Miracle-dz/UniFAR-FTUs huggingface dataset:
Raltegravir Susceptibility and Fitness Progression of HIV Type-1 Integrase in Patients on Long-Term Antiretroviral Therapy

Background HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN. Methods HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses. Results The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples. Conclusions HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.
Building modern land administration systems in developed economies

Land Administration Systems (LAS) are institutional frameworks complicated by the tasks they must perform, by national cultural, political and judicial settings, and by technology. This paper assists sharing LAS capacity among countries with diverse legal systems and institutional structures by identifying an ideal and historically neutral LAS model for : • servicing the needs of governments, business and the public, • utilising the latest technologies, • servicing rights, responsibilities, restrictions and risks in relation to land, and • delivering much broader information about sustainable development. Case studies of Denmark and Victoria are used to test existing systems against the model.
New approaches to immunosuppression in liver transplantation

Abstract With the continued improvements in outcome following liver transplantation, the drawbacks associated with conventional immunosuppression regimens become increasingly apparent. Although up to 70% of patients develop a histological infiltrate of the graft (acute rejection), many of these will resolve spontaneously, and chronic rejection is rare. If a robust form of allograft acceptance or tolerance can be established, then immunosuppression can be withdrawn along with all the accompanying risks. The liver is already known to be associated with downregulated immune responses; the mechanism for this is unclear, but may be related to a number of mechanisms known to be involved in peripheral tolerance. There are many strategies being studied for achieving allograft tolerance, including the use of modern immunosuppressants, antibodies that target key molecules in the immune response, and recruitment of leukocytes to allografts. In the interim, it is necessary to look for safe protocols that allow trials of tolerance strategies without putting patients at increased risk.
Weight change, weight fluctuation, and mortality.

OBJECTIVE To examine the relation between weight change and weight fluctuation (cycling) and mortality in middle-aged men. METHODS A prospective study of 5608 men aged 40 to 59 years at screening, drawn from one general practice in each of 24 British towns. Changes in weight observed during a 12- to 14-year period were related to mortality during the subsequent 8 years. RESULTS There were 943 deaths from all causes: 458 cardiovascular disease (CVD) and 485 non-CVD deaths. Those with stable weight or weight gain had the lowest total, CVD, and non-CVD mortality. Sustained weight loss or weight fluctuation (loss-gain or gain-loss) showed a significantly higher mortality risk than stable weight even after adjustment for lifestyle variables (relative risk [95% confidence interval], 1.60 [1.32-1.95], 1.50 [1.17-1.91], and 1.63 [1.24-2.14], respectively). Adjustment or exclusion of men with preexisting disease markedly attenuated the increased risk of CVD and total mortality associated with sustained weight loss and weight gain-weight loss. In long-term nonsmokers, any weight loss since screening was associated with an increased risk of mortality, but this was markedly attenuated by adjustment for preexisting disease. Recent ex-smokers showed the most marked increase in mortality associated with sustained weight loss. CONCLUSIONS The increased mortality in middle-aged men with sustained weight loss and weight fluctuation (cycling) is determined to a major extent by disadvantageous lifestyle factors and preexisting disease. The evidence suggests that weight loss and weight fluctuation (cycling) in these men does not directly increase the risk of death.
Apoptosis Induced by Withdrawal of Trophic Factors Is Mediated by p38 Mitogen-activated Protein Kinase*

p38 is a member of the mitogen-activated protein (MAP) kinase superfamily activated by stress signals and implicated in cellular processes involving inflammation and apoptosis. Unlike the extracellular signal-regulated kinases (p42 and p44 MAP kinases), which are stimulated by insulin in many cell types, p38 activity is inhibited by insulin in postmitotic fetal neurons for which insulin is a potent survival factor (Heidenreich, K. A., and Kummer, J. L. (1996)J. Biol. Chem. 271, 9891–9894). These data suggested that insulin’s effects on neuronal survival are mediated by inhibition of a p38-mediated apoptotic pathway. To better understand the relationship between p38 activity and cell survival, we induced apoptosis in two cell lines and examined the ability of insulin or a specific p38 inhibitor (a pyridinyl imidazole compound PD169316) to block p38 activity and cell death. In Rat-1 fibroblasts grown in the presence of serum, p38 activity was undetectable by immune complex assays, and the number of apoptotic cells was very low (<0.5%). After the removal of serum for 16 h, p38 activity was markedly elevated, and apoptosis increased by 14–15-fold. Insulin (50 ng/ml) inhibited p38 activity by ∼70% and blocked apoptosis by at least 80%. PD169316 also blocked p38 enzyme activity and apoptosis by approximately 80%. Similar results were obtained in differentiated PC12 cells that were deprived of nerve growth factor (NGF) for 16 h. In the presence of NGF, p38 activity and the number of apoptotic cells was very low (∼1.0%). After NGF withdrawal, p38 activity was selectively elevated and apoptosis increased to 15%. Both insulin and PD169316 markedly blocked the increase in p38 activity and apoptosis. The MAP kinase kinase inhibitor, PD98059, had no effect on apoptosis in Rat-1 fibroblasts and only partially blocked apoptosis in PC12 cells. PD98059 did not influence insulin’s ability to block apoptosis, indicating that the extracellular signal-regulated kinase pathway does not mediate insulin’s survival effects. These data further support the role of p38 in cellular apoptosis and support the hypothesis that insulin promotes cell survival, at least in part, by inhibiting the p38 pathway.
On Measuring Structural Reform

Indicators of government activity must be carefully designed to be relevant, credible and accountable. Frustration with reform pressures suggests that measures of policy activity are not providing accurate information. In fact, indicators of product or labour market regulation fail to measure structural reform as they focus on cross-country comparisons rather than on progress with reform over time. I use the novel EU Semester approach recommending EU Member States to implement reforms and their annual follow-up in the National Reform Programme to develop some indicators of how reform plans are actually implemented. This indicator might be useful for checking progress with policy, but also for empirical studies testing what drives or blocks reform in different policy domains.
Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines

Cytokine profiles were examined 1 month after primary vaccination of infants with a whole-cell pertussis vaccine (wP) (Connaught) or either of two acellular pertussis vaccines, aP-Chiron Biocine (aP-CB) or aP-SmithKline Beecham (aP-SB), each combined with diphtheria-tetanus toxoids (DT), in Bordetella pertussis antigen-stimulated or unstimulated peripheral blood mononuclear cells (PBMC). Pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were used as antigens, and the children were defined as responsive when their PBMC proliferated in response to these antigens. The controls were either children who received only DT or children who received pertussis vaccine but whose PBMC did not proliferate upon stimulation with B. pertussis antigens (unresponsive children). Antigen-stimulated PBMC of responsive wP recipients were characterized by an elevated production of T-helper-cell type 1 cytokines gamma interferon (IFN-gamma) and interleukin 2 (IL-2), low to minimal production of IL-5, and no production of IL-4. The PBMC of aP vaccine-responsive recipients showed, in addition to the elevated IFN-gamma production, a consistent, antigen-dependent production of type 2 cytokines (IL-4 and IL-5), with PRN being the most and PT being the least effective antigen. Type 2 cytokine induction was more pronounced in aP-SB than in aP-CB recipients, as shown by the presence of IL-4 mRNA transcripts and higher IL-5 production in the former (161.6 +/- 36 and 47.9 +/- 44 pg/ml [mean +/- standard error for five subjects each], respectively, after PRN stimulation). Appreciable, antigen-unstimulated (constitutive) IFN-gamma production was also detected in PBMC cultures of all vaccinees. However, this spontaneous IFN-gamma production was, in most vaccinees, significantly lower than the antigen-driven cytokine production. In contrast, no constitutive type 2 cytokine production was ever observed in any vaccine group. PBMC from the two control groups (either DT or pertussis vaccine recipients) did not show any type 2 cytokine production, while IFN-gamma production was comparable in both antigen-stimulated and unstimulated conditions. Absence of type 2 cytokines and low levels of constitutive IFN-gamma production were also seen in prevaccination children. Thus, pertussis vaccines induce in infants a basically type 1 cytokine profile, which is, however, accompanied by some production of type 2 cytokines. The latter are more expressed by aP-SB than by aP-CB recipients, and with PRN than with other antigens, and they are minimally expressed in wP recipients and with PT as antigen. Our data also highlight a constitutive IFN-gamma production in infancy, which might reflect natural immunization and/or the burden of concomitant vaccinations and which may have an impact on T-helper-cell cytokine pattern polarization consequent to pertussis vaccination.
A Review on the Physical Mechanisms That Limit the Reliability of GaN-Based LEDs

We review the failure modes and mechanisms of gallium nitride (GaN)-based light-emitting diodes (LEDs). A number of reliability tests are presented, and specific degradation mechanisms of state-of-the-art LED structures are analyzed. In particular, we report recent results concerning the following issues: 1) the degradation of the active layer induced by direct current stress due to the increase in nonradiative recombination; 2) the degradation of LEDs submitted to reverse-bias stress tests; 3) the catastrophic failure of advanced LED structures related to electrostatic discharge events; 4) the degradation of the ohmic contacts of GaN-based LEDs; and 5) the degradation of the optical properties of the package/phosphors system of white LEDs. The presented results provide important information on the weaknesses of LED technology and on the design of procedures for reliability evaluation. Results are compared with literature data throughout the text.
Coronary intervention in patients>or=75 years old with ST-elevation myocardial infarction: in-hospital and 6-month clinical outcomes.

BACKGROUND ST-segment elevation myocardial infarction (STEMI) in elderly patients presents specific clinical characteristics. The study on percutaneous coronary intervention (PCI) in elderly patients (>or=75 years) with STEMI, however, has less been performed. METHODS In the present study, 522 consecutive STEMI patients undergoing PCI within 12 hours from symptom onset were investigated, and clinical characteristics and in-hospital and 6-month outcomes of 66 elderly patients (>or=75 years, group A) were compared to those of 456 younger patients (<75 years, group B). RESULTS Compared to younger patients, elderly ones had more females (42.4% vs. 17.8%, P<0.005), a history of cerebral vascular events (7.6% vs. 0.9%, P<0.05), higher serum creatinine level ((96.48+/-31.65) mmol/L vs. (84.87+/-19.81) mmol/L, P<0.005) and fewer smokers (28.8% vs. 45.4%, P<0.05). The elderly ones had worse Killip class (Killip I class: 69.7% vs. 85.7%, P<0.05), less drug-eluting stent implantation and lower rates of TIMI flow 3 following PCI (33.3% vs. 47.1%, and 84.8% vs. 94.7%, P<0.05 respectively). Additionally, both in-hospital mortality and myocardial infarction rate were found to be higher in elderly patients (16.7% vs. 1.5%, and 7.6% vs. 2.6%, P<0.05 respectively), which were also observed until 6-month follow-up (9.1% vs. 0, and 6.1% vs. 0, P<0.05 respectively). In multivariable Cox regression analysis, serum creatinine level, history of hypertension, left anterior descending coronary artery as infarct-related artery and Killip class were independent predictors of 6-month overall death in elderly patients. CONCLUSIONS The clinical characteristics of elderly patients with STEMI after PCI are different from those of younger patients. Although PCI in this population is with a low rate of PCI failure, it is still associated with a worse outcome.
Austere Conservation: Understanding Conflicts over Resource Governance in Tanzanian Wildlife Management Areas

We explore how the regime of rules over access to land, natural, and financial resources reflects the degree of community ownership of a Wildlife Management Area (WMA) in Tanzania. Being discursively associated with participatory and decentralised approaches to natural resource management, WMA policies have the ambition to promote the empowerment of communities to decide over rules that govern access to land and resources. Our purpose is to empirically examine the spaces for popular participation in decision-making over rules of management created by WMA policies: that is, in what sense of the word are WMAs actually community-based? We do this by studying conflicts over the regime of rules over access to land and resources. Analytically, we focus on actors, their rights and meaningful powers to exert control over resource management, and on accountability relationships amongst the actors. Our findings suggest that WMAs foster very limited ownership, participation and collective action at the community level, because WMA governance follows an austere logic of centralized control over key resources. Thus, we suggest that it is difficult to argue that WMAs are community-owned conservation initiatives until a genuinely devolved and more flexible conservation model is implemented to give space for popular participation in rule-making.
RNA Granule Assembly and Disassembly Modulated by Nuclear Factor Associated with Double-stranded RNA 2 and Nuclear Factor 45*

Background: RNA granules are associated with translational control and neurodegenerative disease. Results: Nuclear factor associated with dsRNA 2 (NFAR2) enhances RNA granule assembly through two domains, one of which is antagonized by nuclear factor 45 (NF45). Conclusion: NFAR2 and NF45 play novel regulatory roles in RNA granule assembly and disassembly. Significance: Mechanisms of RNA granule assembly and disassembly are the basis for understanding translational control and neurodegenerative disease. RNA granules are large messenger ribonucleoprotein complexes that regulate translation and mRNA translocation to control the timing and location of protein synthesis. The regulation of RNA granule assembly and disassembly is a structural basis of translational control, and its disorder is implicated in degenerative disease. Here, we used proteomic analysis to identify proteins associated with RNA granule protein 105 (RNG105)/caprin1, an RNA-binding protein in RNA granules. Among the identified proteins, we focused on nuclear factor (NF) 45 and its binding partner, nuclear factor associated with dsRNA 2 (NFAR2), and we demonstrated that NF45 promotes disassembly of RNA granules, whereas NFAR2 enhances the assembly of RNA granules in cultured cells. The GQSY domain of NFAR2 was required to associate with messenger ribonucleoprotein complexes containing RNG105/caprin1, and it was structurally and functionally related to the low complexity sequence domain of the fused in sarcoma protein, which drives the assembly of RNA granules. Another domain of NFAR2, the DZF domain, was dispensable for association with the RNG105 complex, but it was involved in positive and negative regulation of RNA granule assembly by being phosphorylated at double-stranded RNA-activated kinase sites and by association with NF45, respectively. These results suggest a novel molecular mechanism for the modulation of RNA granule assembly and disassembly by NFAR2, NF45, and phosphorylation at double-stranded RNA-activated kinase PKR sites.
Cooperation in Polygynous Households

Using a carefully designed series of public goods games, we compare, across monogamous and polygynous households, the willingness of husbands and wives to cooperate to maximize household gains. Compared to monogamous husbands and wives, polygynous husbands and wives are less cooperative, one with another, and co-wives are least cooperative, one with another. The husbands’ and wives’ behavior in a corresponding series of inter-household games indicates that these differences cannot be attributed to selection of less cooperative people into polygyny. Finally, behavior in polygynous households is more reciprocal and less apparently altruistic. (JEL C93, D13, J12, O12)
Activation and integration of bilateral GABA‐mediated synaptic inputs in neonatal rat sympathetic preganglionic neurones in vitro

The role of GABA receptors in synaptic transmission to neonatal rat sympathetic preganglionic neurones (SPNs) was investigated utilizing whole‐cell patch clamp recording techniques in longitudinal and transverse spinal cord slice preparations. In the presence of glutamate receptor antagonists (NBQX, 5 μm and D‐APV, 10 μm), electrical stimulation of the ipsilateral or contralateral lateral funiculi (iLF and cLF, respectively) revealed monosynaptic inhibitory postsynaptic potentials (IPSPs) in 75% and 65% of SPNs, respectively. IPSPs were sensitive to bicuculline (10 μm) in all neurones tested and reversed polarity around −55 mV, the latter indicating mediation via chloride conductances. In three neurones IPSPs evoked by stimulation of the iLF (n= 1) or cLF (n= 2) were partly sensitive to strychnine (2 μm). The expression of postsynaptic GABAA and GABAB receptors were confirmed by the sensitivity of SPNs to agonists, GABA (2 mm), muscimol (10–100 μm) or baclofen (10–100 μm), in the presence of TTX, each of which produced membrane hyperpolarization in all SPNs tested. Muscimol‐induced responses were sensitive to bicuculline (1–10 μm) and SR95531 (10 μm) and baclofen‐induced responses were sensitive to 2‐hydroxy‐saclofen (100–200 μm) and CGP55845 (200 nm). The GABAC receptor agonist CACA (200 μm) was without significant effect on SPNs. These results suggest that SPNs possess postsynaptic GABAA and GABAB receptors and that subsets of SPNs receive bilateral GABAergic inputs which activate GABAA receptors, coupled to a chloride conductance. At resting or holding potentials close to threshold either single or bursts (10–100 Hz) of IPSPs gave rise to a rebound excitation and action potential firing at the termination of the burst. This effect was mimicked by injection of small (10–20 pA) rectangular‐wave current pulses, which revealed a time‐dependent, Cs+‐sensitive inward rectification and rebound excitation at the termination of the response to current injection. Synaptic activation of a rebound excitation mediated by a time‐dependent inward rectification expressed intrinsically by SPNs may provide a novel mechanism enabling SPNs to be entrained to rhythms driven from the brainstem or higher centres.
GUEST EDITORS' INTRODUCTION TO THE SPECIAL ISSUE STRATEGIC ENTREPRENEURSHIP: ENTREPRENEURIAL STRATEGIES FOR WEALTH CREATION

Entrepreneurship involves identifying and exploiting entrepreneurial opportunities. However, to create the most value entrepreneurial firms also need to act strategically. This calls for an integration of entrepreneurial and strategic thinking. We explore this strategic entrepreneurship in several important organizational domains to include external networks and alliances, resources and organizational learning, innovation and internationalization. The research in this special issue examines both traditional (e.g., contingency theory, strategic fit) and new theory (e.g., cultural entrepreneurship, business model drivers). The research also integrates, extends, and tests theory and research from entrepreneurship and strategic management in new ways such as creative destruction (discontinuities), resource-based view, organizational learning, network theory, transaction costs and institutional theory. The research presented herein provides a basis for future research on strategic entrepreneurship for wealth creation.Copyright © 2001 John Wiley & Sons, Ltd. The age of progress is over. It was born in the Renaissance, achieved its exuberant adolescence during the Enlightenment, reached a robust maturity in the industrial age, and died with the dawn of the twenty-first century … We now stand on the threshold of a new age—the age of revolution … it is going to be an age of upheaval, of tumult, of fortunes made and unmade at headsnapping speed. For change has changed. No longer is it additive. No longer does it move in a straight line. In the twenty-first century, change