Miracle-dz/UniFAR-FTUs huggingface dataset:
Nitrogen monoxide activates iron regulatory protein 1 RNA-binding activity by two possible mechanisms: effect on the [4Fe-4S] cluster and iron mobilization from cells.

The iron-regulatory protein 1 (IRP1) regulates the expression of several molecules involved in iron (Fe) metabolism by reversibly binding to iron-responsive elements (IREs) in the untranslated regions (UTR) of particular mRNA transcripts. Several studies have indicated that nitrogen monoxide (NO) may influence IRP1 RNA-binding activity by a direct effect on the [4Fe-4S] cluster of the protein. It has also been suggested that NO may act indirectly on IRP1 by affecting the intracellular Fe pools that regulate the function of this protein [Pantopoulous et al. (1996) Mol. Cell. Biol. 16, 3781-3788]. There is also the possibility that NO may S-nitrosate sulfhydryl groups that are crucial for mRNA binding and decrease IRP1 activity by this mechanism. We have examined the effect of a variety of NO donors [e.g., S-nitroso-N-acetylpenicillamine (SNAP), spermine-NONOate (SperNO), and S-nitrosoglutathione (GSNO)] on IRP1 RNA-binding activity in both LMTK(-) fibroblast lysates and whole cells. In cell lysates, the effects of NO at increasing RNA-binding activity were only observed when cells were made Fe-replete. Under these circumstances, IRP1 contains an [4Fe-4S] cluster that was susceptible to NO. In contrast, when lysates were prepared from cells treated with the Fe chelator desferrioxamine (DFO), NO had no effect on the RNA-binding activity of IRP1. The lack of effect of NO under these conditions was probably because this protein does not have an [4Fe-4S] cluster. In contrast to the NO generators above, sodium nitroprusside (SNP) decreased IRP1 RNA binding when cells were incubated with this compound. However, SNP had no effect on IRP1 RNA-binding activity in lysates, suggesting that the decrease after incubation of cells with SNP was not due to S-nitrosation of critical sulfhydryl groups. Apart from the direct effect of NO on IRP1 in Fe-replete cells, we have shown that NO generated by SNAP, SperNO, and GSNO could also mobilize Fe from cells. When NO generation was induced in RAW 264.7 macrophages, an increase in IRP1 RNA-binding activity occurred but there was only a small increase in Fe release. Our results suggest that NO could activate IRP1 RNA-binding by two possible mechanisms: (1) its direct effect on the [4Fe-4S] cluster and (2) mobilization of (59)Fe from cells resulting in Fe depletion, which then increases IRP1 RNA-binding activity.
Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.
Never amputate without consultation of a vascular surgeon

Lower limb ischaemia is one of the determinants in the development of diabetic foot ulcers and the most important factor preventing their healing. There are a number of misleading factors masking the presence of atherosclerotic disease and tissue damage; these are reduced inflammatory response to infection, autosympathectomy and mediasclerosis, which all diminish the clinical suspicion of ischaemia. Therefore, adequate assessment of the lower limb circulation should be routinely performed in complicated diabetic foot. This evaluation can often be made with simple methods. In addition to clinical examination ankle/brachial pressure index, systolic toe pressure, plethysmographic pulse volume recordings and simple hand‐held Doppler auscultation are most often sufficient to make a decision as to whether angiography is needed or not. Duplex examination can give more profound information on the severity and extent of arterial occlusive disease, but the method is strongly user‐dependent. Early vascular consultation is mandatory in diabetic foot work‐up and should be undertaken within 2 weeks if a new skin lesion shows no tendency to heal. Long bypass grafting procedures and microvascular free flap techniques have been shown to achieve excellent results in relieving critical leg ischaemia, even in the presence of large foot lesions, and should be used to prevent major amputation. The timing of various procedures is a controversial issue. Feet with small ulcers or restricted dry gangrena can be revascularised first, with minor amputations and local surgery of the ulcer being done thereafter. In the septic neuroischaemic foot, major amputation may be unavailable but if the infection is not immediately life‐threatening the infected part of the foot should be drained and debrided properly and left wide open, sometimes with a guillotine amputation in order not to risk the bypass graft, which can be done a couple of days later. Copyright © 2000 John Wiley & Sons, Ltd.
The zebrafish Iroquois gene iro7 positions the r4/r5 boundary and controls neurogenesis in the rostral hindbrain

Early brain regionalisation involves the activation of genes coding for transcription factors in distinct domains of the neural plate. The limits of these domains often prefigure morphological boundaries. In the hindbrain, anteroposterior patterning depends on a segmentation process that leads to the formation of seven bulges called rhombomeres (r). The molecular cues involved in the early subdivision of the hindbrain and in rhombomere formation are not well understood. We show that iro7, a zebrafish gene coding for a transcription factor of the Iroquois family, is expressed at the end of gastrulation in the future midbrain and hindbrain territories up to the prospective r4/r5 boundary. This territory is strictly complementary to the expression domain of another homeobox gene, vhnf1, in the caudal neural plate. We demonstrate that Iro7 represses vhnf1 expression anterior to their common border and that, conversely, vHnf1 represses iro7 expression caudal to it. This suggests that the r4/r5 boundary is positioned by mutual repression between these two transcription factors. In addition, iro7 is involved in the specification of primary neurons in the rostral hindbrain. In particular, it is essential for the formation of the Mauthner neurons in r4. We propose that iro7 has a dual function in the hindbrain of the zebrafish embryo: it is required for the proper positioning of the prospective r4/r5 boundary and it promotes neurogenesis in the anterior hindbrain.
Stereochemical complementary of DNA and steroid agonists and antagonists.

Modelling studies in our laboratories over the past decade have demonstrated that a variety of natural products exhibit stereochemical complementarity with nucleic acids. In the case of steroid hormones, the basic cyclopentanophenanthrene skeleton fits between base pairs in partially unwound double stranded DNA; heteroatoms on the steroids form stereospecific donor/acceptor linkages to hydrogen bonding heteroatoms on the DNA. Each of the hormones appears to fit best in the site, i.e. 5'-dTdG-3'. 5'dCdA-3'; the pattern of donor/acceptor linkages is unique for each type of hormonal activity. Steroid hormone agonists fit into the same site as the parent hormone; degree of fit correlates with degree of hormonal activity. Steroid hormone antagonists (e.g. RU 486; tamoxifen; anandron) fit into the same site as the agonists but possess different donor/acceptor linkages than the parent hormone; these linkages occur within the site between the base pairs or along the outside surface of the DNA helix in the major or minor grooves. A chronological review of the underlying concepts and observations leading to these discoveries is presented. Work in progress and some potential implications of the emerging technology are also discussed.
The Carboxy Terminus of EmbC from Mycobacterium smegmatis Mediates Chain Length Extension of the Arabinan in Lipoarabinomannan*

d-Arabinofurans, attached to either a galactofuran or a lipomannan, are the primary constituents of mycobacterial cell wall, forming the unique arabinogalactan (AG) and lipoarabinomannan (LAM), respectively. Emerging data indicate that the arabinans of AG and LAM are distinguished by virtue of the additional presence of linear termini in LAM, which entails some unknown feature of the EmbC protein for proper synthesis. In common with the two paralogous EmbA and EmbB proteins functionally implicated for the arabinosylation of AG, EmbC is predicted to carry 13 transmembrane spanning helices in an integral N-terminal domain followed by a hydrophilic extracytoplasmic C-terminal domain. To delineate the function of this C-terminal domain, the embC knock-out mutant of Mycobacterium smegmatis was complemented with plasmids expressing truncated embC genes. The expression level of serially truncated EmbC protein thus induced was examined by EmbC-specific peptide antibody, and their functional implications were inferred from ensuing detailed structural analysis of the truncated LAM variants synthesized. Apart from critically showing that the smaller arabinans are mostly devoid of the linear terminal motif, β-d-Araf(1→2)-α-d-Araf(1→5)-α-d-Araf(1→5)-α-d-Araf, our studies clearly implicate the C-terminal domain of EmbC in the chain extension of LAM. For the first time a full range of arabinan chains as large as 18-22 Araf residues and beyond could be released intact by the use of an endogenous endo-d-arabinanase from M. smegmatis, profiled, and sequenced directly by tandem mass spectrometry. In conjunction with NMR studies, our results unequivocally show that the LAM-specific linear termini are an extension on a well defined inner branched Ara-(18-22) core. This hitherto unrecognized feature not only allows a significant revision of the structural model of LAM-arabinan since its first description a decade ago but also furnishes a probable molecular basis of selectivity in biosynthesis, as conferred by the EmbC protein.
2 5 Se p 20 12 On the Quantum Theory of Molecules

Transition state theory was introduced in the 1930s to account for chemical reactions. Central to this theory is the idea of a potential energy surface (PES). It was assumed that such a surface could be constructed using eigensolutions of the Schrödinger equation for the molecular (Coulomb) Hamiltonian but at that time such calculations were not posssible. Nowadays quantum mechanical abinitio electronic structure calculations are routine and from their results PESs can be constructed which are believed to approximate those assumed derivable from the eigensolutions. It is argued here that this belief is unfounded. It is suggested that the potential energy surface construction is more appropriately regarded as a legitimate and effective modification of quantum mechanics for chemical purposes.
Clinical inertia in patients with T2DM requiring insulin in family practice.

OBJECTIVE To describe the clinical status of patients with type 2 diabetes mellitus (T2DM) in the primary care setting at insulin initiation and during follow-up, and to assess the efficacy of insulin initiation and intensification. DESIGN Ontario FPs from the IMS Health database who had prescribed insulin at least once in the 12 months before November 2006 were randomly selected to receive an invitation to participate. Eligible and consenting FPs completed a questionnaire for each of up to 10 consecutive eligible patients. Patient data were recorded from 3 time points. SETTING Family practices in Ontario, Canada. PARTICIPANTS One hundred and nine FPs and 379 of their T2DM patients taking insulin (with or without oral agents). MAIN OUTCOME MEASURES Glycated hemoglobin (HbA₁(c)) levels, daily insulin dose, and use of concomitant oral agents at insulin initiation and 2 subsequent visits. RESULTS Data from each patient were obtained on insulin initiation and intensification, glycemic control, further pharmacologic therapy, and related complications. Mean time from diagnosis of T2DM to insulin initiation was 9.2 years. Mean HbA₁(c) values were 9.5% before insulin initiation, 8.1% at visit 2 (median 1.2 years later), and 7.9% at visit 3 (median 3.9 years after initiation). Mean insulin dose was 24 units at initiation, 48 units at visit 2, and 65 units at visit 3. At visit 3, 20% of patients continued to have very poor glycemic control (HbA₁(c) > 9.0%). With the exception of a decrease in sulfonylurea use, concomitant use of oral antihyperglycemic agents remained static over time. CONCLUSION Even in patients identified as being sufficiently high risk to warrant insulin therapy, a clinical care gap exists in physician efforts to achieve and sustain recommended HbA₁(c) target levels. Family physicians need strategies to facilitate earlier initiation and ongoing intensification of insulin therapy.
Does physical fitness influence intraocular pressure?

The effects of physical fitness on intraocular pressure, was studied. The study was conducted in two parts. Part 1 consisted of three groups of physically fit subjects, each consisting of 50 subjects. In Part 2 subjects were categorized into control and experimental groups, each consisting of 16 subjects. The experimental group took a supervised exercise programme of three months. Intraocular pressure was measured with the Goldman applanation tonometer. As compared to sedentary subjects, intraocular pressures were lower in those who did moderate or severe exercises. In part one, the difference between group 1 consisting of sedentary and group 3 of physically fit subjects was 1.38 +/- 0.08 mmHg, (p < 0.001). In part two of this study, after exercise training the experimental group showed a marked increase in their physical fitness. The first difference between control and experimental groups was 0.13 +/- 0.27 mmHg (p > 0.05). After three months, this difference increased to 0.93 +/- 0.28 mmHg (p < 0.01). This study concludes that physical fitness reduces intraocular pressure. It would seem reasonable at present not to discourage patients who have glaucoma from light exercise, perhaps, on the contrary, it should be encouraged.
Mitigating Financial Risk By Using Hedging Strategies

Financial derivatives are now widely used by corporations to manage exposure to currency, interest rate, and commodity price risks. The motivation for non-financial firms to engage in corporate hedging is one of the most intensively discussed topics in corporate finance research. Recent financial theory suggests that there are several ways through which corporate hedging can increase firm value in the sense of the maximization of shareholder value. A rich body of literature consists of studies that have empirically investigated the theoretical explanations for corporate hedging, literature that presents rather mixed evidence for the drivers of corporate hedging. This paper investigates the effects of hedging activity on non-financial firm value and how operational hedging is related to and differentiated by financial hedging, by providing an extensive overview and synthesis of the existing literature.
The ageing male reproductive tract

Ageing of the male reproductive system is characterized by changes in the endocrine system, hypogonadism, erectile dysfunction and proliferative disorders of the prostate gland. Stochastic damage accumulating within ageing leads to progressive dysregulation at each level of the hypothalamic–pituitary–gonadal (HPG) axis and in local auto/paracrine interactions, thereby inducing morphological changes in reproductive target organs, such as the prostate, testis and penis. Despite age‐related changes in the HPG axis, endocrine functions are generally sufficient to maintain fertility in elderly men. Ageing of the male reproductive system can give rise to clinically relevant manifestations, such as benign prostatic hyperplasia (BPH), prostate cancer (PCa) and erectile dysfunction (ED). In this review, we discuss morphological/histological changes occurring in these organs and current views and concepts of the underlying pathology. Moreover, we emphasize the molecular/cellular pathways leading to reduced testicular/penile function and proliferative disorders of the prostate gland. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Perceived Discrimination and Political Behavior

Abstract Can different experiences with discrimination produce divergent political behaviors? Does it make a difference whether individuals are discriminated against by their peers or community members in the course of everyday life as opposed to political actors or institutions tasked with upholding democratic norms of equality and fairness? Crossing disciplinary boundaries, this study proposes a new theoretical perspective regarding the relationship between discrimination and political behavior. Specifically, it distinguishes between societal (interpersonal) and political (systematic) discrimination when examining the behaviors of racial and ethnic minorities in Great Britain. The results illustrate that although experiences of political discrimination may motivate individuals to take part in mainstream politics for substantive or expressive purposes, the same conclusion cannot necessarily be drawn for those who experience societal rejection. The principal aim of this study is to further highlight the complex and multidimensional nature of discrimination, and to encourage further analyses of how different types of discrimination may impact the civic and political behaviors of minority groups.
Hazardous Alcohol Use Associated with Increased Sexual Risk Behaviors Among People Who Inject Drugs.

BACKGROUND Alcohol is associated with a multitude of severe health consequences. While risk behaviors related to illicit drug use are commonly studied among people who inject drugs (PWID), the role of alcohol use has received substantially less attention in this population. We explored whether drug and sexual risk behaviors as well as experiences of violence were associated with hazardous alcohol use in a cohort of PWID. METHODS Analyses were conducted using observational data from a prospective cohort of community-recruited HIV-negative PWID in Vancouver, Canada. We used the U.S. National Institute on Alcohol Abuse and Alcoholism definition of hazardous alcohol use (i.e., >14 drinks/wk or >4 drinks on 1 occasion for men, and >7 drinks/wk or >3 drinks on 1 occasion for women). We used multivariable generalized estimating equations (GEE) to identify the factors associated with hazardous alcohol use. RESULTS Between 2006 and 2012, 1,114 HIV-negative individuals were recruited, and 186 (16.7%) reported hazardous alcohol use in the previous 6 months at baseline. In multivariable GEE analyses, having multiple sex partners (adjusted odds ratio [AOR] = 1.25), history of sexually transmitted infection (AOR = 1.50), experiencing violence (AOR = 1.36), and incarceration (AOR = 1.29) were each independently associated with hazardous alcohol use. Caucasian ethnicity (AOR = 0.56), ≥ daily heroin injection (AOR = 0.81), and engagement in addiction treatment (AOR = 0.84) were negatively associated with hazardous alcohol use (all p < 0.05). CONCLUSIONS A considerable proportion of PWID reported hazardous alcohol use, which was independently associated with reporting sexual, but not drug-related, HIV risk behaviors and experiencing recent violence. Findings suggest a need to integrate regular screening and evidence-based alcohol interventions into treatment efforts for PWID.
Columbian Cartel Launches Bid for Japanese Firms

Or so one would argue. With one of the brightest and most productive corps of corporate law scholars in the country, the Columbian cartel dominates much of the debate over American "corporate governance. " Now Mark Roe-among the brightest and most productive in the cartel-extends that analysis to governance patterns in Japan (and Germany). The Japanese (and German) practice may even, he suggests tentatively, solve some of the problems the cartel finds in American governance. ' In tying Japan to this debate over "corporate governance," Roe does a brilliant job. Along the way, he raises two loosely related questions: whether the concept of "corporate governance" adequately explains the shareholding practices of Japanese banks and, more broadly, why the concept has become so prominent in recent corporate law scholarship. To explore these issues, I first review Roe's argument (Part I). I then demonstrate why "corporate governance" may not explain the Japanese phenomena he describes (Part II). In the process, I suggest that Japanese banks buy stock in their clients to exploit the inside information they acquire in the course of researching potential borrowers. I reach this conclusion by elimination; none of the explanations that either Roe or anyone else has advanced fits the facts observed. I conclude by asking why so many corporate law academics seem so obsessed with "corporate governance" (Part III). For many academics (including some Columbians but notably excluding Roe), the answer lies in a desire to promote mandatory terms-terms of the corporate contract that
In Vitro and In Vivo Transfection of p21 Gene Enhances Cyclosporin A-Mediated Inhibition of Lymphocyte Proliferation

Cyclosporine has potent antiproliferative properties, some of which may be via the induction of the cyclin inhibitor p21. In this study, we describe the effects of in vitro and in vivo transfection of p21 in lymphoid and nonlymphoid cells. For in vitro studies, p21 sense plasmid DNA was transfected in A-549 cells (lung adenocarcinoma cell line) and Jurkat cells (human lymphoid cell line). This in vitro transfection of p21 resulted in the inhibition of spontaneous and mitogen-induced cellular proliferation ([3H]thymidine uptake) and also augmented the antiproliferative effects of cyclosporine. In vivo transfection of p21 was accomplished in mice via the i.m. injection of p21 sense plasmid DNA complexed with cationic lipids. As was the case in the cell lines, p21 mRNA was augmented in heart, lung, liver, and spleen 7 days after i.m. injection of p21 sense plasmid DNA. The mitogen (anti-CD3)-induced proliferation of splenocytes from p21-overexpressing mice was significantly decreased, and again this effect was augmented by cotreatment with cyclosporine. These novel findings demonstrate the potential of targeting the cell cycle directly to inhibit alloimmune activation in organ transplantation. This may serve as an alternate strategy to induce immunosuppression, perhaps with less toxicity than that which is seen with conventional immunosuppressive agents.