Miracle-dz/UniFAR-FTUs huggingface dataset:
Aquaporins1 and 3 in the tissues of Paramisgurnus dabryanus and their expression profiles in response to ammonia and drought

Aquaporins (Aqp)1 and Aqp3 are the representatives of two types of aquaporins (classical aquaporin and aquaglyceroporin) and have been proven to potentially facilitate ammonia detoxification in air-breathing fishes. Paramisgurnus dabryanus is one of East Asia’s most important commercially farmed species and can breathe air directly through its hindgut. Besides, excellent ammonia tolerance was reported in this species. However, the mechanisms of its tolerance of high ammonia are still unclear. To explore the physiological roles of Aqp1 and Aqp3 in Paramisgurnus dabryanus, we detected the expression pattern of these two Aqps in several tissues and their transcriptional changes in response to different levels (30, and 70 mmol L-1 NH4Cl) and periods (0, 12, 48, and 96 h) of ammonia exposure and different periods (0, 12, 48, and 96 h) of drought stress. The aqp1 mRNA showed a high abundance in the brain and the osmoregulatory tissues, such as the intestine and kidney. While aqp3 was mainly expressed in the epithelium of skin and gills that were directly exposed to the environment. The expression level of aqp3 in gills was more responsive than aqp1 to ammonia challenges, although both of them were up-regulated. Considering the wide difference between aqp1 and aqp3 in the skin, aqp3 increased significantly after 12 h of air exposure. The changes of the two aqps in the intestine of P. dabryanus were relatively stable after ammonia stress. After drought stress, intestinal aqp1 increased significantly, while aqp3 decreased. Combined with the effects of tissue location and environmental stress on Aqps, it was suggested that Aqp1 was mainly involved in osmotic regulation, providing water as raw material for body metabolism. Accordingly, our results suggest that Aqp3 has the positive function of assisting ammonia transportation and epidermal moisturizing.
Refined polysaccharide from Dendrobium devonianum resists H1N1 influenza viral infection in mice by activating immunity through the TLR4/MyD88/NF-κB pathway

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1β, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.
Association between lncRNAs in plasma exosomes and diabetic retinopathy

Background Long noncoding RNA (lncRNA) in plasma exosomes is a potential non-invasive diagnostic biomarker for diabetic retinopathy (DR). However, the changes in plasma exosomal lncRNAs and diagnostic relevance in patients with DR patients remain unclear. Methods A case–control study with type 2 diabetes mellitus (T2DM) and patients with comorbid DR were enrolled, and their clinical information and blood samples were collected. Plasma exosomes were extracted, and the relative expression levels of representative differentially expressed exosomal lncRNAs were determined. A logistic regression model was used to analyze the relationships of DR with relative lncRNA expression and DR-related factors, and receiver operating characteristic (ROC) curve analysis was used to evaluate the value of exosomal lncRNAs for DR diagnosis. Results Sixty-two patients with T2DM and sixty-two patients with DR were matched by age, sex, and disease duration. The fasting blood glucose concentration, glycosylated hemoglobin level (HbA1c), and relative expression of the plasma exosomal lncRNA DLX6-AS1 were significantly higher in the DR group than in the T2DM group, whereas the 2-h C-peptide concentration and relative expression of the lncRNAs PRINS and FAM190A-3 were lower in the DR group. After adjusting for relevant confounders, the fasting blood glucose concentration, HbA1c level, 2-h C-peptide concentration, and relative expression of lncRNA DLX6-AS1, PRINS, and FAM190A-3 were found to be associated with DR. Both DLX6-AS1 [area under the curve (AUC): 0.658 (0.562–0.754)], PRINS [AUC: 0.798 (0.722–0.873)], and FAM190A-3 [AUC: 0.603 (0.503-0.702)] expression had predictive value for DR diagnosis. The combination of DLX6-AS1 and PRINS yielded an AUC of 0.813 (0.740–0.886). In males, the combination of DLX6-AS1 and PRINS yielded an AUC of 0.860 (0.780–0.940). Conclusion The fasting blood glucose concentration, HbA1c level, and exosomal DLX6-AS1 expression were identified as risk factors for DR, whereas the 2-h C-peptide concentration and exosomal PRINS and FAM190A-3 were identified as protective against DR. The combination of exosomal DLX6-AS1 and PRINS had good diagnostic value for DR in the general population and males. More attention should be paid to the role of exosomal PRINS expression as a predictive and diagnostic DR biomarker in females.
The multifaceted roles of common gut microbiota in immune checkpoint inhibitor-mediated colitis: From mechanism to clinical application

With the arrival of the era of tumor immunotherapy, Immune Checkpoint Inhibitors have benefited countless tumor patients. However, the emergence of Immune-Related Adverse Events, especially Immune Checkpoint Inhibitor-Mediated Colitis (IMC), has become an important obstacle to immunotherapy. Therefore, it is very important to clarify the mechanism and influencing factors of IMC. The effect of gut microbiota on IMC is gradually becoming a research hotspot. Gut microbiota from different phyla can affect IMC by regulating innate and acquired immunity of tumor patients in various ways. In this review, we make a systematic and comprehensive introduction of the effect of gut microbiota on IMC. Through understanding the specific effects of gut microbiota on IMC, and then exploring the possibility of reducing IMC by regulating gut microbiota.
Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

Mitochondrial SMAC/Diablo induces apoptosis by binding the inhibitor of apoptosis proteins (IAPs), thereby activating caspases and, subsequently, apoptosis. Previously, we found that despite its pro-apoptotic activity, SMAC/Diablo is overexpressed in cancer, and demonstrated that in cancer it possesses new essential and non-apoptotic functions that are associated with regulating phospholipid synthesis including modulating mitochondrial phosphatidylserine decarboxylase activity. Here, we demonstrate additional functions for SMAC/Diablo associated with inflammation and immunity. CRISPR/Cas9 SMAC/Diablo-depleted A549 lung cancer cells displayed inhibited cell proliferation and migration. Proteomics analysis of these cells revealed altered expression of proteins associated with lipids synthesis and signaling, vesicular transport and trafficking, metabolism, epigenetics, the extracellular matrix, cell signaling, and neutrophil-mediated immunity. SMAC-KO A549 cell-showed inhibited tumor growth and proliferation and activated apoptosis. The small SMAC-depleted “tumor” showed a morphology of alveoli-like structures, reversed epithelial-mesenchymal transition, and altered tumor microenvironment. The SMAC-lacking tumor showed reduced expression of inflammation-related proteins such as NF-kB and TNF-α, and of the PD-L1, associated with immune system suppression. These results suggest that SMAC is involved in multiple processes that are essential for tumor growth and progression. Thus, targeting SMAC’s non-canonical function is a potential strategy to treat cancer.
Multiparametric MRI-based nomograms in predicting positive surgical margins of prostate cancer after laparoscopic radical prostatectomy

Background Positive surgical margins (PSMs) are an independent risk factor of biochemical recurrence in patients with prostate cancer (PCa) after laparoscopic radical prostatectomy; however, limited MRI-based predictive tools are available. This study aimed to develop a novel nomogram combining clinical and multiparametric MRI (mpMRI) parameters to reduce PSMs by improving surgical planning. Methods One hundred and three patients with PCa (55 patients with negative surgical margins [NSMs] and 48 patients with PSMs) were included in this retrospective study. The following parameters were obtained using GE Functool post-processing software: diffusion-weighted imaging (DWI); intravoxel incoherent motion model (IVIM); and diffusion kurtosis imaging (DKI). Patients were divided into different training sets and testing sets for different targets according to a ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) regression algorithm was used to analyze the data set to select the optimal MRI predictors. Preoperatively clinical parameters used to build a clinical nomogram (C-nomogram). Multivariable logistic regression analysis was used to build an MRI nomogram (M-nomogram) by introducing the MRI parameters. Based on the MRI and clinical parameters, build an MRI combined with clinical parameters nomogram (MC-nomogram). Comparisons with the M-nomogram and MC-nomogram were based on discrimination, calibration, and decision curve analysis (DCA). A 3-fold cross-validation method was used to assess the stability of the nomogram. Results There was no statistical difference in AUC between the C-nomogram (sensitivity=64%, specificity=65% and AUC=0.683), the M-nomogram (sensitivity=57%, specificity=88% and AUC=0.735) and the MC-nomogram (sensitivity= 64%, specificity=82% and AUC=0.756). The calibration curves of the three nomograms used to predict the risk of PSMs in patients with PCa showed good agreement. The net benefit of the MC-nomogram was higher than the others (range, 0.2-0.7). Conclusions The mpMRI-based nomogram can predict PSMs in PCa patients. Although its AUC (0.735) is not statistically different from that of the clinical-based nomogram AUC (0.683). However, mpMRI-based nomogram has higher specificity (88% VS. 63%), model stability, and clinical benefit than clinical-based nomogram. And the predictive ability of mpMRI plus clinical parameters for PSMs is further improved.
Loss of fiber cell communication may contribute to the development of cataracts of many different etiologies

The lens is an avascular organ that is supported by an internal circulation of water and solutes. This circulation is driven by ion pumps, channels and transporters in epithelial cells and by ion channels in fiber cells and is maintained by fiber-fiber and fiber-epithelial cell communication. Gap junctional intercellular channels formed of connexin46 and connexin50 are critical components of this circulation as demonstrated by studies of connexin null mice and connexin mutant mice. Moreover, connexin mutants are one of the most common causes of autosomal dominant congenital cataracts. However, alterations of the lens circulation and coupling between lens fiber cells are much more prevalent, beyond the connexin mutant lenses. Intercellular coupling and levels of connexins are decreased with aging. Gap junction-mediated intercellular communication decreases in mice expressing mutant forms of several different lens proteins and in some mouse models of lens protein damage. These observations suggest that disruption of ionic homeostasis due to reduction of the lens circulation is a common component of the development of many different types of cataracts. The decrease in the lens circulation often reflects low levels of lens fiber cell connexins and/or functional gap junction channels.
Harm avoidance, daily stress, and problematic smartphone use in children and adolescents

Objective Temperament is close to susceptibility to stress and the increased level of stress may lead problematic smartphone use (PSU). In this study, the relationships between harm avoidance (HA) as a personality trait, daily traits, and PSU in children and adolescents were investigated. Methods At baseline, all participants (184 children and adolescents, mean age 13.15 years) completed questionnaires on PSU using the Smartphone Addiction Scale-Short Version (SAS-SV) and the Korean Smartphone Addiction Proneness Scale (SAPS). The Daily Hassles Questionnaire (DHQ) and Junior Temperament and Character Inventory (JTCI) were also administered to evaluate stress levels and personality traits. SAS-SV, SAPS, and DHQ were reassessed at 3 and 6 months. Results Among JTCI temperament, HA displayed robust positive correlations with SAS-SV, SAPS, and DHQ at all time points. Mediation effects of daily stress on the relationship between HA and PSU were observed at baseline, 3, and 6 months. Conclusion The findings suggest that managing stress may important in PSU children and adolescents with high HA.
Multiple tachykinins and their receptors characterized in the gastropod mollusk Pacific abalone: Expression, signaling cascades, and potential role in regulating lipid metabolism

Tachykinin (TK) families, including the first neuropeptide substance P, have been intensively explored in bilaterians. Knowledge of signaling of TK receptors (TKRs) has enabled the comprehension of diverse physiological processes. However, TK signaling systems are largely unknown in Lophotrochozoa. This study identified two TK precursors and two TKR isoforms in the Pacific abalone Haliotis discus hannai (Hdh), and characterized Hdh-TK signaling. Hdh-TK peptides harbored protostomian TK-specific FXGXRamide or unique YXGXRamide motifs at the C-termini. A phylogenetic analysis showed that lophotrochozoan TKRs, including Hdh-TKRs, form a monophyletic group distinct from arthropod TKRs and natalisin receptor groups. Although reporter assays demonstrated that all examined Hdh-TK peptides activate intracellular cAMP accumulation and Ca2+ mobilization in Hdh-TKR-expressing mammalian cells, Hdh-TK peptides with N-terminal aromatic residues and C-terminal FXGXRamide motifs were more active than shorter or less aromatic Hdh-TK peptides with a C-terminal YXGXRamide. In addition, we showed that ligand-stimulated Hdh-TKRs mediate ERK1/2 phosphorylation in HEK293 cells and that ERK1/2 phosphorylation is inhibited by PKA and PKC inhibitors. In three-dimensional in silico Hdh-TKR binding modeling, higher docking scores of Hdh-TK peptides were consistent with the lower EC50 values in the reporter assays. The transcripts for Hdh-TK precursors and Hdh-TKR were highly expressed in the neural ganglia, with lower expression levels in peripheral tissues. When abalone were starved for 3 weeks, Hdh-TK1 transcript levels, but not Hdh-TK2, were increased in the cerebral ganglia (CG), intestine, and hepatopancreas, contrasting with the decreased lipid content and transcript levels of sterol regulatory element-binding protein (SREBP). At 24 h post-injection in vivo, the lower dose of Hdh-TK1 mixture increased SREBP transcript levels in the CG and hepatopancreas and accumulative food consumption of abalone. Higher doses of Hdh-TK1 and Hdh-TK2 mixtures decreased the SREBP levels in the CG. When Hdh-TK2-specific siRNA was injected into abalone, intestinal SREBP levels were significantly increased, whereas administration of both Hdh-TK1 and Hdh-TK2 siRNA led to decreased SREBP expression in the CG. Collectively, our results demonstrate the first TK signaling system in gastropod mollusks and suggest a possible role for TK peptides in regulating lipid metabolism in the neural and peripheral tissues of abalone.
High-normal liver enzyme levels in early pregnancy predispose the risk of gestational hypertension and preeclampsia: A prospective cohort study

Background Gestational hypertension (GH) and preeclampsia (PE) are severe adverse gestational complications. Previous studies supported potential link between elevated liver enzyme levels and GH and PE. However, given the transient physiological reduction of liver enzyme levels in pregnancy, little is known whether the associations of the high-normal liver enzyme levels in early pregnancy with GH and PE exist in pregnant women. Methods Pregnant women in this study came from a sub-cohort of Shanghai Preconception Cohort, who were with four liver enzyme levels examined at 9–13 gestational weeks and without established liver diseases, hypertension and preeclampsia. After exclusion of pregnant women with clinically-abnormal liver enzyme levels in the current pregnancy, associations of liver enzyme levels, including alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), with GH and PE status were assessed by multivariable log-binomial regression. Population attributable fraction was measured to estimate the fractions of GH and PE that were attributable to the high-normal liver enzyme levels. Results Among 5,685 pregnant women 160 (2.8%) and 244 (4.3%) developed GH and PE, respectively. After adjustment for potential covariates, higher ALP, ALT and GGT levels were significantly associated with the risk of GH (adjusted risk ratio (aRR):1.21 [95% confidence interval, 1.05–1.38]; 1.21 [1.05–1.38]; and 1.23 [1.09–1.39]), as well as the risk of PE(1.21 [1.13–1.29]; 1.15 [1.03–1.28]; 1.28 [1.16–1.41]), respectively. The cumulative population attributable fraction of carrying one or more high-normal liver enzyme levels (at 80th percentile or over) was 31.4% for GH and 23.2% for PE, respectively. Conclusion Higher ALT, ALP and GGT levels within the normal range in early pregnancy are associated with increased risk of GH and PE. The documented associations provide new insight to the role of hepatobiliary function in GH and PE pathogenesis.
Association between rehabilitation after reperfusion treatment and in-hospital mortality: Results from a national registry study

Background There is no effective regimen to reduce the mortality of patients treated with intravenous thrombolysis or endovascular therapy (EVT). Therefore, we aimed to examine whether sequential therapy by rehabilitation could effectively reduce the in-hospital mortality of patients treated with reperfusion therapy. Methods This prospective registry study included patients with ischemic stroke who were treated by intravenous thrombolysis or endovascular therapy at Stroke Center Work Plan in China between 1 October 2018 and 31 July 2020. The patients were divided into 2 groups: those with (IRT+) or without (IRT–) inpatient rehabilitation therapy (IRT). The primary outcome was all-cause in-hospital mortality. We used Cox proportional hazards models and conducted a propensity score matching analysis to calculate hazard ratios (HRs) for mortality in the thrombolysis-only and EVT groups. Results Of the 189,519 patients in the thrombolysis-only group, 35.7% were women, and the median (interquartile range, IQR) age, onset-to-needle time, and follow-up time were 66 (57–74) years, 165 (119–220) min, and 9 (5–12) days, respectively. Among the 45,211 patients in the EVT group, 35.9% were women, and the median (interquartile range, IQR) age, onset-to-puncture time, and follow-up time were 66 (56–74) years, 297 (205–420) min, and 11 (6–16) days, respectively. In the thrombolysis-only group with a median (IQR) initial National Institutes of Health Stroke Scale (NIHSS) score of 6 (3–11), 105,244 patients (55.5%) treated with IRT had significantly lower all-cause in-hospital mortality [0.6 vs. 2.3%; adjusted HR 0.18 (95% confidence interval (CI) 0.16–0.2)] than those without IRT. In the EVT group with a median (IQR) initial NIHSS score of 15 (10–20), 31,098 patients (68.8%) treated with IRT also had significantly lower all-cause in-hospital mortality [2 vs. 12.1%; adjusted HR, 0.13 (95% CI 0.12–0.15)]. IRT remained significantly associated with reduced in-hospital mortality in sensitivity, subgroup, and propensity score matching analyses among both the thrombolysis-only and EVT groups. Conclusion Among the patients with ischemic stroke treated with intravenous thrombolysis or endovascular therapy, sequential therapy by rehabilitation was associated with lower all-cause in-hospital mortality. These findings suggest the necessity of promoting inpatient rehabilitation therapy after reperfusion in patients with ischemic stroke.
Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020

During the last two decades, kinase inhibitors have become the major drug class for targeted cancer therapy. Although the number of approved kinase inhibitors increases rapidly, comprehensive in vitro profiling and comparison of inhibitor activities is often lacking in the public domain. Here we report the extensive profiling and comparison of 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators on panels of 255 biochemical kinase assays and 134 cancer cell line viability assays. Comparison of the cellular inhibition profiles of the EGFR inhibitors gefitinib, dacomitinib, and osimertinib identified the uncommon EGFR p.G719S mutation as a common response marker for EGFR inhibitors. Additionally, the FGFR inhibitors erdafitinib, infigratinib, and pemigatinib potently inhibited the viability of cell lines which harbored oncogenic alterations in FGFR1-3, irrespective of the specific clinical indications of the FGFR inhibitors. These results underscore the utility of in vitro kinase inhibitor profiling in cells for identifying new potential stratification markers for patient selection. Furthermore, comparison of the in vitro inhibition profiles of the RET inhibitors pralsetinib and selpercatinib revealed they had very similar biochemical and cellular selectivity. As an exception, an NTRK3 fusion-positive cell line was potently inhibited by pralsetinib but not by selpercatinib, which could be explained by the targeting of TRK kinases in biochemical assays by pralsetinib but not selpercatinib. This illustrates that unexpected differences in cellular activities between inhibitors that act through the same primary target can be explained by subtle differences in biochemical targeting. Lastly, FLT3-mutant cell lines were responsive to both FLT3 inhibitors gilteritinib and midostaurin, and the PI3K inhibitor duvelisib. Biochemical profiling revealed that the FLT3 and PI3K inhibitors targeted distinct kinases, indicating that unique dependencies can be identified by combined biochemical and cellular profiling of kinase inhibitors. This study provides the first large scale kinase assay or cell panel profiling study for newly approved kinase inhibitors, and shows that comprehensive in vitro profiling of kinase inhibitors can provide rationales for therapy selection and indication expansion of approved kinase inhibitors.