Miracle-dz/UniFAR-FTUs huggingface dataset:
Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry

Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. De novo sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C16 fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring de novo synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between de novo synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d3 and L-serine-d3. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B1). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid de novo synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates – naturally occurring or chemically tailored – as well as novel inhibitors of enzymes involved in sphingolipid de novo synthesis.
Synthesis of Flower-Like g-C3N4/BiOBr and Enhancement of the Activity for the Degradation of Bisphenol A Under Visible Light Irradiation

The high recombination rates of photogenerated electron-holes greatly inhibit the catalytic activity of semiconductor photocatalysts. Herein, the heterojunctions of the flower-like g-C3N4/BiOBr composites were synthesized as photocatalysts by a simple hydrothermal process. The X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectrometer were utilized to characterize the sample's structure and light absorption properties. The results demonstrated that BiOBr-g-C3N4-4:1 showed excellent photocatalytic properties and 96.6% of bisphenol (BPA) was removed in 120 min with illumination of visible light due to its narrower band gap than that of pure BiOBr. BiOBr offer little electrons during the photocatalytic reaction. Moreover, the heterostructure between BiOBr and g-C3N4 facilitates the separation of photogenerated carriers. Excellent stability was exhibited after five cyclic degradation of methyl orange (MO) with the illumination of visible light. The active species trapping experiment indicated that superoxide radical anions (O2•-) and hole (h+) have a great effect on the reaction. A possible mechanism was proposed to explain the whole process of photocatalytic reaction.
Therapeutic Modulation of the Complement System in Kidney Transplantation: Clinical Indications and Emerging Drug Leads

The complement system is integral to innate immunity, and it is an essential deterrent against infections. The complement apparatus comprises of >30 fluid-phase and surface-bound elements that also engage with the adaptive immune system, clear harmful immune complexes, and orchestrates several salutary physiological processes. An imbalance in the complement system's tightly regulated machinery and the consequent unrestrained complement activation underpins the pathogenesis of a wide array of inflammatory, autoimmune, neoplastic and degenerative disorders. Antibody-mediated rejection is a leading cause of graft failure in kidney transplantation. Complement-induced inflammation and endothelial injury have emerged as the primary mechanisms in the pathogenesis of this form of rejection. Researchers in the field of transplantation are now trying to define the role and efficacy of complement targeting agents in the prevention and treatment of rejection and other complement related conditions that lead to graft injury. Here, we detail the current clinical indications for complement therapeutics and the scope of existing and emerging therapies that target the complement system, focusing on kidney transplantation.
Increased Maternal Prenatal Adiposity, Inflammation, and Lower Omega-3 Fatty Acid Levels Influence Child Negative Affect

Objective Increased maternal adiposity during pregnancy is associated with offspring risk for psychiatric disorders. Inflammation secondary to adiposity is believed to be an important mechanism through which this effect occurs. Although increased adiposity introduces risk, not all children of overweight mothers develop these problems. Gestational factors that modify this risk are not well-understood. If maternal increased adiposity exerts its effects on offspring outcomes by increasing inflammation in the gestational environment, then anti-inflammatory inputs such as omega-3 fatty acids may be one protective factor. The goal of this study was to investigate whether maternal pre-pregnancy body mass index (BMI) and omega-3 fatty acid levels independently and/or interactively predicted offspring infant negative affect, an early life marker of risk for psychopathology. Methods Data came from a prospective study of women recruited during pregnancy and their 6 month old infants (N = 62; 40% female). Maternal pre-pregnancy BMI was pulled from medical charts and third trimester omega-3 fatty acid concentrations were assessed in plasma. Child negative affect was assessed using observer- and maternal-ratings at 6 months of age. Maternal inflammation was indexed by third trimester plasma levels of interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1. Results Maternal pre-pregnancy BMI was associated with increased infant negative affect whereas eicosapentaenoic acid was associated with less infant negative affect. Maternal omega-3 fatty acid levels moderated the effect of BMI on infant negative affect, such that omega-3 fatty acids buffered children against the negative consequences of increased adiposity. Supporting the role of maternal inflammation in these associations, maternal BMI and omega-3 fatty acid levels interacted to predict maternal third trimester inflammation. Further, maternal inflammation was associated with increased infant negative affect. Conclusion Results suggest that omega-3 supplementation during pregnancy may protect against offspring behavioral risk associated with increased maternal adiposity.
Patient Reported Outcome (PRO) Among High-Grade Glioma Patients Receiving TTFields Treatment: A Two Center Observational Study

Study design: A two center, observational study. Introduction: Patient reported outcome (PRO) plays an increasingly important role in the evaluation of novel therapies for tumor patients. It has been shown that tumor treating fields (TTFields) in combination with standard therapy prolong survival in high-grade glioma (hgG) patients. But critics claim that TTFields significantly impacts patients' everyday life due to side effects and average daily time on therapy (18 h) in a patient population with very limited life expectancy and high symptom burden. However, very limited data exist on PRO for TTFields treatment. Methods: This two center, observational study describes PRO of 30 hgG patients receiving TTFields in combination with chemotherapy. We introduced a device-specific questionnaire (DSQ) addressing device-specific restrictions and impact on daily live after 2 months of therapy. Additionally following questionnaires were used: EORTC (European Organization for Research and Treatment of Cancer), QLQ-30 (Quality of life of cancer patients), QLQ BN20 (Quality of life brain cancer module), QLQ FA13 (Cancer-related fatigue), and SSUK-8 (social support). Results: Surveys have been completed by 91% of enrolled patients. EORTC QLQ-30 revealed better physical, emotional, and cognitive function than social and role function of study cohort. TTFields users reported frequently on positive social support and a low level of detrimental interactions. Seventy one percent of patients felt affected in daily life due to TTFields at least 2–3 times per week up to several times per day while maintaining high therapy compliance. Most frequent device-specific restrictions were duration of therapy (74%), size (66%), and weight (70%) of the device and changing time and bonding of the transducer arrays (66%, mean duration: 43.6 min). Restrictions on exercise of hobbies/work (63%/61%), body care (71%), and sexuality/relationship (64%) were most relevant. Seventy percent would recommend TTFields to others and 67% would reuse TTFields treatment again based on their current experience. Conclusion: The study shows that although TTFields treatment frequently affects everyday life in all aspects, therapy compliance was high and 67% of patients would reconsider TTFields for themselves. We propose that findings of PRO be taken into account for medical consultation about TTFields and in future device development to deliver high-value patient-centered care.
Influence of Maternal Inulin-Type Prebiotic Intervention on Glucose Metabolism and Gut Microbiota in the Offspring of C57BL Mice

Scope: Maternal obesity leads to glucose intolerance in the offspring. Changes in the gut microbiota are being increasingly implicated in the pathogenesis of diabetes. We hypothesized that inulin intervention during gestation and lactation improves glucose metabolism disorders in mouse offspring from high-fat diet (HD)-fed dams. Procedures: Female C57BL mice were fed a control diet or HD for 4 weeks before mating. After mating, pregnant mice were randomly divided into three groups through gestation and lactation: control diet (CD) group, HD group, and HD treated with inulin (HD-inulin) group. At weaning, glucose metabolic status was assessed. Gut microbial DNA from offspring cecal contents was isolated and processed for metagenomic shotgun sequencing, and taxonomic and functional profiling were performed. Results: Offspring from dams in the HD-inulin groups demonstrated reduced fasting blood glucose, decreased blood glucose area under the curve during the oral glucose tolerance test, and reduced fasting serum insulin and HOMA-IR compared to offspring from dams in the HD group. Nineteen differentially abundant bacterial species were identified between the HD-inulin and HD groups. The HD-inulin group displayed significantly greater abundances of Bacteroides_acidifaciens, Eubacterium_sp_CAG_786, Clostridium_sp_CAG_343, and Bifidobacterium_breve species and lower abundances of Oscillibacter_sp_1_3, Ruminococcus_gnavus_CAG_126, and Bacteroides_massiliensis species. Differentially abundant bacterial species among the three groups were involved in 38 metabolic pathways, including several glucose and lipid metabolism pathways. Conclusion: Our results show that early inulin intervention in HD-fed mouse dams moderates offspring glucose metabolism and gut dysbiosis.
Screening for Multiple Types of Family Violence: Development and Validation of the Family Polyvictimization Screen

Objective: Different types of violence tend to co-occur within a family where the members often share common family characteristics, a situation described as family polyvictimization. In response to the lack of a validated screening tool, this study developed and validated the Family Polyvictimization Screen (FPS), the first brief screening tool applicable to members of the same family with up to three generations. Methods: The FPS was designed to screen family polyvictimization by assessing and capturing different types of violence, including child abuse and neglect (CAN), intimate partner violence (IPV), and elder abuse. The FPS was compared with the Criterion Standard scales. It is suitable for use as a self-report for individual family members for specific violence or as a proxy report for an adult family member to serve as informant. In this study, a community sample of 445 households was recruited from Hong Kong (n = 250) and Shanghai (n = 195). One adult parent from each three-generation family was selected as the informant to report all family polyvictimization experiences in the preceding year. Results: Moderate to high agreement (79.1–99.8%) was found between the FPS and the standard measurements, such as the revised Conflict Tactics Scales (CTS2) and the Conflict Tactics Scales: Parent-Child Version (CTSPC). Exceptions appeared in regard to physical assault on elders due to the rarity of reported cases. The specificity was high, while the sensitivity estimates appeared low, especially for the more sensitive sexual abuse cases. Conclusion: The validated FPS demonstrated its potential utility as a brief tool for screening family polyvictimization in clinical settings with substantial agreement and satisfactory accuracy in the Chinese population.
Evaluation of the Hippocampal Normal Tissue Complication Model in a Prospective Cohort of Low Grade Glioma Patients—An Analysis Within the EORTC 22033 Clinical Trial

Purpose: To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients. Methods: LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (±4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome. Results: A total of 29 patients met inclusion criteria. Mean dose in EQD2 Gy to the bilateral hippocampus was 39.8 Gy (95% CI 34.3–44.4 Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2 Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score. Conclusions: In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.
Bacille Calmette-Guérin Vaccine Strain Modulates the Ontogeny of Both Mycobacterial-Specific and Heterologous T Cell Immunity to Vaccination in Infants

Differences in Bacille Calmette-Guérin (BCG) immunogenicity and efficacy have been reported, but various strains of BCG are administered worldwide. Since BCG immunization may also provide protection against off-target antigens, we sought to identify the impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life, utilizing two African birth cohorts. A total of 270 infants were studied: 84 from Jos, Nigeria (vaccinated with BCG-Bulgaria) and 187 from Cape Town, South Africa (154 vaccinated with BCG-Denmark and 33 with BCG-Russia). Infant whole blood was taken at birth, 7, 15, and 36 weeks and short-term stimulated (12 h) in vitro with BCG, Tetanus and Pertussis antigens. Using multiparameter flow cytometry, CD4+ T cell memory subset polyfunctionality was measured by analyzing permutations of TNF-α, IL-2, and IFN-γ expression at each time point. Data was analyzed using FlowJo, SPICE, R, and COMPASS. We found that infants vaccinated with BCG-Denmark mounted significantly higher frequencies of BCG-stimulated CD4+ T cell responses, peaking at week 7 after immunization, and possessed durable polyfunctional CD4+ T cells that were in a more early differentiated memory stage when compared with either BCG-Bulgaria and BCG-Russia strains. The latter responses had lower polyfunctional scores and tended to accumulate in a CD4+ T cell naïve-like state (CD45RA+CD27+). Notably, BCG-Denmark immunization resulted in higher magnitudes and polyfunctional cytokine responses to heterologous vaccine antigens (Tetanus and Pertussis). Collectively, our data show that BCG strain was the strongest determinant of both BCG-stimulated and heterologous vaccine stimulated T cell magnitude and polyfunctionality. These findings have implications for vaccine policy makers, manufacturers and programs worldwide and also suggest that BCG-Denmark, the first vaccine received in many African infants, has both specific and off-target effects in the first few months of life, which may provide an immune priming benefit to other EPI vaccines.
Immune Cell-Type Specific Ablation of Adapter Protein ADAP Differentially Modulates EAE

The cytosolic adhesion and degranulation-promoting adapter protein ADAP is expressed in various hematopoietic cells including T cells, NK cells, myeloid cells, and platelets but absent in mature B cells. The role of ADAP in T cell activation, proliferation and integrin activation is well-accepted. We previously demonstrated that conventional ADAP knockout mice show a significantly attenuated course of experimental autoimmune encephalomyelitis (EAE). To dissect the impact of different ADAP expressing cell populations on the reduced EAE severity, here, we generated lineage-specific conditional knockout mice. ADAP was deleted in T cells, myeloid cells, NK cells and platelets, respectively. Specific loss of ADAP was confirmed on the protein level. Detailed immunophenotyping was performed to assess the consequence of deletion of ADAP with regard to the maturation and distribution of immune cells in primary and secondary lymphoid organs. The analysis showed equivalent results as for conventional ADAP knockout mice: impaired thymocyte development in ADAPfl/fl Lck-Cre mice, normal NK cell and myeloid cell distribution in ADAPfl/fl NKp46-Cre mice and ADAPfl/fl LysM-Cre mice, respectively as well as thrombocytopenia in ADAPfl/fl PF4-Cre mice. Active EAE was induced in these animals by immunization with the myelin oligodendrocyte glycoprotein35−55 peptide. The clinical course of EAE was significantly milder in mice with loss of ADAP in T cells, myeloid cells and NK cells compared to ADAP-sufficient control littermates. Surprisingly, specific deletion of ADAP in platelets resulted in a more exacerbated disease. These data show that T cell-independent as well as T cell-dependent mechanisms are responsible for the complex phenotype observed in conventional ADAP knockout mice.
Combining Plasma miRNAs and Computed Tomography Features to Differentiate the Nature of Pulmonary Nodules

Objective: The purpose of this study was to evaluate the diagnostic efficiency of combining plasma microRNAs (miRNAs) and computed tomography (CT) features in the diagnosis of pulmonary nodules. Methods: Ninety-two pulmonary nodule patients who had undergone surgery were enrolled in our study from July 2016 to March 2018 at the Sun Yat-sen University Cancer Center. A prediction model was established by combining 3 miRNAs (miRNA-146a, -200b, and -7) and CT features to identify the pulmonary nodules of these patients. We evaluated the diagnostic performance of this prediction model for pulmonary nodules using the Receiver Operating Characteristic (ROC) curve. Results: The expression levels of miRNA-146a, -200b, and -7 in early-stage non-small cell lung cancer (NSCLC) patients are significantly higher than those in benign nodule patients. We used these three miRNAs and CT features (pleural indentation and speculation) to establish a prediction model for early-stage NSCLC, with a sensitivity and specificity of 92.9%, 83.3% in the training set, respectively. For the validation process, with the sensitivity of 71.8% and the specificity of 69.2%. For ROC curve analyses, area under the curve (AUC) for tumor identification in the training stage and validation stage were 0.929 and 0.781, respectively. Conclusion: Plasma miRNA-146a, miRNA-200b, and miRNA-7 may be potential biomarkers for the early diagnosis of lung cancer. Our prediction model can help to identify the nature of pulmonary nodules with a relatively high diagnostic efficiency.
YangXue QingNao Wan, a Compound Chinese Medicine, Attenuates Cerebrovascular Hyperpermeability and Neuron Injury in Spontaneously Hypertensive Rat: Effect and Mechanism

Objective The purpose of the study was to explore the effect of YangXue QingNao Wan (YXQNW), a compound Chinese medicine, on cerebrovascular hyperpermeability, neuronal injury, and related mechanisms in spontaneously hypertensive rat (SHR). Methods Fourteen-week-old male SHR were used, with Wistar Kyoto (WKY) rats as control. YXQNW (0.5 g/kg/day), enalapril (EN, 8 mg/kg/day), and nifedipine (NF, 7.1 mg/kg/day) were administrated orally for 4 weeks. To assess the effects of the YXQNW on blood pressure, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) were measured. After administering the drugs for 4 weeks, the cerebral blood flow (CBF), albumin leakage from microvessels in middle cerebral artery (MCA)-dominated area, and the number and morphology of microvessels were assessed in the hippocampus area and cortex. Neuronal damage and apoptosis were assessed by Nissl staining and TUNEL staining. To assess the mechanisms of cerebrovascular hyperpermeability, we performed immunofluorescence and Western blot to assess the expression and integrity of cerebral microvascular tight junction (TJ) and caveolin-1 (Cav-1) in cortex. Energy metabolism and Src-MLC-MLCK pathway in cortex were assessed then for elucidating the underlying mechanism of the observed effect of YXQNW. Results Spontaneously hypertensive rat exhibited higher blood pressure, Evans blue (EB) extravasation, albumin leakage, increased brain water content, decreased CBF, perivascular edema, and neuronal apoptosis in the hippocampus and cortex, all of which were attenuated by YXQNW treatment. YXQNW inhibited the downregulation of TJ proteins, mitochondrial Complex I, Complex II, and Complex V, and upregulation of caveolin-1, inhibiting Src/MLCK/MLC signaling in SHR. YXQNW combined with EN + NF revealed a better effect for some outcomes compared with either YXQNW or EN + NF alone. Conclusion The overall result shows the potential of YXQNW to attenuate blood–brain barrier (BBB) breakdown in SHR, which involves regulation of energy metabolism and Src/MLCK/MLC signaling. This result provides evidence supporting the application of YXQNW as an adjuvant management for hypertensive patients to prevent hypertensive encephalopathy.
Utilizing Pragmatic Frames as an analytical tool for children's performance during word learning

Typically, to assess children's performance in a word learning task, a category coding is applied to the answers given by the children, according to which they can score “1” when correct and “0” when incorrect. This paper extends the current methodology: Following a recently re-introduced theory of Pragmatic Frames, the construct of Pragmatic Frames is proposed as an analytical tool which makes it possible (1) to describe children's performance in more detail and (2) to gain more insight into their pragmatic competencies.