Miracle-dz/UniFAR-FTUs huggingface dataset:
Host miR-129-5p reverses effects of ginsenoside Rg1 on morphine reward possibly mediated by changes in B. vulgatus and serotonin metabolism in hippocampus

ABSTRACT Morphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in the development of disease. Ginsenoside Rg1 exhibits an anti-addiction effect and significantly improves intestinal microbiota disorders. In pseudo-germfree mice, supplementation with Bacteroides vulgatus (B. vulgatus) synergistically enhanced Rg1 to alleviate morphine addiction. However, it is currently unknown the relationship between fecal miRNAs in morphine-exposed mice and their potential modulation of gut microbiome, as well as their role in mediating the resistance of ginsenoside Rg1 to drug addiction. Here, we studied the fecal miRNA abundance in mice treated with morphine to explore the different miRNAs expressed, their association with B. vulgatus and their role in the amelioration of morphine reward by ginsenoside Rg1. Our results indicated ginsenoside Rg1 attenuated the significant increase in miR-129-5p expression observed in the feces of morphine-treated mice. The miR-129-5p, specifically, inhibited the growth of B. vulgatus by modulating the transcript of the site-tag BVU_RS11835 and increased the levels of 5-hydroxytryptophan and indole-3-carboxaldehyde in vitro. Subsequently, we noticed that oral administration of synthetic miR-129-5p increased 5-HT levels in the hippocampus and inhibited the reversal effect of ginsenoside Rg1 both on the relative abundance of B. vulgatus in the feces and CPP effect induced by morphine exposure. In short, Ginsenoside Rg1 might play an indirect role in remodeling the B. vulgatus against morphine reward by suppressing miR-129-5p expression. These results highlight the role of miR-129-5p and B. vulgatus in morphine reward and the anti-morphine addiction of ginsenoside Rg1. GRAPHICAL ABSTRACT
Human immunodeficiency virus transmission—Mechanisms underlying the cell‐to‐cell spread of human immunodeficiency virus

Despite the success of combined antiretroviral therapy in controlling viral load and reducing the risk of human immunodeficiency virus (HIV) transmission, an estimated 1.5 million new infections occurred worldwide in 2021. These new infections are mainly the result of sexual intercourse and thus involve cells present on the genital mucosa, such as dendritic cells (DCs), macrophages (Mø) and CD4+ T lymphocytes. Understanding the mechanisms by which HIV interacts with these cells and how HIV exploits these interactions to establish infection in a new human host is critical to the development of strategies to prevent and control HIV transmission. In this review, we explore how HIV has evolved to manipulate some of the physiological roles of these cells, thereby gaining access to strategic cellular niches that are critical for the spread and pathogenesis of HIV infection. The interaction of HIV with DCs, Mø and CD4+ T lymphocytes, and the role of the intercellular transfer of viral particles through the establishment of the infectious or virological synapses, but also through membrane protrusions such as filopodia and tunnelling nanotubes (TNTs), and cell fusion or cell engulfment processes are presented and discussed.
Single-Actuator-Based Three-DoF Planar Manipulation via a Viscoelastic and Nonparallel Hybrid Joint Mechanism

This paper proposes a dexterous nonprehensile manipulation using the vibration of a plate, in which a three-degree-of-freedom (DoF) motion of a part is controlled based on a single actuator. First, a manipulator whose end effector is a flat plate is introduced. The manipulator employs a hybrid joint mechanism with a viscoelasticity and a nonparallel axis layout. The characteristic of the mechanism is that the shape, orientation, and size of the vibrational orbit of the plate vary based on the sinusoidal displacement input to the actuator. Subsequently, the trajectories of multiple point masses on the plate are analyzed to understand the approximated three-DoF motion of a part. The simulation results reveal that the whirlpool-like characteristics of the trajectory map, which aid in the rotational and translational motions of the part, can be managed by the input frequency, offset angle, and amplitude of the sinusoidal displacement input. Based on the trajectory maps, nine primitives for manipulating the part are designed. Finally, the proposed manipulation scheme is experimentally validated using a prototype. After confirming the nine primitives in the experiment, applications to one-DoF, two-DoF, and three-DoF parts feeding tasks are demonstrated.
Hunter: Exploring High-Order Consistency for Point Cloud Registration With Severe Outliers

After decades of investigation, point cloud registration is still a challenging task in practice, especially when the correspondences are contaminated by a large number of outliers. It may result in a rapidly decreasing probability of generating a hypothesis close to the true transformation, leading to the failure of point cloud registration. To tackle this problem, we propose a transformation estimation method, named Hunter, for robust point cloud registration with severe outliers. The core of Hunter is to design a global-to-local exploration scheme to robustly find the correct correspondences. The global exploration aims to exploit guided sampling to generate promising initial alignments. To this end, a hypergraph-based consistency reasoning module is introduced to learn the high-order consistency among correct correspondences, which is able to yield a more distinct inlier cluster that facilitates the generation of all-inlier hypotheses. Moreover, we propose a preference-based local exploration module that exploits the preference information of top-$k$k promising hypotheses to find a better transformation. This module can efficiently obtain multiple reliable transformation hypotheses by using a multi-initialization searching strategy. Finally, we present a distance-angle based hypothesis selection criterion to choose the most reliable transformation, which can avoid selecting symmetrically aligned false transformations. Experimental results on simulated, indoor, and outdoor datasets, demonstrate that Hunter can achieve significant superiority over the state-of-the-art methods, including both learning-based and traditional methods (as shown in Fig. 1). Moreover, experimental results also indicate that Hunter can achieve more stable performance compared with all other methods with severe outliers.
Attentional capture or multisensory integration? (Commentary on Bean et al.,  2021 )

The study by Bean, Stein and Rowland, titled ‘Stimulus value gates multisensory integration’ (Bean et al., 2021), comprises a series of experiments focusing on two highly interesting aspects. First, the behavioural task presented to cats is of multisensory nature, which is not being tested widely in animals in general and thus contributes important data for a comparative approach. Second, the often neglected effect of reward experience on behavioural training and testing is relevant to any study that uses non-naive animals in the (neuro)ethological research field. Despite the interesting approach, the study bears some problems in its current interpretation. There are three main issues that challenge the aspect of multisensory integration and offer an alternative interpretation of the results, namely, an attention-based effect. First, the physical properties of the stimuli may inhibit multisensory binding in its ‘classical’ form. Second, the acoustic stimuli may instead evoke attentional mechanisms that can nicely explain the results. Third, calculating the multisensory enhancement in a more conservative way yields much lower effects. 2 | PHYSICAL PROPERTIES OF THE STIMULI
An optimal variational mode decomposition for rolling bearing fault feature extraction

Rolling bearings usually work in tough conditions, which makes the collected vibration signals complex and the fault features weak. Hence, fault feature extraction methods for rolling bearings have become a research focus. In this paper, a new method termed optimal variational mode decomposition (VMD) is proposed to extract rolling bearing fault features. Firstly, since envelope entropy is very sensitive to fault signal features, envelope entropy is used as a fitness function, which is an objective function for the whale optimization algorithm (WOA). Secondly, the WOA has numerous merits, such as simple operation, fewer adjustment parameters and a strong ability for jumping out of the local optimum, and it is applied to the optimization of VMD. Finally, intrinsic mode function components are processed through a Teager energy operator. The proposed method is employed to analyze the experimental signal collected from rolling bearings. The comparison results show that the proposed method is more effective and demonstrates superiority over empirical mode decomposition, local mean decomposition and wavelet packet decomposition.
Domain-adaptive Graph Attention-supervised Network for Cross-network Edge Classification

Graph neural networks (GNNs) have shown great ability in modeling graphs; however, their performance would significantly degrade when there are noisy edges connecting nodes from different classes. To alleviate negative effect of noisy edges on neighborhood aggregation, some recent GNNs propose to predict the label agreement between node pairs within a single network. However, predicting the label agreement of edges across different networks has not been investigated yet. Our work makes the pioneering attempt to study a novel problem of cross-network homophilous and heterophilous edge classification (CNHHEC) and proposes a novel domain-adaptive graph attention-supervised network (DGASN) to effectively tackle the CNHHEC problem. First, DGASN adopts multihead graph attention network (GAT) as the GNN encoder, which jointly trains node embeddings and edge embeddings via the node classification and edge classification losses. As a result, label-discriminative embeddings can be obtained to distinguish homophilous edges from heterophilous edges. In addition, DGASN applies direct supervision on graph attention learning based on the observed edge labels from the source network, thus lowering the negative effects of heterophilous edges while enlarging the positive effects of homophilous edges during neighborhood aggregation. To facilitate knowledge transfer across networks, DGASN employs adversarial domain adaptation to mitigate domain divergence. Extensive experiments on real-world benchmark datasets demonstrate that the proposed DGASN achieves the state-of-the-art performance in CNHHEC.
SIRT2 inhibition rescues neurodegenerative pathology but increases systemic in�ammation in a transgenic mouse model of Alzheimer’s disease

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, in�ammation, cancer and neurodegenerative diseases; however, its speci�c function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In the present study we demonstrate that pharmacological treatment with 33i improved cognitive dysfunction and LTP, and reduced amyloid pathology and neuroin�ammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of in�ammatory cytokines IL-1 β , Tnf-α , Tgf-β , IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic in�ammation. These results suggest that, although SIRT2 pharmacological inhibition may have bene�cial consequences in neurodegenerative diseases, its systemic adverse side effects should be taken into account. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.
Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease

Abstract Background Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls. Results We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations. Conclusions Overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden. Keywords Untranslated regions, promoters, splicing, rare disease, non-coding, regulatory regions
Excess mortality and long-term disability from healthcare-associated carbapenem-resistant Acinetobacter baumannii infections: A nationwide population-based matched cohort study

Background Carbapenem resistance is perceived as a clinical challenge in the management of debilitated and immunocompromised patients who eventually will die from underlying diseases. We aimed to examine whether carbapenem resistance per se, rather than the underlying diseases, negatively affect outcomes, by comparing the excess mortality and morbidity from healthcare-associated infections (HAIs) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-susceptible A. baumannii (CSAB). Methods This was a nationwide retrospective matched cohort study of hospitalized patients in 96 hospitals which participated in Taiwan Nosocomial Infection Surveillance (TNIS). A total of 2,213 patients with A. baumannii HAIs were individually matched to 4,426 patients without HAIs. Main outcomes were excess risks for one-year all-cause mortality and one-year new-onset chronic ventilator dependence or dialysis-dependent end-stage renal disease. Results Excess one-year mortality was 27.2% in CRAB patients, compared with their matched uninfected inpatients, as well as 15.4% in CSAB patients (also compared with their matched uninfected inpatients), resulting in an attributable mortality of 11.8% (P <0.001) associated with carbapenem resistance. The excess risk associated with carbapenem resistance for new-onset chronic ventilator dependence was 5.2% (P <0.001). Carbapenem resistance was also associated with an extra cost of $2,511 per case of A. baumannii HAIs (P <0.001). Conclusion Carbapenem resistance is associated with a significant disease burden in terms of excess mortality, long-term ventilator dependence, and medical cost. Further studies on effects of antimicrobial stewardship programs in decreasing this burden are warranted.
Plasma exchange plus glucocorticoids in the treatment of immune checkpoint inhibitor‐induced myocarditis: A case series and review

Immune checkpoint inhibitors (ICIs), including antiprogrammed cell‐death (PD)‐1/anti‐PD‐ligand (PDL‐1) monoclonal antibodies, are effective at improving the prognosis of patients with cancer. Among immune‐related adverse events, myocarditis associated with anti‐PD‐1/anti‐PD‐L1 antibodies is rare but lacks effective treatment and mortality is very high. In this study, the authors extracted data from the previous 8 years from electronic medical records housed in the hospital information system to identify patients hospitalized with myocarditis putatively caused by anti‐PD‐1/anti‐PD‐L1 tumor therapy. Clinical data from these patients are reported. Four patients who developed myocarditis after undergoing treatment with anti‐PD‐1/anti‐PD‐L1 antibodies for malignant tumors, all of whom responded favorably to therapy consisting of plasma exchange and glucocorticoids for myocarditis, and all patients improved and were discharged from hospital. Plasma exchange plus systemic glucocorticoids may be effective for treating anti‐PD‐1/anti‐PD‐L1 antibody‐induced myocarditis in patients with cancer.
Stress Biomarkers and Child Development in Young Children in Bangladesh

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders (hereafter referred to as contrasts) using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We observed 135 primary contrasts of the differences in child development outcomes at the 75th and 25th percentiles of stress biomarkers, where we detected significant relationships in 5 out of 30 contrasts (17%) of HPA axis activity, 1 out of 30 contrasts (3%) of SAM activity, and 3 out of 75 contrasts (4%) of oxidative status. These findings revealed that measures of HPA axis activity were associated with poor development outcomes. We did not find consistent evidence that markers of SAM system activity or oxidative status were associated with developmental status. Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.
Diruthenium(II-III)-ibuprofen-loaded chitosan-based microparticles and nanoparticles systems: encapsulation, characterisation, anticancer activity of the nanoformulations against U87MG human glioma cells

Abstract The aim of this work was to investigate novel formulations containing diruthenium(II-III)-ibuprofen (RuIbp) metallodrug encapsulated into the chitosan (CT) biopolymer. Microparticles (RuIbp/CT MPs, ∼ 1 µm) were prepared by spray-drying, and RuIbp/CT-crosslinked nanoparticles (NPs) by ionic gelation (RuIbp/CT-TPP, TPP = tripolyphosphate (1), RuIbp/CT-TPP-PEG, PEG = poly(ethyleneglycol (2)) or pre-gel/polyelectrolyte complex method (RuIbp/CT-ALG, ALG = alginate (3)). Ru analysis was conducted by energy dispersive x-ray fluorescence or inductively coupled plasma atomic emission spectroscopy, and physicochemical characterisation by powder x-ray diffraction, electronic absorption and FTIR spectroscopies, electrospray ionisation mass spectrometry, thermal analysis, scanning electron, transition electron and atomic force microscopies, and dynamic light scattering. The RuIbp-loaded nanosystems exhibited encapsulation efficiency ∼ 20–37%, drug loading∼ 10-20% (w/w), hydrodynamic diameter (nm): 103.2 ± 7.9 (1), 91.7 ± 12.6 (2), 270.2 ± 58.4 (3), zeta potential (mV): +(47.7 ± 2.8) (1), +(49.2 ± 3.6) (2), -(28.2 ± 2.0) (3). Nanoformulation (1) showed the highest cytotoxicity with increased efficacy in relation to the RuIbp free metallodrug against U87MG human glioma cells.
TSLP shapes the pathogenic responses of memory CD4+ T cells in eosinophilic esophagitis

The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4+ T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in TSLP. We showed that about 10% of esophageal-derived memory CD4+ T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4+ T cells were present in the circulation of individuals with EoE. TSLP increased the proliferation of CD4+ T cells, enhanced type 2 cytokine production, induced the increased abundance of its own receptor, and modified the expression of 212 genes. The epigenetic response to TSLP was associated with an enrichment in BATF and IRF4 chromatin-binding sites, and these transcription factors were induced by TSLP, providing a feed-forward loop. The numbers of circulating and esophageal CD4+ T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4+ T cells. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE. Description Patients with eosinophilic esophagitis have more inflammatory T cells that respond to the cytokine TSLP. Editor’s summary The epithelial-derived cytokine TSLP is increased in abundance in the tissues of patients with allergic disorders, including eosinophilic esophagitis (EoE). TSLP induces the differentiation and maintenance of murine T helper 2 (TH2) cells, which secrete type 2 cytokines to maintain allergic responses. Rochman et al. found a subset of TSLP-responsive memory CD4+ T cells that were increased in number in the blood and esophageal tissue of patients with EoE. These pathogenic TH2-like cells produced type 2 cytokines and exhibited feed-forward signaling to increase TSLP receptor abundance. These findings suggest that anti-TSLP therapy should be further explored for the treatment of EoE. —John F. Foley