Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL.

ABSTRACT: Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X- or X::RAR::Y-type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.

Electromagnetic field and cardiovascular diseases: A state-of-the-art review of diagnostic, therapeutic, and predictive values.

Despite encouraging advances in early diagnosis and treatment, cardiovascular diseases (CVDs) remained a leading cause of morbidity and mortality worldwide. Increasing evidence has shown that the electromagnetic field (EMF) influences many biological processes, which has attracted much attention for its potential therapeutic and diagnostic modalities in multiple diseases, such as musculoskeletal disorders and neurodegenerative diseases. Nonionizing EMF has been studied as a therapeutic or diagnostic tool in CVDs. In this review, we summarize the current literature ranging from in vitro to clinical studies focusing on the therapeutic potential (external EMF) and diagnostic potential (internal EMF generated from the heart) of EMF in CVDs. First, we provided an overview of the therapeutic potential of EMF and associated mechanisms in the context of CVDs, including cardiac arrhythmia, myocardial ischemia, atherosclerosis, and hypertension. Furthermore, we investigated the diagnostic and predictive value of magnetocardiography in CVDs. Finally, we discussed the critical steps necessary to translate this promising approach into clinical practice.

Advances towards genome-based acute myeloid leukemia classification: A comparative analysis of WHO-HAEM4R, WHO-HAEM5, and International Consensus Classification.

Two recent guidelines, the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the International Consensus Classification (ICC), were published to refine the diagnostic criteria of acute myeloid leukemia (AML). They both consider genomic features more extensively and expand molecularly defined AML subtypes. In this study, we compared the classifications of 1135 AML cases under both criteria. According to WHO-HAEM5 and ICC, the integration of whole transcriptome sequencing, targeted gene mutation screening, and conventional cytogenetic analysis identified defining genetic abnormalities in 89% and 90% of AML patients, respectively. The classifications displayed discrepancies in 16% of AML cases after being classified using the two guidelines, respectively. Both new criteria significantly reduce the number of cases defined by morphology and differentiation. However, their clinical implementation heavily relies on comprehensive and sophisticated genomic analysis, including genome and transcriptome levels, alongside the assessment of pathogenetic somatic and germline variations. Discrepancies between WHO-HAEM5 and ICC, such as the assignment of RUNX1 mutations, the rationality of designating AML with mutated TP53 as a unique entity, and the scope of rare genetic fusions, along with the priority of concurrent AML-defining genetic abnormalities, are still pending questions requiring further research for more elucidated insights.

DNTT activation, TdT-aided gene length mutation, and better prognosis in ATG-based regimen allo-HSCT in AML.

This study aimed to investigate the relationship between anomalous DNA nucleotidylexotransferase (DNTT) activation and the mutagenesis of gene length mutations (LMs) in acute myeloid leukemia (AML), and the relevance of their prognosis in antithymocyte globulin (ATG)-based regimen allogeneic hematopoietic stem cell transplantation (allo-HSCT). A cohort of 578 AML cases was enrolled. Next-generation sequencing was performed to screen mutations of 86 leukemia driver genes. RNA-seq was used to analyze gene expression. Prognostic analysis was investigated in 239 AML cases who underwent ATG-based regimen allo-HSCT. We report a refined subtyping algorithm of LMs (type I-IV) based on sequence anatomy considering the TdT-aided mutagenesis mechanism. GC content adjacent to LM junctions, inserted nontemplate nucleotide bases, and DNTT expression analysis supported the DNTT activation and TdT-aided mutagenesis in type II/III LMs in the total AML cohort. Both single-variate and multivariate analyses showed a better overall survival of FLT3 type III compared to type I in a subset of ATG-based regimen allo-HSCT cases. The novel LM subtyping algorithm not only deciphers the etiology of the mutagenesis of LMs but also helps to fine-tune prognosis differentiation in AML. The possible prognostic versatility of this novel LM subtyping algorithm in terms of chemotherapy, targeted therapy, and allo-HSCT merits further investigation.

Ultrasensitive Atomic Comagnetometer with Enhanced Nuclear Spin Coherence.

Achieving high energy resolution in spin systems is important for fundamental physics research and precision measurements, with alkali-noble-gas comagnetometers being among the best available sensors. We found a new relaxation mechanism in such devices, the gradient of the Fermi-contact-interaction field that dominates the relaxation of hyperpolarized nuclear spins. We report on precise control over spin distribution, demonstrating a tenfold increase of nuclear spin hyperpolarization and transverse coherence time with optimal hybrid optical pumping. Operating in the self-compensation regime, our ^{21}Ne-Rb-K comagnetometer achieves an ultrahigh inertial rotation sensitivity of 3×10^{-8} rad/s/Hz^{1/2} in the frequency range from 0.2 to 1.0 Hz, which is equivalent to the energy resolution of 3.1×10^{-23} eV/Hz^{1/2}. We propose to use this comagnetometer to search for exotic spin-dependent interactions involving proton and neutron spins. The projected sensitivity surpasses the previous experimental and astrophysical limits by more than 4 orders of magnitude.

Report of PRPF19 as a novel partner of RARG and the recurrence of interposition-type fusion in variant acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) which is characterized by specific clinical and biological features. Typical APL cases are caused by PML::RARA fusion gene and are exquisitely sensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Rarely, APLs are caused by atypical fusions involving RARA or, in fewer cases still, fusions involving other members of the retinoic acid receptors (RARB or RARG). To date, seven partner genes of RARG have been reported in a total of 18 cases of variant APL. Patients with RARG fusions showed distinct clinical resistance to ATRA and had poor outcomes. Here, we report PRPF19 gene as a novel partner of RARG and identify a rare interposition-type gene fusion in a variant APL patient with a rapidly fatal clinical course. The incomplete ligand-binding domain of RARG in the fusion protein may account for the clinical ATRA resistance in this patient. These results broaden the spectrum of variant APL associated molecular aberrations. Accurately and timely identification of these rare gene fusions in variant APL is essential to guide therapeutic decisions.

[Identification of TCF3-ZNF384 fusion by transcriptome sequencing in B cell acute lymphoblastic leukemia and its laboratory and clinical characteristics].

OBJECTIVE: To detect fusion gene with pathological significance in a patient with refractory and relapsed acute B cell lymphoblastic leukemia (B-ALL) and to explore its laboratory and clinical characteristics. METHODS: Transcriptome sequencing was used to detect potential fusion transcripts. Other laboratory results and clinical data of the patient were also analyzed. RESULTS: The patient was found to harbor TCF3 exon 17-ZNF384 exon 7 in-frame fusion transcript. The minimal residual disease (MRD) has remained positive after multiple chemotherapy protocols including CD19-, CD22- targeted chimeric antigen receptor T cells immunotherapy. The patient eventually achieved complete remission and sustained MRD negativity after allogeneic hemopoietic stem cell transplantation (allo-HSCT). CONCLUSION: Transcriptome sequencing can effectively detect potential fusion genes with clinical significance in leukemia. TCF3-ZNF384 positive B-ALL has unique laboratory and clinical characteristics, may not well respond to chemotherapy and immunotherapy, and is more likely to relapse. Timely allo-HSCT treatment may help such patients to achieve long-term disease-free survival. TCF3-ZNF384 positive B-ALL is not uncommon in pediatric patients but has not been effectively identified.

Electrowetting-actuated multifunctional optofluidic lens to improve the quality of computer-generated holography.

This paper presents an electrowetting-actuated multifunctional optofluidic (EAMO) lens to improve the quality of computer-generated holography (CGH). A unique structure of the EAMO lens based on electrowetting effect is designed. When the electrodes of the EAMO lens are applied on different voltages, the functions of focal length change and aperture change can be achieved. Then the proposed lens is used in the reproduction system of the CGH due to the multiple functions. The experimental results show that the CGH with zoom function can be realized and undesirable light can be eliminated due to the unique structure of the EAMO lens. The focal length changes can be varied from 11.6 cm to + ∞ and -∞ to -150.6 cm. The aperture size changes can be varied from 10.1 cm to 6.7 cm. By using the proposed EAMO lens, high-quality CGH can be realized without moving the position of any components mechanically, while the setup of the CGH is greatly simplified.

Effects of pump laser power density on the hybrid optically pumped comagnetometer for rotation sensing.

We investigate the effects of pump laser power density on the hybrid optically pumped comagnetometer operated in the spin-exchange relaxation-free (SERF) regime. The analytic steady-state output model for the comagnetometer considering two alkali metal species and one nuclear species is presented for the first time. And the effects of pump laser power density on the rotation sensitivity, suppression of low-frequency magnetic noise and long-term stability of the comagnetometer are studied experimentally. The results indicate that when the product of pumping rate and density ratio of pumped atom to probed atom is equal to the spin relaxation rate of the probed atom, the maximum response and highest sensitivity of the comagnetometer are achieved. However, the suppression of low-frequency magnetic noise and long-term stability improve with the increasing of pump laser power density due to the increasing of nuclear spin polarization. Our focus is to optimize the performance of the comagnetometer for rotation sensing, but the theory and method presented here are relevant to all applications of the hybrid optical pumping technique.

High-efficiency fluorescence collection for NV- center ensembles in diamond.

The negatively charged nitrogen vacancy (NV-) center ensembles in diamond have been demonstrated to be a promising platform for quantum metrology, but the poor fluorescence collection efficiency of a microscope objective limits the sensitivity of the NV- based sensors. Here we present a method for increasing the collected fluorescence intensity with a total internal reflection (TIR) lens. The detected fluorescence intensity is increased by approximately a factor of 56 compared with detection using a microscope objective with NA = 0.55, leading to a collection efficiency of 47.7% ± 3.1%. The signal-to-noise ratio is improved by a factor of 7.6 using the TIR lens. The proposed method is of great significance for collecting fluorescence from NV- centers in a large volume and can be used in weak fluorescence detection systems.

New Experimental Limits on Exotic Spin-Spin-Velocity-Dependent Interactions by Using SmCo_{5} Spin Sources.

Despite the great success of the standard model (SM), there still exist mysteries like the nature of dark matter, the strong CP problems, etc. To solve them, many theories proposed new bosons beyond the SM that can mediate new forces. Here, we report the latest results of searching for possible new long-range spin-spin-velocity-dependent forces (SSVDFs), based on specially designed iron-shielded SmCo_{5} spin sources and a spin exchange relaxation free comagnetometer. With help from the similarity analysis method, new constraints on some forms of SSVDFs between electrons have been obtained, which represent up to more than 11 orders of magnitude tighter limits than previous experiments for the force range of 5 cm-1 km.

Rotation sensing decoupling of a dual-axis K-Rb-21Ne atomic comagnetometer.

A dual-axis atomic comagnetometer can sense the angular rotation of two measurement axes simultaneously and independently. However, there is a cross-talk coupling effect between the two axes because of the residual magnetic field and the light shift arising from the pumping laser. Here, we propose a scheme to eliminate the rotation coupling of dual-axis K-Rb-N21e atomic comagnetometers. The residual magnetic field can be effectively removed by controlling the comagnetometer at the magnetic compensation point and the magnetic shielding layer. The light shift could be eliminated by using the K atom light shift to counteract the Rb atom light shift, in which the light shift of K atoms was optimized to the decoupling point by finely adjusting the pumping laser wavelength of the K D1 line. The feasibility and efficiency of this decoupling scheme have been experimentally verified. The output response of the coupling axis is reduced by two orders of magnitude compared to the sensitive axis. This scheme can also be applied to any atomic comagnetometer with hybrid optical pumping that experiences cross-talk coupling.

Common-mode noise reduction in an atomic spin gyroscope using optical differential detection.

Optical rotation of linearly polarized light is used to measure atom spin precession in an atomic spin gyroscope (ASG). However, the common-mode noise in the polarization measurement seriously affects the performance of the sensitive ASG. Here we propose an optical differential detection method based on the photoelastic polarization modulation, which could effectively eliminate the light power fluctuation of the laser source and optical elements, while removing the polarization noise and the residual birefringence. The feasibility and efficiency of this method have been verified experimentally. The rotation sensitivity of the ASG is an order of magnitude better, and the long-time stability is significantly improved. In addition, this method is easier to implement because noise sources do not need to be strictly distinguished.

Light intensity stabilization based on the second harmonic of the photoelastic modulator detection in the atomic magnetometer.

The fluctuations of the probe light intensity seriously affect the performance of the sensitive atomic magnetometer. Here we propose a novel method for the intensity stabilization based on the second harmonic component of the photoelastic modulator (PEM) detection in the atomic magnetometer. The method not only could be used to eliminate the intensity fluctuations of the laser source, but also remove the fluctuations from the optical components caused by the environment. A relative fluctuation of the light intensity of 0.035% was achieved and the corresponding fluctuation of the output signal of the atomic magnetometer has decreased about two orders of magnitude from 4.06% to 0.041%. As the scheme proposed here only contains optical devices and does not require additional feedback controlled equipments, it is especially suitable for the integration of the atomic magnetometer.

Case report of pediatric TTMV-related acute promyelocytic leukemia with central nervous system infiltration and rapid accumulation of RARA-LBD mutations.

TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.

Dynamics of an all-optical atomic spin gyroscope.

We present the transfer function of an all-optical atomic spin gyroscope through a series of differential equations and validate the transfer function by experimental test. A transfer function is the basis for further control system design. We build the differential equations based on a complete set of Bloch equations describing the all-optical atomic spin gyroscope, and obtain the transfer function through application of the Laplace transformation to these differential equations. Moreover, we experimentally validate the transfer function in an all-optical Cs-Xe129 atomic spin gyroscope through a series of step responses. This transfer function is convenient for analysis of the form of control system required. Furthermore, it is available for the design of the control system specifically to improve the performance of all-optical atomic spin gyroscopes.

Crystallization of cobalt amorphous alloys under field annealing.

Crystallization of Co-rich amorphous ribbons annealed under a 10 Oe external magnetic field at the early 30 minutes from their glassy status to supercooled liquid status is investigated by high-resolution transmission microscope (HR-TEM), Selected Area Fourier Transform (SA-FT), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results indicate that the short-rang ordering feature can be refined very well in specimen annealed under temperatures about 87.4 degrees C below their glass transition (Tg), showing refined salt-pepper morphologies with a mean length changing from 1.2 +/- 0.8 nm to 0.8 +/- 0.2 nm and a mean width shifting from 0.5 +/- 0.2 nm to 0.3 +/- 0.1 nm. When the amorphous ribbons are field-annealed at temperature near to Tg (i.e., 450 degrees C), ultra-fine nanocrystalline structures can be formed on the top surface of ribbons with size of 3.5 +/- 0.5 nm and inter-grain spacing of about 0.4 +/- 0.2 nm even though the inner parts of the ribbons are still in amorphous phases. The nanocrystalline areas are featured by the formation of doped hcp cobalt phase orientated along the c-axis, with the inter-plane spacing ranging from 4 A to 6 A. When the annealing temperature is above Tg, the grain sizes are increased dramatically with multi-phased nanocrystals precipitating from the amorphous substrate, and finally reaching almost complete crystallization at 600 degrees C, causing greatly coarsening of the nanocrystal structures.

Light-shift measurement and suppression in atomic spin gyroscope.

We present a method to determine and suppress the light shift in an atomic spin gyroscope. This method doesn't require additional drive source or frequency modulation, and it is based on the dynamics of an atomic spin gyroscope to determine a clean curve as a function of the frequency of the pump beam that predicts the zero light shift. We experimentally validate the method in a Cs-(129)Xe atomic spin gyroscope and verify the results through numerical simulations. This method can also be applied to an atomic spin magnetometer based on the spin-exchange relaxation-free exchange that experiences light shift. The method is useful for atomic spin devices because it can improve long-term performance and reduce the influence of the laser.