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Mendelian disorders, arising from pathogenic variations within single genetic loci, often manifest as neurodevelopmental disorders (NDDs), affecting a significant portion of the pediatric population worldwide. These disorders are marked by atypical brain development, intellectual disabilities, and various associated phenotypic traits. Genetic testing aids in clinical diagnoses, but inconclusive results can prolong confirmation processes. Recent focus on epigenetic dysregulation has led to the discovery of DNA methylation signatures, or episignatures, associated with NDDs, accelerating diagnostic precision. Notably, TRIP12 and USP7, genes involved in the ubiquitination pathway, exhibit specific episignatures. Understanding the roles of these genes within the ubiquitination pathway sheds light on their potential influence on episignature formation. While TRIP12 acts as an E3 ligase, USP7 functions as a deubiquitinase, presenting contrasting roles within ubiquitination. Comparison of phenotypic traits in patients with pathogenic variations in these genes reveals both distinctions and commonalities, offering insights into underlying pathophysiological mechanisms. This review contextualizes the roles of TRIP12 and USP7 within the ubiquitination pathway, their influence on episignature formation, and the potential implications for NDD pathogenesis. Understanding these intricate relationships may unveil novel therapeutic targets and diagnostic strategies for NDDs.
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This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 â¼ 2 µM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.
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ATPases Associated with Diverse Cellular Activity (AAA+ATPases) are important enzymatic functional proteins in human cells. Thyroid Hormone Receptor Interacting Protein-13 (TRIP13) is a member of this protein superfamily, that partly regulates DNA repair pathways and spindle assembly checkpoints during mitosis. TRIP13 is reported as an oncogene involving multiple pathways in many human malignancies, including multiple myeloma, brain tumors, etc. The structure of TRIP13 reveals the mechanisms for ATP binding and how TRIP13 recognizes the Mitotic Arrest Deficiency-2 (MAD2) protein, with p31comet acting as an adapter protein. DCZ0415, TI17, DCZ5417, and DCZ5418 are the reported small-molecule inhibitors of TRIP13, which have been demonstrated to inhibit TRIP13's biological functions significantly and effective in suppressing various types of malignant cells, indicating that TRIP13 is a significant anticancer drug target. Currently, no systematic reviews are cutting across the functions, structure, and novel inhibitors of TRIP13. This review provides a comprehensive overview of TRIP13's biological functions, its roles in eighteen different cancers, four small molecule inhibitors, different underlying molecular mechanisms, and its functionality as a potential anticancer drug target.
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BACKGROUND: Falls due to stumbling are prevalent for transfemoral prosthesis users and may lead to increased injury risk. This preliminary case series analyzes the transfemoral prosthesis user stumble recovery response to highlight key deficits in current commercially-available prostheses and proposes potential interventions to improve recovery outcomes. METHODS: Six transfemoral prosthesis users were perturbed on their prosthetic limb at least three times while walking on a treadmill using obstacle perturbations in early, mid and late swing. Kinematic data were collected to characterize the response, while fall rate and key kinematic recovery metrics were used to assess the quality of recovery and highlight functional deficits in current commercially-available prostheses. RESULTS: Across all participants, 13 (54%) of the 24 trials resulted in a fall (defined as > 50% body-weight support) with all but one participant (83%) falling at least once and two participants (33%) falling every time. In contrast, in a previous study of seven young, unimpaired, non-prosthesis users using the same experimental apparatus, no falls occurred across 190 trials. For the transfemoral prosthesis users, early swing had the highest rate of falling at 64%, followed by mid-swing at 57%, and then late swing at 33%. The trend in falls was mirrored by the kinematic recovery metrics (peak trunk angle, peak trunk angular velocity, forward reach of the perturbed limb, and knee angle at ground contact). In early swing all four metrics were deficient compared to non-prosthesis user controls. In mid swing, all but trunk angular velocity were deficient. In late swing only forward reach was deficient. CONCLUSION: Based on the stumble recovery responses, four potential deficiencies were identified in the response of the knee prostheses: (1) insufficient resistance to stance knee flexion upon ground contact; (2) insufficient swing extension after a perturbation; (3) difficulty initiating swing flexion following a perturbation; and (4) excessive impedance against swing flexion in early swing preventing the potential utilization of the elevating strategy. Each of these issues can potentially be addressed by mechanical or mechatronic changes to prosthetic design to improve quality of recovery and reduce the likelihood a fall.
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Accidentes por Caídas , Miembros Artificiales , Humanos , Accidentes por Caídas/prevención & control , Miembros Artificiales/efectos adversos , Masculino , Femenino , Fenómenos Biomecánicos , Adulto , Persona de Mediana Edad , Caminata/fisiología , Fémur/fisiología , Amputados/rehabilitación , Marcha/fisiologíaRESUMEN
The effects of mean normal stress on the deformation properties such as the strain-hardening, strain-induced martensite transformation, and micro-void initiation behaviors of low-carbon ultrahigh-strength TRIP-aided bainitic ferrite (TBF), bainitic ferrite/martensite (TBM), and martensite (TM) steels were investigated to evaluate the various cold formabilities. In addition, the deformation properties were related to the microstructural properties such as the matrix structure, retained austenite characteristics, and second-phase properties. Positive mean normal stress considerably promoted strain-induced martensite transformation and micro-void initiation, with an increased strain-hardening rate in an early strain range in all steels. In TM steel, the primary martensite matrix structure suppressed the micro-void initiation through high uniformity of a primary martensite matrix structure and a low strength ratio, although the strain-induced transformation was promoted, and a large amount of martensite/austenite constituent or phase was contained. A mixed matrix structure of bainitic ferrite/primary martensite in TBM steel also suppressed the micro-void initiation because of the refined microstructure and relatively stable retained austenite. Promoted micro-void initiation of TBF steel was mainly promoted by a high strength ratio.
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For older people, a sufficient mobility offer is an essential prerequisite for participation in social life and a better quality of life. The goal should be self-determined everyday mobility that enables a satisfying and healthy life. Mobility depends on diverse individual abilities and needs. On the other hand, social structures as well as regulatory and spatial framework conditions limit the realisation of mobility services and their transport infrastructure. These framework conditions are characterised by the perception of social roles, the availability of resources and gender-specific attributions. For example, care and caring work is predominantly the responsibility of women in the age group of 50 years plus. The availability of transport infrastructure is geared towards goals that are characterised by the needs of gainful employment and not the goals of care work. Conversely, the availability of flexible means of transport, such as cars, also decreases for women in old age for economic reasons. For this reason, mobility planning should take greater account of specific needs, such as orientation towards care objectives, counselling, and health services and place a greater focus on the local area. For elderly people, especially women, security needs are often an important factor in the decision to become mobile or to forego mobility. This includes perceived subjective safety, accessibility and protection from weather conditions such as slippery surfaces or exposure to excessive heat. If these basic principles are taken into account, more people can be guaranteed self-determined participation in social life.
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Limitación de la Movilidad , Humanos , Alemania , Femenino , Anciano , Masculino , Anciano de 80 o más Años , Distribución por Sexo , Persona de Mediana EdadRESUMEN
Trips and falls are a major concern for older adults. The resulting injury and loss of mobility can have a significant impact on quality of life. An emerging field of study, known as Perturbation Training, has been shown to reduce injury rates associated with trips and falls in older adults. Treadmills traditionally used for Perturbation Training are large, expensive, and immobile, forcing users to travel long distances to receive care. A portable treadmill would serve a larger portion of the at-risk population than current methods. We developed a portable, low-cost, twin-belt perturbation treadmill capable of high-intensity Perturbation Training. Belt speeds are controlled by a custom mechanical and software interface, allowing operators with no programming experience to control the device. The treadmill can accommodate users up to 118 kg and provides a maximum acceleration and speed of 12 m/s2 and 3.3 m/s, respectively, under full load. The total weight is 180 kg, and the treadmill can be moved like a wheelbarrow, with handles in the back and wheels in the front. The prototype was validated with mechanical and human participant testing, showing it as a viable device for Perturbation Training. In this paper, we will go over the design, fabrication, and validation processes used to create the Portable Perturbation Treadmill.
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The ride-sharing trend is booming because of modern technologies and plays a significant role in transitioning to sustainable transportation methods. This study utilizes a comprehensive dataset collected from an online survey administered to over 1300 individuals in Bangladesh in 2023. Its specific focus is to examine the usage patterns of ride-sharing applications, such as Pathao and Uber. It builds upon previous research to analyze the factors influencing the use of these services and current trends in shared transportation. Additionally, it investigates the challenges associated with utilizing shared transportation amenities and proposes potential improvements to make ride-sharing or pooling more attractive. The study diligently worked to establish an inclusive framework and terminology to enhance policies and gain a more detailed understanding of the transportation choices and requirements of communities. To bridge the gap between theory and practice, we adopted an implementation-oriented research approach and conducted a comprehensive quantitative and inferential analysis of the survey data. The inclination of an individual to opt for or perceive collective or merged services depends on several demographic, geographical, and built-environment factors. The findings highlight the necessity of enhanced security measures, increased public awareness of ride-sharing benefits, and the formulation of legislative measures to promote sustainable mobility. Two examples of potential measures we have found to improve and encourage the use of ride-sharing services include reducing uncertainty about shared rides and minimizing passenger discomfort. These measures can be implemented through operational adjustments, government regulations, and employer programs. An essential conclusion was reached regarding the importance of prioritizing improvements in ride-sharing operations, rather than relying solely on cash incentives to promote behavioral change. Furthermore, it was determined that regardless of the changes, policies, or programs implemented, it is imperative to enhance public awareness and education.
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The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Células Acinares , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Ubiquitina-Proteína Ligasas , Animales , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/enzimología , Humanos , Células Acinares/patología , Células Acinares/metabolismo , Células Acinares/enzimología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/enzimología , Metaplasia/patología , Metaplasia/metabolismo , Plasticidad de la Célula , Carcinogénesis/genética , Carcinogénesis/metabolismo , Ratones , Línea Celular Tumoral , Proliferación Celular , Ratones Noqueados , Regulación Neoplásica de la Expresión Génica , Lesiones Precancerosas/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/enzimología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Proteínas PortadorasRESUMEN
Gallbladder cancer (GBC) is a rare but very aggressive most common digestive tract cancer with a high mortality rate due to delayed diagnosis at the advanced stage. Moreover, GBC progression shows asymptomatic characteristics making it impossible to detect at an early stage. In these circumstances, conventional therapy like surgery, chemotherapy, and radiotherapy becomes refractive. However, few studies reported some molecular markers like KRAS (Kirsten Rat Sarcoma) mutation, upregulation of HER2/neu, EGFR (Epidermal Growth Factor Receptor), and microRNAs in GBC. However, the absence of some specific early diagnostic and prognostic markers is the biggest hurdle for the therapy of GBC to date. The present study has been designed to identify some specific molecular markers for precise diagnosis, and prognosis, for successful treatment of the GBC. By In Silico a network-centric analysis of two microarray datasets; (GSE202479) and (GSE13222) from the Gene Expression Omnibus (GEO) database, shows 50 differentially expressed genes (DEGs) associated with GBC. Further network analysis revealed that 12 genes are highly interconnected based on the highest MCODE (Molecular Complex Detection) value, among all three genes; TRIP13 (Thyroid Receptor Interacting Protein), NEK2 (Never in Mitosis gene-A related Kinase 2), and TPX2 (Targeting Protein for Xklp2) having highest network interaction with transcription factors and miRNA suggesting critically associated with GBC. Further survival analysis data corroborate the association of these genes; TRIP13, NEK2, and TPX2 with GBC. Thus, TRIP13, NEK2, and TPX2 genes are significantly correlated with a greater risk of mortality, transforming them from mere biomarkers of the GBC for early detections and may emerge as prognostic markers for treatment.
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Biomarcadores de Tumor , Neoplasias de la Vesícula Biliar , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/metabolismo , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Simulación por Computador , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Pronóstico , Carcinogénesis/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
BACKGROUND: Fidelity to a given foraging location or route may be beneficial when environmental conditions are predictable but costly if conditions deteriorate or become unpredictable. Understanding the magnitude of fidelity displayed by different species and the processes that drive or erode it is therefore vital for understanding how fidelity may shape the demographic consequences of anthropogenic change. In particular, understanding the information that individuals may use to adjust their fidelity will facilitate improved predictions of how fidelity may change as environments change and the extent to which it will buffer individuals against such changes. METHODS: We used movement data collected during the breeding season across eight years for common guillemots, Atlantic puffins, razorbills, and black-legged kittiwakes breeding on the Isle of May, Scotland to understand: (1) whether foraging site/route fidelity occurred within and between years, (2) whether the degree of fidelity between trips was predicted by personal foraging effort, and (3) whether different individuals made more similar trips when they overlapped in time at the colony prior to departure and/or when out at sea suggesting the use of the same local environmental cues or information on the decisions made by con- and heterospecifics. RESULTS: All species exhibited site and route fidelity both within- and between-years, and fidelity between trips in guillemots and razorbills was related to metrics of foraging effort, suggesting they adjust fidelity to their personal foraging experience. We also found evidence that individuals used local environmental cues of prey location or availability and/or information gained by observing conspecifics when choosing foraging routes, particularly in puffins, where trips of individuals that overlapped temporally at the colony or out at sea were more similar. CONCLUSIONS: The fidelity shown by these seabird species has the potential to put them at greater risk in the face of environmental change by driving individuals to continue using areas being degraded by anthropogenic pressures. However, our results suggest that individuals show some flexibility in their fidelity, which may promote resilience under environmental change. The benefits of this flexibility are likely to depend on numerous factors, including the rapidity and spatial scale of environmental change and the reliability of the information individuals use to choose foraging sites or routes, thus highlighting the need to better understand how organisms combine cues, prior experience, and other sources of information to make movement decisions.
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TRIP4 is a conserved transcriptional coactivator that is involved in the regulation of the expression of multiple genes. It consists of a classical N-terminal C2HC5-like zinc-finger domain and a conserved C-terminal ASCH domain. Here, we characterized the DNA-binding properties of the human TRIP4 ASCH domain. Our biochemical data show that TRIP4-ASCH has comparable binding affinities toward ssDNA and dsDNA of different lengths, sequences, and structures. The crystal structures reveal that TRIP4-ASCH binds to DNA substrates in a sequence-independent manner through two adjacent positively charged surface patches: one binds to the 5'-end of DNA, and the other binds to the 3'-end of DNA. Further mutagenesis experiments and binding assays confirm the functional roles of key residues involved in DNA binding. In summary, our data demonstrate that TRIP4-ASCH binds to the 5' and 3'-ends of DNA in a sequence-independent manner, which will facilitate further studies of the biological function of TRIP4.
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Proteínas de Unión al ADN , ADN , Modelos Moleculares , Unión Proteica , Factores de Transcripción , Humanos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/química , Cristalografía por Rayos X , Sitios de Unión , ADN/metabolismo , ADN/química , ADN de Cadena Simple/metabolismo , ADN de Cadena Simple/química , Dominios Proteicos , Secuencia de Aminoácidos , Dedos de Zinc , Proteínas RepresorasRESUMEN
Horses are regularly transported in the United States (U.S.); however, how, and why horses travel by road has not been explored. Consequently, an online nationwide survey was conducted to understand 1) the most common reasons for travel; 2) the types of journeys undertaken when being transported by road in the U.S. and 3) the general management practices when transporting for 3 h or less. Responses were collected from 1294 participants with at least one response from every state in the continental U.S. The most common survey taker was a female (93.9 %), adult amateur (81.2 %), horse owner (64.6 %) who rode recreationally (33.1 %) and transported their own horse (79.4 %). The most common reasons for travel were for trail or leisure riding (34.2 %) followed by showing and competition (25.3 %); however, this varied by discipline. The most common trip duration was less than one hour (46.8 %), with only 12.4 % of the most common trip durations being 4 h or more. The most common specific horse transported by road for 3 h or less was an adult (age 5-15; 59.0 %), Quarter Horse (21.2 %), used for pleasure or trail riding (44.3 %). The biggest concern when transporting was injury to the horse (26.7 %), whilst the biggest factor when planning to travel was the weather (24.1 %). These results provide insight into why horses are being transported by road in the U.S. and that it is more common to transport horses for shorter durations.
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Cell-cell mechanotransduction regulates tissue development and homeostasis. α-catenin, the core component of adherens junctions, functions as a tension sensor and transducer by recruiting vinculin and transducing signals that influence cell behaviors. α-catenin/vinculin complex-mediated mechanotransduction regulates multiple pathways, such as Hippo pathway. However, their associations with the α-catenin-based tension sensors at cell junctions are still not fully addressed. Here, we uncovered the TRIP6/LATS1 complex co-localizes with α-catenin/vinculin at both bicellular junctions (BCJs) and tricellular junctions (TCJs). The localization of TRIP6/LATS1 complex to both TCJs and BCJs requires ROCK1 and α-catenin. Treatment by cytochalasin B, Y-27632 and blebbistatin all impaired the BCJ and TCJ junctional localization of TRIP6/LATS1, indicating that the junctional localization of TRIP6/LATS1 is mechanosensitive. The α-catenin/vinculin/TRIP6/LATS1 complex strongly localized to TCJs and exhibited a discontinuous button-like pattern on BCJs. Additionally, we developed and validated an α-catenin/vinculin BiFC-based mechanosensor that co-localizes with TRIP6/LATS1 at BCJs and TCJs. The mechanosensor exhibited a discontinuous distribution and motile signals at BCJs. Overall, our study revealed that TRIP6 and LATS1 are novel compositions of the tension sensor, together with the core complex of α-catenin/vinculin, at both the BCJs and TCJs.
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Proteínas Serina-Treonina Quinasas , Vinculina , alfa Catenina , alfa Catenina/metabolismo , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Vinculina/metabolismo , Mecanotransducción Celular , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Uniones Intercelulares/metabolismo , Células HEK293 , Quinasas Asociadas a rho/metabolismo , Factores de Transcripción/metabolismoRESUMEN
This paper deals with the analysis of TRIP steel HCT690 deformation behaviour. The mechanical properties and deformation characteristics of the tested material are determined using selected material tests and tests that consider the required stress states used to define the yield criterion boundary condition and subsequent deformation behaviour in the region of severe plastic deformation. The measured data are subsequently implemented in the numerical simulation of sheet metal forming, where they are used as input data for the computational process in the form of a selected material model defining the yield criterion boundary and, furthermore, the material hardening law during deformation of the material. The chosen numerical simulation process corresponds to the sheet metal forming process, including the subsequent spring-back of the material, when the force does not affect the material. Furthermore, the influence of the chosen computational model and selected process parameters on the deformation and spring-back process of the material is evaluated. In addition to that, at the end of the paper, the results from the numerical simulation are compared with experimentally produced sheet stamping.
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BACKGROUND/OBJECTIVE: H. pylori is a recognized bacterial carcinogen in the world to cause gastric cancer (GC). However, the molecular mechanism of H. pylori infection-induced GC is not completely clear. Thus, there is an urgent need to reveal the precise mechanisms regulating cancer development due to H. pylori infection. METHODS: GEO microarray databases and TCGA databases were extracted for the analysis of different expression genes (DEGs). Then, Kaplan-Meier Plotter was used for prognostic analysis. Functional enrichment analysis of TRIP13 was performed by metascape database and TIMER database. Specific role of TRIP13 in GC with H. pylori infection was confirmed by CCK8, cell cycle analysis and WB. RESULTS: A total 10 DEGs were substantially elevated in GC and H. pylori+ tissues and might be associated with H. pylori infection in GC and only the highly expressed TRIP13 was statistically associated with poor prognosis in GC patients. Meanwhile, TRIP13 were upregulated in both CagA-transfected epithelial cells and GC cells. And TRIP13 deficiency inhibited cell proliferation and arrested the cell cycle at the G1 phase. CONCLUSION: Our study suggested that high expression of TRIP13 can promote the proliferation, cell cycle in GC cells, which could be used as a biomarker for H. pylori infection GC.
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Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Pronóstico , Línea Celular Tumoral , Progresión de la Enfermedad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ciclo Celular , ATPasas Asociadas con Actividades Celulares Diversas , Proteínas de Ciclo CelularRESUMEN
Recurrent falls pose a significant challenge for Parkinson's disease (PD) patients and are a leading cause of disability in this population. One contributing factor to these recurring falls is the reduced minimum toe clearance (mTC). Preventing such falls by enhancing mTC has become an important goal in gait training among PD patients. In this paper, we propose a wearable cueing-based novel gait training device in anticipation of improved mTC. The cueing device records the foot strike angle (FSA) and cues the participants if the FSA is observed above a threshold. The patients with PD (n = 8) were recruited and asked to walk under two conditions: (a) with cue and (b) without cue at a self-selected speed during the ON medication state. Kinetic and kinematic gait parameters such as vertical ground reaction force, center of pressure, toe clearance, and FSA were recorded. A Mann-Whitney U test showed a significant increase (p < 0.001) in the toe clearance (within 34% to 64% of the swing phase from the toe-off instance) and FSA, from 87.60 mm and - 5.43degrees respectively during without cue to 94.29 mm and 2.93degrees respectively during with cue walking condition except in one subject. These findings support the potential incorporation of an FSA-based cueing device for toe clearance improvement among PD patients. In addition, the wearable setup supports the cueing device applicability outside laboratory and home settings.
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Señales (Psicología) , Marcha , Enfermedad de Parkinson , Dedos del Pie , Humanos , Enfermedad de Parkinson/fisiopatología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Fenómenos Biomecánicos , Dispositivos Electrónicos VestiblesRESUMEN
This paper examines the endogenous relationship between residential level of accessibility and household trip frequencies to tease out the direct and indirect effects of observed behavioural differences. We estimate a multivariate ordered probit model system, which allows dependence in both observed and unobserved factors, using data from the 2016 Transportation Tomorrow Survey (TTS), a household travel survey in the Greater Golden Horseshoe Area (GGH) in Toronto. The modelling framework is used to analyse the influence of exogenous variables on eight outcome variables of accessibility levels and trip frequencies by four modes (auto, transit, bicycle and walk), and to explore the nature of the relationships between them. The results confirm our hypothesis that not only does a strong correlation exist between the residential level of accessibility and household trip frequency, but there are also direct effects to be observed. The complementarity effect between auto accessibility and transit trips, and the substitution effect observed between transit accessibility and auto trips highlight the residential neighbourhood dissonance of transit riders. It shows that locations with better transit service are not necessarily locations where people who make more transit trips reside. Essentially, both jointness (due to error correlations) as well as directional effects observed between accessibility and trip frequencies of multiple modes offer strong support for the notion that accessibility and trip frequency by mode constitute a bundled choice and need to be considered as such.
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Globally, colorectal cancer (CRC) is one of the leading causes of health problems. More reliable molecular biomarkers for early diagnosis in CRC patients are needed. A crucial role for thyroid hormone receptor interacting protein 6 (TRIP6) is played in tumorigenesis and tumor growth. Our study aims to determine the diagnostic and prognostic roles of TRIP6 at CRC. TRIP6 gene expression levels were analyzed in this study from public databases. The relationship between TRIP6 expression and clinicopathological characteristics was explored by logistic regression analysis. Based on Kaplan-Meier (K-M) survival curves and receiver operating characteristic curves (ROC) analysis, the prognostic and diagnostic values of TRIP6 were determined. Protein-protein interaction (PPI) networks analysis were performed using the STRING database. A Spearman's correlation analysis applied for examining the correlation between TRIP6 expression, immune cell infiltration, and immune checkpoint genes. Moreover, colony formation assay and transwell assay were used to investigate the functions of TRIP6. TRIP6 was highly expressed in CRC cancer tissues and cells. K-M survival analysis indicated that a high expression of TRIP6 was associated with poor prognosis. TRIP6 expression was obviously associated with immune cell infiltration and immune checkpoint gene expression. For validation, the results of collected clinical CRC samples show that TRIP6 levels in CRC tumor tissue were higher than those of paired adjacent colorectal tissues. Additionally, in vitro experiments suggested that TRIP6 knockdown suppressed proliferation and migration in CRC cell line RKO. TRIP6 overexpression promoted the proliferation and migration of normal colon cell line NCM460. High TRIP6 expression is associated with poor prognosis in colorectal cancer and promotes tumor cell proliferation and migration which may be a potential diagnostic and prognostic biomarker and a promising therapeutic target for CRC, providing new insights into its role in CRC.