Biology subjects

Bandi, M.

Publications and source records attributed to Bandi, M..

3 recordsLinked to original sources

bioRxiv2026

Extending Musculoskeletal Modelling Validation Beyond Gait: Knee Loading and Kinematics During Daily Activities

Musculoskeletal (MSK) modelling enables non-invasive estimation of internal body loads, which could inform the design of novel orthopedic implants and guide personalized treatment strategies. Extensive validation is a pre-requisite for the translation of MSK-modelling frameworks into clinical applications. This study validates predicted knee loads and local kinematics across multiple activities of daily living (ADLs) using motion-capture data from 184 activity cycles collected in six subjects performing five ADLs from the CAMS-Knee datasets. Personalized models incorporated subject-specific anthropometric, radiographic, and implantation data, along with a 6-DOF elastic-foundation contact model between implant components and a surgically balanced ligament model derived from cadaveric testing. Across activities, predicted knee contact force magnitudes showed good agreement with instrumented implant measurements (RMSE 0.46 BW; R2 = 0.81). The highest accuracy was found during level walking, whereas stair descent exhibited the largest discrepancies. Predicted implant kinematics showed qualitatively similar trends to fluoroscopic measurements across all ADLs, although with varying levels of accuracy across different degrees of freedom. EMG comparisons revealed broadly consistent activation timing between model predictions and experimental data, although gastrocnemius activation was poorly estimated during stair descent and downhill walking. By validating MSK model predictions across the complete range of activities available in the CAMS-Knee datasets, this study extends validation beyond previously analysed gait or bending tasks and reveals activity-specific discrepancies that reflect current limitations in modelling assumptions and would remain undetected in single-activity analyses. These findings provide a robust basis for future refinement of MSK models and support their development toward clinically meaningful applications.

bioengineering↗

bioRxiv2025

Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer

Chromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion of neighboring genes. This collateral damage can create novel dependencies specific to the co-deleted context. One notable example is the dependency on PRMT5 activity in tumors with MTAP deletion, which co-occurs with CDKN2A/B loss, leading to the development of MTA-cooperative PRMT5 inhibitors. To identify additional collateral damage context/target pairs for chromosome 9p and other common loci of chromosomal deletions, we conducted a combinatorial CRISPR screen knocking out frequently co-deleted genes in combination with a focused target library. We identified the gene encoding the ribosome rescue factor PELO as synthetic lethal with loss of gene encoding the SKI complex interacting protein FOCAD, which is frequently co-deleted alongside MTAP and CDKN2A/B on chromosome 9p. A genome-wide screen in FOCAD isogenic cells further identified the ribosome rescue GTPase and PELO binding partner HBS1L as the top synthetic lethal target for FOCAD loss. Analysis of publicly available data and genetic manipulation of HBS1L using orthogonal modalities validated this interaction. HBS1L dependency in FOCAD-deleted cells was rescued by FOCAD re-expression, and FOCAD intact cells could be rendered HBS1L-dependent by FOCAD knockout, demonstrating the context specificity of this interaction. Mechanistically, HBS1L loss led to translational arrest and activated the unfolded protein response in FOCAD-deleted cells. In vivo, HBS1L deletion eliminated growth of FOCAD-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treating FOCAD-deleted tumors.

cancer biology↗

bioRxiv2022

VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma

Synthetic lethality -- a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone -- can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells results in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, causes nuclear lobulation, blebbing and micronucleation, which subsequently results in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.

cancer biology↗