Miracle-dz/UniFAR-FTUs huggingface dataset:
Conservation of a Packaging Signal and the Viral Genome RNA Packaging Mechanism in Alphavirus Evolution

ABSTRACT Alphaviruses are a group of small, enveloped viruses which are widely distributed on all continents. In infected cells, alphaviruses display remarkable specificity in RNA packaging by encapsidating only their genomic RNA while avoiding packaging of the more abundant viral subgenomic (SG), cellular messenger and transfer RNAs into released virions. In this work, we demonstrate that in spite of evolution in geographically isolated areas and accumulation of considerable diversity in the nonstructural and structural genes, many alphaviruses belonging to different serocomplexes harbor RNA packaging signals (PSs) which contain the same structural and functional elements. Their characteristic features are as follows. (i) Sindbis, eastern, western, and Venezuelan equine encephalitis and most likely many other alphaviruses, except those belonging to the Semliki Forest virus (SFV) clade, have PSs which can be recognized by the capsid proteins of heterologous alphaviruses. (ii) The PS consists of 4 to 6 stem-loop RNA structures bearing conserved GGG sequences located at the base of the loop. These short motifs are integral elements of the PS and can function even in the artificially designed PS. (iii) Mutagenesis of the entire PS or simply the GGG sequences has strong negative effects on viral genome packaging and leads to release of viral particles containing mostly SG RNAs. (iv) Packaging of RNA appears to be determined to some extent by the number of GGG-containing stem-loops, and more than one stem-loop is required for efficient RNA encapsidation. (v) Viruses of the SFV clade are the exception to the general rule. They contain PSs in the nsP2 gene, but their capsid protein retains the ability to use the nsP1-specific PS of other alphaviruses. These new discoveries regarding alphavirus PS structure and function provide an opportunity for the development of virus variants, which are irreversibly attenuated in terms of production of infectious virus but release high levels of genome-free virions.
Clonidine Premedication Reduces Maternal Requirement for Intravenous Morphine After Cesarean Delivery Without Affecting Newborn's Outcome

Background and Objectives The α2-agonist clonidine has several benefits for patients undergoing surgery. During and after elective cesarean delivery (C-section), we assessed the condition of parturient and neonate when one half of the parturients were pretreated with oral clonidine. Methods Forty-six consenting parturients were studied in a randomized, double-blinded manner. Preanesthetic medication was atropine and famotidine with or without clonidine 4 μg/kg. After baseline measurements in parturients and fetuses, combined spinal and epidural anesthesia was established (1.6 mL of 0.5% tetracaine diluted with 10% dextrose in water). C-section was performed while breathing oxygen spontaneously (3 L/min) through a facemask. After delivery, neonates were assessed at 1 and 5 minutes, and the condition of mother and neonate was observed for 48 hours. Results Parturients receiving clonidine showed no hemodynamic instability during and after C-section, and while their visual analog scale (VAS) scores, verbal descriptive scale (VDS) scores, and sedation scores did not differ from those without clonidine, they needed significantly less patient-controlled analgesia (PCA) morphine for postoperative pain for the first 2 days (P < .01). Fetal heart rate, umbilical artery and vein pH and gas tensions, and the Apgar-scores of the newborns showed no intergroup differences. No neonatal depression or bradycardia was observed for 48 hours after delivery. Conclusion The present results indicate that oral clonidine reduces the PCA morphine requirement after C-section without compromising the condition of the fetus or newborn. Further study including larger number of patients would be needed before we conclude that oral clonidine for parturients is safe for their newborns.
Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3*

Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the activity of specific signal transduction pathways. Although powerful, rapid and convenient, this technique can also generate artifactual results, as revealed for instance in the case of high throughput screens of inhibitory molecules. Here we demonstrate that the previously reported inhibitory effect of the Nod-like receptor (NLR) protein NLRX1 on NF-κB- and type I interferon-dependent pathways in LRAs was a nonspecific consequence of the overexpression of the NLRX1 leucine-rich repeat (LRR) domain. By comparing luciferase activity and luciferase gene expression using quantitative PCR from the same samples, we showed that NLRX1 inhibited LRAs in a post-transcriptional manner. In agreement, NLRX1 also repressed LRAs if luciferase was expressed under the control of a constitutive promoter, although the degree of inhibition by NLRX1 seemed to correlate with the dynamic inducibility of luciferase reporter constructs. Similarly, we observed that overexpression of another NLR protein, NLRC3, also resulted in artifactual inhibition of LRAs; thus suggesting that the capacity to inhibit LRAs at a post-transcriptional level is not unique to NLRX1. Finally, we demonstrate that host type I interferon response to Sendai virus infection was normal in NLRX1-silenced human HEK293T cells. Our results thus highlight the fact that LRAs are not a reliable technique to assess the inhibitory function of NLRs, and possibly other overexpressed proteins, on signal transduction pathways.
A STUDY ON DETERMINANTS AND TRENDS IN REMITTANCE FLOWS IN MACEDONIA

Labor migration and remittances have become increasingly important for many developing and transition countries in recent decades. In the case of Macedonia, labor migration has a long history, going back for a century or even more. Yet, remittance flows have ignited considerable interest within the academic and policy community in the last few years, as net private transfers in Macedonia increased from 565.75 Millions of EUR in 2003 to 923.07 Millions of EUR in 2006. Despite the high level of remittances, little is known about the sources of remittances (or the main source countries of remittance transfers), the demographic and educational profile of senders and recipient households, the final use of remittance inflows (household consumption, investments or savings), the role of the formal financial sector, the link between remittances and financial development and the prospective trends. Without proper survey data, accurate estimation of remittance flows and how they are impacting the economy is not possible. No surveys or other in-depth analyses have been conducted in Macedonia on this topic so far. Moreover, the link between migration movements and developments in remittance receipts has not yet been properly analyzed. The official estimate of remittance inflows in Macedonia was $181.45 millions of US $ in 2006, whereas our alternative estimate equals roughly 301.8 millions of US $. Therefore, the true importance of remittances to the Macedonian economy is much higher that the ratio of official remittances to GDP. In addition to shedding light on the size and importance of remittances in Macedonia, we believe that the insights gained on how remittance data are used will be useful to policymakers and donor community.
Transcriptional Profiling Implicates Novel Interactions between Abiotic Stress and Hormonal Responses in Thellungiella, a Close Relative of Arabidopsis1[W]

Thellungiella, an Arabidopsis (Arabidopsis thaliana)-related halophyte, is an emerging model species for studies designed to elucidate molecular mechanisms of abiotic stress tolerance. Using a cDNA microarray containing 3,628 unique sequences derived from previously described libraries of stress-induced cDNAs of the Yukon ecotype of Thellungiella salsuginea, we obtained transcript profiles of its response to cold, salinity, simulated drought, and rewatering after simulated drought. A total of 154 transcripts were differentially regulated under the conditions studied. Only six of these genes responded to all three stresses of drought, cold, and salinity, indicating a divergence among the end responses triggered by each of these stresses. Unlike in Arabidopsis, there were relatively few transcript changes in response to high salinity in this halophyte. Furthermore, the gene products represented among drought-responsive transcripts in Thellungiella associate a down-regulation of defense-related transcripts with exposure to water deficits. This antagonistic interaction between drought and biotic stress response may demonstrate Thellungiella's ability to respond precisely to environmental stresses, thereby conserving energy and resources and maximizing its survival potential. Intriguingly, changes of transcript abundance in response to cold implicate the involvement of jasmonic acid. While transcripts associated with photosynthetic processes were repressed by cold, physiological responses in plants developed at low temperature suggest a novel mechanism for photosynthetic acclimation. Taken together, our results provide useful starting points for more in-depth analyses of Thellungiella's extreme stress tolerance.
Clinical and Pharmacological Determinants of the Therapeutic Response to Dihydroartemisinin-Piperaquine for Drug-Resistant Malaria

ABSTRACT Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults (P = 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults (P < 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] = 6.6 [95% CI: 1.9 to 23]; P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 35]; P = 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group.
Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine

We have studied an aspect of the functional heterogeneity of human mast cells, namely responsiveness to the inhibitory effects of sodium cromoglycate and nedocromil sodium. The effects of these drugs were examined on the release of histamine and PGD2 from mast cells of human skin, lung, tonsils, adenoids and intestine. A high concentration, 1000 μM, of sodium cromoglycate was required to significantly inhibit histamine release from lung and tonsillar mast cells. Nedocromil sodium, 1000 μM, was more effective than sodium cromoglycate against histamine release from lung, tonsillar and adenoidal cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in adenoidal and intestinal mast cells. In contrast, in intestinal mast cells, the effect of nedocromil sodium was weaker and more variable than sodium cromoglycate. Skin mast cells differed from mast cells of the other anatomical sites in being unresponsive to sodium cromoglycate and nedocromil sodium. Our results confirm that high concentrations of sodium cromoglycate and nedocromil sodium are required to achieve even modest inhibition of mediator release from human mast cells under in vitro conditions. Notwithstanding this, the results also indicate that differences exist among skin, lung, tonsillar, adenoidal and intestinal mast cells with respect to their sensitivity to sodium cromoglycate and nedocromil sodium, thus extending our knowledge of functional heterogeneity within the human mast cell populations.
Effects of exercise training on cardiovagal and sympathetic responses to Valsalva's maneuver.

PURPOSE We tested the hypothesis that a strictly-controlled program of aerobic conditioning would increase vagal and decrease sympathetic responses to Valsalva straining. METHODS Eleven young men performed a maximal aerobic capacity test, controlled frequency breathing (0.25 Hz), and three Valsalva maneuvers before and after 4 wk of exercise training on a cycle ergometer (30 min at > or = 70% max heart rate, 3 sessions. week-1). During controlled breathing and Valsalva straining, we recorded the electrocardiogram, noninvasive beat-by-beat arterial pressure, and peroneal nerve muscle sympathetic traffic at the popliteal fossa (pre- and postexercise sympathetic recordings were obtainable in 7 of 11 subjects). Vagal-cardiac tone was estimated from R-R interval standard deviations during controlled frequency breathing. Cardiovagal baroreflex sensitivity was derived from increases of R-R intervals as functions of increases in systolic pressures with linear regression analysis during phase IV pressure increases, and sympathetic sensitivity was derived from the quotient of total muscle sympathetic nerve activity and diastolic pressure changes during phase II pressure reductions. RESULTS Exercise training increased VO2 max (3.38 +/- 0.10 pre-, and 3.64 +/- 0.11 L. min-1 postexercise; mean +/- SE; P = 0.04), R-R interval standard deviations (75 +/- 0.12 pre- and 94 +/- 0.14 ms postexercise; mean +/- SE; P = 0.03), and cardiovagal baroreflex sensitivity (15.0 +/- 1.1 pre-, and 25.0 ms. mm Hg-1 +/- 4.0 postexercise; mean +/- SE; P = 0.03). Exercise training did not change baseline sympathetic traffic (P = 0.31) or sympathetic nerve responses to diastolic pressure reductions (P = 0.12). CONCLUSIONS Exercise training affects vagal and sympathetic mechanisms differently: cardiovagal baroreflex sensitivity is increased, but sympathetic responses to arterial pressure decreases are unchanged.
The use of a molluscicide in conjunction with chemotherapy to control Schistosoma haematobium at the Barombi Lake foci in Cameroon. III. Conclusions and costs.

Although Frescon successfully controlled snails on the margins of the Barombi lakes, and although the continuation of niridazole and Frescon control reduced transmission of S. haematobium very considerably, practical difficulties, which are discussed, rendered the twin goals of snail- and parasite-eradication impossible to achieve. The "break-point" in transmission of S. haematobium appears to lie so low as to be practically synonymous with total eradication. Control operations would thus have had to be maintained indefinitely in order to avoid a rapid return to the pre-control situation. The cost of the control element in this combined chemotherapeutic and molluscicidal research project, at 2 lacustrine foci of S. haematobium transmission in the United Republic of Cameroon, was 9 to 10 U.S. dollars per year per head of population protected. This sum is about three times the country's total estimated expenditure per head of population on all health and social services for the year 1974-1975. The high cost of such operations is only likely to be acceptable where schistosomiasis causes much ill-health and reduced economic productivity, and where tangible benefits may be expected from a reduction in the intensity of infections, short of eradication.
Ly-6A.2 Expression Regulates Antigen-Specific CD4+ T Cell Proliferation and Cytokine Production1

Ly-6 proteins appear to serve cell adhesion and cell signaling function, but the precise role of Ly-6A.2 in CD4+ T lymphocytes is still unclear. Overexpression of Ly-6A.2 in T lymphocytes has allowed us to analyze the influence of elevated Ly-6A.2 expression on T cell function. In this study we report reduced proliferation of CD4+ T cells overexpressing Ly-6A.2 in response to a peptide Ag. Moreover, the Ly-6A.2-overexpressing CD4+ cells generated elevated levels of IL-4, a key factor that propels the differentiation of naive CD4+ T cells into Th2 subset. The hyporesponsiveness of Ly-6A.2 transgenic CD4+ T cells is dependent on the interaction of Ly-6A.2 T cells with the APCs and can be reversed by blocking the interaction between Ly-6A.2 and a recently reported candidate ligand. Overexpression of Ly-6A.2 in CD4+ T cells reduced their Ca2+ responses to TCR stimulation, therefore suggesting effects of Ly-6A.2 signaling on membrane proximal activation events. In contrast to the observed Ag-specific hyporesponsiveness, the Ly-6A.2 transgenic CD4+ T cells produced IL-4 independent of the interactions between Ly-6A.2 and the candidate Ly-6A.2 ligand. Our results suggest that 1) interaction of Ly-6A.2 with a candidate ligand regulates clonal expansion of CD4+ Th cells in response to an Ag (these results also provide further functional evidence for presence of Ly-6A.2 ligand on APC); and 2) Ly-6A.2 expression on CD4+ T cells promotes production of IL-4, a Th2 differentiation factor.
Can 111In-RGD2 Monitor Response to Therapy in Head and Neck Tumor Xenografts?

RGD (arginylglycylaspartic acid)–based imaging tracers allow specific imaging of integrin αvβ3 expression, proteins overexpressed during angiogenesis; however, few studies have investigated the potential of these tracers to monitor responses of antiangiogenic or radiation therapy. In the studies presented here, 111In-RGD2 was assessed for its potential as an imaging tool to monitor such responses to therapies. Methods: DOTA-E-[c(RGDfK)]2 was radiolabeled with 111In (111In-RGD2), and biodistribution studies were performed in mice with subcutaneous FaDu or SK-RC-52 xenografts after treatment with either antiangiogenic therapy (bevacizumab or sorafenib) or tumor irradiation (10 Gy). Micro-SPECT imaging studies and subsequent quantitative analysis were also performed. The effect of bevacizumab, sorafenib, or radiation therapy on tumor growth was determined. Results: The uptake of 111In-RGD2 in tumors, as determined from biodistribution studies, correlated well with that quantified from micro-SPECT images, and both showed that 15 d after irradiation 111In-RGD2 uptake was enhanced. Specific or nonspecific uptake of 111In-RGD2 in FaDu or SK-RC-52 xenografts was not affected after antiangiogenic therapy, except in head and neck squamous cell carcinoma 19 d after the start of sorafenib therapy (P < 0.05). The uptake of 111In-RGD2 followed tumor volume in studies featuring antiangiogenic therapy. However, the uptake of 111In-RGD2 in FaDu xenografts was decreased as early as 4 h after tumor irradiation, despite nonspecific uptake remaining unaltered. Tumor growth was inhibited after antiangiogenic or radiation therapy. Conclusion: Here, it is suggested that 111In-RGD2 could allow in vivo monitoring of angiogenic responses after radiotherapy and may therefore prove a good clinical tool to monitor angiogenic responses early after the start of radiotherapy in patients with head and neck squamous cell carcinoma. Despite clear antitumor efficacy, antiangiogenic therapy did not alter tumor uptake of 111In-RGD2, indicating that integrin expression was not altered.
Serum Nogo-A levels are not elevated in amyotrophic lateral sclerosis patients

Improved biomarkers would facilitate the diagnosis and treatment of amyotrophic lateral sclerosis (ALS). Muscle content of the neuritic outgrowth inhibitor Nogo-A is increased in patients with ALS and other denervating conditions. Seeking a less invasive diagnostic method, we sought to determine whether or not Nogo increases in the serum of ALS patients. We developed a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) protocol to screen serum samples from 172 ALS patients and 172 healthy controls for Nogo-A immunoreactivity. Unexpectedly, there was a trend toward decreased levels of serum Nogo-A in ALS. Mean serum Nogo-A level in ALS patients was 0.71 nM (95% confidence interval (CI) 0.42–1.00), as opposed to 1.15 nM (95% CI 0.72–1.59) in healthy controls. A significantly larger percentage of healthy control sera (11.0% vs 4.7%) displayed markedly elevated levels of Nogo-A. Additional study is required to determine the factors that lead to elevated Nogo-A levels in a subset of both ALS patients and healthy controls.
Asynchronous inputs and NMDA conductances predict excitatory responses in the cortical-CA1 pathway of the hippocampus

In the hippocampus, CA1 place cells are driven by a substantial input from CA3. There is a second pathway to CA1 from the entorhinal cortex. The mode of action of cortex on CA1 through this pathway is not known. The pathway supports CA1 place field activity after CA3 has been lesioned, yet stimulation of the pathway in rat slices results in strong feedforward inhibition that prevents pyramidal cell action potentials. We use a detailed conductance-based model of this pathway to simulate the response to cortical stimulation in slice experiments and in vivo spatial exploration. We find that the presence of NMDA conductances enable CA1 pyramidal cells to integrate cortical inputs over a time scale longer than that which is effective in recruiting the inhibitory response that can suppress action potentials. We then show that this asynchronous response mode supports place field formation in response to experimentally constrained spatially modulated cortical activity. Within this model, the inclusion of GABAB conductances and the hyperpolarisation activated current Ih reduces the strength of the GABAA inputs required to balance the excitatory inputs, and this facilitates place field formation by reducing variability in the inhibitory inputs.
PENGARUH OPINION SHOPPING, DISCLOSURE DAN REPUTASI KAP PADA OPINI AUDIT GOING CONCERN

Auditors have a responsibility to give due consideration to the company's survival. The phenomenon occurs when the liquidation of some companies that obtain an unqualified opinion but went bankrupt the following year. This can happen because the manipulation of accounting in an entity which lead to errors giving opinions by the auditor to companies experiencing financial distress. The purpose of this study is to determine the influence of opinion shopping, disclosure and reputation of KAP on going concern audit opinion in Indonesia Stock Exchange period 2011-2015. The method used in this research is non probability sampling with purposive sampling technique. Data obtained from the research method is 115 companies. Data analysis technique used is the logistic regression analysis. The analysis finds that the opinion shopping, disclosure and reputation of KAP has effect going concern audit opinion.