Miracle-dz/UniFAR-FTUs huggingface dataset:
Horizontal Cell Feedback to Cone Photoreceptors in Mammalian Retina: Novel Insights From the GABA-pH Hybrid Model

How neurons in the eye feed signals back to photoreceptors to optimize sensitivity to patterns of light appears to be mediated by one or more unconventional mechanisms. Via these mechanisms, horizontal cells control photoreceptor synaptic gain and enhance key aspects of temporal and spatial center-surround receptive field antagonism. After the transduction of light energy into an electrical signal in photoreceptors, the next key task in visual processing is the transmission of an optimized signal to the follower neurons in the retina. For this to happen, the release of the excitatory neurotransmitter glutamate from photoreceptors is carefully regulated via horizontal cell feedback, which acts as a thermostat to keep the synaptic transmission in an optimal range during changes to light patterns and intensities. Novel findings of a recently described model that casts a classical neurotransmitter system together with ion transport mechanisms to adjust the alkaline milieu outside the synapse are reviewed. This novel inter-neuronal messaging system carries feedback signals using two separate, but interwoven regulated systems. The complex interplay between these two signaling modalities, creating synaptic modulation-at-a-distance, has obscured it’s being defined. The foundations of our understanding of the feedback mechanism from horizontal cells to photoreceptors have been long established: Horizontal cells have broad receptive fields, suitable for providing surround inhibition, their membrane potential, a function of stimulus intensity and size, regulates inhibition of photoreceptor voltage-gated Ca2+ channels, and strong artificial pH buffering eliminates this action. This review compares and contrasts models of how these foundations are linked, focusing on a recent report in mammals that shows tonic horizontal cell release of GABA activating Cl− and HCO3− permeable GABA autoreceptors. The membrane potential of horizontal cells provides the driving force for GABAR-mediated HCO3− efflux, alkalinizing the cleft when horizontal cells are hyperpolarized by light or adding to their depolarization in darkness and contributing to cleft acidification via NHE-mediated H+ efflux. This model challenges interpretations of earlier studies that were considered to rule out a role for GABA in feedback to cones.
Adenoviral-Vectored Mayaro and Chikungunya Virus Vaccine Candidates Afford Partial Cross-Protection From Lethal Challenge in A129 Mouse Model

Mayaro (MAYV) and chikungunya viruses (CHIKV) are vector-borne arthritogenic alphaviruses that cause acute febrile illnesses. CHIKV is widespread and has recently caused large urban outbreaks, whereas the distribution of MAYV is restricted to tropical areas in South America with small and sporadic outbreaks. Because MAYV and CHIKV are closely related and have high amino acid similarity, we investigated whether vaccination against one could provide cross-protection against the other. We vaccinated A129 mice (IFNAR −/−) with vaccines based on chimpanzee adenoviral vectors encoding the structural proteins of either MAYV or CHIKV. ChAdOx1 May is a novel vaccine against MAYV, whereas ChAdOx1 Chik is a vaccine against CHIKV already undergoing early phase I clinical trials. We demonstrate that ChAdOx1 May was able to afford full protection against MAYV challenge in mice, with most samples yielding neutralizing PRNT80 antibody titers of 1:258. ChAdOx1 May also provided partial cross-protection against CHIKV, with protection being assessed using the following parameters: survival, weight loss, foot swelling and viremia. Reciprocally, ChAdOx1 Chik vaccination reduced MAYV viral load, as well as morbidity and lethality caused by this virus, but did not protect against foot swelling. The cross-protection observed is likely to be, at least in part, secondary to cross-neutralizing antibodies induced by both vaccines. In summary, our findings suggest that ChAdOx1 Chik and ChAdOx1 May vaccines are not only efficacious against CHIKV and MAYV, respectively, but also afford partial heterologous cross-protection.
Gβγ is a direct regulator of endogenous p101/p110γ and p84/p110γ PI3Kγ complexes in mouse neutrophils

PI3Kγ complexes containing p101 or p84 are directly activated by Gβγ in a GPCR-dependent manner in neutrophils. How to activate PI3Kγ in neutrophils A critical effector of GPCRs in neutrophils is PI3Kγ, but how the two PI3Kγ complexes are activated by Gβγ has been controversial, likely due to a reliance on in vitro assays using cultured cells. Rynkiewicz et al. generated mice with knock-in mutations in the Gβγ-binding sites in the PI3Kγ catalytic subunit p110γ or in the regulatory subunit p101. Loss of Gβγ binding to p110γ had greater effects on signaling in response to different GPCR agonists than loss of Gβγ binding to p101. Although the migration of isolated neutrophils was affected only by loss of Gβγ binding to p110γ, neutrophil migration in mouse models of neutrophilic inflammation was strongly impaired by defective Gβγ binding to either p110γ or p101. These results refine our understanding of how PI3Kγ is activated in neutrophils and emphasize the importance of investigating signaling pathways in physiologically relevant contexts. The PI3Kγ isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3Kγ, p101/p110γ and p84/p110γ, receive direct regulation through Gβγ or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent Gβγ binding to p110γ (RK552DD) or to p101 (VVKR777AAAA) and investigated the effects of these mutations in primary neutrophils and in mouse models of neutrophilic inflammation. Loss of Gβγ binding to p110γ substantially reduced the activation of both p101/p110γ and p84/p110γ in neutrophils by various GPCR agonists. Loss of Gβγ binding to p101 caused more variable effects, depending on both the agonist and cellular response, with the biggest reductions seen in PIP3 production by primary neutrophils in response to LTB4 and MIP-2 and in the migration of neutrophils during thioglycolate-induced peritonitis or MIP2-induced ear pouch inflammation. We also observed that p101VVKR777AAAA neutrophils showed enhanced p84-dependent ROS responses to fMLP and C5a, suggesting that competition may exist between p101/p110γ and p84/p110γ for Gβγ subunits downstream of GPCR activation. GPCRs did not activate p110γ in neutrophils from mice lacking both the p101 and p84 regulatory subunits, indicating that RAS binding to p110γ is insufficient to support GPCR activation in this cell type. These findings define a direct role for Gβγ subunits in activating both of the endogenous PI3Kγ complexes and indicate that the regulatory PI3Kγ subunit biases activation toward different GPCRs.
Trichoderma Counteracts the Challenge of Phytophthora nicotianae Infections on Tomato by Modulating Plant Defense Mechanisms and the Expression of Crinkler, Necrosis-Inducing Phytophthora Protein 1, and Cellulose-Binding Elicitor Lectin Pathogenic Effectors

Decoding the mechanisms of plant defense against plant pathogens in a scenario where antagonistic activity and the plant growth-promoting effects of useful organisms intervene simultaneously is a new frontier of plant pathology. Here, we demonstrated that (i) two selected strains of Trichoderma asperellum and Trichoderma atroviride promoted tomato (Solanum lycopersicum) growth and reduced the severity of disease caused by the oomycete Phytophthora nicotianae and (ii) the genetic patterns of the components of the experimental model system tomato–Trichoderma spp. –P. nicotianae were differentially expressed. The beneficial effects in both the promotion of the growth of host plant and the biological control of the pathogen by two selected strains of different Trichoderma species were tested both in planta and in vitro. In both respects, T. atroviride demonstrated to be more effective than T. asperellum. Additionally, the simultaneous transcriptional reprogramming of several plant defense-related genes, pathogen effectors, and mycoparasitism-related genes in tomato, P. nicotianae, and Trichoderma spp. , respectively, was evaluated during the three-component interaction. Results support the hypothesis that Trichoderma spp. elicit the expression of plant defense-related genes. As expected, a mycoparasitism-related gene was significantly up-regulated in Trichoderma-colonizing tomato plants infected by P. nicotianae. Finally, a marked up-regulation of the genes encoding two necrosis-inducing effectors was observed in P. nicotianae infecting tomato plants colonized by Trichoderma. In conclusion, this study is a contribution toward understanding the genetic pathways related with the ability of Trichoderma spp. to counteract the challenge of P. nicotianae infections on tomato. Additionally, the experiments revealed the beneficial effects in the tomato growth promotion of a new T. atroviride strain and its good antagonistic effectiveness in the biological control of root and crown rot incited by P. nicotianae, confirming that Trichoderma spp. can be a powerful tool in integrated pest management strategies of Phytophthora diseases of horticultural crops.
Epidemiology of Tuberculosis in Multi-Host Wildlife Systems: Implications for Black (Diceros bicornis) and White (Ceratotherium simum) Rhinoceros

Cases of tuberculosis (TB) resulting from infection with Mycobacterium tuberculosis complex (MTBC) have been recorded in captive white (Ceratotherium simum) and black (Diceros bicornis) rhinoceros. More recently, cases have been documented in free-ranging populations of both species in bovine tuberculosis (bTB) endemic areas of South Africa. There is limited information on risk factors and transmission patterns for MTBC infections in African rhinoceros, however, extrapolation from literature on MTBC infections in other species and multi-host systems provides a foundation for understanding TB epidemiology in rhinoceros species. Current diagnostic tests include blood-based immunoassays but distinguishing between subclinical and active infections remains challenging due to the lack of diagnostic techniques. In other species, demographic risk factors for MTBC infection include sex and age, where males and adults are generally at higher risk than females and younger individuals. Limited available historical information reflects similar age- and sex-associated patterns for TB in captive black and white rhinoceros, with more reports of MTBC-associated disease in black rhinoceros than in white rhinoceros. The degree of MTBC exposure in susceptible wildlife depends on their level of interaction, either directly with other infected individuals or indirectly through MTBC contaminated environments, which is dependent on the presence and abundance of infected reservoir hosts and the amount of MTBC shed in their excreta. Captive African rhinoceros have shown evidence of MTBC shedding, and although infection levels are low in free-ranging rhinoceros, there is a risk for intraspecies transmission. Free-ranging rhinoceros in bTB endemic areas may be exposed to MTBC from other infected host species, such as the African buffalo (Syncerus caffer) and greater kudu (Tragelaphus strepsiceros), through shared environmental niches, and resource co-utilization. This review describes current knowledge and information gaps regarding the epidemiology of TB in African rhinoceros.
Transcriptomic Analyses and Potential Therapeutic Targets of Pancreatic Cancer With Concomitant Diabetes

Background Type 2 diabetes mellitus (T2DM) known as non-insulin-dependent diabetes mellitus, which is increasingly acknowledged as being associated with an increased risk for a series of cancers. Pancreatic cancer is currently the fourth most common cause of cancer-related mortality, which has been proved to be worsened by internal diabetic condition. However, the underlying molecular mechanisms are less addressed. Furthermore, current knowledge revealed that therapeutic strategy by anti-diabetes for pancreatic cancer under diabetes condition have no satisfactory efficacy, and nor by chemotherapy in our study. Methods To clarify these mysteries and widen our knowledge, both obesity-associated and non-obese-associated T2DM mouse models were generated by chemical induction with streptozotocin (STZ) and leptin receptor knockout (db/db) in mice. Then, the process of tumor progression was researched, and the gene expression profiling of pancreatic cancer in mice was performed using RNA-seq. Results Our results showed that pancreatic cancer malignancy was increased with notable proliferation and metastatic potential in two diabetic mice model. Totally, 136 and 64 significantly differentially expressed genes (DEGs) were identified in STZ and db/db mice by transcriptomic analysis. The results also suggested that different carcinogenesis-related genes and potential molecular mechanisms contribute to the malignancy of pancreatic cancer in obesity-associated and non-obesity-associated T2DM. In obesity-associated db/db mice, the GO subcategories associated with most of the genes with downregulated expression are involved in the immune response. However, in non-obesity-associated STZ mice, in addition to the immune response category, the enriched subcategories also included angiogenesis and the extracellular matrix. While, two genes respectively encoding MMP-2 and MMP-9 were simultaneously abnormal up-regulated in pancreatic cancer tissue from diabetic mice of both STZ and db/db, that could act as potential therapeutic targets for significantly suppressing the malignant progression. Furthermore, an optimizing therapeutic strategy was further proposed that combining MMP-2/9 inhibitor with gemcitabine significantly enhanced anti-tumor effects on pancreatic cancer under diabetic condition, providing a theoretical basis for clinical applications. Conclusions Generally, this study provides a comprehensive insight into diabetes as a risk factor for pancreatic cancer and has the potential to guide the development of enhanced treatment strategies.
Protein Cargo of Extracellular Vesicles From Bovine Follicular Fluid and Analysis of Their Origin From Different Ovarian Cells

Follicular fluid (FF) fills the interior portion of the ovarian antral follicle and provides a suitable microenvironment for the growth of the enclosed oocyte through molecular factors that originate from plasma and the secretions of follicular cells. FF contains extracellular nanovesicles (ffEVs), including 30–100-nm membrane-coated exosomes, which carry different types of RNA, proteins, and lipids and directly influence oocyte competence to develop embryo. In the present study, we aimed to characterize the protein cargo of EVs from the FF of 3–6-mm follicles and uncover the origins of ffEVs by assessing expression levels of corresponding mRNAs in bovine follicular cells and oocyte and cell proteomes. Isolated exosome-like ffEVs were 53.6 + 23.3 nm in size and could be internalized by cumulus-oocyte complex. Proteomes of ffEVs and granulosa cells (GC) were assessed using nanoflow liquid chromatography coupled with high-resolution tandem mass spectrometry after the gel fractionation of total proteins. In total, 460 protein isoforms corresponding to 322 unique proteins were identified in ffEVs; among them, 190 were also identified via GC. Gene Ontology terms related to the ribosome, protein and RNA folding, molecular transport, endocytosis, signal transduction, complement and coagulation cascades, apoptosis, and developmental biology pathways, including PI3K-Akt signaling, were significantly enriched features of ffEV proteins. FfEVs contain numerous ribosome and RNA-binding proteins, which may serve to compact different RNAs to regulate gene expression and RNA degradation, and might transfer ribosomal constituents to the oocyte. Majority of genes encoding ffEV proteins expressed at different levels in follicular cells and oocyte, corroborating with numerous proteins, which were reported in bovine oocyte and cumulus cells in other studies thus indicating possible origin of ffEV proteins. The limited abundance of several mRNAs within follicular cells indicated that corresponding ffEV proteins likely originated from circulating exosomes released by other tissues. Analysis of bovine ffEV transcriptome revealed that mRNAs present in ffEV accounted for only 18.3% of detected ffEV proteins. In conclusion, our study revealed numerous proteins within ffEVs, which originated from follicular and other cells. These proteins are likely involved in the maintenance of follicular homeostasis and may affect oocyte competence.
Hormone Signaling and Its Interplay With Development and Defense Responses in Verticillium-Plant Interactions

Soilborne plant pathogenic species in the fungal genus Verticillium cause destructive Verticillium wilt disease on economically important crops worldwide. Since R gene-mediated resistance is only effective against race 1 of V. dahliae, fortification of plant basal resistance along with cultural practices are essential to combat Verticillium wilts. Plant hormones involved in cell signaling impact defense responses and development, an understanding of which may provide useful solutions incorporating aspects of basal defense. In this review, we examine the current knowledge of the interplay between plant hormones, salicylic acid, jasmonic acid, ethylene, brassinosteroids, cytokinin, gibberellic acid, auxin, and nitric oxide, and the defense responses and signaling pathways that contribute to resistance and susceptibility in Verticillium-host interactions. Though we make connections where possible to non-model systems, the emphasis is placed on Arabidopsis-V. dahliae and V. longisporum interactions since much of the research on this interplay is focused on these systems. An understanding of hormone signaling in Verticillium-host interactions will help to determine the molecular basis of Verticillium wilt progression in the host and potentially provide insight on alternative approaches for disease management.
Scalable unsupervised multi-criteria trajectory segmentation and driving preference mining

We present analysis techniques for large trajectory data sets that aim to provide a semantic understanding of trajectories reaching beyond them being point sequences in time and space. The presented techniques use a driving preference model w.r. t. road segment traversal costs, e.g., travel time and distance, to analyze and explain trajectories. In particular, we present trajectory mining techniques that can (a) find interesting points within a trajectory indicating, e.g., a via-point, and (b) recover the driving preferences of a driver based on their chosen trajectory. We evaluate our techniques on the tasks of via-point identification and personalized routing using a data set of more than 1 million vehicle trajectories collected throughout Denmark during a 3-year period. Our techniques can be implemented efficiently and are highly parallelizable, allowing them to scale to millions or billions of trajectories.
Truly Exploring Multiple References for Machine Translation Evaluation

Multiple references in machine translation evaluation are usually under-explored: they are ignored by alignment-based metrics and treated as bags of n-grams in string matching evaluation metrics, none of which take full advantage of the recurring information in these references. By exploring information on the n-gram distribution and on divergences in multiple references, we propose a method of n-gram weighting and implement it to gen-erate new versions of the popular BLEU and NIST metrics. Our metrics are tested in two into-English machine translation datasets. They lead to a signiﬁcant increase in Pearson’s correlation with human ﬂuency judgements at system-level evaluation. The new NIST metric also outperforms the standard NIST for document-level evaluation.
Identifying Robust Microbiota Signatures and Interpretable Rules to Distinguish Cancer Subtypes

Cancer can be generally defined as a cluster of systematic diseases triggered by abnormal cell proliferation and growth. With the development of biological sciences and biotechnologies, the etiology of cancer is partially revealed, including some of the most substantial pathogenic factors [either endogenous (genetics) or exogenous (environmental)]. However, some remaining factors that contribute to the tumorigenesis but have not been analyzed and discussed in detail remain. For instance, some typical correlations between microorganisms and tumorigenesis have been reported already, but previous studies are just sporadic studies on single microorganism–cancer subtype pairs and do not explain and validate the specific contribution of microbiome on tumorigenesis. On the basis of the systematic microbiome analyses of blood and cancer-associated tissues in cancer patients/controls in public domain, we performed interpretable analyses. We identified several core regulatory microorganisms that contribute to the classification of multiple tumor subtypes and established quantitative predictive models for interpretable prediction by using multiple machine learning methods. We also compared the optimal features (microorganisms) and rules identified from microbiome profiles processed using the Kraken and the SHOGUN. Collectively, our study identified new microbiome signatures and their interpretable classification rules for cancer discrimination and carried out reliable methodological comparison for robust cancer microbiome analyses, thereby promoting the development of tumor etiology at the microbiome level.
Visual–tactile object recognition of a soft gripper based on faster Region-based Convolutional Neural Network and machining learning algorithm

Object recognition is a prerequisite to control a soft gripper successfully grasping an unknown object. Visual and tactile recognitions are two commonly used methods in a grasping system. Visual recognition is limited if the size and weight of the objects are involved, whereas the efficiency of tactile recognition is a problem. A visual–tactile recognition method is proposed to overcome the disadvantages of both methods in this article. The design and fabrication of the soft gripper considering the visual and tactile sensors are implemented, where the Kinect v2 is adopted for visual information, bending and pressure sensors are embedded to the soft fingers for tactile information. The proposed method is divided into three steps: initial recognition by vision, detail recognition by touch, and a data fusion decision making. Experiments show that the visual–tactile recognition has the best results. The average recognition accuracy of the daily objects by the proposed method is also the highest. The feasibility of the visual–tactile recognition is verified.
Is a Change as Good as a Rest? Comparing BreakTypes for Spaced Practice in a Platformer Game

The development of skill in games is of interest to players and designers. Spaced practice in games, i.e., adding breaks to core gameplay, has been shown to improve performance over playing continuously; however, it is unclear if the benefits of spaced practice apply in complex games that combine several skills and elements. Further, many break-like activities are already present in games (e.g., cutscenes, mini-games, leaderboards, loading screens) and we do not know whether engaging with these as breaks reduces the benefits of spaced practice. We built a custom 2D platform game in which players wall-jump, swing, via a grapple hook and double-jump through an obstacle course and used it as the core gameplay activity in two experiments---one to test if spaced practice improves performance in a complex game, and another to determine how spaced practice is affected by the choice of in-game break activity. We show that spaced practice significantly improves skill development in a complex platformer game; that spaced practice is effective across several types of ecologically-valid break activities; and that the use of short breaks does not subvert flow states during play.