Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Immunogenicity of Therapeutic DNA Vaccination in Individuals Treated with Antiretroviral Therapy during Acute/Early HIV-1 Infection

Background An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099) Methods Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17–23 weeks after treatment discontinuation. Results Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log10 HIV-1 RNA copies/mL, respectively. Conclusions The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group. Trial Registration Clinicaltrials.gov NCT00125099
Functional Coexpression of the Mitochondrial Alternative Oxidase and Uncoupling Protein Underlies Thermoregulation in the Thermogenic Florets of Skunk Cabbage1[W][OA]

Two distinct mitochondrial energy dissipating systems, alternative oxidase (AOX) and uncoupling protein (UCP), have been implicated as crucial components of thermogenesis in plants and animals, respectively. To further clarify the physiological roles of AOX and UCP during homeothermic heat production in the thermogenic skunk cabbage (Symplocarpus renifolius), we identified the thermogenic cells and performed expression and functional analyses of these genes in this organism. Thermographic analysis combined with in situ hybridization revealed that the putative thermogenic cells surround the stamens in the florets of skunk cabbage and coexpress transcripts for SrAOX, encoding Symplocarpus AOX, and SrUCPb, encoding a novel UCP that lacks a fifth transmembrane segment. Mitochondria isolated from the thermogenic florets exhibited substantial linoleic acid (LA)-inducible uncoupling activities. Moreover, our results demonstrate that LA is capable of inhibiting the mitochondrial AOX pathway, whereas the proportion of pyruvate-stimulated AOX capacity was not significantly affected by LA. Intriguingly, the protein expression levels for SrAOX and SrUCPb were unaffected even when the ambient air temperatures increased from 10.3°C to 23.1°C or from 8.3°C to 24.9°C. Thus, our results suggest that functional coexpression of AOX and UCP underlies the molecular basis of heat production, and that posttranslational modifications of these proteins play a crucial role in regulating homeothermic heat production under conditions of natural ambient temperature fluctuations in skunk cabbage.
The Yellowing of Epoxy Resin Adhesives: Report on High-Intensity Light Aging

Various room-temperature-cure epoxy resin adhesives suitable for use in glass conservation were tested for their tendency to yellow under high-intensity light. The results were extrapolated to representative museum conditions, taking into account both light-and thermal-induced contributions to yellowing. Life expectancy estimates, the length of time for a thin film of epoxy to yellow unacceptably, were obtained for each adhesive. Although the majority of products demonstrated an unacceptable level of stability, a few formulations were identified with less tendency to yellow than others. Recommendations for the use of specific epoxy resin adhesives are given.
Numerical and experimental investigations of effects of residual stresses on crack behavior in Aluminum 6082-T6

In the structural integrity assessment, residual stresses play an important role. The residual stresses affect both the crack driving forces and the crack-tip constraint. To investigate the interaction of residual stresses with mechanical loading during the onset of crack growth in Aluminum 6082-T6, modified single edge-notched bending specimens were used. Aluminum 6082 has the highest strength of the 6000 series alloys with excellent corrosion resistance. A residual stress field was created in the specimens by pre-loading. To accurately quantify the residual stress field created during this test procedure, the strains were measured during loading and unloading and compared with finite element results. After the introduction of the residual stress field, the specimens were tested under three-point bending to determine the load versus displacement behavior and fracture toughness. Also, a post-processor for finite element calculation was developed to enable determination of the J-integral values for the specimens having residual stresses. The constraint parameters Q and R were calculated at the crack-tip to describe the stress field in this region. The parameter Q is used to characterize the loading and geometry constraint, and the parameter R is used for characterizing the crack-tip constraint due to residual stresses. It is observed that tensile residual stresses around the crack-tip increase the crack-tip constraint and decrease the fracture toughness of the bodies. By increasing the external load, the constraint parameter R goes toward zero and the effects of residual stresses on the crack growth resistance become negligible.
Prevalence and properties of mecC methicillin-resistant Staphylococcus aureus (MRSA) in bovine bulk tank milk in Great Britain

Objectives mecC methicillin-resistant Staphylococcus aureus (MRSA) represent a newly recognized form of MRSA, distinguished by the possession of a divergent mecA homologue, mecC. The first isolate to be identified came from bovine milk, but there are few data on the prevalence of mecC MRSA among dairy cattle. The aim of this study was to conduct a prevalence study of mecC MRSA among dairy farms in Great Britain. Methods Test farms were randomly selected by random order generation and bulk tank samples were tested for the presence of mecC MRSA by broth enrichment and plating onto chromogenic agar. All MRSA isolated were screened by PCR for mecA and mecC, and mecC MRSA were further characterized by multilocus sequence typing, spa typing and antimicrobial susceptibility testing. Results mecC MRSA were detected on 10 of 465 dairy farms sampled in England and Wales (prevalence 2.15%, 95% CI 1.17%–3.91%), but not from 625 farms sampled in Scotland (95% CI of prevalence 0%–0.61%). Seven isolates belonged to sequence type (ST) 425, while the other three belonged to clonal complex 130. Resistance to non-β-lactam antibiotics was uncommon. All 10 isolates produced a negative result by slide agglutination for penicillin-binding protein 2a. mecA MRSA ST398 was detected on one farm in England. Conclusions mecC MRSA is widely distributed among dairy farms in Great Britain, but this distribution is not uniform across the whole country. These results provide an important baseline dataset to monitor the epidemiology of this emerging form of MRSA.
Modelling non-stationary gene regulatory processes with a non-homogeneous Bayesian network and the allocation sampler

METHOD The objective of the present article is to propose and evaluate a probabilistic approach based on Bayesian networks for modelling non-homogeneous and non-linear gene regulatory processes. The method is based on a mixture model, using latent variables to assign individual measurements to different classes. The practical inference follows the Bayesian paradigm and samples the network structure, the number of classes and the assignment of latent variables from the posterior distribution with Markov Chain Monte Carlo (MCMC), using the recently proposed allocation sampler as an alternative to RJMCMC. RESULTS We have evaluated the method using three criteria: network reconstruction, statistical significance and biological plausibility. In terms of network reconstruction, we found improved results both for a synthetic network of known structure and for a small real regulatory network derived from the literature. We have assessed the statistical significance of the improvement on gene expression time series for two different systems (viral challenge of macrophages, and circadian rhythms in plants), where the proposed new scheme tends to outperform the classical BGe score. Regarding biological plausibility, we found that the inference results obtained with the proposed method were in excellent agreement with biological findings, predicting dichotomies that one would expect to find in the studied systems. AVAILABILITY Two supplementary papers on theoretical (T) and experi-mental (E) aspects and the datasets used in our study are available from http://www.bioss. ac.uk/associates/marco/supplement/
Neutrophil Paralysis in Plasmodium vivax Malaria

Background The activation of innate immune responses by Plasmodium vivax results in activation of effector cells and an excessive production of pro-inflammatory cytokines that may culminate in deleterious effects. Here, we examined the activation and function of neutrophils during acute episodes of malaria. Materials and Methods Blood samples were collected from P. vivax-infected patients at admission (day 0) and 30–45 days after treatment with chloroquine and primaquine. Expression of activation markers and cytokine levels produced by highly purified monocytes and neutrophils were measured by the Cytometric Bead Assay. Phagocytic activity, superoxide production, chemotaxis and the presence of G protein-coupled receptor (GRK2) were also evaluated in neutrophils from malaria patients. Principal Findings Both monocytes and neutrophils from P. vivax-infected patients were highly activated. While monocytes were found to be the main source of cytokines in response to TLR ligands, neutrophils showed enhanced phagocytic activity and superoxide production. Interestingly, neutrophils from the malaria patients expressed high levels of GRK2, low levels of CXCR2, and displayed impaired chemotaxis towards IL-8 (CXCL8). Conclusion Activated neutrophils from malaria patients are a poor source of pro-inflammatory cytokines and display reduced chemotactic activity, suggesting a possible mechanism for an enhanced susceptibility to secondary bacterial infection during malaria.
ROMK Inhibitor Actions in the Nephron Probed with Diuretics

More than a billion people worldwide are afflicted with essential hypertension and diuretics are usually the first line of treatment. Diuretics acting on specific nephron segments to inhibit Na+ reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K+ complicate their use to achieve target blood pressure. ROMK is an attractive new diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide‐sensitive Na+‐K+‐2Cl− co‐transporter, NKCC2, and the amiloride‐sensitive epithelial Na+ channel, ENaC. ROMK inhibition is also postulated to prevent urinary K+ wasting caused by NKCC2 inhibition. The development of small‐molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how ROMK inhibition alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC, alters fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another inhibitor, termed Compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na+ excretion when combined with HCTZ, amiloride or benzamil but not when co‐administered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, Compound A inhibited the kaliuretic response to NKCC2 inhibition, an effect we attribute to inhibition of ROMK‐mediated K+ secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow‐sensitive BK channels (Slo1/b1). In conclusion, Compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target.
Enteral and parenteral nutrition: evidence-based approach

Nutrition support for patients in hospital has become an essential form of therapy. Total parenteral nutrition (TPN) was the preferred way of giving nutrition to hospital patients for many years but enteral nutrition (EN) is now the preferred route. EN is believed to promote gut function and prevent translocation of intestinal bacteria, thus reducing the incidence of sepsis in critically ill patients. In consequence, the use of TPN has been discouraged as a dangerous form of therapy. Critical review of the data suggests that in the human subject TPN does not cause mucosal atrophy or increase translocation of bacteria through the small intestine. However, overfeeding, which is easy with TPN, can explain the results of studies which have shown that TPN increases sepsis. Furthermore, the risks of TPN-induced complications have been exaggerated. When there is risk of malnutrition and EN is not tolerated, or there is gut failure, TPN is an equally effective and safe alternative.
Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes

The stem cell protein Lin28 functions to inhibit the biogenesis of a group of miRNAs but also stimulates the expression of a subset of mRNAs at the post-transcriptional level, the underlying mechanism of which is not yet understood. Here we report the characterization of the molecular interplay between Lin28 and RNA helicase A (RHA) known to play an important role in remodeling ribonucleoprotein particles during translation. We show that reducing Lin28 expression results in decreased RHA association with polysomes while increasing Lin28 expression leads to elevated RHA association. Further, the carboxyl terminus of Lin28 is necessary for interaction with both the amino and carboxyl termini of RHA. Importantly, a carboxyl terminal deletion mutant of Lin28 that retains RNA-binding activity fails to interact with RHA and exhibits dominant-negative effects on Lin28-dependent stimulation of translation. Taken together, these results lead us to suggest that Lin28 may stimulate translation by actively recruiting RHA to polysomes.
A Cross-Talk between TrkB and Ret Tyrosine Kinases Receptors Mediates Neuroblastoma Cells Differentiation

Understanding the interplay between intracellular signals initiated by multiple receptor tyrosine kinases (RTKs) to give the final cell phenotype is a major pharmacological challenge. Retinoic acid (RA)-treatment of neuroblastoma (NB) cells implicates activation of Ret and TrkB RTKs as critical step to induce cell differentiation. By studying the signaling interplay between TrkB and Ret as paradigmatic example, here we demonstrate the existence of a cross-talk mechanism between the two unrelated receptors that is needed to induce the cell differentiation. Indeed, we show that TrkB receptor promotes Ret phosphorylation by a mechanism that does not require GDNF. This reveals to be a key mechanism, since blocking either TrkB or Ret by small interfering RNA causes a failure in NB biochemical and morphological differentiation. Our results provide the first evidence that a functional transactivation between distinct tyrosine kinases receptors is required for an important physiological process.
Characterization of the Bacillus subtilis thiC operon involved in thiamine biosynthesis

The characterization of a three-gene operon (the thiC operon) at 331 min, which is involved in thiamine biosynthesis in Bacillus subtilis, is described. The first gene in the operon is homologous to transcription activators in the lysR family. The second and third genes (thiK and thiC) have been subcloned and overexpressed in Escherichia coli. ThiK (30 kDa) catalyzes the phosphorylation of 4-methyl-5-(beta-hydroxyethyl)thiazole. ThiC (27 kDa) catalyzes the substitution of the pyrophosphate of 2-methyl-4-amino-5-hydroxymethylpyrimidine pyrophosphate by 4-methyl-5-(beta-hydroxyethyl)thiazole phosphate to yield thiamine phosphate. Transcription of the thiC operon is not regulated by thiamine or 2-methyl-4-amino-5-hydroxymethylpyrimidine and is only slightly repressed by 4-methyl-5-(beta-hydroxyethyl)thiazole.
An online auction framework for dynamic resource provisioning in cloud computing

Auction mechanisms have recently attracted substantial attention as an efficient approach to pricing and resource allocation in cloud computing. This work, to the authors' knowledge, represents the first online combinatorial auction designed in the cloud computing paradigm, which is general and expressive enough to both (a) optimize system efficiency across the temporal domain instead of at an isolated time point, and (b) model dynamic provisioning of heterogeneous Virtual Machine (VM) types in practice. The final result is an online auction framework that is truthful, computationally efficient, and guarantees a competitive ratio ~ e+ 1 over e-1 ~ 3.30 in social welfare in typical scenarios. The framework consists of three main steps: (1) a tailored primal-dual algorithm that decomposes the long-term optimization into a series of independent one-shot optimization problems, with an additive loss of 1 over e-1 in competitive ratio, (2) a randomized auction sub-framework that applies primal-dual optimization for translating a centralized co-operative social welfare approximation algorithm into an auction mechanism, retaining a similar approximation ratio while adding truthfulness, and (3) a primal-dual update plus dual fitting algorithm for approximating the one-shot optimization with a ratio λ close to e. The efficacy of the online auction framework is validated through theoretical analysis and trace-driven simulation studies. We are also in the hope that the framework, as well as its three independent modules, can be instructive in auction design for other related problems.
Quality of life after surgery for rectal cancer: a systematic review of comparisons with the general population

Rectal cancer treatments may impact negatively on patients’ bowel and sexual functions and, in turn, on health-related quality of life. Information on the likely effects of treatment is essential in order to facilitate the care process and the adaptation of patients to their condition. Studies that report on the comparison between rectal cancer patients and the general population are a useful source of this evidence, providing elements to aid in answering questions such as ‘is my life going to be the same as before? ’ In this article, the authors have systematically reviewed articles published in the last 6 years that report on the comparison between rectal patients’ and the general population’s health-related quality of life. Sixteen out of 645 articles were included. The results are summarized and critically discussed.
A Tetrad Analysis of the Basidiomycete Fungus Cryptococcus neoformans

Cryptococcus neoformans is a basidiomycete fungus that is found worldwide and causes disease in humans and animal species. The fungus grows asexually as a budding yeast. Under laboratory conditions it is capable of sexual reproduction between two mating types. After cell fusion a dikaryotic filament develops, at the tip of which a basidium gives rise to four chains of basidiospores. Because the chains each comprise 10–30 spores, rather than single spores, the analysis of individual meiotic events has not been attempted in C. neoformans in the style of tetrad analyses performed in other fungal species. Here, the basidiospores from >100 basidia were micromanipulated and the resultant >2500 progeny analyzed for three genetic markers to understand the sexual process in this fungus, leading to four observations: (i) Marker segregation provides genetic evidence for a single meiotic event within the basidium followed by multiple rounds of mitosis. (ii) Using each basidium as an unordered tetrad, the ADE2 and URA5 genes are linked to their centromeres, consistent with adjacent genomic regions rich in repetitive elements predicted to comprise Cryptococcus centromeres. (iii) Lack of germination of basidiospores is attributed to aneuploidy, rather than dormancy. (iv) Analysis of basidiospores derived from single chains demonstrates that each chain can contain different genotypes. This mechanism of sexual spore production would benefit the species with a high rate of dispersal and at the same time aid in simultaneous dissemination of both mating types to new locations in the environment.
The importance of being apt: metaphor comprehension in Alzheimer's disease

We investigated the effect of aptness in the comprehension of copular metaphors (e.g., Lawyers are sharks) by Alzheimer's Disease (AD) patients. Aptness is the extent to which the vehicle (e.g., shark) captures salient properties of the topic (e.g., lawyers). A group of AD patients provided interpretations for metaphors that varied both in aptness and familiarity. Compared to healthy controls, AD patients produced worse interpretations, but interpretation ability was related to a metaphor's aptness rather than to its familiarity level, and patients with superior abstraction ability produced better interpretations. Therefore, the ability to construct figurative interpretations for metaphors is not always diminished in AD patients nor is it dependent only on the novelty level of the expression. We show that Alzheimer's patients' capacity to build figurative interpretations for metaphors is related to both item variables, such as aptness, and participant variables, such as abstraction ability.
Increased Oxidative Stress and Iron Overload in Jordanian β-Thalassemic Children

β-Thalassemia (β-thal) is associated with abnormal synthesis of hemoglobin (Hb). Repeated blood transfusions in patients with β-thal major (β-TM) leads to an enhanced generation of reactive oxygen species (ROS), and subjects patients to peroxidative injury. We studied the antioxidant status and oxidative damage to children with β-thal in Jordan. Samples from 40 children with β-thal and 40 healthy controls were used. All children were under 13 years of age. Our results showed that plasma thiobarbituric acid reactive substances (TBARS) were elevated in β-thalassemic children compared to controls together with compensatory increase in superoxide dismutase (SOD) activity and decrease in catalase (CAT) activity. Elevated serum ferritin showed positive correlation with elevated liver enzyme levels except gamma glutamyl transferase (GGT), confirming liver involvement due to iron overload. Serum ferritin also showed a positive correlation with elevated TBARS and SOD, suggesting that iron overload is involed in the oxidative stress shown in cells.