Miracle-dz/UniFAR-FTUs huggingface dataset:
A zero‐inflated beta‐binomial model for microbiome data analysis

The Microbiome is increasingly recognized as an important aspect of the health of host species, involved in many biological pathways and processes and potentially useful as health biomarkers. Taking advantage of high‐throughput sequencing technologies, modern bacterial microbiome studies are metagenomic, interrogating thousands of taxa simultaneously. Several data analysis frameworks have been proposed for microbiome sequence read count data and for determining the most significant features. However, there is still room for improvement. We introduce a zero‐inflated beta‐binomial to model the distribution of microbiome count data and to determine association with a continuous or categorical phenotype of interest. The approach can exploit the mean‐variance relationship to improve power and adjust for covariates. The proposed method is a mixture model with two components: (i) a zero model accounting for excess zeros and (ii) a count model to capture the remaining component by beta‐binomial regression, allowing for overdispersion effects. Simulation studies show that our proposed method effectively controls type I error and has higher power than competing methods to detect taxa associated with phenotype. An R package ZIBBSeqDiscovery is available on R CRAN. Copyright © 2018 John Wiley & Sons, Ltd.
Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate–cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.
Effects of three probiotic Bacillus on growth performance, digestive enzyme activities, antioxidative capacity, serum immunity, and biochemical parameters in broilers.

This study was conducted to evaluate the effects of three Bacillus strains on growth performance, digestive enzyme activities, antioxidative capacity, serum immunity, and biochemical parameters in broilers. A total of 360 one-day-old Ross 308 chicks were randomly allocated into four groups with three replicates per group (n = 30). The control group was fed a basal diet, whereas the other groups fed basal diet supplemented with either Bacillus subtilis natto or Bacillus licheniformis or Bacillus cereus (108 cfu/kg) for 42 days, respectively. The results revealed that the probiotic-treated groups markedly improved final body weight, daily weight gain, and the activities of trypsin, amylase, lipase and total protease (p < 0.05). Moreover, chicks fed probiotics had higher serum glutathione peroxidase activity and O2 - level, as well as hepatic catalase and superoxide dismutase activities, whereas malondialdehyde levels in serum and liver were reduced (p < 0.05). The significant increased IgA (p < 0.05) was observed in the probiotics groups as compared to the control group. In addition, dietary administration of probiotic strain markedly reduced the levels of serum ammonia, uric acid, total cholesterol, and triglyceride. Taken together, these three probiotic Bacillus showed beneficial effects on chickens with minor strain specificity.
Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer’s disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions.
Cycle-Consistent Speech Enhancement

Feature mapping using deep neural networks is an effective approach for single-channel speech enhancement. Noisy features are transformed to the enhanced ones through a mapping network and the mean square errors between the enhanced and clean features are minimized. In this paper, we propose a cycle-consistent speech enhancement (CSE) in which an additional inverse mapping network is introduced to reconstruct the noisy features from the enhanced ones. A cycle-consistent constraint is enforced to minimize the reconstruction loss. Similarly, a backward cycle of mappings is performed in the opposite direction with the same networks and losses. With cycle-consistency, the speech structure is well preserved in the enhanced features while noise is effectively reduced such that the feature-mapping network generalizes better to unseen data. In cases where only unparalleled noisy and clean data is available for training, two discriminator networks are used to distinguish the enhanced and noised features from the clean and noisy ones. The discrimination losses are jointly optimized with reconstruction losses through adversarial multi-task learning. Evaluated on the CHiME-3 dataset, the proposed CSE achieves 19.60% and 6.69% relative word error rate improvements respectively when using or without using parallel clean and noisy speech data.
Active cytomegalovirus retinitis after the start of antiretroviral therapy

Patients with AIDS-related cytomegalovirus (CMV) retinitis receiving combined antiretroviral therapy (cART), but not specific anti-CMV therapy, consistently showed active retinitis for several months. Delayed diagnosis and treatment of CMV retinitis may have severe consequences. Patients first entering care with advanced HIV infection and vulnerability to reactivation of latent CMV infection should be screened immediately for CMV retinitis by dilated indirect ophthalmoscopy and treated with specific anti-CMV therapy without delay, in addition to cART.
Differential Effects of Transcranial Direct Current Stimulation (tDCS) Depending on Previous Musical Training

Previous studies have shown that transcranial direct current stimulation (tDCS) facilitates motor performance, but individual differences such as baseline performance seem to influence this effect. Accordingly, musicians offer an inter-individual differences model due to anatomical and functional variances displayed among the motor cortex regions. The aim of the present work was to study if the baseline motor skill predicts whether tDCS can enhance motor learning. For that objective, we administered anodal (n = 20) or sham (n = 20) tDCS on the right primary motor cortex region of 40 right-handed healthy participants, who were divided into four groups: musicians (tDCS/sham) and non-musicians (tDCS/sham). We measured the skill index (SI) presented in the sequential finger-tapping task (SEQTAP) at baseline, during three 20 min/2 mA stimulation sessions, and in follow-up tests after 20 min and 8 days. Depending on the normality of the data distribution, statistical differences were estimated by ANOVA and Bonferroni post hoc test or Kruskal–Wallis and U Mann–Whitney. Results showed that musicians scored higher in baseline performance than non-musicians. The non-musicians who received tDCS scored higher than the sham group in the first and second stimulation session. This effect was extended to the 20 min and 8 days follow-up test. In musicians, there was no effect of tDCS. The present method seems to be suitable for the achievement of positive and consolidated tDCS effects on motor learning in inexperienced participants, but not in musicians. These data may have an implication for the rehabilitation of motor impairments, contributing to more individualized stimulation protocols.
BiasedWalk: Biased Sampling for Representation Learning on Graphs

Network embedding algorithms are able to learn latent feature representations of nodes, transforming networks into lower dimensional vector representations. Typical key applications, which have effectively been addressed using network embeddings, include link prediction, multilabel classification and community detection. In this paper, we propose Biased-Walk, a scalable, unsupervised feature learning algorithm that is based on biased random walks to sample context information about each node in the network. Our random-walk based sampling can behave as Breath-First-Search (BFS) and Depth-First-Search (DFS) samplings with the goal to capture homophily and role equivalence between the nodes in the network. We have performed a detailed experimental evaluation comparing the performance of the proposed algorithm against various baseline methods, on several datasets and learning tasks. The experiment results show that the proposed method outperforms the baseline ones in most of the tasks and datasets.
Multidrug‐resistant transporter expression does not always result in drug resistance

Dear Editor, With great interest, we have read the paper by Sasaki et al evaluating the role of ATP‐binding cassette (ABC) subfamily G member 2 (ABCG2) in chemoresistance and pluripotency in pancreatic ductal adenocarcinoma (PDAC). Selection for ABCG2‐positive cells did not result in increased chemoresistance, even though these cells were able to efflux fluorescent dye more efficiently than unsorted cells. Furthermore, epithelial‐to‐mesenchymal (EMT) or cancer stem cell (CSC) expression was not increased in ABCG2‐expressing cells in adherent cultures. These unexpected results indicate that the expression of ABC transporters does not always cause chemoresistance or confer stem cell‐like features, and, in fact, other mechanisms likely play an important role in the aggressive nature of PDAC. The ABC transporters have been studied extensively for their correlation between CSC and chemoresistance. Their ability to efflux xenobiotics, such as chemotherapeutics, makes them interesting targets. In our unbiased proteomic screening of a gemcitabine‐ resistant population of PANC1 cells (ATCC), we identified another ABC transporter. Cells that withstood high‐dose gemcitabine exposure showed increased ABCC1 expression and phosphorylation (Figure 1). These results led to the hypothesis that ABCC1 expression and post‐translational modification contribute to gemcitabine resistance and could be a novel target to overcome chemoresistance in PDAC. Pharmacological inhibition of ABCC1 by the drug MK‐571 in combination with gemcitabine resulted in improved sensitivity in vitro (Figure 2A). Interestingly, MK‐571 monotherapy resulted in significantly reduced viability of gemcitabine‐resistant cells (Figure 2B), suggesting additional cellular functions of ABC transporters in carcinogenesis, as described previously. Stable gene silencing of ABCC1 by shRNAs, however, did not enhance response to gemcitabine (Figure 2C). These contradictory results can be explained by functional redundancy in the ABC family and the non‐ selectivity of ABC‐targeting agents for specific ABC transporters. Together with limitations due to toxicity and adverse drug interactions, this might explain why none of the studies aimed at overcoming drug resistance by ABC members translated into successful clinical application.
Religar saberes y sentires para reinventar la convivencialidad

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Minimal Reporting Standards for Active Middle Ear Hearing Implants

There is currently no standardized method for reporting audiological, surgical and subjective outcome measures in clinical trials with active middle ear implants (AMEIs). It is often difficult to compare studies due to data incompatibility and to perform meta-analyses across different centres is almost impossible. A committee of ENT and audiological experts from Germany, Austria and Switzerland decided to address this issue by developing new minimal standards for reporting the outcomes of AMEI clinical trials. The consensus presented here aims to provide a recommendation to enable better inter-study comparability.
The effect of preconceptional exposure of F0 male mice to di(2-ethylhexyl)phthalate on the induction of reproductive toxicity in F2 generation

Abstract The aim of the study was the estimation of the effects of 8 weeks exposure mature and pubescent male mice to DEHP on the prenatal development of the offspring F2 generation. The F1 offspring, of males exposed for whole cycle of spermatogenesis to DEHP (2000 mg/kg bw or 8000 mg/kg bw) and unexposed females, at 8–9 weeks of age were caged males with females from the same group, but from different litter. Eight weeks preconceptional exposure of mature F0 males to 2000 mg/kg bw DEHP induced the significantly higher number of dead fetuses in the F2 offspring; however, the effect on the sperm count and quality of F1 males was not seen. Contrary, after such exposure of pubescent males not significantly decrease in the number of live implants was noted. Results showed that the subchronical, preconceptional exposure of F0 males to DEHP did not influence strongly on the F2 generation of the offspring. Our study did not confirm higher sensitivity germ cells of pubescent males to harmful effects induced by DEHP. The developmental effect was present as the enhanced number of dead implants of F2 generation after exposure of mature F0 males and slight reduction in the number of live fetuses following the exposure of immature males. It may confirm ability to male mediated developmental toxicity.
Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.
The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

Genetic and pathophysiologic criteria prearrange the uncontrolled growth of neoplastic cells that in turn initiates new vessel formation, which is prerequisite for further tumor growth and progression. This first endothelial lining is patchy, disordered in structure and thus, angiogenic tumor vessels were proven to be functionally inferior. As a result, tumors were characterized by areas with an apparent oversupply in addition to areas with an undersupply of vessels, which complicates an efficient administration of intravenous drugs in cancer therapy and might even lower the response e.g. of radiotherapy (RT) because of the inefficient oxygen supply. In addition to the vascular dysfunction, tumor blood vessels contribute to the tumor escape from immunity by the lack of response to inflammatory activation (endothelial anergy) and by repression of leukocyte adhesion molecule expression. However, tumor vessels can remodel by the association with and integration of pericytes and smooth muscle cells which stabilize these immature vessels resulting in normalization of the vascular structures. This normalization of the tumor vascular bed could improve the efficiency of previously established therapeutic approaches, such as chemo- or radiotherapy by a more homogenous drug and oxygen distribution, and/or by overcoming endothelial anergy. This review highlights the current investigations that take advantage of a proper vascular function for improving cancer therapy with a special focus on the endothelial-immune system interplay.
Quantifying Contextual Information For Cognitive Control

1 Laboratory of Neuropsychology, University of the Balearic Islands, Mallorca, Spain, 2 Functional Neuroimaging Laboratory, School of Psychology, University of Newcastle, Newcastle, NSW, Australia, 3 Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Newcastle, NSW, Australia, 4 Priority Research Centre for Brain and Mental Health, University of Newcastle, Newcastle, NSW, Australia
Treating Influenza Infection, From Now and Into the Future

Influenza viruses (IVs) are a continual threat to global health. The high mutation rate of the IV genome makes this virus incredibly successful, genetic drift allows for annual epidemics which result in thousands of deaths and millions of hospitalizations. Moreover, the emergence of new strains through genetic shift (e.g., swine-origin influenza A) can cause devastating global outbreaks of infection. Neuraminidase inhibitors (NAIs) are currently used to treat IV infection and act directly on viral proteins to halt IV spread. However, effectivity is limited late in infection and drug resistance can develop. New therapies which target highly conserved features of IV such as antibodies to the stem region of hemagglutinin or the IV RNA polymerase inhibitor: Favipiravir are currently in clinical trials. Compared to NAIs, these treatments have a higher tolerance for resistance and a longer therapeutic window and therefore, may prove more effective. However, clinical and experimental evidence has demonstrated that it is not just viral spread, but also the host inflammatory response and damage to the lung epithelium which dictate the outcome of IV infection. Therapeutic regimens for IV infection should therefore also regulate the host inflammatory response and protect epithelial cells from unnecessary cell death. Anti-inflammatory drugs such as etanercept, statins or cyclooxygenase enzyme 2 inhibitors may temper IV induced inflammation, demonstrating the possibility of repurposing these drugs as single or adjunct therapies for IV infection. IV binds to sialic acid receptors on the host cell surface to initiate infection and productive IV replication is primarily restricted to airway epithelial cells. Accordingly, targeting therapies to the epithelium will directly inhibit IV spread while minimizing off target consequences, such as over activation of immune cells. The neuraminidase mimic Fludase cleaves sialic acid receptors from the epithelium to inhibit IV entry to cells. While type III interferons activate an antiviral gene program in epithelial cells with minimal perturbation to the IV specific immune response. This review discusses the above-mentioned candidate anti-IV therapeutics and others at the preclinical and clinical trial stage.