Biology subjects

Pasha, S.

Publications and source records attributed to Pasha, S..

5 recordsLinked to original sources

bioRxiv2025

Establishing Comprehensive Transthoracic Echocardiography Reference Ranges for Mouse Models: Insights into the Impact of Anesthesia, Sex, and Age

Mouse models play a critical role in cardiology research, offering valuable insights into the molecular mechanisms, genetics, and potential treatments for cardiovascular diseases. However, the ability to transfer findings in mice between studies is limited by the absence of standardized protocols and valid reference values for the assessment of normal cardiac function in mice. This study aims to establish comprehensive transthoracic echocardiography (TTE) reference ranges for mice, particularly focusing on C57BL/6N wildtype controls. The study, which includes data from over 15,000 mice through the International Mouse Phenotyping Consortium (IMPC), highlights how variables such as sex, age, body weight, and anesthesia affect TTE parameters. The findings showed that anesthesia is the primary predictor of variability in cardiac function. Isoflurane and tribromoethanol anesthetized mice presented with modified cardiac function compared to conscious mice. Additionally, we observed minimal sex differences in cardiac morphology and function, except for small variations influenced by anesthesia. The effects of aging on cardiac function were modest, characterized by a decrease in heart rate and subtle changes in ventricular dimensions without evidence of pathological remodeling, likely attributable to disease-free cardiovascular aging. Validation of the reference ranges across multiple mouse strains showed that these values provide a reliable baseline for experiments involving cardiac function in mice. The data underscore the importance of using anesthesia-specific reference values when interpreting TTE results, ensuring robust comparisons in genetic and pharmacological studies. These reference ranges serve as quality assurance tools for future cardiac studies in mice, offering insights into typical TTE parameter values, supporting the detection of experimental perturbations, and contributing to more effective translation of findings from mouse to human.

genetics↗

bioRxiv2024

Protection of the Telomeric Junction by the Shelterin Complex

Shelterin serves critical roles in suppressing superfluous DNA damage repair pathways on telomeres. The junction between double-stranded telomeric tracts (dsTEL) and single-stranded telomeric overhang (ssTEL) is the most accessible region of the telomeric DNA. The shelterin complex contains dsTEL and ssTEL binding proteins and can protect this junction by bridging between the ssTEL and dsTEL tracts. To test this possibility, we monitored shelterin binding to telomeric DNA substrates with varying ssTEL and dsTEL lengths and quantified its impact on telomere accessibility using single-molecule fluorescence microscopy methods in vitro. We identified the first dsTEL repeat nearest to the junction as the preferred binding site for creating the shelterin bridge. Shelterin requires at least two ssTEL repeats while the POT1 subunit of shelterin that binds to ssTEL requires longer ssTEL tracts for stable binding to telomeres and effective protection of the junction region. The ability of POT1 to protect the junction is significantly enhanced by the 5-phosphate at the junction. Collectively, our results show that shelterin enhances the binding stability of POT1 to ssTEL and provides more effective protection compared to POT1 alone by bridging single- and double-stranded telomeric tracts. Table of Content Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/608453v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a58e79org.highwire.dtl.DTLVardef@12cb172org.highwire.dtl.DTLVardef@135bf40org.highwire.dtl.DTLVardef@19f3fe4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2020

A semi-analytic elastic rod model of pediatric spinal deformity

The mechanism of the scoliotic curve development in healthy adolescents remains unknown in the field of orthopedic surgery. Variations in the sagittal curvature of the spine are believed to be a leading cause of scoliosis in this patient population. Here, we formulate the mechanics of S-shaped slender elastic rods as a model for pediatric spine under physiological loading. Secondarily, applying inverse mechanics to clinical data of the scoliotic spines, with characteristic 3D deformity, we determine the undeformed geometry of the spine before the induction of scoliosis. Our result successfully reproduces the clinical data of the deformed spine under varying loads confirming that the pre-scoliotic sagittal curvature of the spine impacts the 3D loading that leads to scoliosis.

bioengineering↗

bioRxiv2020

A reduced order model of the spine to study pediatric scoliosis

The S-shaped curvature of the spine has been hypothesized as the underlying mechanical cause of adolescent idiopathic scoliosis. In earlier work we proposed a reduced order model in which the spine was viewed as an S-shaped elastic rod under torsion and bending. Here, we simulate the deformation of S-shaped rods of a wide range of curvatures and inflection points under a fixed mechanical loading. Our analysis determines three distinct axial projection patterns of these S-shaped rods: two loop (in opposite directions) patterns and one lemniscate pattern. We further identify the curve characteristics associated with each deformation pattern showing that for rods deforming in a loop 1 shape the position of the inflection point is the highest and the curvature of the rod is smaller compared to the other two types. For rods deforming in the loop 2 shape the position of the inflection point is the lowest (closer to the fixed base) and the curvatures are higher than the other two types. These patterns matched the common clinically observed scoliotic curves - Lenke 1 and Lenke 5. Our elastic rod model predicts deformations that are similar to those of a pediatric spine and it can differentiate between the clinically observed deformation patterns. This provides validation to the hypothesis that changes in the sagittal profile of the spine can be a mechanical factor in parthenogenesis of pediatric idiopathic scoliosis.

bioengineering↗

bioRxiv2020

What causes different coronal curve patterns in idiopathic scoliosis?

BackgroundAdolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spinal column in otherwise healthy adolescents. The underlying mechanisms associated with the spinal deformity development have been explored which delineated the role of the sagittal curvature of the spine. The patterns of the spinal deformity vary between the AIS patients as shown in several classification systems. It remains to further investigate how variations in sagittal profiles result in different coronal plane deformities in AIS and how these deformation patterns are intrinsically different. MethodsA total of 71 Lenke 1 and 52 Lenke 5 AIS patients were included retrospectively. The 3D models of the spine were generated from biplanar radiographs to calculate the clinical spinal parameters, vertebral axial rotations, and the 3D centerline of the spinal curvature. A classification based on the centerlines axial plane projection was developed. The 3D curvature of the centerline was calculated at each point. A 2D elastic rod finite element model (FEM) of the sagittal spinal curvature for each axial subtype was developed to calculate the 3D deformity of the spine under gravity and axial torsion. Differences in the axial clusters clinical parameters, curvature of the spine, and the deformation patterns of the FEM were compared. The characteristics of the sagittal curvature of these axial clusters were determined. ResultsLenke1 was divided into two axial groups (I and II) whereas the Lenke 5 cohort all had the same axial projection pattern (loop shape). T5-T12 kyphosis was significantly different between Lenke1-Group I and the other two groups, p=0.04. The vertebral rotation in both Lenke1-Group I and Lenke 5 had only one maximum value and the FEM deformed in a loop shaped whereas Lenke1-group II showed two maximum values for vertebral rotation and the FEM of the centerline deformed in a lemniscate shape. The ratio of the spinal arc lengths above and below the sagittal inflection points for Lenke1-Groups I and II and Lenke 5 were 0.52, 1.16, and 3.24, respectively. ConclusionVariations in the axial plane projection of the curve were observed within Lenke types. Lenke 1- Group I and Lenke 5 showed similar 3D curve characteristics suggesting one 3D curve whereas Lenke1-Group II, with two 3D curves, behaved differently. The length of the spinal arcs above and below the sagittal inflection point related to the patterns of axial deformity.

bioengineering↗