Miracle-dz/UniFAR-FTUs huggingface dataset:
Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations

Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported between de novo synthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.
Role of Innate lymphoid Cells in Obesity and Insulin Resistance

Obesity, a growing chronic metabolic disease, greatly increases the risk of metabolic syndrome which includes type 2 diabetes, fatty liver and cardiovascular diseases. Obesity-associated metabolic diseases significantly contribute to mortality and reduce life expectancy. Recently, innate lymphoid cells (ILCs) have emerged as crucial regulators of metabolic homeostasis and tissue inflammation. This review focuses on the roles of ILCs in different metabolic tissues, including adipose tissue, liver, pancreas, and intestine. We briefly outline the relationship between obesity, inflammation, and insulin resistance. We then discuss how ILCs in distinct metabolic organs may function to maintain metabolic homeostasis and contribute to obesity and its associated metabolic diseases. The potential of ILCs as the therapeutic target for obesity and insulin resistance is also addressed.
EHBP1, TUBB, and WWOX SNPs, Gene-Gene and Gene-Environment Interactions on Coronary Artery Disease and Ischemic Stroke

The associations among the EH domain-binding protein 1 (EHBP1), tubulin beta class I (TUBB), and WW domain-containing oxidoreductase (WWOX) single nucleotide polymorphisms (SNPs) and coronary artery disease (CAD) and ischemic stroke (IS) are not yet understood. This study aimed to detect the associations of these SNPs, gene-gene and gene-environment interactions and CAD and IS in the Guangxi Han population. A total of 1853 unrelated subjects were recruited into normal control (n = 638), CAD (n = 622), and IS (n = 593) groups. Related genotypes were determined by high-throughput sequencing. The genotypic and minor allelic frequencies of rs2278075 were different between the CAD and control groups, and those of rs2710642, rs3130685, and rs2278075 were also different between the IS and control groups. The rs2278075T allele, rs3130685-rs2222896-rs2278075, rs3130685-rs2222896-diabetes, rs3130685-rs2222896-drinking, and haplotype rs2710642A-rs10496099C-diabetes interactions were associated with increased risk, while G-T-G-C-G-A and G-T-T-T-G-T-drinking were associated with reduced risk of CAD. The rs2278075T and rs2710642G alleles, rs2710642G-rs10496099C haplotype, rs3130685-rs2278075-rs2222896, and rs2710642-rs2278075-hypertension interactions aggravated the association with IS, whereas the rs3130685T allele, rs2710642A-rs10496099C haplotype and the interactions of H1 (s2710642A-rs10496099C)-H2 (rs2710642G-rs10496099C)-drinking and I1 (A-C-G-C-A-A)-I3 (A-C-G-T-A-A)-I4 (A-C-G-T-G-A)-I5 (G-T-G-C-G-A) diminished the association with IS. Carrying WWOX rs2278075T was strongly associated with CAD or IS, while EHBP1 rs2710642 and TUBB rs3130685 might alter the association of IS by modifying the serum lipid profile. This study demonstrates that the EHBP1, TUBB, and WWOX SNPs, gene-gene and gene-environment interactions are associated with the risk of CAD and IS in the Guangxi Han population.
Improving the Behavioral Intention of Continuous Online Learning Among Learners in Higher Education During COVID-19

The COVID-19 pandemic caused colleges and universities to rely heavily on online learning to continue knowledge dissemination to learners. This study used the second-generation model of unified theory of acceptance and use of technology (UTAUT2) to comprehensively analyze the mediating effects of self-efficacy, which affects learners’ effective use of online tools for learning, and capability of metacognition and self-regulation, which can independently adjust learning progress into the UTAUT2 model, on the learner’s willingness to continue online learning [i.e., their behavioral intention (BI)] by constructing a UTAUT2-based e-learning model. This study administered questionnaires to undergraduates in universities in East China to collect data. The effects of performance expectancy, effort expectancy (EE), social influence (SI), and facilitating conditions (FCs), hedonic motivation (HM), price value (PV), and habits on BI (directly or through mediators) were analyzed through data analysis and structural equation modeling, and the UTAUT2-based e-learning model was accordingly modified. The results indicated that the self-efficacy enhanced the effects of EE, SI, FCs, HM, and PV on learners’ BI; that metacognition and self-regulation (MS) capabilities enhanced the effects of EE on learners’ BI; and that habits had a direct and strong effect on BI. This study also provided some suggestions to enhance higher education learners’ willingness to continue online learning, such as improving social recognition and support, careful design of teaching content, easy-to-use technology, financial support. These results and suggestions may guide colleges and universities in conducting, continuing, or enhancing online education, particularly as the pandemic continues.
Effects of Autonomy Support and Emotion Regulation on Teacher Burnout in the Era of the COVID-19 Pandemic

The COVID-19 pandemic has exacerbated levels of stress and anxiety for P-12 teachers around the globe. The present study aims to understand teachers’ emotional experiences and feelings of burnout during the pandemic, and how individual (i.e., emotion regulation strategies) or contextual factors (e.g., school administrative support) intersect with different facets of their emotional experiences. Using a sequential explanatory mixed methods design, we collected and examined survey and interview data from teachers in the southeastern United States. The structural equation model confirmed the relationships among the following latent variables: negative emotion, emotion regulation, autonomy support, burnout, and teacher enthusiasm. Qualitative findings provide further insight in the contextualized nature of these relationships and how they play out across various schools and districts.
Biological Markers in Early Multiple Sclerosis: the Paved Way for Radiologically Isolated Syndrome

Radiologically Isolated Syndrome (RIS) is characterized by MRI-typical brain lesions fulfilling the 2009 Okuda criteria, detected in patients without clinical conditions suggestive of MS. Half of all RIS patients convert to MS within 10 years. The individual course of the disease, however, is highly variable with 12% of RIS converting directly to progressive MS. Demographic and imaging markers have been associated with the risk of clinical MS in RIS: male sex, younger age, infra-tentorial, and spinal cord lesions on the index scan and gadolinium-enhancing lesions on index or follow-up scans. Although not considered as a distinct MS phenotype, RIS certainly shares common pathological features with early active and progressive MS. In this review, we specifically focus on biological markers that may help refine the risk stratification of clinical MS and disability for early treatment. Intrathecal B-cell activation with cerebrospinal fluid (CSF) oligoclonal bands, elevated kappa free light chains, and cytokine production is specific to MS, whereas neurofilament light chain (NfL) levels reflect disease activity associated with neuroaxonal injury. Specific microRNA profiles have been identified in RIS converters in both CSF and blood. CSF levels of chitinases and glial acidic fibrillary protein (GFAP) reflecting astrogliosis might help predict the evolution of RIS to progressive MS. Innovative genomic, proteomic, and metabolomic approaches have provided several new candidate biomarkers to be explored in RIS. Leveraging data from randomized controlled trials and large prospective RIS cohorts with extended follow-up to identify, as early as possible, biomarkers for predicting greater disease severity would be invaluable for counseling patients, managing treatment, and monitoring.
REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats

REL-1017 (esmethadone; dextromethadone; (S)-methadone) is the opioid-inactive dextro-isomer of the racemic mixture, (R, S)-methadone. REL-1017 acts as a low affinity, low potency N-methyl-D-aspartate receptor (NMDAR) channel blocker with rapid, robust, and sustained therapeutic effects in patients with major depressive disorder (MDD). Systemic administration of NMDAR blockers may cause transient and reversible pathomorphological alterations in brain cortical neurons characterized by cytoplasmic vacuolization, which are called Olney’s lesions, and may also lead to irreversible neuronal necrosis. We determined whether REL-1017 administration via oral gavage for 1–4 days to Sprague-Dawley rats could produce Olney’s lesions and cortical neuronal death and microgliosis as compared with MK-801, a known neurotoxic potent NMDAR blocker. As previously reported, MK-801 produced Olney’s lesions, neuronal necrosis and cortical microgliosis, and impaired behavior and activity. In contrast, administration of REL-1017 at low (20–31.25 mg/kg in females and males), medium (40–62.5 mg/kg) or high (80–110 mg/kg) doses did not cause pathomorphological changes in brain neurons and did not cause impaired behavior and activity. In conclusion, REL-1017 did not produce initial or cumulative neurotoxic effects or other evidence of damage to cortical neurons, further encouraging the development of REL-1017 as a potentially safe novel candidate for rapid treatment of MDD.
Predicting Foraging Habitat of European Shags - A Multi-Year and Multi-Colony Tracking Approach to Identify Important Areas for Marine Conservation

Human activity in the coastal zone is increasing worldwide, putting a number of seabird species under pressure. Norway is no exception to this development, and with > 35% of the NE Atlantic population of the currently declining European shag (Gulosus aristotelis) population, Norway has an international responsibility for the conservation of this species, and its important foraging habitats during breeding. We analysed tracking data from shags breeding in five colonies along the Norwegian coast spread over a latitudinal gradient of > 1700 km. We identified foraging locations and associated environmental characteristics. Using model cross-validation, we assessed the transferability of habitat models, both spatially (across colonies) and temporally (within colonies and across years), based on three modelling approaches: Training datasets consisted either of the data from one year at one colony, all years at one colony, or all years from all colonies except the testing colony. Across colonies, foraging activity was associated with shallow depths, proximity to colony, and the presence of kelp forests, while sea surface temperature and sea surface height contributed little to model fit. Transferability of habitat use across colonies was low when based on the training data from only one year and one colony and improved little when using several years of data from one colony for training the models. Transferability was very high for all colonies if the training dataset consisted of data from all years and all colonies except the one to be predicted. Our results highlight the importance of multi-year and multi-colony studies and show that it is possible to make sound fine-scale predictions of important foraging areas for breeding shags without the need to track birds in every colony. This facilitates much needed management of coastal marine ecosystems and the protection of the most important feeding areas for breeding shags.
Categorizing Visual Information in Subpopulations of Honeybee Mushroom Body Output Neurons

Multisensory integration plays a central role in perception, as all behaviors usually require the input of different sensory signals. For instance, for a foraging honeybee the association of a food source includes the combination of olfactory and visual cues to be categorized as a flower. Moreover, homing after successful foraging using celestial cues and the panoramic scenery may be dominated by visual cues. Hence, dependent on the context, one modality might be leading and influence the processing of other modalities. To unravel the complex neural mechanisms behind this process we studied honeybee mushroom body output neurons (MBON). MBONs represent the first processing level after olfactory-visual convergence in the honeybee brain. This was physiologically confirmed in our previous study by characterizing a subpopulation of multisensory MBONs. These neurons categorize incoming sensory inputs into olfactory, visual, and olfactory-visual information. However, in addition to multisensory units a prominent population of MBONs was sensitive to visual cues only. Therefore, we asked which visual features might be represented at this high-order integration level. Using extracellular, multi-unit recordings in combination with visual and olfactory stimulation, we separated MBONs with multisensory responses from purely visually driven MBONs. Further analysis revealed, for the first time, that visually driven MBONs of both groups encode detailed aspects within this individual modality, such as light intensity and light identity. Moreover, we show that these features are separated by different MBON subpopulations, for example by extracting information about brightness and wavelength. Most interestingly, the latter MBON population was tuned to separate UV-light from other light stimuli, which were only poorly differentiated from each other. A third MBON subpopulation was neither tuned to brightness nor to wavelength and encoded the general presence of light. Taken together, our results support the view that the mushroom body, a high-order sensory integration, learning and memory center in the insect brain, categorizes sensory information by separating different behaviorally relevant aspects of the multisensory scenery and that these categories are channeled into distinct MBON subpopulations.
Seasonal River Chemistry and Lithium Isotopes in the Min Jiang at Eastern Tibetan Plateau: Roles of Silicate Weathering and Hydrology

Riverine lithium (Li) isotopes have been considered as a robust tracer for silicate weathering, but processes controlling riverine δ7Li ratios remain controversial. To address the impacts of weathering and hydrology on riverine δ7Li, the seasonal variation of water chemistry in the Min Jiang at the eastern Tibetan Plateau was investigated over December of 2009 to the end of 2010. The results showed distinct seasonal variations in ionic chemistry and δ7Li. Increased river discharge in the monsoon season diluted dissolved ions, and monsoonal hydrological changes caused frequent δ7Li fluctuations. High discharge caused by monsoonal rainfall reduced Li isotope fractionation by shortened rock–fluid interaction time, resulting in lower δ7Li, whereas the input of high δ7Li groundwater and landslide seepage elevated riverine δ7Li, together with lengthened rock–fluid interaction time in less rain intervals. Based on the high-resolution sampling strategy and dataset over one hydrological year, this study highlights that changes of hydrological conditions can have a significant impact on weathering processes and water sources, and therefore on riverine δ7Li variation.
Hyperdense Artery Sign and Clinical Outcomes After Endovascular Treatment in Acute Basilar Artery Occlusion

Background This study aimed to investigate the association between the hyperdense basilar artery sign (HBAS) on non-enhanced computed tomography (CT) and clinical outcomes in patients with acute basilar artery occlusion (BAO) who underwent endovascular treatment (EVT). Methods Eligible patients who underwent EVT due to acute BAO between January 2014 and May 2019 were divided into two groups based on HBAS. HBAS was assessed by two neuroradiologists using five grades on nonenhanced CT. The primary outcome was a favorable functional outcome (defined as a modified Rankin Scale [mRS] of 0–3) at 90 days. Secondary outcomes included successful recanalization and mortality within 90 days. Results Among 829 patients with BAO as assessed with CT angiography, magnetic resonance angiography, or digital subtraction angiography, 643 patients were treated with EVT. Of these, 51.32% (330/643) had HBAS. Patients with HBAS were older and had more severe neurological deficits and a higher frequency of atrial fibrillation than those without HBAS. There was no significant difference in favorable outcome (adjusted odds ratio [aOR]: 1.354, 95% confidence interval [CI]: 0.906–2.024; p = 0.14), successful recanalization (aOR: 0.926, 95% CI: 0.616-−1.393; p = 0.71), and mortality (aOR: 1.193, 95% CI: 0.839–1.695; p = 0.33) between patients with or without HBAS. Subgroup analysis showed that the HBAS predicted a favorable outcome in patients aged <60 years (aOR: 2.574, 95% CI: 1.234–5.368; p = 0.01) and patients with vertebral artery-V4 segment occlusion (aOR: 3.738, 95% CI: 1.212–11.530; p = 0.02). In patients with HBAS, the baseline National Institutes of Health Stroke Scale (NIHSS) score, posterior circulation–Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS), and stent retriever were associated with successful recanalization. Conclusions Our study did not find a significant association between HBAS and favorable outcomes and successful recanalization in patients with BAO who underwent EVT. Moreover, large prospective studies are warranted to further investigate this relationship.
Inhibitors of SARS-CoV-2 PLpro

The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.
Comparative Transcriptome Analysis Revealed the Freezing Tolerance Signaling Events in Winter Rapeseed (Brassica rapa L.)

Winter rapeseed (Brassica rapa L.) is an important oilseed crop in northwest China. Freezing stress severely limits its production and geographical distribution, and frequent extreme freezing events caused by climate change are increasing the chances of winter freeze-injury. However, the underlying mechanism of B. rapa response to freezing stress remains elusive. Here, B. rapa genome (v3.0) was used as a reference for the comparative transcriptomic analysis of Longyou 6 and Tianyou 2 (strong and weak cold tolerance, respectively) under different freezing stress. Before and after freezing stress, 5,982 and 11,630 unique differentially expressed genes (DEGs) between two cultivars were identified, respectively. After freezing stress, the GO terms in Tianyou 2 were mainly involved in “macromolecule biosynthetic process”, and those in Longyou 6 were involved in “response to stimulus” and “oxidoreductase activity”. Morphological and physiological results indicated that Longyou 6 retained a higher basal freezing resistance than Tinayou 2, and that cold acclimation could strengthen the basal freezing resistance. Freezing stress could activate the MAPK signal cascades, and the phosphorylation level of Longyou 6 showed a higher increase in response to freezing treatment than Tianyou 2. Based on our findings, it was speculated that the cell membrane of B. rapa perceives external signals under freezing stress, which are then transmitted to the nucleus through the cold-activated MAPK cascades and Ca2+-related protein kinase pathway, thus leading to activation of downstream target genes to enhance the freezing resistance of B. rapa.