Biology subjects

Stephens, K.

Publications and source records attributed to Stephens, K..

6 recordsLinked to original sources

bioRxiv2023

Replacement of tibialis cranialis tendon with polyester, silicone-coated artificial tendon preserves biomechanical function in rabbits

Artificial tendons may be an effective alternative to autologous and allogenic tendon grafts for repairing critically sized tendon defects. The goal of this study was to quantify the in vivo hindlimb biomechanics (ground contact pressure and sagittal-plane motion) during hopping gait of rabbits having a critically sized tendon defect of the tibialis cranialis and either with or without repair using an artificial tendon. In five rabbits, the tibialis cranialis tendon of the left hindlimb was surgically replaced with a polyester, silicone-coated artificial tendon (PET-SI); five operated control rabbits underwent complete surgical excision of the biological tibialis cranialis tendon in the left hindlimb with no replacement (TE). At 8 weeks post-surgery, peak vertical ground contact force in the left hindlimb was statistically significantly less compared to baseline for the TE group (p=0.0215). Statistical parametric mapping (SPM) analysis showed that, compared to baseline, the knee was significantly more extended during stance at 2 weeks post-surgery and during the swing phase of stride at 2 and 8 weeks post-surgery for the TE group (p<0.05). Also, the ankle was significantly more plantarflexed during swing at 2 and 8 weeks postoperative for the TE group (p<0.05). In contrast, there were no significant differences in the SPM analysis among timepoints in the PET-SI group for the knee or ankle. These findings suggest that the artificial tibialis cranialis tendon effectively replaced the biomechanical function of the native tendon.

bioengineering↗

bioRxiv2022

Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner

Fetal growth restriction (FGR) is associated with increased risk of developing Non-Communicable Diseases. We have a placenta-specific nanoparticle gene therapy protocol that increases placental expression of human insulin-like growth factor 1 (hIGF-1), for the treatment of FGR in utero. We aimed to characterize the effects of FGR on hepatic gluconeogenesis pathways during early stages of FGR establishment, and determine whether treatment of the placenta with nanoparticle mediated hIGF-1 therapy could resolve differences in the FGR fetus. Female Hartley guinea pigs (dams) were fed either a control or maternal nutrient restriction (MNR) diet using established protocols. At GD30-33, dams underwent ultrasound guided, transcutaneous, intra-placental injection of hIGF-1 nanoparticle or PBS (sham), and were sacrificed 5 days post-injection. Fetal liver tissue was fixed and snap frozen for morphology and gene expression analysis. In female and male fetuses, liver weight as a percentage of body weight was reduced by MNR, and not changed with hIGF-1 nanoparticle treatment. In female fetal livers, expression of hypoxia inducible factor 1 (Hif1) and tumor necrosis factor (Tnf) were increased in MNR compared to Control, but reduced towards Control in MNR + hIGF-1 livers. In male fetal liver, MNR increased expression of Igf-1, and decreased expression of Igf-2 compared to Control. Igf-1 and Igf-2 expression was restored to Control levels in the MNR + hIGF-1 group. This data provides further insight into the sex-specific mechanistic adaptations seen in FGR fetuses, and demonstrates that disruption to fetal developmental mechanisms may be returned to normal by treatment of the placenta.

physiology↗

bioRxiv2022

Fast and Accurate Kinship Estimation Using Sparse SNPs in Relatively Large Database Searches

1.Forensic genetic genealogy (FGG) has primarily relied upon dense single nucleotide polymorphism (SNP) profiles from forensic samples or unidentified human remains queried against online genealogy database(s) of known profiles generated with SNP microarrays or from whole genome sequencing (WGS). In these queries, SNPs are compared to database samples by locating contiguous stretches of shared SNP alleles that allow for detection of genomic segments that are identical by descent (IBD) among biological relatives (kinship). This segment-based approach, while robust for detecting distant relationships, generally requires DNA quantity and/or quality that are sometimes not available in forensic casework samples. By focusing on SNPs with maximal discriminatory power and using an algorithm designed for a sparser SNP set than those from microarray typing, performance similar to segment matching was reached even in difficult casework samples. This algorithm locates shared segments using kinship coefficients in "windows" across the genome. The windowed kinship algorithm is a modification of the PC-AiR and PC-Relate tools for genetic relatedness inference, referred to here as the "whole genome kinship" approach, that control for the presence of unknown or unspecified population substructure. Simulated and empirical data in this study, using DNA profiles comprised of 10,230 SNPs (10K multiplex) targeted by the ForenSeq Kintelligence Kit demonstrate that the windowed kinship approach performs comparably to segment matching for identifying first, second and third degree relationships, reasonably well for fourth degree relationships, and with fewer false kinship associations. Selection criteria for the 10K SNP PCR-based multiplex and functionality of the windowed kinship algorithm are described.

genomics↗

bioRxiv2021

Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the guinea pig placenta differentially affects fetal liver gene expression depending on maternal nutrient status

Fetal growth restriction (FGR) significantly contributes to neonatal and perinatal morbidity and mortality. Currently, there are no effective treatment options for FGR during pregnancy. We have developed a nanoparticle gene therapy targeting the placenta to increase expression of human insulin-like growth factor 1 (hIGF-1) to correct fetal growth trajectories. Using the maternal nutrient restriction (MNR) guinea pig model of FGR, an ultrasound-guided, intra-placental injection of non-viral, polymer-based nanoparticle gene therapy containing plasmid with the hIGF-1 gene and placenta-specific Cyp19a1 promotor was administered at mid-pregnancy. Sustained hIGF-1 expression was confirmed in the placenta five days after treatment. Whilst gene therapy treatment did not change fetal weight, circulating fetal glucose concentration were 33-67% higher. This was associated with increased expression of glucose and amino acid transporters in the placenta. Additionally, nanoparticle gene therapy treatment increased the fetal capillary volume density in the placenta, and reduced interhaemal distance between maternal and fetal circulation. Overall, our findings, that gene therapy treatment results in changes to glucose transporter expression and increases fetal glucose concentrations within a short time period, highlights the translational potential this treatment could have in correcting impaired placental nutrient transport in human pregnancies complicated by FGR.

physiology↗

bioRxiv2021

Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.

immunology↗

bioRxiv2019

Leaf -- An open-source, model-agnostic, data-driven web application for cohort discovery and translational biomedical research

ObjectiveAcademic medical centers and health systems are increasingly challenged with supporting appropriate secondary use of data that originate from multiple sources. Enterprise Data Warehouses (EDWs) have emerged as central resources for these data, but they often require an informatician to extract meaningful information, thereby limiting direct access by end users. To overcome this challenge, we have developed Leaf, a lightweight self-service web application for querying and extracting clinical data from heterogeneous data sources.\n\nMaterials and MethodsLeaf utilizes a flexible biomedical concept system to define hierarchical items and ontologies. Each Leaf concept contains both textual representations and associated SQL query building blocks, exposed by a simple drag-and-drop user interface. Leaf generates abstract syntax trees which are compiled into dynamic SQL queries.\n\nResultsLeaf is a successful production-supported tool at the University of Washington, which hosts a central Leaf instance querying an EDW with over 300 active users. Through the support of UW Medicine (https://uwmedicine.org), the Institute of Translational Health Sciences (https://www.iths.org) and the National Center for Data to Health (https://ctsa.ncats.nih.gov/cd2h/), Leaf source code has been released into the public domain at https://github.com/uwrit/leaf.\n\nDiscussionLeaf allows the querying of single or multiple clinical databases simultaneously, even those of different data models. This enables fast installation without costly extraction or duplication from existing databases.\n\nConclusionLeaf differs from existing cohort discovery tools because it does not specify a required data model and is designed to seamlessly integrate with existing enterprise user authentication systems and clinical databases in situ. We demonstrate its unique technical strengths and success alongside its friendly user interface. We believe Leaf to be useful for health system analytics, clinical research data warehouses, precision medicine biobanks and clinical studies involving large patient cohorts.

bioinformatics↗