Miracle-dz/UniFAR-FTUs huggingface dataset:
Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

Significance Hyperuricemia is a metabolic condition intrinsic to gout pathogenesis but also associated with other common metabolic inflammatory diseases. The soluble uric acid-induced priming of monocytes determines a unique shift in cytokine production consisting of high interleukin (IL)-1β but low IL-1 receptor antagonist (IL-1Ra). We investigated metabolic sensors and scanned for transcriptomic pathways and kinase activation to provide mechanistic leads for this process. We describe that uric acid suppresses autophagy and diminishes the antiinflammatory capacity of the cell. The consequences of uric acid exposure are broad and can impact a larger spectrum of inflammatory diseases from gout to metabolic, renal, or cardiovascular diseases or cancer. Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFP–overexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt–PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.
Chronic Stress Induces a Hyporeactivity of the Autonomic Nervous System in Response to Acute Mental Stressor and Impairs Cognitive Performance in Business Executives

The present study examined the incidence of chronic stress in business executives (109 subjects: 75 male and 34 female) and its relationship with cortisol levels, cognitive performance, and autonomic nervous system (ANS) reactivity after an acute mental stressor. Blood samples were collected from the subjects to measure cortisol concentration. After the sample collection, the subjects completed the Lipp Inventory of Stress Symptoms for Adults and the Stroop Color-Word Test to evaluate stress and cognitive performance levels, respectively. Saliva samples were collected prior to, immediately after, and five minutes after the test. The results revealed that 90.1% of the stressed subjects experienced stress phases that are considered chronic stress. At rest, the subjects with chronic stress showed higher cortisol levels, and no gender differences were observed. No differences were found between the stressed and non-stressed subjects regarding salivary amylase activity prior to test. Chronic stress also impaired performance on the Stroop test, which revealed higher rates of error and longer reaction times in the incongruent stimulus task independently of gender. For the congruent stimulus task of the Stroop test, the stressed males presented a higher rate of errors than the non-stressed males and a longer reaction time than the stressed females. After the acute mental stressor, the non-stressed male group showed an increase in salivary alpha-amylase activity, which returned to the initial values five minutes after the test; this ANS reactivity was not observed in the chronically stressed male subjects. The ANS responses of the non-stressed vs stressed female groups were not different prior to or after the Stroop test. This study is the first to demonstrate a blunted reactivity of the ANS when male subjects with chronic psychological stress were subjected to an acute mental stressor, and this change could contribute to impairments in cognitive performance.
Relationships among Parvalbumin-Immunoreactive Neuron Density, Phase-Locked Gamma Oscillations, and Autistic/Schizophrenic Symptoms in PDGFR-β Knock-Out and Control Mice

Cognitive deficits and negative symptoms are important therapeutic targets for schizophrenia and autism disorders. Although reduction of phase-locked gamma oscillation has been suggested to be a result of reduced parvalbumin-immunoreactive (putatively, GABAergic) neurons, no direct correlations between these have been established in these disorders. In the present study, we investigated such relationships during pharmacological treatment with a newly synthesized drug, T-817MA, which displays neuroprotective and neurotrophic effects. In this study, we used platelet-derived growth factor receptor-β gene knockout (PDGFR-β KO) mice as an animal model of schizophrenia and autism. These mutant mice display a reduction in social behaviors; deficits in prepulse inhibition (PPI); reduced levels of parvalbumin-immunoreactive neurons in the medical prefrontal cortex, hippocampus, amygdala, and superior colliculus; and a deficit in of auditory phase-locked gamma oscillations. We found that oral administration of T-817MA ameliorated all these symptoms in the PDGFR-β KO mice. Furthermore, phase-locked gamma oscillations were significantly correlated with the density of parvalbumin-immunoreactive neurons, which was, in turn, correlated with PPI and behavioral parameters. These findings suggest that recovery of parvalbumin-immunoreactive neurons by pharmacological intervention relieved the reduction of phase-locked gamma oscillations and, consequently, ameliorated PPI and social behavioral deficits. Thus, our findings suggest that phase-locked gamma oscillations could be a useful physiological biomarker for abnormality of parvalbumin-immunoreactive neurons that may induce cognitive deficits and negative symptoms of schizophrenia and autism, as well as of effective pharmacological interventions in both humans and experimental animals.
Landscape-Level Variation in Disease Susceptibility Related to Shallow-Water Hypoxia

Diel-cycling hypoxia is widespread in shallow portions of estuaries and lagoons, especially in systems with high nutrient loads resulting from human activities. Far less is known about the effects of this form of hypoxia than deeper-water seasonal or persistent low dissolved oxygen. We examined field patterns of diel-cycling hypoxia and used field and laboratory experiments to test its effects on acquisition and progression of Perkinsus marinus infections in the eastern oyster, Crassostrea virginica, as well as on oyster growth and filtration. P. marinus infections cause the disease known as Dermo, have been responsible for declines in oyster populations, and have limited success of oyster restoration efforts. The severity of diel-cycling hypoxia varied among shallow monitored sites in Chesapeake Bay, and average daily minimum dissolved oxygen was positively correlated with average daily minimum pH. In both field and laboratory experiments, diel-cycling hypoxia increased acquisition and progression of infections, with stronger results found for younger (1-year-old) than older (2-3-year-old) oysters, and more pronounced effects on both infections and growth found in the field than in the laboratory. Filtration by oysters was reduced during brief periods of exposure to severe hypoxia. This should have reduced exposure to waterborne P. marinus, and contributed to the negative relationship found between hypoxia frequency and oyster growth. Negative effects of hypoxia on the host immune response is, therefore, the likely mechanism leading to elevated infections in oysters exposed to hypoxia relative to control treatments. Because there is considerable spatial variation in the frequency and severity of hypoxia, diel-cycling hypoxia may contribute to landscape-level spatial variation in disease dynamics within and among estuarine systems.
A Rhizosphere-Associated Symbiont, Photobacterium spp. Strain MELD1, and Its Targeted Synergistic Activity for Phytoprotection against Mercury

Though heavy metal such as mercury is toxic to plants and microorganisms, the synergistic activity between them may offer benefit for surviving. In this study, a mercury-reducing bacterium, Photobacterium spp. strain MELD1, with an MIC of 33 mg . kg-1 mercury was isolated from a severely mercury and dioxin contaminated rhizosphere soil of reed (Phragmites australis). While the whole genome sequencing of MELD1 confirmed the presence of a mer operon, the mercury reductase MerA gene showed 99% sequence identity to Vibrio shilloni AK1 and implicates its route resulted from the event of horizontal gene transfer. The efficiency of MELD1 to vaporize mercury (25 mg . kg-1, 24 h) and its tolerance to toxic metals and xenobiotics such as lead, cadmium, pentachlorophenol, pentachloroethylene, 3-chlorobenzoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin is promising. Combination of a long yard bean (Vigna unguiculata ssp. Sesquipedalis) and strain MELD1 proved beneficial in the phytoprotection of mercury in vivo. The effect of mercury (Hg) on growth, distribution and tolerance was examined in root, shoot, leaves and pod of yard long bean with and without the inoculation of strain MELD1. The model plant inoculated with MELD1 had significant increases in biomass, root length, seed number, and increased mercury uptake limited to roots. Biolog plate assay were used to assess the sole-carbon source utilization pattern of the isolate and Indole-3-acetic acid (IAA) productivity was analyzed to examine if the strain could contribute to plant growth. The results of this study suggest that, as a rhizosphere-associated symbiont, the synergistic activity between the plant and MELD1 can improve the efficiency for phytoprotection, phytostabilization and phytoremediation of mercury.
Local and Global Limits on Visual Processing in Schizophrenia

Schizophrenia has been linked to impaired performance on a range of visual processing tasks (e.g. detection of coherent motion and contour detection). It has been proposed that this is due to a general inability to integrate visual information at a global level. To test this theory, we assessed the performance of people with schizophrenia on a battery of tasks designed to probe voluntary averaging in different visual domains. Twenty-three outpatients with schizophrenia (mean age: 40±8 years; 3 female) and 20 age-matched control participants (mean age 39±9 years; 3 female) performed a motion coherence task and three equivalent noise (averaging) tasks, the latter allowing independent quantification of local and global limits on visual processing of motion, orientation and size. All performance measures were indistinguishable between the two groups (ps>0.05, one-way ANCOVAs), with one exception: participants with schizophrenia pooled fewer estimates of local orientation than controls when estimating average orientation (p = 0.01, one-way ANCOVA). These data do not support the notion of a generalised visual integration deficit in schizophrenia. Instead, they suggest that distinct visual dimensions are differentially affected in schizophrenia, with a specific impairment in the integration of visual orientation information.
Atypical interactions of integrin αVβ8 with pro-TGF-β1

Significance Integrins are cell-surface molecules that link extracellular ligands to the cytoskeleton. Force exerted by the cytoskeleton that is resisted by the ligand is thought to be important in activating the integrin by stabilizing an extended-open conformational state with high affinity for ligand. However, integrin αVβ8 does not interact with the cytoskeleton in the same way. Here, we show that, although the closely related integrins αVβ8 and αVβ6 bind the same ligand, pro-TGF-β1, their conformational responses to ligand binding and regulation by metal ions are quite different. These differences correlate with their distinct linkage to the cytoskeleton. Integrins αVβ6 and αVβ8 are specialized for recognizing pro-TGF-β and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin αVβ8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine αVβ8 for atypical binding to pro-TGF-β1. In contrast to αVβ6, αVβ8 has a constitutive extended-closed conformation, and binding to pro-TGF-β1 does not stabilize the open conformation of its headpiece. Although Mn2+ potently activates other integrins and increases affinity of αVβ6 for pro-TGF-β1 25- to 55-fold, it increases αVβ8 affinity only 2- to 3-fold. This minimal effect correlates with the inability of Mn2+ and pro-TGF-β1 to stabilize the open conformation of the αVβ8 headpiece. Moreover, αVβ8 was inhibited by high concentrations of Mn2+ and was stimulated and inhibited at markedly different Ca2+ concentrations than αVβ6. These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate αVβ8 binding to and activation of pro-TGF-β.
The expression of thymic stromal lymphopoietin in patients and animal models with eosinophilic otitis media

Abstract Objective: In the present study, we aimed to clarify the expression of thymic stromal lymphopoietin (TSLP), a key trigger of Th2-type allergic disease, in the middle ear mucosa of eosinophilic otitis media (EOM). Methods: An immunohistological study of TSLP was conducted in patients with EOM and in animal models of EOM constructed by intraperitoneal and intratympanic injection of ovalbumin for 7 and 14 days. In addition, the messenger RNA (mRNA) expression of TSLP in the middle ear mucosa of the animal models was analyzed using real-time PCR, and was compared with that of the control animals. Results: Immunoreactivities for TSLP were observed in the middle ear mucosa around the tympanic ostium of the eustachian tube of patients with EOM. In the animal model, strong immunoreactivity for TSLP was also observed in the eustachian tube epithelium, and mRNA expression of TSLP in the seven-day stimulated animals was significantly higher than that in the controls. Conclusion: The present study indicates that the presence of epithelium-derived TSLP in the eustachian tubes plays an important role in the onset of EOM.
Visualizing Peripheral Nerve Regeneration by Whole Mount Staining

Peripheral nerve trauma triggers a well characterised sequence of events both proximal and distal to the site of injury. Axons distal to the injury degenerate, Schwann cells convert to a repair supportive phenotype and macrophages enter the nerve to clear myelin and axonal debris. Following these events, axons must regrow through the distal part of the nerve, re-innervate and finally are re-myelinated by Schwann cells. For nerve crush injuries (axonotmesis), in which the integrity of the nerve is maintained, repair may be relatively effective whereas for nerve transection (neurotmesis) repair will likely be very poor as few axons may be able to cross between the two parts of the severed nerve, across the newly generated nerve bridge, to enter the distal stump and regenerate. Analysing axon growth and the cell-cell interactions that occur following both nerve crush and cut injuries has largely been carried out by staining sections of nerve tissue, but this has the obvious disadvantage that it is not possible to follow the paths of regenerating axons in three dimensions within the nerve trunk or nerve bridge. To try and solve this problem, we describe the development and use of a novel whole mount staining protocol that allows the analysis of axonal regeneration, Schwann cell-axon interaction and re-vascularisation of the repairing nerve following nerve cut and crush injuries.
Non-animal methods to predict skin sensitization (II): an assessment of defined approaches**

Abstract Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non-animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization.
Optimal resource allocation for wireless video over CDMA networks

We present a multiple-channel video transmission scheme in wireless CDMA networks over multipath fading channels. We map an embedded video bitstream, which is encoded into multiple independently decodable layers by 3D-ESCOT video coding technique, to multiple CDMA channels. One video source layer is transmitted over one CDMA channel. Each video source layer is protected by a product channel code structure. A product channel code is obtained by the combination of a row code based on rate compatible punctured convolutional code (RCPC) with cyclic redundancy check (CRC) error detection and a source-channel column code, i.e., systematic rate-compatible Reed-Solomon (RS) style erasure code. For a given budget on the available bandwidth and total transmit power, the transmitter determines the optimal power allocations and the optimal transmission rates among multiple CDMA channels, as well as the optimal product channel code rate allocation, i.e., the optimal unequal Reed-Solomon code source/parity rate allocations and the optimal RCPC rate protection for each channel. In formulating such an optimization problem, we make use of results on the large-system CDMA performance for various multiuser receivers in multipath fading channels. The channel is modeled as the concatenation of wireless BER channel and a wireline packet erasure channel with a fixed packet loss probability. By solving the optimization problem, we obtain the optimal power level allocation and the optimal transmission rate allocation over multiple CDMA channels. For each CDMA channel, we also employ a fast joint source-channel coding algorithm to obtain the optimal product channel code structure. Simulation results show that the proposed framework allows the video quality to degrade gracefully as the fading worsens or the bandwidth decreases, and it offers improved video quality at the receiver.
A New Method to Quantify and Compare the Multiple Components of Fitness—A Study Case with Kelp Niche Partition by Divergent Microstage Adaptations to Temperature

Point 1 Management of crops, commercialized or protected species, plagues or life-cycle evolution are subjects requiring comparisons among different demographic strategies. The simpler methods fail in relating changes in vital rates with changes in population viability whereas more complex methods lack accuracy by neglecting interactions among vital rates. Point 2 The difference between the fitness (evaluated by the population growth rate λ) of two alternative demographies is decomposed into the contributions of the differences between the pair-wised vital rates and their interactions. This is achieved through a full Taylor expansion (i.e. remainder = 0) of the demographic model. The significance of each term is determined by permutation tests under the null hypothesis that all demographies come from the same pool. Point 3 An example is given with periodic demographic matrices of the microscopic haploid phase of two kelp cryptic species observed to partition their niche occupation along the Chilean coast. The method provided clear and synthetic results showing conditional differentiation of reproduction is an important driver for their differences in fitness along the latitudinal temperature gradient. But it also demonstrated that interactions among vital rates cannot be neglected as they compose a significant part of the differences between demographies. Point 4 This method allows researchers to access the effects of multiple effective changes in a life-cycle from only two experiments. Evolutionists can determine with confidence the effective causes for changes in fitness whereas population managers can determine best strategies from simpler experimental designs.
Prophylactic Use of Macrolide Antibiotics for the Prevention of Chronic Obstructive Pulmonary Disease Exacerbation: A Meta-Analysis

Background Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and mortality. Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties. Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs. Methods We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs. The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year. Results Nine RCTs comprising 1666 patients met the inclusion criteria. Pooled evidence showed macrolides could reduce the frequency of exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56–0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43–0.78, P < 0.01). Subgroup analysis showed only 6–12 months of erythromycin or azithromycin therapy could be effective. Moreover, among studies with 6–12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates. The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups. A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003–2.39, P = 0.049). Conclusions Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD. However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance. A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages.