Identification of B cell subsets based on antigen receptor sequences using deep learning.

B cell receptors (BCRs) denote antigen specificity, while corresponding cell subsets indicate B cell functionality. Since each B cell uniquely encodes this combination, physical isolation and subsequent processing of individual B cells become indispensable to identify both attributes. However, this approach accompanies high costs and inevitable information loss, hindering high-throughput investigation of B cell populations. Here, we present BCR-SORT, a deep learning model that predicts cell subsets from their corresponding BCR sequences by leveraging B cell activation and maturation signatures encoded within BCR sequences. Subsequently, BCR-SORT is demonstrated to improve reconstruction of BCR phylogenetic trees, and reproduce results consistent with those verified using physical isolation-based methods or prior knowledge. Notably, when applied to BCR sequences from COVID-19 vaccine recipients, it revealed inter-individual heterogeneity of evolutionary trajectories towards Omicron-binding memory B cells. Overall, BCR-SORT offers great potential to improve our understanding of B cell responses.

A Novel Passive Shoulder Exoskeleton Using Link Chains and Magnetic Spring Joints.

Work-related musculoskeletal disorders represent a major occupational disability issue, and 53.4% of these disorders occur in the back or shoulders. Various types of passive shoulder exoskeletons have been introduced to support the weight of the upper arm and work tools during overhead work, thereby preventing injuries and improving the work environment. The general passive shoulder exoskeleton is constructed with rigid links and joints to implement shoulder rotation, but there exists a challenge to align with the flexible joint movements of the human shoulder. Also, a force-generating part using mechanical springs require additional mechanical components to generate torque similar to the shoulder joint, resulting in increased overall volume and inertia to the upper arm. In this study, we propose a new type of passive shoulder exoskeleton that uses magnetic spring joint and link chain. The redundant degrees of freedom in the link chains enables to follow the shoulder joint movement in the horizontal direction, and the magnetic spring joint generates torque without additional parts in a compact form. Conventional exoskeletons experience a loss in the assisting torque when the center of shoulder rotation changed during arm elevation. Our exoskeleton minimizes the torque loss by customizing the installation height and initial angle of the magnetic spring joint. The performances of the proposed exoskeleton were verified by an electromyographic evaluation of shoulder-related muscles in overhead work and box lifting task.

Bony mallet toe of the hallux treated with screws: a case report.

Traumatic avulsion fracture of the distal phalanx of the hallux, known as the bony mallet toe of the hallux, is rare, and there is no consensus regarding its treatment. Few reports of treatment methods exist, such as nonsurgical treatment using a splint, Kirschner wires, and suture anchors, but there are no reports of screw fixation. We describe the case of a 54-year-old man with a bony mallet toe of the hallux treated with screws and augmented with strong sutures. The interphalangeal joint of the hallux was fixed with a Kirschner wire for 4 weeks after surgery, and weight bearing was allowed on the hallux 5 weeks postoperatively. A total of 20 months after the surgery, the patient had no symptoms or complications. Because of screw fixation and augmentation with strong sutures, fixation strength increased. We showed the feasibility of this new technique for treating an uncommon bony mallet toe of the hallux.

Discovery of Novel, Thienopyridine-Based Tyrosine Kinase Inhibitors Targeting Tumorigenic RON Splice Variants.

Herein, we report the identification, structural optimization, and biological efficacy of thieno[2,3-b]pyridines as potent inhibitors of splice variants of the tyrosine kinase recepteur d'origine nantais (RON). Among synthesized compounds, compound 15f exhibited excellent in vitro kinase inhibition and antiproliferative activity, as well as in vivo antineoplastic efficacy against RON splice variant-expressing tumors. Moreover, compound 15f with excellent pharmacokinetics demonstrated significant activity with greater tumor growth inhibition (74.9% at 10 mg/kg) than compounds 2 and 4 in a patient-derived xenograft model. Collectively, 15f represents a promising, novel anticancer agent targeting RON splice variants.

The anteroposterior distance between the posterior edge of the medial tibial condyle and the posterior edge of the fibular head in the lateral view can be a reference in determining the axis perpendicular to the tibial anteroposterior axis.

BACKGROUND: Obtaining an accurate tibial lateral view is important during high tibial osteotomy. This study investigated whether the posterior edge of the medial/lateral tibial condyle (PEMTC/PELTC) and the posterior edge of the fibular head (PEFH) in a lateral view could be a reference for determining the accurate tibial lateral view. METHODS: A total of 75 lower limbs in 38 subjects were evaluated in this study. In order to target healthy knees, subjects undergoing primary total hip arthroplasty were selected. The MF/LF, comprising the anteroposterior distance between PEMTC/PELTC and PEFH, was measured on the lateral view of the tibial bone model based on the tibial anteroposterior (AP) axis (true lateral view: TLV). In addition, measurements were calculated in the model with a 10° external/internal rotation. Using these measurements, linear regression analysis was performed to predict the tibial rotation with MF/LF. RESULTS: The mean MF/LF was 0.9/4.6 mm (P < 0.001). MF and LF increased with incremental tibial rotation. Regression formulas were derived from these results as follows: Tibial rotation = (1) -1.01 + 1.06 × MF (R2 = 0.87, P < 0.001), (2) -8.70 + 1.86 × LF (R2 = 0.51, P < 0.001). The mean tibial rotation angle when MF was 0 mm was -0.9°. CONCLUSIONS: Based on formula (1) and actual measurements, the mean tibial rotation angle when MF is 0 mm is an internal rotation of about 1°. Therefore, a lateral view, in which PEMTC and PEFH are seen colinearly, can be the approximate TLV. The MF can be a suitable intraoperative reference in determining TLV.

Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions.

CRISPR prime editing (PE) requires a Cas9 nickase-reverse transcriptase fusion protein (known as PE2) and a prime editing guide RNA (pegRNA), an extended version of a standard guide RNA (gRNA) that both specifies the intended target genomic sequence and encodes the desired genetic edit. Here we show that sequence complementarity between the 5' and the 3' regions of a pegRNA can negatively impact its ability to complex with Cas9, thereby potentially reducing PE efficiency. We demonstrate this limitation can be overcome by a simple pegRNA refolding procedure, which improved ribonucleoprotein-mediated PE efficiencies in zebrafish embryos by up to nearly 25-fold. Further gains in PE efficiencies of as much as 6-fold could also be achieved by introducing point mutations designed to disrupt internal interactions within the pegRNA. Our work defines simple strategies that can be implemented to improve the efficiency of PE.

Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype.

Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition-a well-known hallmark of fibrotic disease. Transforming growth factor-ß (TGF-ß) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-ß-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-ß-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-ß, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-ß stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-ß-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-ß-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis.

Water-redispersible and high-yield α-chitin nanocrystals isolated using electron-beam irradiation as adsorbents to remove heavy metals and dye.

An innovative approach to fabricate transparent and redispersible α-chitin nanocrystals (ChNCs) with high overall yields was developed in this work for eventual commercial use. The nanomanufacturing process included electron-beam irradiation (EBI) of chitin for oxidation and degradation in the dried state, high-pressure nanoscale homogenization via swelling, CO2 absorption, and spray-drying to obtain dehydrated products. The resulting EBI-disassociated chitins contained increased amounts of carboxylate (0.19-0.27 mmol g-1) and a negligible fraction of D-glucosamine moiety (from ca. 6.5 to <1.0%) with an intrinsic structure identical to α-chitin derived from shrimp shell prior to purification by conventional methods, such as deproteination. The resulting EBI-induced ChNC series exhibited nano-sized and rod-like morphology with tunable lengths averaging 608-259 nm, uniform widths of ca. 16-12 nm, a high isolation yield of max. 81%, and sufficient anionic surface charges, as zeta potentials of -32 to -34 mV indicate that it is homogenously water-dispersible and stable with background transparency. Unlike ChNC prepared by HCl-hydrolysis, the dehydrated particles of EBI-induced ChNCs were clearly redispersible in water and retained the characteristics of the original nanomaterials. We also tested the redispersible EBI-induced ChNCs as effective adsorbents. Their anionic groups interacted with cationic heavy metals (Cu2+ and Fe3+) and organic blue dye via electrostatic attraction, forming robust hydrogels, which were self-supporting after centrifugation. The EBI-induced ChNCs produced with low environmental impact in this work offer a promising choice of adsorbents for the removal of undesirable chemicals during wastewater treatment.

Spatial and PMF analysis of particle size distributions simultaneously measured at four locations at the roadside of highways.

In urban areas, particulate matter emitted from vehicles directly affects the health of citizens near roads. Thus, in this study, particle size distribution was measured by the horizontal and vertical distances along a highway road with heavy traffic to characterize the dispersion phenomena of particulate matter emitted from vehicles. In addition, the contribution of pollution sources was analyzed using a source-receptor model. A concentration gradient was observed in which the concentration decreased with the increase in the distance from the road when the wind blew from the road to the monitoring locations. The concentration was slightly higher within 50 m of the road when the wind blows parallel to the road, and similar concentrations were found at the other monitoring locations further away from the roads. In particular, the higher the turbulence intensity of the wind, the lower is the concentration gradient coefficient because of the more enhanced mixing and dispersion. A positive matrix factorization (PMF) model with the measured particle size distribution data in the range of 9-300 nm resulted in a contribution of about 70 % (number) and 20 % (mass) to particle concentrations because of six types of vehicles including LPG, two gasoline vehicles (GDI, MPI), and three diesel vehicles with 3rd, 4th, and 5th emission classes. It showed a decrease in the vehicular contribution as the distance from the road increased. Particle number concentrations decreased with increasing altitude up to 30 m above the ground. The results of this study can be useful in deriving generalized gradient equations of particle concentrations exposed by distance and wind direction at the roadside using traffic and meteorological conditions and for establishing environmental policies, such as roadside exposure assessment, in the future. A CAPSULE ABSTRACT: Dispersion of particles emitted from vehicles on a busy highway was characterized by roadside measurements of horizontal and vertical profiles of particle size distributions measured at four locations. The source profiles and contributions were estimated by major sources using a source-receptor model such as PMF.

Feasibility study of a scintillation sheet-based detector for fluence monitoring during external photon beam radiotherapy.

PURPOSE: This study evaluated the properties of a scintillation sheet-based dosimetry system for beam monitoring with high spatial resolution, including the effects of this system on the treatment beam. The dosimetric characteristics and feasibility of this system for clinical use were also evaluated. METHODS: The effects of the dosimetry system on the beam were evaluated by measuring the percentage depth doses, dose profiles, and transmission factors. Fifteen treatment plans were created, and the influence of the dosimetry system on these clinical treatment plans was evaluated. The performance of the system was assessed by determining signal linearity, dose rate dependence, and reproducibility. The feasibility of the system for clinical use was evaluated by comparing intensity distributions with reference intensity distributions verified by quality assurance. RESULTS: The spatial resolution of the dosimetry system was found to be 0.43 mm/pixel when projected to the isocenter plane. The dosimetry system attenuated the intensity of 6 MV beams by about 1.1%, without affecting the percentage depth doses and dose profiles. The response of the dosimetry system was linear, independent of the dose rate used in the clinic, and reproducible. Comparison of intensity distributions of evaluation treatment fields with reference intensity distributions showed that the 1%/1 mm average gamma passing rate was 99.6%. CONCLUSIONS: The dosimetry system did not significantly alter the beam characteristics, indicating that the system could be implemented by using only a transmission factor. The dosimetry system is clinically suitable for monitoring treatment beam delivery with higher spatial resolution than other transmission detectors.

Lipid nanoparticle-mediated mRNA delivery in lung fibrosis.

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.

Charging and Charged Species in Quantum Dot Light-Emitting Diodes.

Despite recent rapid advances in improving quantum dot light-emitting diodes, many fundamental aspects of the device operating mechanism remain unresolved. Through transient electroluminescence and time-resolved photoluminescence measurements, the effects of offset voltage on charging and charge transport are examined. First, capacitive charging occurs with a time constant of ∼500 ns, followed by electron transport through quantum dots with a mobility of ∼10-5 cm2 V-1 s-1. Hole injection then initiates an electroluminescence rise that is independent of offset voltage. The photoluminescence lifetime is also unaffected by the offset voltage, indicating no injection of charges into the quantum dots or on their surfaces prior to the voltage pulse. A slower equilibration to steady-state electroluminescence is dependent on the offset voltage, indicative of another charging process. Elemental mapping shows that ZnO deposition from solution can lead to the diffusion of charged species into the quantum dot layer, which may cause the slower process.

Perovskite solar cells integrated with blue cut-off filters for mitigating light-induced degradation.

The stability of methylammonium (MA)-based perovskite solar cells (PSCs) remains one of the most urgent issues that need to be addressed. Inherent weak binding forces between MAs and halides cause the perovskite structure to become unstable under exposure to various external environmental factors such as moisture, oxygen, ultraviolet radiation, and heat. In particular, the degradation of perovskite films under light exposure accelerates the deterioration of the device, mainly due to the migration of halide ions. In this study, we investigated the effect of light energy on the degradation of inverted PSCs by introducing red ( = 610-800 nm), green (500-590 nm), and blue (300-500 nm) light-pass filters. After 30 h, the inverted PSCs of blue-light-induced devices retained a power conversion efficiency (PCE) of 70%, while those of the green and red light-induced devices retained PCEs of 85% and 90%, respectively. Direct evidence of light-induced degradation was obtained by investigating morphological changes in the perovskite films and the amount of ion accumulation on the Ag electrode. This evidence highlights the varying effect of light with different energies on device degradation. Furthermore, to minimize light-induced device degradation, we designed two types of blue cut-off filters that can selectively block light ranging from = 400 to 500 nm, comprising a multilayered inorganic metasurface. An optical simulation was used to optimize the performance of the designed filters. By investigating the changes in the photovoltaic parameters and the amount of ion accumulation on the Ag electrode, we confirmed that integrating blue cut-off filters into PSCs greatly improved the operational lifetime of the devices.

Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.

Optimization of peripheral blood volume for in silico reconstitution of the human B-cell receptor repertoire.

B cells recognize antigens via membrane-expressed B-cell receptors (BCR) and antibodies. Similar human BCR sequences are frequently found at a significantly higher frequency than that theoretically calculated. Patients infected with SARS-CoV2 and HIV or with autoimmune diseases share very similar BCRs. Therefore, in silico reconstitution of BCR repertoires and identification of stereotypical BCR sequences related to human pathology have diagnostic potential. Furthermore, monitoring changes of clinically significant BCR sequences and isotype conversion has prognostic potential. For BCR repertoire analysis, peripheral blood (PB) is the most convenient source. However, the optimal human PB volume for in silico reconstitution of the BCR repertoire has not been studied in detail. Here, we sampled 5, 10, and 20 mL PB from the left arm and 40 mL PB from the right arm of two volunteers, reconstituted in silico PB BCR repertoires, and compared their composition. In both volunteers, PB sampling over 20 mL resulted in slight increases in functional unique sequences (FUSs) or almost no increase in repertoire diversity. All FUSs with a frequency above 0.08% or 0.03% in the 40 mL PB BCR repertoire were detected even in the 5 mL PB BCR repertoire from each volunteer. FUSs with a higher frequency were more likely to be found in BCR repertoires from reduced PB volume, and those coexisting in two repertoires showed a statistically significant correlation in frequency irrespective of sampled anatomical site. The correlation was more significant in higher-frequency FUSs. These observations support the potential of BCR repertoire analysis for diagnosis.

Transient Dynamics of Charges and Excitons in Quantum Dot Light-Emitting Diodes.

Wide interest in quantum dot (QD) light-emitting diodes (QLEDs) for potential application to display devices and light sources has led to their rapid advancement in device performance. Despite such progress, detailed operation mechanisms of QLEDs, which are necessary for the fundamental understanding and further improvements, have been still uncertain because of the intricate interaction between charges and excitons in electrical operation. In this work, the transient electroluminescence (TREL) signals of dichromatic QLEDs which are purposely designed to consist of two different color-emitting QD layers are analyzed. As a result, not only can the charge injection and exciton recombination processes be visualized but the electron mobility of the QD layer can also be estimated. Furthermore, the effects of Förster resonant energy transfer between two QDs and exciton quenching near the QD layer are quantitatively measured in QLED operation. The authors believe that their results based on TREL analyses will contribute to the understanding and development of high-performance QLEDs.

Spatial epitranscriptomics reveals A-to-I editome specific to cancer stem cell microniches.

Epitranscriptomic features, such as single-base RNA editing, are sources of transcript diversity in cancer, but little is understood in terms of their spatial context in the tumour microenvironment. Here, we introduce spatial-histopathological examination-linked epitranscriptomics converged to transcriptomics with sequencing (Select-seq), which isolates regions of interest from immunofluorescence-stained tissue and obtains transcriptomic and epitranscriptomic data. With Select-seq, we analyse the cancer stem cell-like microniches in relation to the tumour microenvironment of triple-negative breast cancer patients. We identify alternative splice variants, perform complementarity-determining region analysis of infiltrating T cells and B cells, and assess adenosine-to-inosine base editing in tumour tissue sections. Especially, in triple-negative breast cancer microniches, adenosine-to-inosine editome specific to different microniche groups is identified.

Efficacy of a 4-Week Nurse-Led Exercise Rehabilitation Program in Improving the Quality of Life in Women Receiving a Post-Mastectomy Reconstruction Using the Motiva ErgonomixTM Round SilkSurface.

We assessed the efficacy of a 4-week nurse-led exercise rehabilitation (ER) program in improving the quality of life (QOL) of breast cancer survivors (BCS) receiving an implant-based breast reconstruction. The eligible patients were equally randomized to either of both groups: the intervention group (n = 30; a 4-week nurse-led ER program) and the control group (n = 30; a 4-week physical therapist-supervised one). Both after a 4-week ER program and at baseline, the patients were evaluated for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Fatigue Severity Scale (FSS) scores. There was a significantly higher degree of increase in global health status/QOL scores, physical functioning scores, role functioning scores, and emotional functioning scores at 4 weeks from baseline in the intervention group as compared with the control group (p = 0.001). However, there was a significantly higher degree of decrease in fatigue scores, nausea/vomiting scores, pain scores, dyspnea scores, and FSS scores in the intervention group as compared with the control group (p = 0.001). In conclusion, our results indicate that a 4-week nurse-led ER program might be effective in the QOL in BCS receiving a post-mastectomy implant-based reconstruction using the Motiva ErgonomixTM Round SilkSurface.

Implication of AV node blockers in patients with end-stage renal disease undergoing head and neck surgery; BRASH syndrome: a case report.

BRASH (Bradycardia, Renal failure, Atrioventricular [AV]-node blocker medications, Shock, and Hyperkalemia), a novel syndrome, is a synergistic interaction between AV node blockers and hyperkalemia, resulting in bradycardia. We report a case of BRASH syndrome with marked bradycardia in a patient with End-Stage Renal Disease (ESRD) associated with synergistic interaction between mild hyperkalemia and AV node blockers. Anesthesiologists should be aware of these clinical features, in which ESRD patients with baseline mild hyperkalemia are particularly susceptible to bradycardia. This report will help in its early recognition as well as enable comprehensive and appropriate treatment strategies without further invasive therapy.