Genetic Mechanisms of Transcriptional Regulation in Childhood Acute Lymphoblastic Leukemia

Introduction. Advances in genomic profiling and sequencing studies have identified germline and somatic variations that are associated with childhood ALL, improving our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL). Recent genome-wide association studies (GWAS) have identified germline genetic variations of ARID5B and, more recently, IGF2BP1 that are associated with susceptibility to ALL. Genome-wide sequencing studies also discovered a new ALL subtype characterized of ZNF384-mediated chromosomal translocations, providing new insights into genetic heterogeneity in childhood ALL. However, the underlying mechanism by which these genetic variants contribute to the transcriptional regulatory circuitries of ALL is still poorly understood. We tested these hypotheses: 1) A low ARID5B expression will increase the relapse risk of ALL, 2) Genetic variants of ARID5B will affect its expression and thus influence susceptibility to childhood ALL, 3) IGF2BP1 is transcriptionally suppressed by ETV6, 4) ZNF384-mediated fusion genes transcriptionally upregulate FLT3 expression as being a therapeutic target. Specific aims in this study include: 1) identifying the causal variant of ARID5B, 2) identifying molecular mechanism underlying drug resistance, 3) identifying molecular mechanism of transcriptional regulation of IGF2BP1 by ETV6, and 4) identifying molecular mechanism of transcriptional regulation of FLT3 by EP300-ZNF384 fusion protein. Methods. We analyzed association of ARID5B expression in primary human ALL blasts with different molecular subtypes and treatment outcomes. Subsequent mechanistic studies were performed in ALL cell lines by manipulating ARID5B expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. We performed ARID5B targeted sequencing in 5,008 children with ALL and conducted high throughput CRISPR/dCas9 screening in an engineered ARID5B mCherry knock-in cell line. Effects of genetic polymorphism on binding affinity of transcription factor and chromatin accessibility were subsequently assessed. We applied CRISPR/dCas9 to investigate transcriptional regulation of IGF2BP1 by ETV6 in ALL cell lines. We stably knocked down EP300-ZNF384 fusion gene by CRISPR editing in ALL cell line, in which we analyzed FLT3 expression and drug sensitivity. Results. ARID5B expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower ARID5B expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models in vitro, ARID5B knockdown led to resistance specific to antimetabolite drugs. ARID5B downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest partially through upregulating expression the cell-cycle checkpoint regulator p21 (encoded by CDKN1A). Using targeted sequencing in germline DNA of 5,008 children with ALL and high throughput CRISPR/dCas9 screening in an engineered ARID5B mCherry knock-in cell line, we nominated ALL risk variant (rs7090445, P = 1.82 × 10-10) as the causal variant. And its polymorphisms disrupted binding of transcription factor MEF2C and local chromosome accessibility as confirmed by ChIP-Sanger-seq and ATAC-seq. Although it was previously reported that IGF2BP1 expression was significantly higher in ETV6-RUNX1 ALL as well as other cancers, the underlying transcriptional regulatory mechanism remains elusive. In ALL cell models, we identified a cis-regulatory element (CRE) blocking of which by dCas9-KRAB strongly influenced transcription of IGF2BP1. Moreover, we presented a CRISPR-based approach to comprehensively investigate the transcriptional regulatory mechanism of IGF2BP1 by identifying its CREs and upstream transcriptional regulators. In tissue-specific overexpression mouse models, we demonstrated that role of Igf2bp1 in B-cell development was stage-specific. In a novel ALL subtype characterized of ZNF384-mediated rearrangements, for the first time we reported overexpression of FLT3 in this new ALL subtype, providing a novel therapeutic target for ALL patient with high expression of FLT3. Furthermore, we defined EP300-ZNF384 fusion protein as a transcriptional activator of FLT3 gene with direct binding at its 5’UTRand knocking down this fusion gene led to downregulation of FLT3 expression as well as decreased sensitivity to FLT3 inhibitor in vitro. Conclusions. Our studies have demonstrated that a causal variant of ARID5B affected its transcription in-cis and that a low expression of ARID5B increased ALL relapse risk. As a downstream effector of ETV6, IGF2BP1 expression influenced B-cell development in vivo in a stage-specific manner. Moreover, expression of FLT3 was transcriptionally upregulated by ZNF384-mediated fusion genes. This study sheds light on the underlying mechanism by which genetic variations altered transcriptional programs in childhood ALL and refined our understanding of the genetic basis of childhood ALL, providing new molecular targets which can be harnessed for development of new therapies for patients with ALL

Fashion Matrix: Editing Photos by Just Talking

The utilization of Large Language Models (LLMs) for the construction of AI systems has garnered significant attention across diverse fields. The extension of LLMs to the domain of fashion holds substantial commercial potential but also inherent challenges due to the intricate semantic interactions in fashion-related generation. To address this issue, we developed a hierarchical AI system called Fashion Matrix dedicated to editing photos by just talking. This system facilitates diverse prompt-driven tasks, encompassing garment or accessory replacement, recoloring, addition, and removal. Specifically, Fashion Matrix employs LLM as its foundational support and engages in iterative interactions with users. It employs a range of Semantic Segmentation Models (e.g., Grounded-SAM, MattingAnything, etc.) to delineate the specific editing masks based on user instructions. Subsequently, Visual Foundation Models (e.g., Stable Diffusion, ControlNet, etc.) are leveraged to generate edited images from text prompts and masks, thereby facilitating the automation of fashion editing processes. Experiments demonstrate the outstanding ability of Fashion Matrix to explores the collaborative potential of functionally diverse pre-trained models in the domain of fashion editing.Comment: 13 pages, 5 figures, 2 table

Antiperovskite Li3OCl Superionic Conductor Films for Solid-State Li-Ion Batteries.

Antiperovskite Li3OCl superionic conductor films are prepared via pulsed laser deposition using a composite target. A significantly enhanced ionic conductivity of 2.0 × 10-4 S cm-1 at room temperature is achieved, and this value is more than two orders of magnitude higher than that of its bulk counterpart. The applicability of Li3OCl as a solid electrolyte for Li-ion batteries is demonstrated

Kernel filtering of spot volatility in presence of Lévy jumps and market microstructure noise

This paper considers the problem of estimating spot volatility in the simultaneous presence of Lévy jumps and market microstructure noise. We propose to use the pre-averaging approach and the threshold kernel-based method to construct a spot volatility estimator, which is robust to both microstructure noise and jumps of either finite or infinite activity. The estimator is consistent and asymptotically normal, with a fast convergence rate. Our estimator is general enough to include many existing kernel-based estimators as special cases. When the kernel bandwidth is fixed, our estimator leads to widely used estimators of integrated volatility. Monte Carlo simulations show that our estimator works very well

Kernel filtering of spot volatility in presence of Lévy jumps and market microstructure noise

This paper considers the problem of estimating spot volatility in the simultaneous presence of Lévy jumps and market microstructure noise. We propose to use the pre-averaging approach and the threshold kernel-based method to construct a spot volatility estimator, which is robust to both microstructure noise and jumps of either finite or infinite activity. The estimator is consistent and asymptotically normal, with a fast convergence rate. Our estimator is general enough to include many existing kernel-based estimators as special cases. When the kernel bandwidth is fixed, our estimator leads to widely used estimators of integrated volatility. Monte Carlo simulations show that our estimator works very well

4,4′-[(2,7-Dibromo­fluorene-9,9-di­yl)dimethyl­ene]dipyridinium bis­(perchlorate)

In the crystal of the title compound, C25H20Br2N2 2+·2ClO4 −, inter­molecular N—H⋯O and C—H⋯O hydrogen bonds, along with C—H⋯π inter­actions, stabilize the crystal structure

Diabetic Inhibition of Preconditioning- and Postconditioning-Mediated Myocardial Protection against Ischemia/Reperfusion Injury

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2–6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3β pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries

Pressure-induced charge orders and their postulated coupling to magnetism in hexagonal multiferroic LuFe\u3csub\u3e2\u3c/sub\u3eO\u3csub\u3e4\u3c/sub\u3e

Hexagonal LuFe2O4 is a promising charge order (CO) driven multiferroic material with high charge and spin-ordering temperatures. The coexisting charge and spin orders on Fe3+/Fe2+ sites result in magnetoelectric behaviors, but the coupling mechanism between the charge and spin orders remains elusive. Here, by tuning external pressure, we reveal three charge-ordered phases with suggested correlation to magnetic orders in LuFe2O4: (i) a centrosymmetric incommensurate three-dimensional CO with ferrimagnetism, (ii) a non-centrosymmetric incommensurate quasi-two-dimensional CO with ferrimagnetism, and (iii) a centrosymmetric commensurate CO with antiferromagnetism. Experimental in situ single-crystal X-ray diffraction and X-ray magnetic circular dichroism measurements combined with density functional theory calculations suggest that the charge density redistribution caused by pressure-induced compression in the frustrated double-layer [Fe2O4] cluster is responsible for the correlated spin-charge phase transitions. The pressure-enhanced effective Coulomb interactions among Fe-Fe bonds drive the frustrated (1/3, 1/3) CO to a less frustrated (1/4, 1/4) CO, which induces the ferrimagnetic to antiferromagnetic transition. Our results not only elucidate the coupling mechanism among charge, spin, and lattice degrees of freedom in LuFe2O4, but also provide a new way to tune the spin-charge orders in a highly controlled manner

Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia.

FLT3 is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts FLT3 activation and decreases ALL cell sensitivity to FLT3 inhibitor gilteritinib in vitro. In patient-derived xenograft models of ZNF384-rearranged ALL, gilteritinib exhibits significant anti-leukemia efficacy as a monotherapy in vivo. Collectively, our results provide insights into FLT3 regulation in ALL and point to potential genomics-guided targeted therapy for this patient population