Effects of biomass co-pyrolysis and herbaceous plant colonization on the transformation of tailings into soil like substrate.

Enhancing soil organic matter characteristics, ameliorating physical structure, mitigating heavy metal toxicity, and hastening mineral weathering processes are crucial approaches to accomplish the transition of tailings substrate to a soil-like substrate. The incorporation of biomass co-pyrolysis and plant colonization has been established to be a significant factor in soil substrate formation and soil pollutant remediation. Despite this, there is presently an absence of research efforts aimed at synergistically utilizing these two technologies to expedite the process of mining tailings soil substrate formation. The current study aimed to investigate the underlying mechanism of geochemical changes and rapid mineral weathering during the process of transforming tailings substrate into a soil-like substrate, under the combined effects of biomass co-smoldering pyrolysis and plant colonization. The findings of this study suggest that the incorporation of smoldering pyrolysis and plant colonization induces a high-temperature effect and biological effects, which enhance the physical and chemical properties of tailings, while simultaneously accelerating the rate of mineral weathering. Notable improvements include the amelioration of extreme pH levels, nutrient enrichment, the formation of aggregates, and an increase in enzyme activity, all of which collectively demonstrate the successful attainment of tailings substrate reconstruction. Evidence of the accelerated weathering was verified by phase and surface morphology analysis using X-ray diffraction and scanning electron microscopy. Discovered corrosion and fragmentation on the surface of minerals. The weathering resulted in corrosion and fragmentation of the surface of the treated mineral. This study confirms that co-smoldering pyrolysis of biomass, combined with plant colonization, can effectively promote the transformation of tailings into soil-like substrates. This method has can effectively address the key challenges that have previously hindered sustainable development of the mining industry and provides a novel approach for ecological restoration of tailings deposits.

Deep learning-based deformable image registration with bilateral pyramid to align pre-operative and follow-up magnetic resonance imaging (MRI) scans.

Background: The evaluation of brain tumor recurrence after surgery is based on the comparison between tumor regions on pre-operative and follow-up magnetic resonance imaging (MRI) scans in clinical practice. Accurate alignment of MRI scans is important in this evaluation process. However, existing methods often fail to yield accurate alignment due to substantial appearance and shape changes of tumor regions. The study aimed to improve this misalignment situation through multimodal information and compensation for shape changes. Methods: In this work, a deep learning-based deformation registration method using bilateral pyramid to create multi-scale image features was developed. Moreover, morphology operations were employed to build correspondence between the surgical resection on the follow-up and pre-operative MRI scans. Results: Compared with baseline methods, the proposed method achieved the lowest mean absolute error of 1.82 mm on the public BraTS-Reg 2022 dataset. Conclusions: The results suggest that the proposed method is potentially useful for evaluating tumor recurrence after surgery. We effectively verified its ability to extract and integrate the information of the second modality, and also revealed the micro representation of tumor recurrence. This study can assist doctors in registering multiple sequence images of patients, observing lesions and surrounding areas, analyzing and processing them, and guiding doctors in their treatment plans.

Scale Invariance of a Spherical Unitary Fermi Gas.

A unitary Fermi gas in an isotropic harmonic trap is predicted to show scale and conformal symmetry that have important consequences in its thermodynamic and dynamical properties. By experimentally realizing a unitary Fermi gas in an isotropic harmonic trap, we demonstrate its universal expansion dynamics along each direction and at different temperatures. We show that as a consequence of SO(2,1) symmetry, the measured release energy is equal to that of the trapping energy. We further observe the breathing mode with an oscillation frequency twice the trapping frequency and a small damping rate, providing the evidence of SO(2,1) symmetry. In addition, away from resonance when scale invariance is broken, we determine the effective exponent γ that relates the chemical potential and average density along the BEC-BCS crossover, which qualitatively agrees with the mean field predictions. This Letter opens the possibility of studying nonequilibrium dynamics in a conformal invariant system in the future.

Targeting ferroptosis by natural products in pathophysiological conditions.

Ferroptosis is a form of cell death that is induced by iron-mediated accumulation of lipid peroxidation. The involvement of ferroptosis in different pathophysiological conditions has offered new perspectives on potential therapeutic interventions. Natural products, which are widely recognized for their significance in drug discovery and repurposing, have shown great promise in regulating ferroptosis by targeting various ferroptosis players. In this review, we discuss the regulatory mechanisms of ferroptosis and its implications in different pathological conditions. We dissect the interactions between natural products and ferroptosis in cancer, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury, liver injury, and cardiomyopathy, with an emphasis on the relevance of ferroptosis players to disease targetability.

Structural basis of tethered agonism and G protein coupling of protease-activated receptors.

Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming ß-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1's versatility in G protein coupling.

Odor Fingerprinting of Chitosan and Source Identification of Commercial Chitosan: HS-GC-IMS, Multivariate Statistical Analysis, and Tracing Path Study.

Chitosan samples were prepared from the shells of marine animals (crab and shrimp) and the cell walls of fungi (agaricus bisporus and aspergillus niger). Fourier-transform infrared spectroscopy (FT-IR) was used to detect their molecular structures, while headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) was employed to analyze their odor composition. A total of 220 volatile organic compounds (VOCs), including esters, ketones, aldehydes, etc., were identified as the odor fingerprinting components of chitosan for the first time. A principal component analysis (PCA) revealed that chitosan could be effectively identified and classified based on its characteristic VOCs. The sum of the first three principal components explained 87% of the total variance in original information. An orthogonal partial least squares discrimination analysis (OPLS-DA) model was established for tracing and source identification purposes, demonstrating excellent performance with fitting indices R2X = 0.866, R2Y = 0.996, Q2 = 0.989 for independent variable fitting and model prediction accuracy, respectively. By utilizing OPLS-DA modeling along with a heatmap-based tracing path study, it was found that 29 VOCs significantly contributed to marine chitosan at a significance level of VIP > 1.00 (p < 0.05), whereas another set of 20 VOCs specifically associated with fungi chitosan exhibited notable contributions to its odor profile. These findings present a novel method for identifying commercial chitosan sources, which can be applied to ensure biological safety in practical applications.

LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner.

The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.

Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

Association between brominated flame retardants (PBDEs and PBB153) exposure and hypertension in U.S. adults: results from NHANES 2005-2016.

BACKGROUND: Brominated Flame Retardants (BFRs) have attracted widespread concern due to their environmental persistence and potential toxicity. This study aims to examine the association between BFRs exposure and hypertension. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2016 for the cross-sectional analysis. To evaluate the individual and combined impacts of BFRs exposure on hypertension, we utilized multivariate models, including generalized additive models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. RESULTS: 9882 individuals (48% male) aged ≥ 20 were included in the final analysis, of whom 4114 had hypertension. After controlling for potential covariates, higher serum concentrations of PBDE100 (OR: 1.26; 95% CI: 1.01, 1.57) and PBDE153 (OR: 1.50; 95% CI: 1.18, 1.88) were significantly associated with hypertension. A nonlinear relationship between PBDE28 and hypertension was observed (P = 0.03). Moreover, BFRs mixture were positively associated with the prevalence of hypertension in both the WQS (ß:1.09; 95% CI: 1.02, 1.17; P = 0.02) and BKMR models. CONCLUSION: Our study suggested that BFRs exposure is positively associated with hypertension in the general population. To confirm this association and elucidate the mechanisms, further research is required.

Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

Genes associated with cellular senescence as diagnostic markers of major depressive disorder and their correlations with immune infiltration.

Background: Emerging evidence links cellular senescence to the pathogenesis of major depressive disorder (MDD), a life-threatening and debilitating mental illness. However, the roles of cellular senescence-related genes in MDD are largely unknown and were investigated in this study using a comprehensive analysis. Methods: Peripheral blood microarray sequencing data were downloaded from Gene Expression Omnibus (GEO) database and retrieved cellular senescence-related genes from CellAge database. A weighted gene co-expression network analysis was used to screen MDD-associated genes. Protein-protein interactions (PPI) were predicted based on STRING data, and four topological algorithms were used to identify hub genes from the PPI network. Immune infiltration was evaluated using CIBERSORT, followed by a correlation analysis between hub genes and immune cells. Results: A total of 84 cell senescence-related genes were differentially expressed in patients with MDD compared to healthy control participants. Among the 84 genes, 20 were identified to be associated with the MDD disease phenotype, and these genes were mainly involved in hormone-related signaling pathways (such as estrogen, steroid hormone, and corticosteroid) and immune and inflammatory pathways. Three genes, namely, JUN, CTSD, and CALR, which were downregulated in MDD, were identified as the hub genes. The expression of hub genes significantly moderate correlated with multiple immune cells, such as Tregs, NK cells, and CD4+ T cells, and the abundance of these immune cells markedly differed in MDD samples. Multiple microRNAs, transcription factors, and small-molecule drugs targeting hub genes were predicted to explore their molecular regulatory mechanisms and potential therapeutic value in MDD. Conclusion: JUN, CTSD, and CALR were identified as potential diagnostic markers of MDD and may be involved in the immunoinflammatory mechanism of MDD.

A homologous membrane-camouflaged self-assembled nanodrug for synergistic antitumor therapy.

Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe2+ through coordination interactions, forming a stable DOX-Fe2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H2O2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: Ferroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H2O2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe2+ sources, H2O2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy.

Assembly and comparative analysis of the complete mitochondrial genome of Brassica rapa var. Purpuraria.

BACKGROUND: Purple flowering stalk (Brassica rapa var. purpuraria) is a widely cultivated plant with high nutritional and medicinal value and exhibiting strong adaptability during growing. Mitochondrial (mt) play important role in plant cells for energy production, developing with an independent genetic system. Therefore, it is meaningful to assemble and annotate the functions for the mt genome of plants independently. Though there have been several reports referring the mt genome of in Brassica species, the genome of mt in B. rapa var. purpuraria and its functional gene variations when compared to its closely related species has not yet been addressed. RESULTS: The mt genome of B. rapa var. purpuraria was assembled through the Illumina and Nanopore sequencing platforms, which revealed a length of 219,775 bp with a typical circular structure. The base composition of the whole B. rapa var. purpuraria mt genome revealed A (27.45%), T (27.31%), C (22.91%), and G (22.32%). 59 functional genes, composing of 33 protein-coding genes (PCGs), 23 tRNA genes, and 3 rRNA genes, were annotated. The sequence repeats, codon usage, RNA editing, nucleotide diversity and gene transfer between the cp genome and mt genome were examined in the B. rapa var. purpuraria mt genome. Phylogenetic analysis show that B. rapa var. Purpuraria was closely related to B. rapa subsp. Oleifera and B. juncea. Ka/Ks analysis reflected that most of the PCGs in the B. rapa var. Purpuraria were negatively selected, illustrating that those mt genes were conserved during evolution. CONCLUSIONS: The results of our findings provide valuable information on the B.rapa var. Purpuraria genome, which might facilitate molecular breeding, genetic variation and evolutionary researches for Brassica species in the future.

Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1ß.

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1ß in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1ß. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1ß, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1ß. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

From first encounters to longitudinal exposure: a repeated exposure-test paradigm for monitoring speech adaptation.

Perceptual difficulty with an unfamiliar accent can dissipate within short time scales (e.g., within minutes), reflecting rapid adaptation effects. At the same time, long-term familiarity with an accent is also known to yield stable perceptual benefits. However, whether the long-term effects reflect sustained, cumulative progression from shorter-term adaptation remains unknown. To fill this gap, we developed a web-based, repeated exposure-test paradigm. In this paradigm, short test blocks alternate with exposure blocks, and this exposure-test sequence is repeated multiple times. This design allows for the testing of adaptive speech perception both (a) within the first moments of encountering an unfamiliar accent and (b) over longer time scales such as days and weeks. In addition, we used a Bayesian ideal observer approach to select natural speech stimuli that increase the statistical power to detect adaptation. The current report presents results from a first application of this paradigm, investigating changes in the recognition accuracy of Mandarin-accented speech by native English listeners over five sessions spanning 3 weeks. We found that the recognition of an accent feature (a syllable-final /d/, as in feed, sounding/t/-like) improved steadily over the three-week period. Unexpectedly, however, the improvement was seen with or without exposure to the accent. We discuss possible reasons for this result and implications for conducting future longitudinal studies with repeated exposure and testing.

In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals.

Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.

Grinding siderite with ferric sulfate to generate an active ferrous source for Cr(VI) reduction.

Activated siderite, endowed with excellent properties, was simply prepared by co-grinding with Fe sulfate to enhance its high reducing ability for Cr(VI). Batch experiments were conducted to investigate the main affecting parameters, such as material ratio, pH, temperature, etc. The removal of Cr(VI) by activated siderite was completed within 4 h of the reaction. The activated siderite maintained a high removal effect of Cr(VI) within a wide pH range (3-9). Various analytical methods, including XRD, SEM/EDS, XPS, etc., were employed to characterize the samples and discover variations before and after the reaction. The Fe (Ⅱ) in activated siderite becomes highly active, and it can even be released from the solid phase in the mildly acidic liquid phase to efficiently reduce Cr(VI) and mitigate its toxicity. These findings introduce an innovative approach for activating various minerals widely distributed in nature to promote the recovery of the ecological system.

Numerical Simulation of Segregation in Slabs under Different Secondary Cooling Electromagnetic Stirring Modes.

Secondary cooling electromagnetic stirring (S-EMS) significantly impacts the internal quality of continuous casting slabs. In order to investigate the effects of S-EMS modes on segregation in slabs, a three-dimensional numerical model of the full-scale flow field, solidification, and mass transfer was established. A comparative analysis was conducted between continuous electromagnetic stirring and alternate stirring modes regarding their impacts on steel flow, solidification, and carbon segregation. The results indicated that adopting the alternate stirring mode was more advantageous for achieving uniform flow fields and reducing the disparity in solidification endpoints, thus mitigating carbon segregation. Specifically, the central carbon segregation index under continuous stirring at 320 A was 1.236, with an average of 1.247, while under alternate stirring, the central carbon segregation index decreased to 1.222 with an average of 1.227.

Topoisomerase Inhibitors and PIM1 Kinase Inhibitors Improve Gene Editing Efficiency Mediated by CRISPR-Cas9 and Homology-Directed Repair.

The CRISPR-Cas9 system has emerged as the most prevalent gene editing technology due to its simplicity, high efficiency, and low cost. However, the homology-directed repair (HDR)-mediated gene knock-in in this system suffers from low efficiency, which limits its application in animal model preparation, gene therapy, and agricultural genetic improvement. Here, we report the design and optimization of a simple and efficient reporter-based assay to visualize and quantify HDR efficiency. Through random screening of a small molecule compound library, two groups of compounds, including the topoisomerase inhibitors and PIM1 kinase inhibitors, have been identified to promote HDR. Two representative compounds, etoposide and quercetagetin, also significantly enhance the efficiency of CRISPR-Cas9 and HDR-mediated gene knock-in in mouse embryos. Our study not only provides an assay to screen compounds that may facilitate HDR but also identifies useful tool compounds to facilitate the construction of genetically modified animal models with the CRISPR-Cas9 system.

Efficacy of rituximab-containing regimens used as first-line and rescue therapy for giant cell hepatitis with autoimmune hemolytic anemia a retrospective study.

OBJECTIVE: To evaluate the efficacy of rituximab (RTX)-containing therapy as first-line as well as rescue treatment for giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA). METHODS: This retrospective study recruited patients diagnosed with GCH-AHA and treated with conventional immunosuppressor regimens consisting of prednisone or RTX-containing regimes consisting of RTX and prednisone, with or without another immunosuppressor. The primary outcomes were the complete remission (CR) rate and time-period required for CR. The secondary outcomes included relapses and adverse events. RESULTS: Twenty patients (8 females and 12 males; age range 1-26 months), 15 receiving conventional regimens and 5 receiving RTX-containing regimens, were included. The CR rates were 73.3 % (11/15) and 100 % (5/5) in the conventional and RTX-containing groups, respectively. The time-period required for CR was significantly shorter in the RTX-containing group than in the conventional group (6 (3-8) versus 14 (5-25) months, P = 0.015). Relapses occurred in 30.8 % (4/13) of patients in the conventional group; all achieved CR after adding RTX. Relapses occurred in 40.0 % (2/5) of patients in the RTX-containing group; both achieved CR after adding intravenous immune globulins or tacrolimus. Transient low immunoglobulin and infections were recorded in both groups. Treatment withdrawal was achieved in 73.3 % (11/15) and 60.0 % (3/5) of patients receiving conventional and RTX-containing regimens after 36 (2-101) and 22 (4-41) months, respectively. Two patients in conventional group died of disease progression and infection. CONCLUSIONS: RTX-containing first-line therapy achieves CR of GCH-AHA more quickly than the conventional therapy. RTX is efficacious when added to rescue therapy.