Publications by authors named "Susan Walsh"

128 Publications

Improving Referrals to Preschool Special Education in Pediatric Primary Care.

J Pediatr Health Care 2021 Jun 28. Epub 2021 Jun 28.

Introduction: The American Academy of Pediatrics created evidence-based guidelines that encourage early identification and referral for children with developmental delays. Although pediatric primary care providers are poised to link 3-to-5-year-old children to school-based services, there are gaps in making referrals.

Method: Educational dissemination of streamlined referral packets was introduced. Knowledge and perceived confidence were measured following an educational presentation. Retrospective chart reviews compared referral rates to preschool special education services when developmental delays were identified.

Results: Mean pretest to posttest knowledge and perceived confidence to refer children to preschool special education increased following education. Referral rates for 3-5 years-old by pediatric primary care providers doubled during the initial 8-week implementation period and remained constant 9 months later.

Discussion: Educational dissemination of a streamlined referral process in pediatric primary care is a sustainable approach that ensures preschool-aged children with developmental delays receive timely referrals for further school-based evaluations and interventions.
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http://dx.doi.org/10.1016/j.pedhc.2021.05.003DOI Listing
June 2021

Large-scale open-source three-dimensional growth curves for clinical facial assessment and objective description of facial dysmorphism.

Sci Rep 2021 Jun 9;11(1):12175. Epub 2021 Jun 9.

Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.
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http://dx.doi.org/10.1038/s41598-021-91465-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190313PMC
June 2021

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies.

PLoS Genet 2021 May 13;17(5):e1009528. Epub 2021 May 13.

Department of Human Genetics, KU Leuven, Leuven, Belgium.

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.
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http://dx.doi.org/10.1371/journal.pgen.1009528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118281PMC
May 2021

A Telehealth Initiative to Decrease No-Show Rates in a Pediatric Asthma Mobile Clinic.

J Pediatr Nurs 2021 Jul-Aug;59:143-150. Epub 2021 Apr 19.

University of Illinois at Chicago, Chicago, IL, United States of America. Electronic address:

Background/problem: Failed patient care appointments (no-shows) can lead to negative patient health outcomes and increased healthcare costs. There is evidence that telehealth is a safe, effective, and a cost-efficient option for those unable to attend in-person visits. No-show rates in pediatrics are unique due to reliance on caregivers to attend appointments. A pediatric asthma mobile van, which provides specialty care to children at schools in low-income communities in Chicago, was experiencing a high no-show rate.

Methods/interventions: Building on evidence that the use of telehealth technology improves access to care, the purpose of this quality improvement initiative was to implement a new telehealth option for off-site parents to attend their child's on-site appointment. The designed initiative followed the Plan-Do-Study-Act model with three small phases of change. The first phase assessed telehealth interest using a Likert-scale questionnaire. The second phase designed and implemented a telehealth option and collected no-show rates pre- and post- implementation. The final phase assessed parental satisfaction using a Telehealth Usability Questionnaire.

Results: Over 50% of participants stated interest in the parent off-site telehealth option for their child's appointment. No-show rates decreased from 36% to 7.9%-18% per month over a 10-month implementation period. Post-telehealth surveys completed by parents revealed this version of telehealth improved access to care for their child, saved them time, and was simple to use.

Conclusion: No-show rates decreased after successful implementation of an innovative approach to telehealth. This parent off-site telehealth model can be another approach toward increasing pediatric healthcare access.
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http://dx.doi.org/10.1016/j.pedn.2021.04.005DOI Listing
July 2021

Evaluation of supervised machine-learning methods for predicting appearance traits from DNA.

Forensic Sci Int Genet 2021 07 23;53:102507. Epub 2021 Mar 23.

Cologne Center for Genomics, University of Cologne, Cologne, Germany; Faculty of Medicine and the Cologne University Hospital, Cologne, Germany. Electronic address:

The prediction of human externally visible characteristics (EVCs) based solely on DNA information has become an established approach in forensic and anthropological genetics in recent years. While for a large set of EVCs, predictive models have already been established using multinomial logistic regression (MLR), the prediction performances of other possible classification methods have not been thoroughly investigated thus far. Motivated by the question to identify a potential classifier that outperforms these specific trait models, we conducted a systematic comparison between the widely used MLR and three popular machine learning (ML) classifiers, namely support vector machines (SVM), random forest (RF) and artificial neural networks (ANN), that have shown good performance outside EVC prediction. As examples, we used eye, hair and skin color categories as phenotypes and genotypes based on the previously established IrisPlex, HIrisPlex, and HIrisPlex-S DNA markers. We compared and assessed the performances of each of the four methods, complemented by detailed hyperparameter tuning that was applied to some of the methods in order to maximize their performance. Overall, we observed that all four classification methods showed rather similar performance, with no method being substantially superior to the others for any of the traits, although performances varied slightly across the different traits and more so across the trait categories. Hence, based on our findings, none of the ML methods applied here provide any advantage on appearance prediction, at least when it comes to the categorical pigmentation traits and the selected DNA markers used here.
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http://dx.doi.org/10.1016/j.fsigen.2021.102507DOI Listing
July 2021

Shared heritability of human face and brain shape.

Nat Genet 2021 06 5;53(6):830-839. Epub 2021 Apr 5.

Department of Human Genetics, KU Leuven, Leuven, Belgium.

Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain-face cross-talk. Brain shape heritability is equivalently enriched near regulatory regions active in either forebrain organoids or facial progenitors. However, we do not detect significant overlap between shared brain-face genome-wide association study signals and variants affecting behavioral-cognitive traits. These results suggest that early in embryogenesis, the face and brain mutually shape each other through both structural effects and paracrine signaling, but this interplay may not impact later brain development associated with cognitive function.
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http://dx.doi.org/10.1038/s41588-021-00827-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232039PMC
June 2021

Defining breast cancer awareness and identifying barriers to breast cancer awareness for women with an intellectual disability: A review of the literature.

J Intellect Disabil 2021 Mar 26:1744629521999548. Epub 2021 Mar 26.

8795University College Cork, Ireland.

Introduction: Incidence rates for developing breast cancer are similar for women regardless of intellectual ability. However, women with an intellectual disability present with advanced breast cancers, which often have a poor prognosis.

Method: A structured narrative review of the literature was performed to explore the concepts of breast awareness and breast cancer awareness and subsequently, identify barriers to breast cancer awareness encountered by women with an intellectual disability.

Results: A total of 22 studies involving people with varying levels of intellectual disability informed this review. The barriers to breast cancer awareness encountered by women with an intellectual disability include: lack of their understanding, the role of the carer and literacy issues.

Conclusion: Identifying the barriers to breast cancer awareness for women with an intellectual disability will help to facilitate breast cancer awareness which has the potential to result in better long-term outcomes through an early diagnosis of breast cancer.
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http://dx.doi.org/10.1177/1744629521999548DOI Listing
March 2021

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation.

Front Genet 2021 22;12:626403. Epub 2021 Feb 22.

Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance ( ≤ 0.05) and 52 segments at Bonferroni corrected significance ( < 1.2 × 10), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated ( < 5 × 10) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold ( < 8.47 × 10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.
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http://dx.doi.org/10.3389/fgene.2021.626403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937973PMC
February 2021

Fluctuating Asymmetry and Sexual Dimorphism in Human Facial Morphology: A Multi-Variate Study.

Symmetry (Basel) 2021 Feb 10;13(2). Epub 2021 Feb 10.

Evolutionary Ecology Group, Department of Biology, University of Antwerp, 2610 Antwerp, Belgium.

Background: Fluctuating asymmetry is often used as an indicator of developmental instability, and is proposed as a signal of genetic quality. The display of prominent masculine phenotypic features, which are a direct result of high androgen levels, is also believed to be a sign of genetic quality, as these hormones may act as immunosuppressants. Fluctuating asymmetry and masculinity are therefore expected to covary. However, there is lack of strong evidence in the literature regarding this hypothesis.

Materials And Methods: In this study, we examined a large dataset of high-density 3D facial scans of 1260 adults (630 males and 630 females). We mapped a high-density 3D facial mask onto the facial scans in order to obtain a high number of quasi-landmarks on the faces. Multi-dimensional measures of fluctuating asymmetry were extracted from the landmarks using Principal Component Analysis, and masculinity/femininity scores were obtained for each face using Partial Least Squares. The possible correlation between these two qualities was then examined using Pearson's coefficient and Canonical Correlation Analysis.

Results: We found no correlation between fluctuating asymmetry and masculinity in men. However, a weak but significant correlation was found between average fluctuating asymmetry and masculinity in women, in which feminine faces had higher levels of fluctuating asymmetry on average. This correlation could possibly point to genetic quality as an underlying mechanism for both asymmetry and masculinity; however, it might also be driven by other fitness or life history traits, such as fertility.

Conclusions: Our results question the idea that fluctuating asymmetry and masculinity should be (more strongly) correlated in men, which is in line with the recent literature. Future studies should possibly focus more on the evolutionary relevance of the observed correlation in women.
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http://dx.doi.org/10.3390/sym13020304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929517PMC
February 2021

Effects of Male Facial Masculinity on Perceived Attractiveness.

Adapt Human Behav Physiol 2021 Mar 12;7(1):73-88. Epub 2020 Nov 12.

Evolutionary Ecology Group, Department of Biology, University of Antwerp, Antwerp, Belgium.

Studies suggest that high levels of masculinity in men can be a signal of 'better genes' as well as low parental investment. It is the trade-off between these two qualities that has led to the hypothesis that women's preferences for male masculinity are condition-dependent, yet, not all studies support this hypothesis. In addition, there is evidence that more average faces would be perceived as more attractive. Here we study the variation in masculinity preferences of a cohort of heterosexual women (n=769), using manipulated 3D faces of male subjects. We used linear mixed models to test for effects of various covariates such as relationship status, use of hormonal contraception, sociosexual orientation and self-perceived attractiveness on preference for masculinity. Our results show that women's sociosexual orientation has a positive correlation with masculinity preference while using hormonal contraception decreases this preference. None of the other covariates displayed any significant effect on masculinity preference. The initial level of masculinity of the faces (very low, low, average, high and very high) was also shown to affect this preference, where we found a significant preference for higher masculinity in the very low and average group, while no preference was found in the other groups. Our findings support the notion that condition-dependent variables have very small effects, if any, on women's preference for masculinity in men.
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http://dx.doi.org/10.1007/s40750-020-00156-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872150PMC
March 2021

A Multivariate Approach to Determine the Dimensionality of Human Facial Asymmetry.

Symmetry (Basel) 2020 Mar 1;12(3). Epub 2020 Mar 1.

Evolutionary Ecology Group, Department of Biology, University of Antwerp, 2610 Antwerp, Belgium; stefan.

Many studies have suggested that developmental instability (DI) could lead to asymmetric development, otherwise known as fluctuating asymmetry (FA). Several attempts to unravel the biological meaning of FA have been made, yet the main step in estimating FA is to remove the effects of directional asymmetry (DA), which is defined as the average bilateral asymmetry at the population level. Here, we demonstrate in a multivariate context that the conventional method of DA correction does not adequately compensate for the effects of DA in other dimensions of asymmetry. This appears to be due to the presence of between-individual variation along the DA dimension. Consequently, we propose to decompose asymmetry into its different orthogonal dimensions, where we introduce a new measure of asymmetry, namely fluctuating directional asymmetry (F-DA). This measure describes individual variation in the dimension of DA, and can be used to adequately correct the asymmetry measurements for the presence of DA. We provide evidence that this measure can be useful in disentangling the different dimensions of asymmetry, and further studies on this measure can provide valuable insight into the underlying biological processes leading to these different asymmetry dimensions.
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http://dx.doi.org/10.3390/sym12030348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872143PMC
March 2020

Insights into the genetic architecture of the human face.

Nat Genet 2021 01 7;53(1):45-53. Epub 2020 Dec 7.

Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.
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http://dx.doi.org/10.1038/s41588-020-00741-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796995PMC
January 2021

Testing the impact of trait prevalence priors in Bayesian-based genetic prediction modeling of human appearance traits.

Forensic Sci Int Genet 2021 01 4;50:102412. Epub 2020 Nov 4.

Cologne Center for Genomics, University of Cologne, Cologne, Germany; University Hospital Cologne, Cologne, Germany. Electronic address:

The prediction of appearance traits by use of solely genetic information has become an established approach and a number of statistical prediction models have already been developed for this purpose. However, given limited knowledge on appearance genetics, currently available models are incomplete and do not include all causal genetic variants as predictors. Therefore such prediction models may benefit from the inclusion of additional information that acts as a proxy for this unknown genetic background. Use of priors, possibly informed by trait category prevalence values in biogeographic ancestry groups, in a Bayesian framework may thus improve the prediction accuracy of previously predicted externally visible characteristics, but has not been investigated as of yet. In this study, we assessed the impact of using trait prevalence-informed priors on the prediction performance in Bayesian models for eye, hair and skin color as well as hair structure and freckles in comparison to the respective prior-free models. Those prior-free models were either similarly defined either very close to the already established ones by using a reduced predictive marker set. However, these differences in the number of the predictive markers should not affect significantly our main outcomes. We observed that such priors often had a strong effect on the prediction performance, but to varying degrees between different traits and also different trait categories, with some categories barely showing an effect. While we found potential for improving the prediction accuracy of many of the appearance trait categories tested by using priors, our analyses also showed that misspecification of those prior values often severely diminished the accuracy compared to the respective prior-free approach. This emphasizes the importance of accurate specification of prevalence-informed priors in Bayesian prediction modeling of appearance traits. However, the existing literature knowledge on spatial prevalence is sparse for most appearance traits, including those investigated here. Due to the limitations in appearance trait prevalence knowledge, our results render the use of trait prevalence-informed priors in DNA-based appearance trait prediction currently infeasible.
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http://dx.doi.org/10.1016/j.fsigen.2020.102412DOI Listing
January 2021

The impact of correlations between pigmentation phenotypes and underlying genotypes on genetic prediction of pigmentation traits.

Forensic Sci Int Genet 2021 01 24;50:102395. Epub 2020 Sep 24.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address:

Predicting appearance phenotypes from genotypes is relevant for various areas of human genetic research and applications such as genetic epidemiology, human history, anthropology, and particularly in forensics. Many appearance phenotypes, and thus their underlying genotypes, are highly correlated, with pigmentation traits serving as primary examples. However, all available genetic prediction models, including those for pigmentation traits currently used in forensic DNA phenotyping, ignore phenotype correlations. Here, we investigated the impact of appearance phenotype correlations on genetic appearance prediction in the exemplary case of three pigmentation traits. We used data for categorical eye, hair and skin colour as well as 41 DNA markers utilized in the recently established HIrisPlex-S system from 762 individuals with complete phenotype and genotype information. Based on these data, we performed genetic prediction modelling of eye, hair and skin colour via three different strategies, namely the established approach of predicting phenotypes solely based on genotypes while not considering phenotype correlations, and two novel approaches that considered phenotype correlations, either incorporating truly observed correlated phenotypes or DNA-predicted correlated phenotypes in addition to the DNA predictors. We found that using truly observed correlated pigmentation phenotypes as additional predictors increased the DNA-based prediction accuracies for almost all eye, hair and skin colour categories, with the largest increase for intermediate eye colour, brown hair colour, dark to black skin colour, and particularly for dark skin colour. Outcomes of dedicated computer simulations suggest that this prediction accuracy increase is due to the additional genetic information that is implicitly provided by the truly observed correlated pigmentation phenotypes used, yet not covered by the DNA predictors applied. In contrast, considering DNA-predicted correlated pigmentation phenotypes as additional predictors did not improve the performance of the genetic prediction of eye, hair and skin colour, which was in line with the results from our computer simulations. Hence, in practical applications of DNA-based appearance prediction where no phenotype knowledge is available, such as in forensic DNA phenotyping, it is not advised to use DNA-predicted correlated phenotypes as predictors in addition to the DNA predictors. In the very least, this is not recommended for the pigmentation traits and the established pigmentation DNA predictors tested here.
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http://dx.doi.org/10.1016/j.fsigen.2020.102395DOI Listing
January 2021

Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes.

Cell Metab 2020 10;32(4):561-574.e7

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, IA, USA.

Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.
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http://dx.doi.org/10.1016/j.cmet.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819711PMC
October 2020

The Evolution of Duplicated Genes of the Cpi-17/Phi-1 () Family of Protein Phosphatase 1 Inhibitors in Teleosts.

Int J Mol Sci 2020 Aug 9;21(16). Epub 2020 Aug 9.

Department of Biological Sciences, University of the Pacific, Stockton, CA 98211, USA.

The Cpi-17 () gene family is an evolutionarily conserved, vertebrate specific group of protein phosphatase 1 (PP1) inhibitors. When phosphorylated, Cpi-17 is a potent inhibitor of myosin phosphatase (MP), a holoenzyme complex of the regulatory subunit Mypt1 and the catalytic subunit PP1. Myosin phosphatase dephosphorylates the regulatory myosin light chain (Mlc2) and promotes actomyosin relaxation, which in turn, regulates numerous cellular processes including smooth muscle contraction, cytokinesis, cell motility, and tumor cell invasion. We analyzed zebrafish homologs of the Cpi-17 family, to better understand the mechanisms of myosin phosphatase regulation. We found single homologs of both Kepi () and Gbpi () in silico, but we detected no expression of these genes during early embryonic development. Cpi-17 () and Phi-1 () each had two duplicate paralogs, ( and ) and ( and ), which were each expressed during early development. The spatial expression pattern of these genes has diverged, with and expressed primarily in smooth muscle and skeletal muscle, respectively, while and are primarily expressed in neural tissue. We observed that, in in vitro and heterologous cellular systems, the Cpi-17 paralogs both acted as potent myosin phosphatase inhibitors, and were indistinguishable from one another. In contrast, the two Phi-1 paralogs displayed weak myosin phosphatase inhibitory activity in vitro, and did not alter myosin phosphorylation in cells. Through deletion and chimeric analysis, we identified that the difference in specificity for myosin phosphatase between Cpi-17 and Phi-1 was encoded by the highly conserved PHIN (phosphatase holoenzyme inhibitory) domain, and not the more divergent N- and C- termini. We also showed that either Cpi-17 paralog can rescue the knockdown phenotype, but neither Phi-1 paralog could do so. Thus, we provide new evidence about the biochemical and developmental distinctions of the zebrafish Cpi-17 protein family.
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http://dx.doi.org/10.3390/ijms21165709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460850PMC
August 2020

Robust genome-wide ancestry inference for heterogeneous datasets: illustrated using the 1,000 genome project with 3D facial images.

Sci Rep 2020 07 16;10(1):11850. Epub 2020 Jul 16.

Medical Imaging Research Center, MIRC, University Hospitals Leuven, Leuven, Belgium.

Estimates of individual-level genomic ancestry are routinely used in human genetics, and related fields. The analysis of population structure and genomic ancestry can yield insights in terms of modern and ancient populations, allowing us to address questions regarding admixture, and the numbers and identities of the parental source populations. Unrecognized population structure is also an important confounder to correct for in genome-wide association studies. However, it remains challenging to work with heterogeneous datasets from multiple studies collected by different laboratories with diverse genotyping and imputation protocols. This work presents a new approach and an accompanying open-source toolbox that facilitates a robust integrative analysis for population structure and genomic ancestry estimates for heterogeneous datasets. We show robustness against individual outliers and different protocols for the projection of new samples into a reference ancestry space, and the ability to reveal and adjust for population structure in a simulated case-control admixed population. Given that visually evident and easily recognizable patterns of human facial characteristics co-vary with genomic ancestry, and based on the integration of three different sources of genome data, we generate average 3D faces to illustrate genomic ancestry variations within the 1,000 Genome project and for eight ancient-DNA profiles, respectively.
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http://dx.doi.org/10.1038/s41598-020-68259-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367291PMC
July 2020

Hayes Yard virus: a novel ephemerovirus isolated from a bull with severe clinical signs of bovine ephemeral fever is most closely related to Puchong virus.

Vet Res 2020 Apr 29;51(1):58. Epub 2020 Apr 29.

CSIRO Health and Biosecurity, Australian Animal Health Laboratory, 5 Portarlington Road, Geelong, VIC, 3220, Australia.

Bovine ephemeral fever is a vector-borne disease of ruminants that occurs in tropical and sub-tropical regions of Africa, Asia and Australia. The disease is caused by a rhabdovirus, bovine ephemeral fever virus (BEFV), which occurs as a single serotype globally. Although several other closely related ephemeroviruses have been isolated from cattle and/or arthropods, only kotonkan virus from Nigeria and (tentatively) Mavingoni virus from Mayotte Island in the Indian Ocean have been previously associated with febrile disease. Here, we report the isolation of a novel virus (Hayes Yard virus; HYV) from blood collected in February 2000 from a bull (Bos indicus) in the Northern Territory of Australia. The animal was suffering from a severe ephemeral fever-like illness with neurological involvement, including recumbency and paralysis, and was euthanised. Histological examination of spinal cord and lung tissue identified extensive haemorrhage in the dura mata with moderate perineuronal oedema and extensive emphysema. HYV displayed cone-shaped morphology, typical of rhabdoviruses, and was found to be most closely related antigenically to Puchong virus (PUCV), isolated in 1965 from mosquitoes in Malaysia. Analysis of complete genome sequences of HYV (15 025 nt) and PUCV (14 932 nt) indicated that each has a complex organisation (3' N-P-M-G-G-α1-α2-β-γ-L 5') and expression strategy, similar to that of BEFV. Based on an alignment of complete L protein sequences, HYV and PUCV cluster with other rhabdoviruses in the genus Ephemerovirus and appear to represent two new species. Neutralising antibody to HYV was also detected in a retrospective survey of cattle sera collected in the Northern Territory.
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http://dx.doi.org/10.1186/s13567-020-00781-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191811PMC
April 2020

Three dimensional (3D) printed polylactic acid with nano-hydroxyapatite doped with europium(III) ions (nHAp/[email protected]) composite for osteochondral defect regeneration and theranostics.

Mater Sci Eng C Mater Biol Appl 2020 May 9;110:110634. Epub 2020 Jan 9.

Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, PL-50-422 Wroclaw, Poland; Centre for Advanced Materials and Smart Structures, Polish Academy of Sciences, Okolna 2, 50-950 Wroclaw, Poland. Electronic address:

In the current research previously developed composites composed from poly (l-lactide) (PLLA) and nano-hydroxyapatite (10 wt% nHAp/PLLA) were functionalized with different concentrations of europium (III) (Eu). The aim of this study was to determine whether Eu ions doped within the 10 wt% nHAp/PLLA scaffolds will improve the bioactivity of composites. Therefore, first set of experiments was designed to evaluate the effect of Eu ions on morphology, viability, proliferation and metabolism of progenitor cells isolated from adipose tissue (hASC). Three different concentration were tested i.e. 1 mol%, 3 mol% and 5%mol. We identified the 10 wt% nHAp/[email protected] mol% Eu scaffolds as the most cytocompatible. Further, we investigated the influence of the composites doped with 3 mol% Eu ions on differentiation of hASC toward bone and cartilage forming cells. Our results showed that 10 wt% nHAp/[email protected] mol% Eu scaffolds promotes osteogenesis and chondrogenesis of hASCs what was associated with improved synthesis and secretion of extracellular matrix proteins specific for bone and articular cartilage tissue. We also proved that obtained biomaterials have bio-imaging function and their integration with bone can be monitored using micro computed tomography (μCT).
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http://dx.doi.org/10.1016/j.msec.2020.110634DOI Listing
May 2020

HIrisPlex-S system for eye, hair, and skin color prediction from DNA: Massively parallel sequencing solutions for two common forensically used platforms.

Forensic Sci Int Genet 2019 11 26;43:102152. Epub 2019 Aug 26.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address:

Forensic DNA Phenotyping (FDP) provides the ability to predict externally visible characteristics from minute amounts of crime scene DNA, which can help find unknown perpetrators who are typically unidentifiable via conventional forensic DNA profiling. Fundamental human genetics research has led to a better understanding of the specific DNA variants responsible for physical appearance characteristics, particularly eye, hair, and skin color. Recently, we introduced the HIrisPlex-S system for the simultaneous prediction of eye, hair, and skin color based on 41 DNA variants generated from two forensically validated SNaPshot multiplex assays using capillary electrophoresis (CE). Here we introduce massively parallel sequencing (MPS) solutions for the HIrisPlex-S (HPS) system on two MPS platforms commonly used in forensics, Ion Torrent and MiSeq, that cover all 41 DNA variants in a single assay, respectively. Additionally, we present the forensic developmental validation of the two HPS-MPS assays. The Ion Torrent MPS assay, based on Ion AmpliSeq technology, illustrated the successful generation of full HIrisPlex-S genotypic profiles from 100 pg of input control DNA, while the MiSeq MPS assay based on an in-house design yielded complete profiles from 250 pg of input DNA. Assessing simulated forensic casework samples such as saliva, hair (bulb), blood, semen, and low quantity touch DNA, as well as artificially damaged DNA samples, concordance testing, and samples from numerous species, all illustrated the ability of both versions of the HIrisPlex-S MPS assay to produce results that motivate forensic applications. By also providing an integrated bioinformatics analysis pipeline, MPS data can now be analyzed and a file generated for upload to the publically accessible HIrisPlex online webtool (https://hirisplex.erasmusmc.nl). In addition, we updated the website to accept VCF input data for those with genome sequence data. We thus provide a user-friendly and semi-automated MPS workflow from DNA sample to individual eye, hair, and skin color prediction probabilities. Furthermore, we present a 2-person mixture separation tool that not only assesses genotype reliability with regards genotyping confidence but also provides the most fitting mixture scenario for both minor and major contributors, including profile separation. We envision this MPS implementation of the HIrisPlex-S system for eye, hair, and skin color prediction from DNA as a starting point for further expanding MPS-based forensic DNA phenotyping. This may include the future addition of SNPs predictive for more externally visible characteristics, as well as SNPs for bio-geographic ancestry inference, provided the statistical framework for DNA prediction of these traits is in place.
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http://dx.doi.org/10.1016/j.fsigen.2019.102152DOI Listing
November 2019

DNA Testing Reveals the Putative Identity of JB55, a 19th Century Vampire Buried in Griswold, Connecticut.

Genes (Basel) 2019 08 22;10(9). Epub 2019 Aug 22.

Armed Forces Medical Examiner System's Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, Dover, DE 19902, USA.

In 1990 in Griswold, Connecticut, archaeologists excavated a burial found in a "skull and crossbones" orientation. The lid of the 19th century coffin had brass tacks that spelled "JB55", the initials of the person lying there and age at death. JB55 had evidence of chronic pulmonary infection, perhaps tuberculosis. It is possible that JB55 was deemed a vampire due to his disease, and therefore had to be "killed" by mutilating his corpse. In an attempt to reveal the identity of JB55, DNA testing was performed. Ancestry informative single nucleotide polymorphism (SNP) analysis using the Precision ID Ancestry Panel indicated European ancestry. A full Y-chromosomal short tandem repeat (Y-STR) profile was obtained, belonging to haplogroup R1b. When the Y-STR profile was searched in the publicly accessible FamilyTreeDNA R1b Project website, the two closest matches had the surname "Barber". A search of historical records led to a death notice mentioning John Barber, whose son Nathan Barber was buried in Griswold in 1826. The description of Nathan Barber closely fits the burial of "NB13," found near JB55. By applying modern forensic DNA tools to a historical mystery, the identity of JB55 as John Barber, the 19th century Connecticut vampire, has been revealed.
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http://dx.doi.org/10.3390/genes10090636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769528PMC
August 2019

Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma.

Mol Pharm 2019 09 31;16(9):3904-3915. Epub 2019 Jul 31.

Viewpoint Molecular Targeting, Inc. , Coralville , Iowa 52241 , United States.

Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAF) and histone deacetylase inhibitors (HDAC) to enhance the delivery of MC1R-targeted radiolabeled peptide ([Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAF cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAF and/or HDAC was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAF and HDAC significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAF and BRAF cells. Combining [Pb]DOTA-MC1L with BRAF and/or HDAC improved the tumor response by increasing the delivery of Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDAC and BRAF could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765223PMC
September 2019

Odyssey: a semi-automated pipeline for phasing, imputation, and analysis of genome-wide genetic data.

BMC Bioinformatics 2019 Jun 28;20(1):364. Epub 2019 Jun 28.

Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, Indianapolis, IN, USA.

Background: Genome imputation, admixture resolution and genome-wide association analyses are timely and computationally intensive processes with many composite and requisite steps. Analysis time increases further when building and installing the run programs required for these analyses. For scientists that may not be as versed in programing language, but want to perform these operations hands on, there is a lengthy learning curve to utilize the vast number of programs available for these analyses.

Results: In an effort to streamline the entire process with easy-to-use steps for scientists working with big data, the Odyssey pipeline was developed. Odyssey is a simplified, efficient, semi-automated genome-wide imputation and analysis pipeline, which prepares raw genetic data, performs pre-imputation quality control, phasing, imputation, post-imputation quality control, population stratification analysis, and genome-wide association with statistical data analysis, including result visualization. Odyssey is a pipeline that integrates programs such as PLINK, SHAPEIT, Eagle, IMPUTE, Minimac, and several R packages, to create a seamless, easy-to-use, and modular workflow controlled via a single user-friendly configuration file. Odyssey was built with compatibility in mind, and thus utilizes the Singularity container solution, which can be run on Linux, MacOS, and Windows platforms. It is also easily scalable from a simple desktop to a High-Performance System (HPS).

Conclusion: Odyssey facilitates efficient and fast genome-wide association analysis automation and can go from raw genetic data to genome: phenome association visualization and analyses results in 3-8 h on average, depending on the input data, choice of programs within the pipeline and available computer resources. Odyssey was built to be flexible, portable, compatible, scalable, and easy to setup. Biologists less familiar with programing can now work hands on with their own big data using this easy-to-use pipeline.
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http://dx.doi.org/10.1186/s12859-019-2964-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599316PMC
June 2019

Effects of Early Initiation of Breastfeeding on Exclusive Breastfeeding Practices of Mothers in Rural Haiti.

J Pediatr Health Care 2019 Sep - Oct;33(5):561-567. Epub 2019 May 30.

Introduction: Rates and relationships of early initiation of breastfeeding (EIBF) and exclusive breastfeeding (EBF) of mothers in rural Haiti were examined. Prelacteal and complementary feedings were identified.

Methods: With a cross-sectional descriptive design, survey data from mothers (N = 195) were collected at three intervals after birth. Data were analyzed for indicators of EIBF, EBF, and complementary feedings.

Results: Overall, 148 (75.9%) mothers reported EIBF, and 75 (38.5%) reported EBF. EIBF was associated with EBF, with an adjusted relative risk 1.35 (95% confidence interval = [0.84, 2.18]). Several nutritive and nonnutritive substances interrupted EBF during the first 6 months of life.

Discussion: Haiti has an under-five mortality rate of 67.0/1,000 live births, exceeding the mean of 46.5/1,000 live births for developing regions. Both EIBF and EBF are associated with decreased neonatal and early infant mortality. Country-specific data are needed to inform and develop breastfeeding initiatives and community-level campaigns to improve the prevalence of EIBF and EBF in Haiti.
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http://dx.doi.org/10.1016/j.pedhc.2019.02.010DOI Listing
September 2020

Author Correction: Ancient genomes indicate population replacement in Early Neolithic Britain.

Nat Ecol Evol 2019 Jun;3(6):986-987

Department of Earth Sciences, Natural History Museum, London, UK.

In the version of this Article originally published, there were errors in the colour ordering of the legend in Fig. 5b, and in the positions of the target and surrogate populations in Fig. 5c. This has now been corrected. The conclusions of the study are in no way affected. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41559-019-0912-4DOI Listing
June 2019
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