reconstruct the process by which animals entered into domestic relationships with humans and were subjected to novel selection pressures. Here, we discuss and update key concepts in animal domestication in light of recent contributions from ancient genomics.
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http://dx.doi.org/10.1038/s41576-020-0225-0DOI Listing
August 2020

Feasibility of implementing a virtual reality program as an adjuvant tool for peri-operative pain control; Results of a randomized controlled trial in minimally invasive foregut surgery.

Complement Ther Med 2020 Mar 26;49:102356. Epub 2020 Feb 26.

Foundation for Surgical Innovation and Education, Portland, OR, United States; Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland, OR, United States. Electronic address:

Background: Post-operative pain control and narcotic over-utilization are challenging issues for surgeons in all fields. While virtual reality (VR) has been increasingly applied in various fields, its feasibility and efficacy in the peri-operative period has not been evaluated. The aim of this study was to examine the experience of an integrated VR protocol in the perioperative setting.

Methods: Patients undergoing minimally invasive foregut surgery at a single institution were randomized to receive a series of VR meditation/mindfulness sessions (VR) or to standard care after surgery (non-VR). Post-operative pain levels, narcotic utilization and patient satisfaction were tracked.

Results: Fifty-two patients were enrolled with 26 in each arm. Post-operative pain scores, total narcotic utilization, and overall satisfaction scores were not significantly different between the two groups. For patients in the VR arm, sessions were able to be incorporated into the perioperative routine with little disruption. Most (73.9 %) were able complete all six VR sessions and reported low pain, anxiety, and nausea scores while using the device. A high proportion responded that they would use VR again (76.2 %) or would like a VR program designed for pain (62.0 %). There were no complications from device usage.

Conclusion: VR is a safe and simple intervention that is associated with high patient satisfaction and is feasible to implement in the perioperative setting. While the current study is underpowered to detect difference in narcotic utilization, this device holds promise as an adjuvant tool in multimodal pain and anxiety control in the peri-operative period.
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http://dx.doi.org/10.1016/j.ctim.2020.102356DOI Listing
March 2020

Intraoperative Three-dimensional Virtual Reality and Computed Tomographic Guidance in Temporomandibular Joint Arthroplasty of Syndromic Craniofacial Dysostoses.

Plast Reconstr Surg Glob Open 2019 Sep 10;7(9):e2388. Epub 2019 Sep 10.

Division of Plastic and Reconstructive Surgery, University of California Los Angeles David Geffen School of Medicine, Los Angeles, Calif.

Bony ankylosis of the temporomandibular joints (TMJ) occurs in up to 28% of patients with syndromic mandibular dysostoses. Release of complete osseous ankylosis is particularly challenging due to the lack of tissue planes separating the mandible from the skull base and the presence of congenital skeletal abnormalities. One recent advance in surgical imaging technology is three-dimensional virtual reality (3D VR), now in common use in neurosurgical resections. In this study, we describe the usage of 3D VR in TMJ arthroplasty and compare 3D VR to traditional computed tomographic (CT) guidance. Pediatric patients with syndromic mandibular micrognathia including Treacher Collins, Nager, and cerebrocostomandibular syndrome were retrospectively evaluated between 2008 and 2016. Patient characteristics, complications, inpatient times, and operative times were recorded. Of the 29 children with syndromic mandibular micrognathia treated between 2008 and 2016, 7 were diagnosed with TMJ ankyloses. Four consecutive pediatric patients (mean 8.7 years) undergoing interpositional TMJ arthroplasty with Matthews device placement were retrospectively evaluated. Two patients underwent traditional CT-guided versus 3D VR-guided temporomandibular joint arthroplasty (TMJA). No statistically significant differences were found among the age, complications, or inpatient hospitalization times. The average operative time in the traditional CT guidance group was 300 minute versus 134 minutes in the 3D VR group. Three-dimensional VR is a useful preoperative planning and intraoperative guidance tool. The major difference between VR and older technologies is the improved imaging in 3 dimensions for guidance, thereby potentially decreasing operative times.
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http://dx.doi.org/10.1097/GOX.0000000000002388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799397PMC
September 2019

Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe.

Proc Natl Acad Sci U S A 2019 08 12;116(35):17231-17238. Epub 2019 Aug 12.

OD Earth and History of Life, Royal Belgian Institute of Natural Sciences, 1000 Brussels, Belgium.

Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
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http://dx.doi.org/10.1073/pnas.1901169116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717267PMC
August 2019

Ancient cattle genomics, origins, and rapid turnover in the Fertile Crescent.

Science 2019 07;365(6449):173-176

Institut National des Sciences de l'Archéologie et du Patrimoine de Maroc (INSAP) Hay Riad, Madinat al Ifrane, Rabat Instituts, 10000 Rabat, Morocco.

Genome-wide analysis of 67 ancient Near Eastern cattle, remains reveals regional variation that has since been obscured by admixture in modern populations. Comparisons of genomes of early domestic cattle to their aurochs progenitors identify diverse origins with separate introgressions of wild stock. A later region-wide Bronze Age shift indicates rapid and widespread introgression of zebu, from the Indus Valley. This process was likely stimulated at the onset of the current geological age, ~4.2 thousand years ago, by a widespread multicentury drought. In contrast to genome-wide admixture, mitochondrial DNA stasis supports that this introgression was male-driven, suggesting that selection of arid-adapted zebu bulls enhanced herd survival. This human-mediated migration of zebu-derived genetics has continued through millennia, altering tropical herding on each continent.
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http://dx.doi.org/10.1126/science.aav1002DOI Listing
July 2019

Searching for meaning in sound: Learning and interpreting alarm signals in visual environments.

J Exp Psychol Appl 2020 Mar 8;26(1):89-107. Epub 2019 Jul 8.

Cognition Institute.

Given the ease with which the diverse array of environmental sounds can be understood, the difficulties encountered in using auditory alarm signals on medical devices are surprising. In two experiments, with nonclinical participants, alarm sets which relied on similarities to environmental sounds (concrete alarms, such as a heartbeat sound to indicate "check cardiovascular function") were compared to alarms using abstract tones to represent functions on medical devices. The extent to which alarms were acoustically diverse was also examined: alarm sets were either acoustically different or acoustically similar within each set. In Experiment 1, concrete alarm sets, which were also acoustically different, were learned more quickly than abstract alarms which were acoustically similar. Importantly, the abstract similar alarms were devised using guidelines from the current global medical device standard (International Electrotechnical Commission 60601-1-8, 2012). Experiment 2 replicated these findings. In addition, eye tracking data showed that participants were most likely to fixate first on the correct medical devices in an operating theater scene when presented with concrete acoustically different alarms using real world sounds. A new set of alarms which are related to environmental sounds and differ acoustically have therefore been proposed as a replacement for the current medical device standard. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/xap0000238DOI Listing
March 2020

Evaluation of aldosterone antagonist utilization in heart failure with reduced and preserved ejection fraction at an academic medical center.

Pharm Pract (Granada) 2019 Jan-Mar;17(1):1376. Epub 2019 Mar 10.

Medical University of South Carolina. Charleston, SC (United States).

Background: Aldosterone antagonists (AA) have historically been underutilized despite evidence that they reduce morbidity, mortality, and readmission rates to the hospital when used appropriately.

Objective: We sought to determine if AAs were being prescribed in accordance with the 2013 ACCF/AHA guidelines and if there was any benefit surrounding 30-day readmissions or 30-day mortality for patients taking AAs with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

Methods: We performed a retrospective chart review of adult patients who were discharged between October 1, 2015 and February 1, 2016 with any ICD-10 code for heart failure to assess compliance with guideline directed medical therapy. At baseline, patients were stratified by HFpEF and HFrEF. Patients were excluded if they died during the admission, discharged with hospice care, received a heart transplant or ventricular assist device, if they were miscoded or left against medical advice. Descriptive statistics, and Chi Square were used to evaluate the data.

Results: We reviewed 601 patient charts for eligibility in our study, and determined 438 met the criteria for inclusion. Ninety-seven patients (22%) received an AA. Within the HFrEF group, only 37% of patients who were eligible per 2013 ACCF/AHA guidelines, received an AA at time of discharge. Fourteen percent of HFpEF patients were discharged on an AA. We found a trend towards decreased rates of our 30-day outcomes in patients who took AAs in both the HFpEF and HFrEF groups.

Conclusions: AAs were underutilized during the timeframe we evaluated, despite the evidence for their use.
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http://dx.doi.org/10.18549/PharmPract.2019.1.1376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463419PMC
March 2019

Non-invasive imaging of disrupted protein homeostasis induced by proteasome inhibitor treatment using chemical exchange saturation transfer MRI.

Sci Rep 2018 10 10;8(1):15068. Epub 2018 Oct 10.

Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, WC1E 6DD, United Kingdom.

Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T, T). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types.
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http://dx.doi.org/10.1038/s41598-018-33549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180115PMC
October 2018

Recurrent Rathke's Cleft Cysts: Incidence and Surgical Management in a Tertiary Pituitary Center over 2 Decades.

Oper Neurosurg (Hagerstown) 2019 06;16(6):675-684

Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.

Background: Limited data exist pertaining to outcomes following surgery for recurrent Rathke's cleft cysts (RCC).

Objective: To determine treatment outcomes in patients undergoing reoperation for recurrent or residual RCCs.

Methods: A retrospective analysis of 112 consecutive RCC operations in 109 patients between 1995 and 2017 was conducted.

Results: Eighteen patients underwent 21 RCC reoperations with a mean follow-up of 58 mo. Patient symptoms prior to reoperation included headaches (14, 66.7%) and vision loss (12, 57.1%). Thirteen of 18 patients (72.2%) required hormone supplementation prior to reoperation including 5 with diabetes insipidus (DI). Mean RCC diameter was 16 mm and 76% had suprasellar extension. Compared to index RCC cases, intraoperative cerebrospinal fluid leak repair was more common in reoperation cases (15/21, 71% vs 43/91, 47%, P = .05). There was 1 carotid artery injury without neurological sequelae, and 2 postoperative cerebrospinal fluid (CSF) leaks (9.5%). Rates of transient hyponatremia (3/10, 30% vs 4/91, 4.4%, P = .04) and transient DI (5/10, 50% vs 17/91, 18.7%, P = .04) were higher in the reoperation vs index group. Improved headaches and vision were reported in 4/12 (33%) and 8/12 (61.5%) of RCC reoperation patients, respectively. Two patients developed new permanent DI. A higher proportion of reoperation patients had RCC squamous metaplasia (24% vs 5.4%, P = .02) or wall inflammation (42.9% vs 2.2%, P < .001) on pathological examination.

Conclusion: Reoperation for RCCs is generally safe at tertiary pituitary centers and often results in improved vision. Hypopituitarism is less likely to improve following reoperation for recurrent RCCs. Several histopathological features may help characterize "atypical RCCs" with a higher likelihood of recurrence/progression.
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http://dx.doi.org/10.1093/ons/opy258DOI Listing
June 2019

The Iceman's Last Meal Consisted of Fat, Wild Meat, and Cereals.

Curr Biol 2018 07 12;28(14):2348-2355.e9. Epub 2018 Jul 12.

SLING, Life Sciences Institute, National University of Singapore, Singapore; Department of Biochemistry, National University of Singapore, Singapore.

The history of humankind is marked by the constant adoption of new dietary habits affecting human physiology, metabolism, and even the development of nutrition-related disorders. Despite clear archaeological evidence for the shift from hunter-gatherer lifestyle to agriculture in Neolithic Europe [1], very little information exists on the daily dietary habits of our ancestors. By undertaking a complementary -omics approach combined with microscopy, we analyzed the stomach content of the Iceman, a 5,300-year-old European glacier mummy [2, 3]. He seems to have had a remarkably high proportion of fat in his diet, supplemented with fresh or dried wild meat, cereals, and traces of toxic bracken. Our multipronged approach provides unprecedented analytical depth, deciphering the nutritional habit, meal composition, and food-processing methods of this Copper Age individual.
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http://dx.doi.org/10.1016/j.cub.2018.05.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065529PMC
July 2018

Ancient goat genomes reveal mosaic domestication in the Fertile Crescent.

Science 2018 07;361(6397):85-88

Institut für Archäologische Wissenschaften, Goethe Universität, Frankfurt am Main, Germany.

Current genetic data are equivocal as to whether goat domestication occurred multiple times or was a singular process. We generated genomic data from 83 ancient goats (51 with genome-wide coverage) from Paleolithic to Medieval contexts throughout the Near East. Our findings demonstrate that multiple divergent ancient wild goat sources were domesticated in a dispersed process that resulted in genetically and geographically distinct Neolithic goat populations, echoing contemporaneous human divergence across the region. These early goat populations contributed differently to modern goats in Asia, Africa, and Europe. We also detect early selection for pigmentation, stature, reproduction, milking, and response to dietary change, providing 8000-year-old evidence for human agency in molding genome variation within a partner species.
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http://dx.doi.org/10.1126/science.aas9411DOI Listing
July 2018

Whole-genome resequencing reveals world-wide ancestry and adaptive introgression events of domesticated cattle in East Asia.

Nat Commun 2018 06 14;9(1):2337. Epub 2018 Jun 14.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.

Cattle domestication and the complex histories of East Asian cattle breeds warrant further investigation. Through analysing the genomes of 49 modern breeds and eight East Asian ancient samples, worldwide cattle are consistently classified into five continental groups based on Y-chromosome haplotypes and autosomal variants. We find that East Asian cattle populations are mainly composed of three distinct ancestries, including an earlier East Asian taurine ancestry that reached China at least ~3.9 kya, a later introduced Eurasian taurine ancestry, and a novel Chinese indicine ancestry that diverged from Indian indicine approximately 36.6-49.6 kya. We also report historic introgression events that helped domestic cattle from southern China and the Tibetan Plateau achieve rapid adaptation by acquiring ~2.93% and ~1.22% of their genomes from banteng and yak, respectively. Our findings provide new insights into the evolutionary history of cattle and the importance of introgression in adaptation of cattle to new environmental challenges in East Asia.
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http://dx.doi.org/10.1038/s41467-018-04737-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002414PMC
June 2018

Relationships between the spread of Caulerpa filiformis and fish communities on temperate rocky reefs.

J Fish Biol 2018 Jul;93(1):12-20

Centre for Marine Bio-innovation, School of Biological, Earth and Environmental Science, University of New South Wales, Sydney, Australia.

The previously sub-dominant native marine macrophyte Caulerpa filiformis is now dominant on many sub-tidal rocky reefs in New South Wales (NSW), Australia and is expanding its distribution. As C. filiformis is highly chemically defended and structurally different to co-occurring habitat-forming macrophytes, two key attributes that govern fish assemblages, we hypothesized that fish assemblages, particularly herbivorous fishes, would be different at sites where C. filiformis occurred from where it was previously absent and within sites, fish community structure would be correlated to the cover of C. filiformis. We investigated these hypotheses by determining reef-associated fish assemblage attributes (assemblage structure, species richness, total abundance, Shannon-Weiner diversity, abundance of herbivorous species) along transects within sites where C. filiformis was present and absent. Surprisingly, despite large patches and very high densities of C. filiformis on the reefs we sampled, at larger spatial scales (i.e., among sites) no fish assemblage metrics differed between sites with large stands of C. filiformis and sites without the alga. Moreover the abundance of one dominant herbivore, the rock cale Aplodactylus lophodon, was greater at sites within large beds of C. filiformis. At smaller spatial scales, however, i.e. within sites where C. filiformis was present, fish assemblages did vary as a function of C. filiformis cover along transects, although this was not consistent across sampling times. Overall, our results suggest that the potential effects of the spread of this alga on faunal communities warrants further investigation.
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http://dx.doi.org/10.1111/jfb.13664DOI Listing
July 2018

Long-term surgical outcomes following transsphenoidal surgery in patients with Rathke's cleft cysts.

J Neurosurg 2018 05;130(3):831-837

1Department of Neurological Surgery, and.

Objective: Rathke's cleft cysts (RCCs) are benign epithelial lesions of the sellar region typically treated via a transsphenoidal approach with cyst fenestration and drainage. At present, there is limited evidence to guide patient selection for operative treatment. Furthermore, there is minimal literature describing factors contributing to cyst recurrence.

Methods: The authors conducted a retrospective analysis of 109 consecutive cases of pathology-confirmed RCCs treated via a transsphenoidal approach at a single center from 1995 to 2016. The majority of cases (86.2%) involved cyst fenestration, drainage, and partial wall resection. Long-term outcomes were analyzed.

Results: A total of 109 surgeries in 100 patients were included, with a mean follow-up duration of 67 months (range 3-220 months). The mean patient age was 44.6 years (range 12-82 years), and 73% were women. The mean maximal cyst diameter was 14.7 mm. Eighty-eight cases (80.7%) were primary operations, and 21 (19.3%) were reoperations. Intraoperative CSF leak repair was performed in 53% of cases and was more common in reoperation cases (71% vs 48%, p < 0.001). There were no new neurological deficits or perioperative deaths. Two patients (1.8%) developed postoperative CSF leaks. Transient diabetes insipidus (DI) developed in 24 cases (22%) and permanent DI developed in 6 (5.5%). Seven cases (6.4%) developed delayed postoperative hyponatremia. Of the 66 patients with preoperative headache, 27 (44.3%) of 61 reported postoperative improvement and 31 (50.8%) reported no change. Of 31 patients with preoperative vision loss, 13 (48.1%) reported subjective improvement and 12 (44.4%) reported unchanged vision. Initial postoperative MRI showed a residual cyst in 25% of cases and no evidence of RCC in 75% of cases. Imaging revealed evidence of RCC recurrence or progression in 29 cases (26.6%), with an average latency of 28.8 months. Of these, only 10 (9.2% of the total 109 cases) were symptomatic and underwent reoperation.

Conclusions: Transsphenoidal fenestration and drainage of RCCs is a safe and effective intervention for symptomatic lesions, with many patients experiencing improvement of headaches and vision. RCCs show an appreciable (although usually asymptomatic) recurrence rate, thereby mandating serial follow-up. Despite this, full RCC excision is typically not recommended due to risk of hypopituitarism, DI, and CSF leaks.
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http://dx.doi.org/10.3171/2017.11.JNS171498DOI Listing
May 2018

Dual-Isotope Cryoimaging Quantitative Autoradiography: Investigating Antibody-Drug Conjugate Distribution and Payload Delivery Through Imaging.

J Nucl Med 2018 09 4;59(9):1461-1466. Epub 2018 May 4.

Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.

In vitro properties of antibody-drug conjugates (ADCs) such as binding, internalization, and cytotoxicity are often well characterized before in vivo studies. Interpretation of in vivo studies might be significantly enhanced by molecular imaging tools. We present here a dual-isotope cryoimaging quantitative autoradiography (CIQA) methodology combined with advanced 3-dimensional imaging and analysis allowing for the simultaneous study of both antibody and payload distribution in tissues of interest in a preclinical setting. TAK-264, an investigational ADC targeting anti-guanylyl cyclase C (GCC), was synthesized using tritiated monomethyl auristatin E. The tritiated ADC was then conjugated to diethylenetriaminepentaacetic acid, labeled with In, and evaluated in vivo in animals bearing GCC-positive and GCC-negative tumors. CIQA revealed the time course of drug release from ADC and its distribution into various tumor regions that are less accessible to the antibody. For GCC-positive tumors, a representative section obtained 96 h after tracer injection showed only 0.8% of the voxels to have colocalized signal, versus over 15% of the voxels for a GCC-negative tumor section, suggesting successful and specific cleaving of the toxin in the GCC-positive lesions. The combination of a veteran established autoradiography technology with advanced image analysis methodologies affords an experimental tool that can support detailed characterization of ADC tumor penetration and pharmacokinetics.
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http://dx.doi.org/10.2967/jnumed.118.207753DOI Listing
September 2018
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