Miracle-dz/UniFAR-FTUs huggingface dataset:
The Nrf1 CNC-bZIP Protein Is Regulated by the Proteasome and Activated by Hypoxia

Background Nrf1 (nuclear factor-erythroid 2 p45 subunit-related factor 1) is a transcription factor mediating cellular responses to xenobiotic and pro-oxidant stress. Nrf1 regulates the transcription of many stress-related genes through the electrophile response elements (EpREs) located in their promoter regions. Despite its potential importance in human health, the mechanisms controlling Nrf1 have not been addressed fully. Principal Findings We found that proteasomal inhibitors MG-132 and clasto-lactacystin-β-lactone stabilized the protein expression of full-length Nrf1 in both COS7 and WFF2002 cells. Concomitantly, proteasomal inhibition decreased the expression of a smaller, N-terminal Nrf1 fragment, with an approximate molecular weight of 23 kDa. The EpRE-luciferase reporter assays revealed that proteasomal inhibition markedly inhibited the Nrf1 transactivational activity. These results support earlier hypotheses that the 26 S proteasome processes Nrf1 into its active form by removing its inhibitory N-terminal domain anchoring Nrf1 to the endoplasmic reticulum. Immunoprecipitation demonstrated that Nrf1 is ubiquitinated and that proteasomal inhibition increased the degree of Nrf1 ubiquitination. Furthermore, Nrf1 protein had a half-life of approximately 5 hours in COS7 cells. In contrast, hypoxia (1% O2) significantly increased the luciferase reporter activity of exogenous Nrf1 protein, while decreasing the protein expression of p65, a shorter form of Nrf1, known to act as a repressor of EpRE-controlled gene expression. Finally, the protein phosphatase inhibitor okadaic acid activated Nrf1 reporter activity, while the latter was repressed by the PKC inhibitor staurosporine. Conclusions Collectively, our data suggests that Nrf1 is controlled by several post-translational mechanisms, including ubiquitination, proteolytic processing and proteasomal-mediated degradation as well as by its phosphorylation status.
Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity

Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl4-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4′-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG2 and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G2/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G2/M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.
On the uniformity of software evolution patterns

Preparations for Y2K reminded the software engineering community of the extent to which long-lived software systems are embedded in our daily environments. As systems are maintained and enhanced throughout their lifecycles they appear to follow generalized behaviors described by the laws of software evolution. Within this context, however, there is some question of how and why systems may evolve differently. The objective of this work is to answer the question: do systems follow a set of identifiable evolutionary patterns? In this paper we use software volatility to describe the lifecycle evolution of a portfolio of 23 software systems. We show by example that a vector of software volatility levels can represent lifecycle behavior of a software system. We further demonstrate that the portfolio's 23 software volatility vectors can be grouped into four distinguishable patterns. Thus, we show by example that there are different patterns of system lifecycle behavior, i.e. software evolution.
Automatically suggesting topics for augmenting text documents

We present a method for automated topic suggestion. Given a plain-text input document, our algorithm produces a ranking of novel topics that could enrich the input document in a meaningful way. It can thus be used to assist human authors, who often fail to identify important topics relevant to the context of the documents they are writing. Our approach marries two algorithms originally designed for linking documents to Wikipedia articles, proposed by Milne and Witten [15] and West et al. [22]. While neither of them can suggest novel topics by itself, their combination does have this capability. The key step towards finding missing topics consists in generalizing from a large background corpus using principal component analysis. In a quantitative evaluation we conclude that our method achieves the precision of human editors when input documents are Wikipedia articles, and we complement this result with a qualitative analysis showing that the approach also works well on other types of input documents.
Assessing Student-Generated Design Justifications in Virtual Engineering Internships

Engineering virtual internships are simulations where students role play as interns at fictional companies, working to create engineering designs. To improve the scalability of these virtual internships, a reliable automated assessment system for tasks submitted by students is necessary. Therefore, we propose a machine learning approach to automatically assess student generated textual design justifications in two engineering virtual internships, Nephrotex and RescuShell . To this end, we compared two major categories of models: domain expert-driven vs. general text analysis models. The models were coupled with machine learning algorithms and evaluated using 10-fold cross validation. We found no quantitative differences among the two major categories of models, domain expert-driven vs. general text analysis, although there are major qualitative differences as discussed in the paper.
THE COST OF PREDATOR DAMAGE CONTROL USING TRAPPING AS THE PRIMARY CONTROL TECHNIQUE

Author(s): Thompson, Ronald A. | Abstract: The justification and economics of the operational animal damage control program in California as conducted by the U. S. Fish and Wildlife Service are discussed. Emphasis is given to the necessity for use of the steel trap. Nearly 83 percent of the depredators are taken by trapping. Annual agricultural losses due to predation were estimated at $4.7 million in California for Fiscal Year 1975. The projected cost-benefit ratio was 1:3.9.
Connective tissue growth factor increases matrix metalloproteinase‐2 and suppresses tissue inhibitor of matrix metalloproteinase‐2 production by cultured renal interstitial fibroblasts

The involvement of gelatinase (matrix metalloproteinase‐2 [MMP‐2] and MMP‐9) in the matrix remodeling and development of tubulointerstitial fibrosis has been studied recently, but relatively little is known about the regulators and the mechanisms controlling the activation and expression of gelatinase in renal fibroblasts. In these studies, the production and underlying signaling pathway for gelatinase by exogenous connective tissue growth factor (CTGF) treatment were investigated. Here, we show that CTGF acts as a potent promoter of the activation and expression of MMP‐2, but not MMP‐9 in normal rat kidney fibroblasts cell line (NRK‐49F). We found that CTGF significantly increased the activity of MMP‐2, as well as MMP‐2 protein in conditioned medium and MMP‐2 mRNA levels in cells. In studies to address the mechanisms involved in the regulation of MMP‐2 activity, we found that the tissue inhibitor of matrix metalloproteinase‐2 (TIMP‐2), the inhibitor of MMP‐2, decreased significantly when cells were treated with CTGF. Further studies showed that extracellular signal‐regulated kinase (ERK) signaling is responsible for most of the CTGF‐induced MMP‐2 expression and TIMP‐2 suppression. When NRK‐49F fibroblasts were incubated with CTGF, activation of ERK1/2 signaling was observed. Suppression of ERK1/2 activation with nontoxic concentrations of PD98059, a specific inhibitor of ERK activation, was associated with a reduction of CTGF‐stimulated MMP‐2 activity and protein expression. In addition, the CTGF‐mediated reduction of TIMP‐2 activity and protein expression was prevented when ERK1/2 activation was inhibited by PD98059. These results provide evidence that CTGF augments activation of MMP‐2 through an effect on MMP‐2 protein expression and TIMP‐2 suppression, and that these effects are dependent on the activation of the ERK1/2 pathway.
Cross-bridge kinetics, cooperativity, and negatively strained cross- bridges in vertebrate smooth muscle. A laser-flash photolysis study

The effects of laser-flash photolytic release of ATP from caged ATP [P3- 1(2-nitrophenyl)ethyladenosine-5'-triphosphate] on stiffness and tension transients were studied in permeabilized guinea pig protal vein smooth muscle. During rigor, induced by removing ATP from the relaxed or contracting muscles, stiffness was greater than in relaxed muscle, and electron microscopy showed cross-bridges attached to actin filaments at an approximately 45 degree angle. In the absence of Ca2+, liberation of ATP (0.1-1 mM) into muscles in rigor caused relaxation, with kinetics indicating cooperative reattachment of some cross- bridges. Inorganic phosphate (Pi; 20 mM) accelerated relaxation. A rapid phase of force development, accompanied by a decline in stiffness and unaffected by 20 mM Pi, was observed upon liberation of ATP in muscles that were released by 0.5-1.0% just before the laser pulse. This force increment observed upon detachment suggests that the cross- bridges can bear a negative tension. The second-order rate constant for detachment of rigor cross-bridges by ATP, in the absence of Ca2+, was estimated to be 0.1-2.5 X 10(5) M-1s-1, which indicates that this reaction is too fast to limit the rate of ATP hydrolysis during physiological contractions. In the presence of Ca2+, force development occurred at a rate (0.4 s-1) similar to that of intact, electrically stimulated tissue. The rate of force development was an order of magnitude faster in muscles that had been thiophosphorylated with ATP gamma S before the photochemical liberation of ATP, which indicates that under physiological conditions, in non-thiophosphorylated muscles, light-chain phosphorylation, rather than intrinsic properties of the actomyosin cross-bridges, limits the rate of force development. The release of micromolar ATP or CTP from caged ATP or caged CTP caused force development of up to 40% of maximal active tension in the absence of Ca2+, consistent with cooperative attachment of cross-bridges. Cooperative reattachment of dephosphorylated cross-bridges may contribute to force maintenance at low energy cost and low cross-bridge cycling rates in smooth muscle.
What Makes a Person a Perpetrator? The Intellectual, Moral, and Methodological Arguments for Revisiting Milgram's Research on the Influence of Authority

In this article, we outline the rationale for reexamining Milgram's explanation of how ordinary people can become perpetrators of atrocity. We argue, first, that any consideration of these issues cannot ignore the impact of Milgram's ideas in psychology, in other disciplines such as history, and in society at large. Second, we outline recent research in both psychology and history which challenges Milgram's perspective—specifically his “agentic state” account. Third, we identify the moral dangers as well as the analytic weaknesses of his work. Fourth, we point to recent methodological developments that make it ethically possible to revisit Milgram's studies. Combining all four elements we argue that there is a compelling and timely case for reexamining Milgram's legacy and developing our understanding of perpetrator behavior. We then outline how the various articles in this special issue contribute to such a project.
Peer Effects Among Swimmers

We develop a novel identification strategy and examine various aspects of peer effects using swimming data. We find that the performance of adjacent competitors positively influences swimmers' performances. In particular, swimmers are influenced by slower-lane peers, suggesting that being chased improves one's performance. We use absenteeism data to directly compare the performances of swimmers with and without peers. We have found that swimmers swim faster with peers swimming behind them than when swimming alone, but that they swim slower with peers swimming ahead. Finally, we find that observability is a key determinant of peer effects, by comparing freestyle and backstroke competitions.
Thrombomodulin and induced tissue factor expression on monocytes as markers of diabetic microangiopathy: A prospective study on hemostasis and lipoproteins in insulin‐dependent diabetes mellitus

Vascular complications are the main cause of morbidity in diabetes mellitus. To evaluate lipoprotein and hemostatic parameters and their relationship with clinically detectable microangiopathy, we studied 58 insulin‐dependent diabetes mellitus patients and 60 controls matched for age, sex, and body mass index. Thirteen patients presented clinically detectable microangiopathy (8 retinopathy and 5 both retinopathy and microalbuminuria). A cross‐sectional study of lipid profile, coagulation parameters, and a flow‐cytometric evaluation of tissue factor expression in normal monocytes induced by patient plasma were performed. Patients were re‐evaluated for microangiopathy in a 3‐year median follow‐up. Patients showed triglyceride enrichment in low (P = 0.00002) and high density lipoproteins (P = 0.004) and increased levels of D‐dimer (P < 0.00001), prothrombin fragment 1 + 2 (P < 0.00001), and thrombin‐antithrombin III complex (P = 0.0001). Patients with clinically detectable microangiopathy had increased type 1 plasminogen activator inhibitor (P = 0.00001), thrombomodulin (P = 0.02), and induced monocyte tissue factor expression (P < 0.00001). Nine patients developed clinically detectable microangiopathy in the follow‐up and the only predictive variable was increased induced tissue factor expression. In conclusion, in these patients elevated thrombin and fibrin generation reflects a hypercoagulable state but clinically detectable microangiopathy seems related to endothelial cell injury markers and to increased induced tissue factor expression on monocytes. Am. J. Hematol. 56:93–99, 1997. © 1997 Wiley‐Liss, Inc.
Stages of Change for Increasing Fruit and Vegetable Consumption among Adults and Young Adults Participating in the National 5-a-Day for Better Health Community Studies

Higher fruit and vegetable consumption is associated with a reduced risk of certain cancers and chronic diseases. The 5-a-Day for Better Health community studies are evaluating population-based strategies to achieving dietary behavior change using the stages-of-change model and associated theories. The authors present baseline comparisons of stages of change for fruit and vegetable consumption among adults and young adults in eight study sites representing diverse regions of the United States and diverse populations and settings. Three dominant stages, precontemplation, preparation, and maintenance, were found across sites. Women and those with college degrees were more likely to be in action/maintenance. Fruit and vegetable consumption, self-efficacy, and knowledge of the 5-a-Day recommendation were positively associated with more advanced stages of change in all study sites. The authors discuss the findings in relation to possible limitations of this and other dietary stages-of-change measures and suggest directions for future research.
Effects of Uric Acid on Lipid Levels in CKD Patients in a Randomized Controlled Trial

Background Few studies have been conducted that compared lipid levels and uric acid in CKD or End-Stage Renal Disease (ESRD) patients with most using animal models. The purpose of the study was to explore effects on lipids while controlling uric acid levels in CKD patients. Methods Twenty-four CKD patients (N = 24) volunteered to participate in this study. The study was conducted using a double-blind, randomized, placebo controlled experimental protocol. The experimental group was prescribed 300 mg of allopurinol PO daily by their treating physician and followed prospectively for 8-weeks. The control group consumed a similar pill once a day for 8-weeks. Results ANCOVA revealed significant differences in total cholesterol (P = 0.009) and Apo B (P = 0.006) with lower levels in the allopurinol group. A trend emerged with LDL (P = 0.052) with lower levels in the allopurinol group. No significant differences were discovered in triglycerides (P = 0.403), HDL (P = 0.762) and total Cholesterol/HDL Ratio (P = 0.455). Conclusions After statistically controlling for compliance and inflammation significant differences between groups were observed for total cholesterol and Apo B. In both instances the allopurinol group had lower concentrations than the placebo group. Similarly, a trend was observed in LDL with the allopurinol group having lower concentrations than the placebo group.
Bias Toward Bisexual Women and Men in a Marriage-Matching Task

SUMMARY The current research represents the first empirical study to examine attitudes towards bisexual women and men in the context of both traditional and same-sex marriage relationships. One-hundred fifty-five heterosexual women and men participated in a marriage matching task in which they created ideal marriage matches for profiles that differed across sexual orientation and HIV status. The results showed a clear perception that bisexual partners were best suited to other bisexual individuals (whether those individuals were of the same- or other-sex). In general, bisexual women and men were not seen as viable partners in cross-orientation marriages with heterosexual, lesbian, or gay individuals. Additionally, the results overwhelmingly emphasize the belief that HIV concordant pairings are ideal in marriage relationships.
HÆMODYNAMIC BASIS OF ACUTE PRESSOR REACTIONS AND HYPERTENSION*

To be the first Haile Selassie lecturer is a unique privilege. My pleasure at having been chosen for this task has two further causes. The first is that we have in our country a great admiration for the gallant people of Abyssinia and their noble representative H.M. the Emperor Haile Selassie ever since their heroic fight for independence and liberty. The second is being allowed to give this lecture under the auspices of the Institute of Cardiology. Dr. Paul Wood has in his kind introductory words mentioned our long association in military hospitals in Africa and Italy. What he did not say was that under primitive conditions in the Algerian desert and in the wild Italian mountains he created a model medical unit which attained a level of clinical work that could have matched the work of any medical department of a first class teaching hospital. It was thanks to his interest and support that I was even able to do original research work. It is, therefore, with a feeling of great indebtedness and gratitude that I begin this lecture.
[Transfer of amino acids across the rumen epithelium in sheep: interaction between leucine and lysine].

Experiments were conducted on six head of sheep of the Slovak Merino breed with average live weight of 40 kg. The sheep received 0.4 kg of industrially produced molasses feed M and 1 kg of meadow hay once a day. The feed ration for a head of sheep per day contained: 1177.58 g dry matter, 89 g digestible crude protein (SNL), 0.554 starch units. The animals had free choice of water. Rumen epithelium with submucosa was used in the experiment. Amino acid transfer was measured in a mucosa-serosa direction. Amino acids were dissolved in Thyrode's solution with pH value 6.9 on the mucosa side and 7.4 on the serosa side. A constant temperature of 39 degrees C was maintained during the experiment. The epithelium area was 13.2 cm2 for either part of the experiment. Lysine and leucine were incubated separately in the first part of experiment. These concentrations were used: 5, 25, 50 and 75 mumol/l. The values of lysine and leucine readings are denoted as control lysine (lysine K) and control leucine (leucine K) in the result section. Lysine and leucine were incubated simultaneously in the second part of experiment: Lys 5 mumol/l-Leu 5 mumol/l; Lys 5 mumol/l--Leu 15 mumol/l; Lys 5 mumol/l--Leu 20 mumol/l; Lys 25 mumol/l--Leu 25 mumol/l; Lys 25 mumol/l--Leu 75 mumol/l. The values of lysine readings on the other part of experiment are denoted as experimental lysine (lysine P). Figs. 1 and 2 show transfer of control lysine and leucine through the rumen epithelium as depending upon their concentrations. (ABSTRACT TRUNCATED AT 250 WORDS)
Liver-directed gene transfer in non-human primates.

To develop a primate model for liver-directed gene therapy, we studied several gene transfer vehicles and routes in eight rhesus monkeys (Macaca mulatta). For this purpose, we used first-generation, replication-deficient adenoviral vectors carrying the Escherichia coli lacZ gene (Ad.CMVlacZ) or a lacZ-containing plasmid (pCMV beta) with lipofectamine for transfection. The reporter gene construct was infused into either the portal vasculature, common bile duct, or saphenous vein. Adenovirus-mediated gene transfer via the portal vein resulted in expression of lacZ in over 70% of hepatocytes by days 3-7, but was accompanied by acute hepatitis. Adenovirus-mediated gene transfer via the common bile duct resulted in lacZ expression in less than 10% of hepatocytes and was accompanied by portal inflammation. The animals mounted a significant immune response, as demonstrated by adenoviral antigen-induced T-cell proliferation and production of neutralizing anti-adenovirus antibodies and antibodies to E. coli beta-galactosidase (beta-Gal). Activation of the immune response was associated with rapid decrease of the reporter gene by days 13-21. Lipofectamine-mediated gene transfer was inefficient, and no lacZ expression in the liver was detected. To limit the host immune response, 4 animals were immunosuppressed by cyclophosphamide/prednisone and then infused with the Ad.CMVlacZ via the portal vein or the saphenous vein. The monkeys showed sustained expression of lacZ for up to 35 days with no evidence of inflammation. The primates transduced via the saphenous vein showed a level of beta-Gal expression in the liver similar to that of the portal vein-infused animals. In conclusion, adenovirus-mediated gene transfer to non-human primate livers via the portal vein or saphenous vein is efficient, but it results in transient expression and is accompanied by an immune response to both vector and transgene products and acute hepatitis, whereas lipofectamine-mediated transfer is inefficient. Manipulation of the host immune response may expand potential applications of adenoviral vectors for liver-directed gene transfer.