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1.
Gait Posture ; 112: 59-66, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38744022

RESUMEN

BACKGROUND: Transhumeral (TH) limb loss leads to loss of body mass and reduced shoulder range of motion. Despite most owning a prosthesis, prosthesis abandonment is common. The consequence of TH limb loss and prosthesis use and disuse during gait may be compensation in the upper body, contributing to back pain or injury. Understanding the impact of not wearing a TH prosthesis on upper body asymmetries and spatial-temporal aspects of gait will inform how TH prosthesis use and disuse affects the body. RESEARCH QUESTION: Does TH limb loss alter upper body asymmetries and spatial-temporal parameters during gait when wearing and not wearing a prosthesis compared to able-bodied controls? METHODS: Eight male TH limb loss participants and eight male control participants completed three gait trials at self-selected speeds. The TH limb loss group performed trials with and without their prosthesis. Arm swing, trunk angular displacement, trunk-pelvis moment, and spatial-temporal aspects were compared using non-parametric statistical analyses. RESULTS: Both TH walking conditions showed greater arm swing in the intact limb compared to the residual (p≤0.001), resulting in increased asymmetry compared to the control group (p≤0.001). Without the prosthesis, there was less trunk flexion and lateral flexion compared to the control group (p≤0.001). Maximum moments between the trunk and pelvis were higher in the TH group than the control group (p≤0.05). Spatial-temporal parameters of gait did not differ between the control group and either TH limb loss condition. SIGNIFICANCE: Prosthesis use affects upper body kinematics and kinetics, but does not significantly impact spatial-temporal aspects of gait, suggesting these are compensatory actions. Wearing a prosthesis helps achieve more normative upper body kinematics and kinetics than not wearing a prosthesis, which may help limit back pain. These findings emphasize the importance of encouraging at least passive use of prostheses for individuals with TH limb loss.


Asunto(s)
Miembros Artificiales , Marcha , Humanos , Masculino , Fenómenos Biomecánicos , Marcha/fisiología , Adulto , Rango del Movimiento Articular/fisiología , Húmero/fisiología , Persona de Mediana Edad , Amputados/rehabilitación , Extremidad Superior/fisiología , Estudios de Casos y Controles
2.
J Biomech ; 168: 112075, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38631186

RESUMEN

Whole-body angular momentum (WBAM) represents the cancellations of angular momenta that are produced during a reciprocal gait pattern. WBAM is sensitive to small changes and is used to compare dynamic gait patterns under different walking conditions. Study designs and the normalization techniques used to define WBAM vary and make comparisons between studies difficult. To address this problem, WBAM about each anatomical axis of rotation from a healthy control population during normal gait were investigated within four metrics: 1) range of WBAM, 2) integrated WBAM, 3) statistical parametric mapping (SPM), and 4) principal component analysis (PCA). These data were studied as a function of walking speed and normalization. Normalization techniques included: 1) no normalization, 2) normalization by height, body mass and walking speed, and 3) normalization by height, body mass and a scalar number, gravity×height, that is independent of walking velocity. Significant results were obtained as a function of walking speed regardless of normalization technique. However, the interpretation of significance within each metric was dependent on the normalization technique. Method 3 was the most robust technique as the differences were not altered from the expected relationships within the raw data. Method 2 actually inverted the expected relationship in WBAM amplitude as a function of walking speed, which skewed the results and their interpretation. Overall, SPM and PCA statistical methods provided better insights into differences that may be important. However, depending on the normalization technique used, caution is advised when interpreting significant findings when comparing participants with disparate walking speeds.


Asunto(s)
Marcha , Velocidad al Caminar , Humanos , Velocidad al Caminar/fisiología , Masculino , Marcha/fisiología , Femenino , Adulto , Caminata/fisiología , Fenómenos Biomecánicos , Análisis de Componente Principal , Adulto Joven
3.
Nat Cell Biol ; 25(8): 1185-1195, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37488435

RESUMEN

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.


Asunto(s)
Células Madre Adultas , Proteómica , Animales , Ratones , Células Madre Adultas/metabolismo , Diferenciación Celular , Cromatina/genética , Epigénesis Genética , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo
4.
Prosthet Orthot Int ; 47(3): 272-280, 2023 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-36723391

RESUMEN

BACKGROUND: This study investigated whether the time to amputation (TtoA) after a work-related injury had a significant effect on the medical costs accrued in the first year after injury. DATA SOURCE: Six thousand nine hundred fifty-three person-level workers' compensation claims data from the state of California, USA, from 2007 to 2018. METHODS: Multiple quantile regression was used to assess the impact of TtoA on medical costs accrued during the first 12 months after injury. Three time intervals for TtoA were investigated: immediate (0, 1 days), short-delay (2-31 days), and long-delay (>31 days). RESULTS: The median (interquartile range) medical dollars paid per claim during the first 12 months for the study population was $12,414 ($6,324-$29,347). Amputations that occurred during the short-delay time interval resulted in significant ( p < 0.001) median (95% CI) savings of -$3,196 (-$3,968 to -$2,424) compared with the immediate amputation group. The long-delay time interval resulted in significantly ( p < 0.001) increased median (95% CI) spending of $5,613 ($4,675-$6,551) compared with the immediate amputation group. Covariates that significantly increased costs were medical intensity, medical complexity, use of a prosthesis, and if the injured worker pursued legal action in addition to a workers' compensation claim. CONCLUSIONS: This study presents the impact of TtoA on medical spending in the first year after a work-related injury that results in an amputation. Amputations that occurred within the first month after an injury resulted in reduced medical spending compared with immediate amputations, and amputations that occurred after the first month resulted in increased medical spending.


Asunto(s)
Traumatismos Ocupacionales , Indemnización para Trabajadores , Humanos , California , Amputación Quirúrgica
5.
Heliyon ; 8(11): e11223, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36353172

RESUMEN

Background: A defining clinical characteristics of Parkinson disease is reduced upper-extremity movements. Irregular terrain, the presence of a cross slope, and dual-task conditions have been found to alter the lower-limb gait characteristics of persons with Parkinson disease but there is little information how different environmental and cognitive conditions impact upper-limb kinematics as well as interlimb movement correlation. Research question: Do environmental conditions, such as irregular terrain and the presence of cross slope, as well as dual-task condition impact the upper-extremity kinematics and interlimb movement correlation of persons with Parkinson disease compared to healthy, age-matched controls? Methods: Three-dimensional whole-body gait data were collected for nine participants with mild-to-moderate Parkinson disease and nine healthy age-matched control participants. All participants ambulated on a regular terrain, irregular terrain, with and without cross slope, and under dual and single-task conditions. The primary outcomes were arm swing magnitude, arm swing asymmetry, and normalized cross-correlation between the ipsilateral arms and contralateral legs, which characterized movement correlation. Results: For all conditions, persons with Parkinson disease exhibited reduced arm swing magnitude and greater arm swing asymmetry compared to the healthy controls. All participants increased their arm swing magnitude on the irregular surface and under the dual-task condition. In the healthy group, the arm swing asymmetry was invariant to terrain but declined under the dual-task condition while the persons with Parkinson disease exhibited increased asymmetry on the cross slope, on the irregular terrain, and under the dual-task condition. Interlimb movement correlation decreased on the irregular terrain for the persons with Parkinson disease while the healthy group exhibited decreased interlimb movement correlation on the cross slope as well as under the dual-task condition. Significance: Persons with Parkinson disease were able to increase their arm swing magnitude when their balance was challenged and the most significant threat to their safety as defined by the greatest reduction in the interlimb movement correlation was the irregular terrain.

6.
Clin Biomech (Bristol, Avon) ; 99: 105766, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36156430

RESUMEN

BACKGROUND: Persons with Parkinson's disease have impaired motor control that increases their chance of falling when walking, especially on difficult terrains. This study investigated how persons with Parkinson's disease regulate their dynamic balance on a regular and an irregular surface. METHODS: Nine participants with Parkinson's disease and nine healthy, age-matched control participants ambulated on both a regular and an irregular surface. Whole-body and segmental angular momenta were calculated using three-dimensional motion capture data. Major modes of variability between health groups on the two surfaces were investigated using principal component analysis, while differences within each health group between surfaces was investigated using statistical parametric mapping t-tests. FINDINGS: Between groups, the Parkinson participants had greater sagittal, frontal, and transverse whole-body angular momentum on both surfaces, primarily following heel-strike, and the magnitude difference on the irregular surface was greater than on the regular surface. The greatest between group segmental differences on the irregular compared to the regular surface were the legs in the sagittal plane and the head/trunk/pelvis in the transverse plane, with the Parkinson group having greater magnitudes. The within-group comparison found the Parkinson participants had poorer regulation of whole-body angular momentum in the sagittal plane, while the healthy participants showed no consistent differences between surfaces. INTERPRETATION: On an irregular surface, persons with Parkinson's disease exhibit poor control of dynamic balance in the frontal and sagittal planes. These results emphasize the need for weight transfer techniques and training in both the sagittal and frontal planes to maximize balance and reduce fall risk.


Asunto(s)
Enfermedad de Parkinson , Fenómenos Biomecánicos/fisiología , Marcha/fisiología , Humanos , Movimiento (Física) , Equilibrio Postural/fisiología , Caminata/fisiología
7.
Ann Biomed Eng ; 49(12): 3438-3451, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34853920

RESUMEN

Sex, head and neck posture, and cervical muscle preparation are contributing factors in the severity of head and neck injuries. However, it is unknown how these factors modulate the head kinematics. In this study, twenty-four (16 male and 8 female) participants experienced 50 impulsive forces to their heads with and without an acoustic warning. Female participants demonstrated a 71 ms faster (p = 0.002) muscle activation onset compared to males after warning. The magnitude of muscle activation was not significant between sexes. Females exhibited 21% (p < 0.008) greater peak angular velocity in all force directions and 18% (p < 0.04) greater peak angular acceleration in sagittal plane compared to males. Females exhibited 15% (p = 0.03) greater peak linear acceleration compared to males only in sagittal flexion. Preparation attenuated head kinematics significantly (p < 0.03) in 11 out of 18 investigated head kinematics for both sexes. A warning eliciting a startle response 420 ms prior to the impact resulted in significant attenuation of all measured head kinematics in sagittal extension (p < 0.037). In conclusion, both sex and warning type were significant factors in head kinematics. These data provide insight into the complex relationship of muscle activation and sex, and may help identify innovative strategies to reduce head and neck injury risk in sports.


Asunto(s)
Traumatismos Craneocerebrales/fisiopatología , Traumatismos del Cuello/fisiopatología , Músculos del Cuello/fisiología , Reflejo de Sobresalto/fisiología , Aceleración , Acústica , Factores de Edad , Traumatismos en Atletas/fisiopatología , Fenómenos Biomecánicos , Electromiografía , Femenino , Humanos , Masculino , Contracción Muscular , Cuello/anatomía & histología , Músculos del Cuello/anatomía & histología , Postura/fisiología
8.
J Biomech ; 128: 110732, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34509052

RESUMEN

Concerns surrounding concussions from impacts to the head necessitate research to generate new knowledge about ways to prevent them and reduce risk. In this paper, we report the relative temporal characteristics of the head resulting from neck muscle co-contraction and postural changes following a sudden force applied to the head in four different directions. In the two "prepared" conditions (i.e., co-contraction and postural), participants experienced impulsive forces to the head after hearing a warning. The warning given for the postural condition informed both the direction and timing of the impulsive force. Participants responded to the postural warning by altering their head posture, whereas in the co-contraction warning, the force direction was unknown to them, and they were asked to isometrically co-contract their neck muscles after the warning. Peak angular velocity reduced by 29% in sagittal extension, 18% in sagittal flexion, and 23% in coronal lateral flexion in prepared vs. unwarned conditions. Peak linear acceleration was attenuated by 15% in sagittal extension, 8% in sagittal flexion, and 18% in coronal lateral flexion in prepared vs. unwarned conditions. Changes in peak angular acceleration were not uniform. We also measured a significant delay in the peak angular velocity (22 vs. 44.8 ms) and peak angular acceleration (7 vs. 20 ms) after peak linear acceleration in prepared compared to unwarned conditions. An increase in muscle activation significantly reduced the peak angular velocity and linear acceleration. Gross head movement was significantly decreased with preparation. These findings suggest that a warning prior to impact can reduce head kinematics associated with injury.


Asunto(s)
Traumatismos del Cuello , Músculos del Cuello , Aceleración , Fenómenos Biomecánicos , Cabeza , Humanos , Cuello
9.
Health Sci Rep ; 4(3): e319, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34250271

RESUMEN

BACKGROUND: Detailed information regarding workers who experience an amputation in the workplace over the last decade is limited. To better understand the financial and functional impact of a work-related amputation, this study quantifies the incidence of work-related amputations in the California workforce from 2007 to 2018 as well as the relationship between medical costs and lost workdays as a function of amputation level. METHODS: Workers' compensation claims data from California spanning the years 2007 to 2018 were evaluated to describe trends in amputation incidence (N = 16 931). Quartile values for medical costs, indemnity costs, and lost workdays were reported as a function of amputation level. Correlations were performed between medical costs and lost workdays to examine their relationship. RESULTS: The average incidence from 2007 to 2018 was 8.9 (95% CI 8.5, 9.4) amputations per 100 000 workers. There was a significant spike in amputations in 2008. Partial-hand amputations were the most common with 73.3 (95% CI 69.2, 77.7) cases per 1 000 000 workers, and the industry with the highest incidence was construction with 26.0 (95% CI 22.4, 30.0) cases per 100 000 workers. Overall, medical costs were moderately correlated with lost workdays (Spearman's rho = 0.51), and that level of correlation remained relatively consistent across all levels of amputation (Spearman's rho = 0.48-0.62). CONCLUSIONS: Amputations represent high medical costs and number of lost workdays. Considering the type of amputation and the industry the injury occurred in is important in order to work toward returning this population to work. Our results present the status of amputations in the California workplace and establish a basis for using medical costs to infer lost work productivity for this population.

10.
Ann Biomed Eng ; 49(9): 2260-2272, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33768412

RESUMEN

Mild traumatic brain injury (mTBI) and whiplash-associated disorder are the most common head and neck injuries and result from a sudden head or body acceleration. The head and neck injury potential is correlated with the awareness, level of muscle activation, and posture changes at the time of the perturbation. Environmental acoustic stimuli or a warning system can influence muscle activation and posture during a head perturbation. In this study, different acoustic stimuli, including Non-Directional, Directional, and Startle, were provided 1000 ms before a head impact, and the amplitude and timing of cervical muscle electromyographic (EMG) data were characterized based on the type of warning. The startle warning resulted in 49% faster and 80% greater EMG amplitude compared to the Directional and Non-Directional warnings after warning and before the impact. The post-impact peak EMG amplitudes in Unwarned trials were lower by 18 and 21% in the retraction and rebound muscle groups, respectively, compared to any of the warned conditions. When there was no warning before the impact, the retraction and rebound muscle groups also reached their maximum activation 38 and 54 ms sooner, respectively, compared to the warned trials. Based on these results, the intensity and complexity of information that a warning sound carries change the muscle response before and after a head impact and has implications for injury potential.


Asunto(s)
Estimulación Acústica , Movimientos de la Cabeza/fisiología , Músculos del Cuello/fisiología , Reflejo de Sobresalto/fisiología , Adulto , Electromiografía , Humanos , Masculino , Postura/fisiología , Adulto Joven
11.
Methods Mol Biol ; 2226: 285-302, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33326110

RESUMEN

Ewing sarcoma is a highly malignant tumor characterized by a chromosomal translocation that modifies the activity of an ETS family transcription factor. The most prevalent translocation product, EWSR1-FLI1, exploits a permissive and unique chromatin environment of stem cells, and transforms them into an oncogenic state through alterations to gene expression and gene regulatory programs. Though the transformation ability of, and subsequent reliance on EWSR1-FLI1 had been previously described, the advent of genome-wide sequencing technologies allowed for the specific identification of genomic loci and genes targeted by EWSR1-FLI1. Furthermore, the characterization of the chromatin environment in these, and other, cell types could not have been accomplished without the computational and statistical methods that enable large-scale data analysis. Here, we outline in detail the tools and steps needed to analyze genome-wide transcription factor binding and histone modification data (chromatin immunoprecipitation, ChIP-seq), as well as chromatin accessibility data (assay for transposase-accessible chromatin, ATAC-seq) from Ewing sarcoma cells. Our protocol includes a compilation of data quality control metrics, trimming of adapter sequences, reference genome alignment, identification of enriched sites ("peaks") and motifs, as well as annotation and visualization, using real-world data. These steps should provide a platform on which molecular biologists can build their own analytical pipelines to aid in data processing, analysis, and interpretation.


Asunto(s)
Neoplasias Óseas/genética , Epigénesis Genética , Epigenómica , Regulación Neoplásica de la Expresión Génica , Sarcoma de Ewing/genética , Biomarcadores de Tumor , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Biología Computacional/métodos , Bases de Datos Genéticas , Epigenómica/métodos , Humanos , Programas Informáticos , Navegador Web
12.
J Appl Biomech ; 37(1): 59-65, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33285513

RESUMEN

The factors that contribute to the difficulties persons with Parkinson Disease (PwPD) have when negotiating transitions in walking surfaces are not completely known. The authors investigated if PwPD adjusted their step characteristics when negotiating a familiar outdoor surface transition between synthetic concrete and synthetic turf. Force plate and motion capture data were collected for 10 participants with mild to moderate Parkinson disease and 5 healthy older control participants ambulating bidirectionally across the transition between synthetic concrete and synthetic turf. Between groups, PwPD had a significantly higher minimum toe clearance (P = .007) for both directions of travel compared with the healthy control group. Within groups, PwPD significantly increased their hip (P < .001) and ankle (P = .016) range of motion walking from concrete to turf, while the healthy control participants significantly increased their minimum toe clearance (P = .013), margin of stability (P = .019), hip (P < .001) and ankle (P = .038) range of motion, and step length (P < .001). Walking from turf to concrete, both the Parkinson disease group (P = .014) and the healthy control group (P < .001) increased their knee range of motion. Both groups adjusted their step characteristics when negotiating known surface transitions, indicating that surface transitions result in step changes regardless of health status. However, PwPD exhibited overcompensations, particularly in their minimum toe clearance.


Asunto(s)
Marcha , Enfermedad de Parkinson/fisiopatología , Rango del Movimiento Articular , Anciano , Tobillo , Estudios de Casos y Controles , Femenino , Cadera , Humanos , Rodilla , Masculino , Persona de Mediana Edad
13.
Genes Dev ; 34(23-24): 1713-1734, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33184221

RESUMEN

Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.


Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Diferenciación Celular/genética , Melanocitos/citología , Transducción de Señal/genética , Células Madre/citología , Animales , Linaje de la Célula/genética , Perfilación de la Expresión Génica , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Ratones , Factor de Transcripción Asociado a Microftalmía/metabolismo , Análisis de la Célula Individual
14.
Proc Natl Acad Sci U S A ; 117(10): 5339-5350, 2020 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-32094197

RESUMEN

Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.


Asunto(s)
Folículo Piloso/fisiología , Regeneración/fisiología , Envejecimiento de la Piel/fisiología , Nicho de Células Madre/fisiología , Células Madre/fisiología , Animales , Dermis/fisiología , Células Epidérmicas/fisiología , Epidermis/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculos/fisiología , Repitelización , Regeneración/genética , Células Receptoras Sensoriales/fisiología , Envejecimiento de la Piel/genética , Nicho de Células Madre/genética , Trasplante de Células Madre , Transcriptoma , Cicatrización de Heridas/genética , Cicatrización de Heridas/fisiología
15.
Elife ; 82019 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-31556874

RESUMEN

During mammalian embryogenesis, extensive cellular remodeling is needed for tissue morphogenesis. As effectors of cytoskeletal dynamics, Rho GTPases and their regulators are likely involved, but their daunting complexity has hindered progress in dissecting their functions. We overcome this hurdle by employing high throughput in utero RNAi-mediated screening to identify key Rho regulators of skin morphogenesis. Our screen unveiled hitherto unrecognized roles for Rho-mediated cytoskeletal remodeling events that impact hair follicle specification, differentiation, downgrowth and planar cell polarity. Coupling our top hit with gain/loss-of-function genetics, interactome proteomics and tissue imaging, we show that RHOU, an atypical Rho, governs the cytoskeletal-junction dynamics that establish columnar shape and planar cell polarity in epidermal progenitors. Conversely, RHOU downregulation is required to remodel to a conical cellular shape that enables hair bud invagination and downgrowth. Our findings underscore the power of coupling screens with proteomics to unravel the physiological significance of complex gene families.


Asunto(s)
Regulación de la Expresión Génica , Morfogénesis , Piel/embriología , Proteínas de Unión al GTP rho/metabolismo , Animales , Silenciador del Gen , Pruebas Genéticas , Ratones , Interferencia de ARN
16.
Nature ; 569(7757): 497-502, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31092920

RESUMEN

Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imaging, lineage tracing, single-cell transcriptomics and genetics, we identify two cell competition mechanisms that sequentially shape and maintain the architecture of stratified tissue during skin development in mice. In the single-layered epithelium of the early embryonic epidermis, winner progenitors kill and subsequently clear neighbouring loser cells by engulfment. Later, as the tissue begins to stratify, the basal layer instead expels losers through upward flux of differentiating progeny. This cell competition switch is physiologically relevant: when it is perturbed, so too is barrier formation. Our findings show that cell competition is a selective force that optimizes vertebrate tissue function, and illuminate how a tissue dynamically adjusts cell competition strategies to preserve fitness as its architectural complexity increases during morphogenesis.


Asunto(s)
Comunicación Celular , Células Epidérmicas/citología , Epidermis/embriología , Morfogénesis , Animales , Apoptosis , Células Clonales/citología , Drosophila melanogaster/citología , Drosophila melanogaster/embriología , Células Epidérmicas/metabolismo , Femenino , Masculino , Ratones , Fagocitosis , RNA-Seq , Análisis de la Célula Individual
17.
Mol Cell Biol ; 39(14)2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31036566

RESUMEN

Ewing sarcoma is characterized by a pathognomonic chromosomal translocation that generates the EWSR1-FLI1 chimeric transcription factor. The transcriptional targets of EWSR1-FLI1 that are essential for tumorigenicity are incompletely defined. Here, we found that EWSR1-FLI1 modulates the expression of cancer/testis (CT) antigen genes, whose expression is biased to the testes but is also activated in cancer. Among these CT antigens, fetal and adult testis expressed 1 (FATE1) is most robustly induced. EWSR1-FLI1 associates with the GGAA repeats in the proximal promoter of FATE1, which exhibits accessible chromatin exclusively in mesenchymal progenitor cells (MPCs) and Ewing sarcoma cells. Expression of EWSR1-FLI1 in non-Ewing sarcoma cells and in MPCs enhances FATE1 mRNA and protein expression. Conversely, depletion of EWSR1-FLI1 in Ewing sarcoma cells leads to a loss of FATE1 expression. Importantly, we found that FATE1 is required for survival and anchorage-independent growth in Ewing sarcoma cells via attenuating the accumulation of BNIP3L, a BH3-only protein that is toxic when stabilized. This action appears to be mediated by the E3 ligase RNF183. We propose that engaging FATE1 function can permit the bypass of cell death mechanisms that would otherwise inhibit tumor progression.


Asunto(s)
Neoplasias Óseas/genética , Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Ewing/genética , Factores de Transcripción/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HeLa , Células Hep G2 , Humanos , Proteínas de la Membrana/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , Sarcoma de Ewing/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
18.
Nature ; 560(7716): E2, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29973713

RESUMEN

In Fig. 2g of this Article, a panel was inadvertently duplicated. The 'D30 IMQ' image was a duplicate of the 'D6 Ctrl' image. Fig. 2g has been corrected online to show the correct 'D30 IMQ' image (showing skin inflammation induced by the NALP3 agonist imiquimod, IMQ). The Supplementary Information to this Amendment contains the old, incorrect Fig. 2 for transparency.

19.
Int J Med Inform ; 112: 1-5, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29500006

RESUMEN

OBJECTIVE: Machine learning in healthcare, and innovative healthcare technology in general, require complex interactions within multidisciplinary teams. Healthcare hackathons are being increasingly used as a model for cross-disciplinary collaboration and learning. The aim of this study is to explore high school student learning experiences during a healthcare hackathon. By optimizing their learning experiences, we hope to prepare a future workforce that can bridge technical and health fields and work seamlessly across disciplines. METHODS: A qualitative exploratory study utilizing focus group interviews was conducted. Eight high school students from the hackathon were invited to participate in this study through convenience sampling Participating students (n = 8) were allocated into three focus groups. Semi structured interviews were completed, and transcripts evaluated using inductive thematic analysis. FINDINGS: Through the structured analysis of focus group transcripts three major themes emerged from the data: (1) Collaboration, (2) Transferable knowledge and skills, and (3) Expectations about hackathons. These themes highlight strengths and potential barriers when bringing this multidisciplinary approach to high school students and the healthcare community. CONCLUSION: This study found that students were empowered by the interdisciplinary experience during a hackathon and felt that the knowledge and skills gained could be applied in real world settings. However, addressing student expectations of hackathons prior to the event is an area for improvement. These findings have implications for future hackathons and can spur further research into using the hackathon model as an educational experience for learners of all ages.


Asunto(s)
Servicios de Salud Comunitaria/organización & administración , Atención a la Salud/organización & administración , Personal de Salud/educación , Servicios de Salud/normas , Aprendizaje , Estudiantes , Grupos Focales , Humanos , Relaciones Interprofesionales
20.
Nature ; 550(7677): 475-480, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-29045388

RESUMEN

The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1ß, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.


Asunto(s)
Células Epiteliales/citología , Inflamación/genética , Inflamación/patología , Piel/citología , Piel/patología , Células Madre/citología , Cicatrización de Heridas/fisiología , Aminoquinolinas/farmacología , Animales , Enfermedades Autoinmunes/patología , Caspasa 1/metabolismo , Linaje de la Célula , Cromatina/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Imiquimod , Inflamasomas/metabolismo , Inflamación/inducido químicamente , Inflamación/inmunología , Interleucina-1beta/metabolismo , Macrófagos , Ratones , Neoplasias/patología , Regeneración/efectos de los fármacos , Regeneración/genética , Piel/efectos de los fármacos , Piel/inmunología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Estrés Fisiológico/genética , Linfocitos T , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/genética
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