Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Smart Sensor-Based Monitoring Technology for Machinery Fault Detection.

Rotary machines commonly use rolling element bearings to support rotation of the shafts. Most machine performance imperfections are related to bearing defects. Thus, reliable bearing condition monitoring systems are critically needed in industries to provide early warning of bearing fault so as to prevent machine performance degradation and reduce maintenance costs. The objective of this paper is to develop a smart monitoring system for real-time bearing fault detection and diagnostics. Firstly, a smart sensor-based data acquisition (DAQ) system is developed for wireless vibration signal collection. Secondly, a modified variational mode decomposition (MVMD) technique is proposed for nonstationary signal analysis and bearing fault detection. The proposed MVMD technique has several processing steps: (1) the signal is decomposed into a series of intrinsic mode functions (IMFs); (2) a correlation kurtosis method is suggested to choose the most representative IMFs and construct the analytical signal; (3) envelope spectrum analysis is performed to identify the representative features and to predict bearing fault. The effectiveness of the developed smart sensor DAQ system and the proposed MVMD technique is examined by systematic experimental tests.

A New Recursive Trigonometric Technique for FPGA-Design Implementation.

This paper presents a new recursive trigonometric (RT) technique for Field-Programmable Gate Array (FPGA) design implementation. The traditional implementation of trigonometric functions on FPGAs requires a significant amount of data storage space to store numerous reference values in the lookup tables. Although the coordinate rotation digital computer (CORDIC) can reduce the required FPGA storage space, their implementation process can be very complex and time-consuming. The proposed RT technique aims to provide a new approach for generating trigonometric functions to improve communication accuracy and reduce response time in the FPGA. This new RT technique is based on the trigonometric transformation; the output is calculated directly from the input values, so its accuracy depends only on the accuracy of the inputs. The RT technique can prevent complex iterative calculations and reduce the computational errors caused by the scale factor K in the CORDIC. Its effectiveness in generating highly accurate cosine waveform is verified by simulation tests undertaken on an FPGA.

A New Monitoring Technology for Bearing Fault Detection in High-Speed Trains.

In this work, a new monitoring system is developed for bearing fault detection in high-speed trains. Firstly, a data acquisition system is developed to collect vibration and other related signals wirelessly. Secondly, a new multiple correlation analysis (MCA) technique is proposed for bearing fault detection. The MCA technique consists of the three processing steps: (1) the collected vibration signal is decomposed by variational modal decomposition (VMD) to formulate the representative intrinsic mode functions (IMFs); (2) the MCA is used to process and identify the characteristic features for signal analysis; (3) bearing fault is diagnosed by examining bearing characteristic frequency information on the envelope power spectrum. The effectiveness of the proposed MCA fault detection technique is verified by experimental tests corresponding to different bearing conditions.

Development of a Smart Clinical Bluetooth Thermometer Based on an Improved Low-Power Resistive Transducer Circuit.

Smart sensors have been used in many engineering monitoring and control applications. This work focuses on the development of a new type of clinical Bluetooth thermometer, based on an improved low-power resistive transducer circuit. Most existing resistive transducers use relatively complicated circuits with higher cost and power consumption. To tackle these problems, especially in real applications, an improved low-power resistive transducer circuit is proposed in this work and is used to develop smart Bluetooth thermometers. The parameters of the resistive transducer circuit are selected by quantitative analysis and optimization to improve the performance of the low-power resistive transducer circuit. The effectiveness of the proposed design technology was verified by tests. The temperature measurement error of the new smart Bluetooth thermometer is less than 0.1 °C, which can not only meet the clinical use requirements but also has lower cost and power consumption.

Macrophages protect mycoplasma-infected chronic myeloid leukemia cells from natural killer cell killing.

Macrophages (Mϕ) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and Mϕ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (Mϕ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and Mϕ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that Mϕ protects CML from NK attack only when CML was itself mycoplasma-infected and under chronic infection-inflammation condition. We found that the Mϕ-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in Mϕ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by Mϕ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating Mϕ-mediated retention of NK surface CD16.

Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis.

DNA alterations have been extensively reported in multiple myeloma (MM); however, they cannot yet fully explain all the biological and molecular abnormalities in MM, which remains to this day an incurable disease with eventual emergence of refractory disease. Recent years have seen abnormalities at the RNA levels being reported to possess potential biological relevance in cancers. ADAR1-mediated A-to-I editing is an important posttranscriptional mechanism in human physiology, and the biological implication of its abnormality, especially at the global level, is underexplored in MM. In this study, we define the biological implications of A-to-I editing and how it contributes to MM pathogenesis. Here, we identified that the MM transcriptome is aberrantly hyperedited because of the overexpression of ADAR1. These events were associated with patients' survival independent of 1q21 amplifications and could affect patients' responsiveness to different treatment regimes. Our functional assays established ADAR1 to be oncogenic, driving cellular growth and proliferation in an editing-dependent manner. In addition, we identified NEIL1 (base-excision repair gene) as an essential and a ubiquitously edited ADAR1 target in MM. The recoded NEIL1 protein showed defective oxidative damage repair capacity and loss-of-function properties. Collectively, our data demonstrated that ADAR1-mediated A-to-I editing is both clinically and biologically relevant in MM. These data unraveled novel insights into MM molecular pathogenesis at the global RNA level.

Power-Saving Design of Radio Frequency Identification Sensor Networks in Bus Seatbelt Monitoring Systems.

Seatbelt state monitoring is important in intercity buses for passenger safety. This paper discusses the issues and challenges in power-saving design of radio frequency identification (RFID) sensor networks in bus seatbelt monitoring. A new design approach is proposed in this work for low-power layout and parameter setting in RFID sensor nodes in hardware and software design. A one-to-many pairing registration method is suggested between the concentrator and the seat nodes. Unlike using extra computer software to write seat identification (ID) into an integrated circuit (IC) card, the node ID in this project can be stored into the concentrator directly, which can reduce intermediate operations and reduce development costs. The effectiveness of the proposed low-power design approach is verified by some experimental tests.

What Is the Role of Diagnostic and Therapeutic Sonication in Periprosthetic Joint Infections?

BACKGROUND: Periprosthetic joint infection (PJI) is one of the most dreaded complications in joint replacement surgery. Diagnosis and treatment can be difficult and biofilms are of major concern due to their low susceptibility toward antibiotics. METHODS: This review focuses on the use of sonication as an evolving diagnostic and adjunct treatment modality in the context of PJI. Therapeutic application of sonication is discussed separately for its (i) direct action on bacteria, (ii) synergistic effects with antibiotics, and (iii) effects on release of antibiotics from bone cement. RESULTS: Used as a diagnostic tool, sonication shows promising results with respect to sensitivity and specificity when compared to conventional methods, notably after previous administration of antibiotics. As an adjunct treatment modality, the chemical, physical, and mechanical effects of sonication are primarily driven by cavitation and recognized as the main cause for bactericidal effects but the exact underlying mechanisms have not been identified yet. Sonication alone does not have the ability to completely eradicate biofilms but synergistic effects when used in conjunction with antibiotics have been reported. There is also evidence for enhanced antibiotic release from bone cement. CONCLUSION: Sonication is as an evolving modality in the context of PJIs. As a diagnostic tool, it has not been introduced in routine clinical practice and sonication as a treatment modality in PJIs is still in an experimental stage. Factors such as frequency, pressure, chemical activity, intensity, and exposure time need to be evaluated for optimal application of sonication and may also improve study comparison.

Outcome of Patellar Tendon Versus 4-Strand Hamstring Tendon Autografts for Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis of Prospective Randomized Trials.

PURPOSE: To compare clinical outcomes of anterior cruciate ligament (ACL) reconstruction and investigate whether the clinical results of 4-strand hamstring tendon (HT) reconstruction are still inferior to that of the patellar tendon (PT). METHODS: We performed a comprehensive systematic review and meta-analysis of the English literature on PubMed, Scopus, Web of Science, and the Cochrane register for papers that compared clinical outcomes of PT versus HT for ACL reconstruction. Outcome measures analyzed included rate of rerupture, KT-1000, International Knee Documentation Committee grade, Lachman, pivot shift, Lysholm score, Tegner Activity Scale, anterior knee pain, and discomfort on kneeling. RESULTS: We included 19 studies from an initial 1,168 abstracts for the systematic review, and, eventually, 19 studies were included in the meta-analysis. The study population consisted of a total of 1784 patients. The average follow-up duration was 58.8 months. We found significant differences in favor of the HT technique in the domains of anterior knee pain, kneeling pain, and restriction in the range of active extension ("extension deficit"). We found no differences between the PT and HT technique in terms of rerupture rate. There were no clinically significant differences for the outcomes of Lysholm score and Tegner Activity Scale as well as the KT-1000 side-to-side at maximum manual force. CONCLUSIONS: Contemporary 4-strand HT ACL reconstruction is comparable with the PT technique in terms of clinical stability and postoperative functional status across most parameters studied. The HT technique carries lower risk of postoperative complications such as anterior knee pain, kneeling discomfort, and extension deficit. Primary ACL reconstruction using the 4-strand HT technique achieves clinical results that are comparable with the PT technique with significantly less postoperative complications. LEVEL OF EVIDENCE: Level I, systemic review and meta-analysis of Level I studies.

Mechanically-enhanced three-dimensional scaffold with anisotropic morphology for tendon regeneration.

Tissue engineering has showed promising results in restoring diseased tendon tissue functions. Herein, a hybrid three-dimensional (3D) porous scaffold comprising an outer portion rolled from an electrohydrodynamic jet printed poly(ɛ-caprolactone) (PCL) fiber mesh, and an inner portion fabricated from uniaxial stretching of a heat-sealed PCL tube, was developed for tendon tissue engineering (TE) application. The outer portion included three layers of micrometer-scale fibrous bundles (fiber diameter: ~25 µm), with an interconnected spacing and geometric anisotropy along the scaffold length. The inner portion showed orientated micro-ridges/grooves in a parallel direction to that of the outer portion. Owning to the addition of the inner portion, the as-fabricated scaffold exhibited comparable mechanical properties to those of the human patellar tendon in terms of Young's modulus (~227 MPa) and ultimate tensile stress (~50 MPa). Compared to the rolled electrospun fibers, human tenocytes cultured in the tendon scaffolds showed increased cellular metabolism. Furthermore, the 3D tendon scaffold resulted in up-regulated cell alignment, cell elongation and formation of collagen type I. These results demonstrated the potential of mechanically-enhanced 3D fibrous scaffold for applications in tendon TE, with desired cell alignment and functional differentiation.

Interventions for Proliferative Vitreoretinopathy.

Clinical Question: What is the efficacy of pharmacologic interventions in preventing proliferative vitreoretinopathy? Bottom Line: There is limited high-quality evidence to support currently available pharmacological options for prevention of proliferative vitreoretinopathy.

Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study.

BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).

Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy.

OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Combined effects of direct current stimulation and immobilized BMP-2 for enhancement of osteogenesis.

Direct current (DC) stimulation has been used to promote bone repair and osteogenesis, but problems associated with the implanted metal electrodes may limit its application and compromise the therapeutic results. The replacement of the metal electrodes with a biodegradable conductive polymer film can potentially overcome these problems. In our work, polypyrrole/chitosan films comprising polypyrrole nanoparticles dispersed in a chitosan matrix were prepared. The polypyrrole/chitosan film meets the requirements for DC delivery, as indicated by its electrical conductivity, biodegradability, and mechanical properties. The film supports osteoblast growth to the same degree as dentine discs (a bone-like mineralized substrate), confirming that it is non-cytotoxic. Our results showed that optimal DC stimulation was achieved with 200 µA for 4 h per day, and under this condition, osteoblast metabolic activity on Day 7 increased by 1.8-fold over that without DC stimulation. To further improve osteogenesis on the polypyrrole/chitosan film, bone morphogenetic protein-2 (BMP-2) was covalently immobilized on the film surface. Osteoblasts cultured on the BMP-2-functionalized polypyrrole/chitosan film and subjected to the optimal DC stimulation exhibited a significant increase in cellular metabolic activity (2.3-fold on Day 7), ALP activity (1.7-fold on Day 21) and mineralization (twofold on Day 21) over those cultured on polypyrrole/chitosan film without DC stimulation. Osteogenic gene expression results showed that BMP-2 and DC stimulation by itself enhanced osteoblast differentiation, and a combination of these two factors resulted in synergistic effects on osteoblast differentiation and maturation.

Covalently grafted BMP-7 peptide to reduce macrophage/monocyte activity: an in vitro study on cobalt chromium alloy.

Cobalt chromium (CoCr) alloy is widely used in orthopedic implants but its functional longevity is susceptible to inflammation related complications. Reduction of the development of chronic inflammation on the biomaterial surface would enhance direct bone-implant bonding and improve implant survival and long-term results. The BMP-7 peptide was derived from the knuckle epitope of bone morphogenic protein-7 (BMP-7) and was conjugated via a cysteine amino acid at the N-terminus. Mouse RAW 264.7 monocytes/macrophages were seeded on the CoCr substrates and inflammation was induced via lipopolysaccharide (LPS) challenge. The effects of BMP-7 peptide on inflammation were evaluated by measuring the expression of inflammatory markers like toll-like receptor-4 (TLR-4), tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1). ELISA and qPCR assays were used to study the inflammatory signals. BMP-7 signaling pathway activation was shown by the presence of phosphorylation of Smad1/5/8. Utilizing the reactivity of polydopamine films to immobilize BMP-7 peptide onto metal substrates may provide a promising approach for applications in situations where reduction of inflammation around implants would be beneficial in improving surgical outcome, bone healing, and implant integration.

A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen.

Tamoxifen significantly reduces tumor recurrence in certain patients with early-stage estrogen receptor-positive breast cancer, but markers predictive of treatment failure have not been identified. Here, we generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.

An evolving neuro-fuzzy classifier for fault diagnosis of gear systems.

Gear systems (or gearboxes) are widely used in rotating machinery. Reliable gear fault diagnostic techniques and systems are critically needed to provide early warning of a possible defect so as to prevent machinery operation degradation and to reduce costs related to predictive maintenance. In this work, a new evolving neuro-fuzzy (eNF) classifier is proposed for real-time gear system fault diagnostics. In evolving process, the constraints related to gear health states are used to guide the partition of the output space, to prevent possible misleading clusters. A new training algorithm based on the normalized Adadelta function is suggested to improve eNF training convergence and accuracy. The effectiveness of the proposed eNF classifier is tested by simulation and experiment tests.

Linear-based gain-determining method for adaptive backstepping controller.

This paper presents a linear-based gain-determining method for nonlinear adaptive backstepping controllers. Usually, the gains for nonlinear controllers are tuned by the trial and error method. This method becomes more difficult as the number of gains increases. A user-friendly method is proposed in this work to deal with the problem. Firstly, a linear auxiliary system is formed by separating the linear parts from the nonlinear system. Then, linear state-space techniques are used to determine the gains for state-feedback by the linear auxiliary system. After that, by converting the state-feedback gains to backstepping gains, the gains of the nonlinear backstepping controller can be determined. The proficiency of the gain-determining method is proved by simulations with two linear techniques.