Miracle-dz/UniFAR-FTUs huggingface dataset:
Specificity evolution of the ADP‐dependent sugar kinase family –in silico studies of the glucokinase/phosphofructokinase bifunctional enzyme from Methanocaldococcus jannaschii

In several archaea of the Euryarchaeota, the glycolytic flux proceeds through a modified version of the Embden–Meyerhof pathway, where the phosphofructokinase and glucokinase enzymes use ADP as the phosphoryl donor. These enzymes are homologous to each other. In the hyperthermophilic methanogenic archaeon Methanocaldococcus jannaschii, it has been possible to identify only one homolog for these enzymes, which shows both ADP‐dependent glucokinase and phosphofructokinase activity. This enzyme has been proposed as an ancestral form in this family. In this work we studied the evolution of this protein family using the Bayesian method of phylogenetic inference and real value evolutionary trace in order to test the ancestral character of the bifunctional enzyme. Additionally, to search for specificity determinants of these two functions, we have modeled the bifunctional protein and its interactions with both sugar substrates using protein–ligand docking and restricted molecular dynamics. The results show that the evolutionary story of this family is complex. The root of the family is located inside the glucokinase group, showing that the bifunctional enzyme is not an ancestral form, but could be a transitional form from glucokinase to phosphofructokinase, due to its basal location within the phosphofructokinase group. The evolutionary trace and the molecular modeling experiments showed that the specificity for fructose 6‐phosphate is mainly related to the stabilization of a negative charge in the phosphate group, whereas the specificity for glucose is related to the presence of some histidines instead of glutamines/asparagines and to the interaction of this ligand with a glutamic acid residue corresponding to Glu82 in the bifunctional enzyme.
Nano-Mesosphere Drug Carriers for Localized Cancer Chemotherapy

The therapeutic activity of most cancer drugs is dose dependant. Systemic toxicity prevents the use of aggressive high dose chemotherapy. There is a great need for more efficient localized and nonsystemic drug delivery. Reported here is research devoted to the synthesis, properties, and therapeutic evaluation of drug loaded nano-mesospheres (meso-MS) designed for administration as aqueous dispersions by local intratumoral (IT) injection. Clinically practical compositions have been synthesized using mitoxantrone (MXN) with biodegradable proteins (i.e. albumin, collagen, casein) or with deoxyribonucleic acid (DNA) as the meso-MS matrix. In vivo IT studies in a murine mammary adenocarcinoma demonstrated greatly prolonged survival (>500%) with no systemic toxicity at MS-loaded drug concentrations more than 6x the toxic dose for systemic drug delivery.
Event-Based Second-Order Consensus Control for Multi-Agent Systems via Synchronous Periodic Event Detection

This technical note studies the consensus problem of multiple double-integrator networks under undirected topologies. A consensus protocol based on sampled-data control and edge event-driven techniques is proposed, and two associated event-triggering rules are presented. These edge events rely on the information of the corresponding two neighboring agents, and the event-triggering actions over edges are independent of each other. It is proved that the proposed protocol can solve the state consensus problem when the topology is connected, and also can reduce the controller-updating costs and communication costs. Finally, simulations are given to demonstrate the effectiveness of our theoretical results.
Corporate social responsibility and gambling industry : an exploratory study

Corporate Social Responsibility (CSR) is one important response to the increasing levels of criticism that corporations experience. Despite the growing importance of CSR in accounting, financial management and management more generally, it remains a contentious term. Some studies have concentrated on CSR in specific industries – notably the oil (Coupland, 2005), banking (Coupland, 2006) and retailing (Islam and Deegan, 2008) industries; however, some contentious industries, for example, the gambling industry remain unexplored. The nature of the gambling industry seems to be a source of conflict that is potentially so important in CSR and may be more explicit and thereby clearer in this industry. Thus, the gambling industry may represent a special case in the CSR literature.
Skin autofluorescence increases postprandially in human subjects.

BACKGROUND Skin autofluorescence (SAF) is a property used for the noninvasive assessment of skin advanced glycation end products (AGEs) and concentration of redox-regulated fluorophores. SAF was shown to closely mirror cardiovascular risk and to constitute a more sensitive parameter for diabetes screening than fasting glucose and hemoglobin A1c. It has also been suggested that SAF measurement is independent of fasting status. Our study was designed in order to test whether SAF changes postprandially. METHODS We have investigated 21 Caucasian subjects (10 healthy subjects, 11 subjects with type 2 diabetes mellitus). SAF was measured in the fasting state, as well as 2 and 4 h following a meal with a medium AGE content. RESULTS Two hours postprandially, SAF significantly increased by 10.2% in the whole group, by 11.6% in the group of individuals with diabetes, and by 8.7% in healthy subjects (for all measurements P < 0.05 vs. baseline). CONCLUSIONS SAF increases postprandially in individuals with diabetes mellitus and in healthy subjects. Therefore, we suggest that measurements of SAF should be performed in the fasting state in order to increase sensitivity and specificity of the method for assessing cardiovascular risk and diabetes screening.
Effects of Long-Term Administration of Recombinant Human Protein C in Xenografted Primates

Background. The role potential of recombinant human activated protein C (rhaPC), a recently developed molecule with anticoagulant and antiinflammatory properties, in prolonging survival in immunosuppressed primate recipients of porcine renal xenografts has been evaluated. Methods. rhaPC was administered daily for 5 days (24 &mgr;g/kg/hr; group A; n=3) or throughout the postoperative period (8–24 &mgr;g/kg/hr; group B; n=2; or 24–48 &mgr;g/kg/hr; group C; n=4). Animals in group D (n=2) received rhaPC daily (24 &mgr;g/kg/hr) combined with recombinant human antithrombin (84 U/kg every 8 hr). Two animals served as control (group E). Results. The results indicate that rhaPC is protective against fibrin deposition early after transplantation but does not prevent fibrin deposition and the occurrence of acute humoral xenograft rejection (AHXR) later on. Animals in the study survived between 8 and 55 days. At the dose used, rhaPC is able to prevent fibrin deposition in the graft in the first 2 weeks after xenotransplantation, except when it is administered in conjunction with antithrombin. However, rhaPC did not prevent the eventual occurrence of AHXR in primate recipients of porcine xenografts. Conclusions. In this pig to primate model, rhaPC confers a short advantage in the prevention of early perioperative xenograft damage but does not represent an effective strategy for preventing AHXR.
Can intervention modify adverse lifestyle variables in a rheumatoid population? Results of a pilot study

Background: Rheumatoid arthritis (RA) is associated with significant excess morbidity and mortality. Cardiovascular disease is the commonest cause of premature death in patients with RA. In recognition of this, blood pressure, weight, and smoking history are routinely ascertained in the clinic and appropriate advice and treatment started. Aims: To ascertain if attending a specialist nurse, in addition to routine medical care, would increase the success in dealing with lifestyle variables in a cohort of patients with RA. Methods: Twenty two consecutive patients starting treatment with the disease modifying antirheumatic drug (DMARD) sulfasalazine were invited to attend an additional clinic dealing with lifestyle factors every 12 weeks over a 48 week follow up. Smoking and alcohol history, baseline demographic and metrology assessments were determined for all patients. Body mass index (BMI) was calculated, blood pressure recorded, function assessed by the Health Assessment Questionnaire (HAQ), and social deprivation determined by the Carstairs Index. Patients were advised on exercise and diet, and serum cholesterol was measured. Results: Twenty women and two men, with a mean age of 52 years and mean disease duration of five years, were enrolled. Eight patients smoked and, unfortunately, none were persuaded to discontinue. Fifteen of the cohort were already taking regular exercise; one additional patient began swimming regularly. At baseline, 10 patients were found to have a high cholesterol, with a mean of 6.8 mmol/l. A 14% reduction in mean cholesterol was achieved by dietary modification, and three patients merited statin treatment. Obesity is a major problem in our population and 15 of the patients had grade I obesity with a mean BMI of 30.6; five of these gained a further 4.5 kg. Six patients with previously untreated hypertension were identified, but unfortunately five remained hypertensive and only two had received anti-hypertensive drugs. Conclusions: Educating patients in order to change lifestyle habits and influence outcome is a long term challenge facing all healthcare workers. In our cohort, most adverse lifestyle factors had already been recognised and discussed by the general practitioner or at prior clinic visits. Additional advice and input led to only modest improvement.
Toward Online Line Switching for Increasing Load Margins to Static Stability Limit

A novel online line switching methodology for increasing load margins to static stability limit of a look-ahead power system is developed. A design goal of the methodology is to balance speed (for online computation) and effectiveness (for quality of line switching solutions). Instead of dealing with the combinatorial nature of line switching problem, the proposed methodology employs the strategy of screening, ranking and identifying to find a set of high-quality solutions. The proposed methodology ensures the satisfaction of operational and engineering constraints of (look-ahead) post-switching power system. The proposed methodology also determines multiple solutions of line switching for operators to choose a desired one. The effectiveness of the online line switching methodology is evaluated on the IEEE 118-bus and a 1648-bus power systems with very promising results.
Study of the structure of the air and blood capillaries of the gas exchange tissue of the avian lung by serial section three‐dimensional reconstruction

We have previously reconstructed the gas exchange tissue of the adult muscovy duck, Cairina moschata using a method of manually aligning sections and tracing the contours of the components of the gas exchange tissue. This reconstruction method demonstrated that the air capillaries are comprised of an expanded globular part interconnected by narrow air channels. The blood capillaries completely surround the air capillaries forming an anastomosing meshwork of short segments. However, the resulting reconstruction was limited in scope because of the laborious process of tracing the profiles of each component through the sequence of micrographs. We have now reconstructed a larger proportion of the exchange tissue by using a cross‐correlation based alignment strategy and have demonstrated that the staining intensity of each of the exchange tissue components is sufficiently different to allow them to be identified by simple filtering and thresholding. The resulting reconstructions sample a much larger proportion of the exchange tissue and demonstrate the heterogeneity of structures from different locations in the parabronchus. We have shown that a sheet‐flow‐type arrangement of blood capillaries surrounds the infundibulum; this represents an unexpected functional convergence with the arrangement of blood capillaries surrounding the mammalian alveoli. It is feasible, using this reconstruction strategy, to analyse the exchange tissue of a large number of avian species in order to determine structural correlates of function. The resulting reconstructions could be analysed in order to determine the basis of the functional efficiency and rigidity of the avian lung.
Ni(2+), a double-acting inhibitor of neuronal nitric oxide synthase interfering with L-arginine binding and Ca(2+)/calmodulin-dependent enzyme activation.

Ni(2+), a toxic and carcinogenic pollutant and one of the leading causes of contact dermatitis, is shown to inhibit neuronal nitric oxide synthase (nNOS) in a competitive, reversible manner with respect to the substrate l-arginine (K(i) = 30 +/- 4 microM). The IC(50) values were dependent on calmodulin (CaM) concentration, but proved independent of Ca(2+), tetrahydrobiopterin (BH(4)) and other essential cofactors. Ni(2+) also inhibited CaM-dependent cytochrome c reduction, NADPH oxidation, and H(2)O(2) production by nNOS. Overall, the action profile of Ni(2+) was suggestive of an unusual, double-acting inhibitor of nNOS affecting l-arginine-binding and Ca(2+)/CaM-dependent enzyme activation.
Risk-Based Locational Marginal Pricing and Congestion Management

This paper develops a new electricity market clearing mechanism, called risk-based locational marginal pricing (RLMP). The RLMP is derived from the risk-based security-constrained economic dispatch model, where risk is modeled to capture the system's overall security level. Compared to the traditional locational marginal pricing (LMP) which is composed of three components: energy, congestion, and loss, the RLMP consists of an additional risk component. The risk component is a price signal to reflect the system's overall security level. This paper discusses the features of RLMP, and analyzes its benefits over traditional LMPs. The proposed concept and method are illustrated on a six-bus system and the WECC 240-bus system.
Cutaneous sarcoidosis by interferon therapy in a patient with melanoma

Editor A 38-year-old woman presented with two asymptomatic plaques located one in each knee (fig. 1) that she had noticed 2 months before. They had appeared after 27 months’ adjuvant therapy with interferon (IFN) alpha-2b (Intron-A®, Schering-Plough Corporation, Kenilworth, NJ), which had been started following the excision of a malignant melanoma on her left thigh. The patient referred no symptoms of systemic disease at the time of assessment of skin lesions. They were brownish-red and slightly infiltrated at clinical inspection, showing a lupoid appearance under diascopy. Skin biopsy of one of the lesions revealed typical sarcoid granulomata on the reticular dermis (fig. 2). Cultures and stains for acid-fast bacilli and fungal organisms were negative and examination under polarized light could not demonstrate foreign body material. A complete work-up to rule out systemic sarcoidosis was undertaken at this point. Chest radiography, thoracic computed tomographic scan, pulmonary function tests, tuberculin skin test, ophthalmological and neurological examinations were either negative or normal. Laboratory analysis only yielded a discrete hypergammaglobulinemia and positivity for antinuclear antibodies (ANA), with a title of 1/160. Serum angiotensin-converting enzyme (SACE) levels were normal at 20.7 U/L (N: 0–50). Treatment with IFNα was discontinued and the skin lesions rapidly faded over a 1-month period. No clinical or radiological signs of sarcoidosis have been detected 9 months later. Induction of sarcoidosis by interferons was first suggested by Abdi et al . in 1987 when they described the development of pulmonary sarcoidosis in a patient with a metastatic renal cell carcinoma under treatment with IFNβ . 1 To date, more than 40 cases have been published with this association, the vast majority being chronic hepatitis C and chronic myelogenous leukaemia patients. In 2004, Toulemonde et al . reported the first case of IFNα induced sarcoidosis in a patient with malignant melanoma. 2
Single channel measurements demonstrate the voltage dependence of permeation through N-type and L-type CaV channels

The delivery of Ca2+ into cells by CaV channels provides the trigger for many cellular actions, such as cardiac muscle contraction and neurotransmitter release. Thus, a full understanding of Ca2+ permeation through these channels is critical. Using whole-cell voltage-clamp recordings, we recently demonstrated that voltage modulates the apparent affinity of N-type (CaV2.2) channels for permeating Ca2+ and Ba2+ ions. While we took many steps to ensure the high fidelity of our recordings, problems can occur when CaV currents become large and fast, or when currents run down. Thus, we use here single channel recordings to further test the hypothesis that permeating ions interact with N-type channels in a voltage-dependent manner. We also examined L-type (CaV1.2) channels to determine if these channels also exhibit voltage-dependent permeation. Like our whole-cell data, we find that voltage modulates N-channel affinity for Ba2+ at voltages > 0 mV, but has little or no effect at voltages < 0 mV. Furthermore, we demonstrate that permeation through L-channel is also modulated by voltage. Thus, voltage-dependence may be a common feature of divalent cation permeation through CaV1 and CaV2 channels (i.e. high-voltage activated CaV channels). The voltage dependence of CaV1 channel permeation is likely a mechanism mediating sustained Ca2+ influx during the plateau phase of the cardiac action potential.
Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis

Objective Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Design Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. Results Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. Conclusions p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
Improving methyl parathion hydrolase to enhance its chlorpyrifos‐hydrolysing efficiency

Methyl parathion hydrolase (MPH) can degrade a wide range of organophosphorus compounds, but its efficiency in hydrolysing chlorpyrifos, one of the most popular pesticides applied for crop protection, is much lower than that in hydrolysing the preferred substrate methyl parathion. In this study, random mutagenesis was adopted to improve MPH to enhance its efficiency in hydrolysing the poorly hydrolysed substrate chlorpyrifos. Rapid screening of the improved MPH variants was carried out using Bacillus subtilis WB800 secretory expression system to investigate the distribution of improved MPH variants based on the size of clear haloes as a result of chlorpyrifos hydrolysis. Four improved MPH variants were isolated, and one variant K3, in particular, showed a 5‐fold increase in kcat value for chlorpyrifos hydrolysis. Furthermore, most of the MPH variants obtained in this study possessed enhanced thermostability and pH stability. The approaches adopted in this study could be extended to create other MPH variants with increased activity for hydrolysing other poorly hydrolysed substrates.
Cultural Transmission Can Inhibit the Evolution of Altruistic Helping

The study of culturally inherited traits has led to the suggestion that the evolution of helping behaviors is more likely with cultural transmission than without. Here we evaluate this idea through a comparative analysis of selection on helping under both genetic and cultural inheritance. We develop two simple models for the evolution of helping through cultural group selection: one in which selection on the trait depends solely on Darwinian fitness effects and one in which selection is driven by nonreproductive factors, specifically imitation of strategies achieving higher payoffs. We show that when cultural variants affect Darwinian fitness, the selection pressure on helping can be markedly increased relative to that under genetic transmission. By contrast, when variants are driven by nonreproductive factors, the selection pressure on helping may be reduced relative to that under genetic inheritance. This occurs because, unlike biological offspring, the spread of cultural variants from one group to another through imitation does not reduce the number of these variants in the source group. As a consequence, there is increased within‐group competition associated with traits increasing group productivity, which reduces the benefits of helping. In these cases, selection for harming behavior (decreasing the payoff to neighbors) may occur rather than selection for helping.
Molecular cloning of viral DNA from leukemogenic Gross passage A murine leukemia virus and nucleotide sequence of its long terminal repeat

The viral DNA genome of the leukemogenic Gross passage A virus was cloned in phage Charon 21A as an infectious molecule. The virus recovered by transfection with this infectious DNA was ecotropic, N-tropic, fibrotropic, and XC+. It was leukemogenic when reinjected into newborn SIM mice, indicating that ecotropic murine leukemia virus (MuLV) from an AKR mouse thymoma can harbor leukemogenic sequences. Its restriction map was similar to that of nonleukemogenic AKR MuLV, its putative parent, but differed at the 3' end and in the long terminal repeat (LTR). The nucleotide sequence of the Gross A virus LTR was identical to the AKR MuLV LTR sequence (Van Beveren et al., J. Virol. 41:542-556, 1982) in U5, R, and part of U3. All differences between both LTRs were found in U3. Only one copy of the U3 tandem direct repeat was conserved in the Gross A virus LTR, and it was rearranged by the insertion of a 36-base-pair sequence and by five point mutations. Only one additional point mutation common to several oncogenic MuLVs was present in U3. These structural changes in the U3 LTR and at the 3' end of the genome may be related to the leukemogenicity of this virus.