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The incorporation of physical environmental performance as a primary consideration in building design can facilitate the harmonization of the built environment with the surrounding site and climate, enhance the building's environmental adaptability and environmental friendliness, and contribute to the achievement of energy-saving and emission-reduction objectives through the integration of natural lighting and ventilation. General computational fluid dynamics (CFD) can help architects make accurate predictions and effectively control the building's wind environment. However, CFD integration into the design workflow in the preliminary stages is frequently challenging due to program uncertainty, intricate parameter settings, and substantial computational expenses. This study offers a methodology and framework based on machine learning to overcome the complexity and computational cost barriers in simulating outdoor wind environments of buildings. In this framework, the machine learning model is trained using an automated CFD simulation system based on Butterfly and implemented within the Rhino and Grasshopper environment. This framework provides real-time simulation feedback within the design software and exhibits promising accuracy, with a Structural Similarity Index Measure (SSIM) ranging from 90–97% on a training dataset of 1200 unique urban geometries in Xinjiekou Area of Nanjing, China. Furthermore, we programmatically integrate various parts of the simulation and computation process to automate multiscenario CFD simulations and computations. This automation saves a significant amount of time in producing machine-learning training sets. Finally, we demonstrate the effectiveness and accuracy of the proposed working framework in the design process through a case study. Although our approach cannot replace CFD simulation computation in the later design stages, it can support architects in making design decisions in the preliminary stages with minimal effort and immediate performance feedback. [ABSTRACT FROM AUTHOR]

Based on five periods of Landsat remote sensing data from 1980 to 2020, this study constructs a landscape ecological risk-ecosystem service value evaluation model and integrates it with a geodetector model to analyse the environmental benefits of the development of the "production–living–ecological space" pattern and its driving factors in the Xuzhou planning area. The results of the study are as follows: (1) Over the past 40 years, the expansion of living spaces has significantly encroached upon adjacent agricultural production areas and ecological spaces, such as forests and grasslands. Specifically, the areas of agricultural land, forests, and grassland have been diminished by 277.39 km2, 23.8 km2 and 12.93 km2, respectively; in contrast, urban and rural living spaces have increased by 238.62 km2 and 58.92 km2, alongside a rise in industrial production areas, water bodies, and other ecological spaces. (2) Throughout the 40-year period, both the landscape ecological risk (ERI) and ecosystem service value (ESV) in the study area have shown a decreasing trend. The proportion of high- and medium-high-risk areas of the ERI have decreased by 5.19% and 7.50%, respectively, while low, lower, and medium ecological risk areas have increased by 6.40%, 3.22% and 3.07%, respectively. In addition, low-ESV areas have increased by 14.22%, while the proportion of high- and medium-high-ESV areas have decreased by 1.16%. (3) There is a significant positive spatial correlation between the ERI and ESV. Regions with dense ecological spaces comprising forests, water bodies, and grasslands, particularly in the northeastern part of the Jiawang District and the southeastern part of the Tongshan District, demonstrate superior regional ecosystem service quality. The ERI and ESV are dominated by "high–high" and "low–high" aggregation. Conversely, in the southwestern part of the study area, the expansion of living space has led to the transformation of some agricultural land, forest land, and grassland into less risky construction land, resulting in a decline in the quality of regional ecosystem services. The local spatial correlation between the ERI and ESV changed from "high–high", "low–low", "low–high" agglomeration to "low–low" agglomeration. (4) Key factors influencing the spatial differentiation of the "production–living–ecological space" include the GDP, population density, soil type, and the distance to towns and roads. Among these, the interaction between population density and soil type has the most significant effect on the changes in the pattern of the "production–living–ecological space". [ABSTRACT FROM AUTHOR]

Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption. [ABSTRACT FROM AUTHOR]

In building massing design, using passive design strategies is a critical approach to reducing energy consumption while offering comfortable indoor environments. However, it is often impractical for architects to systematically explore passive design strategies at the outset of the building massing design and architectural form-finding processes, which may result in inefficient or ineffective utilization of the strategies. To address this issue, this study presents a reverse passive design strategy exploration approach that leverages the capability of computational optimization and parametric modeling to help architects identify feasible passive design strategies for building massing design. The approach is achieved using a building massing design generation and optimization tool, called EvoMass, and various building performance simulation tools in Rhino-Grasshopper. The optimization can produce site-specific design references that reflect rich performance implications associated with passive design strategies, such as atriums and self-shading. As such, architects can screen out promising passive design strategies corresponding to different performance factors from the optimization result. Two case studies related to daylighting, sky exposure, and solar heat utility are presented to demonstrate the approach, and the relevant utility and limitations are discussed. [ABSTRACT FROM AUTHOR]

A large number of aerospace practices have confirmed that the aerospace microgravity environment can lead to cognitive function decline. Mitochondria are the most important energy metabolism organelles, and some studies demonstrate that the areospace microgravity environment can cause mitochondrial dysfunction. However, the relationships between cognitive function decline and mitochondrial dysfunction in the microgravity environment have not been elucidated. In this study, we simulated the microgravity environment in the Sprague-Dawley (SD) rats by -30° tail suspension for 28 days. We then investigated the changes of mitochondrial morphology and proteomics in the hippocampus. The electron microscopy results showed that the 28-day tail suspension increased the mitochondria number and size of rat hippocampal neuronal soma. Using TMT-based proteomics analysis, we identified 163 differentially expressed proteins (DEPs) between tail suspension and control samples, and among them, 128 proteins were upregulated and 35 proteins were downregulated. Functional and network analyses of the DEPs indicated that several of mitochondrial metabolic processes including the tricarboxylic acid (TCA) cycle were altered by simulating microgravity (SM). We verified 3 upregulated proteins, aconitate hydratase (ACO2), dihydrolipoamide S-succinyltransferase (DLST), and citrate synthase (CS), in the TCA cycle process by western blotting and confirmed their differential expressions between tail suspension and control samples. Taken together, our results demonstrate that 28-day tail suspension can cause changes in the morphology and metabolic function of hippocampus mitochondria, which might represent a mechanism of cognitive disorder caused by aerospace microgravity. [ABSTRACT FROM AUTHOR]

Abstract Background The tumor suppressor gene CDKN2A generates at least three different transcriptional variants, each of which is thought to encode a tumor suppressor. However, the inhibitory activities of these variants have not yet been compared in the same cells. Protein therapy is known to have several advantages over gene therapy. Thus, investigation of the exogenous protein molecule of the most effective suppressor may yield meaningful information regarding protein-based cancer therapy. Methods The inhibitory effects of p16INK4a, p14ARF and p12 were studied in the human lung cancer cell line A549 which lacks the CDKN2A locus. The eukaryotic expression plasmids of the three transcriptional variants were constructed and stably transfected into the cells. RNA and protein expression by the plasmids was confirmed using RT-PCR and fluorescence immunocytochemistry, respectively. Cell growth inhibition and cell-cycle redistribution after transfection were investigated based on growth curve and flow cytometry analyses. An exogenous His-tag fusion p16INK4a protein was obtained and purified by affinity chromatography. Cell growth inhibition and cell cycle arrest induced by the expression of p16INK4a protein were measured in A549 cells transduced with the exogenous protein. Results While all three variants suppressed cell growth, p16INK4a had the strongest effect. Marked G1-phase accumulation and S-phase inhibition were induced by p16INK4a and p14ARF but not by p12. Exogenous p16INK4a protein was successfully expressed and purified and transduction of the fusion protein into A549 cells inhibited cell growth by G1→S arrest. Conclusions Among the three transcript variants, p16INK4a has a greater inhibitory effect than p14ARF and p12; exogenous p16INK4a protein should be further investigated for use in cancer therapy as a protein agent.

Gene amplification chiefly manifests as homogeneously stained regions (HSRs) or double minutes (DMs) in cytogenetically and extrachromosomal DNA (ecDNA) in molecular genetics. Evidence suggests that gene amplification is becoming a hotspot for cancer research, which may be a new treatment strategy for cancer. DMs usually carry oncogenes or chemoresistant genes that are associated with cancer progression, occurrence and prognosis. Defining the molecular structure of DMs will facilitate understanding of the molecular mechanism of tumorigenesis. In this study, we re‐identified the origin and integral sequence of DMs in human colorectal adenocarcinoma cell line NCI‐H716 by genetic mapping and sequencing strategy, employing high‐resolution array‐based comparative genomic hybridization, high‐throughput sequencing, multiplex‐fluorescence in situ hybridization and chromosome walking techniques. We identified two distinct populations of DMs in NCI‐H716, confirming their heterogeneity in cancer cells, and managed to construct their molecular structure, which were not investigated before. Research evidence of amplicons distribution in two different populations of DMs suggested that a multi‐step evolutionary model could fit the module of DM genesis better in NCI‐H716 cell line. In conclusion, our data implicated that DMs play a very important role in cancer progression and further investigation is necessary to uncover the role of the DMs. [ABSTRACT FROM AUTHOR]

Significant research has been undertaken focusing on the application of evolutionary algorithms for design exploration at conceptual design stages. However, standard evolutionary algorithms are typically not well-suited to supporting such optimization-based design exploration due to the lack of design diversity in the optimization result and the poor search efficiency in discovering high-performing design solutions. In order to address the two weaknesses, this paper proposes a hybrid evolutionary algorithm, called steady-stage island evolutionary algorithm (SSIEA). The implementation of SSIEA integrates an island model approach and a steady-state replacement strategy with an evolutionary algorithm. The combination aims to produce optimization results with rich design diversity while achieving significant fitness progress in a reasonable amount of time. Moreover, the use of the island model approach allows for an implicit clustering of the design population during the optimization process, which helps architects explore different alternative design directions. The performance of SSIEA is compared against other optimization algorithms using two case studies. The result shows that, in contrast to the other algorithms, SSIEA is capable of achieving a good compromise between design diversity and search efficiency. The case studies also demonstrate how SSIEA can support conceptual design exploration. For architects, the optimization results with diverse and high-performing solutions stimulate richer reflection and ideation, rendering SSIEA a helpful tool for conceptual design exploration. [ABSTRACT FROM AUTHOR]

Background: Polycystic kidney disease (PKD) is an inherited disease that is life‐threatening. Multiple cysts are present in the bilateral kidneys of PKD patients. The progressively enlarged cysts cause structural damage and loss of kidney function. Methods: This study examined and analyzed 12 families with polycystic kidney disease. Whole exome sequencing (WES) or whole genome sequencing (WGS) of the probands was performed to detect the pathogenic genes. The candidate gene segments for lineal consanguinity in the family were amplified by the nest PCR followed by Sanger sequencing. The variants were assessed by pathogenic and conservational property prediction analysis and interpreted according to the American College of Medical Genetics and Genomics. Results: Nine of the 12 pedigrees were identified the disease causing variants. Among them, four novel variants in PKD1, c.6930delG:p.C2311Vfs*3, c.1216T>C:p.C406R, c.8548T>C:p.S2850P, and c.3865G>A:p.V1289M (NM_001009944.2) were detected. After assessment, the four novel variants were considered to be pathogenic variants and cause autosomal dominant polycystic kidney disease in family. The detected variants were interpreted. Conclusion: The four novel variants in PKD1, c.6930delG:p.C2311Vfs*3, c.1216T>C:p.C406R, c.8548T>C:p.S2850P, and c.3865G>A:p.V1289M (NM_001009944.2) are pathogenic variants and cause autosomal dominant polycystic kidney disease in family. [ABSTRACT FROM AUTHOR]

Sleep loss is one of large challenges during space missions. A variety of sleep problems have been shown in space. We aimed to further characterize more representative and consecutive sleep-wake patterns and to investigate sleep-wake cycle on heart rate during short duration spaceflight mission. Here, we evaluated sleep quality using Pittsburgh Sleep Quality Index, analyzed sleep time, sleep efficiency, and periods of sleep-wake rhythm via the activity data from Actiwatch, and evaluated heart rate data via the Actiheart in three crew members before, during and after a 15-day spaceflight. The study showed that the sleep quality before and during the flight were lower than that after the space flight. Crew members slept less during spaceflight relative to on Earth. The mean sleep duration during spaceflight was 6.5 ± 1.3 h, but after flight, it was 7.2 ± 1.2 h, and the sleep efficiency was significantly higher during the flight than that on Earth. The periods of sleep-wake rhythm could keep at 23.92 h during flight mission. Moreover, the heart rate decreased during spaceflight and it was more obvious during wakeful state than during sleep. These data could help us better understand the effects of short-duration spaceflight on sleep pattern. [ABSTRACT FROM AUTHOR]

Physiological changes in humans are evident under environmental conditions similar to those on a Mars mission involving both a space factor (long-term isolation) and a time factor (the Mars solar day). However, very few studies have investigated the response of the liver to those conditions. Serum protein levels, bilirubin levels, aminotransferase activities, blood alkaline phosphatase, gamma-glutamyltransferase, lipid levels, and serum cytokines interleukin-6 and interferon-γ levels were analyzed 30 days before the mock mission; on days 2, 30, 60, 75, 90, 105, 120, 150, and 175 of the mission; and 30 days after the mission, in four subjects in 4-person 180-day Controlled Ecological Life Support System Experiment. Serum protein levels (total protein and globulin) decreased and bilirubin increased under the isolation environment from day 2 and exhibited chronic acclimatization from days 30 to 175. Effects of the Mars solar day were evident on day 75. Blood lipid levels were somewhat affected. No obvious peak in any enzyme level was detected during the mission. The change tendency of these results indicated that future studies should explore whether protein parameters especially globulin could serve as indicators of immunological function exposure to the stress of a Mars mission. [ABSTRACT FROM AUTHOR]

The circadian rhythm is a widespread physiological phenomenon present in almost all forms of life and is constituted by a system of interlocked transcriptional/translational feedback loops (TTFLs). External zeitgebers regulate biological rhythms through the direct or indirect regulation of circadian genes. Oxidative stress is involved in many diseases and injuries, such as ageing, diabetes, Alzheimer's disease, and cancer. Despite an increasing number of studies on circadian rhythm disorders caused by oxidative stress, little is known about the effects of oxidants on clock gene expression and the underlying mechanism. In this study, we found that the protein expression of circadian genes Clock , Bmal1 , Per1/2 , and Cry1/2 in NIH3T3 cells was upregulated by hydrogen peroxide (H 2 O 2), an important mediator of oxidative stress. In addition, H 2 O 2 modulated the circadian rhythm of Bmal1-luciferase via RORα, REV-ERBα (NR1D1), and REV-ERBβ (NR1D2). Further studies showed that H 2 O 2 regulated biological rhythm by PRX2-STAT3-REV-ERBα/β pathway. These findings provide an accessory loop-related mechanism by which non-transcriptional oscillation interplays with TTFLs. Image 1 • H 2 O 2 up-regulate the protein expression of core clock genes. • H 2 O 2 modulate the circadian rhythm of Bmal1-luciferase. • The effects of H 2 O 2 are mediated by PRX2-STAT3-NR1D1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is a life-threatening inherited disease with a morbidity of 1:500–1,000 worldwide. Numerous progressively enlarging cysts are observed in the bilateral kidneys of patients with PKD, inducing structural damage and loss of kidney function. The present study analyzed one family with PKD. Whole exome sequencing of the proband was performed to detect the pathogenic gene present in the family. Candidate gene segments for lineal consanguinity in the family were amplified by nest polymerase chain reaction, followed by Sanger sequencing. One novel duplication variant (NM_001009944.2:c.9359dupA:p.Y3120_E3121delinsX) and one missense mutation (c.G9022A:p.V3008M) were detected in PKD1. Additionally, the pathogenic substitutions in PKD1 published from the dataset were analyzed. Following analysis and confirmation, the duplication variant NM_001009944.2:c.9359dupA:p.Y3120_E3121delinsX in PKD1, within the polycystin-1, lipoxygenase, α-toxin domain, was considered to be the pathogenic factor in the examined family with autosomal dominant PKD. Additionally, based on the analysis of 4,805 pathogenic substitutions in PKD1 within various regions, the presence of the missense mutation in the N-terminal domain of polycystin-1 may present high pathogenicity in ADPKD. [ABSTRACT FROM AUTHOR]

The present study aimed to determine how the learning and memory gradually change with the prolonged hindlimb unloading (HU) treatment in rats. Different HU durations (7 d, 14 d, 21 d, and 28 d) in Sprague-Dawley (SD) rats were implemented. Cognitive function was assessed using the Morris water maze (MWM) and the shuttle box test. Additionally, parameters about cholinergic activity and oxidative stress were tested. Results showed that longer-than-14 d HU led to the inferior performances in the behavioral tasks. Besides, acetylcholine esterase (AChE) activity, malondialdehyde (MDA) level in brain, reactive oxygen species (ROS), and 8-hydroxy-2-deoxyguanosine (8-OHdG) concentrations of HU rats were significantly increased. Furthermore, choline acetyltransferase (ChAT), superoxide dismutase (SOD), and catalase (CAT) activity in brain were notably attenuated. Most of these effects were more pronounced after longer exposure (21 d and 28 d) to HU, although some indicators had their own characteristics of change. These results indicate that cholinergic dysfunction and oxidative damage were involved in the learning and memory impairments induced by longer-than-14 d HU. Moreover, the negative effects of HU tend to be augmented as the HU duration becomes longer. The results may be helpful to present possible biochemical targets for countermeasures development regarding the memory deficits under extreme environmental conditions. [ABSTRACT FROM AUTHOR]

Background: Integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is widely performed for staging solitary pulmonary nodules (SPNs). However, the diagnostic efficacy of SPNs based on PET/CT is not optimal. Here, we propose a method of detection based on PET/CT that can differentiate malignant and benign SPNs with few false-positives. Method: Our proposed method combines the features of positron-emission tomography (PET) and computed tomography (CT). A dynamic threshold segmentation method was used to identify lung parenchyma in CT images and suspicious areas in PET images. Then, an improved watershed method was used to mark suspicious areas on the CT image. Next, the support vector machine (SVM) method was used to classify SPNs based on textural features of CT images and metabolic features of PET images to validate the proposed method. Results: Our proposed method was more efficient than traditional methods and methods based on the CT or PET features alone (sensitivity 95.6%; average of 2.9 false positives per scan). [ABSTRACT FROM AUTHOR]

SOD2 (superoxide dismutase 2) is one of the endogenous antioxidant enzymes that protect against reactive oxygen species. While explorations of SOD2 expression regulation are mainly focused on transcriptional and post-translational activation, there are few reports about the post-transcriptional regulation of SOD2. MicroRNAs (miRNAs) are 21nt-25nt (nucleotide) small noncoding RNAs that have emerged as indispensable regulators of gene expression. Here we show that miR-146a, a widely expressed miRNA, is up-regulated by H2O2-induced stress. By sequence analysis we found a binding site for miR-146a in the sod2 mRNA 3′UTR, and a luciferase reporter assay confirmed that miR-146a can interact with this sod2 regulatory region. Our results further show that miR-146a could down-regulate the SOD2 protein expression, and antisense-miR-146a could reverse the decrease of both the SOD2 level and cell viability in H2O2 treated PC12 cells. In conclusion, here we have identified a novel function of miR-146a in the post-transcriptional regulation of SOD2 expression. [ABSTRACT FROM AUTHOR]

For sustainable building design, performance-based optimization incorporating parametric modelling and evolutionary optimization can allow architects to leverage building massing design to improve energy performance. However, two key challenges make such applications of performance-based optimization difficult in practice. First, due to the parametric modelling approaches, the topological variability in the building massing variants is often very limited. This, in turn, limits the scope for the optimization process to discover high-performing solutions. Second, for architects, the process of creating parametric models capable of generating the necessary topological variability is complex and time-consuming, thereby significantly disrupting the design processes. To address these two challenges, this paper presents a parametric massing algorithm based on the subtractive form generation principle. The algorithm can generate diverse building massings with significant topological variability by removing different parts from a predefined volume. Additionally, the algorithm can be applied to different building massing design scenarios without additional parametric modelling being required. Hence, using the algorithm can help architects achieve an explorative performance-based optimization for building massing design while streamlining the overall design process. Two case studies of daylighting performance optimizations are presented, which demonstrate that the algorithm can enhance the exploration of the potential in building massing design for energy performance improvements. [ABSTRACT FROM AUTHOR]

The core circadian clock gene, Clock , is a positive component of the transcription/translation feedback loop in the master pacemaker suprachiasmatic nucleus (SCN) in mammals. The robust daytime peak of some clock genes in the wild-type SCN is absent in Clock mutant mice. However, very little is known about the impact of Clock mutation on the expression of other functional genes in SCN. Here, we performed cDNA microarray and found 799 differentially expressed genes (DEGs) at zeitgeber time 2 (ZT2) and 1289 DEGs at ZT14 in SCN of Clock △19/△19 mutant mice. KEGG pathway analysis showed that the changed mRNAs were highly associated with hedgehog signaling pathway, retinol metabolism, allograft rejection, drug metabolism, hematopoietic cell lineage and neuroactive ligand-receptor interaction. The top 14 and 71 hub genes were identified from the protein–protein interaction (PPI) network at ZT2 and ZT14, respectively. The sub-networks revealed hub genes were involved in olfactory transduction and neuroactive ligand-receptor interaction pathways. These results demonstrate the Clock △19/△19 mutation alters the expression of various genes involved in a wide spectrum of biological function in mouse SCN, which are helpful for better understanding the function of Clock and potential regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Microgravity has many detrimental impact on brain functions, however the underlying mechanism remain unclear. In present study, 28 days of tail-suspension (30°) was used to simulate microgravity in rats. We showed that oxidative stress in hippocampus was increased after 28 days of simulated microgravity in consideration of the decreased expression of NF-E2-related factor 2 (Nrf2) and the declined activities of total superoxide dismutase (T-SOD), CuZn-SOD, glutathione peroxidase (GSH-PX) and total antioxidant capacity (T-AOC). Using RNA-seq, we further investigated the effect of simulated microgravity on the expression of genes in hippocampus, and 849 genes were found to be differentially expressed. According to pathway analysis, the differentially expressed genes involved in cytoskeleton, metabolism, immunity, transcription regulation, etc. It is interesting to note that the differentially expressed genes were involved in hypoxia-associated pathway. In agreement with this, the expression of hypoxia induced factor-1α (HIF-1α), the master regulator of oxygen homeostasis, was significantly increased. Meanwhile, HIF-2α, a HIF-1α paralog, was elevated compared with the control group. The expression of pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA) and vascular endothelial growth factor (VEGF), three well-defined downstream targets of HIF-1α, were up-regulated in hippocampus after 28 days of simulated microgravity exposure. Additionally, brain oxygen saturation (SO 2 ) and blood flow analyzed by the tissue oxygen analysis system were also significantly reduced. These findings indicate that simulated microgravity might cause an alteration in oxygen homeostasis, providing novel insight into better understanding of how simulated microgravity affects the function of hippocampus and a new direction to the development of countermeasure for brain dysfunction during spaceflight (actual microgravity). [ABSTRACT FROM AUTHOR]

Abstract: Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that regulates cell growth, differentiation, migration, apoptosis and extracellular matrix remodeling. TGF-β1 transduces signals from the cell membrane to the cell nucleus through serine/threonine kinase receptors and their downstream effectors, Smad molecules. Although many studies have been focused on TGF-β1–Smad signaling pathway, the role of TGF-β1/Smad in tongue squamous cell carcinoma is not fully understood. In the present study, we used a series of cell function assays to examine the role of TGF-β–Smad4 signaling in tongue squamous cell carcinoma. We observed the effects of TGF-β1 on the growth and metastatic potential of the tongue squamous cell carcinoma cell line Ts, which expresses lower level of Smad4 protein. We found that Smad4 could decrease TGF-β1-induced cell proliferation, and that Smad4 overexpression promoted Ts cell apoptosis. In Ts vector control cells, TGF-β1 increased the expression of TβRII, as well as MMP-2, and enhanced cell invasion through the basement membrane, and then induced cell metastasis. However in Ts cells stably expressing Smad4, Smad4 mediated TGF-β1-induced p21 expression promoted cell apoptosis and inhibited cell proliferation, delayed MMP-2 expression, and decreased cell metastasis. Therefore, TGF-β1 plays distinct roles in the Smad4-dependent and -independent signaling pathways. [Copyright &y& Elsevier]