Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeling of Hepatic Drug Metabolism and Responses in CYP2C19 Poor Metabolizer Using Genetically Manipulated Human iPS cells

Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate–treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human induced pluripotent stem cells (human iPS cells) and our highly efficient genome-editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between wild-type iPS cell–derived hepatocyte-like cells (WT HLCs) and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring S-mephenytoin metabolites using ultra-performance liquid chromatography-tandem mass spectrometry. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogrel- and ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogrel- and DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome-editing technologies for pharmaceutical research. SIGNIFICANCE STATEMENT Although unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 poor metabolizers, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 poor metabolizers because there is currently no model for this phenotype. Using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells as a novel CYP2C19 poor metabolizer model for drug development and research.
Consolidation with 90Y ibritumomab tiuxetan radioimmunotherapy in mantle cell lymphoma patients ineligible for high dose therapy: results of the phase II multicentre Polish Lymphoma Research Group trial, after 8-year long follow-up

Abstract Polish Lymphoma Research Group performed a phase-II trial to test whether 90Y ibritumomab tiuxetan radioimmunotherapy (Y90) may constitute an alternative consolidation for mantle cell lymphoma patients unfit for high-dose therapy. Forty-six patients were consolidated with Y90 following response to the 1st (n = 34) or 2nd line (n = 12) (immuno)chemotherapy. Majority of the patients had advanced disease (stage IV and presence of B-symptoms in 85% and 70%, respectively) and high MIPI (5.8, range 4–7). Consolidation with Y90 increased the complete remission (CR) rate obtained by the 1st line therapy from 41% to 91% and allowed for median PFS of 3.3 and OS of 6.5 years. In the first relapse, CR rate increased from 16% to 75%, while median PFS and OS totaled 2.2 and 6.5 years, respectively. At 8 years, 30% of patients, consolidated in the 1st line CR were alive, without relapse. Toxicity associated with Y90 is manageable, more severe after fludarabine-based regimens.
Oxidative Depolymerization of Cellulolytic Enzyme Lignin over Silicotungvanadium Polyoxometalates

The aim of this study was to explore the catalytic performance of the oxidative depolymerization of enzymatic hydrolysis lignin from cellulosic ethanol fermentation residue by different vanadium substituted Keggin-type polyoxometalates (K5[SiVW11O40], K6[SiV2W10O40], and K6H[SiV3W9O40]). Depolymerized products were analyzed by gel permeation chromatography (GPC), gas chromatography–mass spectrometer (GC/MS), and two-dimensional heteronuclear single quantum coherence nuclear magnetic resonance (2D HSQC NMR) analysis. All catalysts showed an effective catalytic activity. The best result, concerning the lignin conversion and lignin oil production, was obtained by K6[SiV2W10O40], and the highest yield of oxidative depolymerization products of 53 wt % was achieved and the main products were monomer aromatic compounds. The HSQC demonstrated that the catalysts were very effective in breaking the β-O-4 structure, the dominant linkage in lignin, and the GPC analysis demonstrated that the molecular of lignin was declined significantly. These results demonstrate the vanadium substituted silicotungstic polyoxometalates were of highly active and stable catalysts for lignin conversion, and this strategy has the potential to be applicable for production of value-added chemicals from biorefinery lignin.
Adipose‐derived mesenchymal stem cells stereotactic transplantation alleviate brain edema from intracerebral hemorrhage

Adipose‐derived mesenchymal stromal cells (ADSCs) exhibited high potential in tissue repair and regeneration, and it has been proved that ADSCs could protect brain cells from apoptosis and maintaining blood‐brain barrier stability after cerebral vascular disease. In this study, we evaluated the therapeutic potential and mechanism of ADSCs stereotactic transplantation in intracerebral hemorrhage (ICH) mice model and hemin‐treated astrocytes. Mice were divided into three groups: sham group, ICH + PBS group, and ICH + ADSC group. Mice in ICH + ADSC group received ADSCs cell suspension stereotactic transplantation into the area beside the bleeding region. Astrocytes were divided into three groups: control group, hemin group, and hemin + ADSC group. Astrocytes in hemin + ADSC group were cultured in ADSCs‐astrocyte no‐contact coculture system and treated with 30 μM hemin solution. The results showed that ADSCs stereotactic transplantation improved functional outcomes and reduced cell apoptosis after ICH. Moreover, ADSCs stereotactic transplantation could alleviate brain edema and inflammation and AQP4 protein expression contributed to the alleviation of brain edema. In addition, mitogen‐activated protein kinase (MAPK) pathways, including p38/MAPK pathway and c‐Jun N‐terminal kinase pathway, were involved in AQP4 modulation by ADSCs transplantation in ICH. In conclusion, ADSCs transplantation could alleviate the nervous tissue injury, reduce cell apoptosis, and relieve brain edema in ICH. And the edema regulation effect of ADSCs transplantation is associated with inhibition of inflammation and AQP4 protein expression.
Evaluation of Fertilizing Ability of Frozen Equine Sperm Using a Bovine Zona Pellucida Binding Assay.

BACKGROUND Frozen equine semen has lower fertility compared to cooled semen. Due to the difficulty to obtain equine oocytes, a heterologous zona pellucida binding assay (ZBA) is an alternative method to predict the fertilizing capability of equine frozen sperm. The rate of capacitated and hyperactivated sperm according to their motility characteristics were analyzed with a Computer Assisted Sperm Analyzer. We believe this report describes for the first time the in vitro hyperactivation induction and the heterologous ZBA to predict the fertilizing ability of frozen equine sperm. OBJECTIVE This work aimed at developing an assay to evaluate the fertilizing ability of frozen equine sperm using a bovine ZBA with the use of an in vitro capacitation and hyperactivation media with procaine and calcium ionophore A23187, respectively. MATERIALS AND METHODS The sperm motility characteristics, intact and acrosome reacted sperm rates, and number of stallion sperm bound to the bovine ZP were calculated. RESULTS The procaine group showed a hyperactivation motility pattern, although it improved ZP sperm binding similarly to the capacitation group. CONCLUSION The capacitation medium improved the IVF capability of frozen equine sperm, allowing the highest possibility of sperm-oocyte interaction.
Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial

Significance Application of antigen-specific immune tolerance in autoimmune disease is a long-sought goal. We studied diseases with abundant information on the autoimmune target: in multiple sclerosis (MS), various myelin antigens are known targets of T cells and antibodies, whereas in neuromyelitis optica (NMO), the aquaporin-4 channel is attacked by T cells and antibodies. We tested whether engineered dendritic cells might induce a tolerogenic immune response in these two conditions. In this in-human clinical study, individual regulatory T cells, secreting IL-10, a key tolerogenic cytokine, were detected after treatment. These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS, NMO, myasthenia gravis, and Graves disease. There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.
Flexible 3D-Printed EEG Electrodes

For electroencephalography (EEG) in haired regions of the head, finger-based electrodes have been proposed in order to part the hair and make a direct contact with the scalp. Previous work has demonstrated 3D-printed fingered electrodes to allow personalisation and different configurations of electrodes to be used for different people or for different parts of the head. This paper presents flexible 3D-printed EEG electrodes for the first time. A flexible 3D printing element is now used, with three different base mechanical structures giving differently-shaped electrodes. To obtain improved sensing performance, the silver coatings used previously have been replaced with a silver/silver-chloride coating. This results in reduced electrode contact impedance and reduced contact noise. Detailed electro-mechanical testing is presented to demonstrate the performance of the operation of the new electrodes, particularly with regards to changes in conductivity under compression, together with on-person tests to demonstrate the recording of EEG signals.
Goal-directed versus outcome-based financial incentives for weight loss among low-income patients with obesity: rationale and design of the Financial Incentives foR Weight Reduction (FIReWoRk) randomised controlled trial

Introduction Obesity is a major public health challenge and exacerbates economic disparities through employment discrimination and increased personal health expenditures. Financial incentives for weight management may intensify individuals’ utilisation of evidence-based behavioural strategies while addressing obesity-related economic disparities in low-income populations. Trials have focused on testing incentives contingent on achieving weight loss outcomes. However, based on social cognitive and self-determination theories, providing incentives for achieving intermediate behavioural goals may be more sustainable than incentivising outcomes if they enhance an individual’s skills and self-efficacy for maintaining long-term weight loss. The objective of this paper is to describe the rationale and design of the Financial Incentives foR Weight Reduction study, a randomised controlled trial to test the comparative effectiveness and cost-effectiveness of two financial incentive strategies for weight loss (goal directed vs outcome based) among low-income adults with obesity, as well as compared with the provision of health behaviour change resources alone. Methods and analysis We are recruiting 795 adults, aged 18–70 years with a body mass index ≥30 kg/m2, from three primary care clinics serving residents of socioeconomically disadvantaged neighbourhoods in New York City and Los Angeles. All participants receive a 1-year commercial weight loss programme membership, self-monitoring tools (bathroom scale, food journal and Fitbit Alta HR), health education and monthly check-in visits. In addition to these resources, those in the two intervention groups can earn up to $750 over 6 months for: (1) participating in an intensive weight management programme, self-monitoring weight and diet and meeting physical activity guidelines (goal-directed arm); or (2) a ≥1.5% to ≥5% reduction in baseline weight (outcome-based arm). To maximise incentive efficacy, we incorporate concepts from behavioural economics, including immediacy of payments and framing feedback to elicit regret aversion. We will use generalised mixed effect models for repeated measures to examine intervention effects on weight at 6, 9 and 12 months. Ethics and dissemination Human research protection committees at New York University School of Medicine, University of California Los Angeles (UCLA) David Geffen School of Medicine and Olive-View–UCLA Medical Center granted ethics approval. We will disseminate the results of this research via peer-reviewed publications, conference presentations and meetings with stakeholders. Trial registration number NCT03157713.
FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex

Members of the human FET family of RNA‐binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor‐coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy.
Tuberculosis at the animal–human interface in the Ugandan cattle corridor using a third-generation sequencing platform: a cross-sectional analysis study

Introduction Mycobacterial diseases are a significant source of disease burden, with Mycobacterium tuberculosis being the most common infectious cause of death worldwide. Given this, the emergence of antibiotic resistance in these species is of particular interest. By examining the epidemiology of mycobacteria in humans and cattle in an area of intense human–animal contact (the Ugandan cattle corridor [UCC]) and using a novel whole-genome sequencing technique to analyse organism diversity, this study will explore the role bidirectional transmission of mycobacteria plays in the local ecology, as well the significance of zoonotic Mycobacterium bovis in the human population. Methods and analysis This ongoing study includes both a cross-sectional analysis of the UCC mycobacteria-positive population and novel laboratory-based research focused on differentiating the species causing M. tuberculosis complex-linked disease. We will use a third-generation sequencing platform (the MinION sequencer from Oxford Nanopore Technology), comparing data from a sample subset to the Illumina platform as a means of measuring viability of the MinION platform in this specific setting. Our full sample set will be sequenced on Illumina and the data will be used to perform epidemiological and phylogenetic analyses. Ethics and dissemination Ethical approval was obtained from both the University of Minnesota IRB committee and the Ugandan National Council for Science and Technology—Research Ethics Committee. Samples were obtained after patients signed an informed consent indicating samples could be retained and used for research purposes. All samples are deidentified, with only basic demographic and geographic information being retained per national tuberculosis (TB) recording guidelines. Significant drug resistance results will be referred back to the local TB control officer to inform patient care. Final results of the study will be submitted to infectious disease-specific journals and will be submitted to the annual Infectious Diseases Society of America (IDSA) meeting.
Adipocyte lineage differentiation potential of MSCs isolated from reaming material

Mesenchymal stem cells (MSCs) obtained from various sources have been used for different therapeutic applications including tissue regeneration. Reamer/irrigator/aspirator (RIA) has been increasingly used in recent years for the derivation of MSCs. Here in this investigation we have comparatively analyzed MSCs obtained from iliac crest bone marrow (ICBM) and RIA for their morphology, cluster determinant (CD) markers, and adipogenic differentiation capacity. MSCs were isolated, cultured, and purified from both sources and then flow cytometric studies were performed to study their characteristics. The differentiation potential of RIA and ICBM was examined by an Oil Red O staining protocol. Moreover, the tissue‐specific markers related to adipogenesis were analyzed by real‐time polymerase chain reaction (RT‐PCR). The cells were cultured in the relevant induction medium and then adipogenic lineage differentiation was tested and confirmed for all MSC preparations. Additionally, analysis by flow cytometer was indicative of RIA derived MSCs (RIA‐MSCs) having a more homogenous population than ICBM derived MSCs. The RIA‐MSCs differentiation toward adipogenic lineage was more efficient compared with ICBM‐MSCs. Direct comparative analysis of RIA to ICBM‐MSCs indicated that the RIA‐MSCs had a higher potential toward adipocyte lineage differentiation compared with ICBM‐MSCs.
Novel MenA Inhibitors Are Bactericidal against Mycobacterium tuberculosis and Synergize with Electron Transport Chain Inhibitors

Mycobacterium tuberculosis is the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible disease burden, combined with the long course of drug treatment and an increasing incidence of antimicrobial resistance among M. tuberculosis isolates, necessitates novel drugs and drug targets for treatment of this deadly pathogen. ABSTRACT Mycobacterium tuberculosis is the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible disease burden, combined with the long course of drug treatment and an increasing incidence of antimicrobial resistance among M. tuberculosis isolates, necessitates novel drugs and drug targets for treatment of this deadly pathogen. Recent work has produced several promising clinical candidates targeting components of the electron transport chain (ETC) of M. tuberculosis, highlighting this pathway’s potential as a drug target. Menaquinone is an essential component of the M. tuberculosis ETC, as it functions to shuttle electrons through the ETC to produce the electrochemical gradient required for ATP production for the cell. We show that inhibitors of MenA, a component of the menaquinone biosynthetic pathway, are highly active against M. tuberculosis. MenA inhibitors are bactericidal against M. tuberculosis under both replicating and nonreplicating conditions, with 10-fold higher bactericidal activity against nutrient-starved bacteria than against replicating cultures. MenA inhibitors have enhanced activity in combination with bedaquiline, clofazimine, and inhibitors of QcrB, a component of the cytochrome bc1 oxidase. Together, these data support MenA as a viable target for drug treatment against M. tuberculosis. MenA inhibitors not only kill M. tuberculosis in a variety of physiological states but also show enhanced activity in combination with ETC inhibitors in various stages of clinical trial testing.
Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

Previous studies by our lab have established that placental‐ischemia stimulated T‐helper 17 cells (TH17s) cause increased cytolytic natural killer (cNK) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 (IL‐17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL‐17 into a subset of normal pregnant (NP) Sprague Dawley rats from gestation day (GD) 12–19 (NP+IL‐17). On GD 19, mean arterial pressure (MAP), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP+IL‐17 (P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP+IL‐17 as did placental weight (NP: 0.65 ± 0.03 g; NP+IL‐17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF‐α increased to 281.4 ± 55.07 pg/mL in NP+IL‐17 from 145.3 ± 16.03 pg/mL in NP (P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP+IL‐17. Total NK cells were increased in the placenta (NP: 14.3 ± 3.49%; NP+IL‐17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells (NP: 3.31 ± 1.25%; NP+IL‐17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/mL in NP to 20.9 ± 7.76 pg/mL in NP+IL‐17 (P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/mL in NP to 14.9 ± 0.98 pg/mL in NP+IL‐17(P < 0.05). In the placenta, both granzyme A (NP: 246.1 ± 16.7 pg/mg; NP+IL‐17: 324.3 ± 15.07 pg/mg, P < 0.05) and granzyme B (NP: 15.18 ± 3.79 pg/mg; NP+IL‐17: 27.25 ± 2.34 pg/mg, P < 0.05) increased in response to IL‐17 infusion. Finally, vascular reactivity of uterine arteries was significantly impaired in response to IL‐17 infusion. The results of this study suggest that IL‐17 plays a significant role in the activation of cNK cells during pregnancy.