Miracle-dz/UniFAR-FTUs huggingface dataset:
Establishment and effect evaluation of an aortic dissection model induced by different doses of β-aminopropionitrile in rats

Introduction Given the controversy regarding the appropriate dose of β-aminopropionitrile for induction of aortic dissection models in rats, the purpose of this study was to explore the most suitable concentration of β-aminopropionitrile to establish a high-incidence and low-mortality aortic dissection model. Methods Eighty three-week-old male Sprague-Dawley rats were equally divided into four groups: a control group, a 0.06% β-aminopropionitrile group, a 0.08% β-aminopropionitrile group and a 0.1% β-aminopropionitrile group. Initial experiments were performed on the control group, which was not treated with β-aminopropionitrile (and drank water freely), and the other three groups, which were given different concentrations of β-aminopropionitrile solution daily (0.06%, 0.08% and 0.1%). Subsequently, on the 40th day, osmotic minipumps administering 1 μg/kg per min angiotensin II (Ang II) were implanted subcutaneously into the β-aminopropionitrile groups, while the control group was continuously pumped with normal saline. The rats were euthanized 48 h after implantation. All rats that died before the expected end time of the experiment were autopsied immediately, and the aortas were dissected. The rats surviving at the end of the experiment were sacrificed by an overdose of sodium pentobarbital, and tissue samples were harvested for further analyses. Results The mean survival days were significantly different among the groups, with 39.1 ± 6.04 days in the 0.08% β-aminopropionitrile group and 32.7 ± 9.85 days in the 0.1% β-aminopropionitrile group (P = 0.0178) at the end of the experiment. Compared with those in the 0.06% β-aminopropionitrile group, the rates of aortic dissection were significantly higher in the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (P = 0.0015 and P = 0.0005, respectively), while there was no significant difference between the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (P = 0.723) at 70% and 75%, respectively. However, the rupture rates were significantly different between the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (55% versus 20%, P = 0.022). Hematoxylin-eosin staining of the aortic tissue sections of the β-aminopropionitrile group showed that red blood cells entered the pseudocavity in the vascular wall, while the vascular wall structure of the control group was intact. Compared with control rats, which were intact and free from fracture, β-aminopropionitrile-treated rats had fewer collagen fibers and exhibited fracture. Magnetic resonance imaging showed that the aortic intimae of the aortic dissection rats showed double lumens and intimal tears. Conclusions An aortic dissection model with a high incidence and low mortality was successfully and stably developed with 0.08% β-aminopropionitrile. This model will enable further studies investigating aortic dissection pathogenesis and drug therapy. Magnetic resonance imaging may be a reliable technique for imaging the aorta in rats.
Applicability of Egyptian diatomite for uptake of heavy metals

ABSTRACT Three types of natural, classified, and refined diatomite were examined for their abilities to remove metal ions from aqueous solutions at different operating conditions including pH, contact time, amount of adsorbent, and metal concentrations. Batch adsorption experiments revealed that equilibrium was practically attained after 15 min for Cd and Zn, and after 30 min for Cu. On the other hand, Ni and Pb attained equilibrium after 60 min. The optimum dose for the removal of all understudied metals was recorded to be 9.0 g/L at an optimum pH of 4.7. According to the optimum condition study, refined (acid-washed) diatomite is the most efficient one with the selectivity sequence given as Pb2+ > Cd2+ > Zn2+ > Cu2+ > Ni2+ due to the correlation between the ionic radii of heavy metals with external and internal pore diameters of diatomite.
Role of coronary flow regulation and cardiac-coronary coupling in mechanical dyssynchrony associated with right ventricular pacing.

Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bi-directionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX 1.9%), LAD passive flow (21.6%) and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared to RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/ml2 in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts (1) the loading conditions that further affect the coronary flow, which may explain some of the changes in , and (2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure.
The effect of feedback valence and source on perception and metacognition: An fMRI investigation

ABSTRACT Receiving feedback from our environment that informs us about the outcomes of our actions helps us assess our abilities (e.g., metacognition) and to flexibly adapt our behavior, consequently increasing our chances of success. However, a detailed examination of the effect of feedback on the brain activation during perceptual and confidence judgments as well as the interrelations between perceptual accuracy, prospective and retrospective confidence remains unclear. Here we used functional magnetic resonance imaging (fMRI) to examine the neural response to feedback valence and source in visual contrast discrimination together with prospective confidence judgments at the beginning of each block and retrospective confidence judgments after every decision. Positive feedback was associated with higher activation (or lower deactivation depending on the area) in areas previously involved in attention, performance monitoring and visual regions during the perceptual judgment than during the confidence judgment. Changes in prospective confidence were positively related to changes in perceptual accuracy as well as to the corresponding retrospective confidence. Thus, feedback information impacted multiple, qualitatively different brain processing states, and we also revealed the dynamic interplay between prospective, perceptual accuracy and retrospective self-assessment.
Acute cytokine release syndrome after a first dose of pembrolizumab as second-line treatment for metastatic, programmed death-ligand 1-positive, non-small-cell lung cancer

Introduction The use of programmed death-ligand 1 (PD-L1) checkpoint inhibitor therapy is expanding, although its adverse effects are not completely known. We report on a rare case of acute cytokine release syndrome related to pembrolizumab use in a patient with lung cancer. Case report A 79-year-old man with metastatic, PD-L1-positive, non-small-cell lung cancer developed a febrile condition associated with a systemic inflammatory response syndrome and suffered haemodynamic compromise four hours after the first intravenous administration of pembrolizumab. A thorough medical workup found no alternative cause and a grade 2 cytokine release syndrome (CRS) was diagnosed. Management and outcome: Aggressive fluid resuscitation and supportive therapy led to restitutio ad integrum. Discussion Acute CRS after the administration of a PD-L1 inhibitor is infrequent but could be a fatal condition. Supportive treatment and, if necessary, corticosteroids should be considered.
Risk of short‐term biodiversity loss under more persistent precipitation regimes

Recent findings indicate that atmospheric warming increases the persistence of weather patterns in the mid‐latitudes, resulting in sequences of longer dry and wet periods compared to historic averages. The alternation of progressively longer dry and wet extremes could increasingly select for species with a broad environmental tolerance. As a consequence, biodiversity may decline. Here we explore the relationship between the persistence of summer precipitation regimes and plant diversity by subjecting experimental grassland mesocosms to a gradient of dry–wet alternation frequencies whilst keeping the total precipitation constant. The gradient varied the duration of consecutive wet and dry periods, from 1 up to 60 days with or without precipitation, over a total of 120 days. An alternation of longer dry and wet spells led to a severe loss of species richness (up to –75% relative to the current rainfall pattern in W‐Europe) and functional diversity (enhanced dominance of grasses relative to nitrogen (N)‐fixers and non‐N‐fixing forbs). Loss of N‐fixers and non‐N‐fixing forbs in severe treatments was linked to lower baseline competitive success and higher physiological sensitivity to changes in soil moisture compared to grasses. The extent of diversity losses also strongly depended on the timing of the dry and wet periods. Regimes in which long droughts (≥20 days) coincided with above‐average temperatures showed significantly more physiological plant stress over the experimental period, greater plant mortality, and impoverished communities by the end of the season. Across all regimes, the duration of the longest period below permanent wilting point was an accurate predictor of mortality across the communities, indicating that increasingly persistent precipitation regimes may reduce opportunities for drought stress alleviation. We conclude that without recruitment, which was precluded in this experiment, summer precipitation regimes with longer dry and wet spells will likely diminish plant diversity, at least in the short term.
Chronopharmacology of the alpha-lipoic acid/nifedipine/glimepiride combination in the amelioration of retinopathy in rats

ABSTRACT Time of drug administration affects both the kinetics and dynamics of medications. This study investigated diurnal efficacy of alpha-lipoic acid (ALA), nifedipine, and glimepiride combination in the treatment of diabetic retinopathy. The study design comprised seven groups of rats, with groups 1 and 2 serving as non-diabetic and diabetic controls, respectively, receiving 1 ml/kg distilled water. All other groups were diabetic, and received 10 mg/kg glimepiride at 20:00 h. Groups 4–7 also received 20 mg/kg nifedipine at 08:00 h. In addition, groups 5–7 received 100 mg/kg ALA at 08:00 h, 14:00 h, and 20:00 h, respectively. Oral drug administration was for 28 days during which fasting and random blood glucose sampling were done weekly at 07:30 h and 13:30 h, respectively. On the 29th day, rats were euthanized; blood was collected via the jugular veins for determination of serum ocular markers like magnesium, cholesterol, and triglyceride. Furthermore, the eyes were excised and their relative organ/body weight ratios determined. The right eyes were persevered in phosphate buffer for homogenization and determination of retina antioxidant profile (MDA, SOD, CAT, GSH), while the left eyes were preserved in formalin for histological examination. Results showed that treatment with ALA and glimepiride at 20:00 h along with nifedipine at 08:00 h resulted in better prognosis than other treatment groups and with improved glycemic control. Also, all their serum markers for retinopathy, organ weight, and histology did not differ significantly from that of the non-diabetic rats. Findings imply that diurnal efficacy in alpha-lipoic acid, nifedipine and glimepiride combination ameliorates diabetic retinopathy in rats and may be beneficial in the treatment of diabetic retinopathy.
Comprehensive metabolism study of swertiamarin in rats using ultra high-performance liquid chromatography coupled with Quadrupole-Exactive Orbitrap mass spectrometry

Abstract Swertiamarin, a natural ingredient with potent pharmacological activities in the iridoid glycoside family, had been reported to have significant therapeutic effects on a variety of human diseases. In this study, a systematic and efficient strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry was established to reveal the metabolic profile of swertiamarin in rat urine, plasma, and faeces. First of all, post-acquisition data-mining methods, including multiple mass defect filters (MMDFs) and high-resolution extracted ion chromatograms (HREICs), were developed to screen the metabolite candidates of swertiamarin from the complete mass scan data sets. Second, according to the diagnostic product ions (DPIs), neutral loss fragments (NLFs), chromatographic retention time, accurate mass measurement and calculated Clog P values, all metabolite candidates were rapidly identified. As a consequence, 49 metabolites altogether, including archetype compound, were preliminarily characterised. The corresponding in vivo biotransformation processes, such as dehydration, dehydrogenation, hydroxylation, hydrogenation, methylation, sulphonation, N-acetylcysteine (NAC) formation, N-heterocyclisation and their composite reactions, were all discovered in the study. In conclusion, our results not only detailedly elucidated many new metabolites and metabolic pathways of swertiamarin, but also provided a reference for further study of its pharmacological mechanism and evaluation of its safety.
CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.
A critical review on advances in the practices and perspectives for the treatment of dye industry wastewater

ABSTRACT Rapid industrialization has provided comforts to mankind but has also impacted the environment harmfully. There has been severe increase in the pollution due to several industries, in particular due to dye industry, which generate huge quantities of wastewater containing hazardous chemicals. Although tremendous developments have taken place for the treatment and management of such wastewater through chemical or biological processes, there is an emerging shift in the approach, with focus shifting on resource recovery from such wastewater and also their management in sustainable manner. This review article aims to present and discuss the most advanced and state-of-art technical and scientific developments about the treatment of dye industry wastewater, which include advanced oxidation process, membrane filtration technique, microbial technologies, bio-electrochemical degradation, photocatalytic degradation, etc. Among these technologies, microbial degradation seems highly promising for resource recovery and sustainability and has been discussed in detail as a promising approach. This paper also covers the challenges and future perspectives in this field. GRAPHICAL ABSTARCT
Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1 associated membranous nephropathy.

Primary membranous nephropathy (pMN) is a leading cause of the nephrotic syndrome in adults. In most cases, this autoimmune kidney disease is associated with autoantibodies against the M-type phospholipase A2 receptor (PLA2R1) expressed on kidney podocytes, but the mechanisms leading to glomerular damage remain elusive. Here, we developed a cell culture model using human podocytes and found that anti-PLA2R1 positive pMN patient sera or isolated IgG4, but not IgG4-depleted sera, induce proteolysis of the two essential podocyte proteins synaptopodin and NEPH1 in the presence of complement, resulting in perturbations of the podocyte cytoskeleton. Specific blockade of the lectin pathway prevented degradation of synaptopodin and NEPH1. Anti-PLA2R1-IgG4 directly bound mannose-binding lectin in a glycosylation-dependent manner. In a cohort of pMN patients, we identified increased levels of galactose-deficient IgG4, which correlated with anti-PLA2R1-titers and podocyte damage induced by patient sera. Assembly of the terminal C5b-9 complement complex and activation of the complement receptors C3aR1 or C5aR1 was required to induce proteolysis of synaptopodin and NEPH1 by two distinct proteolytic pathways, mediated by cysteine and aspartic proteinases, respectively. Together, these results demonstrate a mechanism by which aberrantly glycosylated IgG4 activates the lectin pathway and induces podocyte injury in primary membranous nephropathy.
Ambient mass spectrometry: Approaching the chemical analysis of things as they are

As G.E. F. Lundell once indicated, the goal of the analytical sciences is to provide the chemical analysis of things as they are; however, this concept is often ignored in the development, and especially in the use, of analytical techniques. The field of ambient desorption/ionization mass spectrometry seeks to reverse this trend by enabling direct, sensitive, and selective analysis of untreated samples. Because of this ability, significant interest has surrounded the field since its introduction in 2004. In fact, the response seems to follow a Hype Cycle model, in which we are currently at the peak of inflated expectations. To lessen the impact of negative hype (i.e. the trough of disillusionment), which could destroy the field, more effort must be expended on fundamentally understanding the processes involved in ambient mass-spectrometric analyses. Examples are cited here to illustrate the limitations of and fundamental research on plasma-based ambient desorption/ionization in an effort to evaluate the current state of the field.
Evaluation of Tissue Stem Cell–Derived Human Intestinal Organoids, a Physiologically Relevant Model to Evaluate Cytochrome P450 Induction in Gut

Induction of cytochrome P450 can cause drug-drug interactions and efficacy failure. Induction risk in liver and gut is typically inferred from experiments with plated hepatocytes. Organoids are physiologically relevant, multicellular structures originating from stem cells. Intestinal stem cell–derived organoids retain traits of normal gut physiology, such as an epithelial barrier and cellular diversity. Matched human enteroid and colonoid lines, generated from ileal and colon biopsies from two donors, were cultured in extracellular matrix for 3 days, followed by a single 48-hour treatment with rifampin, omeprazole, CITCO, and phenytoin at concentrations that induce target genes in hepatocytes. After treatment, mRNA was analyzed for induction of target genes. Rifampin induced CYP3A4; estimated EC50 and maximal fold induction were 3.75 µM and 8.96-fold, respectively, for ileal organoids and 1.40 µM and 11.3-fold, respectively, for colon organoids. Ileal, but not colon, organoids exhibited nifedipine oxidase activity, which was induced by rifampin up to 14-fold. The test compounds did not increase mRNA expression of CYP1A2, CYP2B6, multidrug resistance transporter 1 (P-glycoprotein), breast cancer resistance protein, and UDP-glucuronosyltransferase 1A1 in ileal organoids. Whereas omeprazole induced CYP3A4 (up to 5.3-fold, geometric mean, n = 4 experiments), constitutive androstane receptor activators phenytoin and CITCO did not. Omeprazole failed to induce CYP1A2 mRNA but did induce CYP1A1 mRNA (up to 7.7-fold and 15-fold in ileal and colon organoids, respectively, n = 4 experiments). Despite relatively high intra- and interexperimental variability, data suggest that the model yields induction responses that are distinct from hepatocytes and holds promise to enable evaluation of CYP1A1 and CYP3A4 induction in gut. Significance Statement An adult intestinal stem cell–derived organoid model to test P450 induction in gut was evaluated. Testing several prototypical inducers for mRNA induction of P450 isoforms, UDP-glucuronosyltransferase 1A1, P-glycoprotein, and breast cancer resistance protein with both human colon and ileal organoids resulted in a range of responses, often distinct from those found in hepatocytes, indicating the potential for further development of this model as a physiologically relevant gut induction test system.
Mutations altering acetylated residues in the CTD of HIV-1 integrase cause defects in proviral transcription at early times after integration of viral DNA

The central function of the retroviral integrase protein (IN) is to catalyze the integration of viral DNA into the host genome to form the provirus. The IN protein has also been reported to play a role in a number of other processes throughout the retroviral life cycle such as reverse transcription, nuclear import and particle morphogenesis. Studies have shown that HIV-1 IN is subject to multiple post-translational modifications (PTMs) including acetylation, phosphorylation and SUMOylation. However, the importance of these modifications during infection has been contentious. In this study we attempt to clarify the role of acetylation of HIV-1 IN during the retroviral life cycle. We show that conservative mutation of the known acetylated lysine residues has only a modest effect on reverse transcription and proviral integration efficiency in vivo. However, we observe a large defect in successful expression of proviral genes at early times after infection by an acetylation-deficient IN mutant that cannot be explained by delayed integration dynamics. We demonstrate that the difference between the expression of proviruses integrated by an acetylation mutant and WT IN is likely not due to altered integration site distribution but rather directly due to a lower rate of transcription. Further, the effect of the IN mutation on proviral gene expression is independent of the Tat protein or the LTR promoter. At early times after integration when the transcription defect is observed, the LTRs of proviruses integrated by the mutant IN have altered histone modifications as well as reduced IN protein occupancy. Over time as the transcription defect in the mutant virus diminishes, histone modifications on the WT and mutant proviral LTRs reach comparable levels. These results highlight an unexpected role for the IN protein in regulating proviral transcription at early times post-integration.