Global and local ancestry estimation in a captive baboon colony.

The last couple of decades have highlighted the importance of studying hybridization, particularly among primate species, as it allows us to better understand our own evolutionary trajectory. Here, we report on genetic ancestry estimates using dense, full genome data from 881 olive (Papio anubus), yellow (Papio cynocephalus), or olive-yellow crossed captive baboons from the Southwest National Primate Research Center. We calculated global and local ancestry information, imputed low coverage genomes (n = 830) to improve marker quality, and updated the genetic resources of baboons available to assist future studies. We found evidence of historical admixture in some putatively purebred animals and identified errors within the Southwest National Primate Research Center pedigree. We also compared the outputs between two different phasing and imputation pipelines along with two different global ancestry estimation software. There was good agreement between the global ancestry estimation software, with R2 > 0.88, while evidence of phase switch errors increased depending on what phasing and imputation pipeline was used. We also generated updated genetic maps and created a concise set of ancestry informative markers (n = 1,747) to accurately obtain global ancestry estimates.

Identifying signatures of natural selection in Indian populations.

In this study, we present the results of a genome-wide scan for signatures of positive selection using data from four tribal groups (Kokana, Warli, Bhil, and Pawara) and two caste groups (Deshastha Brahmin and Kunbi Maratha) from West of the Maharashtra State In India, as well as two samples of South Asian ancestry from the 1KG project (Gujarati Indian from Houston, Texas and Indian Telugu from UK). We used an outlier approach based on different statistics, including PBS, xpEHH, iHS, CLR, Tajima's D, as well as two recently developed methods: Graph-aware Retrieval of Selective Sweeps (GRoSS) and Ascertained Sequentially Markovian Coalescent (ASMC). In order to minimize the risk of false positives, we selected regions that are outliers in all the samples included in the study using more than one method. We identified putative selection signals in 107 regions encompassing 434 genes. Many of the regions overlap with only one gene. The signals observed using microarray-based data are very consistent with our analyses using high-coverage sequencing data, as well as those identified with a novel coalescence-based method (ASMC). Importantly, at least 24 of these genomic regions have been identified in previous selection scans in South Asian populations or in other population groups. Our study highlights genomic regions that may have played a role in the adaptation of anatomically modern humans to novel environmental conditions after the out of Africa migration.

The hybrid skull of the eastern coyote (Canis latrans var.): Nonmetric traits and craniomandibular shape.

The increasing awareness that hybridization, and resultant gene flow, plays a major role in animal diversification has led to a growing number of studies that have focused on assessing the morphological consequences of this process. Analyses of mammalian hybrids have identified skeletal effects of hybridization, including a suite of anomalous dental and sutural traits on the skull that are present at high frequencies in hybrid populations. These studies have also detected consistent patterns of morphological shape and size differences between hybrids and parental taxa across a wide variety of organisms. However, more research is required to understand the universality of these traits and shape/size differences. Building on these previous studies, a sample of genetically determined canid hybrids was examined, specifically the eastern coyote (Canis latrans var.), a hybrid between coyotes, wolves, and dogs, to test whether this group exhibits a comparable pattern of anomalous nonmetric characters, and to assess differences in craniomandibular shape and size. First, specimens of C. latrans var., C. latrans, and C. lupus were scored for anomalous traits, including supernumerary and rotated teeth, dental crowding, and sutural anomalies. Geometric morphometric analyses were then conducted on a subset of these individuals to explore craniomandibular size and shape variation, as well as allometry. The results are largely consistent with other studies, indicating that the incidence of dental anomalies, dental crowding, and sutural anomalies is significantly higher in hybrids. However, differences are not significant for supernumerary teeth. The exploration of morphometric variation identifies intermediate morphology in the hybrids, and some indication of greater morphological variability in the mandible. When these results are combined with previous studies, they suggest that skeletal signatures of hybridization are common to different mammalian taxa across multiple generations; however, some traits such as supernumerary teeth may be lost after a few generations.

Integrating Active Learning and Transfer Learning for Carotid Intima-Media Thickness Video Interpretation.

Cardiovascular disease (CVD) is the number one killer in the USA, yet it is largely preventable (World Health Organization 2011). To prevent CVD, carotid intima-media thickness (CIMT) imaging, a noninvasive ultrasonography method, has proven to be clinically valuable in identifying at-risk persons before adverse events. Researchers are developing systems to automate CIMT video interpretation based on deep learning, but such efforts are impeded by the lack of large annotated CIMT video datasets. CIMT video annotation is not only tedious, laborious, and time consuming, but also demanding of costly, specialty-oriented knowledge and skills, which are not easily accessible. To dramatically reduce the cost of CIMT video annotation, this paper makes three main contributions. Our first contribution is a new concept, called Annotation Unit (AU), which simplifies the entire CIMT video annotation process down to six simple mouse clicks. Our second contribution is a new algorithm, called AFT (active fine-tuning), which naturally integrates active learning and transfer learning (fine-tuning) into a single framework. AFT starts directly with a pre-trained convolutional neural network (CNN), focuses on selecting the most informative and representative AU s from the unannotated pool for annotation, and then fine-tunes the CNN by incorporating newly annotated AU s in each iteration to enhance the CNN's performance gradually. Our third contribution is a systematic evaluation, which shows that, in comparison with the state-of-the-art method (Tajbakhsh et al., IEEE Trans Med Imaging 35(5):1299-1312, 2016), our method can cut the annotation cost by >81% relative to their training from scratch and >50% relative to their random selection. This performance is attributed to the several advantages derived from the advanced active, continuous learning capability of our AFT method.

Ancient human parallel lineages within North America contributed to a coastal expansion.

Little is known regarding the first people to enter the Americas and their genetic legacy. Genomic analysis of the oldest human remains from the Americas showed a direct relationship between a Clovis-related ancestral population and all modern Central and South Americans as well as a deep split separating them from North Americans in Canada. We present 91 ancient human genomes from California and Southwestern Ontario and demonstrate the existence of two distinct ancestries in North America, which possibly split south of the ice sheets. A contribution from both of these ancestral populations is found in all modern Central and South Americans. The proportions of these two ancestries in ancient and modern populations are consistent with a coastal dispersal and multiple admixture events.

Complementary landmarks facilitate ant navigation.

Visual landmarks are important navigational aids to many animals, and when more than one is available their juxtaposition can convey valuable new information to a navigator about progress toward a goal, depending on the landmarks' comparative distinctiveness. We investigated the effect of presenting rock ant colonies (Temnothorax albipennis) with identical horizontal landmarks either side of their route, versus one horizontal landmark paired with a sloping landmark, as they navigated to a new nest site. Our findings suggest that ants can obtain more navigational information from a combination of dissimilar landmarks: the average tortuosity of the route taken between old and new nests was significantly lower when a horizontal landmark was paired with a monotonically downward sloping landmark (the paths were more direct). The impact on available navigational information from the similarity or dissimilarity of nearby landmarks is likely made through more distinctive visual panoramas, and could be an influential factor in individual and collective animal decision-making about which routes are followed. Furthermore, the effect of landmark complementarity may be relevant to a wide range of species, including other insects or birds, and highlights the possibility that there is an intrinsic difference in the informational content of natural vs. artificial environments.

Left Ventricular Septal Hypertrophy in Elderly Patients With Aortic Stenosis.

OBJECTIVES: Left ventricular (LV) septal hypertrophy in aortic stenosis raises diagnostic and therapeutic questions. However, the etiology and clinical consequences of this finding have not been well studied. The aim of this study was to perform a morphologic evaluation of the LV in aortic stenosis and to investigate the contributing factors and consequences of septal hypertrophy. METHODS: Patients with moderate or severe aortic stenosis were prospectively enrolled. Patients with previous myocardial infarction, wall motion abnormalities, at least moderate valvular regurgitation, known cardiomyopathy, an LV ejection fraction of less than 50%, and age younger than 65 years were excluded. RESULTS: Forty-one patients underwent a final analysis. Septal hypertrophy (LV septal wall thickness ≥15 mm) was confirmed in 21 of 41 patients. The septal hypertrophy group had higher peak aortic valve velocity, a higher diabetes mellitus rate, and a higher rate and longer duration of hypertension than those without septal hypertrophy. The peak aortic valve velocity (odds ratio, 7.1; 95% confidence interval, 1.4-37.1) and diabetes mellitus (odds ratio, 7.4; 95% confidence interval, 1.2-46.2) were the significant factors associated with septal hypertrophy by multivariate analysis. Intraventricular conduction disturbance on electrocardiography was more frequent in the septal hypertrophy group (P = .021). CONCLUSIONS: Left ventricular septal hypertrophy was commonly observed in elderly patients with aortic stenosis, and a higher aortic valve velocity, hypertension, and diabetes mellitus were associated factors. Intraventricular conduction disturbance occurred more often in patients with septal hypertrophy than those without, which implies the pathophysiologic consequence. Further studies are needed to determine the impact of septal hypertrophy and intraventricular conduction disturbance on the prognosis of patients after aortic valve interventions.

Convolutional Neural Networks for Medical Image Analysis: Full Training or Fine Tuning?

Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data.

Risk Stratification for Cardiovascular Disease in Women in the Primary Care Setting.

BACKGROUND: Traditional risk assessment tools classify the majority of middle-aged women at low risk despite cardiovascular (CV) disease's affecting >50% of women and remaining the leading cause of death. Ultrasound-determined carotid intima-media thickness (CIMT) and/or computed tomographic coronary artery calcium score (CACS) quantify subclinical atherosclerosis and add incremental prognostic value. The aim of this study was to assess the utility of CIMT and CACS to detect subclinical atherosclerosis in younger women. METHODS: Asymptomatic women aged 50 to 65 years with at least one CV risk factor and low Framingham risk scores were identified prospectively at primary care and cardiology clinics. Mean intimal thickness, plaque on CIMT, and Agatston calcium score for CACS were obtained. RESULTS: Of 86 women (mean age, 58 ± 4.6 years; mean Framingham risk score, 1.9 ± 1.2; mean low-density lipoprotein cholesterol level, 138.9 ± 37.0 mg/dL), 53 (62%) had high-risk CIMT (51% plaque, 11% CIMT > 75th percentile). In contrast, three women (3.5%) had CACS > 100, all of whom had plaque by CIMT. Of the 58 women with CACS of 0, 32 (55%) had high-risk CIMT (48% plaque, 7% CIMT > 75th percentile). CONCLUSIONS: In patients referred by their physicians for assessment of CV risk, CIMT in asymptomatic middle-aged women with at least one CV risk factor and low risk by the Framingham risk score identified a large number with advanced subclinical atherosclerosis despite low CACS. Our results suggest that CIMT may be a more sensitive method for CV risk assessment than CACS or traditional risk tools in this population. Further studies are needed to determine if earlier detection would be of clinical benefit.

Papillary fibroelastoma of the pulmonary valve--a systematic review.

The pulmonary valve is the least affected site for valvular papillary fibroelastoma. With increasing use of routine echocardiography and other modalities of imaging, pulmonary valve papillary fibroelastomas (PVPFE) are being recognized more frequently. PVPFE is more often an incidental diagnosis and symptomatic patients usually present with shortness of breath. Embolic phenomena and right ventricular outflow tract obstruction are the most serious complications of PVPFE. Since PVPFE is rare, the purpose of this systematic review is to address demographic characteristics, the clinical presentation, management, and outcome of this benign tumor of the pulmonary valve.

Left ventricular assist devices: physiologic assessment using echocardiography for management and optimization.

Left ventricular assist devices (LVAD) are being deployed increasingly in patients with severe left ventricular dysfunction and medically refractory congestive heart failure of any etiology. The United States Food and Drug Administration (FDA) recently approved the use of the Thoratec Heartmate II (Thoratec Corporation, Pleasanton, CA, USA) for outpatient use. Echocardiography is fundamental during each stage of patient management, pre-LVAD placement, during LVAD placement, for postoperative LVAD optimization and long-term follow-up. We present a pragmatic and systematic echocardiographic approach that serves as a guide for the management of left ventricular assist devices.

Carotid intimal-medial thickness in active professional American football players aged 23 to 35 years.

Risk of cardiovascular disease and death in retired professional American football players may be higher than that in the general population. Previously published data have demonstrated that American football players have less glucose intolerance, less smoking, similar lipid profiles, and higher blood pressure despite a much larger body compared to the general population, although the presence of subclinical atherosclerosis in these subjects has not been evaluated. This study compared the prevalence of subclinical atherosclerosis in active professional American football players to that in age-, gender-, and race-matched controls derived from the Bogalusa Heart Study. Carotid intimal-medial thickness (CIMT) was used as an indicator of subclinical atherosclerosis in 75 active American football players (23 to 35 years old, 31 white, 44 African-American) as measured by B-mode ultrasonography at Mayo Clinic, Scottsdale, Arizona, on September 13 and 14, 2009. CIMT measurements of 75 athletes were compared to those of 518 matched controls who had CIMT determinations in 1995 and 1996. Two-group t tests determined population similarities between groups. In a generalized linear model, players (overall and by race) had lower CIMT values than controls after age and race adjustment (p <0.001 for all comparisons). Nonlinemen and linemen had lower CIMT values than controls (p < 0.001 and p = 0.004, respectively). In conclusion, active professional American football players, regardless of position, had mean CIMT values similar to or lower than those in a matched general population cohort, suggesting that if the prevalence of subclinical atherosclerosis is increased in retired professional American football players, this occurs after retirement.

Synthesis of potent and orally efficacious 11ß-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016.

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11ß-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11ß-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.

Parachute mitral valve in adults-a systematic overview.

Parachute mitral valve (PMV) is a rare congenital anomaly of the mitral valve apparatus seen in infants and young children. In most instances PMV is associated with other congenital anomalies of the heart, in particular obstructive lesions of the mitral inflow (mitral valve ring) and left ventricular outflow tract (subaortic stenosis), and coarctation of aorta and is referred to as Shone's complex or Shone's anomaly. PMV may also occur as an isolated lesion or in association with other congenital cardiac anomalies. Not much is known about PMV in adults as an isolated anomaly or in association with other congenital cardiac anomalies. We reviewed the literature to identify cases of PMV (isolated or associated with other lesions) in adults, to address prevalence, clinical presentation, diagnosis, treatment, and outcome of such patients. (Echocardiography 2010;27:581-586).

Incidence of subclinical atherosclerosis as a marker of cardiovascular risk in retired professional football players.

The purpose of this study was to evaluate subclinical atherosclerosis in retired professional football players. Two hundred one healthy former professional football players (mean age 50.8 years; mean body mass index 31.5 kg/m(2)) were screened for the prevalence of cardiovascular risk factors, metabolic syndrome, and subclinical atherosclerosis by carotid artery ultrasound and compared with a cohort of men of similar body mass index referred for the assessment of subclinical atherosclerosis by carotid ultrasound. The prevalence of carotid artery plaque in the players was not significantly different from that of the body mass index-matched patients (33.3% vs 29.3%, p = 0.45). For the 2 groups, the prevalence of carotid artery plaque was >3 times higher than that reported in general population studies of patients with the same age range, gender, and exclusions. Metabolic syndrome prevalence was higher in linemen than in nonlinemen (45.8% vs 22.5%, p = 0.001), but there was no statistical difference in plaque presence between linemen and nonlinemen (27.1% vs 35.9%, p = 0.23). In conclusion, despite their elite athletic histories, former professional football players have a similar prevalence of advanced subclinical atherosclerosis as a clinically referred population of overweight and obese men.

HPLC determinations of enantiomeric ratios.

Evaporative light-scattering detection (ELSD) is widely applied in the HPLC analysis of organic compounds lacking a UV chromophore. However, this detection method is generally unsuitable for determination of enantiomeric ratios (er). The er calculated from a UV trace and an ELS trace of the same compound differs significantly. Because of the nonlinear concentration response of the ELS detector, a compound with an er of 95:5 appears to be enantiomerically pure by ELS detection. It is possible to obtain a calibration curve and to calculate a correction factor, but this procedure is time consuming and therefore not very practical for routine analyses. In contrast, a charged aerosol detector allows a very accurate determination of the enantiomeric ratios. Like the ELS detection, the CA detection is independent of the chromophore properties of the substrate. Therefore, we recommend the use of CA instead of ELS detection for determination of the enantiomeric ratios of non-UV active compounds.

Structure and reactivity of a new anionic N-heterocyclic carbene silver(I) complex.

The efficient synthesis of aN-benzoyliminoimidazolium ylide provides access to a new type of N-hetereocyclic anionic carbene, from which air stable Ag(I) and Cu(II) complexes and a catalytically active Rh(I) complex were formed.

A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development.

Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. In this article, we report the synthesis and identification of novel PXR agonists from a library of peptide isosteres. Compound S20, a C-cyclopropylalkylamide, was found to be a PXR agonist with both enantiomer- and species-specific selectivity. S20 has three chiral carbons and was resolved into its two enantiomers. The individual S20 enantiomers exhibited striking mouse/human-specific PXR activation, whereby enantiomer (+)-S20 preferentially activated hPXR, and enantiomer (-)-S20 was a better activator for mPXR. As a human PXR (hPXR) agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the ligand binding domain residue Phe305 is critical for the preference for the (-)-S20 enantiomer by the rodent PXR. Treatment of S20 induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays, in primary human hepatocytes, and in "humanized" hPXR transgenic mice. To our knowledge, S20 represents the first compound whose enantiomers have opposite species preference in activating a xenobiotic receptor. The stereoselectivity may be used to guide the development of safer drugs to avoid drug-drug interactions or to achieve human-specific therapeutic effects when a xenobiotic receptor is being used as a drug target.