Miracle-dz/UniFAR-FTUs huggingface dataset:
Rubicon-Dependent Lc3 Recruitment to Salmonella-Containing Phagosomes Is a Host Defense Mechanism Triggered Independently From Major Bacterial Virulence Factors

Intracellular pathogens such as Salmonella depend on their molecular virulence factors to evade host defense responses like autophagy. Using a zebrafish systemic infection model, we have previously shown that phagocytes, predominantly macrophages, target Salmonella Typhimurium by an autophagy-related pathway known as Lc3-associated phagocytosis (LAP), which is dependent on the host protein Rubicon. Here, we explore the influence of Salmonella virulence factors on pathogenicity in the zebrafish model and induction of LAP as a defense response. We investigated five mutant strains that all could trigger GFP-Lc3 recruitment as puncta or rings around single bacteria or bacterial clusters, in a Rubicon-dependent manner. We found that S. Typhimurium strains carrying mutations in PhoP or PurA, responsible for adaptation to the intracellular environment and efficient metabolism of purines, respectively, are attenuated in the zebrafish model. However, both strains show increased virulence when LAP is inhibited by knockdown of Rubicon. Mutations in type III secretion systems 1 and 2, SipB and SsrB, which are important for invading and replicating in non-phagocytic cells, did not affect the ability to establish successful infection in the zebrafish model. This observation is in line with our previous characterization of this infection model revealing that macrophages actively phagocytose the majority of S. Typhimurium. In contrast to SipB mutants, SsrB mutants were unable to become more virulent in Rubicon-deficient hosts, suggesting that type III system 2 effectors are important for intracellular replication of Salmonella in the absence of LAP. Finally, we found that mutation of FlhD, required for production of flagella, renders S. Typhimurium hypervirulent both in wild type zebrafish embryos and in Rubicon-deficient hosts. FlhD mutation also led to lower levels of GFP-Lc3 recruitment compared with the wild type strain, indicating that recognition of flagellin by the host innate immune system promotes the LAP response. Together, our results provide new evidence that the Rubicon-dependent LAP process is an important defense mechanism against S. Typhimurium.
Delivery of Antigen to CD8+ Dendritic Cells by Fusing Antigen With Formyl Peptide Receptor-Like 1 Inhibitor Protein Induces Antitumor Immunity

A major challenge for vaccine development is targeting antigens to dendritic cells (DCs) in vivo, enabling cross-presentation, and inducing the memory responses. Fcγ receptors (FcγRs) are expressed on many cell types including DCs. Therefore, targeting of antigen to DCs via FcγRs is an attractive strategy for vaccine development. This study employ formyl peptide receptor-like 1 inhibitory protein (FLIPr), an FcγR binding protein secreted by Staphylococcus aureus, to deliver antigen to DCs. Our results show that FLIPr is a competent vehicle in delivering antigen to CD8+ DCs for induction of potent immunities without extra adjuvant formulation. Fusion antigen with FLIPr enables effective antigen presentation on both MHC class II and class I to induce memory T cell responses. Altogether, using FLIPr as an antigen delivery vector has great potential to apply antigens for cancer immunotherapy as well as other infectious disease vaccines.
Effects of Cerebrolysin® in Patients With Minimally Conscious State After Stroke: An Observational Retrospective Clinical Study

Introduction: The neurotrophic drug Cerebrolysin is composed of low-molecular-weight peptides and amino acids and has been shown to have neuroprotective and neuroplastic properties. Cerebrolysin has been reported to promote the recovery of motor functions in central nervous system disorders; however, the effects on the consciousness improvements in post-stroke patients have not yet been studied extensively. Therefore, we aimed to examine the effectiveness of Cerebrolysin on improving the consciousness level of stroke patients with minimally conscious state (MCS). Materials and Methods: In this retrospective study we included ischemic and/or hemorrhagic stroke patients with MCS according to the Coma Recovery Scale-Revised (CRS-R), who were admitted to our hospital between 2014 and 2017. All patients received comprehensive rehabilitation therapy including physical and occupational therapy. We compared patients treated with Cerebrolysin against patients who did not receive Cerebrolysin. Patients were included in the verum group if they received 10 mL of Cerebrolysin IV for at least 20 days. CRS-R scores were assessed at admission and discharge. Results: Of 1,531 patients screened, 75 were included in the study (Cerebrolysin, n = 43; control, n = 32). Baseline characteristics were similar between groups. At discharge, ~2 months after onset of stroke, Cerebrolysin-treated patients improved significantly in the CRS-R (p = 0.010) after adjustment for confounders using linear mixed model (LMM), especially in the Oromotor (p = 0.003) and Arousal subscales (p = 0.038). No safety issues were observed. Conclusion: This retrospective study suggests that Cerebrolysin may improve the level of consciousness in stroke patients with MCS, which should be further investigated in a well-designed, double-blind, placebo-controlled, randomized trial.
Polysaccharide Chain Length of Lipopolysaccharides From Salmonella Minnesota Is a Determinant of Aggregate Stability, Plasma Residence Time and Proinflammatory Propensity in vivo

Lipopolysaccharides (LPS) originate from the outer membrane of Gram-negative bacteria and trigger an inflammatory response via the innate immune system. LPS consist of a lipid A moiety directly responsible for the stimulation of the proinflammatory cascade and a polysaccharide chain of variable length. LPS form aggregates of variable size and structure in aqueous media, and the aggregation/disaggregation propensity of LPS is known as a key determinant of their biological activity. The aim of the present study was to determine to which extent the length of the polysaccharide chain can affect the nature of LPS structures, their pharmacokinetics, and eventually their proinflammatory properties in vivo. LPS variants of Salmonella Minnesota with identical lipid A but with different polysaccharide moieties were used. The physical properties of LPS aggregates were analyzed by zetametry, dynamic light scattering, and microscopy. The stability of LPS aggregates was tested in the presence of plasma, whole blood, and cultured cell lines. LPS pharmacokinetics was performed in wild-type mice. The accumulation in plasma of rough LPS (R-LPS) with a short polysaccharidic chain was lower, and its hepatic uptake was faster as compared to smooth LPS (S-LPS) with a long polysaccharidic chain. The inflammatory response was weaker with R-LPS than with S-LPS. As compared to S-LPS, R-LPS formed larger aggregates, with a higher hydrophobicity index, a more negative zeta potential, and a higher critical aggregation concentration. The lower stability of R-LPS aggregates could be illustrated in vitro by a higher extent of association of LPS to plasma lipoproteins, faster binding to blood cells, and increased uptake by macrophages and hepatocytes, compared to S-LPS. Our data indicate that a long polysaccharide chain is associated with the formation of more stable aggregates with extended residence time in plasma and higher inflammatory potential. These results show that polysaccharide chain length, and overall aggregability of LPS might be helpful to predict the proinflammatory effect that can be expected in experimental settings using LPS preparations. In addition, better knowledge and control of LPS aggregation and disaggregation might lead to new strategies to enhance LPS detoxification in septic patients.
Role of Regulatory Immune Cells and Molecules in Autoimmune Bullous Dermatoses

Autoimmune bullous dermatoses (AIBD) include a series of typical organ-specific autoimmune diseases characterized by extensive mucocutaneous blisters. It is generally accepted to be caused by pathological autoantibodies that directly target specific adhesion components of the skin or the adjacent mucous membranes. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Recent studies have indicated that the dysfunction of regulatory T cells, regulatory B cells, and complement regulatory proteins that play essential roles in maintaining a healthy immune environment is also closely related to immune disorders in AIBD. It is important to summarize these studies, elucidate the changes in these regulatory immune cells and molecules for the pathogenesis of AIBD, and reveal the mechanisms by which they lose their ability to regulate immune disorders. In this review, we highlight the role of regulatory immune cells and molecules in the pathogenesis of pemphigus vulgaris and bullous pemphigoid, the two most representative forms of AIBD, and indicate issues that should be addressed in future investigations.
The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer

Glypican-3 (GPC3) is a cell-surface glycoprotein consisting of heparan sulfate glycosaminoglycan chains and an inner protein core. It has important functions in cellular signaling including cell growth, embryogenesis, and differentiation. GPC3 has been linked to hepatocellular carcinoma and a few other cancers, however, the mechanistic role of GPC3 in cancer development remains elusive. Recent breakthroughs including the structural modeling of GPC3 and GPC3–Wnt complexes represent important steps toward deciphering the molecular mechanism of action for GPC3 and how it may regulate cancer signaling and tumor growth. A full understanding of the molecular basis of GPC3-mediated signaling requires elucidation of the dynamics of partner receptors, transducer complexes, and downstream players. Herein, we summarize current insights into the role of GPC3 in regulating cancer development through Wnt and other signaling pathways, including YAP and hedgehog cascades. We also highlight the growing body of work which underlies deciphering how GPC3 is a key player in liver oncogenesis.
Explaining the Media's Framing of Renewable Energies: An International Comparison

The use of renewable energies has been rapidly expanding worldwide; however, in numerous countries this has resulted in public controversy. Building upon Entman’s framing concept, a quantitative content analysis was conducted to examine the media’s framing of renewable energies in 11 countries between 2010 and 2012. To explain the observed differences in media coverage, we considered national structural conditions. Furthermore, we investigated whether media framing changed after an external shock, the Fukushima accident. The findings show that renewable energies were covered through three different frames, (1) the first highlighting economic and technological problems, (2) the second focusing on environmental and social problems and (3) the third considering positive aspects of the technologies. To some extent, the occurrence of these frames is influenced by the national structural conditions. The study revealed that the Fukushima accident did not cause the expected changes in framing.
The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment

Cancer-associated fibroblasts (CAFs) are prominent components of the microenvironment in most types of solid tumors, and were shown to facilitate cancer progression by supporting tumor cell growth, extracellular matrix remodeling, promoting angiogenesis, and by mediating tumor-promoting inflammation. In addition to an inflammatory microenvironment, tumors are characterized by immune evasion and an immunosuppressive milieu. In recent years, CAFs are emerging as central players in immune regulation that shapes the tumor microenvironment. CAFs contribute to immune escape of tumors via multiple mechanisms, including secretion of multiple cytokines and chemokines and reciprocal interactions that mediate the recruitment and functional differentiation of innate and adaptive immune cells. Moreover, CAFs directly abrogate the function of cytotoxic lymphocytes, thus inhibiting killing of tumor cells. In this review, we focus on recent advancements in our understanding of how CAFs drive the recruitment and functional fate of tumor-infiltrating immune cells toward an immunosuppressive microenvironment, and provide outlook on future therapeutic implications that may lead to integration of preclinical findings into the design of novel combination strategies, aimed at impairing the tumor-supportive function of CAFs.
Tool Use Modulates Somatosensory Cortical Processing in Humans

Tool use leads to plastic changes in sensorimotor body representations underlying tactile perception. The neural correlates of this tool-induced plasticity in humans have not been adequately characterized. This study used ERPs to investigate the stage of sensory processing modulated by tool use. Somatosensory evoked potentials, elicited by median nerve stimulation, were recorded before and after two forms of object interaction: tool use and hand use. Compared with baseline, tool use—but not use of the hand alone—modulated the amplitude of the P100. The P100 is a mid-latency component that indexes the construction of multisensory models of the body and has generators in secondary somatosensory and posterior parietal cortices. These results mark one of the first demonstrations of the neural correlates of tool-induced plasticity in humans and suggest that tool use modulates relatively late stages of somatosensory processing outside primary somatosensory cortex. This finding is consistent with what has been observed in tool-trained monkeys and suggests that the mechanisms underlying tool-induced plasticity have been preserved across primate evolution.
Traditional Chinese Medicine for Coronary Heart Disease: Clinical Evidence and Possible Mechanisms

Coronary heart disease (CHD) remains a major cause of mortality with a huge economic burden on healthcare worldwide. Here, we conducted a systematic review to investigate the efficacy and safety of Chinese herbal medicine (CHM) for CHD based on high-quality randomized controlled trials (RCTs) and summarized its possible mechanisms according to animal-based researches. 27 eligible studies were identified in eight database searches from inception to June 2018. The methodological quality was assessed using seven-item checklist recommended by Cochrane Collaboration. All the data were analyzed using Rev-Man 5.3 software. As a result, the score of study quality ranged from 4 to 7 points. Meta-analyses showed CHM can significantly reduce the incidence of myocardial infarction and percutaneous coronary intervention, and cardiovascular mortality (P < 0.05), and increase systolic function of heart, the ST-segment depression, and clinical efficacy (P < 0.05). Adverse events were reported in 11 studies, and CHMs were well tolerated in patients with CHD. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammatory, anti-oxidation, anti-apoptosis, improving the circulation, and regulating energy metabolism. In conclusion, the evidence available from present study revealed that CHMs are beneficial for CHD and are generally safe.
On the Way to Become a Natural Killer Cell

Natural Killer (NK) cells are innate lymphocytes playing pivotal roles in host defense and immune-surveillance. The homeostatic modulation of germ-line encoded/non-rearranged activating and inhibitory NK cell receptors (NKRs) determines the capability of these innate lymphocytes to either spare “self” cells or to kill viral-infected, tumor-transformed and heterologous cell targets. However, despite being discovered more than 40 years ago, several aspects of NK cell biology remain unknown or are still being debated. In particular, our knowledge of human NK cell ontogenesis and differentiation is still in its infancy as the majority of our experimental evidence on this topic mainly comes from findings obtained in vitro or with animal models in vivo. Although both the generation and the maintenance of human NK cells are sustained by hematopoietic stem cells (HSCs), the precise site(s) of NK cell development are still poorly defined. Indeed, HSCs and hematopoietic precursors are localized in different anatomical compartments that also change their ontogenic commitments before and after birth as well as in aging. Currently, the main site of NK cell generation and maturation in adulthood is considered the bone marrow, where their interactions with stromal cells, cytokines, growth factors, and other soluble molecules support and drive maturation. Different sequential stages of NK cell development have been identified on the basis of the differential expression of specific markers and NKRs as well as on the acquisition of specific effector-functions. All these phenotypic and functional features are key in inducing and regulating homing, activation and tissue-residency of NK cells in different human anatomic sites, where different homeostatic mechanisms ensure a perfect balance between immune tolerance and immune-surveillance. The present review summarizes our current knowledge on human NK cell ontogenesis and on the related pathways orchestrating a proper maturation, functions, and distributions.
Identification and Isolation of Cardiac Fibroblasts From the Adult Mouse Heart Using Two-Color Flow Cytometry

Background: Cardiac fibroblasts represent a main stromal cell type in the healthy myocardium. Activation of cardiac fibroblasts has been implicated in the pathogenesis of many heart diseases. Profibrotic stimuli activate fibroblasts, which proliferate and differentiate into pathogenic myofibroblasts causing a fibrotic phenotype in the heart. Cardiac fibroblasts are characterized by production of type I collagen, but non-transgenic methods allowing their identification and isolation require further improvements. Herein, we present a new and simple flow cytometry-based method to identify and isolate cardiac fibroblasts from the murine heart. Methods and Results: Wild-type and reporter mice expressing enhanced green fluorescent protein (EGFP) under the murine alpha1(I) collagen promoter (Col1a1-EGFP) were used in this study. Hearts were harvested and dissociated into single cell suspensions using enzymatic digestion. Cardiac cells were stained with the erythrocyte marker Ter119, the pan-leukocyte marker CD45, the endothelial cell marker CD31 and gp38 (known also as podoplanin). Fibroblasts were defined in a two-color flow cytometry analysis as a lineage-negative (Lin: Ter119−CD45−CD31−) and gp38-positive (gp38+) population. Analysis of hearts isolated from Col1a1-EGFP reporter mice showed that cardiac Lin−gp38+ cells corresponded to type I collagen-producing cells. Lin−gp38+ cells were partially positive for the mesenchymal markers CD44, CD140a, Sca-1 and CD90.2. Sorted Lin−gp38+ cells were successfully expanded in vitro for up to four passages. Lin−gp38+ cells activated by Transforming Growth Factor Beta 1 (TGF-β1) upregulated myofibroblast-specific genes and proteins, developed stress fibers positive for alpha smooth muscle actin (αSMA) and showed increased contractility in the collagen gel contraction assay. Conclusions: Two-color flow cytometry analysis using the selected cell surface antigens allows for the identification of collagen-producing fibroblasts in unaffected mouse hearts without using specific reporter constructs. This strategy opens new perspectives to study the physiology and pathophysiology of cardiac fibroblasts in mouse models.
Prediction of microsleeps from EEG using Bayesian approaches.

Microsleeps are brief unintentional episodes of sleep-related loss of consciousness up to 15 s during an active task, such as driving. Such episodes of unresponsiveness are of particularly high importance in people who perform high-risk occupations requiring extended and unimpaired visuomotor performance, such as truck drivers, train drivers, pilots, and air-traffic controllers, where microsleeps can, and do, result in catastrophic accidents and fatalities. Therefore, prediction and even early detection of microsleeps has the potential to prevent sleep-related accidents and save lives. The aim of this study was to investigate Bayesian methods in the prediction of microsleeps from the EEG. Bayesian methods were also investigated as a measure of improving performance in microsleep detection. This study used data from a previous study, ‘Study A’, in which 15 healthy non-sleep-deprived participants performed two 1-h sessions of 1-D continuous tracking task (CTT). Participants who experienced at least one definite microsleep during the two CTT sessions, i.e., 8 subjects, were included for the analyses. The original gold-standard was formed by integrating two independent measures: the video-rating from a human expert and tracking flat-spots. In this study, we first refined the gold-standard to improve its accuracy and minimize potential false labels. A microsleep was defined as a non-tracking episode in conjunction with a deep-drowsy or lapse video rating, whereas a responsive episode was defined as a satisfactory tracking performance for at least of 5 s irrespective of video ratings. The remainder of the gold-standard was labelled uncertain and pruned out. We then proposed four Bayesian models for feature reduction. The first Bayesian model was variational Bayesian robust factor analysis (VBRFA), which is an extension of variational Bayesian FA (VBFA) that finds a robust latent space. This model was then extended to variational Baysian multi-subject RFA (VBMSRFA), which assumes independent mean and noise terms for individual subjects. Variational Bayesian hierarchical MSRFA (VBHMSRFA) finds a group level loading matrix and allows individual subjects to have slightly different loading matrices. Finally, variational Bayesian hierarchical multi-subject robust joint matrix factorization (VBHMSRJMF) incorporates the information of class labels while finding a less subject-variable latent space. All of these proposed methods used variational inference to approximate the posterior probabilities. Moreover, automatic relevance determination (ARD) motivated prior distributions were used in all models to automatically find the optimum number of latent variables.
Can a diversity statement increase diversity in MOOCs?

Despite the fact that anyone can sign up for open online courses, their enrollment patterns reflect the historical underrepresentation of certain sociodemographic groups (e.g. women in STEM disciplines). We theorize that enrollment choices online are shaped by contextual cues that activate stereotypes about numeric representation and climate in brick-and-mortar institutions. A longitudinal matched-pairs experiment with 14 MOOCs (N=29,000) tested this theory by manipulating the presence of a diversity statement on course pages and measuring effects on who enrolls. We found a 3% increase in the proportion of students with lower socioeconomic status. The effect size varied across courses between -0.5 and 7 percentage points. No significant changes in enrollment patterns by gender, age, and national development level occurred. Implications for the use and content of diversity statements and their alternatives are discussed.