nils-herrmann/clean_scirepeval huggingface dataset:
Viscoelasticity of multicellular surfaces.
Venue: Journal of biomechanics

Various modeling approaches have been applied to describe viscoelasticity of multicellular surfaces. The viscoelasticity is considered within three time regimes: (1) short time regime for milliseconds to seconds time scale which corresponds to sub-cellular level; (2) middle time regime for several tens of seconds to several minutes time scale which corresponds to cellular level; and (3) long time regime for several tens of minutes to several hours time scale which corresponds to supra-cellular level. Short and middle time regimes have been successfully elaborated in the literature, whereas long time viscoelasticity remains unclear. Long time regime accounts for collective cell migration. Collective cell migration could induce uncorrelated motility which has an impact to energy storage and dissipation during cell surface rearrangement. Uncorrelated motility influences: (1) volume fraction of migrating cells, (2) distribution of migrating cells, (3) shapes of migrating cell groups. These parameters influence mechanical coupling between migrating and resting subpopulations and consequently the constitutive model for long time regime. This modeling consideration indicates that additional experimental work is needed to confirm the feasibility of constitutive models which have been applied in literature for long time regime as: (1) relaxation of stress and strain, (2) storage and loss moduli as the function of time, (3) distribution of migrating cells.
The effect of leg dominance and landing height on ACL loading among female athletes.
Venue: Journal of biomechanics

Female athletes are more prone to anterior cruciate ligament (ACL) injury. A neuromuscular imbalance called leg dominance may provide a biomechanical explanation. Therefore, the purpose of this study was to compare the side-to-side lower limb differences in movement patterns, muscle forces and ACL forces during a single-leg drop-landing task from two different heights. We hypothesized that there will be significant differences in lower limb movement patterns (kinematics), muscle forces and ACL loading between the dominant and non-dominant limbs. Further, we hypothesized that significant differences between limbs will be present when participants land from a greater drop-landing height. Eight recreational female participants performed dominant and non-dominant single-leg drop landings from 30 to 60cm. OpenSim software was used to develop participant-specific musculoskeletal models and to calculate muscle forces. We also predicted ACL loading using our previously established method. There were no significant differences between dominant and non-dominant leg landing except in ankle dorsiflexion and GMED muscle forces at peak GRF. Landing from a greater height resulted in significant differences among most kinetics and kinematics variables and ACL forces. Minimal differences in lower-limb muscle forces and ACL loading between the dominant and non-dominant legs during single-leg landing may suggest similar risk of injury across limbs in this cohort. Further research is required to confirm whether limb dominance may play an important role in the higher incidence of ACL injury in female athletes with larger and sport-specific cohorts.
Influence of overlapping pattern of multiple overlapping uncovered stents on the local mechanical environment: A patient-specific parameter study.
Venue: Journal of biomechanics

Multiple overlapping uncovered stents (MOUS) system has shown potentials in managing complex aortic aneurysms with side branches involvement. It promotes the development of thrombus by modulating local flow pattern that reduces the wall tension, while maintaining patency of side branches. However the modulation of local hemodynamic parameters depends on various factors that have not been assessed comprehensively.



Aneurysm 3D geometry was reconstructed based on CT images. One-way fluid-structure interaction analysis was performed to quantify structural stress concentration in the wall, and changes of blood velocity, wall shear stress (WSS), oscillatory shear index (OSI), relative residence time (RRT) and pressure in the sac due to the stent deployment.



High structural stress concentration due to stent deployment was found in the landing zone and it increased linearly with the number of stents deployed. The wall tension in the sac was unaffected by the stent deployment. Stress within the wall was insensitive to the different overlapping pattern. After one stent was deployed, the mean flow velocity in the sac reduced by 36.4%. The deployment of the 2nd stent further reduced the mean sac velocity by 10%. WSS decreased while both OSI and RRT increased after stent deployment, however pressure in the sac remained nearly unchanged. Except for the cases with complete stents struts alignment, different overlapping pattern had little effect on flow parameters.



Mechanical parameters modulated by the MOUS are insensitive to different overlapping pattern suggesting that endovascular procedure can be performed with less attention to the overlapping pattern.
Investigating the effect of cell substrate on cancer cell stiffness by optical tweezers.
Venue: Journal of biomechanics

The mechanical properties of cells are influenced by their microenvironment. Here we report cell stiffness alteration by changing the cell substrate stiffness for isolated cells and cells in contact with other cells. Polydimethylsiloxane (PDMS) is used to prepare soft substrates with three different stiffness values (173, 88 and 17kPa respectively). Breast cancer cells lines, namely HBL-100, MCF-7 and MDA-MB-231 with different level of aggressiveness are cultured on these substrates and their local elasticity is investigated by vertical indentation of the cell membrane. Our preliminary results show an unforeseen behavior of the MDA-MB-231 cells. When cultured on glass substrate as isolated cells, they are less stiff than the other two types of cells, in agreement with the general statement that more aggressive and metastatic cells are softer. However, when connected to other cells the stiffness of MDA-MB-231 cells becomes similar to the other two cell lines. Moreover, the stiffness of MDA-MB-231 cells cultured on soft PDMS substrates is significantly higher than the stiffness of the other cell types, demonstrating thus the strong influence of the environmental conditions on the mechanical properties of the cells.
Mechanical demands on the lower back in patients with non-chronic low back pain during a symmetric lowering and lifting task.
Venue: Journal of biomechanics

There is limited information in the literature related to the lower back loading in patients with LBP, particularly those with non-chronic LBP. Toward addressing such a research gap, a case-control study was conducted to explore the differences in lower back mechanical loads between a group of females (n=19) with non-chronic, non-specific LBP and a group of asymptomatic females (n=19). The differences in lower back mechanical loads were determined when participants completed one symmetric lowering and lifting of a 4.5kg load at their preferred cadence. The axial, shearing, and moment components of task demand at the time of peak moment component as well as measures of peak trunk kinematics were analyzed. Patient vs. asymptomatic group performed the task with smaller peak thoracic rotation and peak lumbar flexion. While no differences in the moment component of task demand on the lower back between the patients and controls were found, the shearing (40-50 age group) and axial components of task demand were, respectively, larger and smaller in patients vs.


CONTROLS
Whether alterations in lower back loads in patients with non-chronic LBP are in response to pain or preceded the pain, the long-term exposure to abnormal lower back mechanics may adversely affect spinal structure and increase the likelihood of further injury or pain. Therefore, the underlying reason(s) as well as the potential consequence(s) of such altered lower back mechanics in patients with non-chronic LBP should to be further investigated.
On estimating intraventricular hemodynamic forces from endocardial dynamics: A comparative study with 4D flow MRI.
Venue: Journal of biomechanics

Intraventricular pressure gradients or hemodynamic forces, which are their global measure integrated over the left ventricular volume, have a fundamental importance in ventricular function. They may help revealing a sub-optimal cardiac function that is not evident in terms of tissue motion, which is naturally heterogeneous and variable, and can influence cardiac adaptation. However, hemodynamic forces are not utilized in clinical cardiology due to the unavailability of simple non-invasive measurement tools. Hemodynamic forces depend on the intraventricular flow; nevertheless, most of them are imputable to the dynamics of the endocardial flow boundary and to the exchange of momentum across the mitral and aortic orifices. In this study, we introduce a simplified model based on first principles of fluid dynamics that allows estimating hemodynamic forces without knowing the velocity field inside the LV. The model is validated with 3D phase-contrast MRI (known as 4D flow MRI) in 15 subjects, (5 healthy and 10 patients) using the endocardial surface reconstructed from the three standard long-axis projections. Results demonstrate that the model provides consistent estimates for the base-apex component (mean correlation coefficient r=0.77 for instantaneous values and r=0.88 for root mean square) and good estimates of the inferolateral-anteroseptal component (r=0.50 and 0.84, respectively). The present method represents a potential integration to the existing ones quantifying endocardial deformation in MRI and echocardiography to add a physics-based estimation of the corresponding hemodynamic forces. These could help the clinician to early detect sub-clinical diseases and differentiate between different cardiac dysfunctional states.
Effects of the basic multicellular unit and lamellar thickness on osteonal fatigue life.
Venue: Journal of biomechanics

A remodeling cycle sets the size of the osteon and associated lamellae in the basic multicellular unit. Treatments and aging affect these micro-structural features. We previously demonstrated decreased fatigue life with an unexplained mechanism and decreased osteon size in cortical bone treated with high-dose bisphosphonate. Here, three finite element models were examined: type-1: a single osteon, as a homogeneous unit and with heterogeneous lamellae and interlamellae, type-2: a control, interstitial-only tissue and type-3: the osteon with cement line, set within the interstitial tissue. Models were loaded in simulated, sinusoidal bending fatigue. As osteon size was decreased, lamellar number and lamellar thickness were incrementally adjusted for each model. As hypothesized, lamellae within the larger type-1 models attained greater cycles to failure and the addition of an osteon to type-2 models (generating a type-3 model set) yielded increased fatigue life. However, as the osteon size was decreased, the potential for compressive damage nucleation was increased within the lamellae of the osteons versus the interstitium. Also, osteons with fewer, thicker lamellae displayed increased fatigue life. Osteonal microstructure plays a role in damage initiation location, especially when BMU size is smaller. Previous findings by us and others could partially be explained by this further understanding of increased probability for damage nucleation in smaller osteons.
Actin cytoskeleton stiffness grades metastatic potential of ovarian carcinoma Hey A8 cells via nanoindentation mapping.
Venue: Journal of biomechanics

Recent studies have indicated that the nanoindentation measured stiffness of carcinoma adherent cells is in general lower than normal cells, thus suggesting that cell stiffness may serve as a bio-marker for carcinoma. However, the proper establishment of such a conclusion would require biophysical understanding of the underlying mechanism of the cell stiffness. In this work, we compared the elastic moduli of the actin cytoskeletons of Hey A8 ovarian carcinoma cells with and without metastasis (HM and NM), as measured by 2D atomic force microscopy (AFM) with low-depth nanoindentation via a rate-jump method. The results indicate clearly that HM cells showed lower actin cytoskeleton stiffness atop of their nucleus position and higher actin cytoskeleton stiffness at their rims, compared to NM cells, suggesting that the local stiffness on the cytoskeleton can reflect actin filament distribution. Immunofluorescence staining and scanning electron microscopy (SEM) also indicated that the difference in stiffness in Hey A8 cells with different metastasis is associated with their F-actin rearrangement. Finite-element modelling (FEM) shows that a migrating cell would have its actin filaments bundled together to form stress fibers, which would exhibit lower indentation stiffness than the less aligned arrangement of filaments in a non-migrating cell. The results here indicate that the actin cytoskeleton stiffness can serve as a reliable marker for grading the metastasis of adherent carcinoma cells due to their cytoskeleton change and potentially predicting the migration direction of the cells.
Spatially Stable Mitochondrial Compartments Fuel Local Translation during Plasticity
Venue: Cell

Local translation meets protein turnover and plasticity demands at synapses, however, the location of its energy supply is unknown. We found that local translation in neurons is powered by mitochondria and not by glycolysis. Super-resolution microscopy revealed that dendritic mitochondria exist as stable compartments of single or multiple filaments. To test if these mitochondrial compartments can serve as local energy supply for synaptic translation, we stimulated individual synapses to induce morphological plasticity and visualized newly synthesized proteins. Depletion of local mitochondrial compartments abolished both the plasticity and the stimulus-induced synaptic translation. These mitochondrial compartments serve as spatially confined energy reserves, as local depletion of a mitochondrial compartment did not affect synaptic translation at remote spines. The length and stability of dendritic mitochondrial compartments and the spatial functional domain were altered by cytoskeletal disruption. These results indicate that cytoskeletally tethered local energy compartments exist in dendrites to fuel local translation during synaptic plasticity.
A Genome-wide Framework for Mapping Gene Regulation via Cellular Genetic Screens
Venue: Cell

Over one million candidate regulatory elements have been identified across the human genome, but nearly all are unvalidated and their target genes uncertain. Approaches based on human genetics are limited in scope to common variants and in resolution by linkage disequilibrium. We present a multiplex, expression quantitative trait locus (eQTL)-inspired framework for mapping enhancer-gene pairs by introducing random combinations of CRISPR/Cas9-mediated perturbations to each of many cells, followed by single-cell RNA sequencing (RNA-seq). Across two experiments, we used dCas9-KRAB to perturb 5,920 candidate enhancers with no strong a priori hypothesis as to their target gene(s), measuring effects by profiling 254,974 single-cell transcriptomes. We identified 664 (470 high-confidence) cis enhancer-gene pairs, which were enriched for specific transcription factors, non-housekeeping status, and genomic and 3D conformational proximity to their target genes. This framework will facilitate the large-scale mapping of enhancer-gene regulatory interactions, a critical yet largely uncharted component of the cis-regulatory landscape of the human genome.
METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis
Venue: Cell

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10
Venue: Cell

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
Venue: Cell

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier
Venue: Cell

into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family.
Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma
Venue: Cell

Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.
Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication
Venue: Cell

The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these "early replication control elements" (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.
The Implication of Early Chromatin Changes in X Chromosome Inactivation
Venue: Cell

During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing.