Hundreds of clinical studies have demonstrated associations between the human microbiome and disease, yet fundamental questions remain on how we can generalize this knowledge. Results from individual studies can be inconsistent, and comparing published data is further complicated by a lack of standard processing and analysis methods. Here we introduce the MicrobiomeHD database, which includes 28 published case-control gut microbiome studies spanning ten diseases. We perform a cross-disease meta-analysis of these studies using standardized methods. We find consistent patterns characterizing disease-associated microbiome changes. Some diseases are associated with over 50 genera, while most show only 10-15 genus-level changes. Some diseases are marked by the presence of potentially pathogenic microbes, whereas others are characterized by a depletion of health-associated bacteria. Furthermore, we show that about half of genera associated with individual studies are bacteria that respond to more than one disease. Thus, many associations found in case-control studies are likely not disease-specific but rather part of a non-specific, shared response to health and disease.

To compare the clinical outcomes of right hepatectomy for large hepatocellular carcinoma via the anterior and conventional approach.

Lead (Pb) is a well-known neurotoxicant and a risk factor for neurologic disorders. The blood brain barrier (BBB) plays an important role in the maintenance of optimal brain function. BBB is a target of Pb, and studies have shown that Pb induced barrier loss and decreased the expression of tight junction proteins, but the detailed mechanisms are not fully understood. Matrix metalloproteinases (MMPs) are important components of extracellular matrix proteasome and can affect the remodeling and degradation of tight junction (TJ). The role of MMP-2/9 in Pb-induced damage of BBB is not known. In our study, we used an in vitro BBB model by co-culturing human umbilical vascular endothelial cells (ECV304 cells) with rat glioma cells (C6 cells), and detected the expression of related TJ proteins and MMP-2/9. Our results showed that Pb increased the permeability of the in vitro BBB model, and stimulating C6 cells with Pb could decrease the protein level of ZO-1 (zonula occludens-1) and occludin in ECV304 cells. Pb could increase the mRNA and protein level of MMP-2/9 in C6 cells, and inhibition of MMP-2/9 by SB-3CT could partially alleviate Pb-induced down-regulation of TJ proteins in ECV304 cells and Pb-induced barrier damage in the in vitro BBB model. Our research established potential therapeutic targets for modulating and preserving optimal BBB function.

RAC3 coactivator overexpression has been implicated in tumorigenesis, contributing to inhibition of apoptosis and autophagy. Both mechanisms are involved in resistance to treatment with chemotherapeutic agents. The aim of this study was to investigate its role in chemoresistance of colorectal cancer.

Axon regeneration, fundamental to nerve repair, and functional recovery, relies on rapid changes in gene expression attributable to microRNA (miRNA) regulation. MiR-133b has been proved to play an important role in different organ regeneration in zebrafish, but its role in regulating axon regeneration in vivo is still controversial. Here, combining single-cell electroporation with a vector-based miRNA-expression system, we have modulated the expression of miR-133b in Mauthner-cells (M-cells) at the single-cell level in zebrafish. Through in vivo imaging, we show that overexpression of miR-133b inhibits axon regeneration, whereas down-regulation of miR-133b, promotes axon outgrowth. We further show that miR-133b regulates axon regeneration by directly targeting a novel regeneration-associated gene, tppp3, which belongs to Tubulin polymerization-promoting protein family. Gain or loss-of-function of tppp3 experiments indicated that tppp3 was a novel gene that could promote axon regeneration. In addition, we observed a reduction of mitochondrial motility, which have been identified to have a positive correlation with axon regeneration, in miR-133b overexpressed M-cells. Taken together, our work provides a novel way to study the role of miRNAs in individual cell and establishes a critical cell autonomous role of miR-133b in zebrafish M-cell axon regeneration. We propose that up-regulation of the newly founded regeneration-associated gene tppp3 may enhance axonal regeneration.

The medial prefrontal cortex (mPFC) receives dense noradrenergic projections from the locus coeruleus. Adrenergic innervation of mPFC pyramidal neurons plays an essential role in both physiology (control of memory formation, attention, working memory, and cognitive behavior) and pathophysiology (attention deficit hyperactivity disorder, posttraumatic stress disorder, cognitive deterioration after traumatic brain injury, behavioral changes related to addiction, Alzheimer's disease and depression). The aim of this study was to elucidate the mechanism responsible for adrenergic receptor-mediated control of the resting membrane potential in layer V mPFC pyramidal neurons. The membrane potential or holding current of synaptically isolated layer V mPFC pyramidal neurons was recorded in perforated-patch and classical whole-cell configurations in slices from young rats. Application of noradrenaline (NA), a neurotransmitter with affinity for all types of adrenergic receptors, evoked depolarization or inward current in the tested neurons irrespective of whether the recordings were performed in the perforated-patch or classical whole-cell configuration. The effect of noradrenaline depended on β1- and not α1- or α2-adrenergic receptor stimulation. Activation of β1-adrenergic receptors led to an increase in inward Na+ current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which carry a mixed Na+/K+ current. The protein kinase A- and C-, glycogen synthase kinase-3β- and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between β1-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the βγ subunit of G-protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through β1-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the βγ subunit.

The function of the nervous system in complex animals is reflected by the achievement of specific behaviors. For years in Drosophila, both simple and complex behaviors have been studied and their genetic bases have emerged. The neuromuscular junction is maybe one of the prototypal simplest examples. A motor neuron establishes synaptic connections on its muscle cell target and elicits behavior: the muscle contraction. Different muscles in adult fly are related to specific behaviors. For example, the thoracic muscles are associated with flight and the leg muscles are associated with locomotion. However, specific tools are still lacking for the study of cellular physiology in distinct motor neuron subpopulations. Here we decided to use the abdominal muscles and in particular the ventral abdominal muscles (VAMs) in adult Drosophila as new model to link a precise behavior to specific motor neurons. Hence, we developed a new behavioral test based on the folding movement of the adult abdomen. Further, we performed a genetic screen and identify two specific Gal4 lines with restricted expression patterns to the adult motor neurons innervating the VAMs or their precursor cells. Using these genetic tools, we showed that the lack of the VAMs or the loss of the synaptic transmission in their innervating motor neurons lead to a significant impairment of the abdomen folding behavior. Altogether, our results allow establishing a direct link between specific motor neurons and muscles for the realization of particular behavior: the folding behavior of the abdomen in Drosophila.

Electroencephalographic (EEG) recordings are thought to reflect the network-wide operations of canonical neural computations, making them a uniquely insightful measure of brain function. As evidence of these virtues, numerous candidate biomarkers of different psychiatric and neurological diseases have been advanced. Presumably, we would only need to apply powerful machine-learning methods to validate these ideas and provide novel clinical tools. Yet, the reality of this advancement is more complex: the scale of data required for robust and reliable identification of a clinical biomarker transcends the ability of any single laboratory. To surmount this logistical hurdle, collective action and transparent methods are required. Here we introduce the Patient Repository of EEG Data + Computational Tools (PRED+CT: predictsite.com). The ultimate goal of this project is to host a multitude of available tasks, patient datasets, and analytic tools, facilitating large-scale data mining. We hope that successful completion of this aim will lead to the development of novel EEG biomarkers for differentiating populations of neurological and psychiatric disorders.

Background: Smart Aging is a Serious games (SGs) platform in a 3D virtual environment in which users perform a set of screening tests that address various cognitive skills. The tests are structured as 5 tasks of activities of daily life in a familiar environment. The main goal of the present study is to compare a cognitive evaluation made with Smart Aging with those of a classic standardized screening test, the Montreal Cognitive Assessment (MoCA). Methods: One thousand one-hundred thirty-one healthy adults aged between 50 and 80 (M = 64.3 ± 8.3) were enrolled in the study. They received a cognitive evaluation with the MoCA and the Smart Aging platform. Participants were grouped according to their MoCA global and specific cognitive domain (i.e., memory, executive functions, working memory, visual spatial elaboration, language, and orientation) scores and we explored differences among these groups in the Smart Aging indices. Results: One thousand eighty-six older adults (M = 64.0 ± 8.0) successfully completed the study and were stratified according to their MoCA score: Group 1 with MoCA < 27 (n = 360); Group 2 with 27 ≥ MoCA < 29 (n = 453); and Group 3 with MoCA ≥ 29 (n = 273). MoCA groups significantly differed in most of the Smart Aging indices considered, in particular as concerns accuracy (ps < 0.001) and time (ps < 0.001) for completing most of the platform tasks. Group 1 was outperformed by the other two Groups and was slower than them in these tasks, which were those supposed to assess memory and executive functions. In addition, significant differences across groups also emerged when considering the single cognitive domains of the MoCA and the corresponding performances in each Smart Aging task. In particular, this platform seems to be a good proxy for assessing memory, executive functions, working memory, and visual spatial processes. Conclusion: These findings demonstrate the validity of Smart Aging for assessing cognitive functions in normal aging. Future studies will validate this platform also in the clinical aging populations.

Video games have been found to have positive influences on executive function in older adults; however, the underlying neural basis of the benefits from video games has been unclear. Adopting a task-based functional magnetic resonance imaging (fMRI) study targeted at the flanker task, the present study aims to explore the neural basis of the improved executive function in older adults with video game experiences. Twenty video game players (VGPs) and twenty non-video game players (NVGPs) of 60 years of age or older participated in the present study, and there are no significant differences in age (t = 0.62, p = 0.536), gender ratio (t = 1.29, p = 0.206) and years of education (t = 1.92, p = 0.062) between VGPs and NVGPs. The results show that older VGPs present significantly better behavioral performance than NVGPs. Older VGPs activate greater than NVGPs in brain regions, mainly in frontal-parietal areas, including the right dorsolateral prefrontal cortex, the left supramarginal gyrus, the right angular gyrus, the right precuneus and the left paracentral lobule. The present study reveals that video game experiences may have positive influences on older adults in behavioral performance and the underlying brain activation. These results imply the potential role that video games can play as an effective tool to improve cognitive ability in older adults.

Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel.

Background: In the last years, inflammatory bowel disease (IBD) and hepatitis C virus (HCV) infection management has completely changed. However, the role of direct-acting antivirals (DAAs) and the correct timing of antiviral drugs administration in IBD patients needing biologics has not been evaluated. Objective: To discuss the management of HCV-infected IBD patients, focusing our attention on the timing of DAAs administration subjects needing biologics. Methods: Relevant articles addressing HCV management in patients needing biologics were identified by searching from PubMed, MEDLINE and Scopus. Results: Three possible timing strategies were identified: (1) sequential strategy, meaning the choice of treating firstly the active IBD with biologics and then, once the acute phase has been controlled, treating the HCV infection; (2) concomitant strategy, that is the contemporaneous beginning of DAAs and biologics administration; (3) inverted sequential strategy-the administration of antiviral therapy before biologics in HCV-infected IBD patients. The potential pharmacological interactions between biologics and DAAs have also been reported. Conclusions: Clinical management of HCV-infected IBD patients remains a challenging problem for clinicians, especially in terms of timing choice. Recent published data about DAAs are very encouraging also in IBD patients. All strategies could be considered safe and effective. However, further data are immediately required in order to evaluate hepatic toxicity of novel immunosuppressive drugs in IBD.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising in silico TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (Cmax). However, when drug effects were extrapolated above 10× Cmax, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC50-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC50-values in vitro. Thus, we demonstrate that UQ provides valuable information about in silico modeling predictions that can inform future proarrhythmic risk evaluation of drugs under the CiPA paradigm.

Aim: The use of external and internal load is an important aspect of monitoring systems in team sport. The aim of this study was to validate a novel measure of training load by quantifying the training-performance relationship of elite Australian footballers. Methods: The primary training measure of each of 36 players was weekly load derived from a weighted combination of Global Positioning System (GPS) data and perceived wellness over a 24-week season. Smoothed loads representing an exponentially weighted rolling average were derived with decay time constants of 1.5, 2, 3, and 4 weeks. Differential loads representing rate of change in load were generated in similar fashion. Other derived measures of training included monotony, strain and acute:chronic ratio. Performance was a proprietary score derived from match performance indicators. Effects of a 1 SD within-player change below and above the mean of each training measure were quantified with a quadratic mixed model for each position (defenders, forwards, midfielders, and rucks). Effects were interpreted using standardization and magnitude-based inferences. Results: Performance was generally highest near the mean or ~1 SD below the mean of each training measure, and 1 SD increases in the following measures produced small impairments: weekly load (defenders, forwards, and midfielders); 1.5-week smoothed load (midfielders); 4-week differential load (defenders, forwards, and midfielders); and acute:chronic ratio (defenders and forwards). Effects of other measures in other positions were either trivial or unclear. Conclusion: The innovative combination of load was sensitive to performance in this elite Australian football cohort. Periods of high acute load and sustained increases in load impaired match performance. Positional differences should be taken into account for individual training prescription.

The hippocampus is known as a neuronal structure involved in learning, memory and spatial navigation using multi-sensory cues. However, the basic features of its response to acoustic stimuli without any behavioral tasks (conditioning) remains poorly studied. Here, we investigated the CA3 response to auditory stimuli using in vivo loose-patch recordings in awake and anesthetized C57 mice. Different acoustic stimuli in addition to broadband noise such as click, FM sound and pure tone were applied to test the response of CA3 in awake animals. It was found that the wakefulness of the animal is important for the recorded neurons to respond. The CA3 neurons showed a stronger response to broadband noise rather than the other type of stimuli which suggested that auditory information arrived at CA3 via broadband pathways. Finally, we investigated the excitatory and inhibitory inputs to CA3 neurons by using in vivo whole-cell voltage-clamp techniques with the membrane potential holding at -70 and 0 mV, respectively. In awake animals, the excitatory and inhibitory inputs CA3 neurons receive induced by noise are balanced by showing stable intervals and proportional changes of their latencies and peak amplitudes as a function of the stimulation intensities.

Previous studies have shown changes in empathy in patients with depression, including an elevated level of trait personal distress. This study examined if low mood causes changes in self-reported empathic distress when seeing others in pain. To test this, we conducted an initial (n = 26) and close replication study (n = 46) in which sad mood was induced in healthy participants (overall mean age M = 21, SD = 5, range = 18-41 years). Participants viewed and rated video stimuli inferring pain experienced by other people. Results showed that participants perceived the videos depicting others' pain (versus no-pain) to be more distressing under a sad mood compared to a neutral mood condition, implying that sadness enhances one's emotional reactivity toward others' distress. This supports previous depression literature suggesting an impaired emotional processing ability, and could contribute to some of the unhelpful behaviors seen in depression such as social withdrawal and avoidance.

This study examines whether coding open answers in a picture-based test, as to the extent they reflect the fear of being laughed at (i.e., gelotophobia), demonstrates sufficient validity to construct a semi-projective test for the assessment of gelotophobia. Previous findings indicate that cartoon stimuli depicting laughter situations (i.e., in the pilot version of the Picture-Geloph; Ruch et al., 2009) on average elicit fear-typical responses in gelotophobes stronger than in non-gelotophobes. The present study aims to (a) develop a standardized scoring procedure based on a coding scheme, and (b) examine the properties of the pilot version of the Picture-Geloph in order to select the most acceptable items for a standard form of the test. For Study 1, a sample of N = 126 adults, with scores evenly distributed across the gelotophobia spectrum, completed the pilot version of the Picture-Geloph by noting down what they assumed the protagonist in each of 20 cartoons would say or think. Furthermore, participants answered the GELOPH<15> (Ruch and Proyer, 2008), the established questionnaire for the subjective assessment of the fear of being laughed at. Agreement between two independent raters indicated that the developed coding scheme allows for objective and reliable scoring of the Picture-Geloph (mean of intraclass correlations = 0.66). Nine items met the criteria employed to identify the psychometrically most reliable and valid items. These items were unidimensional and internally consistent (Cronbach's alpha = 0.78). The total score of this selection (i.e., the Picture-Geloph<9>) discriminated significantly between non-fearful, slightly, markedly, and extremely fearful individuals; furthermore, it correlated sufficiently high (r = 0.66; rc = 0.79 when corrected for reliability of both measures) with the GELOPH<15>. Cronbach's alpha (0.73) was largely comparable whereas the estimate of convergent validity was found to be lower in one (r = 0.50; rc = 0.61; N = 103) of the two samples in Study 2. Combining all three samples (N = 313) yielded a linear relationship between the self-report and the Picture-Geloph. With the Picture-Geloph<9> and the developed coding scheme, an unobtrusive and valid alternative instrument for the assessment of gelotophobia is provided. Possible applications are discussed.

Foodborne diseases are an important cause of morbidity and mortality. According to the World Health Organization, there are 31 main global hazards, which caused in 2010 600 million foodborne illnesses and 420000 deaths. Among them, Salmonella spp. is one of the most important human pathogens, accounting for more than 90000 cases in Europe and even more in the United States per year. In the current study we report the development, and thorough evaluation in food samples, of a microfluidic system combining loop-mediated isothermal amplification with gold nanoparticles (AuNPs). This system is intended for low-cost, in situ, detection of different pathogens, as the proposed methodology can be extrapolated to different microorganisms. A very low limit of detection (10 cfu/25 g) was obtained. Furthermore, the evaluation of spiked food samples (chicken, turkey, egg products), completely matched the expected results, as denoted by the index kappa of concordance (value of 1.00). The results obtained for the relative sensitivity, specificity and accuracy were of 100% as well as the positive and negative predictive values.

Rhizobia induce root nodules and fix atmospheric N2 for most legume species in exchange for carbon. However, the diverse endophytic non-rhizobial bacteria in legume nodules that co-exist with rhizobia are often ignored because they are difficult to cultivate using routine cultivation approaches. To enhance our understanding of the incidence and diversity of legume-bacteria associations, a high-throughput sequencing analysis of bacterial 16S rRNA genes was used to examine the bacterial community in the rhizospheres and root nodules of Dalbergia odorifera seedlings that were uninoculated or inoculated with Bradyrhizobium elkanii H255, Rhizobium multihospitium-like HT221, or Burkholderia pyrrocinia-like H022238, in two growth media (nitrogen [N]-supplied soil or N-omitted potting mix). Seedlings inoculated with Bradyrhizobium had significantly more nodules than seedlings in the other inoculation conditions, regardless of growth media. Using the 15N natural abundance method, it was shown that the inoculated plants had significantly higher N2 fixation efficiency (48-57%) and specific nodule activity [269-313 μg N mg-1 of dry weight (dwt) nodule] compared to the uninoculated plants (203 μg N mg-1 dwt nodule). The 16S rRNA gene analysis showed that there was generally a higher bacterial diversity in the rhizosphere than in the nodules in the corresponding condition. Both rhizobial inoculation and media status significantly altered the bacterial communities in the rhizospheres and nodules (P < 0.05), with the exception of the inoculated soil rhizospheres. Regarding non-rhizobial bacteria, three genera, i.e., Lactococcus, Bacillus, and Pseudomonas, were consistently enriched in the rhizosphere and Bradyrhizobium, Chloroplast norank (which belongs to Cyanobacteria), and Lactococcus were commonly found in the nodules. In contrast, common rhizobial genera (including Rhizobium, Mesorhizobium, and Burkholderia) were only present in the nodules at low relative abundances (0.01-3.41%). Regarding non-rhizobial bacteria, 32 genera were found in the nodules, with non-rhizobial bacteria being predominant in the N omitted potting mix (with a relative abundance of 56-87%). This study suggests that legume nodules are inhabited by a high diversity of non-rhizobial bacteria, which may play a vital role in nodulation and N2 fixation in the host plants.

Staphylococcus aureus is one of the most common causes of zoonotic agent in the world, which are attributable to the contamination of food with enterotoxins. In this study, a total of 1,150 S. aureus isolates were cultured from 27,000 retail foods items from 203 cities of 24 provinces in China in 2015 and were test for antimicrobial susceptibility. Additionally, the role of the genes responsible for the staphylococcal enterotoxins (SEA to SEE), methicillin resistance (mecA) and the toxigenic capabilities were also assessed. The results showed that 4.3% retail foods were contaminated with S. aureus, and 7.9% retail foods isolates were mecA positive. Some 97.6% of S. aureus isolates were resistant to at least one antimicrobial compound, and 57.5% of these were multi drug resistant (MDR). Resistance to penicillin (83.7%, 963/1,150), was common, followed by linezolid (67.7%, 778/1,150) and erythromycin (52.1%, 599/1,150). The isolates cultured from raw meats showed high levels of resistant to tetracycline (42.8%), ciprofloxacin (17.4%), and chloramphenicol (12.0%) and expressed a MDR phenotype (62.4%). A total of 29.7% S. aureus isolates harbored the classical SEs genes (sea, seb, sec, and sed). The sea and seb genes were the most frequent SEs genes detected. Of note, 22% of the SEs genes positive S. aureus harbored two or three SEs genes, and 16 isolates were confirmed with the capacity to simultaneously produce two or three enterotoxin types. Moreover, nearly 50% of the MRSA isolates were positive for at least one SE gene in this study. Therefore, it is important to monitor the antimicrobial susceptibility and enterotoxigenicity of MDR S. aureus and MRSA in the food chain and to use these data to develop food safety measures, designed to reduce the contamination and transmission of this bacterium.