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Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes after liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor (TGF)-β, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte αvβ8, after partial hepatectomy, hepatocyte proliferation and liver-to-body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared with control mice. Antibody-mediated blockade of hepatocyte αvβ8 in vitro, with assessment of TGF-β signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin αvβ8 inhibition alters hepatocyte TGF-β signaling toward a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, used to examine the possibility that this pro-proliferative phenotype might be oncogenic, revealed no difference in either tumor number or size between Itgb8flox/flox;Alb-Cre and control mice. Immunohistochemistry for integrin αvβ8 in healthy and injured human liver demonstrated that human hepatocytes express integrin αvβ8. Depletion of hepatocyte integrin αvβ8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin αvβ8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases.

Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma, is the leading cause of death from lung malignancies and has a poor prognosis due to metastasis. Suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown to be involved in growth control. Here, we show that SOCS2 were significantly downregulated in tumour foci in NSCLC patients. The expression levels of SOCS2 significantly correlated with clinical stage, lymph node metastasis, histological subtype and survival time. In particular, the decreased expression of SOCS2 significantly associated with advanced pathological stage, lymph node metastasis and shorter overall survival in lung adenocarcinoma patients. In vivo animal results showed that overexpressed SOCS2 attenuated the metastatic characteristics of lung adenocarcinoma, including by inhibiting the epithelial–mesenchymal transition (EMT). Further functional studies indicated that insulin-like growth factor 1 (IGF1)-driven migratory and invasive behaviours of lung adenocarcinoma cells can be partially suppressed by exogenous SOCS2 expression. Investigations into the mechanism of action revealed that SOCS2 inhibits EMT by inactivating signal transducer and activator of transcription 3 (STAT3) and STAT5 via the competitive binding of SOCS2 to the STAT binding sites on IGF1R. Altogether, our results reveal an important role for SOCS2 dysregulation in the pathogenicity of lung adenocarcinoma, suggest its potential use as a biomarker for diagnosing lung adenocarcinoma, and paves the way to develop novel therapy targets as the axis of SOCS2–IGF1R–STAT in lung adenocarcinoma.

The bone morphogenic protein signaling (BMP) is intricately involved in the quiescence and regulation of stem cells through activation of BMP receptors. Hair follicle stem cells play a critical role in cutaneous homeostasis and regeneration. Here, we utilize a novel mouse model with targeted overexpression of the BMP receptor ALK2/ACVR1 in hair follicle stem cells, to characterize its role in skin development and postnatal wound healing. Initial histologic evaluation demonstrated significant dysregulation in hair follicle morphogenesis in mutant mice. These demonstrated increased numbers of individual hair follicles with altered morphology and localization. Mutant follicles were found to exhibit elevated proliferative activity as well as increased prevalence of CD34 and ITGA6 positive follicle stem cells. Interestingly, constitutive overexpression of ALK2 resulted in attenuation of cutaneous wound healing. These findings demonstrate that hair follicle specific ALK2 is intricately involved in maintenance of the stem cell niche and wound healing.

Arsenic (As) is the element of greatest ecotoxicological concern in aquatic environments. Effective monitoring and diagnosis of As pollution via a biological early warning system is a great challenge for As-affected regions. The purpose of this study was to synthesize water chemistry-based bioavailability and valve daily rhythm in Corbicula fluminea to design a biomonitoring system for detecting waterborne As. We integrated valve daily rhythm dynamic patterns and water chemistry-based Hill dose-response model to build into a programmatic mechanism of inductance-based valvometry technique for providing a rapid and cost-effective dynamic detection system. A LabVIEW graphic control program in a personal computer was employed to demonstrate completely the functional presentation of the present dynamic system. We verified the simulated dissolved As concentrations based on the valve daily rhythm behavior with published experimental data. Generally, the performance of this proposed biomonitoring system demonstrates fairly good applicability to detect waterborne As concentrations when the field As concentrations are less than 1 mg L(-1). We also revealed that the detection times were dependent on As exposure concentrations. This biomonitoring system could particularly provide real-time transmitted information on the waterborne As activity under various aquatic environments. This parsimonious C. fluminea valve rhythm behavior-based real-time biomonitoring system presents a valuable effort to promote the automated biomonitoring and offers early warnings on potential ecotoxicological risks in regions with elevated As exposure concentrations.

Freshwater clam Corbicula fluminea, a surrogate species in metal toxicity testing, is a promising bioindicator of impairment in aquatic ecosystems. Little is known, however, about the relationship between clam valve daily rhythmic response and metal bioavailability related to a metal biological early warning system (BEWS) design. The purpose of this study was to link biotic ligand model (BLM)-based bioavailability and valve daily rhythm in C. fluminea to design a biomonitoring system for online in situ detection of waterborne copper (Cu). We integrated the Hill-based dose-time-response function and the fitted daily rhythm function of valve closure into a constructed programmatic mechanism. The functional presentation of the present dynamic system was completely demonstrated by employing a LabVIEW graphic control program in a personal computer. We used site-specific effect concentration causing 10% of total valve closure response (EC10) as the detection threshold to implement the proposed C. fluminea-based Cu BEWS. Here our results show that the proposed C. fluminea-based BEWS could be deliberately synthesized to online in situ transmit rapidly the information on waterborne bioavailable Cu levels under various aquatic environmental conditions through monitoring the valve daily rhythmic changes. We suggested that the developed C. fluminea-based dynamic biomonitoring system could assist in developing technically defensible site-specific water quality criteria to promote more efficient uses in water resources for protection of species health in aquatic environments.

The purpose of this study is to develop a mechanistic model to describe a conceptually new “flux–biological response” approach based on biotic ligand model (BLM) and Michaelis–Menten (M–M) kinetics to allow the linkage between valve closure behavior and sodium (Na) transport mechanism in freshwater clam Corbicula fluminea in response to waterborne copper (Cu). We test the proposed model against published data regarding Na uptake kinetics in rainbow trout and Na uptake profile in C. fluminea , confirming that the predictive model is robust. Here, we show that the predicted M–M maximum Cu internalization flux in C. fluminea is 0.369 μmol g −1 h −1 with a half-saturation affinity constant of 7.87 × 10 −3 μM. Dynamics of Na uptake and valve closure daily rhythm driven by external Cu can also be predicted simultaneously. We suggest that this “Na transport–valve closure behavior” approach might provide the basis of a future design of biomonitoring tool.

We introduce a novel on-line biomonitoring system based on a valvometric conversion technique for clam Corbicula fluminea, allowing for rapid, continuous, and ecological relevant water quality control. Our model builds upon the basic principles of biological early warning system model in two ways. We first adopted a risk-based methodology to build a dynamic artificial clam for simulating how the bivalve closure rhythm in response to waterborne copper (Cu) and cadmium (Cd). Secondly, we integrated a probabilistic model associated with the time-varying dose-response relationships of valve closing behavior into the mechanisms of a dynamic artificial clam, allowing estimation of the time-varying waterborne Cu/Cd concentrations for on-line providing the outcomes of the toxicity detection technique. Measurements with Cu/Cd were performed and the calculated EC50 values were compared with published data for the valve movement test with C. fluminea. This proposed dynamic artificial clam provides a better quantitative understanding of on-line biomonitoring measurements of waterborne metals and may foster applications in clam farm management strategy and ecotoxicological risk assessment.

This study successfully applied an improved valvometry technique to measure waterborne copper (Cu), based on valve activity dynamics of the freshwater clam Corbicula fluminea. The improved valvometry technique allows the use of free-range bivalves and avoids causing stresses from experimental artifacts. The proposed daily valve rhythm models and a toxicodynamics-based Hill model were linked to predict valve dynamic responses under different Cu exposures with a circadian valve rhythm endpoint. Cu-specific detection threshold was 5.6 (95 % CI 2.1-9.3) and 19.5 (14.6-24.3) μg L(-1) for C. fluminea, based on response times of 300 and 30 min, respectively. Upon exposure to Cu concentrations in excess of 50 μg L(-1), the alteration of valve rhythm behavior was correlated with Cu concentration within 30 min, indicating notable sensing ability. This study outlines the feasibility of an in situ early warning dynamic biomonitoring system for detection of waterborne Cu based on circadian valve activities of C. fluminea.

It has been proposed that irreversible responses of organisms exposed to contaminants are due to a systems-level feedback. Here we tested this hypothesis by reanalyzing the published data on toxicokinetics and survival probability based on a systems-level threshold damage model (TDM) incorporating with a positive damage feedback to explore the steady-state response and dynamic behavior of damage for tilapia and freshwater clam exposed to waterborne arsenic (As). We found that ultrasensitivity appeared in As-tilapia and freshwater clam systems with Hill coefficient n ≥ 4, indicating that the positive damage feedback mechanism has been triggered. We confirmed that damage can trigger a positive feedback loop that together with As stressor increases irreversibility. This study also showed that TDM with positive feedback gave a much better predictability than that of TDM at As concentrations ranging from 100 to 500 mg l(-1) for freshwater clam, whereas for tilapia, two models had nearly same performance on predictability. We suggested that mortality-time profile derived Hill coefficient could be used as a new risk indicator to assess the survival probability for species exposed to waterborne metals. We anticipated that the proposed toxicokinetics/toxicodynamics with a positive damage feedback may facilitate our understanding and manipulation of complex mechanisms of metal susceptibility among species and improve current risk assessment strategies.

The purpose of this study is to conduct a long-term site-specific risk assessment for zinc (Zn) susceptibility of bivalves, green mussel Perna viridis and hard clam Ruditapes philippinarum, based on published experimental data by linking the biologically-based damage assessment model with the subcellular partitioning concept. A comprehensive risk modeling framework was developed to predict susceptibility probability of two bivalve species exposed to waterborne Zn. The results indicated that P. viridis accumulates more Zn toxicity, whereas both toxic potency and the recovery rate of Zn are higher for R. philippinarum. We found that negative linear correlations exist in elimination-recovery and elimination-detoxification relationships, whereas a positive linear correlation was observed in recovery-detoxification relationships for bivalves exposed to waterborne Zn. Simulation results showed that the spatial differences of susceptibility primarily resulted from the variation of waterborne Zn concentration under field conditions. We found that R. philippinarum is more susceptible of Zn than P. viridis under the same exposure condition. Results also suggested that Zn posed no significant susceptibility risk to two bivalve species in Taiwan. We suggested that these two species can be used to biomonitor the water quality on Taiwan coastal areas.

There are many bioindicators. However, it remains largely unknown which metal-bioindicator systems will give the reasonable detection ranges of bioavailable metals in the aquatic ecosystem. Various experimental data make the demonstration of biomonitoring processes challenging. Ingested inorganic arsenic is strongly associated with a wide spectrum of adverse health outcomes. Freshwater clam Corbicula fluminea, one of the most commonly used freshwater biomomitoring organisms, presents daily activity in valve movement and demonstrates biotic uptake potential to accumulate arsenic. Here, a systematical way was provided to dynamically link valve daily activity in C. fluminea and arsenic bioavailability and toxicokinetics to predict affinity at arsenic-binding site in gills and arsenic body burden. Using computational ecotoxicology methods, a valve daily rhythm model can be tuned mathematically to the responsive ranges of valve daily activity system in response to varied bioavailable arsenic concentration. The patterned response then can be used to predict the site-specific bioavailable arsenic concentration at the specific measuring time window. This approach can yield predictive data of results from toxicity studies of specific bioindicators that can assist in prediction of risk for aquatic animals and humans.

We developed an inductance-based valvometry technique as a detection system to measure the valve daily activity in freshwater clam Corbicula fluminea in response to waterborne arsenic. Our findings reveal that C. fluminea experiences a valve opening in the absence of arsenic predominantly in the morning hours (03:00-08:00) with a mean daily opening/closing period of 21.32 (95% CI: 20.58-22.05) h. Amplification of daily activity occurred in the presence of arsenic. Behavioral toxicity assays revealed arsenic detection thresholds of 0.60 (95% CI: 0.53-0.66) mg l(-1) and 0.35 (95% CI: 0.30-0.40) mg l(-1) for response times of 60 and 300 min, respectively. The proposed valve daily activity model was linked with response time-specific Hill dose-response functions to predict valve opening/closing behavior in response to arsenic. The predictive capabilities were verified satisfactory with the measurements. Our results implicate a biomonitoring system by valve daily activity in C. fluminea to identify safe water uses in areas with elevated arsenic.

Arsenic is a potent human carcinogen of skin, lung, and urinary bladder. Freshwater clam Corbicula fluminea is a commercially important native species in Taiwan. C. fluminea is also a suitable biomonitoring test organism. Little is known, however, about the actual effects of arsenic on C. fluminea. The objectives of this study were to provide information on the acute toxicity and bioaccumulation kinetics of arsenic in C. fluminea. We carried out a 14-day exposure experiment to obtain bioaccumulation parameters. Uptake was very rapid when C. fluminea was first exposed and then slightly decayed during the uptake phase of the experiment and an uptake rate constant of 1.718 +/- 6.70 (mean +/- SE) mL g(-1) d(-1) was estimated. The elimination of arsenic from C. fluminea obeyed first-order depuration kinetics (r(2) = 0.85, p < 0.05) with a calculated half-life of 6.80 days. The derived bioaccumulation factor of 16.84 suggests that arsenic has a high potential for bioaccumulation in C. fluminea. This had important implications for dietary exposure of arsenic to humans who eat contaminated clams, because the soft tissue usually constitutes the majority of tissue consumed. The 96-h LC50 value was estimated to be 20.74 (95% CI: 11.74-30.79) mg L(-1) obtained from a 7-day acute toxicity bioassay. We also kinetically linked an acute toxicity model and a Hill sigmoid model to reconstruct an internal effect concentration based dose-response profile to assess the effect of soft tissue arsenic burden on the C. fluminea mortality. This result could be used to support the establishment of an ecological risk assessment to prevent possible ecosystem and human health consequences.

The objective of this paper is to employ biotic ligand model (BLM) to link between acute cop- per (Cu) toxicity and its effect on valve closure behavior of freshwater clam Corbicula fluminea in order to further support for the BLM that potentially offers a rapid and cost-effective method to conduct the acute toxicity tests for freshwater clam exposed to waterborne Cu. Reanalysis of published experimental data of C. fluminea closure daily rhythm and dose-response profiles based on the laboratory-acclimated clams showed that a BLM-based Hill model best described the free Cu 2þ -activity-valve closure response rela- tionships. Our proposed Cu-BLM-Corbicula model shows that free ionic form of waterborne Cu binds specifically to a biotic ligand (i.e., clam gills) and impairs normal valve closure behavior, indicating that a fixed-level of metal accumulation at a biotic ligand is required to elicit specific biological effects. With derived mechanistic-based Cu-BLM-Corbicula model, we show that the site-specific EC50(t) and valve closure behavior at any integrated time can be well predicted, indicating that our model has the potential to develop a biomonitoring system as a bioassay tool to on-line measure waterborne Cu levels in aquatic systems. Our results confirm that BLM can be improved to analytically and rigorously describe the bio- available fraction of metal causing toxicity to valve closure behavior in freshwater C. fluminea. We suggest that the Cu-BLM-Corbicula model can be used to assist in developing technically defensible site-specific water quality criteria and performing ecological risk assessment and to promote more focused and effi- cient uses of resources in the regulation and control of metals and the protection of the aquatic ecosys

We developed a risk-based approach to assess how the valve closure behavior of Asiatic clam Corbicula fluminea responds to waterborne copper (Cu) and cadmium (Cd). We reanalyzed the valve closure response data from published literature to reconstruct the response time-dependent dose-response profiles based on an empirical three-parameter Hill equation model. We integrated probabilistic exposure profiles of measured environmental Cu and Cd concentrations in the western coastal areas of Taiwan with the reconstructed dose-response relationships at different integration times of response to quantitatively estimate the valve response risk. The risk assessment results implicate exposure to waterborne Cu and Cd may pose no significant risk to clam valve activity in the short-time response periods (e.g.