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Belli, I.

Publications and source records attributed to Belli, I..

4 recordsLinked to original sources

Modeling glenohumeral stability in musculoskeletal simulations: A validation study with in vivo contact forces

Common optimization approaches to solve the muscle redundancy problem in musculoskeletal simulations can predict shoulder contact forces that violate joint stability with lines of action outside the glenohumeral joint border. Approaches with simple joint stability constraints were previously introduced imposing an upper limit on the direction of the contact force to stay within a specified stability perimeter. Such approaches predicted higher rotator cuff muscle activation than without constraints, but the estimated joint contact forces were oriented along the specified perimeter, raising questions about validity. In this study, several glenohumeral stability formulations were investigated, and tested against in vivo measurements of glenohumeral contact forces from the Orthoload dataset on one participant data in three dumbbell tasks: lateral raise, posterior raise, and and anterior raise. The investigated formulations either imposed inequality constraints on the contact force direction to remain within a stability perimeter whose shape was varied, or added a penalty term as a criterion measure to the objective function that made the objective function costly for contact force directions to deviate from the glenoid cavity center. All stability formulations predicted contact force magnitudes that agreed relatively well to the in vivo measured forces except for the strictest formulation that constrained the joint contact force to be directed at the glenoid cavity center. Models that restricted the force direction to lie within a specified shape estimated force vectors that largely lay along the perimeters. Models that instead penalized force directions that deviated from the glenoid cavity center estimated relatively more accurate contact force directions within the glenoid cavity, though still not entirely in agreement with in vivo measurements. Our findings support the proposed penalty formulations as more reasonable and accurate than other investigated existing glenohumeral stability formulations. Author summaryIn musculoskeletal models, the glenohumeral joint is often simplified as a purely rotational joint with no translation, whereas the actual joint movement involves both rotation and some translation, requiring stabilizing forces to prevent dislocation. Models that compute muscle forces based on a minimal effort strategy without specifically addressing glenohumeral stability may underestimate co-activation of the stabilizing rotator cuff muscles, and inaccurately predict that the contact force between the humerus and the glenoid is directed outside the articular surface of the joint. In this study, we compared existing stability models and proposed a new approach that penalized joint contact force whose direction deviates from the glenoid cavity center. We integrated these approaches into a muscle redundancy solver and estimated muscle and joint forces using the thoracoscapular shoulder musculoskeletal model. We compared model estimates to in vivo measurements of joint contact forces. We found that the penalty formulation reproduced the contact force direction most accurately, and promoted greater muscle co-contraction. These findings support the proposed penalty approach as a benchmark for more accurate analysis of shoulder biomechanics using musculoskeletal simulations.

bioengineering↗

Cell type-specific associations with Alzheimer's Disease conserved across racial and ethnic groups

Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimers Disease (AD), but have not examined common features across broad, multi-ethnic populations, and across multiple regions. To bridge this gap, we performed single-nucleus RNA-seq and ATAC-seq profiling of cortical and subcortical brain regions from post-mortem samples across Non-Latin White, African American, and Latin donors (the latter of any race). Using discrete and continuous dissection of molecular programs, we elucidate cell-type-specific glial and neuronal signatures associated with AD across multiple population groups. Notably, we found that multiple microglial (GPNMB+, CD74+, and CR1+ subgroups) and astrocyte (SERPINH1+ and WIF1+ subgroups) signatures are associated with worse clinical and pathological phenotypes across all three population groups. We also report continuous gene expression factors in oligodendrocytes that are not captured by discrete clusters, yet still show strong associations with disease phenotypes. Finally, we observe these discrete cellular identities and continuous gene programs separate cognitively impaired donors into 6 molecularly distinct subgroups that span racial and ethnic population groups. Overall, our study identifies key cell types and gene programs implicated in AD that are shared across population groups, and provides an initial data set that underscores how representative sampling can capture conserved signatures as well as disease heterogeneity, leading to better prioritization of key cell types for further investigation.

neuroscience↗

Does enforcing glenohumeral joint stability matter? A new rapid muscle redundancy solver highlights the importance of non-superficial shoulder muscles

The complexity of the human shoulder girdle enables the large mobility of the upper extremity, but also introduces instability of the glenohumeral (GH) joint. Shoulder movements are generated by coordinating large superficial and deeper stabilizing muscles spanning numerous degrees-of-freedom. How shoulder muscles are coordinated to stabilize the movement of the GH joint remains widely unknown. Musculoskeletal simulations are powerful tools to gain insights into the actions of individual muscles and particularly of those that are difficult to measure. In this study, we analyze how enforcement of GH joint stability in a musculoskeletal model affects the estimates of individual muscle activity during shoulder movements. To estimate both muscle activity and GH stability from recorded shoulder movements, we developed a Rapid Muscle Redundancy (RMR) solver to include constraints on joint reaction forces (JRFs) from a musculoskeletal model. The RMR solver yields muscle activations and joint forces by minimizing the weighted sum of squared-activations, while matching experimental motion. We implemented three new features: first, computed muscle forces include active and passive fiber contributions; second, muscle activation rates are enforced to be physiological, and third, JRFs are efficiently formulated as linear functions of activations. Muscle activity from the RMR solver without GH stability was not different from the computed muscle control (CMC) algorithm and electromyography of superficial muscles. The efficiency of the solver enabled us to test 3600 trials sampled within the uncertainty of the experimental movements to test the differences in muscle activity with and without GH joint stability enforced. We found that enforcing GH stability significantly increases the estimated activity of the rotator cuff muscles but not of most superficial muscles. Therefore, a comparison of shoulder model muscle activity to EMG measurements of superficial muscles alone is insufficient to validate the activity of rotator cuff muscles estimated from musculoskeletal models.

systems biology↗

Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain

Chronic stress and elevated levels of glucocorticoids (GCs), the main stress hormones, accelerate Alzheimers disease (AD) onset and progression. A major driver of AD progression is the spreading of pathogenic Tau protein between brain regions, precipitated by neuronal Tau secretion. While stress and high GC levels are known to induce intraneuronal Tau pathology (i.e. hyperphosphorylation, oligomerization) in animal models, their role in trans-neuronal Tau spreading is unexplored. Here, we find that GCs promote secretion of full-length, vesicle-free, phosphorylated Tau from murine hippocampal neurons and ex vivo brain slices. This process occurs via type 1 unconventional protein secretion (UPS) and requires neuronal activity and the kinase GSK3{beta}. GCs also dramatically enhance trans-neuronal Tau spreading in vivo, and this effect is blocked by an inhibitor of Tau oligomerization and type 1 UPS. These findings uncover a potential mechanism by which stress/GCs stimulate Tau propagation in AD.

neuroscience↗