Publications by authors named "John Reid"

221 Publications

Homelessness Is Socially Created: Cluster Analysis of Social Determinants of Homelessness (SODH) in North West England in 2020.

Int J Environ Res Public Health 2021 03 16;18(6). Epub 2021 Mar 16.

Asmait Skincare and Design, Stamford, CT 06902, USA.

Poverty creates social conditions that increase the likelihood of homelessness. These include exposure to traumatic life experiences; social disadvantages such as poor educational experiences; being raised in a broken family, care homes or foster care; physical, emotional, and sexual abuse; and neglect at an early age. These conditions reduce people's ability to negotiate through life challenges. This cross-sectional study documents the clustering and frequency of adverse social conditions among 152 homeless people from four cities in North West England between January and August 2020. Two-step cluster analysis showed that having parents with a criminal record, care history, and child neglect/abuse history was predictive of homelessness. The cluster of indicator variables among homeless people included sexual abuse (χ2 (N = 152) = 220.684, < 0.001, Cramer's V = 0.7), inappropriate sexual behaviour (χ2 (N = 152) = 207.737, < 0.001, Cramer's V = 0.7), emotional neglect (χ2 (N = 152) = 181.671, < 0.001, Cramer's V = 0.7), physical abuse by step-parent (χ2 (N = 152) = 195.882, < 0.001, Cramer's V = 0.8), and physical neglect (χ2 (N = 152) = 205.632, < 0.001, Cramer's V = 0.8). Poverty and homelessness are intertwined because of the high prevalence of poverty among the homeless. Poverty sets up a chain of interactions between social conditions that increase the likelihood of unfavourable outcomes: homelessness is at the end of the interaction chain. Interventions supporting families to rise out of poverty may also reduce entry into homelessness.
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http://dx.doi.org/10.3390/ijerph18063066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002255PMC
March 2021

Vascular Access Complications and Clinical Outcomes of Vascular Surgical Repairs Following Transcatheter Aortic Valve Implantation (TAVI).

Ann Vasc Surg 2021 Feb 4. Epub 2021 Feb 4.

Division of Vascular Surgery, University of British Columbia, Vancouver, BC, Canada.

Background: Transcatheter aortic valve implantation (TAVI) procedures have revolutionized the treatment of aortic stenosis. However, due to large sheaths, improperly deployed closure devices, and the comorbidities and challenges innate to this population, vascular access complications can be devastating. The objective of this study is to evaluate vascular access complications in one of the largest TAVI sites in North America.

Methods: This was a retrospective single center review between January 2014 and December 2018 of vascular access complications necessitating operative intervention by vascular surgery. Patient demographics and preoperative comorbidities were collected. Type of vascular access complication, types of repair, closure device used, and postoperative outcomes were analyzed.

Results: A total of 37 cases out of a total of 985 TAVI procedures were identified. TAVI was carried out in the operating suite (70%) or the catheterization lab (30%). Consults to vascular surgery were requested intraoperatively (60%), immediately postoperative (14%), later in the day of the TAVI (20%), and on postoperative day 1 (6%). The location of injury included common femoral artery (49%), superficial femoral artery (11%) and external iliac artery (41%), with some cases injuring multiple vessels. Closure devices were found in the subcutaneous tissue (26%), anterior wall (37%), posterior wall (11%), intra-arterial (11%), closing the anterior to the posterior wall (16%), and in the inguinal ligament (5%). Injuries included tears (11%), dissections (38%), and vessel rupture (19%). The majority of repairs were done primarily (64%), with patch (28%) and bypass (8%) less frequently. Four patients died perioperatively (11%), 2 from hemorrhage, 1 from cardiac arrest, and 1 from progressive respiratory disease.

Conclusions: Access complications during TAVI procedures predispose complex patients to increased risk of morbidity and mortality. Careful patient selection, proper access techniques, and performing high risk patients in the operating suite with vascular surgery are fundamental in minimizing complications.
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http://dx.doi.org/10.1016/j.avsg.2020.12.032DOI Listing
February 2021

Examining outcomes following thrombolysis in an increasingly older and dependent stroke population.

J R Coll Physicians Edinb 2020 12;50(4):372-378

Acute Stroke Unit, Aberdeen Royal Infirmary, Aberdeen, UK, Email:

Background: Thrombolysis for acute ischaemic stroke (AIS) patients aged ˜80 years is evidence based, although its use in previously dependent patients is controversial.

Methods: Data from 831 thrombolysed AIS patients in our centre from 2009-2017 were used to compare demographic trends and outcomes (haemorrhage, mortality, three-month independence) in patients aged <80 and ˜80 years and with prior dependency. Comparison with UK and world registry data regarding age and pre-stroke dependency was made.

Results: The percentage of treated patients aged ˜80 years increased year-on-year, doubling from 25% to 50% (p <0.01), with increasing average age and pre-stroke dependency in world centres. Patients ˜80 years had higher (p <0.001) stroke severity, symptomatic intracerebral haemorrhage (5% vs. 1.5%), mortality (35% vs. 13%) and lower three month independent survival (24% vs. 60%). Patients with pre-stroke dependency had especially higher three month mortality (57-71%, OR 3.75 [95% CI 1.97-7.15]) in both age groups.

Conclusion: Patients aged ˜80 years and with dependency increasingly receive thrombolysis. Given poorer outcomes thrombolysis trials are needed in pre-stroke dependent patients.
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http://dx.doi.org/10.4997/JRCPE.2020.405DOI Listing
December 2020

Development of a robust crystallization platform for immune receptor TREM2 using a crystallization chaperone strategy.

Protein Expr Purif 2021 Mar 20;179:105796. Epub 2020 Nov 20.

Department of Computational and Structural Sciences, Merck & Co., Inc., West Point, PA, USA.

TREM2 has been identified by genomic analysis as a potential and novel target for the treatment of Alzheimer's disease. To enable structure-based screening of potential small molecule therapeutics, we sought to develop a robust crystallization platform for the TREM2 Ig-like domain. A systematic set of constructs containing the structural chaperone, maltose binding protein (MBP), fused to the Ig domain of TREM2, were evaluated in parallel expression and purification, followed by crystallization studies. Using protein crystallization and high-resolution diffraction as a readout, a MBP-TREM2 Ig fusion construct was identified that generates reproducible protein crystals diffracting at 2.0 Å, which makes it suitable for soaking of potential ligands. Importantly, analysis of crystal packing interfaces indicates that most of the surface of the TREM2 Ig domain is available for small molecule binding. A proof of concept co-crystallization study with a small library of fragments validated potential utility of this system for the discovery of new TREM2 therapeutics.
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http://dx.doi.org/10.1016/j.pep.2020.105796DOI Listing
March 2021

Arthroscopic Posterior Capsular Release for Loss of Knee Extension.

Arthrosc Tech 2020 Oct 15;9(10):e1439-e1446. Epub 2020 Sep 15.

Taos Orthopaedic Institute, Taos, New Mexico, U.S.A.

Arthrofibrosis, as a result of osteoarthritis, after trauma, or after knee surgery, can have significant implications for patient function, satisfaction, and outcomes. When extensive conservative management fails to achieve satisfactory results, surgical intervention may be necessary. Arthroscopic techniques to release anterior adhesions are often viewed as easier and safer than posterior releases required for flexion contractures. We present our technique of a safe, effective, and reproducible arthroscopic complete posterior capsulotomy.
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http://dx.doi.org/10.1016/j.eats.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587019PMC
October 2020

Factors Related to Postoperative Osteochondritis Dissecans of the Lateral Femoral Condyle After Meniscal Surgery in Juvenile Patients With a Discoid Lateral Meniscus.

J Pediatr Orthop 2020 Oct;40(9):e853-e859

Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine.

Purpose: The purpose was to assess the incidence of postoperative osteochondritis dissecans (OCD) and the related epidemiologic factors following meniscal surgery for juvenile discoid lateral meniscus (DLM).

Methods: The study was a retrospective review of 103 knees in 89 patients with a mean age of 12.1 years who underwent arthroscopic meniscal surgery for DLM. Mean follow-up was 4.2 years. The surgical procedures were either saucerization, saucerization with repair or subtotal meniscectomy, depending on the type of DLM tear. Postoperative OCD lesions were identified radiographically. Age, sex, weight, Lysholm score, Tegner activity scale, exercise frequency, and surgical procedure were compared between the postoperative OCD diagnosis group and non-OCD control group.

Results: Postoperative OCD was diagnosed in 8/103 (7.8%) knees following DLM surgery. The incidence of postoperative OCD was significantly greater for patients age less than 10 years old, and male sex, low weight, Lysholm score, Tegner activity scale preinjury and after returning to sports, and exercise frequency per week on univariate analyses. On multivariate analyses, postoperative OCD occurred more commonly with subtotal meniscectomy than with saucerization or saucerization with repair, and in patients less than 11 years of age. Receiver operating characteristic curve analysis revealed a cutoff value of age at surgery of 10 years.

Conclusions: Subtotal meniscectomy and patients younger than 10 years at the time of surgery are at greater risk for postoperative OCD. To decrease this risk, if possible, we recommend performing saucerization or saucerization with repair in patients undergoing surgery for DLM.

Level Of Evidence: Level III-retrospective comparative study.
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http://dx.doi.org/10.1097/BPO.0000000000001636DOI Listing
October 2020

Mind your Language: Discursive Practices Produce Unequal Power and Control Over Infectious Disease: A Critical Discourse Analysis.

Int J Prev Med 2020 16;11:37. Epub 2020 Mar 16.

Faculty of Health and Social Care, Department of Public Health and Wellbeing, University of CHESTER, Riverside Campus, Chester, CH1 1SL, United Kingdom.

Background: Power, socioeconomic inequalities, and poverty are recognized as some of the fundamental determinants of differences in vulnerability of societies to infectious disease threats. The economic south is carrying a higher burden than those in the economic north. This raises questions about whether social preventions and biomedical preventions for infectious disease are given equal consideration, and about social institutions and structures that frame the debate about infectious disease. This article examines how institutionalized ways of talking about infectious disease reinforces, creates, and sustains health inequalities.

Methods: Critical discourse analysis was considered to be epistemologically and ontologically consistent with the aims and context of this study.

Results: The study examined three types of infectious disease: • Emerging infectious diseases/pathogens • Neglected tropical diseases • Vector-borne infections. Examination revealed that poverty is the most common determinant of all three.

Conclusions: A sustainable reduction in infectious disease in the southern countries is most likely to be achieved through tackling socioeconomic determinants. There is a need for a change in the discourse on infectious disease, and adopt a discourse that promotes self-determination, rather than one that reinforces the hero-victim scenario and power inequalities.
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http://dx.doi.org/10.4103/ijpvm.IJPVM_431_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187553PMC
March 2020

Technique for Double Row Superior Capsule Reconstruction with Dermal Allograft.

Arthrosc Tech 2020 Jan 18;9(1):e91-e96. Epub 2019 Dec 18.

Taos Orthopaedic Institute, Taos, New Mexico, U.S.A.

Superior capsular reconstruction (SCR) is increasingly being used as a procedure for addressing irreparable rotator cuff tears. The procedure was initially described for failed rotator cuff repairs where the retears are severely retracted and when grade 3-4 fatty infiltration and atrophy exist. The SCR procedure can also be considered for irreparable rotator cuff tears in patients that are either too young or too high demand to be appropriate candidates for arthroplasty. Early short and medium term follow up studies support SCR with favorable outcomes compared with other salvage procedures.
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http://dx.doi.org/10.1016/j.eats.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993533PMC
January 2020

Prevention, Reduction, and Stabilization of Dog-Ear Deformities During Arthroscopic Rotator Cuff Repair.

Arthrosc Tech 2020 Jan 4;9(1):e15-e19. Epub 2019 Dec 4.

Taos Orthopaedic Institute, Taos, New Mexico, U.S.A.

Arthroscopic rotator cuff repairs (ARCRs) are common procedures that have been increasing in incidence. When performing ARCR, the surgeon often identifies an undesirable flap or fold, referred to as a "dog-ear" deformity, between sutures or knots. The height and/or thickness of a dog-ear deformity may decrease the rotator cuff-to-acromion distance, resulting in possible impingement and repair compromise. Furthermore, the goal of ARCR is to achieve complete restoration of the tendon-to-footprint relation. To restore the entire footprint, this lesion must be reduced and stabilized. We present a technique using looped sutures to augment the rotator cuff repair and prevent dog-ear formation.
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http://dx.doi.org/10.1016/j.eats.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993111PMC
January 2020

GPseudoClust: deconvolution of shared pseudo-profiles at single-cell resolution.

Bioinformatics 2020 03;36(5):1484-1491

MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SR, UK.

Motivation: Many methods have been developed to cluster genes on the basis of their changes in mRNA expression over time, using bulk RNA-seq or microarray data. However, single-cell data may present a particular challenge for these algorithms, since the temporal ordering of cells is not directly observed. One way to address this is to first use pseudotime methods to order the cells, and then apply clustering techniques for time course data. However, pseudotime estimates are subject to high levels of uncertainty, and failing to account for this uncertainty is liable to lead to erroneous and/or over-confident gene clusters.

Results: The proposed method, GPseudoClust, is a novel approach that jointly infers pseudotemporal ordering and gene clusters, and quantifies the uncertainty in both. GPseudoClust combines a recent method for pseudotime inference with non-parametric Bayesian clustering methods, efficient Markov Chain Monte Carlo sampling and novel subsampling strategies which aid computation. We consider a broad array of simulated and experimental datasets to demonstrate the effectiveness of GPseudoClust in a range of settings.

Availability And Implementation: An implementation is available on GitHub: https://github.com/magStra/nonparametricSummaryPSM and https://github.com/magStra/GPseudoClust.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703763PMC
March 2020

The revolution will be open-source: how 3D bioprinting can change 3D cell culture.

Oncotarget 2019 Jul 30;10(46):4724-4726. Epub 2019 Jul 30.

School of Medical Diagnostic & Translational Sciences, Old Dominion University, Norfolk, VA, USA.

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http://dx.doi.org/10.18632/oncotarget.27099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730589PMC
July 2019

A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein.

Nat Commun 2019 09 12;10(1):4153. Epub 2019 Sep 12.

Department of Infectious Diseases and Vaccines Research, Merck & Co., Inc, West Point, PA, USA.

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.
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http://dx.doi.org/10.1038/s41467-019-12137-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742648PMC
September 2019

3D bioprinted mammary organoids and tumoroids in human mammary derived ECM hydrogels.

Acta Biomater 2019 09 21;95:201-213. Epub 2019 Jun 21.

School of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA. Electronic address:

The extracellular matrix (ECM) of tissues is an important mediator of cell function. Moreover, understanding cellular dynamics within their specific tissue context is also important for developmental biology, cancer research, and regenerative medicine. However, robust in vitro models that incorporate tissue-specific microenvironments are lacking. Here we describe a novel mammary-specific culture protocol that combines a self-gelling hydrogel comprised solely of ECM from decellularized rat or human breast tissue with the use of our previously described 3D bioprinting platform. We initially demonstrate that undigested and decellularized mammary tissue can support mammary epithelial and tumor cell growth. We then describe a methodology for generating mammary ECM extracts that can spontaneously gel to form hydrogels. These ECM hydrogels retain unique structural and signaling profiles that elicit differential responses when normal mammary and breast cancer cells are cultured within them. Using our bioprinter, we establish that we can generate large organoids/tumoroids in the all mammary-derived hydrogel. These findings demonstrate that our system allows for growth of organoids/tumoroids in a tissue-specific matrix with unique properties, thus providing a suitable platform for ECM and epithelial/cancer cell studies. STATEMENT OF SIGNIFICANCE: Factors within extracellular matrices (ECMs) are specific to their tissue of origin. It has been shown that tissue specific factors within the mammary gland's ECM have pronounced effects on cellular differentiation and cancer behavior. Understanding the role of the ECM in controlling cell fate has major implications for developmental biology, tissue engineering, and cancer therapy. However, in vitro models to study cellular interactions with tissue specific ECM are lacking. Here we describe the generation of 3D hydrogels consisting solely of human or mouse mammary ECM. We demonstrate that these novel 3D culture substrates can sustain large 3D bioprinted organoid and tumoroid formation. This is the first demonstration of an all mammary ECM culture system capable of sustaining large structural growths.
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http://dx.doi.org/10.1016/j.actbio.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710129PMC
September 2019

Integration of multiple epigenomic marks improves prediction of variant impact in saturation mutagenesis reporter assay.

Hum Mutat 2019 09 23;40(9):1280-1291. Epub 2019 Jun 23.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.

The integrative analysis of high-throughput reporter assays, machine learning, and profiles of epigenomic chromatin state in a broad array of cells and tissues has the potential to significantly improve our understanding of noncoding regulatory element function and its contribution to human disease. Here, we report results from the CAGI 5 regulation saturation challenge where participants were asked to predict the impact of nucleotide substitution at every base pair within five disease-associated human enhancers and nine disease-associated promoters. A library of mutations covering all bases was generated by saturation mutagenesis and altered activity was assessed in a massively parallel reporter assay (MPRA) in relevant cell lines. Reporter expression was measured relative to plasmid DNA to determine the impact of variants. The challenge was to predict the functional effects of variants on reporter expression. Comparative analysis of the full range of submitted prediction results identifies the most successful models of transcription factor binding sites, machine learning algorithms, and ways to choose among or incorporate diverse datatypes and cell-types for training computational models. These results have the potential to improve the design of future studies on more diverse sets of regulatory elements and aid the interpretation of disease-associated genetic variation.
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http://dx.doi.org/10.1002/humu.23797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879779PMC
September 2019

A 3D bioprinter platform for mechanistic analysis of tumoroids and chimeric mammary organoids.

Sci Rep 2019 05 16;9(1):7466. Epub 2019 May 16.

School of Medical Diagnostic & Translational Sciences, Old Dominion University, Norfolk, Virginia, 23529, USA.

The normal mammary microenvironment can suppress tumorigenesis and redirect cancer cells to adopt a normal mammary epithelial cell fate in vivo. Understanding of this phenomenon offers great promise for novel treatment and detection strategies in cancer, but current model systems make mechanistic insights into the process difficult. We have recently described a low-cost bioprinting platform designed to be accessible for basic cell biology laboratories. Here we report the use of this system for the study of tumorigenesis and microenvironmental redirection of breast cancer cells. We show our bioprinter significantly increases tumoroid formation in 3D collagen gels and allows for precise generation of tumoroid arrays. We also demonstrate that we can mimic published in vivo findings by co-printing cancer cells along with normal mammary epithelial cells to generate chimeric organoids. These chimeric organoids contain cancer cells that take part in normal luminal formation. Furthermore, we show for the first time that cancer cells within chimeric structures have a significant increase in 5-hydroxymethylcytosine levels as compared to bioprinted tumoroids. These results demonstrate the capacity of our 3D bioprinting platform to study tumorigenesis and microenvironmental control of breast cancer and highlight a novel mechanistic insight into the process of microenvironmental control of cancer.
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http://dx.doi.org/10.1038/s41598-019-43922-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522494PMC
May 2019

Technique for Arthroscopically Assisted Superficial and Deep Medial Collateral Ligament-Meniscotibial Ligament Repair With Internal Brace Augmentation.

Arthrosc Tech 2018 Nov 29;7(11):e1215-e1219. Epub 2018 Oct 29.

Taos Orthopaedic Institute, Taos, New Mexico, U.S.A.

Deep medial collateral ligament (MCL) injury leads to meniscal lift-off and extrusion of the medial meniscus, resulting in instability and increased medial compartment pressures with subsequent cartilage damage. Repair of the deep MCL meniscotibial ligament in concert with superficial MCL repair or reconstruction is intended to restore the native anatomy , stability, and function of the medial meniscus. We present an arthroscopically assisted technique using standard arthroscopy portals and a medial open approach.
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http://dx.doi.org/10.1016/j.eats.2018.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261746PMC
November 2018

Machine learning based classification of cells into chronological stages using single-cell transcriptomics.

Sci Rep 2018 11 21;8(1):17156. Epub 2018 Nov 21.

MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK.

Age-associated deterioration of cellular physiology leads to pathological conditions. The ability to detect premature aging could provide a window for preventive therapies against age-related diseases. However, the techniques for determining cellular age are limited, as they rely on a limited set of histological markers and lack predictive power. Here, we implement GERAS (GEnetic Reference for Age of Single-cell), a machine learning based framework capable of assigning individual cells to chronological stages based on their transcriptomes. GERAS displays greater than 90% accuracy in classifying the chronological stage of zebrafish and human pancreatic cells. The framework demonstrates robustness against biological and technical noise, as evaluated by its performance on independent samplings of single-cells. Additionally, GERAS determines the impact of differences in calorie intake and BMI on the aging of zebrafish and human pancreatic cells, respectively. We further harness the classification ability of GERAS to identify molecular factors that are potentially associated with the aging of beta-cells. We show that one of these factors, junba, is necessary to maintain the proliferative state of juvenile beta-cells. Our results showcase the applicability of a machine learning framework to classify the chronological stage of heterogeneous cell populations, while enabling detection of candidate genes associated with aging.
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http://dx.doi.org/10.1038/s41598-018-35218-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249247PMC
November 2018

Correction to: Consistent and reproducible cultures of large-scale 3D mammary epithelial structures using an accessible bioprinting platform.

Breast Cancer Res 2018 11 19;20(1):136. Epub 2018 Nov 19.

School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, 5115 Hampton Blvd, Norfolk, VA, 23529, USA.

Following publication of the original article [1], the authors reported a typesetting error in the spelling of the second author's name.
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http://dx.doi.org/10.1186/s13058-018-1069-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245868PMC
November 2018

Branch-recombinant Gaussian processes for analysis of perturbations in biological time series.

Bioinformatics 2018 09;34(17):i1005-i1013

Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, Cambridge, UK.

Motivation: A common class of behaviour encountered in the biological sciences involves branching and recombination. During branching, a statistical process bifurcates resulting in two or more potentially correlated processes that may undergo further branching; the contrary is true during recombination, where two or more statistical processes converge. A key objective is to identify the time of this bifurcation (branch or recombination time) from time series measurements, e.g. by comparing a control time series with perturbed time series. Gaussian processes (GPs) represent an ideal framework for such analysis, allowing for nonlinear regression that includes a rigorous treatment of uncertainty. Currently, however, GP models only exist for two-branch systems. Here, we highlight how arbitrarily complex branching processes can be built using the correct composition of covariance functions within a GP framework, thus outlining a general framework for the treatment of branching and recombination in the form of branch-recombinant Gaussian processes (B-RGPs).

Results: We first benchmark the performance of B-RGPs compared to a variety of existing regression approaches, and demonstrate robustness to model misspecification. B-RGPs are then used to investigate the branching patterns of Arabidopsis thaliana gene expression following inoculation with the hemibotrophic bacteria, Pseudomonas syringae DC3000, and a disarmed mutant strain, hrpA. By grouping genes according to the number of branches, we could naturally separate out genes involved in basal immune response from those subverted by the virulent strain, and show enrichment for targets of pathogen protein effectors. Finally, we identify two early branching genes WRKY11 and WRKY17, and show that genes that branched at similar times to WRKY11/17 were enriched for W-box binding motifs, and overrepresented for genes differentially expressed in WRKY11/17 knockouts, suggesting that branch time could be used for identifying direct and indirect binding targets of key transcription factors.

Availability And Implementation: https://github.com/cap76/BranchingGPs.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129282PMC
September 2018

Consistent and reproducible cultures of large-scale 3D mammary epithelial structures using an accessible bioprinting platform.

Breast Cancer Res 2018 10 10;20(1):122. Epub 2018 Oct 10.

School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, 5115 Hampton Blvd, Norfolk, VA, 23529, USA.

Background: Standard three-dimensional (3D) in vitro culture techniques, such as those used for mammary epithelial cells, rely on random distribution of cells within hydrogels. Although these systems offer advantages over traditional 2D models, limitations persist owing to the lack of control over cellular placement within the hydrogel. This results in experimental inconsistencies and random organoid morphology. Robust, high-throughput experimentation requires greater standardization of 3D epithelial culture techniques.

Methods: Here, we detail the use of a 3D bioprinting platform as an investigative tool to control the 3D formation of organoids through the "self-assembly" of human mammary epithelial cells. Experimental bioprinting procedures were optimized to enable the formation of controlled arrays of individual mammary organoids. We define the distance and cell number parameters necessary to print individual organoids that do not interact between print locations as well as those required to generate large contiguous organoids connected through multiple print locations.

Results: We demonstrate that as few as 10 cells can be used to form 3D mammary structures in a single print and that prints up to 500 μm apart can fuse to form single large structures. Using these fusion parameters, we demonstrate that both linear and non-linear (contiguous circles) can be generated with sizes of 3 mm in length/diameter. We confirm that cells from individual prints interact to form structures with a contiguous lumen. Finally, we demonstrate that organoids can be printed into human collagen hydrogels, allowing for all-human 3D culture systems.

Conclusions: Our platform is adaptable to different culturing protocols and is superior to traditional random 3D culture techniques in efficiency, reproducibility, and scalability. Importantly, owing to the low-cost accessibility and computer numerical control-driven platform of our 3D bioprinter, we have the ability to disseminate our experiments with absolute precision to interested laboratories.
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http://dx.doi.org/10.1186/s13058-018-1045-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180647PMC
October 2018

Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.

EMBO J 2019 01 26;38(1). Epub 2018 Sep 26.

Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK

An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naïve pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.
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http://dx.doi.org/10.15252/embj.201899518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315289PMC
January 2019

GPseudoRank: a permutation sampler for single cell orderings.

Bioinformatics 2019 02;35(4):611-618

MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Motivation: A number of pseudotime methods have provided point estimates of the ordering of cells for scRNA-seq data. A still limited number of methods also model the uncertainty of the pseudotime estimate. However, there is still a need for a method to sample from complicated and multi-modal distributions of orders, and to estimate changes in the amount of the uncertainty of the order during the course of a biological development, as this can support the selection of suitable cells for the clustering of genes or for network inference.

Results: In applications to scRNA-seq data we demonstrate the potential of GPseudoRank to sample from complex and multi-modal posterior distributions and to identify phases of lower and higher pseudotime uncertainty during a biological process. GPseudoRank also correctly identifies cells precocious in their antiviral response and links uncertainty in the ordering to metastable states. A variant of the method extends the advantages of Bayesian modelling and MCMC to large droplet-based scRNA-seq datasets.

Availability And Implementation: Our method is available on github: https://github.com/magStra/GPseudoRank.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230469PMC
February 2019

Clock Drawing Test in acute stroke and its relationship with long-term functional and cognitive outcomes.

Clin Neuropsychol 2019 07 9;33(5):817-830. Epub 2018 Jul 9.

b Department of Psychiatry , Dalhousie University , Halifax , Canada.

The Clock Drawing Test (CDT) is commonly used as a screening tool for the assessment of dementia. The association between the CDT in acute stroke and long-term functional and cognitive outcomes in this population is unknown. The present prospective study is the first to examine if CDT scores in the acute stage after stroke are related to long-term outcomes and to compare the predictive ability of two scoring systems in a large sample of stroke patients. A total of 340 patients admitted to an acute stroke unit were included in the present study. Separate stepwise multiple linear regression analyses were performed with eight independent variables (demographic/pre-stroke variables - age, sex, premorbid functioning; stroke-related variables - stroke severity, localization; cognitive variables - Orientation Test, CDT [2 scoring systems]), and four dependent variables administered one year post-stroke (Barthel Index, modified Rankin Scale, Reintegration to Normal Living index, Global Deterioration Scale). Although both CDT scoring methods were related to all long-term outcome measures, the more comprehensive scoring system was the only baseline variable that significantly explained the variance in outcome measures in all four multiple regression models. Performance on the CDT in acute stroke is related to long-term outcomes including patients' degree of independence in performing activities of daily living, the degree to which they achieved reintegration into daily occupations, and the degree of cognitive decline observed one-year post-stroke. Future studies are needed to clarify the nature of the relationship between different CDT scoring systems and post-stroke outcomes.
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http://dx.doi.org/10.1080/13854046.2018.1494307DOI Listing
July 2019

Epigenetic alterations mediate iPSC-induced normalization of DNA repair gene expression and TNR stability in Huntington's disease cells.

J Cell Sci 2018 07 6;131(13). Epub 2018 Jul 6.

Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region is affected by global epigenetic changes through cellular reprogramming and early neurodifferentiation. We find that early stage HD-affected neural stem cells (HD-NSCs) contain increased levels of global 5-hydroxymethylation (5-hmC) and normalized DNA repair gene expression. We confirm TNR stability is induced in iPSCs, and maintained in HD-NSCs. We also identify that upregulation of 5-hmC increases ten-eleven translocation 1 and 2 (TET1/2) protein levels, and show their knockdown leads to a corresponding decrease in the expression of select DNA repair genes. We further confirm decreased expression of TET1/2-regulating miR-29 family members in HD-NSCs. Our findings demonstrate that mechanisms associated with pluripotency induction lead to a recovery in the expression of select DNA repair gene and stabilize pathogenic TNRs in HD.
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http://dx.doi.org/10.1242/jcs.215343DOI Listing
July 2018

3D bioprinter applied picosecond pulsed electric fields for targeted manipulation of proliferation and lineage specific gene expression in neural stem cells.

J Neural Eng 2018 10 31;15(5):056021. Epub 2018 May 31.

Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia, 23529, United States of America. Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, Virginia, 23529, United States of America.

Objective: Picosecond pulse electric fields (psPEF) have the potential to elicit functional changes in mammalian cells in a non-contact manner. Such electro-manipulation of pluripotent and multipotent cells could be a tool in both neural interface and tissue engineering. Here, we describe the potential of psPEF in directing neural stem cells (NSCs) gene expression, metabolism, and proliferation. As a comparison mesenchymal stem cells (MSCs) were also tested.

Approach: A psPEF electrode was anchored on a customized commercially available 3D printer, which allowed us to deliver pulses with high spatial precision and systematically control the electrode position in three-axes. When the electrodes are continuously energized and their position is shifted by the 3D printer, large numbers of cells on a surface can be exposed to a uniform psPEF. With two electric field strengths (20 and 40 kV cm), cell responses, including cell viability, proliferation, and gene expression assays, were quantified and analyzed.

Main Results: Analysis revealed both NSCs and MSCs showed no significant cell death after treatments. Both cell types exhibited an increased metabolic reduction; however, the response rate for MSCs was sensitive to the change of electric field strength, but for NSCs, it appeared independent of electric field strength. The change in proliferation rate was cell-type specific. MSCs underwent no significant change in proliferation whereas NSCs exhibited an electric field dependent response with the higher electric field producing less proliferation. Further, NSCs showed an upregulation of glial fibrillary acidic protein (GFAP) after 24 h to 40 kV cm, which is characteristic of astrocyte specific differentiation.

Significance: Changes in cell metabolism, proliferation, and gene expression after picosecond pulsed electric field exposure are cell type specific.
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http://dx.doi.org/10.1088/1741-2552/aac8ecDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145167PMC
October 2018

Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species.

Bioorg Med Chem Lett 2018 04 10;28(6):1122-1126. Epub 2018 Feb 10.

Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
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http://dx.doi.org/10.1016/j.bmcl.2018.01.039DOI Listing
April 2018

The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design.

Bioorg Med Chem Lett 2017 12 23;27(23):5167-5171. Epub 2017 Oct 23.

Discovery Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.

We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (K = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bmcl.2017.10.054DOI Listing
December 2017

Clusternomics: Integrative context-dependent clustering for heterogeneous datasets.

PLoS Comput Biol 2017 Oct 16;13(10):e1005781. Epub 2017 Oct 16.

MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.

Integrative clustering is used to identify groups of samples by jointly analysing multiple datasets describing the same set of biological samples, such as gene expression, copy number, methylation etc. Most existing algorithms for integrative clustering assume that there is a shared consistent set of clusters across all datasets, and most of the data samples follow this structure. However in practice, the structure across heterogeneous datasets can be more varied, with clusters being joined in some datasets and separated in others. In this paper, we present a probabilistic clustering method to identify groups across datasets that do not share the same cluster structure. The proposed algorithm, Clusternomics, identifies groups of samples that share their global behaviour across heterogeneous datasets. The algorithm models clusters on the level of individual datasets, while also extracting global structure that arises from the local cluster assignments. Clusters on both the local and the global level are modelled using a hierarchical Dirichlet mixture model to identify structure on both levels. We evaluated the model both on simulated and on real-world datasets. The simulated data exemplifies datasets with varying degrees of common structure. In such a setting Clusternomics outperforms existing algorithms for integrative and consensus clustering. In a real-world application, we used the algorithm for cancer subtyping, identifying subtypes of cancer from heterogeneous datasets. We applied the algorithm to TCGA breast cancer dataset, integrating gene expression, miRNA expression, DNA methylation and proteomics. The algorithm extracted clinically meaningful clusters with significantly different survival probabilities. We also evaluated the algorithm on lung and kidney cancer TCGA datasets with high dimensionality, again showing clinically significant results and scalability of the algorithm.
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http://dx.doi.org/10.1371/journal.pcbi.1005781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658176PMC
October 2017

Technique for Transtibial Knotless Repair of Lateral Meniscus Root Avulsion.

Arthrosc Tech 2017 Jun 26;6(3):e845-e851. Epub 2017 Jun 26.

Taos Orthopaedic Institute, Taos, New Mexico, U.S.A.

Tear of the meniscal root results in loss of circumferential hoop tension in the meniscus and increased tibiofemoral contact pressure, leading to cartilage wear. Repair of the meniscal root can restore function of the meniscus. Many techniques for root repair have recently been described. We present a technique for root repair using a transtibial socket and knotless suture technique that can be performed through standard arthroscopy portals.
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http://dx.doi.org/10.1016/j.eats.2017.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496117PMC
June 2017