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The Raman tensors of the three modes at ∼55, ∼80, and ∼160 cm−1 for the non-van der Waals layered material Bi2O2Se, which were assigned to Eu, Eg, and A1g, respectively, were experimentally investigated. Two modes at ∼55 and ∼80 cm−1, which were not observable in perfect crystal Bi2O2Se in the backscattering configuration, owing to the Raman selection rule, were activated by defects. These two modes exhibit strong polarization dependence at line defects and the excitation energy; thus, their Raman polarizability tensors exhibit strong dependence on the defect morphology and geometric characteristics of Bi2O2Se. The results of this study confirm that the Raman tensors of nanocrystalline structures can be modulated by defects.

Abstract This paper exhibits a proportional-type robust current controller for permanent magnet synchronous motors (PMSMs), incorporating the variable bandwidth technique driven by the proposed online auto-tuner and the disturbance observer (DOB) as the subsystems. There are two contributions: (a) the proposed online auto-tuner implements the variable bandwidth for the closed-loop system to boost the transient current tracking performance and (b) the combination of proportional-type feedback controller and DOB eliminates the requirement of the integral action, ensuring the steady-state error rejection property. Moreover, it is proved that the resultant feedback system recovers the target current tracking performance without steady-state errors. The experimental study is conducted to verify the efficacy of the proposed controller using a 700-W prototype PMSM.

Abstract Objective Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. Methods OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Results Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Conclusion Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.

Mitochondrial dysfunction increases ROS production and is closely related to many degenerative cellular organelle diseases. The NOX4-p22phox axis is a major contributor to ROS production and its dysregulation is expected to disrupt mitochondrial function. However, the field lacks a competitive inhibitor of the NOX4-p22phox interaction. Here, we created a povidone micelle-based Prussian blue nanozyme that we named “Mitocelle” to target the NOX4-p22phox axis, and characterized its impact on the major degenerative cellular organelle disease, osteoarthritis (OA). Mitocelle is composed of FDA-approved and biocompatible materials, has a regular spherical shape, and is approximately 88 nm in diameter. Mitocelle competitively inhibits the NOX4-p22phox interaction, and its uptake by chondrocytes can protect against mitochondrial malfunction. Upon intra-articular injection to an OA mouse model, Mitocelle shows long-term stability, effective uptake into the cartilage matrix, and the ability to attenuate joint degradation. Collectively, our findings suggest that Mitocelle, which functions as a competitive inhibitor of NOX4-p22phox, may be suitable for translational research as a therapeutic for OA and cellular organelle diseases related to dysfunctional mitochondria.

Abstract Background While significant research exists on gut microbiota changes after anti-tumor necrosis factor-alpha (anti TNF-α) therapy for ulcerative colitis, little is known about the longitudinal changes related to the effects of anti TNF-α. This study aimed to investigate the dynamics of gut microbiome changes during anti TNF-α (adalimumab) therapy in patients with ulcerative colitis (UC). Results The microbiota composition was affected by the disease severity and extent in patients with UC. Regardless of clinical remission status at each time point, patients with UC exhibited microbial community distinctions from healthy controls. Distinct amplicon sequence variants (ASVs) differences were identified throughout the course of Adalimumab (ADA) treatment at each time point. A notable reduction in gut microbiome dissimilarity was observed only in remitters. Remitters demonstrated a decrease in the relative abundances of Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus as the treatment progressed. Additionally, there was an observed increase in the relative abundances of Bifidobacterium and Dorea. Given the distribution of the 48 ASVs with high or low relative abundances in the pre-treatment samples according to clinical remission at week 8, a clinical remission at week 8 with a sensitivity and specificity of 72.4% and 84.3%, respectively, was predicted on the receiver operating characteristic curve (area under the curve, 0.851). Conclusions The gut microbiota undergoes diverse changes according to the treatment response during ADA treatment. These changes provide insights into predicting treatment responses to ADA and offer new therapeutic targets for UC.

Surgical treatment for patients with cervical spine deformities is challenging for both patients and doctors. For successful surgical treatment, mastery of processes is important to objectively evaluate and classify the degree of deformity. Recently, efforts have been increasing to systematically understand, evaluate, and effectively treat complex cervical spine deformities. Various parameters are being developed to quantify and objectively evaluate the degree of cervical spine deformity, and classification methods are being introduced to help establish the treatment scope by categorizing it according to the degree of deformity. However, a comprehensive and systematic understanding of complex deformities using only the currently introduced classification methods and related knowledge is not easy. Through this review, we aimed to introduce various classification methods and their pros and cons to evaluate cervical deformities, analyze their meaning, and provide a basic understanding of the evaluation and classification of patients with cervical spine deformities. This review also aimed to aid in the decision-making process for the treatment of cervical spine deformities by presenting a structured treatment algorithm based on recently known classification systems and lay the foundation for efficient treatment.

Background: Weakness of gluteus medius (Gmed) is related with musculoskeletal disorders. Individuals who experience weakness in the Gmed may activate the tensor fasciae latae (TFL) as a compensatory mechanism. Application of isometric hip extension (IHE) with Thera-band may affect the activities of the Gmed, gluteus maximus (Gmax), and TFL, and the activity ratio of Gmed/TFL during side-lying hip abduction (SHA). Objects: To determine the influences of IHE during SHA on Gmed, Gmax, and TFL activities in participants with Gmed weakness. Methods: Three types of SHA exercises were performed: 1) traditional SHA in the frontal plane (SHA-T), 2) SHA with IHE applying Thera-band in the frontal plane (SHA-IHE), 3) and SHA with isometric hip flexion (IHF) applying Thera-band in the frontal plane (SHA-IHF). Results: SHA-IHE significantly showed higher Gmed and Gmax activities than SHA-T and SHA-IHF. SHA-IHF significantly showed higher activity of TFL than SHA-T or SHA-IHE. The ac-tivity ratio of Gmed/TFL was significantly higher in the SHA-IHE, SHA-T, and SHA-IHF, in that order. Conclusion: The SHA-IHE resulted in higher activities of Gmed, Gmax and a higher muscle ratio of Gmed/TFL.

Abstract Genomic analysis of structural variants(SVs) in breast cancer (BC) patients has been conducted, but the relationship between genomic alterations and BC prognosis remains unclear. We performed RNA sequencing of 297 early BC fresh-frozen tissues. We identified SVs using three tools (STAR.Arriba, STAR.fusion, and STAR.SEQR) with the COSMIC and Mitelman databases as guide references. We found a median of five to eight fusions per sample. In BC intrinsic subtypes, normal subtype had the fewest fusions (median: 1, interquartile range [IQR]: 0, 3) followed by luminal A (median: 5.5, IQR: 2.75, 10.25), luminal B (median: 9, IQR: 6, 16.5), HER2-enriched (median: 9, IQR: 6, 16.5) and basal (median 10, IQR: 6, 15.5) subtypes (p

Biliary strictures are characterized by the narrowing of the bile duct lumen, usually caused by surgical biliary injury, cancer, inflammation, and scarring from gallstones. Endoscopic stent placement is a well-established method for the management of biliary strictures. However, maintaining optimal mechanical properties of stents and designing surfaces that can prevent stent-induced tissue hyperplasia and biofilm formation are challenges in the fabrication of biodegradable biliary stents (BBSs) for customized treatment. This study proposes a novel approach to fabricating functionalized polymer BBSs with nanoengineered surfaces using 3D printing. The 3D printed stents, fabricated from bioactive silica poly(ε-carprolactone) (PCL) via a sol–gel method, exhibited tunable mechanical properties suitable for supporting the bile duct while ensuring biocompatibility. Furthermore, a nanoengineered surface layer was successfully created on a sirolimus (SRL)-coated functionalized PCL (fPCL) stent using Zn ion sputtering-based plasma immersion ion implantation (S-PIII) treatment to enhance the performance of the stent. The nanoengineered surface of the SRL-coated fPCL stent effectively reduced bacterial responses and remarkably inhibited fibroblast proliferation and initial burst release of SRL in vitro systems. The physicochemical properties and biological behaviors, including in vitro biocompatibility and in vivo therapeutic efficacy in the rabbit bile duct, of the Zn-SRL@fPCL stent demonstrated its potential as a versatile platform for clinical applications in bile duct tissue engineering.

Octacalcium phosphate (OCP) is a precursor of biological apatite minerals that can be used in synthetic bone grafts. In this work, a new type of synthetic bone grafts was developed by adding water glass to OCP (W-OCP). The OCP phase is generally known to be thermodynamically unstable and rapidly hydrolyzes to apatite. However, X-ray diffraction confirmed that OCP can remain stable even in the presence of water glass. In a rabbit calvarial defect model, W-OCP increased the bone area by 22.4 %, which was significantly higher than that of defects only at week 4 (p

Fecal microbiota transplantation (FMT) and probiotics therapies represent key clinical options, yet their complex effects on the host are not fully understood. We evaluated the comprehensive effects of FMT using diarrheal or normal feces, as well as probiotic therapies, on multiple anatomical sites in healthy cynomolgus macaques through colonoscopy and surgery. Our research revealed that FMT led to a partial microbiome transplantation without exhibiting the donor’s fecal clinical characteristics. Notably, FMT increased insulin and C-peptide levels in each animal according time series, regardless of fecal conditions. Immunologically, a reduction in neutrophil-to-lymphocyte ratio were exclusively observed in femoral veins of FMT group. In blood chemistry analyses, reductions in aspartate aminotransferase, blood urea nitrogen, and creatinine were observed in the femoral veins, while elevated levels of alanine aminotransferase and calcium were exclusively detected in the portal veins. These changes were not observed in the probiotic group. Also, short chain fatty acids were significantly higher increase in portal veins rather than femoral veins. Transcriptome analysis of liver tissues showed that metabolic pathways were primarily affected by both FMT and probiotics therapies. In summary, FMT therapy significantly influenced metabolic, immunologic and transcriptomic responses in normal macaque models, regardless of fecal conditions. Also, these macaque models, which utilize surgery and colonoscopy, serve as a human-like preclinical platform for evaluating long-term effects and anatomically specific responses to gut-targeted interventions, without the need for animal sacrifice.

IntroductionA single bout of aerobic exercise is known to induce a temporary reduction in post-exercise blood pressure termed post-exercise hypotension (PEH). Meanwhile, an ischemic preconditioning (IPC), a series of short ischemia-reperfusion intervention, has also shown antihypertensive effects showing a potential nonpharmacologic intervention for hypertension. While the acute BP reduction effects of aerobic exercise and IPC are individually well-investigated, it remains unclear if combining both interventions has an additive effect on PEH.MethodsA total of twelve pre- or hypertensive men (six prehypertension, six stage 1 hypertension) underwent either 30 min of aerobic exercise at 50% VO2peak (CON) or IPC before exercise, in a counterbalanced order. IPC involved inflating cuffs on both thighs to 200 mmHg for 5 min, alternating between right and left thighs for three cycles, totaling 30 min. Brachial BP was measured during exercise and 1-h post-exercise recovery whereas muscle oxygen saturation (SmO2) from the rectus femoris was monitored using NIRs during exercise and recovery. Heart rate variability (HRV) and baroreflex sensitivity (BRS) together with a head-up tilt test (at 0 and 50°) were measured at the pre-test, post-test, and 24-h post-test. After the completion of each experiment, 24-h ambulatory blood pressure (ABP) was monitored to assess post-exercise hypotension within a 24-h window.ResultsBP and heart rate responses during exercise and 1-h recovery did not differ between conditions while SmO2 was significantly elevated during exercise in IPC (p = 0.004). There was no difference in HRV and supine BRS. However, significantly reduced titled BRS after exercise was found in CON while IPC preserved BRS similar to pre-exercise value, extending to 24-h post period (p = 0.047). ABP monitoring revealed a significant reduction in systolic BP during sleep in IPC compared to CON (p = 0.046).ConclusionThe present findings suggest that IPC with a single session of aerobic exercise results in a notable decrease in systolic ABP, particularly during sleep, compared to aerobic exercise alone. This supplementary antihypertensive effect was associated with a sustained BRS, persisting up to 24 h in contrast to the significant decrease observed in CON. Future studies are warranted to investigate long-term adaptations to IPC.

IntroductionThe rate of adjustment in a movement, driven by feedback error, is referred to as the adaptation rate, and the rate of recovery of a newly adapted movement to its unperturbed condition is called the de-adaptation rate. The rates of adaptation and de-adaptation are dependent on the training mechanism and intrinsic factors such as the participant's sensorimotor abilities. This study investigated the facilitation of the motor adaptation and de-adaptation processes for spatiotemporal features of an asymmetric gait pattern by sequentially applying split-belt treadmill (SBT) and asymmetric rhythmic auditory cueing (ARAC).MethodsTwo sessions tested the individual gait characteristics of SBT and ARAC, and the remaining four sessions consisted of applying the two interventions sequentially during training. The adjustment process to the second intervention is referred to as “re-adaptation” and is driven by feedback error associated with the second intervention.ResultsTen healthy individuals participated in the randomized six-session trial. Spatiotemporal asymmetries during the adaptation and post-adaptation (when intervention is removed) stages were fitted into a two-component exponential model that reflects the explicit and implicit adaptation processes. A double component was shown to fit better than a single-component model. The decay constants of the model were indicative of the corresponding timescales and compared between trials. Results revealed that the explicit (fast) component of adaptation to ARAC was reduced for step length and step time when applied after SBT. Contrarily, the explicit component of adaptation to SBT was increased when it was applied after ARAC for step length. Additionally, the implicit (slow) component of adaptation to SBT was inhibited when applied incongruently after ARAC for step time.DiscussionThese outcomes show that the role of working motor memory as a translational tool between different gait interventions is dependent on (i) the adaptation mechanisms associated with the interventions, (ii) the targeted motor outcome of the interventions; the effects of factors (i) and (ii) are specific to the explicit and implicit components of the adaptation processes; these effects are unique to spatial and temporal gait characteristics.

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Abstract N 6-adenosine methylation (m6A) is critical for controlling cancer cell growth and tumorigenesis. However, the function and detailed mechanism of how m6A methyltransferases modulate m6A levels on specific targets remain unknown. In the current study, we identified significantly elevated levels of RBM15, an m6A writer, in basal-like breast cancer (BC) patients compared to nonbasal-like BC patients and linked this increase to worse clinical outcomes. Gene expression profiling revealed correlations between RBM15 and serine and glycine metabolic genes, including PHGDH, PSAT1, PSPH, and SHMT2. RBM15 influences m6A levels and, specifically, the m6A levels of serine and glycine metabolic genes via direct binding to target RNA. The effects of RBM15 on cell growth were largely dependent on serine and glycine metabolism. Thus, RBM15 coordinates cancer cell growth through altered serine and glycine metabolism, suggesting that RBM15 is a new therapeutic target in BC.

Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disease that may be associated with hypertension, autoregulatory failure, and the use of calcineurin inhibitors following heart transplantation (HT). In this article, we present a case series of PRES, discussing its potential causes and management strategies. Among the 126 HT recipients at our hospital, four were diagnosed with PRES. Three of these patients developed PRES within 7 days after HT. Prior to the onset of PRES, all patients experienced sustained hypertension, and strict blood pressure (BP) control was maintained. Three of the four patients recovered without PRES recurrence, while one patient died of sepsis after an episode of altered consciousness. Hypertension was observed in all patients prior to the onset of PRES, and the majority experienced symptom improvement with BP control. While most cases of PRES were reversible with conservative treatment, including the administration of antiepileptics, one irreversible case resulted in in-hospital mortality. Thus, PRES can have serious outcomes and is not invariably benign.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has changed respiratory infection patterns globally. However, its impact on community-acquired pneumonia (CAP) in high-risk patients with haematological malignancies (HM) is uncertain. We aimed to examine how community-acquired pneumonia aetiology in patients with haematological malignancies changed during the COVID-19 pandemic. Methods This was a retrospective study that included 524 patients with haematological malignancies hospitalised with community-acquired pneumonia between March 2018 and February 2022. Patients who underwent bronchoscopy within 24 h of admission to identify community-acquired pneumonia aetiology were included. Data on patient characteristics, laboratory findings, and results of bronchioalveolar lavage fluid cultures and polymerase chain reaction tests were analysed and compared to identify changes and in-hospital mortality risk factors. Results Patients were divided into the ‘pre-COVID-19 era’ (44.5%) and ‘COVID-19 era’ (55.5%) groups. The incidence of viral community-acquired pneumonia significantly decreased in the COVID-19 era, particularly for influenza A, parainfluenza, adenovirus, and rhinovirus (pre-COVID-19 era vs. COVID-19 era: 3.0% vs. 0.3%, P = 0.036; 6.5% vs. 0.7%, P = 0.001; 5.6% vs. 1.4%, P = 0.015; and 9.5% vs. 1.7%, P

Abstract Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10–20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3–152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers (P = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P

Abstract We investigated three-dimensional (3D) eyeball protrusion and its association with the offset between the lamina cribrosa (LC) and Bruch’s membrane opening (BMO). 3D-MRI scans were taken from 93 subjects (186 eyes). An ellipsoid was fitted along the posterior 2/3 contour of each eyeball. Eyeball asymmetry with focal bulging was determined by the existence of an adjacent outward protrusion/reciprocal inward depression pair, and the angular deviation of the outermost protruded point (OPP) was measured from the nasal side of the fovea-BMO axis. The LC/BMO offset was evaluated by measuring the central retinal vascular trunk (CRVT) location from the BMO center: (1) the angular deviation and (2) the offset index as the ratio between the CRVT-BMO center distance and the BMO radius in the same direction. Seventy-nine eyes (42%) were classified as having eyeball asymmetry, which had a more superior LC/BMO offset (P

Abstract We investigated optic nerve head factors associated with initial parafoveal scotoma (IPFS) in primary open-angle glaucoma. Eighty (80) patients with an IPFS and 84 patients with an initial nasal step (INS) were compared. Central retinal vascular trunk (CRVT) deviation from the Bruch’s membrane opening (BMO) center was measured as a surrogate of lamina cribrosa (LC)/BMO offset, and its obliqueness was defined as the absolute value of angular deviation from the fovea-BMO axis. Proximity of retinal nerve fiber layer defect (RNFLD) was defined as the angular deviation of the inner RNFLD margin from the fovea-BMO axis. Microvasculature dropout (MvD) was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, as compared with INS, were assessed using logistic regression analyses and conditional inference tree analysis. The IPFS group had more oblique CRVT offset (P

Abstract Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic‐acid‐based therapeutics, but challenges related to their large‐scale production and cargo‐loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel “shock wave extracellular vesicles engineering technology” (SWEET) as a non‐genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C‐targeting siRNA into small bovine‐milk‐derived EVs (sBMEVs), with high efficiency. The siRNA‐loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non‐small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large‐scale production of cargo‐loaded EVs for use in a wide range of therapeutic applications.

Phthalate esters (PAEs) are primary plasticizers and endocrine-disrupting chemicals (EDCs) that are extensively used in numerous everyday consumer products. Although the adverse effects of single PAEs have been studied, our understanding of the effect of multiple phthalate exposure on male germ cell vitality remains limited. Therefore, this study aimed to investigate the collective effects of a mixture of PAEs (MP) comprising diethyl-, bis (2-ethylhexyl)-, dibutyl-, diisononyl-, diisobutyl-, and benzyl butyl-phthalates in the proportions of 35, 21, 15, 15, 8, and 5%, respectively, on differentiated male germ cells using GC-1 spermatogonia (spg) cells. As a mixture, MP substantially hindered GC-1 spg cell proliferation at 3.13 μg/mL, with a half-maximal inhibitory concentration of 16.9 μg/mL. Treatment with 25 μg/mL MP significantly induced reactive oxygen species generation and promoted apoptosis. Furthermore, MP activated autophagy and suppressed phosphorylation of phosphoinositide 3-kinase, protein kinase B, and mammalian target of rapamycin (mTOR). The triple inhibitor combination treatment comprising parthenolide, N-acetylcysteine, and 3-methyladenine effectively reversed MP-induced GC-1 spg cell proliferation inhibition, mitigated apoptosis and autophagy, and restored mTOR phosphorylation. This study is the first to elucidate the mechanism underlying MP-induced male germ cell toxicity and the restoration of male germ cell proliferation mediated by chemical inhibitors. Therefore, it provides valuable insights into the existing literature by proposing a combinatorial toxicity mitigation strategy to counteract male germ cell toxicity induced by various EDCs exposure.

Benzyl butyl phthalate (BBP) is a widely used plasticizer that poses various potential health hazards. Although BBP has been extensively studied, the direct mechanism underlying its toxicity in male germ cells remains unclear. Therefore, we investigated BBP-mediated male germ cell toxicity in GC-1 spermatogonia (spg), a differentiated mouse male germ cell line. This study investigated the impact of BBP on reactive oxygen species (ROS) generation, apoptosis, and autophagy regulation, as well as potential protective measures against BBP-induced toxicity. A marked dose-dependent decrease in GC-1 spg cell proliferation was observed following treatment with BBP at 12.5 μM. Exposure to 50 μM BBP, approximating the IC50 of 53.9 μM, markedly increased cellular ROS generation and instigated apoptosis, as evidenced by augmented protein levels of both intrinsic and extrinsic apoptosis-related markers. An amount of 50 μM BBP induced marked upregulation of autophagy regulator proteins, p38 MAPK, and extracellular signal-regulated kinase and substantially downregulated the phosphorylation of key kinases involved in regulating cell proliferation, including phosphoinositide 3-kinase, protein kinase B, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase. The triple combination of N-acetylcysteine, parthenolide, and 3-methyladenine markedly restored cell proliferation, decreased BBP-induced apoptosis and autophagy, and restored mTOR phosphorylation. This study provides new insights into BBP-induced male germ cell toxicity and highlights the therapeutic potential of the triple inhibitors in mitigating BBP toxicity.

Abstract COVID-19 caused by SARS-CoV-2 spread rapidly around the world, endangering the health of people globally. The SARS-CoV-2 spike protein initiates entry into target cells by binding to human angiotensin-converting enzyme 2 (ACE2). In this study, we developed DNA aptamers that specifically bind to the SARS-CoV-2 spike protein, thereby inhibiting its binding to ACE2. DNA aptamers are small nucleic acid fragments with random structures that selectively bind to various target molecules. We identified nine aptamers targeting the SARS-CoV-2 spike protein using the systematic evolution of ligands by exponential enrichment (SELEX) method and selected three optimal aptamers by comparing their binding affinities. Additionally, we confirmed that the DNA aptamers suppressed pro-inflammatory cytokines induced by the SARS-CoV-2 spike protein in ACE2-overexpressing HEK293 cells. Overall, the DNA aptamer developed in this study has the potential to bind to the SARS-CoV-2 spike protein and inhibit or block its interaction with ACE2. Thus, our DNA aptamers can be used as new biological tools for the prevention and diagnosis of SARS-CoV-2 infection.

The purpose of this study is to report the clinical application of Hominis Placenta Pharmacopunture for Alopecia areata. Patient was diagnosed as stress-induced Alopecia areata 1 years ago. To reduce symptom, we treated a patient 8 times using Hominis Placenta Pharmacopunture. Hominis Placenta was injected subcutaneously into the lesion of head scalp alopecia. According to photographs, the lesion had been replaced with new terminal hair and the size of the lesion had decreased. This case has shown that stress-induced Alopecia areata patient could be treated by Hominis Placenta Pharmacopunture.

Abstract Background Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. Methods A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. Results There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160–23.190) in non-pCRw/mic group and 5.970 (1.840–19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130–34.090) in non-pCRw/mic group, 9.120 (2.850–29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230–21.500) without statistical significance (p = 0.486). Conclusions Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.

This study presents a password strength evaluation method using the GPT-4 model with prompt-based metrics. Unlike traditional algorithmic approaches, this method leverages GPT-4 to provide more flexible and adaptive password evaluations without the need for additional model training. The proposed evaluation metrics focus on Complexity, Memorability, and Personal Information (PI) Inclusion. To validate its effectiveness, comparisons were made with existing algorithmic metrics such as LUDS and zxcvbn, using 2,000 randomly sampled real-world passwords. The results revealed a strong correlation between LUDS and the Complexity score with a Pearson correlation of 0.7281, but a weaker correlation between zxcvbn and Memorability with a Pearson correlation of 0.4717. Additionally, the PI score evaluation demonstrated a significant gap between PI-included and non-PI-included passwords. A further comparison between English and Korean PI-based passwords showed that English PI inclusion yielded lower evaluation scores. These findings indicate that the GPT based prompt evaluation method has the potential to be used as an adaptable tool for assessing password security strength.

This study presents a low-cost digital compensator design for a flyback converter featuring a full digital feedback loop. This design replaces the traditional analog compensation circuit with a digital compensator, where the external resistance and capacitor are removed. The system parameters of the digital compensator are engineered to allow for universal adaptability. An 8-bit successive-approximation analog-to-digital converter circuit facilitates the conversion of analog signals into digital data. These circuits are fabricated using a 180-nm BCD processor. The output voltage ranges from 3.5 to 9 V, while the output current varies from 1 to 3 A. The flyback converter equipped with the designed digital compensator achieves a maximum power efficiency of 83%. The total chip area, encompassing both the digital compensator and data converter circuit, measures $950~\mu $ m $\times 460~\mu $ m.

Background The implication of the presence of tumor-infiltrating T lymphocytes (TIL-T) in diffuse large B-cell lymphoma (DLBCL) is yet to be elucidated. We aimed to investigate the effect of TIL-T levels on the prognosis of patients with DLBCL. Methods Ninety-six patients with DLBCL were enrolled in the study. The TIL-T ratio was measured using QuPath, a digital pathology software package. The TIL-T ratio was investigated in three foci (highest, intermediate, and lowest) for each case, resulting in TIL-T–Max, TIL-T–Intermediate, and TIL-T–Min. The relationship between the TIL-T ratios and prognosis was investigated. Results When 19% was used as the cutoff value for TIL-T–Max, 72 (75.0%) and 24 (25.0%) patients had high and low TIL-T–Max, respectively. A high TIL-T–Max was significantly associated with lower serum lactate dehydrogenase levels (p < .001), with patient group who achieved complete remission after RCHOP therapy (p < .001), and a low-risk revised International Prognostic Index score (p < .001). Univariate analysis showed that patients with a low TIL-T–Max had a significantly worse prognosis in overall survival compared to those with a high TIL-T–Max (p < .001); this difference remained significant in a multivariate analysis with Cox proportional hazards (hazard ratio, 7.55; 95% confidence interval, 2.54 to 22.42; p < .001). Conclusions Patients with DLBCL with a high TIL-T–Max showed significantly better prognosis than those with a low TIL-T–Max, and the TIL-T–Max was an independent indicator of overall survival. These results suggest that evaluating TIL-T ratios using a digital pathology system is useful in predicting the prognosis of patients with DLBCL.

We developed an internal environment prediction model for smart greenhouses using machine learning models. Machine learning models were developed by finding certain rules based on the data obtained from the target system and have the advantage of learning various characteristics that are difficult to define theoretically. However, the model accuracy and precision can change according to the model structure (hyperparameters, algorithms, epoch) and data characteristics. In this study, the analysis was performed according to the collected weather data characteristics. The model performance was low when the amount of training data was obtained over less than three days (4320 ea). The model performance improved with an increase in the amount of training data. Model performance stabilized when the training data volume exceeded seven days (10,080 ea). The optimal amount of data was determined to be between three and seven days, with an average model r2 of 0.8811 and an RMSE of 2.056 for the gated recurrent unit algorithm. This study verified the possibility of developing a predictive model for the internal environment of a greenhouse based on weather data from outside. This study is limited to a specific target greenhouse, and further analysis of data from various greenhouses and climates is necessary to achieve global optimization.

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the glioma cohorts at our institute. We reviewed medical records spanning a 15-year period and examined pathological slides for an updated diagnosis according to the 2021 WHO classification of CNS tumors. We examined the IDH1/2 mutation and CDKN2A deletion using NGS analysis with ONCOaccuPanel®. Further, we examined traditional prognostic factors, including age, WHO performance status, extent of resection, and MGMT promoter methylation status. Results: The mean follow-up duration was 27.5 months (range: 4.1–43.5 months) and mean overall survival (OS) was 20.7 months (SD, ±1.759). After the exclusion of six patients with a poor status of pathologic samples, a total of 136 glioblastoma cases diagnosed by previous WHO classification criteria were newly classified into 29 (21.3%) astrocytoma, IDH-mutant, and CNS WHO grade 4 cases, and 107 (78.7%) glioblastoma, IDH-wildtype, and CNS WHO grade 4 cases. Among them, 61 (56.0%) had CDKN2A deletions. The high-risk group with CDKN2A deletion regardless of IDH1/2 mutation had a mean OS of 16.65 months (SD, ±1.554), the intermediate-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 21.85 months (SD, ±2.082), and the low-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 33.38 months (SD, ±2.946). Multifactor analysis showed that age (≥50 years vs. MGMT promoter methylation, (methylated vs. unmethylated; HR 5.078), IDH1/2 mutation (mutant vs. wildtype; HR 6.352), and CDKN2A deletion (absence vs. presence; HR 13.454) were associated with OS independently. Conclusions: The present study suggests that CDKN2A deletion plays a powerful prognostic role in CNS WHO grade 4 gliomas. Even if CNS WHO grade 4 gliomas have mutant IDH1/2, they may have poor clinical outcomes because of CDKN2A deletion.

Recently, interest in cancer immunotherapy has increased over traditional anti-cancer therapies such as chemotherapy or targeted therapy. Natural killer (NK) cells are part of the immune cell family and essential to tumor immunotherapy as they detect and kill cancer cells. However, the disadvantage of NK cells is that cell culture is difficult. In this study, porous microgels have been fabricated using microfluidic channels to effectively culture NK cells. Microgel fabrication using microfluidics can be mass-produced in a short time and can be made in a uniform size. Microgels consist of photo cross-linkable polymers such as methacrylic gelatin (GelMa) and can be regulated via controlled GelMa concentrations. NK92 cell-laden three-dimensional (3D) microgels increase mRNA expression levels, NK92 cell proliferation, cytokine release, and anti-tumor efficacy, compared with two-dimensional (2D) cultures. In addition, the study confirms that 3D-cultured NK92 cells enhance anti-tumor effects compared with enhancement by 2D-cultured NK92 cells in the K562 leukemia mouse model. Microgels containing healthy NK cells are designed to completely degrade after 5 days allowing NK cells to be released to achieve cell-to-cell interaction with cancer cells. Overall, this microgel system provides a new cell culture platform for the effective culturing of NK cells and a new strategy for developing immune cell therapy.

Navigation of microcarriers in complex environments as a vascular network remains an open challenge due to limited solutions for effective targeting strategy. Simultaneous real‐time visualization and manipulation of microcarriers at any depth in the human body is far to be achieved even though one of each task has been successfully proven. Herein, a novel targeting strategy is proposed that employs field‐free region (FFR) scanning to guide microcarriers through multiple bifurcations within a predefined vessel network. The main challenge of this method lies on how, where, and when to activate FFR to steer a particle to a desired direction, regardless of its spatial feedback. To achieve it, first, a mathematical model of particle motion in a vessel network is developed to predict particle behaviors and positions. Subsequently, an optimization algorithm is formulated to place FFR well‐coordinated around each bifurcation at a designated moment. The established solution for targeting a magnetic microcarrier is preemptively evaluated through finite element simulations and then successfully implemented in in vitro multibranched vessels.

Abstract Zika virus infection causes multiple clinical issues, including Guillain–Barré syndrome and neonatal malformation. Vaccination is considered as the only strategy for the prevention of ZIKV-induced clinical issues. This study developed a plant-based recombinant vaccine that transiently expressed the ZIKV envelope protein (ZikaEnv:aghFc) in Nicotiana benthamiana and evaluated the protective immunity afforded by it in immunocompetent mice. ZikaEnv:aghFc induced both humoral and cellular immunity at a low dose (1–5 μg). This immune-inducing potential was enhanced further when adjuvanted CIA09A. In addition, antigen-specific antibodies and neutralizing antibodies were vertically transferred from immunized females to their progeny and afforded both protective immunity to ZIKV and cross-protection to Dengue virus infection. These results suggest that our plant-based ZIKV vaccine provides a safe and efficient protective strategy with a competitive edge.

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

Abstract Background The role of visiting health services has been proven to be effective in promoting the health of older populations. Hence, developing a web system for nurses may help improve the quality of visiting health services for community-dwelling frail older adults. This study was conducted to develop a web application that reflects the needs of visiting nurses. Methods Visiting nurses of public health centers and community centers in South Korea participated in the design and evaluation process. Six nurses took part in the focus group interviews, and 21 visiting nurses and community center managers participated in the satisfaction evaluation. Focus group interviews were conducted to identify the needs of visiting nurses with respect to system function. Based on the findings, a web application that can support the effective delivery of home visiting services in the community was developed. An artificial intelligence (AI) algorithm was also developed to recommend health and welfare services according to each patient’s health status. After development, a structured survey was conducted to evaluate user satisfaction with system features using Kano’s model. Results The new system can be used with mobile devices to increase the mobility of visiting nurses. The system includes 13 features that support the management of patient data and enhance the efficiency of visiting services (e.g., map, navigation, scheduler, protocol archives, professional advice, and online case conferencing). The user satisfaction survey revealed that nurses showed high satisfaction with the system. Among all features, the nurses were most satisfied with the care plan, which included AI-based recommendations for community referral. Conclusions The system developed from the study has attractive features for visiting nurses and supports their essential tasks. The system can help with effective case management for older adults requiring in-home care and reduce nurses' workload. It can also improve communication and networking between healthcare and long-term care institutions.

Abstract Colorectal cancer (CRC) presents a formidable challenge, characterized by a steadily increasing incidence. Current approaches to manage CRC, including chemotherapy and targeted therapies, are burdened with significant limitations such as resistance development, adverse events, and high costs. Hence, there is an urgent demand for a more promising alternative. Autocrine motility factor (AMF), known for its role in promoting cancer cell motility, exhibits a unique ability to selectively impede the growth of cancer cells. In our study, we have elucidated the specific inhibitory effect of AMF derived from DU145 prostate cancer cells (D-AMF) on the proliferation of CRC cells. D-AMF effectively downregulated the expression of glucose-6-phosphate dehydrogenase (G6PD) at both the mRNA and protein levels, resulting in a concurrent increase in the generation of reactive oxygen species (ROS). Notably, the combination of D-AMF and curcumin proved highly effective in eliminating curcumin-resistant CRC cells. Therefore, the use of D-AMF in conjunction with curcumin holds promise as an alternative treatment approach for CRC.

Abstract Background Cancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors modulate their metabolic flexibility in the naturally serine/glycine (S/G)-deficient brain microenvironment remain unknown. Methods We used a range of primary/stem-like and established glioblastoma (GBM) cell models in vitro and in vivo. To identify the regulatory mechanisms of S/G deprivation-induced metabolic flexibility, we employed high-throughput RNA-sequencing, transcriptomic analysis, metabolic flux analysis, metabolites analysis, chromatin immunoprecipitation (ChIP), luciferase reporter, nuclear fractionation, cycloheximide-chase, and glucose consumption. The clinical significances were analyzed in the genomic database (GSE4290) and in human GBM specimens. Results The high-throughput RNA-sequencing and transcriptomic analysis demonstrate that the de novo serine synthesis pathway (SSP) and glycolysis are highly activated in GBM cells under S/G deprivation conditions. Mechanistically, S/G deprivation rapidly induces reactive oxygen species (ROS)-mediated AMP-activated protein kinase (AMPK) activation and AMPK-dependent hypoxia-inducible factor (HIF)-1α stabilization and transactivation. Activated HIF-1α in turn promotes the expression of SSP enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). In addition, the HIF-1α-induced expression of glycolytic genes (GLUT1, GLUT3, HK2, and PFKFB2) promotes glucose uptake, glycolysis, and glycolytic flux to fuel SSP, leading to elevated de novo serine and glycine biosynthesis, NADPH/NADP+ ratio, and the proliferation and survival of GBM cells. Analyses of human GBM specimens reveal that the levels of overexpressed PHGDH, PSAT1, and PSPH are positively correlated with levels of AMPK T172 phosphorylation and HIF-1α expression and the poor prognosis of GBM patients. Conclusion Our findings reveal that metabolic stress-enhanced glucose-derived de novo serine biosynthesis is a critical metabolic feature of GBM cells, and highlight the potential to target SSP for treating human GBM.

Abstract Nucleic acid sensing is involved in viral infections, immune response-related diseases, and therapeutics. Based on the composition of nucleic acids, nucleic acid sensors are defined as DNA or RNA sensors. Pathogen-associated nucleic acids are recognized by membrane-bound and intracellular receptors, known as pattern recognition receptors (PRRs), which induce innate immune-mediated antiviral responses. PRR activation is tightly regulated to eliminate infections and prevent abnormal or excessive immune responses. Nucleic acid sensing is an essential mechanism in tumor immunotherapy and gene therapies that target cancer and infectious diseases through genetically engineered immune cells or therapeutic nucleic acids. Nucleic acid sensing supports immune cells in priming desirable immune responses during tumor treatment. Recent studies have shown that nucleic acid sensing affects the efficiency of gene therapy by inhibiting translation. Suppression of innate immunity induced by nucleic acid sensing through small-molecule inhibitors, virus-derived proteins, and chemical modifications offers a potential therapeutic strategy. Herein, we review the mechanisms and regulation of nucleic acid sensing, specifically covering recent advances. Furthermore, we summarize and discuss recent research progress regarding the different effects of nucleic acid sensing on therapeutic efficacy. This study provides insights for the application of nucleic acid sensing in therapy.