-
Life Science Alliance Aug 2024Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for...
Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.
Topics: Animals; Actins; Mice; Humans; Female; Cell Line, Tumor; Neoplasm Metastasis; Breast Neoplasms; Lung Neoplasms; Microfilament Proteins; Cell Movement; Actin Cytoskeleton; Cell Proliferation; Cell Adhesion; Protein Binding
PubMed: 38760173
DOI: 10.26508/lsa.202302307 -
Seminars in Thrombosis and Hemostasis May 2024
PubMed: 38759956
DOI: 10.1055/s-0044-1786751 -
Cell Reports Methods May 2024Organoids, self-organizing three-dimensional (3D) structures derived from stem cells, offer unique advantages for studying organ development, modeling diseases, and... (Review)
Review
Organoids, self-organizing three-dimensional (3D) structures derived from stem cells, offer unique advantages for studying organ development, modeling diseases, and screening potential therapeutics. However, their translational potential and ability to mimic complex in vivo functions are often hindered by the lack of an integrated vascular network. To address this critical limitation, bioengineering strategies are rapidly advancing to enable efficient vascularization of organoids. These methods encompass co-culturing organoids with various vascular cell types, co-culturing lineage-specific organoids with vascular organoids, co-differentiating stem cells into organ-specific and vascular lineages, using organoid-on-a-chip technology to integrate perfusable vasculature within organoids, and using 3D bioprinting to also create perfusable organoids. This review explores the field of organoid vascularization, examining the biological principles that inform bioengineering approaches. Additionally, this review envisions how the converging disciplines of stem cell biology, biomaterials, and advanced fabrication technologies will propel the creation of increasingly sophisticated organoid models, ultimately accelerating biomedical discoveries and innovations.
PubMed: 38759654
DOI: 10.1016/j.crmeth.2024.100779 -
Stem Cell Reports May 2024Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their...
Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44 subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44 cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1 endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44 AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44 AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44 AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.
PubMed: 38759645
DOI: 10.1016/j.stemcr.2024.04.009 -
PloS One 2024The use of the Sequential Organ Failure Assessment (SOFA) score, originally developed to describe disease morbidity, is commonly used to predict in-hospital mortality....
The use of the Sequential Organ Failure Assessment (SOFA) score, originally developed to describe disease morbidity, is commonly used to predict in-hospital mortality. During the COVID-19 pandemic, many protocols for crisis standards of care used the SOFA score to select patients to be deprioritized due to a low likelihood of survival. A prior study found that age outperformed the SOFA score for mortality prediction in patients with COVID-19, but was limited to a small cohort of intensive care unit (ICU) patients and did not address whether their findings were unique to patients with COVID-19. Moreover, it is not known how well these measures perform across races. In this retrospective study, we compare the performance of age and SOFA score in predicting in-hospital mortality across two cohorts: a cohort of 2,648 consecutive adult patients diagnosed with COVID-19 who were admitted to a large academic health system in the northeastern United States over a 4-month period in 2020 and a cohort of 75,601 patients admitted to one of 335 ICUs in the eICU database between 2014 and 2015. We used age and the maximum SOFA score as predictor variables in separate univariate logistic regression models for in-hospital mortality and calculated area under the receiver operator characteristic curves (AU-ROCs) and area under precision-recall curves (AU-PRCs) for each predictor in both cohorts. Among the COVID-19 cohort, age (AU-ROC 0.795, 95% CI 0.762, 0.828) had a significantly better discrimination than SOFA score (AU-ROC 0.679, 95% CI 0.638, 0.721) for mortality prediction. Conversely, age (AU-ROC 0.628 95% CI 0.608, 0.628) underperformed compared to SOFA score (AU-ROC 0.735, 95% CI 0.726, 0.745) in non-COVID-19 ICU patients in the eICU database. There was no difference between Black and White COVID-19 patients in performance of either age or SOFA Score. Our findings bring into question the utility of SOFA score-based resource allocation in COVID-19 crisis standards of care.
Topics: Humans; COVID-19; Male; Hospital Mortality; Middle Aged; Female; Organ Dysfunction Scores; Aged; Retrospective Studies; Age Factors; Intensive Care Units; Adult; SARS-CoV-2; ROC Curve; Aged, 80 and over
PubMed: 38758942
DOI: 10.1371/journal.pone.0301013 -
PloS One 2024We have previously shown that polygenic risk scores (PRS) can improve risk stratification of peripheral artery disease (PAD) in a large, retrospective cohort. Here, we...
We have previously shown that polygenic risk scores (PRS) can improve risk stratification of peripheral artery disease (PAD) in a large, retrospective cohort. Here, we evaluate the potential of PRS in improving the detection of PAD and prediction of major adverse cardiovascular and cerebrovascular events (MACCE) and adverse events (AE) in an institutional patient cohort. We created a cohort of 278 patients (52 cases and 226 controls) and fit a PAD-specific PRS based on the weighted sum of risk alleles. We built traditional clinical risk models and machine learning (ML) models using clinical and genetic variables to detect PAD, MACCE, and AE. The models' performances were measured using the area under the curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), and Brier score. We also evaluated the clinical utility of our PAD model using decision curve analysis (DCA). We found a modest, but not statistically significant improvement in the PAD detection model's performance with the inclusion of PRS from 0.902 (95% CI: 0.846-0.957) (clinical variables only) to 0.909 (95% CI: 0.856-0.961) (clinical variables with PRS). The PRS inclusion significantly improved risk re-classification of PAD with an NRI of 0.07 (95% CI: 0.002-0.137), p = 0.04. For our ML model predicting MACCE, the addition of PRS did not significantly improve the AUC, however, NRI analysis demonstrated significant improvement in risk re-classification (p = 2e-05). Decision curve analysis showed higher net benefit of our combined PRS-clinical model across all thresholds of PAD detection. Including PRS to a clinical PAD-risk model was associated with improvement in risk stratification and clinical utility, although we did not see a significant change in AUC. This result underscores the potential clinical utility of incorporating PRS data into clinical risk models for prevalent PAD and the need for use of evaluation metrics that can discern the clinical impact of using new biomarkers in smaller populations.
Topics: Humans; Peripheral Arterial Disease; Female; Male; Aged; Middle Aged; Risk Assessment; Risk Factors; Machine Learning; Cardiovascular Diseases; Retrospective Studies; Multifactorial Inheritance; Case-Control Studies; Area Under Curve; Genetic Risk Score
PubMed: 38758931
DOI: 10.1371/journal.pone.0303610 -
PloS One 2024Walking on sloped surfaces is challenging for many lower limb prosthesis users, in part due to the limited ankle range of motion provided by typical prosthetic...
Walking on sloped surfaces is challenging for many lower limb prosthesis users, in part due to the limited ankle range of motion provided by typical prosthetic ankle-foot devices. Adding a toe joint could potentially benefit users by providing an additional degree of flexibility to adapt to sloped surfaces, but this remains untested. The objective of this study was to characterize the effect of a prosthesis with an articulating toe joint on the preferences and gait biomechanics of individuals with unilateral below-knee limb loss walking on slopes. Nine active prosthesis users walked on an instrumented treadmill at a +5° incline and -5° decline while wearing an experimental foot prosthesis in two configurations: a Flexible toe joint and a Locked-out toe joint. Three participants preferred the Flexible toe joint over the Locked-out toe joint for incline and decline walking. Eight of nine participants went on to participate in a biomechanical data collection. The Flexible toe joint decreased prosthesis Push-off work by 2 Joules during both incline (p = 0.008; g = -0.63) and decline (p = 0.008; g = -0.65) walking. During incline walking, prosthetic limb knee flexion at toe-off was 3° greater in the Flexible configuration compared to the Locked (p = 0.008; g = 0.42). Overall, these results indicate that adding a toe joint to a passive foot prosthesis has relatively small effects on joint kinematics and kinetics during sloped walking. This study is part of a larger body of work that also assessed the impact of a prosthetic toe joint for level and uneven terrain walking and stair ascent/descent. Collectively, toe joints do not appear to substantially or consistently alter lower limb mechanics for active unilateral below-knee prosthesis users. Our findings also demonstrate that user preference for passive prosthetic technology may be both subject-specific and task-specific. Future work could investigate the inter-individual preferences and potential benefits of a prosthetic toe joint for lower-mobility individuals.
Topics: Humans; Biomechanical Phenomena; Walking; Male; Artificial Limbs; Female; Middle Aged; Gait; Adult; Range of Motion, Articular; Toe Joint; Prosthesis Design; Foot; Aged
PubMed: 38758923
DOI: 10.1371/journal.pone.0295465 -
PloS One 2024Unmyelinated C-Tactile (CT) fibres are activated by caress-like touch, eliciting a pleasant feeling that decreases for static and faster stroking. Previous studies... (Comparative Study)
Comparative Study
Unmyelinated C-Tactile (CT) fibres are activated by caress-like touch, eliciting a pleasant feeling that decreases for static and faster stroking. Previous studies documented this effect also for vicarious touch, hypothesising simulation mechanisms driving the perception and appreciation of observed interpersonal touch. Notably, less is known about appreciation of vicarious execution of touch, that is as referred to the one giving gentle touch. To address this issue, 53 healthy participants were asked to view and rate a series of videoclips displaying an individual being touched by another on hairy (i.e., hand dorsum) or glabrous (i.e., palm) skin sites, with touch being delivered at CT-optimal (5 cm/s) or non-CT optimal velocities (0 cm/s or 30 cm/s). Following the observation of each clip, participants were asked to rate self-referred desirability and model-referred pleasantness of vicarious touch for both executer (toucher-referred) and receiver (touchee-referred). Consistent with the CT fibres properties, for both self-referred desirability and model-referred pleasantness judgements of vicarious touch execution and reception, participants provided higher ratings for vicarious touch delivered at CT-optimal than other velocities, and when observed CT-optimal touch was delivered to the hand-dorsum compared to the palm. However, higher ratings were attributed to vicarious reception compared to execution of CT-optimal touch. Notably, individual differences in interoceptive trusting and attitude to interpersonal touch were positively correlated with, respectively, toucher- and touchee-related overall appraisal ratings of touch. These findings suggest that the appreciation of both toucher- and touchee-referred vicarious touch is specifically attuned to CT-optimal touch, even though they might rely on different neurocognitive mechanisms to understand affective information conveyed by interpersonal tactile interactions.
Topics: Humans; Male; Female; Adult; Touch; Touch Perception; Young Adult; Interpersonal Relations
PubMed: 38758835
DOI: 10.1371/journal.pone.0293164 -
PloS One 2024White matter (WM) changes occur throughout the lifespan at a different rate for each developmental period. We aggregated 10879 structural MRIs and 6186...
White matter (WM) changes occur throughout the lifespan at a different rate for each developmental period. We aggregated 10879 structural MRIs and 6186 diffusion-weighted MRIs from participants between 2 weeks to 100 years of age. Age-related changes in gray matter and WM partial volumes and microstructural WM properties, both brain-wide and on 29 reconstructed tracts, were investigated as a function of biological sex and hemisphere, when appropriate. We investigated the curve fit that would best explain age-related differences by fitting linear, cubic, quadratic, and exponential models to macro and microstructural WM properties. Following the first steep increase in WM volume during infancy and childhood, the rate of development slows down in adulthood and decreases with aging. Similarly, microstructural properties of WM, particularly fractional anisotropy (FA) and mean diffusivity (MD), follow independent rates of change across the lifespan. The overall increase in FA and decrease in MD are modulated by demographic factors, such as the participant's age, and show different hemispheric asymmetries in some association tracts reconstructed via probabilistic tractography. All changes in WM macro and microstructure seem to follow nonlinear trajectories, which also differ based on the considered metric. Exponential changes occurred for the WM volume and FA and MD values in the first five years of life. Collectively, these results provide novel insight into how changes in different metrics of WM occur when a lifespan approach is considered.
Topics: Humans; White Matter; Adult; Male; Female; Adolescent; Middle Aged; Aged; Young Adult; Child; Aged, 80 and over; Infant; Child, Preschool; Aging; Longevity; Infant, Newborn; Diffusion Tensor Imaging; Diffusion Magnetic Resonance Imaging; Anisotropy; Brain; Gray Matter
PubMed: 38758830
DOI: 10.1371/journal.pone.0301520 -
Science Advances May 2024Bases can promote keto-enol tautomerism, a prevalent form of prototropic tautomerism, and facilitate the ring opening of anhydride ring structures. The intrinsic...
Bases can promote keto-enol tautomerism, a prevalent form of prototropic tautomerism, and facilitate the ring opening of anhydride ring structures. The intrinsic chemical distinctions between these processes provide an opportunity to modulate these seemingly parallel reactions. However, this potential remains largely unexplored. In this work, we report homophthalic anhydride, the first molecule exhibiting simultaneous halochromism, turn-on fluorescence (halofluorochromism), and subsequent self-destruction. Through comprehensive spectroscopic analysis and theoretical calculations, we unravel the mechanisms underlying these phenomena, revealing that the pivotal roles of the base's basicity and nucleophilicity specifically allow us to achieve controlled durations of color change and turn-on fluorescence. Capitalizing on these intriguing properties, we develop a highly dynamic CMY (cyan-magenta-yellow) palette ideal for entity encryption and anti-counterfeiting applications. Our work reshapes the understanding of the relationship between the basicity and nucleophilicity of bases, enriching the comprehension of keto-enol tautomerism and homophthalic anhydride chemistry, and unveils a spectrum of potential applications.
PubMed: 38758781
DOI: 10.1126/sciadv.adn9692