ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects.

Transforming growth factor ß (TGFß) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFß/VEGF is more effective than targeting TGFß alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFß and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFß signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

Dynamic interplay of reactive oxygen and nitrogen species (ROS and RNS) in plant resilience: unveiling the signaling pathways and metabolic responses to biotic and abiotic stresses.

KEY MESSAGE: Plants respond to environmental challenges by producing reactive species such as ROS and RNS, which play critical roles in signaling pathways that lead to adaptation and survival strategies. Understanding these pathways, as well as their detection methods and effects on plant development and metabolism, provides insight into increasing crop tolerance to combined stresses. Plants encounter various environmental stresses (abiotic and biotic) that affect plant growth and development. Plants sense biotic and abiotic stresses by producing different molecules, including reactive species, that act as signaling molecules and stimulate secondary messengers and subsequent gene transcription. Reactive oxygen and nitrogen species (ROS and RNS) are produced in both physiological and pathological conditions in the plasma membranes, chloroplasts, mitochondria, and endoplasmic reticulum. Various techniques, including spectroscopy, chromatography, and fluorescence methods, are used to detect highly reactive, short-half-life ROS and RNS either directly or indirectly. In this review, we highlight the roles of ROS and RNS in seed germination, root development, senescence, mineral nutrition, and post-harvest control. In addition, we provide information on the specialized metabolism involved in plant growth and development. Secondary metabolites, including alkaloids, flavonoids, and terpenoids, are produced in low concentrations in plants for signaling and metabolism. Strategies for improving crop performance under combined drought and pathogen stress conditions are discussed in this review.

Exploring Spectrogram-Based Audio Classification for Parkinson's Disease: A Study on Speech Classification and Qualitative Reliability Verification.

Patients suffering from Parkinson's disease suffer from voice impairment. In this study, we introduce models to classify normal and Parkinson's patients using their speech. We used an AST (audio spectrogram transformer), a transformer-based speech classification model that has recently outperformed CNN-based models in many fields, and a CNN-based PSLA (pretraining, sampling, labeling, and aggregation), a high-performance model in the existing speech classification field, for the study. This study compares and analyzes the models from both quantitative and qualitative perspectives. First, qualitatively, PSLA outperformed AST by more than 4% in accuracy, and the AUC was also higher, with 94.16% for AST and 97.43% for PSLA. Furthermore, we qualitatively evaluated the ability of the models to capture the acoustic features of Parkinson's through various CAM (class activation map)-based XAI (eXplainable AI) models such as GradCAM and EigenCAM. Based on PSLA, we found that the model focuses well on the muffled frequency band of Parkinson's speech, and the heatmap analysis of false positives and false negatives shows that the speech features are also visually represented when the model actually makes incorrect predictions. The contribution of this paper is that we not only found a suitable model for diagnosing Parkinson's through speech using two different types of models but also validated the predictions of the model in practice.

Separation of Lipoproteins for Quantitative Analysis of 14C-Labeled Lipid-Soluble Compounds by Accelerator Mass Spectrometry.

To date, 14C tracer studies using accelerator mass spectrometry (AMS) have not yet resolved lipid-soluble analytes into individual lipoprotein density subclasses. The objective of this work was to develop a reliable method for lipoprotein separation and quantitative recovery for biokinetic modeling purposes. The novel method developed provides the means for use of small volumes (10-200 µL) of frozen plasma as a starting material for continuous isopycnic lipoprotein separation within a carbon- and pH-stable analyte matrix, which, following post-separation fraction clean up, created samples suitable for highly accurate 14C/12C isotope ratio determinations by AMS. Manual aspiration achieved 99.2 ± 0.41% recovery of [5-14CH3]-(2R, 4'R, 8'R)-α-tocopherol contained within 25 µL plasma recovered in triacylglycerol rich lipoproteins (TRL = Chylomicrons + VLDL), LDL, HDL, and infranatant (INF) from each of 10 different sampling times for one male and one female subject, n = 20 total samples. Small sample volumes of previously frozen plasma and high analyte recoveries make this an attractive method for AMS studies using newer, smaller footprint AMS equipment to develop genuine tracer analyses of lipophilic nutrients or compounds in all human age ranges.

Concurrent primary splenic lymphoma and mammary gland tumour with polycystic ovaries in a dog.

Here, we report a rare case of concurrent primary splenic lymphoma and mammary gland tumour (MGT) with polycystic ovaries in a 10-year-old, intact female Jindo dog. The dog was presented with multiple masses in the fourth left mammary gland, the largest of which measured 6 cm in diameter, along with enlargement of the left inguinal lymph node on physical examination. Ultrasonography, radiography, and computed tomography scans revealed polycystic ovaries and a mass in the tail of the spleen, after total splenectomy and mastectomy with ovariohysterectomy, histopathological examination identified splenic diffuse large B cell lymphoma and malignant myoepithelioma of the mammary gland was found. To our knowledge, this is the first report of the concurrent occurrence of splenic lymphoma, MGT, and polycystic ovaries in a dog.

Canine multiple primary tumours: Mammary tubular carcinoma, uterine leiomyosarcoma, and facial sebaceous epithelioma.

Multiple primary malignant tumours (MPMTs) are multiple neoplasms with independent pathogenetic origins, placing great importance on the tumorigenesis and clinical treatment. However, due to the rare occurrence and diagnostic confusion, MPMTs have rarely been investigated in veterinary medicine. In this report, a 10-year-old intact female Maltese dog had MPMTs, consisting of two malignant tumours and one benign tumour each derived from a topographically different site: tubular carcinoma in the mammary glands, leiomyosarcoma in the uterus and sebaceous epithelioma in the cheek. The unique combination of MPMTs would be the first case in veterinary research to give insight into the diagnosis, disease characteristics, and surgical treatment.

Optimizing an Optical Cavity-Based Biosensor for Enhanced Sensitivity.

The rapid advancement of biosensor technology has revolutionized healthcare, offering improved sensitivity, specificity, and portability. We have developed an optical cavity-based biosensor (OCB) as a promising solution due to its label-free detection, high sensitivity, real-time monitoring, multiplexing capability, and versatility. The OCB consists of an optical cavity structure (OCS), optical components, and a low-cost camera. The OCS is created by two partially reflective surfaces separated by a small gap, where the interaction between target analytes and immobilized receptors leads to a shift in the resonance transmission spectrum, caused by minute changes in the local refractive index (RI). In our previous work, we successfully detected these small changes with a simple OCS and cost-effective components using a differential detection method. Building upon these achievements, this study focuses on optimizing the OCS, improving the camera settings, and enhancing the differential detection approach. By increasing the reflectance of the surfaces and optimizing the optical cavity widths correspondingly, we achieved an improved limit of detection (LOD). We also investigated how the charge-coupled device (CCD) camera shutter time affects the LOD. Additionally, we introduced a new differential equation to further enhance the sensitivity of our system. Through these advancements, we could improve the LOD of the OCB by 7.2 times, specifically for an OCS with a cavity thickness of 9.881 µm and a silver thickness of 46.87 nm. These findings not only contribute to the ongoing effort of optimizing the OCB, but also pave the way for the development of advanced point-of-care biosensors with enhanced detection capabilities.

Double-Sided Tape in Microfluidics: A Cost-Effective Method in Device Fabrication.

The demand for easy-to-use, affordable, accessible, and reliable technology is increasing in biological, chemical, and medical research. Microfluidic devices have the potential to meet these standards by offering cost-effective, highly sensitive, and highly specific diagnostic tests with rapid performance and minimal sample volumes. Traditional microfluidic device fabrication methods, such as photolithography and soft lithography, are time-consuming and require specialized equipment and expertise, making them costly and less accessible to researchers and clinicians and limiting the applicability and potential of microfluidic devices. To address this, researchers have turned to using new low-cost materials, such as double-sided tape for microfluidic device fabrication, which offers simple and low-cost processes. The innovation of low-cost and easy-to-make microfluidic devices improves the potential for more devices to be transitioned from laboratories to commercialized products found in stores, offices, and homes. This review serves as a comprehensive summary of the growing interest in and use of double-sided tape-based microfluidic devices in the last 20 years. It discusses the advantages of using double-sided tape, the fabrication techniques used to create and bond microfluidic devices, and the limitations of this approach in certain applications.

Impact of nanopollution on plant growth, photosynthesis, toxicity, and metabolism in the agricultural sector: An updated review.

Nanotechnology provides distinct benefits to numerous industrial and commercial fields, and has developed into a discipline of intense interest to researchers. Nanoparticles (NPs) have risen to prominence in modern agriculture due to their use in agrochemicals, nanofertilizers, and nanoremediation. However, their potential negative impacts on soil and water ecosystems, as well as plant growth and physiology, have caused concern for researchers and policymakers. Concerns have been expressed regarding the ecological consequences and toxicity effects associated with nanoparticles as a result of their increased production and usage. Moreover, the accumulation of nanoparticles in the environment poses a risk, not only because of the possibility of plant damage but also because nanoparticles may infiltrate the food chain. In this review, we have documented the beneficial and detrimental effects of NPs on seed germination, shoot and root growth, plant biomass, and nutrient assimilation. Nanoparticles exert toxic effects by inducing ROS generation and stimulating cytotoxic and genotoxic effects, thereby leading to cell death in several plant species. We have provided possible mechanisms by which nanoparticles induce toxicity in plants. In addition to the toxic effects of NPs, we highlighted the importance of nanomaterials in the agricultural sector. Thus, understanding the structure, size, and concentration of nanoparticles that will improve plant growth or induce plant cell death is essential. This updated review reveals the multifaceted connection between nanoparticles, soil and water pollution, and plant biology in the context of agriculture.

Long-term Outcomes of Bilateral Lateral Rectus Recession Using a Modified Normogram for Targeting Small Overcorrection in Intermittent Exotropia.

Purpose: To evaluate the surgical outcomes of a modified normogram for bilateral lateral rectus recession (BLR) in the surgical management of intermittent exotropia, with a focus on achieving small overcorrection. Methods: A retrospective medical chart review of 242 patients who underwent surgery for intermittent exotropia between October 2014 and June 2020 was performed. Our modified normogram reducing amount of recession targeted for small postoperative overcorrection within 5 prism diopters (PD). Patients were observed for at least 3 years. Esodeviation was denoted by negative numbers and positive values indicated exodeviation. A satisfactory outcome was defined as if distant angle of deviation ranged between ≤10 PD of exotropia and ≤5 PD of esotropia. Recurrence was defined as an exodeviation of >10 PD at distance. Overcorrection was defined as an esodeviation of >5 PD at distance. Results: The mean preoperative deviation angles were 29.32±3.92 PD at distance and 29.88±4.41 PD at near. At postoperative day 1, the mean deviation angles at distance and near were -6.22±1.44 PD and -6.22±1.49 PD, respectively. Overcorrection within 6 PD of esodeviation was seen in 168 patients (69.42%), undercorrection with exophoria was noted in 11 patients (4.55%), and overcorrection by more than 6 PD of esodeviation was seen in 63 patients (26.03%) at postoperative day 1. The long-term success rate at postoperative 3 years was 77.27% (187/242), with a recurrence rate of 19.83% (48/242) and an overcorrection rate of 2.89% (7/242). A positive correlation between the angle of deviation at postoperative day 1 and 3 years was observed (r= 0.22, p=0.001). The final success rate at the final examination after a mean follow-up of 38.60±7.99 months was 83.06%. Conclusion: Our modified normogram for BLR in intermittent exotropia surgery resulted in successful surgical outcomes with small overcorrection, reducing the risk of consecutive esotropia due to excessive overcorrection.

Improved organic and pesticide-free rice (Oryza sativa L.) authentication based on multiple stable isotope ratio analysis and rice milling state.

This study looked at the application of multiple bulk stable isotope ratio analysis to accurately authenticate organic rice and counteract organic fraud within the expanding global organic market. Variations of δ13C, δ15N, δ18O, and δ34S in organic, pesticide-free, and conventional rice were assessed across different milling states (brown, milled, and bran). Individual stable isotope ratio alone such as δ15N demonstrated limited capacity to correctly differentiate organic, pesticide-free, and conventional rice. A support vector machine model-incorporating δ13C, δ15N, δ18O, and δ34S in milled rice-yielded overall predictability (95%) in distinguishing organic, pesticide-free, and conventional rice, where δ18O emerged as the pivotal variable based on the feature weights in the SVM model. These findings suggest the potential of multi-isotope and advanced statistical approaches in combating organic fraud and ensuring authenticity in the food supply chain.

Histopathologic Change in the Anterior Part of the Posterior Fixation Suture After a Faden Operation in an Animal Model.

PURPOSE: To observe postoperative histological changes in the anterior part of the posterior fixation suture after a Faden operation in an animal model. METHODS: A posterior fixation suture was placed at two points 6 mm posterior to the insertion of the extraocular muscle on the superior rectus muscle of the right eye in eight rabbits. The superior rectus muscle of the left eye was used as a control. The eyes were enucleated and the anterior portion of the posterior fixation suture, including the myoscleral junction, was extracted 4 weeks after surgery. Postoperative adhesion was graded from 0 to 4 based on histologic findings (hematoxylin-eosin and Masson's trichrome staining). RESULTS: Histological evaluation revealed diffuse fibrosis at the myoscleral junction and the anterior part of the posterior fixation suture after the Faden operation. The graded scores for fibrosis, acute inflammation, chronic inflammation, and foreign body reactions in the Faden operation group were significantly higher than those in the control group (P < .05). Postoperative diffuse fibrosis of the myoscleral junction and anterior-to-posterior fixation sutures were observed in an animal model. CONCLUSIONS: Histologic changes may affect ocular alignment and motility, making reoperation unpredictable after the Faden procedure. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XX-XX.].

Introduction to the feature issue: Advances in Optical Biosensors for Biomedical Applications.

The feature issue of Biomedical Optics Express titled "Advances in Optical Biosensors for Biomedical Applications" presents a comprehensive collection of cutting-edge optical biosensor research. With the growing demand for sensitive, label-free, and real-time detection of biological analytes, optical biosensors have emerged as important devices in a wide range of biomedical applications, including medical diagnostics, bioanalysis, and personalised healthcare. This collection of 26 papers highlights recent advances and innovations in the development, design, and implementation of optical biosensors. The feature issue serves as an opportunity for disseminating ground-breaking findings, promoting new ideas, and inspiring further developments in optical biosensors for medical applications. The authors provide breakthrough technology, innovative approaches, and practical clinical applications that have the potential to revolutionize healthcare and biomedical research.

Human Pluripotent Stem Cell-Derived Retinal Organoids: A Viable Platform for Investigating the Efficacy of Adeno-Associated Virus Gene Therapy.

With recent advances in adeno-associated virus (AAV)-based gene therapy, efficacy and toxicity screening have become essential for developing gene therapeutic drugs for retinal diseases. Retinal organoids from human pluripotent stem cells (hPSCs) offer a more accessible and reproducible human test platform for evaluating AAV-based gene therapy. In this study, hPSCs were differentiated into retinal organoids composed of various types of retinal cells. The transduction efficiencies of AAV2 and AAV8, which are widely used in clinical trials of inherited retinal diseases, were analyzed using retinal organoids. These results suggest that retinal organoids derived from hPSCs serve as suitable screening platforms owing to their diverse retinal cell types and similarity to the human retina. In summary, we propose an optimal stepwise protocol that includes the generation of retinal organoids and analysis of AAV transduction efficacy, providing a comprehensive approach for evaluating AAV-based gene therapy for retinal diseases.

Association of exposure to indoor molds and dampness with allergic diseases at water-damaged dwellings in Korea.

This study aims to characterize levels of molds, bacteria, and environmental pollutants, identify the associations between indoor mold and dampness exposures and childhood allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, using three different exposure assessment tools. A total of 50 children with their parents who registered in Seoul and Gyeonggi-do in Korea participated in this study. We collated the information on demographic and housing characteristics, environmental conditions, and lifestyle factors using the Korean version of the International Study of Asthma and Allergies in Childhood questionnaire. We also collected environmental monitoring samples of airborne molds and bacteria, total volatile organic compounds, formaldehyde, and particulate matter less than 10 µm. We evaluated and determined water damage, hidden dampness, and mold growth in dwellings using an infrared (IR) thermal camera and field inspection. Univariate and multivariate regression analyses were performed to evaluate the associations between prevalent allergic diseases and exposure to indoor mold and dampness. Indoor mold and bacterial levels were related to the presence of water damage in dwellings, and the mean levels of indoor molds (93.4 ± 73.5 CFU/m3) and bacteria (221.5 ± 124.2 CFU/m3) in water-damaged homes were significantly higher than those for molds (82.0 ± 58.7 CFU/m3) and for bacteria (152.7 ± 82.1 CFU/m3) in non-damaged dwellings (p < 0.05). The crude odds ratios (ORs) of atopic dermatitis were associated with < 6th floor (OR = 3.80), and higher indoor mold (OR = 6.42) and bacterial levels (OR = 6.00). The crude ORs of allergic diseases, defined as a group of cases who ever suffered from two out of three allergic diseases, e.g., asthma and allergic rhinitis, and allergic rhinitis were also increased by 3.8 and 9.3 times as large, respectively, with water damage (+) determined by IR camera (p < 0.05). The adjusted OR of allergic rhinitis was significantly elevated by 10.4 times in the water-damaged dwellings after adjusting age, sex, and secondhand smoke. Therefore, a longitudinal study is needed to characterize dominant mold species using DNA/RNA-based sequencing techniques and identify a causal relationship between mold exposure and allergic diseases in the future.

Recent Developments in (K, Na)NbO3-Based Lead-Free Piezoceramics.

(K0.5Na0.5)NbO3 (KNN)-based ceramics have been extensively investigated as replacements for Pb(Zr, Ti)O3-based ceramics. KNN-based ceramics exhibit an orthorhombic structure at room temperature and a rhombohedral-orthorhombic (R-O) phase transition temperature (TR-O), orthorhombic-tetragonal (O-T) phase transition temperature (TO-T), and Curie temperature of -110, 190, and 420 °C, respectively. Forming KNN-based ceramics with a multistructure that can assist in domain rotation is one technique for enhancing their piezoelectric properties. This review investigates and introduces KNN-based ceramics with various multistructures. A reactive-templated grain growth method that aligns the grains of piezoceramics in a specific orientation is another approach for improving the piezoelectric properties of KNN-modified ceramics. The piezoelectric properties of the [001]-textured KNN-based ceramics are improved because their microstructures are similar to those of the [001]-oriented single crystals. The improvement in the piezoelectric properties after [001] texturing is largely influenced by the crystal structure of the textured ceramics. In this review, [001]-textured KNN-based ceramics with different crystal structures are investigated and systematically summarized.

Comparative study for metabolomics, antioxidant activity, and molecular docking simulation of the newly bred Korean red rice accessions.

This study analyzed the metabolite profiles and antioxidant capacities of two waxy and non-waxy Korean red rice accessions newly bred. Fifteen phenolic compounds were detected in the rice samples. Accession1 had high fatty acids, phytosterols, and vitamin E; accession3 had high vitamin E and phytosterol; and accession4 had a high total flavonoid. The correlation analysis findings from this study validated the positive association between all the metabolites and antioxidant activity. in silico results revealed that protocatechuic acid had a docking score of -9.541, followed by luteolin, quercetin, and caffeic acid, all of which had significant docking scores and a significant number of contacts. Similarly, molecular dynamics simulations showed that phytochemicals had root mean square deviation values of <2.8 Å with Keap 1, indicating better stability. This study provides valuable insights into potential directions for future investigations and improvements in the functional qualities of other colored rice varieties.

Corrosion behavior of Ti-Pt-coated stainless steel for bipolar plates in polymer electrolyte membranes under water electrolysis conditions.

In this study, the corrosion behavior and degradation mechanism of Ti-Pt-coated stainless steel bipolar plates were investigated through electrochemical tests and surface analysis in a polymer electrolyte membrane water electrolysis (PEMWE) operating environment. The coated bipolar plate has a corrosion current density of only 1.68 × 10-8 A/cm2, which is an order of magnitude lower than that of the bare SS316L substrate (1.94 × 10-7 A/cm2), indicating that its corrosion resistance is superior to that of bare SS316L substrate. However, in the PEMWE operating environment, the protection efficiency of the coating and the corrosion resistance of the coated bipolar plate decreased. The degradation of the coated bipolar plate can be attributed to electrolyte penetration into the blistering areas of the coating layer with micro voids. Defects in the coating layer occur because of the pressure of oxygen gas generated within the coating layer under high-potential conditions, thereby exposing the substrate to the electrolyte and corrosion.

Comparison of Surgical Outcomes of Two New Techniques Complementing Robotic Single-Site Myomectomy: Coaxial Robotic Single-Site Myomectomy vs. Hybrid Robotic Single-Site Myomectomy.

BACKGROUND: This study aimed to compare surgical outcomes between two new robotic single-site myomectomy (RSSM)-complementary techniques: coaxial robotic single-site myomectomy (Coaxial-RSSM) and hybrid robotic single-site myomectomy (Hybrid-RSSM). METHODS: Medical records for 132 women undergoing Coaxial-RSSM and 150 undergoing Hybrid-RSSM, consecutively, were retrospectively reviewed. Patient characteristics and surgical outcomes were assessed and compared after propensity score matching (PSM). RESULTS: In the outcomes of PSM, the Coaxial-RSSM group showed significantly reduced blood loss (79.71 vs. 163.75 mL, p < 0.001) and reduced hospital duration (4.18 ± 0.62 vs. 4.63 ± 0.90) relative to the Hybrid-RSSM group. Conversely, Hybrid-RSSM allowed for a shorter operative time compared with Coaxial-RSSM (119.19 vs. 156.01 min, p = 0.007). No conversions to conventional laparoscopy or laparotomy or any need for the multi-site robotic approach occurred in either group. Postoperative complications, including ileus, fever, and wound dehiscence, showed no statistically significant differences between the two groups. CONCLUSIONS: Blood loss was lower with Coaxial-RSSM, and operative time was shorter for Hybrid-RSSM. A follow-up prospective study is warranted for more comprehensive comparison of surgical outcomes between the two techniques.

Physical Unclonable Functions Employing Circularly Polarized Light Emission from Nematic Liquid Crystal Ordering Directed by Helical Nanofilaments.

This study proposes the use of physical unclonable functions employing circularly polarized light emission (CPLE) from nematic liquid crystal (NLC) ordering directed by helical nanofilaments in a mixed system composed of a calamitic NLC mixture and a bent-core molecule. To achieve this, an intrinsically nonemissive NLC is blended with a high concentration of a luminescent rod-like dye, which is miscible up to 10 wt % in the calamitic NLC without a significant decrease in the degree of alignment. The luminescence dissymmetry factor of CPLEs in the mixed system strongly depends on the degree of alignment of the dye-doped NLCs. Furthermore, the mixed system prepared in this study exhibits two randomly generated chiral domains with CPLEs of opposite signs. These chiral domains are characterized not only by their CPLE performances but also by their ability to generate random patterns up to several millimeters, making them promising candidates for high-performance secure authentication applications.