Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural and Functional Dysbiosis of Fecal Microbiota in Chinese Patients With Alzheimer's Disease

Increasing evidence suggests that gut dysbiosis plays vital roles in a variety of gut–brain disorders, such as Alzheimer's disease (AD). However, alterations of the gut microbiota as well as their correlations with cognitive scores and host immunity have remained unclear in well-controlled trials on Chinese AD patients. In this study, samples from 100 AD patients, and 71 age- and gender-matched, cognitively normal controls were obtained to explore the structural and functional alterations of the fecal microbiota targeting the V3–V4 region of the 16S rRNA gene by MiSeq sequencing, and to analyze their associations with clinical characteristics. Our data demonstrated a remarkably reduction in the bacterial diversity and alterations in the taxonomic composition of the fecal microbiota of the AD patients. Interestingly, the abundant butyrate-producing genera such as Faecalibacterium decreased significantly, where this was positively correlated with such clinical indicators as the MMSE, WAIS, and Barthel scores in the AD patients. On the contrary, abundant lactate-producing genera, such as Bifidobacterium, increased prominently, and were inversely correlated with these indicators. This shift in the gut dysbiosis of the microbiota, from being butyrate producers to lactate producers, contributed to immune disturbances in the host that could be used as non-invasive biomarkers to distinguish the controls from the AD patients. Moreover, several predicted functional modules, including the biosynthesis and the metabolism of fatty acids, that were altered in the microbiota of the AD patients could be utilized by the bacteria to produce immunomodulatory metabolites. Our study established the structural and functional dysbiosis of fecal microbiota in AD patients, and the results suggest the potential for use of gut bacteria for the early, non-invasive diagnosis of AD, personalized treatment, and the development of tailor-made probiotics designed for Chinese AD patients.
Prognostic and Therapeutic Potentials of OncomiRs Modulating mTOR Pathways in Virus-Associated Hepatocellular Carcinoma

Background Dysregulated oncomiRs are attributed to hepatocellular carcinoma (HCC) through targeting mTOR signaling pathway responsible for cell growth and proliferation. The potential of these oncomiRs as biomarker for tumor response or as target for therapy needs to be evaluated. AIM Tumor response assessment by OncomiR changes following locoregional therapy (LRT) and targeting of these oncomiRs modulating pathway Methods All consecutive viral-HCC patients of BCLC stage-A/B undergoing LRT were included. OncomiRs (miR-21, -221, and -16) change in circulation and AFP-ratio at 1-month post-LRT to baseline was estimated to differentiate various categories of response as per mRECIST criteria. OncomiR modulating mTOR pathway was studied by generating miR-21 and miR-221 overexpressing Huh7 stable cell lines. Results Post-LRT tumor response was assessed in 90 viral-HCC patients (CR, 40%; PR, 31%, and PD, 29%). Significant increase of miRNA-21 and -221 expression was observed in PD (p = 0.040, 0.047) and PR patients (miR-21, p = 0.045). Fold changes of miR-21 can differentiate response in group (CR from PR+PD) at AUROC 0.718 (95% CI, 0.572–0.799) and CR from PD at AUROC 0.734 (95% CI, 0.595–0.873). Overexpression of miR-21 in hepatoma cell line had shown increased phosphorylation p70S6K, the downstream regulator of cell proliferation in mTOR pathway. Upregulation of AKT, mTOR, and RPS6KB1 genes were found significant (P < 0.005) and anti-miR-21 specifically reduced mTOR gene (P = 0.02) expression. Conclusions The miR-21 fold change correlates well with imaging in predicting tumor response. Overexpression of miR-21 has a role in HCC through mTOR pathway activation and can be targeted.
Orexin-A/Hypocretin-1 Controls the VTA-NAc Mesolimbic Pathway via Endocannabinoid-Mediated Disinhibition of Dopaminergic Neurons in Obese Mice

Disinhibition of orexin-A/hypocretin-1 (OX-A) release occurs to several output areas of the lateral hypothalamus (LH) in the brain of leptin knockout obese ob/ob mice. In this study, we have investigated whether a similar increase of OX-A release occurs to the ventral tegmental area (VTA), an orexinergic LH output area with functional effects on dopaminergic signaling at the mesolimbic circuit. By confocal and correlative light and electron microscopy (CLEM) morphological studies coupled to molecular, biochemical, and pharmacological approaches, we investigated OX-A-mediated dopaminergic signaling at the LH-VTA-nucleus accumbens (NAc) pathway in obese ob/ob mice compared to wild-type (wt) lean littermates. We found an elevation of OX-A trafficking and release to the VTA of ob/ob mice and consequent orexin receptor-1 (OX1R)-mediated over-activation of dopaminergic (DA) neurons via phospholipase C (PLC)/diacylglycerol lipase (DAGL-α)-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). In fact, by retrograde signaling to cannabinoid receptor type 1 (CB1R) at inhibitory inputs to DA neurons, 2-AG inhibited GABA release thus inducing an increase in DA concentration in the VTA and NAc of ob/ob mice. This effect was prevented by the OX1R antagonist SB-334867 (30 mg/Kg, i.p.), or the CB1R antagonist AM251 (10 mg/Kg, i.p.) and mimicked by OX-A injection (40 μg/Kg, i.p.) in wt lean mice. Enhanced DA signaling to the NAc in ob/ob mice, or in OX-A-injected wt mice, was accompanied by β-arrestin2-mediated desensitization of dopamine D2 receptor (D2R) in a manner prevented by SB-334867 or the D2R antagonist L741 (1.5 mg/Kg, i.p.). These results further support the role of OX-A signaling in the control of neuroadaptive responses, such as compulsive reward-seeking behavior or binge-like consumption of high palatable food, and suggest that aberrant OX-A trafficking to the DA neurons in the VTA of ob/ob mice influences the D2R response at NAc, a main target area of the mesolimbic pathway, via 2-AG/CB1-mediated retrograde signaling.
A New Horizon of Liquid Biopsy in Thymic Epithelial Tumors: The Potential Utility of Circulating Cell-Free DNA

Background Thymic epithelial tumors (TETs) are rare thoracic malignancies, commonly divided into two different histopathological entities, thymoma (T) and thymic carcinoma (TC). To date, there are no specific biomarkers for monitoring the biological course of these rare tumors. We carried out a single center study aiming at the detection of circulating cell-free DNA (ccfDNA) and the correlation of its levels with metastatic dissemination and histological subtype in patients with TETs. Methods From July 2018 to January 2020, 5-ml blood samples from 26 patients with advanced TET (aTET) (11 patients with TC and 15 patients with T) and from six patients with completely resected TET (cr-TET), were prospectively obtained before the initiation of systemic therapy. Blood samples from 10 healthy donors were used as control. The QIAamp MinElute ccfDNA Kits was used for ccfDNA isolation from plasma; real-time PCR was used for cfDNA quantification. Results We found significantly higher ccfDNA amount in patients with T and TC compared to controls, with median ccfDNA level of 3.3 ng/µl, 11.4 ng/µl and 25.6 ng/µl, for healthy donors, T and TC patients, respectively (p<0.001). No significant difference was found between cr-TET and controls (p = 0.175). ccfDNA concentrations were higher in metastatic (M1a and M1b) compared to non-metastatic (M0) TETs (25.6 ng/µl versus 7.2 ng/µl; p= 0.037). No significant correlation was found either between ccfDNA and disease stage, according to both the Masaoka-Koga (p= 0.854) and the TNM 8th edition staging systems (p = 0.66), or between ccfDNA levels and overall tumor burden, estimated according RECIST 1.1 criteria (r = 0.07, p = 0.725). Conclusions To the best of our knowledge, this is the first study that prospectively explores detection and quantification of ccfDNA in TETs. Higher baseline cfDNA levels have been observed in both advanced T and TC comparing to the control group.
Compartmentalization of Photoreceptor Sensory Cilia

Functional compartmentalization of cells is a universal strategy for segregating processes that require specific components, undergo regulation by modulating concentrations of those components, or that would be detrimental to other processes. Primary cilia are hair-like organelles that project from the apical plasma membranes of epithelial cells where they serve as exclusive compartments for sensing physical and chemical signals in the environment. As such, molecules involved in signal transduction are enriched within cilia and regulating their ciliary concentrations allows adaptation to the environmental stimuli. The highly efficient organization of primary cilia has been co-opted by major sensory neurons, olfactory cells and the photoreceptor neurons that underlie vision. The mechanisms underlying compartmentalization of cilia are an area of intense current research. Recent findings have revealed similarities and differences in molecular mechanisms of ciliary protein enrichment and its regulation among primary cilia and sensory cilia. Here we discuss the physiological demands on photoreceptors that have driven their evolution into neurons that rely on a highly specialized cilium for signaling changes in light intensity. We explore what is known and what is not known about how that specialization appears to have driven unique mechanisms for photoreceptor protein and membrane compartmentalization.
Characterizing the Structural Pattern of Heavy Smokers Using Multivoxel Pattern Analysis

Background: Smoking addiction is a major public health issue which causes a series of chronic diseases and mortalities worldwide. We aimed to explore the most discriminative gray matter regions between heavy smokers and healthy controls with a data-driven multivoxel pattern analysis technique, and to explore the methodological differences between multivoxel pattern analysis and voxel-based morphometry. Methods: Traditional voxel-based morphometry has continuously contributed to finding smoking addiction-related regions on structural magnetic resonance imaging. However, voxel-based morphometry has its inherent limitations. In this study, a multivoxel pattern analysis using a searchlight algorithm and support vector machine was applied on structural magnetic resonance imaging to identify the spatial pattern of gray matter volume in heavy smokers. Results: Our proposed method yielded a voxel-wise accuracy of at least 81% for classifying heavy smokers from healthy controls. The identified regions were primarily located at the temporal cortex and prefrontal cortex, occipital cortex, thalamus (bilateral), insula (left), anterior and median cingulate gyri, and precuneus (left). Conclusions: Our results suggested that several regions, which were seldomly reported in voxel-based morphometry analysis, might be latently correlated with smoking addiction. Such findings might provide insights for understanding the mechanism of chronic smoking and the creation of effective cessation treatment. Multivoxel pattern analysis can be efficient in locating brain discriminative regions which were neglected by voxel-based morphometry.
Self-Learning Event Mistiming Detector Based on Central Pattern Generator

A repetitive movement pattern of many animals, a gait, is controlled by the Central Pattern Generator (CPG), providing rhythmic control synchronous to the sensed environment. As a rhythmic signal generator, the CPG can control the motion phase of biomimetic legged robots without feedback. The CPG can also act in sensory synchronization, where it can be utilized as a sensory phase estimator. Direct use of the CPG as the estimator is not common, and there is little research done on its utilization in the phase estimation. Generally, the sensory estimation augments the sensory feedback information, and motion irregularities can reveal from comparing measurements with the estimation. In this work, we study the CPG in the context of phase irregularity detection, where the timing of sensory events is disturbed. We propose a novel self-supervised method for learning mistiming detection, where the neural detector is trained by dynamic Hebbian-like rules during the robot walking. The proposed detector is composed of three neural components: (i) the CPG providing phase estimation, (ii) Radial Basis Function neuron anticipating the sensory event, and (iii) Leaky Integrate-and-Fire neuron detecting the sensory mistiming. The detector is integrated with the CPG-based gait controller. The mistiming detection triggers two reflexes: the elevator reflex, which avoids an obstacle, and the search reflex, which grasps a missing foothold. The proposed controller is deployed and trained on a hexapod walking robot to demonstrate the mistiming detection in real locomotion. The trained system has been examined in the controlled laboratory experiment and real field deployment in the Bull Rock cave system, where the robot utilized mistiming detection to negotiate the unstructured and slippery subterranean environment.
Poly(dA:dT) Suppresses HSV-2 Infection of Human Cervical Epithelial Cells Through RIG-I Activation

Epithelial cells of the female reproductive tract (FRT) participate in the initial innate immunity against viral infections. Poly(dA:dT) is a synthetic analog of B form double-stranded (ds) DNA which can activate the interferon (IFN) signaling pathway-mediated antiviral immunity through DNA-dependent RNA Polymerase III. Here we investigated whether poly(dA:dT) could inhibit herpes simplex virus type 2 (HSV-2) infection of human cervical epithelial cells (End1/E6E7). We demonstrated that poly(dA:dT) treatment of End1/E6E7 cells could significantly inhibit HSV-2 infection. Mechanistically, poly(dA:dT) treatment of the cells induced the expression of the intracellular IFNs and the multiple antiviral IFN-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15), IFN-stimulated gene 56 (ISG56), 2’-5’-oligoadenylate synthetase 1 (OAS1), 2’-5’-oligoadenylate synthetase 2 (OAS2), myxovirus resistance protein A (MxA), myxovirus resistance protein B (MxB), virus inhibitory protein, endoplasmic reticulum-associated, IFN-inducible (Viperin), and guanylate binding protein 5 (GBP5). Further investigation showed that the activation of RIG-I was largely responsible for poly(dA:dT)-mediated HSV-2 inhibition and IFN/ISGs induction in the cervical epithelial cells, as RIG-I knockout abolished the poly(dA:dT) actions. These observations demonstrate the importance for design and development of AT-rich dsDNA-based intervention strategies to control HSV-2 mucosal transmission in FRT.
CD52 Is Elevated on B cells of SLE Patients and Regulates B Cell Function

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.
A New Record of Oxytricha granulifera granulifera Foissner and Adam, 1983 (Protozoa, Ciliophora, Oxytrichidae) From a Hot Spring in Iceland, With Notes on Its Abnormal Form During Cultivation

We isolated a population of Oxytricha granulifera granulifera Foissner and Adam (1983) from a hot spring in Iceland. The pure culture of this isolate was established at room temperature in the laboratory. This allowed for a detailed investigation, informed by integrated approaches, of the isolate’s morphology and morphogenesis, as well as molecular phylogeny. Results showed that the morphological and morphogenetic characteristics of the Iceland population are consistent with those of other populations. During the 3-year long period of laboratory cultivation, some abnormal individuals appeared repeatedly in the culture system. Interestingly, the morphological characteristics of these abnormal cells were rather stable, and were as follows: 1) body slender and elliptical-shaped; 2) remarkably shortened adoral zone and significantly reduced number of adoral membranelles; and 3) loss of undulating membranes. Resting cysts, binary fission and conjugate reproduction were not found in abnormal specimens. Although the morphology of abnormal individuals changed significantly, the sequences of the SSU rDNA of the normal and abnormal morphotypes were the same. Phylogenetic analyses showed that the two morphotypes clustered in a clade with other populations of O. granulifera granulifera.
Students’ Perception of Teachers’ Reference Norm Orientation and Cheating in the Classroom

Students’ cheating is a serious problem: It undermines the chance to adequately promote, support, and evaluate them. To explain cheating behavior, research seldom focuses on perceived teachers’ characteristics. Thus, we investigate the relationship between students’ cheating behavior and an important teacher characteristic, individual reference norm orientation (IRNO; i.e., the tendency to evaluate students based on their performance development over time). We examined cheating on written exams, on homework, and in oral exams among N = 601 students (64.2% girls; M age = 16.07 years) in N = 31 language classes. Results from doubly manifest multi-level analyses showed that, on the classroom level, cheating on written exams and on homework occurred less frequently the more the classroom of students perceived their teachers as having an IRNO. We found no further evidence for other cheating factors or student characteristics. This supports the idea that teacher characteristics are associated with some forms of students’ cheating behavior.
Quinolinate Phosphoribosyltransferase Promotes Invasiveness of Breast Cancer Through Myosin Light Chain Phosphorylation

Perturbed Nicotinamide adenine dinucleotide (NAD+) homeostasis is involved in cancer progression and metastasis. Quinolinate phosphoribosyltransferase (QPRT) is the rate-limiting enzyme in the kynurenine pathway participating in NAD+ generation. In this study, we demonstrated that QPRT expression was upregulated in invasive breast cancer and spontaneous mammary tumors from MMTV-PyVT transgenic mice. Knockdown of QPRT expression inhibited breast cancer cell migration and invasion. Consistently, ectopic expression of QPRT promoted cell migration and invasion in breast cancer cells. Treatment with QPRT inhibitor (phthalic acid) or P2Y11 antagonist (NF340) could reverse the QPRT-induced invasiveness and phosphorylation of myosin light chain. Similar reversibility could be observed following treatment with Rho inhibitor (Y16), ROCK inhibitor (Y27632), PLC inhibitor (U73122), or MLCK inhibitor (ML7). Altogether, these results indicate that QPRT enhanced breast cancer invasiveness probably through purinergic signaling and might be a potential prognostic indicator and therapeutic target in breast cancer.
Reliance on Visual Input for Balance Skill Transfer in Older Adults: EEG Connectome Analysis Using Minimal Spanning Tree

Skill transfer from trained balance exercises is critical to reduce the rate of falls in older adults, who rely more on vision to control postural responses due to age-dependent sensory reweighting. With an electroencephalography (EEG) minimum spanning tree (MST) structure, the purpose of this study was to compare the organization of supraspinal neural networks of transfer effect after postural training using full and intermittent visual feedbacks for older adults. Thirty-two older adults were randomly assigned to the stroboscopic vision (SV) (n = 16; age = 64.7 ± 3.0 years) and control (16; 66.3 ± 2.7 years) groups for balance training on a stabilometer (target task) with on-line visual feedback. Center-of-pressure characteristics and an MST-based connectome of the weighted phase-lag index during the bilateral stance on a foam surface (transfer task) were compared before and after stabilometer training. The results showed that both the SV and control groups showed improvements in postural stability in the trained task (p < 0.001). However, unlike the control group (p = 0.030), the SV group who received intermittent visual feedback during the stabilometer training failed to reduce the size of postural sway in the anteroposterior direction of the postural transfer task (unstable stance on the foam surface) in the post-test (p = 0.694). In addition, network integration for the transfer task in the post-test was absent in the SV group (p > 0.05). For the control group in the post-test, it manifested with training-related increases in leaf fraction in beta band (p = 0.015) and maximum betweenness in alpha band (p = 0.018), but a smaller diameter in alpha (p = 0.006)/beta (p = 0.021) bands and average eccentricity in alpha band (p = 0.028). In conclusion, stabilometer training with stroboscopic vision impairs generalization of postural skill to unstable stance for older adults. Adequate visual information is a key mediating factor of supraspinal neural networks to carry over balance skill in older adults.