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Knowledge tracing (KT) is the problem of predicting students' future performance based on their historical interactions with intelligent tutoring systems. Recent studies have applied multiple types of deep neural networks to solve the KT problem. However, there are two important factors in real-world educational data that are not well represented. First, most existing works augment input representations with the co-occurrence matrix of questions and knowledge components\footnote{\label{ft:kc}A KC is a generalization of everyday terms like concept, principle, fact, or skill.} (KCs) but fail to explicitly integrate such intrinsic relations into the final response prediction task. Second, the individualized historical performance of students has not been well captured. In this paper, we proposed \emph{AT-DKT} to improve the prediction performance of the original deep knowledge tracing model with two auxiliary learning tasks, i.e., \emph{question tagging (QT) prediction task} and \emph{individualized prior knowledge (IK) prediction task}. Specifically, the QT task helps learn better question representations by predicting whether questions contain specific KCs. The IK task captures students' global historical performance by progressively predicting student-level prior knowledge that is hidden in students' historical learning interactions. We conduct comprehensive experiments on three real-world educational datasets and compare the proposed approach to both deep sequential KT models and non-sequential models. Experimental results show that \emph{AT-DKT} outperforms all sequential models with more than 0.9\% improvements of AUC for all datasets, and is almost the second best compared to non-sequential models. Furthermore, we conduct both ablation studies and quantitative analysis to show the effectiveness of auxiliary tasks and the superior prediction outcomes of \emph{AT-DKT}., Accepted at WWW'23: The 2023 ACM Web Conference, 2023

The purpose of this study was to compare hospitalization outcomes among US inpatients with brain metastases who received stereotactic radiosurgery (SRS) and/or non-SRS radiation therapies without neurosurgical intervention. A cross-sectional study was conducted whereby existing data on 35,199 hospitalization records (non-SRS alone: 32,981; SRS alone: 1035; SRS + non-SRS: 1183) from 2005 to 2014 Nationwide Inpatient Sample were analyzed. Targeted maximum likelihood estimation and Super Learner algorithms were applied to estimate average treatment effects (ATE), marginal odds ratios (MOR) and causal risk ratio (CRR) for three distinct types of radiation therapy in relation to hospitalization outcomes, including length of stay (‘ ≥ 7 days’ vs. ‘

In mangrove wetlands, leaves make up a high proportion of the plant biomass and can accumulate heavy metals from contaminated sediment. Despite this, it is still unclear how heavy metal concentrations in leaves change as they develop and how metals in senescence leaves are recycled back into the mangrove ecosystems during decomposition. The present study aims to investigate the dynamics of six heavy metals (Cu, Zn, Cr, Ni, Cd, and Pb) in leaves of two common mangrove plants, Avicennia marina and Kandelia obovata, at different stages of development (young, mature, and senescent) and leaf litter decomposition (from 0 to 20 weeks). Based on litterbag experiments in a subtropical mangrove swamp, both plant species showed similar trends in alternations of the six heavy metals during leaf development, that was, decreased in Cu and Zn but increased in Pb, while Cr, Ni, and Cd remained steady. All heavy metals in litter gradually increased in concentration during decomposition. By the end of the 20-weeks decomposition, the concentrations of Cu, Zn, and Cd in decayed leaves were comparable to those in sediment, with Cu, Zn, and Cd at approximately 18, 75, and 0.2 mg·kg

Objective To evaluate the longitudinal relationship in insomnia symptoms over time with incident memory problems and dementia diagnoses among U.S. adults aged 65 years and older. Methods Secondary analyses were performed on 9518 elderly participants (≥65 years) who completed the 2006 wave of the Health and Retirement Study (HRS) and were followed-up to determine if insomnia symptom scores (2006–2014) were associated with time-to-onset of [1] physician-diagnosed “memory-related disease”, “Alzheimer's disease” and/or “dementia, senility or any other serious memory impairment” and [2] diagnosis of dementia based on HRS-specific criteria. Cox proportional hazards models were constructed adjusting for socio-demographic, lifestyle, and health characteristics. Results In fully adjusted models, severe insomnia symptoms were associated with increased risk of physician-diagnosed memory problems. Individuals reporting any change (increase or decrease) in insomnia symptoms during the 2006–2010 period were more likely to be diagnosed with dementia based on HRS criteria. Finally, those who experienced an increase in the severity of insomnia symptoms over time exhibited 41–72% increased risks of physician-diagnosed memory problems and 45–58% increased risks of dementia diagnosis based on HRS criteria. Conclusions When severe insomnia symptoms increased over time, physician-diagnosed memory problems and dementia diagnoses also increased among U.S. elderly people over a 10-year follow-up period. More studies are required to confirm these findings using large prospective cohort designs and validated tools.

Acquiring high-fidelity 3D models from real-world scans is challenging. Existing shape completion-methods are incapable of generating details of objects or learning complex point distributions. To address this problem, we propose two transformer-based point-cloud-completion networks and a coarse-to-fine strategy to extract object shape features by way of self-attention (SA) and multi-resolution (MR), respectively. Specifically, in the first stage, the model extracts incomplete point-cloud features based on self-attention and multi-resolution encoders and predicts the missing partial with a set of parametric surface elements. Then, in the second stage, it merges the coarse-grained prediction with the input point cloud by iterative furthest point sampling (IFPS), to obtain a complete but coarse-grained point cloud. Finally, in the third stage, the complete but coarse point-cloud distribution is improved by a point-refiner network based on a point-cloud transformer (PCT). The results from comparison to state-of-the-art methods and ablation experiments on the ShapeNet-Part dataset both verified the effectiveness of our method.

Berberine was reported to exert beneficial effects on cardiac hypertrophy. However, its cellular and molecular mechanisms still remained unclear. Cardiac hypertrophy was induced in male Sprague-Dawley (SD) rats by transverse aorta constriction (TAC), with or without 6-week treatment of berberine. Echocardiography was performed to evaluate cardiac function. Rats were then sacrificed for histological assay, with detection for proteins and mRNA. H9c2 cells were pretreated with berberine of different concentrations (0, 1 μM, and 10 μM), followed by treatment with 2 μM norepinephrine (NE). Cells of different groups were measured for cell surface area, with mRNA detected by qRT-PCR and proteins by western blot. Compared with the sham group, rats of the TAC group showed significantly increased cardiac hypertrophy and fibrosis, which could be ameliorated by treatment with berberine. Western blot showed that mammalian target of rapamycin (mTOR) signaling-related protein expressions, including phospho-mTOR, phospho-4EBP1, and phospho-p70 S6K (Thr389), but not phospho-p70 S6K (Ser371), were significantly increased in the TAC group, which were inhibited by berberine treatment. H9c2 cells were treated with NE to induce hypertrophy with increased cell surface area and mRNA expressions of anp and bnp. Berberine of 10 μM, but not 1 μM, significantly ameliorated NE-induced hypertrophy and inhibited protein expressions of mTOR signaling pathway similar to those in the rat model. Berberine can exert cardioprotective effects on both pressure-overloaded cardiac hypertrophy and failure in vivo and NE-induced hypertrophy in vitro. Our results suggest berberine could be a potential treatment for patients with cardiac hypertrophy and failure.

Overharvesting Asian horseshoe crabs for food is a primary threat to their populations. In the present study, 451 residents were interviewed from the northern Beibu Gulf, the coastal area that is believed to accommodate the highest density of the Chinese horseshoe crab Tachypleus tridentatus worldwide, to obtain baseline information on their consumption behaviour and underlying drivers. Based on the survey data, it is estimated that a mean individual consumption rate of ten meals per year. Nearly half of the respondents (49.7%) claimed that they had previously eaten at least two horseshoe crab meals. Among the six occupation categories (managers, professionals, workers, environmental‐related workers, fishers and farmers, and students), fishers and farmers were identified as the group that had eaten a significantly higher number of horseshoe crab meals, had consumed them more frequently, and had a greater intention of eating them than that of students. The age, education level, and salary of participants were the important socio‐demographic variables related to their consumption behaviour. More than one‐third of respondents decided to consume horseshoe crabs because they perceived them as tasty ‘seafood’ and valuable ingredients of traditional Chinese medicine. Eighty‐three per cent of participants reported an overall decrease in the number of horseshoe crabs in the region. Although the community was supportive towards horseshoe crab conservation, their ecological knowledge of horseshoe crabs was limited. The findings may be useful for providing insights to merge the gap between scientific data and management planning for the horseshoe crab population in the region. Conservation management initiatives, such as the involvement of fishers in monitoring and enforcement, developing a reporting system for landings and by‐catch, and implementing long‐term conservation education through the school curriculum could promote the protection and management of the population.

A microprocessor supervisory circuit with high efficiency and low power consumption is proposed and implemented using a mixed 0.35-μm CMOS process. With a novel reference voltage circuit and an additional voltage detection circuit, the precision of the threshold voltage and the efficiency of the reset signal are improved. With a turn-off control circuit, the current supply is reduced. As the simulation and experiment on ten package samples shown, the threshold voltage is about 2.91 V with the precision of 5.97%. In the power voltage range of 3 V to 6 V, the reset time is 235.5 ms with the precision of 4.1%, the supply current is about 10 μA, and the chip area is 510 μm × 560 μm. Thus, the proposed microprocessor supervisory circuit is superior performance in precision of the threshold voltage, the efficiency of reset time and low supply current.

Objective This study aimed to examine patterns of sleep disorders among hospitalized adults 65 years and older as related to Parkinson's disease (PD) status and to evaluate sex differences in the associations between PD with sleep disorders. Methods A cross-sectional study was conducted using 19,075,169 hospital discharge records (8,169,503 men and 10,905,666 women) from the 2004-2014 Nationwide Inpatient Sample databases. PD and sleep disorder diagnoses were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification coding. Logistic regression models were constructed for each sleep disorder as a correlate of PD status; adjusted odds ratios (aOR) with their 95% confidence intervals (CIs) were calculated taking into account patient and hospital characteristics. Results Period prevalences of PD and sleep disorder were estimated to be 2.1% and 8.1%, respectively. Most sleep disorder types, with the exception of sleep-related breathing disorders, were positively associated with PD diagnosis. Statistically significant interactions by sex were noted for associations of insomnia (men: aOR = 1.29, 95% CI = 1.24-1.36; women: aOR = 1.17, 95% CI = 1.12-1.22), parasomnia (men: aOR = 3.74, 95% CI = 3.44-4.07; women: aOR = 2.69, 95% CI = 2.44-2.96), sleep-related movement disorder (men: aOR = 1.09, 95% CI = 1.07-1.11; women: aOR = 1.22, 95% CI = 1.20-1.25), and any sleep disorder (men: aOR = 1.06, 95% CI = 1.05-1.08; women: aOR = 1.15, 95% CI = 1.13-1.17) with PD status. Conclusions Overall, hospitalized men are more likely to experience PD with insomnia or parasomnia, whereas hospitalized women are more likely to experience PD with sleep-related movement disorder or any sleep disorder. Prospective cohort studies are needed to replicate these cross-sectional findings.

Background: The 2010 Affordable Care Act aimed at reducing healthcare costs, improving healthcare quality and expanding health insurance coverage among uninsured individuals in the United States. We examined trends in utilization of radiation therapies and stereotactic radiosurgery before and after its implementation among U.S. adults hospitalized with brain metastasis.Methods: Interrupted time-series analyses of data on 383934 2005-2014 Nationwide Inpatient Sample hospitalizations were performed, whereby yearly and quarterly cross-sectional data were evaluated and Affordable Care Act implementation was considered the main exposure variable, stratifying by patient and hospital characteristics. Results: We observed consistently declining trends in radiation therapy over time and post-Affordable Care Act status with variability in level of utilization among specific sub-groups. Stereotactic radiosurgery prevalence increased over time among Hispanics, elective admissions, Midwestern hospitals, non-teaching hospitals and hospitals with medium bed size. Post-Affordable Care Act was associated with increased stereotactic radiosurgery prevalence among African-Americans, non-elective and weekend admissions, with changes in slope in the context of weekend admissions and hospitals with large bed size. Conclusions: Whereas hospitalized adults in the United States utilized less radiation therapy and slightly more stereotactic radiosurgery over the ten-year period, utilization levels and trends were not consistent among distinct sub-groups defined by patient and hospital characteristics, with some traditionally underserved populations more likely to receive healthcare services post-Affordable Care Act implementation. The Affordable Care Act may be helpful at reducing the need for radiation therapy and closing the gap in access to technological advances such as stereotactic radiosurgery for treating brain metastases.

Previous studies have shown the effectiveness of deep learning algorithms in improving the detection of credit card fraud, which has become a major issue for financial institutions. This paper discusses how two deep learning methods, Convolutional Neural Network (CNN) and auto-encoder, perform in the fraud detection task using two different datasets. This research utilizes a brand-new dataset with all raw input variables and a Universite Libre de Bruxelles (ULB) transaction dataset, which has been preprocessed with PCA technology. Since imbalanced datasets can affect the training quality, we further preprocess the datasets using random under-sampling and the Synthetic Minority Oversampling Techniques (SMOTE) to balance the datasets. Through the experimental results, we find that the networks perform well for the ULB dataset with 93% accuracy in prediction, but perform poorly for the independent input dataset, and the performance can be improved when increasing the complexity of the network. We also notice that the under-sampling method helps improve prediction accuracy better than the oversampling method. The results indicate that more complicated networks are required to detect fraud when the criterion for fraud is stricter, while balancing the dataset before training will improve the results.

Horseshoe crabs, the most well-known example of "living fossils", are iconic and ecologically important macroinvertebrates in coastal and estuarine ecosystems. Their blood is a crucial resource for manufacturing Limulus or Tachypleus amebocyte lysate to detect bacterial endotoxins or fungal contamination in drug and medical devices. An enhanced understanding of their ecological roles and trophic interactions in the food webs is fundamental to facilitate resource management for the declining populations in Asia. Foraging information of the Asian species, however, is mainly derived from preliminary, scattered reports from a limited number of study locations. In this study, resource utilization, trophic niche dynamics, and trophic interaction of the juvenile tri-spine horseshoe crab, Tachypleus tridentatus (instars 1-12, approximately 0.5-8 years old) across ontogeny was assessed in diversified nursery habitats along the northern Beibu Gulf, China, using carbon and nitrogen stable isotopes. Our results suggest that: (i) T. tridentatus are ecological generalists given the vast range of carbon isotopic values and trophic niche width estimates exhibited between multiple instar groups; (ii) juvenile T. tridentatus across most habitat types predominantly assimilated energy from a variety of basal production sources in the food web, but primarily depended on sedimentary organic matter and seagrass resource pools; (iii) ontogenetic shifts in juvenile dietary proportions were evident, with decreased reliance on sedimentary organic matter, coupled with increased reliance on benthic macroinvertebrate grazers, detritivores, and omnivores with age; and (iv) nearly all juvenile instars occupied similar trophic positions in the food web with slight shifts in trophic position present with increasing size. Our findings indicate that resource availability and ontogenetic diet shifts strongly influence horseshoe crab trophic dynamics, and age should be accounted when formulating habitat conservation measures based on resource use for Asian horseshoe crabs.

The ventral tegmental area (VTA) is the origin of dopaminergic neurons and the dopamine (DA) reward pathway. This pathway has been widely studied in addiction and drug reinforcement studies and is believed to be the central processing component of the reward circuit. In this study, we used a well-established rat model to expose mother dams to alcohol, nicotine-alcohol, and saline perinatally. DA and non-DA neurons collected from the VTA of the rat pups were used to study expression profiles of miRNAs and mRNAs. miRNA pathway interactions, putative miRNA-mRNA target pairs, and downstream modulated biological pathways were analyzed. In the DA neurons, 4607 genes were differentially upregulated and 4682 were differentially downregulated following nicotine-alcohol exposure. However, in the non-DA neurons, only 543 genes were differentially upregulated and 506 were differentially downregulated. Cell proliferation, differentiation, and survival pathways were enriched after the treatments. Specifically, in the PI3K/AKT signaling pathway, there were 41 miRNAs and 136 mRNAs differentially expressed in the DA neurons while only 16 miRNAs and 20 mRNAs were differentially expressed in the non-DA neurons after the nicotine-alcohol exposure. These results depicted that chronic nicotine and alcohol exposures during pregnancy differentially affect both miRNA and gene expression profiles more in DA than the non-DA neurons in the VTA. Understanding how the expression signatures representing specific neuronal subpopulations become enriched in the VTA after addictive substance administration helps us to identify how neuronal functions may be altered in the brain.

Nicotine and alcohol are two of the most commonly used and abused recreational drugs, are often used simultaneously, and have been linked to significant health hazards. Furthermore, patients diagnosed with dependence on one drug are highly likely to be dependent on the other. Several studies have shown the effects of each drug independently on gene expression within many brain regions, including the ventral tegmental area (VTA). Dopaminergic (DA) neurons of the dopamine reward pathway originate from the VTA, which is believed to be central to the mechanism of addiction and drug reinforcement. Using a well-established rat model for both nicotine and alcohol perinatal exposure, we investigated miRNA and mRNA expression of dopaminergic (DA) neurons of the VTA in rat pups following perinatal alcohol and joint nicotine–alcohol exposure. Microarray analysis was then used to profile the differential expression of both miRNAs and mRNAs from DA neurons of each treatment group to further explore the altered genes and related biological pathways modulated. Predicted and validated miRNA-gene target pairs were analyzed to further understand the roles of miRNAs within these networks following each treatment, along with their post transcription regulation points affecting gene expression throughout development. This study suggested that glutamatergic synapse and axon guidance pathways were specifically enriched and many miRNAs and genes were significantly altered following alcohol or nicotine–alcohol perinatal exposure when compared to saline control. These results provide more detailed insight into the cell proliferation, neuronal migration, neuronal axon guidance during the infancy in rats in response to perinatal alcohol/ or nicotine–alcohol exposure.

The mesoporous Co/KIT-6 catalysts with 10 wt% Co loading were prepared at different reduction temperatures. The physicochemical properties of the Co/KIT-6 catalysts were characterized by TEM, BET, XRD, XPS, and CO2-TPD, and the effect of reduction temperature on CO2 hydrogenation catalytic performance of Co/KIT-6 catalysts was studied. The results show that reduction temperature has a significant impact on the specific surface area, crystallinity and content of Co0 species, and CO2 adsorption performance of the prepared Co/KIT-6 catalysts. The low reduction temperature is not conduct to the reduction of CoOx, while the high reduction temperature lead to the increase of Co0 species crystallinity and the formation of Co2SiO4 and/or CosbndOsbndSi species which are unfavorable to the form Co0 species. The RT400 catalyst exhibits the highest Co0 species content and the best CO2 adsorption performance. Both the CO2 hydrogenation catalytic activity and CH4 selectivity of the Co/KIT-6 catalysts follow the order: RT400 > RT350 > RT450 > RT500 > RT550, with a small amount of by-product CO. At the reaction temperature of 340 °C, the CO2 reaction rate (CO2 conversion) of the RT400 catalyst can reach 2.98 × 10−5 mol/gcat/s (40%), the CH4 and CO selectivity are 86.7% and 13.3%, respectively.

Introduction Healed rates of endodontic microsurgery (EMS) may decrease over time, but research on the long-term outcomes is scarce. The aims of this retrospective cohort study were to evaluate the 5- to 9-year healed and survival rates of EMS, to identify associations between prognostic factors and healing status, and to compare the short-term (1- to 2-year) with long-term (5- to 9-year) outcomes. Methods One hundred fifty-one eligible patients (166 teeth) who underwent EMS in 2007–2010 were invited for a follow-up examination. Eighty-three patients (94 teeth) participated in the study. Survival status and reasons for extraction of all teeth were determined, and survival rates were calculated by Kaplan-Meier analyses. Outcomes were determined on the basis of clinical and radiographic findings and associated with potential prognostic variables via multivariate Cox regression analyses. Results Thirty-two teeth were extracted: 6 because of endodontic failure, 20 for unrelated reasons, and 6 for unknown reasons. Outcomes were categorized as healed and not healed. Multivariate analysis revealed that adjusted hazard ratio for failure was 5.95 times higher (95% confidence interval, 1.54–22.91) for teeth treated with intermediate restorative material than with mineral trioxide aggregate and 3.38 times higher (95% confidence interval, 1.05–10.9) for teeth with no known history of nonsurgical retreatment. Teeth classified as healed in the 1- to 2-year review mostly remained healed at 5- to 9-year review (45/48 teeth); those with uncertain healing had varied outcomes at long-term review. Conclusions EMS results in high long-term healed (78.3%, 72/92 teeth) and survival (95.2%) rates. Root-end filling material and nonsurgical retreatment before EMS may influence the long-term outcome.

In this study, we design and present a five-fold digital slit-lamp microscope (DSLM) with built-in photographic lens and CCD. The initial structures of the front objective, Galilean telescope system, and photographic lens are systematically investigated and discussed in the design. A progressive optimization process is employed in the non-coaxial system design after the coaxial system achieves high performance. The analysis of spot diagrams and the modulation transfer function (MTF) show that this DSLM optical system achieves quasi-diffraction-limited performance and enables high-quality imaging for ophthalmic examination. Furthermore, tolerance analysis of this optical system is also performed, which provides a theoretical basis for machining and assembly. This design provides an idea for the design of a digital-zoom microscope in biomedical imaging instruments.

Nonviral methods have been explored as the replacement of viral systems for their low toxicity and immunogenicity. However, they have yet to reach levels competitive to their viral counterparts. In this paper, we combined physical and chemical methods to improve the performance of polyplex delivery of DNA and small interfering RNA. Specifically, gold nanoparticles (AuNPs) were used to carry polyplex (a chemical approach) while electroporation (a physical approach) was applied for fast and direct cytosolic delivery. In this hybrid approach, cationic polymer molecules condense and/or protect genetic probes as usual while AuNPs help fix polycations to reduce their cytotoxicity and promote the transfection efficiency of electroporation. AuNPs of various sizes were first coated with polyethylenimine, which were further conjugated with DNA plasmids or small interfering RNA molecules to form AuNPs-polyplex. The hybrid nanoparticles were then mixed with cells and introduced into cell cytosol by electroporation. The delivery efficiency was evaluated with both model anchor cells (i.e., NIH/3T3) and suspension cells (i.e., K562), together with their impact on cell viability. We found that AuNP-polyplex showed 1.5∼2 folds improvement on the transfection efficiency with no significant increase of toxicity when compared to free plasmid delivery by electroporation alone. Such a combination of physical and chemical delivery concept may stimulate further exploration in the delivery of various therapeutic materials for both in vitro and in vivo applications.

Electroporation serves as a promising non-viral gene delivery approach, while its current configuration carries several drawbacks associated with high-voltage electrical pulses and heterogeneous treatment on individual cells. Here we developed a new micropillar array electroporation (MAE) platform to advance the electroporation-based delivery of DNA and RNA probes into mammalian cells. By introducing well-patterned micropillar array texture on the electrode surface, the number of pillars each cell faces varies with its plasma membrane surface area, despite their large population and random locations. In this way, cell size specific electroporation is conveniently carried out, contributing to a 2.5~3 fold increase on plasmid DNA transfection and an additional 10–55% transgene knockdown with siRNA probes, respectively. The delivery efficiency varies with the number and size of micropillars as well as their pattern density. As MAE works like many single cell electroporation are carried out in parallel, the electrophysiology response of individual cells is representative, which has potentials to facilitate the tedious, cell-specific protocol screening process in current bulk electroporation (i.e., electroporation to a large population of cells). Its success might promote the wide adoption of electroporation as a safe and effective non-viral gene delivery approach needed in many biological research and clinical treatments.

This secondary analysis of survey data examined mediating-moderating effects of allostatic load score (calculated using the Rodriquez method) on the association between nutrient-based Dietary Approaches to Stop Hypertension (DASH) diet score (Mellen Index) and the all-cause and cause-specific mortality risks among 11,630 adults &ge, 30 years of age from the 2001&ndash, 2010 National Health and Nutrition Examination Surveys with no history of cardiovascular disease or cancer at baseline, and who were followed-up for ~9.35 years. Multivariable models were adjusted for demographic, socioeconomic, lifestyle, and health characteristics. All-cause, cardiovascular disease, and cancer-specific mortality rates were estimated at 6.5%, 1.1%, and 1.9%, respectively. The median DASH total score was 3.0 (range: 1&ndash, 8) (with 78.3% scoring &lt, 4.5), whereas the median allostatic load score was 3 (range: 0&ndash, 9). The DASH diet, fiber, and magnesium were negatively correlated with allostatic load, whereas allostatic load predicted higher all-cause mortality, irrespective of the DASH diet. Whereas protein was protective, potassium increased all-cause mortality risk, irrespective of allostatic load. Potassium was protective against cardiovascular disease-specific mortality but was a risk factor for cancer-specific mortality. Although no moderating effects were observed, mediation by the allostatic load on cardiovascular disease-specific mortality was observed for DASH total score and selected component scores. Direct (but not indirect) effects of DASH through the allostatic load were observed for all-cause mortality, and no direct or indirect effects were observed for cancer-specific mortality. From a public health standpoint, the allostatic load may be a surrogate for the preventive effects of the DASH diet and its components on cardiovascular disease-specific mortality risk.

The DNA-damaging drug doxorubicin (Dox) induces cell senescence at concentrations significantly lower than those required for induction of apoptosis. At low Dox concentrations, tumor suppressor p53 is activated, which enhances the expression of p21(Waf1/Cip1) (p21). At high concentrations, Dox activates p53 leading to apoptosis without enhancing p21 expression. The underlying mechanisms and factors that govern the differential effects of Dox in inducing senescence and apoptosis are unclear. Here, we report that the DNA methyltransferase (DNMT) DNMT3a was upregulated by Dox especially at concentrations that induced apoptosis in HCT116 colorectal cancer cells, and this process was regulated by p53. Meanwhile, p21 expression was significantly upregulated at senescence-inducing concentrations and kept low on treatment with apoptosis-inducing concentrations of Dox. The differential expression of DNMT3a and p21 in response to Dox suggests that DNMT3a may be a key factor in switches between Dox-induced senescence and apoptosis. Moreover, when DNMT3a was silenced, treatment of HCT116 cells with apoptosis-inducing concentration of Dox increased the percentage of cells undergoing senescence, accompanied by upregulation of p21. Contrarily, senescence-inducing concentration of Dox promoted apoptosis rate, and p21 expression was repressed. Surprisingly, no changes in DNA methylation status at p21 promoter were detected at either ranges of Dox, although DNMT3a and HDAC1 were recruited to p21 promoter at apoptosis-inducing Dox concentration, where they were present in the same complex. Overall, these data demonstrate that DNMT3a impacts the expression of p21 and plays a role in determining the Dox-induced senescence and apoptosis in HCT116 cells.

The sex-determining region Y-box 7 (Sox7) is a member of high mobility group (HMG) transcription factor family, essential for embryonic development and endoderm differentiation. Deregulation of Wnt signaling pathway is a hallmark of colorectal cancer. Our results showed that the expression level of SOX7 was frequently down-regulated in human colorectal cancer cell lines and in primary colorectal tumor tissues, and the SOX7 silencing was partially due to the aberrant DNA methylation of the gene. Restoration of SOX7 induced colorectal cancer cell apoptosis, inhibited cell proliferation and colony formation. In addition, SOX7 efficiently suppressed beta-catenin-mediated transcriptional activity.

Helicobacter pylori has a highly variable genome with ongoing diversification via inter- and intragenomic recombination and spontaneous mutation. DNA repair genes modulating mutation and recombination rates that influence diversification have not been well characterized for H. pylori . To examine the role of putative base excision repair ung and mutY glycosylase and xthA apurinic/apyrimidinic endonuclease genes in H. pylori , mutants of each were constructed in strain JP26 by allelic exchange. Spontaneous mutation frequencies of JP26 mutY mutants, assessed by rifampin resistance, were consistently higher (26-fold) than that of the wild type, whereas the ung and xthA mutants showed smaller increases. In trans complementation of the JP26 mutY mutant restored spontaneous mutation frequencies to wild-type levels. In cross-species studies, H. pylori mutY complemented an Escherichia coli mutY mutant and vice versa. In contrast, the ung and mutY mutants did not show higher frequencies of intergenomic recombination or greater sensitivity to UV-induced DNA damage than the wild type. The H. pylori mutY open reading frame contains an eight-adenine homonucleotide tract; we provide evidence that this is subject to slipped-strand mispairing, leading to frameshifts that eliminate gene function. Our findings indicate that H. pylori possesses phase-variable base excision repair, consistent with a tension between repair and mutation.