Miracle-dz/UniFAR-FTUs huggingface dataset:
Intestinal microbiota in inflammation and insulin resistance: relevance to humans

Purpose of reviewThe gut microbiota is a very complex ecosystem which interacts extensively with the host, influencing multiple metabolic and physiological functions. Several diseases have been shown to be associated with specific alterations in gut microbiota. It is more and more underscored as playing a major role in the development of insulin resistance and inflammation associated with excess weight gain. Recent findingsRecent studies in obese patients have shown perturbations in gut microbiota with a weight gain-associated increase in the Firmicutes/Bacteroidetes ratio ameliorated by various attempts at inducing weight loss. SummaryIntestinal microbiota may contribute to the development of inflammation and insulin resistance by two main mechanisms. First, gut microbiota might facilitate energy harvest from the gut leading via perturbation in energy homeostasis to fat deposition and increased adipokine production and plasma free fatty acid levels both contributing to insulin resistance and inflammation. Alternatively, it can initiate an inflammatory process either originating from the intestine or generated at the peripheral level via endotoxin leakage into the blood from the intestine, both leading secondarily to insulin resistance.
Natural Killer p46 Controls Hepatitis B Virus Replication and Modulates Liver Inflammation

Natural killer (NK) cells play an important role in hepatitis B virus (HBV) infection control, and are regulated by a complex network of activating and inhibitory receptors. However, NK cell activity in HBV patients remains poorly understood. The objective of this study was to investigate the phenotypic and functional characteristics of circulating NK cells in patients during different chronic hepatitis B (CHB) infection stages. We investigated NK cell phenotypes, receptor expression and function in 86 CHB patients and 20 healthy controls. NK cells were purified and NK cell subsets were characterized by flow cytometry. Cytotoxic activity (CD107a) and interferon-gamma (IFN-γ) secretion were examined, and Natural Killer p46 (NKP46) blockade and spontaneous NK cell cytolytic activity against K562, HepG2 and HepG2.215 cell lines was studied. Activating NKp46 receptor expression was higher in inactive HBsAg carriers when compared with other groups (p = 0.008). NKp46 expression negatively correlated with HBV DNA (R = -0.253, p = 0.049) and ALT (R = -0.256, p = 0.045) levels. CD107a was higher in immune-activated groups when compared with immune-tolerant groups (p = 0.039). CD107a expression was related to viral load (p = 0.02) and HBeAg status (p = 0.024). In vitro NKp46 blockade reduced NK cell cytolytic activity against HepG2 and HepG2.215 cell lines (p = 0.02; p = 0.039). Furthermore, NK cells from high viral load CHB patients displayed significantly lower specific cytolytic activity against anti-NKp46-loaded K562 targets (p = 0.0321). No significant differences were observed in IFN-γ secretion (p > 0.05). In conclusion, NKp46 expression regulates NK cell cytolytic function. NKp46 may moderate NK cell activity during HBV replication suppression and HBV-associated liver damage and may be critical for NK cell activity during CHB infection.
Recruitment of genes and enzymes conferring resistance to the nonnatural toxin bromoacetate

Microbial niches contain toxic chemicals capable of forcing organisms into periods of intense natural selection to afford survival. Elucidating the mechanisms by which microbes evade environmental threats has direct relevance for understanding and combating the rise of antibiotic resistance. In this study we used a toxic small-molecule, bromoacetate, to model the selective pressures imposed by antibiotics and anthropogenic toxins. We report the results of genetic selection experiments that identify nine genes from Escherichia coli whose overexpression affords survival in the presence of a normally lethal concentration of bromoacetate. Eight of these genes encode putative transporters or transmembrane proteins, while one encodes the essential peptidoglycan biosynthetic enzyme, UDP-N-acetylglucosamine enolpyruvoyl transferase (MurA). Biochemical studies demonstrate that the primary physiological target of bromoacetate is MurA, which becomes irreversibly inactivated via alkylation of a critical active-site cysteine. We also screened a comprehensive library of E. coli single-gene deletion mutants and identified 63 strains displaying increased susceptibility to bromoacetate. One hypersensitive bacterium lacks yliJ, a gene encoding a predicted glutathione transferase. Herein, YliJ is shown to catalyze the glutathione-dependent dehalogenation of bromoacetate with a kcat/Km value of 5.4 × 103 M-1 s-1. YliJ displays exceptional substrate specificity and produces a rate enhancement exceeding 5 orders of magnitude, remarkable characteristics for reactivity with a nonnatural molecule. This study illustrates the wealth of intrinsic survival mechanisms that can be exploited by bacteria when they are challenged with toxins.
Association Between Chronic Pain and Leisure Time Physical Activity and Sedentary Behavior in Schoolteachers

ABSTRACT Chronic pain (CP) is a public health problem with harmful social and individual effects, and its relationships with physical activity (PA) and sedentary behaviors are unclear. This study examined the relationship between CP and PA and time spent watching television as an indicator of leisure time sedentary behavior, and explored the effects of major confounding factors. The information was obtained between 2012 and 2013 from individual interviews with 943 teachers from public schools in Londrina, Brazil. Statistical analysis was performed in 2014 using a logistic regression model adjusted for sociodemographic, lifestyle, depression, and working conditions variables. The prevalence of CP was 31.9%. No statistically significant association was observed between PA and CP. In the adjusted analyses, CP was associated with time > 60 minutes/day spent watching television (odds ratio [OR] = 1.39, 95% confidence interval [CI] 1.03, 1.89) on weekdays. In analyses stratified according to body areas affected by CP, only pain in the lower limbs was associated with more time watching television (OR = 1.62, 95% CI 1.06, 2.47). Watching television on a weekday for > 60 minutes is a sedentary behavior associated with a greater likelihood of teachers having chronic pain, especially in the lower limbs. This association was observed independently of the main confounders such as sex, age, leisure time physical activity, depression and working conditions.
Modelling the Wind-Borne Spread of Highly Pathogenic Avian Influenza Virus between Farms

A quantitative understanding of the spread of contaminated farm dust between locations is a prerequisite for obtaining much-needed insight into one of the possible mechanisms of disease spread between farms. Here, we develop a model to calculate the quantity of contaminated farm-dust particles deposited at various locations downwind of a source farm and apply the model to assess the possible contribution of the wind-borne route to the transmission of Highly Pathogenic Avian Influenza virus (HPAI) during the 2003 epidemic in the Netherlands. The model is obtained from a Gaussian Plume Model by incorporating the dust deposition process, pathogen decay, and a model for the infection process on exposed farms. Using poultry- and avian influenza-specific parameter values we calculate the distance-dependent probability of between-farm transmission by this route. A comparison between the transmission risk pattern predicted by the model and the pattern observed during the 2003 epidemic reveals that the wind-borne route alone is insufficient to explain the observations although it could contribute substantially to the spread over short distance ranges, for example, explaining 24% of the transmission over distances up to 25 km.
Best-First Fixed-Depth Game-Tree Search in Practice

We present a new paradigm for minimax search algorithms: MT, a memory-enhanced version of Pearl's Test procedure. By changing the way MT is called, a number of practical best-first search algorithms can be simply constructed. Reformulating SSS* as an instance of MT eliminates all its perceived implementation drawbacks. Most assessments of minimax search performance are based on simulations that do not address two key ingredients of high performance game-playing programs: iterative deepening and memory usage. Instead, we use experimental data gathered from tournament checkers, Othello and chess programs. The use of iterative deepening and memory makes our results differ significantly from the literature. One new instance of our framework, MTD(I), out-performs our best Alpha-Beta searcher on leaf nodes, total nodes and execution time. To our knowledge, these are the first reported results that compare both depth-first and best-first algorithms given the same amount of memory.
Luteinizing hormone on Leydig cell structure and function.

The effects of luteinizing hormone (LH) and human chorionic gonadotrophic hormone (hCG) on Leydig cell structure and function are reviewed in this paper under two main headings; responses to LH and hCG stimulation and responses to LH deprivation. With acute LH stimulation, up to 2 hours following the LH injection, there was no change in the volume of a Leydig cell. However, Leydig cell peroxisomal volume and intraperoxisomal SCP2 content showed a rapid and transient change. These changes can be considered to be specific because: i) no other Leydig cell organelle including smooth endoplasmic reticulum (SER) showed such a change, and ii) only the intraperoxisomal SCP2 but not catalase (a marker enzyme for peroxisomes) showed such a change within 30 minutes of LH stimulation. As these changes occurred prior to the peak testosterone levels following this treatment, it is suggested that SCP2 and peroxisomes may have an association with testosterone biosynthesis prior to cholesterol transport into mitochondria. With LH or hCG stimulation for longer periods, i.e. one day or more, the same morphological changes are produced in Leydig cells irrespective of the age of the species, dosage of LH or hCG, and with single or multiple doses. These changes include, Leydig cells hypertrophy and/or hyperplasia, increase in the cellular organelle content (mostly SER and mitochondria) and depletion of lipid droplets. In addition, a recent study showed that Leydig cell peroxisomal volume, SCP2 content, the amount of intraperoxisomal SCP2 and testosterone secretory capacity were also significantly increased in response to chronic LH treatment. The effects of LH deprivation by whatever means (e.g. hypophysectomy, with testosterone and 17 beta-estradiol silastic implants, LH antisera) on Leydig cell structure and function is generally described as opposite to those observed following LH or hCG stimulation. These include Leydig cell hypotrophy and hypoplasia, reductions in the cytoplasmic organelle content in general and specific reductions in SER and peroxisomal volumes, reductions in total catalase and SCP2 in Leydig cells together with reductions in the intraperoxisomal SCP2 content in Leydig cells and their testosterone secretory capacity.
Rise and fall of the X-ray flash 080330: An off-axis jet?

Context. X-ray flashes (XRFs) are a class of gamma-ray bursts (GRBs) with a peak energy of the time-integrated νFν spectrum, Ep, typically below 30 keV, whereas classical GRBs have Ep of a few hundreds of keV. Apart from Ep and the systematically lower luminosity, the properties of XRFs, such as their duration or spectral indices, are typical of the classical GRBs. Yet, the nature of XRFs and their differences from GRBs are not understood. In addition, there is no consensus on the interpretation of the shallow decay phase observed in most X-ray afterglows of both XRFs and GRBs. Aims. We examine in detail the case of XRF 080330 discovered by Swift at redshift 1.51. This burst is representative of the XRF class and exhibits an X-ray shallow decay. The rich broadband (from NIR to UV) photometric data set we collected during this phase makes it an ideal candidate for testing the off-axis jet interpretation proposed to explain both the softness of XRFs and the shallow decay phase. Methods. We present prompt γ-ray, early and late NIR/visible/UV and X-ray observations of the XRF 080330. We derive a spectral energy distribution from NIR to X-ray bands across the shallow/plateau phase and describe the temporal evolution of the multiwavelength afterglow within the context of the standard afterglow model. Results. The multiwavelength evolution of the afterglow is achromatic from ∼10 2 st o∼8 × 10 4 s. The energy spectrum from NIR to X-ray is reproduced well by a simple power-law, Fν ∝ ν −βox , with βox = 0.79 ± 0.01 and negligible rest-frame dust extinction. The light curve can be modelled by either a piecewise power-law or the combination of a smoothly broken power law with an initial rise up to ∼600 s, a plateau lasting up to ∼2 ks, followed by a gradual steepening to a power-law decay index of ∼2 until 82 ks. At this point, a bump appears to be modelled well with a second component, while the corresponding optical energy spectrum, Fν ∝ ν −βo , reddens by Δβo = 0.26 ± 0.06. Conclusions. A single-component jet viewed off-axis can explain the light curve of XRF 080330, the late-time reddening being due to the reverse shock of an energy injection episode and its being an XRF. Other possibilities, such as the optical rise marking the pre-deceleration of the fireball within a wind environment, cannot be excluded definitely, but appear to be contrived. We exclude the possibility of a dust decreasing column density being swept up by the fireball as explaining the rise of the afterglow.
Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non–small cell lung cancer cells (H1299)

We compared the effects of monotherapy (photodynamic therapy or chemotherapy) versus combination therapy (photodynamic therapy plus a specific drug) on the non–small cell lung cancer cell line H1299. Our aim was to evaluate whether the additive/synergistic effects of combination treatment were such that the cytostatic dose could be reduced without affecting treatment efficacy. Photodynamic therapy was done by irradiating Photofrin-preloaded H1299 p53/p16-null cells with a halogen lamp equipped with a bandpass filter. The cytotoxic drugs used were cis-diammine-dichloroplatinum [II] (CDDP or cisplatin) and 2′,2′-difluoro-2′-deoxycytidine (gemcitabine). Various treatment combinations yielded therapeutic effects (trypan blue dye exclusion test) ranging from additive to clearly synergistic, the most effective being a combination of photodynamic therapy and CDDP. To gain insight into the cellular response mechanisms underlying favorable outcomes, we analyzed the H1299 cell cycle profiles and the expression patterns of several key proteins after monotherapy. In our conditions, we found that photodynamic therapy with Photofrin targeted G0-G1 cells, thereby causing cells to accumulate in S phase. In contrast, low-dose CDDP killed cells in S phase, thereby causing an accumulation of G0-G1 cells (and increased p21 expression). Like photodynamic therapy, low-dose gemcitabine targeted G0-G1 cells, which caused a massive accumulation of cells in S phase (and increased cyclin A expression). Although we observed therapeutic reinforcement with both drugs and photodynamic therapy, reinforcement was more pronounced when the drug (CDDP) and photodynamic therapy exert disjointed phase-related cytotoxic activity. Thus, if photodynamic therapy is appropriately tuned, the dose of the cytostatic drug can be reduced without compromising the therapeutic response. [Mol Cancer Ther 2006;5(3):776–85]
Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6

ABSTRACT Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6. Summary: The spinocerebellar ataxia type 6 (SCA6) protein, α1ACT, causes polyglutamine length-dependent toxicity and aggregation in new Drosophila transgenic lines, opening the door for additional studies of this disease.
Polymorphism and Structural Maturation of Bunyamwera Virus in Golgi and Post-Golgi Compartments

ABSTRACT The Golgi apparatus is the assembly site for a number of complex enveloped viruses. Using high-preservation methods for electron microscopy, we have detected two previously unknown maturation steps in the morphogenesis of Bunyamwera virus in BHK-21 cells. The first maturation takes place inside the Golgi stack, where annular immature particles transform into dense, compact structures. Megalomicin, a drug that disrupts the trans side of the Golgi complex, reversibly blocks transformation, showing that a functional trans-Golgi is needed for maturation. The second structural change seems to take place during the egress of viral particles from cells, when a coat of round-shaped spikes becomes evident. A fourth viral assembly was detected in infected cells: rigid tubular structures assemble in the Golgi region early in infection and frequently connect with mitochondria. In Vero cells, the virus induces an early and spectacular fragmentation of intracellular membranes while productive infection progresses. Assembly occurs in fragmented Golgi stacks and generates tubular structures, as well as the three spherical viral forms. These results, together with our previous studies with nonrelated viruses, show that the Golgi complex contains key factors for the structural transformation of a number of enveloped viruses that assemble intracellularly.
Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

Background The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro. Methodology/Principal Findings Human umbilical vein endothelial cells (HUVECs) were treated with insulin in presence of glucose 30 mM (HG) and glucosamine 10 mM (Gluc-N) with or without sildenafil. Insulin increased the expression of PDE5 and eNOS mRNA assayed by Real time-PCR. Cytofluorimetric analysis showed that sildenafil significantly increased NO production in basal condition. This effect was partially inhibited by the PI3K inhibitor LY 294002 and completely inhibited by the NOS inhibitor L-NAME. Akt-1 and eNOS activation was reduced in conditions mimicking insulin resistance and completely restored by sildenafil treatment. Conversely sildenafil treatment can counteract this noxious effect by increasing NO production through eNOS activation and reducing oxidative stress induced by hyperglycaemia and glucosamine. Conclusions/Significance These data indicate that sildenafil might improve NOS activity of endothelial cells in insulin resistance conditions and suggest the potential therapeutic use of sildenafil for improving vascular function in diabetic patients.
The fate of bacterial carbon in an intertidal sediment: Modeling an in situ isotope tracer experiment

We report the results of an integrated modeling and in situ isotope tracer experiment study examining the fate of bacterial carbon in an intertidal sediment. 13C‐glucose was injected into the upper 10 cm of an intertidal sediment, which successfully tagged the bacterial community as evidenced by 13C enrichment of bacterial specific polar‐lipid‐derived fatty acids. Over a period of 4.5 months, 13C enrichment was monitored in sediment organic carbon, bacteria, meiobenthos, macrobenthos, and dissolved inorganic carbon. A mechanistic model accurately simulated label transfer among the biotic and abiotic compartments and was used to derive bacterial production and the loss processes grazing, mortality, respiration, and exchange. Bacterial production averaged 67 mmol C m‐2 d‐1, of which 8% was lost from the sediment by exchange processes, 3% was grazed by meiobenthos and 24% by macrobenthos. The primary fate of bacterial production was mortality (65%) and the released bacterial carbon was recycled back to dissolved organic carbon, resulting in recycling of carbon within the dissolved organic carbon‐bacteria loop. Bacterial respiration was the main loss process from this loop. Although a significant fraction of bacterial carbon production was grazed, our results show that bacterial carbon is primarily a sink of organic carbon in the food web of intertidal sediments.
Training Data Enrichment for Infrequent Discourse Relations

Discourse parsing is a popular technique widely used in text understanding, sentiment analysis and other NLP tasks. However, for most discourse parsers, the performance varies significantly across different discourse relations. In this paper, we first validate the underfitting hypothesis, i.e., the less frequent a relation is in the training data, the poorer the performance on that relation. We then explore how to increase the number of positive training instances, without resorting to manually creating additional labeled data. We propose a training data enrichment framework that relies on co-training of two different discourse parsers on unlabeled documents. Importantly, we show that co-training alone is not sufficient. The framework requires a filtering step to ensure that only “good quality” unlabeled documents can be used for enrichment and re-training. We propose and evaluate two ways to perform the filtering. The first is to use an agreement score between the two parsers. The second is to use only the confidence score of the faster parser. Our empirical results show that agreement score can help to boost the performance on infrequent relations, and that the confidence score is a viable approximation of the agreement score for infrequent relations.