Search

Study region: The Three Gorges cascade (TGC) reservoirs, China. Study focus: Since uncertainties inherent in inflow forecasting, elevation-storage, discharge capacity, flood routing, and the preferences of decision makers (DMs) persist in the attribute measurements (AMs) and weights (AWs), problems where multiple DMs select the best compromise scheme for the long-term comprehensive operation of cascade reservoirs considering numerous attributes become a stochastic multi-attribute group decision-making (MAGDM) process. To represent uncertain AMs and AWs and consider the bounded rationality of DMs, we propose a stochastic MAGDM with integrated stochastic multicriteria acceptability analysis (SMAA) and gray cumulative prospect theory (GCPT), namely, SMAA-GCPT. After quantifying the uncertainties, SMAA-GCPT is used to model uncertain AMs and imperfect AWs with calculable probability distributions and map the sampled AMs and AWs to utility values to reflect the overall performance assuming bounded rationality. New hydrological insights for the region: Experiments on the TGC indicate that SMAA-GCPT can effectively differentiate alternative schemes and select the best compromise scheme to harmonize the conflicting benefits and risks of the TGC, with higher reliability than SMAA-2 and SMAA-GRA. The influence of uncertain AMs on the reliability of SMAA-GCPT is more obvious than that of uncertain AWs. The decision-making error risk is primarily sensitive to the inflow forecasting uncertainty, followed by the flood routing uncertainty, and is less affected by the uncertainties in elevation-storage and discharge capacity curves.

For the controller structure design problem, a controller design method based on the integration of structure search and parameter optimization is proposed with the idea of ENAS, which automates the controller structure design work, and searches for the most suitable controller structure and completes the parameter optimization in a relatively short time. The simulation study with the galvano scanner as the controlled plant shows that the number of iterations and the consumption time of the method are only 15% of the traditional method in achieving the same performance compared with the traditional design method.

Abstract Background To introduce a new and simple classification and management of coronary artery involvement in aortic dissection and report results. Methods Coronary artery involvement was classified into two types according to the integrity of coronary intima: simple lesion (type S) and complex lesion (type C). Complex lesions were treated by CABG and simple lesions were treated by ostial repair or reimplantation. Data were collected and analyzed retrospectively. Results From January 2010 to December 2019, 267 consecutive patients were enrolled in the study, and among them complex lesions occurred in 27 patients (11.1%) and simple lesions was found in 240 patients(89.9%). Eleven untreated vessels with simple lesion were found to be involved again in the same operation and treated by CABG. The two type groups had comparable operative mortality (type S vs. type C, 9.6% vs. 18.5%, P = 0.28). 221 patients received follow-up with a median duration of 52 months. The overall survival rates at 1, 5, and 10 years postoperatively were 88.9%, 85.7%, and 79.8% in type S group and 79.2%, 79.2%, and 79.2% in type C group, respectively (P = 0.47). For the patients who received CABG and survived at discharge, radiographic follow-up with a median duration of 28 (IQR 7-55.5) months showed the freedom from occlusion of vein graft at 1, 5, and 10 years postoperatively were 87.5%, 70.0%, 28.0%. Conclusions According to the new classification, two types of lesions could be treated by corresponding methods with satisfactory early and long-term results. Unrepaired coronary artery was at a risk of re-involvement. Vein graft onto arteries without atherosclerosis still had a high occlusion rate.

Conventional reservoir operation emphasizes power generation (PG) with ignoring downstream river ecosystem and water supply benefits for sustainable development. Compared with the model defining water supply and ecological flow requirements as constraints, a novel long-term multi-objective scheduling model in complex parallel reservoir system (LTMOSCPRS) is developed to assess and achieve win–win and sustainable development for energy, water supply, and ecological benefits. The suitable and ideal ecological water requirements are calculated based on the requirement level index. Afterward, the novel multi-objective shuffled frog leaping algorithm (NMOSFLA) including renewed frog grouping, local search, and external elite frog set mutation strategies is proposed. Results indicate that three optimization objectives expose a mutual competing relationship. The benefit of the river ecosystem will increase at a loss of PG and water supply guarantee rate (WSGR). Therefore, the parallel reservoir system should be adjusted to improve the benefits of WSGR and ecological water spill and shortage (EWSS) with minimizing the loss of PG, simultaneously. Finally, the NMOSFLA is verified to outperform other compared methods at the solution diversity and convergence which is evaluated by multiple indicators. Overall, the NMOSFLA provides efficient reservoir operation schemes for decision-makers to select optimal trade-off schemes and feasible ways to solve the LTMOSCPRS. HIGHLIGHTS Propose a novel multi-objective shuffled frog leaping algorithm (NMOSFLA) based on multiple improvement strategies.; Adopt the NMOSFLA to efficiently solve long-term multi-objective scheduling of complex reservoir systems.; Calculate the suitable and ideal ecological water requirements based on the requirement level index (RLI).; Verify that the NMOSFLA outperforms other methods on the solution diversity and convergence.;

Background: Dry eye disease is a common ocular surface disease affecting tens of millions of people worldwide. It is characterized by an unstable tear film and increasing prevalence. Different commercial formulations of cyclosporine A for dry eye have been approved, however, it is still unclear whether the differences in formulations of these products will make a difference in clinical efficacy and safety.Methods: Randomized controlled trials of commercial cyclosporine A formulation for dry eye disease were searched in Pubmed, EMBASE, Scopus, and Cochrane controlled trials registries and Web of Science from inception till 1 December 2021. Independent literature screening, data extraction, quality evaluation, and the study in line with quality standards were analyzed by using Stata16.0 software. The study is registered with PROSPERO under the number CRD42022301423. Code and data for this study is publicly available (https://github.com/DongYangGao/Dongyang.github.io.git).Results: 21 randomized clinical trials with a total of 4,107 participants were included in this study. Restasis® (OR-4.82, 95% CI-6.18 to 3.45, SUCRA 77.2%) was the most effective commercial formulation for reducing OSDI, Zirun® (SUCRA 73.9%) performed better in improving Schirmer’s test. TJ Cyporin® (SUCRA 65.3%) ranked first in terms of improving tear film break-up time. For treatment-emergent adverse events incidence, Clacier® was close to placebo. The risk of reporting bias is considered low.Conclusion: In the comparison of outcomes included in this study, the optimal order of various commercial cyclosporine A formulations is different, so it is difficult to select the optimal formula. Appropriate commercial formulations should be selected according to patients’ conditions in clinical practice.

Palmitoylation occurs when fatty acids (such as palmitic acid) create covalent bonds between cysteine, serine, threonine, or other residues in proteins. The downstream effect of palmitoylation depends on the protein being palmitoylated because its blockage can render the protein useless in terms of its physiological function. Based on this, modulating the palmitoylation process becomes a good strategy for influencing cell proliferation, differentiation, metabolism, and apoptosis, allowing diabetes, obesity, and even cancer to be efficiently treated. As a determinant of the palmitoylation process, palmitoyltransferase is defined as an enzyme that catalyzes the transfer of the palmitate groups from Self-palmitoylated palmitoyl coenzyme A to another substrate. When it comes to the three most commonly cited palmitoyltransferases, serine palmitoyltransferase (SPT), carnitine palmitoyltransferase (CPT), and protein palmitoyltransferase (PAT), some similarities were found in the procedures by which they function, and in the structures of the small-molecule drugs that inhibit them. For this reason, we introduce the three above-mentioned palmitoyltransferases and describe the development of small molecule inhibitors for them to provide inspiration for the discovery of palmitoyltransferase inhibitors.

Cycloastragenol (CAG) is a sapogenin of Astragaloside IV (AG-IV), isolated from the dried roots of legumes Astragalus mongolica or Astragalus membranaceus. Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possess diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection. In addition, cycloastragenol is the only telomerase activator reported in natural products, which is closely related to MAPK and PI3K/Akt signaling pathways. This review provides a theoretical basis for the development of cycloastragenol into the candidate for the treatment of multi-factorial diseases in clinic, focusing on the extensively biological activities as well as the mechanism of action and structural modification and aiming to attract researchers to conduct in-depth studies on cycloastragenol. Meanwhile, the pharmacokinetics and toxicology studies of CAG are also described for further druggability exploration to provides valuable reference.

Developing an accurate and timely inflow forecast model continues to be an integral part of modern reservoir operation and has been greatly promoted by the combination of data preprocessing and data-driven techniques. This paper integrates variational mode decomposition (VMD) and long short-term memory (LSTM) into a hybrid model named A-VMD-S-LSTM. After dividing data for calibration and validation periods, A-VMD-S-LSTM decomposes the calibration inflow time series into subseries and cast them into a single LSTM forecast model to output final inflow predictands directly. When new inflow data are appended to the calibration time series, the VMD and LSTM models will be updated to adapt to all available inflow information to avoid transmitting future inflow information. The parameter settings of VMD and LSTM and the meaningful lags corresponding to each subseries are well identified by grid search and partial autocorrelation function (PACF), respectively. Finally, the proposed model is applied to the 1-, 3- 5-, and 7-day ahead inflow forecasts of the Three Gorges Reservoir (TGR) along with five competitive models. Results show that A-VMD-S-LSTM achieves the best forecast accuracy and fourth computational efficiency among the six candidates, demonstrating its best comprehensive forecast performance. Furthermore, using two or three LSTM layers in A-VMD-S-LSTM is redundant since the change in forecast accuracy is negligible and the increase of run time is remarkable. Therefore, a practical reservoir inflow forecast model with high forecast accuracy and relatively low computational cost is provided in this paper.

AIM: To detect the thickness of tear film lipid layer(LLT)in children with abnormal blink, to explore the relationship between abnormal blink and LLT, and to find out the diagnostic value of LLT in children with abnormal blink.METHODS: Prospective comparative study. Selecting 46 cases of children with "frequent blink" as the first reason in our ophthalmic outpatient clinic in 2016-11/2017-02 as abnormal blink group. In the same period, 46 children with non-anomalous blink were selected as control group. The history collection, slit lamp examination, refractive examination, Schirmer I test(SⅠt), tear film break-up time(BUT), and the number of times of LLT and incomplete blink(PB)were measured and compared surface light interferometer were compared.RESULTS: The LLT of the abnormal blink group was 72.17(22.13, 91.00)nm, which was lower than that of the control group 81.97(30.25,95.27)nm,(U=674.5, P=0.028); The mean equivalent spherical degrees(-0.98±3.09D)and SⅠt(11.39±2.46mm/5min)in the abnormal blink group were not different from those in the control group(-0.24±3.06D, 11.74±2.10mm/5min)(P>0.05). Mean PB(0.58±0.28)and mean BUT in the eyes of blink group There was a difference(18.27±5.51s)from the control group(0.43±0.17, 21.01±6.14s)(PCONCLUSION: Children's abnormal blinks are associated with many factors, and the LLT decline may be an important factor in children's abnormal blink.

Multiobjective long-term generation scheduling (MOLTGS) plays a vital role in coordinating the contradiction between the generation and reliability of cascade hydroelectricity system (CHS). In this paper, a multiobjective quantum-behaved particle swarm optimization based on decomposition (MOQPSO/D) is presented to solve the MOLTGS problem of maximizing total hydroelectricity generation and firm hydroelectricity output. In MOQPSO/D, the improved logistic map is adopted to initialize the population in the feasible space, where various equality and inequality constraints are handled by a constraint handling method based on conversion and repair strategies. An improved Tchebycheff decomposition with a modified generator of direction vectors, a modified QPSO operator and normal cloud mutation are the key components of MOQPSO/D in addressing the nonlinearity and complexity of MOLTGS. The feasibility and effectiveness of MOQPSO/D are verified first on numerical experiments of benchmark instances and then on real engineering examples of the Three Gorges (TG) and Gezhouba (GZB) plants within three representative years. The results show that MOQPSO/D can not only perform better robustness, convergence and diversity performance than other seven competitors but also output a group of Pareto optimal schemes within a reasonable amount of time. So, this paper provides a new effective alternative to solve the MOLTGS problem of CHS when considering both generation and reliability objectives.

Summary: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, causing defects of social interaction and repetitive behaviors. Here, we identify a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene in people with ASD without neurodevelopmental delay. We find that Senp1+/− mice exhibit core autistic-like symptoms such as social deficits and repetitive behaviors but normal learning and memory ability. Moreover, we find that inhibitory and excitatory synaptic functions are severely affected in the retrosplenial agranular (RSA) cortex of Senp1+/− mice. Lack of Senp1 leads to increased SUMOylation and degradation of fragile X mental retardation protein (FMRP), also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescues the defects of synaptic function and autistic-like symptoms of Senp1+/− mice. Together, these results demonstrate that disruption of the SENP1-FMRP regulatory axis in the RSA causes autistic symptoms, providing a candidate region for ASD pathophysiology.

The choice of Z-R relationship is an essential source of error in radar Quantitative Precipitation Estimation (QPE). A QPE algorithm combining the Optimization process of precipitation Classification and Dynamical adjustments (OCD) is proposed to improve the accuracy of QPE in Yinchuan city, China. A detailed evaluation and study of Z = 300R1.4 (fixed Z-R), Optimization Processing (OP), Optimization processing of Dynamical Adjustments (ODA) and OCD were performed using various evaluation metrics. The results show that ODA and OCD can significantly reduce the error of QPE, with OCD being the best estimator, reaching a correlation coefficient (CC) of 0.7 and reducing mean absolute error (MAE) and root mean square error (RMSE) by 31% and 34%, respectively. OCD outperforms other algorithms in terms of MAE and RMSE for different rain rates (RR), and the various assessment metrics at hourly scales are also more concentrated in reasonable intervals. OP gives fair results at weaker rain rates (0.2 ≤ RR < 8 mm/h) but underestimates rainfall more incorrectly at stronger rain rates (8 mm/h ≤ RR). Both the OCD and ODA provide a more significant improvement in the estimation of the area and magnitude of strong rainfall, with the OCD providing a better description of the local characteristics of the rainfall distribution, further demonstrating the advantages of the ODA.

This study determined the degradation of lindane in soil amended with biochar to evaluate the effects of biochar aging and microbial toxicity. Two biochars were prepared at 400 and 600 °C (BC400 and BC600) and subjected to acid washing to remove nutrition (WBC400 and WBC600). After 89 days of incubation under the alternate “wet–dry” conditions, scanning electron microscopy showed that acid washing rendered biochars especially susceptible to aging with structural collapse and fragmentation, with less surface covering. Aging impeded the release of toxic substances in BC400 and BC600 with reduced toxicity to degrading microorganisms. Lindane degradation was somewhat stimulated by biochar nutrition but mainly inhibited by adsorption. Acid washing facilitated the release of toxic substances and additionally reduced lindane degradation. The variations in fatty acid saturation degree (SFA/UFA) in soils confirmed the microbial toxicity of 5% WBC400 > 5% BC400 > 5% BC600 > 5% WBC600. High-throughput DNA sequencing showed that biochar delayed the formation of dominant degrading microbial communities in soil. Lindane degradation was completed by joint Sphingomonas, Flaviolibacter, Parasegetibacter, Azoarcus, Bacillus and Anaerolinaea. These findings are helpful for better understanding the effect of biochar in soil on long-term degradation of persistent organic pollutants.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. ALS has heavy genetic components in which a series of genetic mutations have been identified. In 2013, Mutations of the CREST gene (also known as SS18L1), which functions as a calcium-regulated transcriptional activator, were found in sporadic ALS patients. However, the pathogenic causality and mechanisms of ALS-associated mutations of CREST remain to be determined. Methods In this study, we constructed CREST knockout and Q394X knock-in mice with CRISPR/Cas9 system. Using biochemical and imaging tools, we illustrated core pathological phenotypes in CREST mutant mice and claimed the possible pathogenic mechanisms. Furthermore, we also observed locomotion defects in CREST mutant mice with behavioural tests. Results We demonstrate that ALS-related CREST-Q388X mutation exhibits loss-of-function effects. Importantly, the microglial activation was prevalent in CREST haploinsufficiency mice and Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficiency and Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses within mice lack of CREST. Conclusion Our findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.

In this study, we propose a multi-agent glowworm swarm optimization (MAGSO) algorithm for the economic load dispatch (ELD) problem of a large-scale hydropower station. The MAGSO integrates the idea of the evolution of glowworm swarm optimization (GSO) and the interindividual cooperation of multi-agent system (MAS). In this structure, each glowworm of the GSO is treated as an agent cooperating in the MAS before entering the evolutionary process. The proposed mechanisms enable the algorithm to escape from local extremum, capture the optimal solution and expand the diversity of solution space. The test results of four benchmark functions verify the advantages of the algorithm in global search, convergence speed and avoiding prematurity. In comparison of two case studies with the real genetic algorithm (RGA), the evolution programming (EP), the particle swarm optimization (PSO), the ant colony optimization (ACO), and the standard glowworm swarm optimization (GSO), the MAGSO provides significantly robust solutions of ELD problem of a large-scale hydropower station. Keywords: Glowworm swarm optimization (GSO), Multi-agent system (MAS), Multi-agent glowworm swarm optimization (MAGSO), Benchmark function, Economic load dispatch (ELD), Large-scale hydropower station

To explore the roles of glutamate acid decarboxylase 65 (GAD65) and angiotensin II type 1 receptor (AT1R) in the action of renal sympathetic denervation (RSD) on obesity-induced hypertension in canines. Thirty-two beagles were randomly divided into a hypertensive model (n = 22) and control (n = 10) groups. A hypertensive canine model was established by feeding a high-fat diet. Twenty hypertensive beagles were randomized equally to a sham-surgery and RSD-treated group receiving catheter-based radiofrequency RSD. Compared with the control group, the sham-surgery group exhibited significant increases in blood pressure, serum angiotensin II level, rostral ventrolateral medulla (RVLM) glutamate level, and AT1R mRNA and protein expression and decreases in γ-amino acid butyric acid (γ-GABA) level and GAD65 mRNA and protein expression in the RVLM (all P

As a very attractive computing paradigm, cloud computing makes it possible for resource-constrained users to enjoy cost-effective and flexible resources of diversity. Considering the untrustworthiness of cloud servers and the data privacy of users, it is necessary to encrypt the data before outsourcing it to the cloud. However, the form of encrypted storage also poses a series of problems, such as: How can users search over the outsourced data? How to realize user-side verifiability of search results to resist malicious cloud servers? How to enable server-side verifiability of outsourced data to check malicious data owners? How to achieve payment fairness between the user and the cloud without introducing any third party? Towards addressing these challenging issues, in this paper, we introduce TKSE, a trustworthy keyword search scheme over encrypted data without any third party, trusted or not. In TKSE, the encrypted data index based on digital signature allows a user to search over the outsourced encrypted data and check whether the search result returned by the cloud fulfills the pre-specified search requirements. In particular, for the first time, TKSE realizes server-side verifiability which protects honest cloud servers from being framed by malicious data owners in the data storage phase. Furthermore, blockchain technologies and hash functions are used to enable payment fairness of search fees without introducing any third party even if the user or the cloud is malicious. Our security analysis and performance evaluation indicate that TKSE is secure and efficient and it is suitable for cloud computing.

With the rapid development of energy-efficient cloud computing technologies, mobile users can share information with each other in different communities. However, due to the ever-increasing population of mobile users and the scale of networks, the energy-efficient delivery of information in mobile social networks (MSNs) becomes a new challenge. Therefore, in this paper, we propose an optimal control theorybased epidemic information spreading scheme for mobile users with energy constraint. First, we divide the social relationships of mobile users into four types based on blood, geography, work, and interest relationship. Second, we develop an analytical model to evaluate the influences of social relationships on the information spreading process in MSNs. Third, we present a control theory-based information spreading scheme to optimize the tradeoff between the consumed energy and delay. Finally, numerical results demonstrate that the presented scheme can save the energy and improve the quality of experience during information spreading for mobile users.

The Internet of Things (IoT) aims to achieve the interconnection of all devices in our lives. Due to the complex network environment, the IoT with mobile devices often faces many security problems, such as privacy leakages and identity forgery attacks. As a developing technology in mobile IoT, near field communication (NFC) is widely used in electronic payments and identity authentications. The current NFC studies mainly focus on payment technology, but there are a few studies on privacy protection and the lightweight requirements in the mobile IoT authentication protocol. We focus on the lightweight privacy protection authentication technology in mobile IoT. In the paper, we summarize the clustering model in mobile IoT networks and propose a lightweight authentication protocol. A security analysis shows that the protocol can resist many security threats, such as privacy leakages, identity forgeries, and replay attacks. The simulation also shows that the protocol is lightweight, with the utilization of look-up-tables (LUTs) and registers in our protocol being less than 0.5%. Our work can provide a secure and lightweight mobile authentication serve in the NFC-based mobile IoT network such as smart home and office attendance.

PURPOSE: To investigate the effect of renal denervation (RDN) on the blood pressure, left ventricular hypertrophy and myocardial expression of TLR4/NF-κB in spontaneously hypertensive rats (SHR). METHODS: A total of 36 SHR were randomly assigned into control group (D0), RDN group (D) and sham group (S). 12 WKY rats of same age served as controls (WKY group). Rats in the D0 and WKY groups were sacrificed, but rats in the D and S group were sacrificed at one week and six weeks after surgery. The heart was collected and the left ventricle weighted followed by calculation of left ventricular mass index (LVMI). RESULTS: In the D0 group, the blood pressure, LVMI and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were markedly higher than that in the WKY group (pOBJETIVO: Investigar o efeito da denervação renal na pressão sanguínea, na hipertrofia do ventrículo esquerdo e a expressão miocárdica de TLR4/NF-kB em ratos espontaneamente hipertensos. MÉTODOS: Trinta e seis SHR ratos foram aleatoriamente distribuídos em grupo controle, grupo denervação renal (D) e grupo sham(S). 12 WKY ratos de mesma idade serviram de controle. Os ratos controles foram sacrificados, mas os ratos com denervação renal e sham foram sacrificados uma semana e seis semanas após a cirurgia. O coração foi retirado e o ventrículo esquerdo pesado seguido pelo cálculo da massa ventricular (LVMI). RESULTADOS: No grupo DO, a pressão sanguínea, LVMI e a expressão proteica de TLR4, NF-κB, TNF-α e IL-6, no miocárdio foram marcadamente maiores do que o grupo WKY (p

We examined the effect of hyodeoxycholic acid (HDCA) on plasma cholesterol levels and atherosclerosis in mice. In wild-type C57BL/6 mice, feeding increasing amounts of HDCA resulted in i) progressive decrease in dietary cholesterol absorption, ii) increased concentrations of HDCA in the gallbladder bile, iii) decreased liver cholesterol content, iv) increased liver cholesterol synthesis, and v) increased plasma concentrations of HDCA. In C57BL/6 LDL-receptor knockouts (LDLR-KO) the addition of HDCA to chow and a 0.5% cholesterol diet decreased their total plasma cholesterol levels by 21% and 62%, respectively, because of a decrease in VLDL and LDL cholesterol. Turnover studies showed that HDCA has no effect on VLDL removal from plasma. Furthermore, the addition of HDCA to chow- and 0.5% cholesterol-fed LDLR-KO mice decreased the aortic root atherosclerosis lesion area by 50% and 80%, respectively. Finally, we tested the effect of HDCA on intestinal tumor formation. Feeding C57BL/6 ApcMin mice with HDCA did not affect the number of tumors but decreased the tumor volume in these animals. These results suggest that HDCA might have beneficial effects in the treatment of increased plasma cholesterol levels and atherosclerosis. —Sehayek, E., J. G. Ono, E. M. Duncan, A. K. Batta, G. Salen, S. Shefer, L. B. Neguyen, K. Yang, M. Lipkin, and J. L. Breslow. Hyodeoxycholic acid efficiently suppresses atherosclerosis formation and plasma cholesterol levels in mice.

Western‐style diets (WDs) trigger and sustain the early phases of tumorigenesis in mouse colon, and when continued throughout the life span lead to the development of dysplastic crypts. In order to evaluate the roles both of cell proliferation and programmed cell death (PCD) in WD‐induced tumorigenesis, immunohistochemical detection of proliferating nuclear antigen (PCNA), in situ end labeling (TUNEL) of DNA breaks, and p53 protein were carried out in mouse colonic mucosa during prolonged feeding of two WDs. PCNA Labeling Index of colonic crypts was significantly higher in WD‐treated animals than in controls only at the beginning of the nutritional study, the gap rapidly bridged by increased cell proliferation spontaneously occurring in the colonic mucosa during aging. A transient early homeostatic activation of PCD at the base of the crypt also was observed in WD groups. No changes in PCD were seen in the upper third of the crypt or in surface epithelium throughout the study, indicating that PCD in that colonic crypt segment produces a constant flux of cell loss, uninfluenced by homeostatic fluctuations. A major finding was an irreversible, progressive, age‐related decline of PCD at the crypt base in both control and treated animals that occurred during the second half of the rodents life span. p53 protein was not immunohistochemically detected, suggesting that neither overexpression of wild‐type nor mutated forms of the protein are involved in the above mentioned changes.

DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3(-/-);Apc(1638N) and Mlh3(-/-);Pms2(-/-);Apc(1638N) (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1(-/-);Apc(1638N) mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression.