Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects*

Matrix metalloproteinase-13 (MMP13) is a Zn2+-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
Généralisation du bâti : structure spatiale de type graphe et représentation cartographique

La base de donnees topographique de l'Institut geographique national (BDTopo) est actuellement utilisee a divers fins dont la production des cartes au 1:25000e. Une extension possible serait de deriver aussi des cartes a de plus petites echelles (notamment au 1:50000e ) et ce de maniere automatique. Le principal obstacle a cette automatisation est la phase de generalisation cartographique, qui doit extraire de la base l'information pertinente pour la nouvelle echelle. D'une maniere plus generale, cette fonctionalite importante des systemes d'information geographiques, n'est presente a l'heure actuelle que sous la forme d'outils specifiques proposes a l'utilisateur du systeme pour traiter des cas precis. On peut faire l'analogie par exemple avec la generation automatique de resume de texte : la generalisation cartographique est a la carte ce que le resume de texte est au texte, il ne s'agit pas de jouer sur la taille des caracteres mais de supprimer ce qui n'est pas essentiel, de regrouper et reduire les developpements tout en conservant leur sens, parfois de conserver ce qui est exceptionnel. Nous avons limite le contexte de nos recherches au cas du bâti, avec pour objectif d'identifier les liens qui existent entre les donnees initiales et leurs representations graphiques a une echelle plus petite. Le but est ensuite de definir un outil automatique pour associer a un lot de donnees representant une zone de bâti dense une representation graphique adaptee a une echelle donnee. La premiere partie est consacree a la modelisation de la perception visuelle des groupements de bâtiments sur une carte. Le but est d'extraire les structures qui sont visuellement reperables. On utilise pour cela un graphe de plus proche voisinage sur les bâtiments, sur lequel on fait des mesures selon des criteres issus de la theorie de Gestalt (perception de groupes). Le resultat de cette analyse fournit l'information geographique associee a chacune des strutures, c'est a dire leur caractere : taille moyenne des bâtiments, forme du groupe, densite, ces informations sont independants de l'echelle. A partir de ces structures, nous definissons une methode permettant de leur associer d'autres representations a differentes echelles. Nous avons enfin defini des methodes d'evaluation du resultat permettant d'assurer la bonne integration du processus dans un systeme de generalisation automatique. Les eventuelles degradations constatees sont evalues et stockees au niveau des objets de la classe structure. La modelisation des structures et leur stockage permettent au processus global lorsqu'il effectue des modifications individuelles sur un bâtiment (deplacement), de determiner a quelle structure il appartient et de verifier que les modifications n'ont pas degrade la perceptibilite de la structure. Si une degradation est survenue, alors un traitement local au groupe peut etre entrepris. La structure peut donc servir d'index spatial intelligent pour acceder aux bâtiments.
Visuoperceptual sequelae in children with hemophilia and intracranial hemorrhage.

BACKGROUND The goal of this study was to examine the impact of focal brain injuries on the outcomes of visual perception and visuospatial abilities in Mexican children with hemophilia who have experienced intracranial hemorrhages. METHODS We assessed ten boys who had hemophilia with intracranial hemorrhage (HIC), six boys who had hemophilia without intracranial hemorrhage (HH), and ten boys without hemophilia (CTL). The Verbal (VIQ), Performance IQs (PIQ), and Full Scale IQs (FSIQ) from the Wechsler Intelligence Scale for Children-Mexican Revision, Visual Perception, and Visuospatial Abilities domains, which are from a neuropsychological assessment battery for Spanish-speaking children (ENI), were employed for our analysis. RESULTS The results showed that the HIC group performed in the low-average range on the PIQ and FSIQ, which was lower than the HH group. The HIC group showed low performance on visual perception tests, such as line orientation, fragmented objects, and overlapping figures, compared with their matched controls. CONCLUSIONS The results suggest that it is not the ability to recognize objects that is impaired in the HIC group, but the ability to identify objects under less favorable conditions. Our findings may have therapeutic and rehabilitative implications for the management of children with hemophilia and early focal brain lesions.
Processing Italian Relative Clauses: Working Memory Span and Word Order Effects on RTs

ABSTRACT In this study, the authors aim to clarify whether the subject–object asymmetry in relative clause comprehension is due to the use of parsing strategies (Active Filler Theory) or to a greater memory load generated by object sentences. Two experiments investigate how individual differences in working memory span may influence the reading times of relative sentences in Italian, a language characterized by a flexible structure. The results of Experiment 1 indicate that object extraction is more complex than subject extraction when sentences have a canonical structure. Furthermore, low-span participants have particular difficulties with object relative sentence comprehension. The results of Experiment 2 show that subject-relative clauses with uncanonical structures are more complex to understand than object-relative clauses, and low-span participants have more difficulties than high-span participants in elaborating both subject and object relative clauses. These data seem to be coherent with the Active Filler Theory.
Ownership Structure and Firm Performance: A Pragmatic Evidence From Pakistan

Agency theory suggests that allowing managers to participate in firm’s ownership assists as an operative instrument to cut agency costs and augment performance of the firm. While the managerial ownership’s role in corporate performance has been profoundly scrutinized for the firms in developed countries, there is a lack of such research, in black and white, on the non-financial firms in developing countries. The study aims seeks to inspect the impression of managerial ownership on the performance of Pakistani firms. This observational investigation endeavours to look for a connection between managerial ownership and firm execution on the 75 firms from 2009 to 2013 in Pakistan. Using panel data models, this study finds mixed results in different methods. We find no strong evidence for the managerial ownership as a significant determinant of the corporate performance for the given sample of Pakistani firms. Besides, the connection is vigorous to various procedures of firm.
Escherichia coli Ghost Production by Expression of Lysis Gene E and Staphylococcal Nuclease

ABSTRACT The production of bacterial ghosts from Escherichia coli is accomplished by the controlled expression of phage φX174 lysis gene E and, in contrast to other gram-negative bacterial species, is accompanied by the rare detection of nonlysed, reproductive cells within the ghost preparation. To overcome this problem, the expression of a secondary killing gene was suggested to give rise to the complete genetic inactivation of the bacterial samples. The expression of staphylococcal nuclease A in E. coli resulted in intracellular accumulation of the protein and degradation of the host DNA into fragments shorter than 100 bp. Two expression systems for the nuclease are presented and were combined with the protein E-mediated lysis system. Under optimized conditions for the coexpression of gene E and the staphylococcal nuclease, the concentration of viable cells fell below the lower limit of detection, whereas the rates of ghost formation were not affected. With regard to the absence of reproductive cells from the ghost fractions, the reduction of viability could be determined as being at least 7 to 8 orders of magnitude. The lysis process was characterized by electrophoretic analysis and absolute quantification of the genetic material within the cells and the culture supernatant via real-time PCR. The ongoing degradation of the bacterial nucleic acids resulted in a continuous quantitative clearance of the genetic material associated with the lysing cells until the concentrations fell below the detection limits of either assay. No functional, released genetic units (genes) were detected within the supernatant during the lysis process, including nuclease expression.
Regulatory and Effector CD4 T Cells in Nonobese Diabetic Mice Recognize Overlapping Determinants on Glutamic Acid Decarboxylase and Use Distinct Vβ Genes1

The 524–543 region of glutamic acid decarboxylase (GAD65), GAD65(524–543), is one of the first fragments of this islet Ag to induce proliferative T cell responses in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes. Furthermore, NOD mice given tolerogenic doses of GAD65(524–543) are protected from spontaneous and cyclophosphamide-induced diabetes. In this study, we report that there are at least two I-Ag7-restricted determinants present in the GAD65(524–543) sequence, each capable of recruiting unique T cell repertoires characterized by distinct TCR Vβ gene use. CD4+ T cells arise spontaneously in young NOD mice to an apparently dominant determinant found within the GAD65 peptide 530–543 (p530); however, T cells to the overlapping determinant 524–538 (p524) dominate the response only after immunization with GAD65(524–543). All p530-responsive T cells used the Vβ4 gene, whereas the Vβ12 gene is preferentially used to encode the TCR of p524-responsive T cell populations. T cell clones and hybridomas from both of these T cell groups were responsive to APC pulsed with GAD65(524–543) or whole rGAD65. p524-reactive cells appeared to be regulatory upon adoptive transfer into young NOD mice and could inhibit insulin-dependent diabetes mellitus development, although they were unable to produce IL-4, IL-10, or TGFβ upon antigenic challenge. Furthermore, we found that i.p. injection with p524/IFA was very effective in providing protection from cyclophosphamide-induced insulin-dependent diabetes mellitus. These data demonstrate that the regulatory T cells elicited by immunizing with GAD65(524–543) are unique and distinct from those that arise from spontaneous endogenous priming, and that T cells to this limited region of GAD65 may be either regulatory or pathogenic.
Comparison of Acute Effects of Nifedipine in Normotensive and Hypertensive Man

Acute sublingual administration of nifedipine, 10 or 20 mg, caused a rapid dose-related decrease in blood pressure (BP) in hypertensive subjects (n = 17), whereas no significant reduction of blood pressure was observed in a group of normotensive subjects (n = 12). Forearm vascular resistance (CVR) decreased significantly in both groups (31.1 and 17.2%, respectively; inter-group difference nonsignificant). The vasodilatating effect of nifedipine tended to be stronger in hypertensives than in normotensives, as reflected by a higher CVR (%)/log plasma concentration of nifedipine index. A significant negative correlation was found between the change in CVR and the change in heart rate (HR) in normotensive subjects (r = −0.72, p < 0.05), whereas no such relationship was present in hypertensive patients. There was no significant correlation between the change in BP and the change in HR in any of the groups. The rise in plasma noradrenaline and resting HR did not differ significantly in hypertensive patients and in normotensive subjects receiving nifedipine 20 mg. The results suggest that the contrasting BP response is caused mainly by a decreased sensitivity of the baroreceptor mechanism in arterial hypertension. A larger decrease in CVR in hypertensive patients than in normotensive subjects could be due at least partly to morphological changes of the resistance vessels. However, a more marked relaxing effect of the calcium antagonist in hypertensive vessels than in normotensive vessels may have contributed to the observed difference in effect.
Individualised funding and its implications for the skills and competencies required by disability support workers in Australia

ABSTRACT Within Australia, the National Disability Insurance Scheme (NDIS) has been heralded as one of the most significant social policy initiatives of recent times. The introduction of the NDIS follows similar moves towards individualised funding and consumer-directed care in the aged care sector. International evidence provides examples of the implications of individualised funding for workers within the social care sector; however, little attention has been paid to how the shift to individualised funding impacts on the skills and competencies required by disability support workers and in an Australian context. Our study aims to provide such an examination. We use qualitative data from in-depth interviews with key stakeholders including disability support workers; people with disability, and their families and carers; disability service providers; and training providers to investigate the impact of the NDIS on the skills and competencies required by disability support workers. Findings suggest that disability support workers require new skills to support choice and control, to be more customer-orientated and, to move from task-focused to person-centred care. As a consequence of these changes, the training of disability support workers is adapting to take account of these new skills and competencies.
Antibodies against Lagos Bat Virus in Megachiroptera from West Africa

To investigate the presence of Lagos bat virus (LBV)–specific antibodies in megachiroptera from West Africa, we conducted fluorescent antibody virus neutralization tests. Neutralizing antibodies were detected in Eidolon helvum (37%), Epomophorus gambianus (3%), and Epomops buettikoferi (33%, 2/6) from Ghana. These findings confirm the presence of LBV in West Africa.
A novel grid computing approach for probabilistic small signal analysis

Grid computing is an advanced technique for collaboratively solving complicated scientific problems using geographically and organisational dispersed computational, data storage and other recourses. Application of grid computing could provide significant benefits to all aspects of power system that involves using computers. Based on our previous research, this paper presents a novel grid computing approach for probabilistic small signal stability (PSSS) analysis in electric power systems with uncertainties. A prototype computing grid is successfully implemented in our research lab to carry out PSSS analysis on two benchmark systems. Comparing to traditional computing techniques, the gird computing has given better performances for PSSS analysis in terms of computing capacity, speed, accuracy and stability. In addition, a computing grid framework for power system analysis has been proposed based on the recent study
Long term bisphosphonate use in osteoporotic patients; a step forward, two steps back.

PURPOSE Bisphosphonates are the main class of drugs widely used in prevention and treatment of osteoporosis. Along with the beneficial effects, recent studies point to the harms of long-term treatment with bisphosphonates. METHODS The most relevant articles reporting serious adverse effects of bisphosphonates were selected and reviewed with the aim of assessing the risk-benefit of bisphosphonates. We searched PubMed, Web of Science, and Scopus using keywords bisphosphonates, risk of fracture, atrial fibrillation, osteonecrosis jaw, esophageal cancer, and adverse effects with no time limitation. We limited our s research to English articles. RESULTS Our review shows that bisphosphonates reduce vertebral fractures in short term use while in long-term can cause osteonecrosis jaw, esophageal cancer, atrial fibrillation, and increase the risk of atypical fractures and probably adynamic bone disease. There is no consensus on the time limitation of bisphosphonate usage or its long term adverse effects. Thus, more studies on long-term side effects of bisphosphonates are highly recommended. In addition, new approaches for prevention and treatment of osteoporosis seem necessary. CONCLUSION Prescribers should act cautionary and consider full assessment of risk-benefit and the duration of treatment.
Financial frictions and the business cycle

This dissertation emphasizes the financial instability inherent in modern financial markets and the real economy and introduces a different aspect to dynamic stochastic general equilibrium (DSGE) models with financial frictions. Specifically, I introduce a role for the equity market in financial intermediation, firm production and household consumption—termed the equity price channel. This innovative model forms the foundation of three research papers which successively studies: the systemic and pro-cyclical effect of equity, the sources of credit spread variability, and the role of contingent convertible capital (CoCos) in Basel III macroprudential regulation. In chapter two, I show that the equity price channel significantly exacerbates business cycle fluctuations through both financial accelerator and bank capital channels. I find that a NewKeynesian DSGE model with an equity price channel well mimics the U.S. business cycle and reproduces the strong procyclicality of equity. The results also reflect the increasing emphasis on common equity capital in Basel regulations. This is beneficial in terms of financial stability, but amplifies and propagates shocks to the real economy. In chapter three, I establish the prevailing financial factors that influence credit spread variability, and its impact on the U.S. business cycle over the Great Moderation and Great Recession periods. Over both periods, I find an important role for bank market power (sticky rate adjustments and loan rate markups) on credit spread variability in the U.S. business cycle. Equity prices exacerbate movements in credit spreads through the financial accelerator channel, but cannot be regarded as a main driving force of credit spread variability. Both the financial accelerator and bank capital channels play a significant role in propagating the movements of credit spreads. Across the last three U.S. recession periods (1990−91, 2001, and 2007−09) I observe a remarkable decline in the influence of technology and monetary policy shocks. Whereas, there is an increasing trend in the contribution of loan rate markup shocks to the variability of retail credit spreads. The influence of loan-to-value shocks has declined since the 1990−91 recession, while the bank capital requirement shock exacerbates and prolongs credit spread variability over the 2007−09 recession period. In chapter four, I show that countercyclical capital requirements (as in Basel III) and contingent convertible capital provide an effective dual approach to macroprudential policy. On the one hand, a countercyclical capital adequacy rule dominates CoCos in the stabilization of real shocks. That ii Stellenbosch University http://scholar.sun.ac.za
Environmental implications of crop insurance subsidies in Southern Italy

The changing environment affects agriculture with uncertainty. On the other hand, policies to cope with risks may have strong impacts on the environment. We evaluate the effects of public risk management programmes, such as subsidized crop insurance, fertilizer use and land allocation to crops. We implement a mathematical programming model of a representative wheat–tomato farm in Puglia, a Southern Italy region. The results show that under the current crop insurance programmes, tomato production is expected to expand and will require larger amounts of fertilizer, whereas the opposite is true for wheat production. Policy and environmental implications are discussed.
Uncertain Futures: An Examination of Intimate Partner Violence and Contraceptive Use in Kenya

Author(s): Narasimhan, Subasri | Advisor(s): Pebley, Anne R. | Abstract: Kenya has had a history of promoting both family planning and efforts against gender-based violence. However, intimate partner violence (IPV) remains a significant factor in women’s lives. Although experience of IPV has been shown to create a significant burden on reproductive health outcomes, less work has focused on the impact of IPV on women’s contraceptive use particularly in Kenya. Using the data from the 2003, 2008-09, and 2014 Kenya Demographic and Health Surveys (Kenya National Bureau of Statistics (KNBS) a ICF Macro 2004, 2010, 2015) this dissertation focused on the association between IPV, fertility intentions, women’s autonomy, and contraceptive use. I integrate the theory of gender and power and the social-ecological model to examine the association between IPV and contraceptive use.In the first study I focus on the impact of IPV on women’s fertility intentions. IPV experience increases the likelihood women would want to limit their childbearing as compared to wanting to space births or have children soon. This indicates that women would be less likely to want to raise children in an environment they are unsure is safe or supportive, a concept I call the uncertain futures hypothesis. The second study examines whether exposure to IPV reduced contraceptive use. I find that IPV did not uniformly reduce contraceptive use. Instead, IPV exposure decreased the likelihood of traditional contraceptive use but increased the likelihood of modern contraceptive use. This lends further credence to the possibility that women are making planful contraceptive decisions in IPV situations. In the final study I examine whether healthcare decision making, representing a facet of women’s autonomy, mediates the relationship between intimate partner violence and recent modern contraceptive use. This study found that there no mediated effect of healthcare decision making. However, healthcare decision-making remained significant in all models underscoring the need to consider ability to make healthcare decisions as a possible barrier to contraceptive access for women in abusive partnerships. This dissertation improves the evidence that IPV may facilitate women’s greater use of modern contraceptives in African contexts. It also underscores the need to consider IPV experiences when advising women on family planning.