The prognostic utility of Lactate/Albumin*Age score in septic patient with normal lactate level.

Background: A previous study has shown that the lactate/albumin*age (LAA) score is useful for predicting mortality in patients with sepsis admitted to the ICU. We aimed to evaluate the clinical significance of the LAA score in patients with sepsis who presented to the emergency department (ED). Methods: This retrospective observational study used data from the Korean Shock Society Registry collected between January 2017 and December 2021. The prognostic performance of the LAA score for predicting the 28-day mortality was evaluated. Lactate and albumin levels were measured immediately after arrival to the ED. Results: Of the 5346 patients with sepsis, data from 3240 were analyzed. The area under the receiver operating characteristic curve (AUROC) of the LAA score (0.737, 95 % confidence interval (CI) 0.716-0.757), was higher than that of lactate (0.699, 95 % CI 0.677-0.720, p < 0.001), lactate/albumin (LA) ratio (0.730, 95 % CI 0.709-0.751, p = 0.016), and Sequential Organ Failure Assessment (SOFA) score (0.698, 95 % confidence interval 0.676-0.720, p = 0. 004), and Acute Physiology and Chronic Health Evaluation (APACHE) II scores (0.672; 95 % confidence interval 0.649-0.694, p < 0.001). The optimal cut-off value for the LAA score was 119.9. In the Kaplan-Meier analysis according to the optimal cutoff value, the 28-day mortality rates were higher in the high LAA score group (log-rank test, p < 0.001). The LAA score was independently associated with 28-day mortality in the multivariate Cox proportional hazards model (adjusted hazard ratio 2.07, 95 % CI 1.76-2.43, p < 0.001). In the normal (<2 mmol/L) lactate group, the AUROC value for LAA score was higher than LA ratio (normal group 0.674 vs 0.634, p < 0.004). In patients over 65 years old, LAA score (0.731) showed a higher AUROC value than LA ratio (0.725). (p < 0.001). Conclusion: The LAA score may be used as an independent predictor of mortality in patients with sepsis in the emergency department. Our results show that it performs better than serum lactate alone, LA ratio, and SOFA and APACHE II scores. While this suggests that the LAA could provide clinicians with a useful tool for timely early intervention and care planning in patients with a poor prognosis, further validation in large multicenter prospective studies are necessary to confirm its reliability and practicality as a readily available and objective biomarker.

The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive type of cancer in the brain and has an inferior prognosis because of the lack of suitable medicine, largely due to its tremendous invasion. GBM has selfish metabolic pathways to promote migration, invasion, and proliferation compared to normal cells. Among various metabolic pathways, NAD (nicotinamide adenine dinucleotide) is essential in generating ATP and is used as a resource for cancer cells. LbNOX (Lactobacillus brevis NADH oxidase) is an enzyme that can directly manipulate the NAD+/NADH ratio. In this study, we found that an increased NAD+/NADH ratio by LbNOX or mitoLbNOX reduced intracellular glutamate and calcium responses and reduced invasion capacity in GBM. However, the invasion was not affected in GBM by rotenone, an ETC (Electron Transport Chain) complex I inhibitor, or nicotinamide riboside, a NAD+ precursor, suggesting that the crucial factor is the NAD+/NADH ratio rather than the absolute quantity of ATP or NAD+ for the invasion of GBM. To develop a more accurate and effective GBM treatment, our findings highlight the importance of developing a new medicine that targets the regulation of the NAD+/NADH ratio, given the current lack of effective treatment options for this brain cancer.

Histological Assessment and Interobserver Agreement in Major Pathologic Response for Non-Small Cell Lung Cancer with Neoadjuvant Therapy.

Purpose: Major pathologic response (MPR), defined as ≤10% of residual viable tumor (VT), is a prognostic factor in non-small cell lung cancer (NSCLC) after neoadjuvant therapy. This study evaluated interobserver reproducibility in assessing MPR, compared area-weighted and unweighted VT (%) calculation, and determined optimal VT (%) cutoffs across histologic subtypes for survival prediction. Materials and Methods: This retrospective study included 108 patients with NSCLC who underwent surgical resection after neoadjuvant chemotherapy or chemoradiation at Seoul National University Bundang Hospital between 2009-2018. Three observers with varying expertise independently assessed tumor bed and VT (%) based on digital whole-slide images. Results: Reproducibility in tumor bed delineation was reduced in squamous cell carcinoma (SqCC) with smaller tumor bed, although overall concordance was high (Dice coefficient, 0.96; IoU score, 0.92). Excellent agreement was achieved for VT (%) (ICC=0.959) and MPR using 10% cutoff (Fleiss' kappa=0.911). Shifting between area-weighted and unweighted VT (%) showed only one case differing in MPR status out of 81 cases. The optimal cutoff was 10% for both adenocarcinoma (ADC) and SqCC. MPR+ was observed in 18 patients (17%), with SqCC showing higher MPR+ rates (p=0.044), lower VT (%) (p<0.001), and better event-free survival (p=0.015) than ADC. MPR+ significantly improved overall survival (p=0.023), event-free survival (p=0.001), and lung cancer-specific survival (p=0.012). Conclusion: While MPR assessment demonstrated robust reproducibility with minimal impact from the tumor bed, attention is warranted when evaluating smaller tumor beds in SqCC. A 10% cutoff reliably predicted survival across histologic subtypes with higher interobserver reproducibility.

Activity-based protein profiling and global proteome analysis reveal MASTL as a potential therapeutic target in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases. METHODS: We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data. RESULTS: Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells. CONCLUSIONS: Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.

Development of a Web-Based Interactive Tool for Visualizing Breast Cancer Clinical Trial Tolerability Data.

PURPOSE: Longitudinal patient tolerability data collected as part of randomized controlled trials are often summarized in a way that loses information and does not capture the treatment experience. To address this, we developed an interactive web application to empower clinicians and researchers to explore and visualize patient tolerability data. METHODS: We used adverse event (AE) data (Common Terminology Criteria for Adverse Events) and patient-reported outcomes (PROs) from the NSABP-B35 phase III clinical trial, which compared anastrozole with tamoxifen for breast cancer-free survival, to demonstrate the tools. An interactive web application was developed using R and the Shiny web application framework that generates Sankey diagrams to visualize AEs and PROs using four tools: AE Explorer, PRO Explorer, Cohort Explorer, and Custom Explorer. RESULTS: To illustrate how users can use the interactive tool, examples for each of the four applications are presented using data from the NSABP-B35 phase III trial and the NSABP-B30 trial for the Custom Explorer. In the AE and PRO explorers, users can select AEs or PROs to visualize within specified time periods and compare across treatments. In the cohort explorer, users can select a subset of patients with a specific symptom, severity, and treatment received to visualize the trajectory over time within a specified time interval. With the custom explorer, users can upload and visualize structured longitudinal toxicity and tolerability data. CONCLUSION: We have created an interactive web application and tool for clinicians and researchers to explore and visualize clinical trial tolerability data. This adaptable tool can be extended for other clinical trial data visualization and incorporated into future patient-clinician interactions regarding treatment decisions.

Surface-binding molecular multipods strengthen the halide perovskite lattice and boost luminescence.

Reducing the size of perovskite crystals to confine excitons and passivating surface defects has fueled a significant advance in the luminescence efficiency of perovskite light-emitting diodes (LEDs). However, the persistent gap between the optical limit of electroluminescence efficiency and the photoluminescence efficiency of colloidal perovskite nanocrystals (PeNCs) suggests that defect passivation alone is not sufficient to achieve highly efficient colloidal PeNC-LEDs. Here, we present a materials approach to controlling the dynamic nature of the perovskite surface. Our experimental and theoretical studies reveal that conjugated molecular multipods (CMMs) adsorb onto the perovskite surface by multipodal hydrogen bonding and van der Waals interactions, strengthening the near-surface perovskite lattice and reducing ionic fluctuations which are related to nonradiative recombination. The CMM treatment strengthens the perovskite lattice and suppresses its dynamic disorder, resulting in a near-unity photoluminescence quantum yield of PeNC films and a high external quantum efficiency (26.1%) of PeNC-LED with pure green emission that matches the Rec.2020 color standard for next-generation vivid displays.

Development of an Automated Free Flap Monitoring System Based on Artificial Intelligence.

Importance: Meticulous postoperative flap monitoring is essential for preventing flap failure and achieving optimal results in free flap operations, for which physical examination has remained the criterion standard. Despite the high reliability of physical examination, the requirement of excessive use of clinician time has been considered a main drawback. Objective: To develop an automated free flap monitoring system using artificial intelligence (AI), minimizing human involvement while maintaining efficiency. Design, Setting, and Participants: In this prognostic study, the designed system involves a smartphone camera installed in a location with optimal flap visibility to capture photographs at regular intervals. The automated program identifies the flap area, checks for notable abnormalities in its appearance, and notifies medical staff if abnormalities are detected. Implementation requires 2 AI-based models: a segmentation model for automatic flap recognition in photographs and a grading model for evaluating the perfusion status of the identified flap. To develop this system, flap photographs captured for monitoring were collected from patients who underwent free flap-based reconstruction from March 1, 2020, to August 31, 2023. After the 2 models were developed, they were integrated to construct the system, which was applied in a clinical setting in November 2023. Exposure: Conducting the developed automated AI-based flap monitoring system. Main Outcomes and Measures: Accuracy of the developed models and feasibility of clinical application of the system. Results: Photographs were obtained from 305 patients (median age, 62 years [range, 8-86 years]; 178 [58.4%] were male). Based on 2068 photographs, the FS-net program (a customized model) was developed for flap segmentation, demonstrating a mean (SD) Dice similarity coefficient of 0.970 (0.001) with 5-fold cross-validation. For the flap grading system, 11 112 photographs from the 305 patients were used, encompassing 10 115 photographs with normal features and 997 with abnormal features. Tested on 5506 photographs, the DenseNet121 model demonstrated the highest performance with an area under the receiver operating characteristic curve of 0.960 (95% CI, 0.951-0.969). The sensitivity for detecting venous insufficiency was 97.5% and for arterial insufficiency was 92.8%. When applied to 10 patients, the system successfully conducted 143 automated monitoring sessions without significant issues. Conclusions and Relevance: The findings of this study suggest that a novel automated system may enable efficient flap monitoring with minimal use of clinician time. It may be anticipated to serve as an effective surveillance tool for postoperative free flap monitoring. Further studies are required to verify its reliability.

SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.

OBJECTIVE: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. METHODS: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. RESULTS: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. INTERPRETATION: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024.

Overall side effect assessment of oxaliplatin toxicity in rectal cancer patients in NRG oncology/NSABP R04.

PURPOSE: Regulatory guidance suggests capturing patient-reported overall side effect impact in cancer trials. We examined whether the Functional Assessment of Cancer Therapy (FACT) GP5 item ("I am bothered by side effects of treatment") post-neoadjuvant chemotherapy/radiotherapy differed between oxaliplatin vs. non- oxaliplatin arms in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial of stage II-III rectal cancer patients. METHODS: The R-04 neoadjuvant trial compared local-regional tumor control between patients randomized to receive 5-fluorouracil or capecitabine with radiation, with or without oxaliplatin (4 treatment arms). Participants completed surveys at baseline and immediately after chemoradiotherapy. GP5 has a 5-point response scale: "Not at all" (0), "A little bit" (1), "Somewhat" (2), "Quite a bit" (3), and "Very much" (4). Logistic regression compared the odds of reporting moderate-high side effect impact (GP5 2-4) between patients receiving oxaliplatin or not after chemoradiotherapy, controlling for relevant patient characteristics. We examined associations between GP5 and other patient-reported outcomes reflecting side effects. RESULTS: Analyses were performed among 1132 study participants. Participants receiving oxaliplatin were 1.58 times (95% CI: 1.22-2.05) more likely to report moderate-high side effect bother at post-chemotherapy/radiation. In both arms, worse overall side effect impact was associated with patient-reported diarrhea, nausea, vomiting, and peripheral sensory neuropathy (p < 0.01 for all). CONCLUSION: This secondary analysis of R-04 found that GP5 distinguished between patients receiving oxaliplatin or not as part of their post-neoadjuvant chemoradiotherapy, adding patient-centric evidence on the reduced tolerability of oxaliplatin and demonstrating that GP5 is sensitive to known toxicity differences between treatments. CLINICALTRIALS: GOV: NCT00058474.

Deep-learning-based segmentation using individual patient data on prostate cancer radiation therapy.

PURPOSE: Organ-at-risk segmentation is essential in adaptive radiotherapy (ART). Learning-based automatic segmentation can reduce committed labor and accelerate the ART process. In this study, an auto-segmentation model was developed by employing individual patient datasets and a deep-learning-based augmentation method for tailoring radiation therapy according to the changes in the target and organ of interest in patients with prostate cancer. METHODS: Two computed tomography (CT) datasets with well-defined labels, including contoured prostate, bladder, and rectum, were obtained from 18 patients. The labels of the CT images captured during radiation therapy (CT2nd) were predicted using CT images scanned before radiation therapy (CT1st). From the deformable vector fields (DVFs) created by using the VoxelMorph method, 10 DVFs were extracted when each of the modified CT and CT2nd images were deformed and registered to the fixed CT1st image. Augmented images were acquired by utilizing 110 extracted DVFs and spatially transforming the CT1st images and labels. An nnU-net autosegmentation network was trained by using the augmented images, and the CT2nd label was predicted. A patient-specific model was created for 18 patients, and the performances of the individual models were evaluated. The results were evaluated by employing the Dice similarity coefficient (DSC), average Hausdorff distance, and mean surface distance. The accuracy of the proposed model was compared with those of models trained with large datasets. RESULTS: Patient-specific models were developed successfully. For the proposed method, the DSC values of the actual and predicted labels for the bladder, prostate, and rectum were 0.94 ± 0.03, 0.84 ± 0.07, and 0.83 ± 0.04, respectively. CONCLUSION: We demonstrated the feasibility of automatic segmentation by employing individual patient datasets and image augmentation techniques. The proposed method has potential for clinical application in automatic prostate segmentation for ART.

High-Throughput 3D-Printed Model of the Feto-Maternal Interface for the Discovery and Development of Preterm Birth Therapies.

Spontaneous preterm birth (PTB) affects around 11% of births, posing significant risks to neonatal health due to the inflammation at the fetal-maternal interface (FMi). This inflammation disrupts immune tolerance during pregnancy, often leading to PTB. While organ-on-a-chip (OOC) devices effectively mimic the physiology, pathophysiology, and responses of FMi, their relatively low throughput limits their utility in high-throughput testing applications. To overcome this, we developed a three-dimensional (3D)-printed model that fits in a well of a 96-well plate and can be mass-produced while also accurately replicating FMi, enabling efficient screening of drugs targeting FMi inflammation. Our model features two cell culture chambers (maternal and fetal cells) interlinked via an array of microfluidic channels. It was thoroughly validated, ensuring cell viability, metabolic activity, and cell-specific markers. The maternal chamber was exposed to lipopolysaccharides (LPS) to induce an inflammatory state, and proinflammatory cytokines in the culture supernatant were quantified. Furthermore, the efficacy of anti-inflammatory inhibitors in mitigating LPS-induced inflammation was investigated. Results demonstrated that our model supports robust cell growth, maintains viability, and accurately mimics PTB-associated inflammation. This high-throughput 3D-printed model offers a versatile platform for drug screening, promising advancements in drug discovery and PTB prevention.

A dynamic flow fetal membrane organ-on-a-chip system for modeling the effects of amniotic fluid motion.

Fetal membrane (amniochorion), the innermost lining of the intrauterine cavity, surround the fetus and enclose amniotic fluid. Unlike unidirectional blood flow, amniotic fluid subtly rocks back and forth, and thus, the innermost amnion epithelial cells are continuously exposed to low levels of shear stress from fluid undulation. Here, we tested the impact of fluid motion on amnion epithelial cells (AECs) as a bearer of force impact and their potential vulnerability to cytopathologic changes that can destabilize fetal membrane functions. A previously developed amnion membrane (AM) organ-on-chip (OOC) was utilized but with dynamic flow to culture human fetal amnion membrane cells. The applied flow was modulated to perfuse culture media back and forth for 48 h to mimic fluid motion. A static culture condition was used as a negative control, and oxidative stress (OS) condition was used as a positive control representing pathophysiological changes. The impacts of fluidic motion were evaluated by measuring cell viability, cellular transition, and inflammation. Additionally, scanning electron microscopy (SEM) imaging was performed to observe microvilli formation. The results show that regardless of the applied flow rate, AECs and AMCs maintained their viability, morphology, innate meta-state, and low production of pro-inflammatory cytokines. E-cadherin expression and microvilli formation in the AECs were upregulated in a flow rate-dependent fashion; however, this did not impact cellular morphology or cellular transition or inflammation. OS treatment induced a mesenchymal morphology, significantly higher vimentin to cytokeratin 18 (CK-18) ratio, and pro-inflammatory cytokine production in AECs, whereas AMCs did not respond in any significant manner. Fluid motion and shear stress, if any, did not impact AEC cell function and did not cause inflammation. Thus, when using an amnion membrane OOC model, the inclusion of a dynamic flow environment is not necessary to mimic in utero physiologic cellular conditions of an amnion membrane.

Ultrasmall 2D Sn-Doped MAPbBr3 Nanoplatelets Enable Bright Pure-Blue Emission.

Synthesis of perovskites that exhibit pure-blue emission with high photoluminescence quantum yield (PLQY) in both nanocrystal solutions and nanocrystal-only films presents a significant challenge. In this work, a room-temperature method is developed to synthesize ultrasmall, monodispersed, Sn-doped methylammonium lead bromide (MAPb1- xSnxBr3) perovskite nanoplatelets (NPLs) in which the strong quantum confinement effect endows pure blue emission (460 nm) and a high quantum yield (87%). Post-treatment using n-hexylammonium bromide (HABr) repaired surface defects and thus substantially increased the stability and PLQY (80%) of the NPL films. Concurrently, high-precision patterned films (200-µm linewidth) are successfully fabricated by using cost-effective spray-coating technology. This research provides a novel perspective for the preparation of high PLQY, highly stable, and easily processable perovskite nanomaterials.

Thigh muscle mass evaluated by point-of-care ultrasound is associated with short-term mortality in patients with sepsis in the emergency department.

Muscle mass depletion is associated with mortality and morbidity in various conditions including sepsis. However, few studies have evaluated muscle mass using point-of-care ultrasound in patients with sepsis. This study aimed to evaluate the association between thigh muscle mass, evaluated using point-of-care ultrasound with panoramic view in patients with sepsis in the emergency department, and mortality. From March 2021 to October 2022, this prospective observational study used sepsis registry. Adult patients who were diagnosed with sepsis at the emergency department and who underwent point-of-care ultrasounds for lower extremities were included. The thigh muscle mass was evaluated by the cross-sectional area of the quadriceps femoris (CSA-QF) on point-of-care ultrasound using panoramic view. The primary outcome was 28 day mortality. Multivariable Cox proportional hazard model was performed. Of 112 included patients with sepsis, mean CSA-QF was significantly lower in the non-surviving group than surviving group (49.6 [34.3-56.5] vs. 63.2 [46.9-79.6] cm2, p = 0.002). Each cm2 increase of mean CSA-QF was independently associated with decreased 28 day mortality (adjusted hazard ratio 0.961, 95% CI 0.928-0.995, p = 0.026) after adjustment for potential confounders. The result of other measurements of CSA-QF were similar. The muscle mass of the quadriceps femoris evaluated using point-of-care ultrasound with panoramic view was associated with mortality in patients with sepsis. It might be a promising tool for determining risk factors for mortality in sepsis patients in the early stages of emergency department.

A multi-organ, feto-maternal interface organ-on-chip, models pregnancy pathology and is a useful preclinical extracellular vesicle drug trial platform.

Pregnant women and their fetuses are often excluded from clinical trials due to missing drug-related pre-clinical trial information at the human feto-maternal interface (FMi). The two interfaces-placenta/decidua and fetal membranes/decidua are gatekeepers of drug transport; however, testing their functions is impractical during pregnancy. Limitations of current in-vivo/in-vitro models have hampered drug development and testing during pregnancy. Hence, major complications like preterm births and maternal and neonatal mortalities remain high. Advancements in organ-on-chip (OOC) platforms to test drug kinetics and efficacy and novel extracellular vesicle-based fetal drug delivery are expected to accelerate preclinical trials related to pregnancy complications. Here we report the development and testing of a humanized multi-organ fetal membrane/placenta (fetal)-decidua (maternal) interface OOC (FMi-PLA-OOC) that contains seven cell types interconnected through microchannels to maintain intercellular interactions as seen in-utero. Cytotoxicity, propagation, mechanism of action, and efficacy of engineered extracellular vesicles containing anti-inflammatory interleukin (IL)-10 (eIL-10) were evaluated to reduce FMi inflammation associated with preterm birth. A healthy and disease model (lipopolysaccharide-infectious inflammation) of the FMi-PLA-OOC was created and co-treated with eIL-10. eIL-10 propagated from the maternal to fetal side within 72-hours, localized in all cell types, showed no cytotoxicity, activated IL-10 signaling pathways, and reduced lipopolysaccharide-induced inflammation (minimized NF-kB activation and proinflammatory cytokine production). These data recapitulated eIL-10s' ability to reduce inflammation and delay infection-associated preterm birth in mouse models, suggesting FMi-PLA-OOC as an alternative approach to using animal models. Additionally, we report the utility of eIL-10 that can traverse through FMis to reduce inflammation-associated pregnancy complications.

A Dynamic Flow Fetal Membrane Organ-on-a-Chip System for Modeling the Effects of Amniotic Fluid Motion.

Fetal membrane(amniochorion), the innermost lining of the intrauterine cavity, surround the fetus and enclose amniotic fluid. Unlike unidirectional blood flow, amniotic fluid subtly rocks back and forth, and thus, the innermost amnion epithelial cells are continuously exposed to low levels of shear stress from fluid undulation. Here, we tested the impact of fluid motion on amnion epithelial cells (AECs) as a bearer of force impact and their potential vulnerability to cytopathologic changes that can destabilize fetal membrane functions. An amnion membrane (AM) organ-on-chip (OOC) was utilized to culture human fetal amnion membrane cells. The applied flow was modulated to perfuse culture media back and forth for 48 hours flow culture to mimic fluid motion. Static culture condition was used as a negative control, and oxidative stress (OS) condition was used as a positive control for pathophysiological changes. The impacts of fluidic motion were evaluated by measuring cell viability, cellular transition, and inflammation. Additionally, scanning electron microscopy (SEM) imaging was performed to observe microvilli formation. The results show that regardless of the applied flow rate, AECs and AMCs maintained their viability, morphology, innate meta-state, and low production of pro-inflammatory cytokines. E-cadherin expression and microvilli formation in the AECs were upregulated in a flow rate-dependent fashion; however, this did not impact cellular morphology or cellular transition or inflammation. OS treatment induced a mesenchymal morphology, significantly higher vimentin to CK-18 ratio, and pro-inflammatory cytokine production in AECs, whereas AMCs did not respond in any significant manner. Fluid motion and shear stress, if any, did not impact AEC cell function and did not cause inflammation. Thus, when using an amnion membrane OOC model, the inclusion of a flow culture environment is not necessary to mimic any in utero physiologic cellular conditions of fetal membrane-derived cells.

Uniform sized cancer spheroids production using hydrogel-based droplet microfluidics: a review.

Three-dimensional (3D) cell culture models have been extensively utilized in various mechanistic studies as well as for drug development studies as superior in vitro platforms than conventional two-dimensional (2D) cell culture models. This is especially the case in cancer biology, where 3D cancer models, such as spheroids or organoids, have been utilized extensively to understand the mechanisms of cancer development. Recently, many sophisticated 3D models such as organ-on-a-chip models are emerging as advanced in vitro models that can more accurately mimic the in vivo tissue functions. Despite such advancements, spheroids are still considered as a powerful 3D cancer model due to the relatively simple structure and compatibility with existing laboratory instruments, and also can provide orders of magnitude higher throughput than complex in vitro models, an extremely important aspects for drug development. However, creating well-defined spheroids remain challenging, both in terms of throughputs in generation as well as reproducibility in size and shape that can make it challenging for drug testing applications. In the past decades, droplet microfluidics utilizing hydrogels have been highlighted due to their potentials. Importantly, core-shell structured gel droplets can avoid spheroid-to-spheroid adhesion that can cause large variations in assays while also enabling long-term cultivation of spheroids with higher uniformity by protecting the core organoid area from external environment while the outer porous gel layer still allows nutrient exchange. Hence, core-shell gel droplet-based spheroid formation can improve the predictivity and reproducibility of drug screening assays. This review paper will focus on droplet microfluidics-based technologies for cancer spheroid production using various gel materials and structures. In addition, we will discuss emerging technologies that have the potential to advance the production of spheroids, prospects of such technologies, and remaining challenges.

Enhancing Genomic Prediction Accuracy for Body Conformation Traits in Korean Holstein Cattle.

The Holstein breed is the mainstay of dairy production in Korea. In this study, we evaluated the genomic prediction accuracy for body conformation traits in Korean Holstein cattle, using a range of π levels (0.75, 0.90, 0.99, and 0.995) in Bayesian methods (BayesB and BayesC). Focusing on 24 traits, we analyzed the impact of different π levels on prediction accuracy. We observed a general increase in accuracy at higher levels for specific traits, with variations depending on the Bayesian method applied. Notably, the highest accuracy was achieved for rear teat angle when using deregressed estimated breeding values including parent average as a response variable. We further demonstrated that incorporating parent average into deregressed estimated breeding values enhances genomic prediction accuracy, showcasing the effectiveness of the model in integrating both offspring and parental genetic information. Additionally, we identified 18 significant window regions through genome-wide association studies, which are crucial for future fine mapping and discovery of causal mutations. These findings provide valuable insights into the efficiency of genomic selection for body conformation traits in Korean Holstein cattle and highlight the potential for advancements in the prediction accuracy using larger datasets and more sophisticated genomic models.

Vertically Stackable Ovonic Threshold Switch Oscillator Using Atomic Layer Deposited Ge0.6Se0.4 Film for High-Density Artificial Neural Networks.

Nanodevice oscillators (nano-oscillators) have received considerable attention to implement in neuromorphic computing as hardware because they can significantly improve the device integration density and energy efficiency compared to complementary metal oxide semiconductor circuit-based oscillators. This work demonstrates vertically stackable nano-oscillators using an ovonic threshold switch (OTS) for high-density neuromorphic hardware. A vertically stackable Ge0.6Se0.4 OTS-oscillator (VOTS-OSC) is fabricated with a vertical crossbar array structure by growing Ge0.6Se0.4 film conformally on a contact hole structure using atomic layer deposition. The VOTS-OSC can be vertically integrated onto peripheral circuits without causing thermal damage because the fabrication temperature is <400 °C. The fabricated device exhibits oscillation characteristics, which can serve as leaky integrate-and-fire neurons in spiking neural networks (SNNs) and coupled oscillators in oscillatory neural networks (ONNs). For practical applications, pattern recognition and vertex coloring are demonstrated with SNNs and ONNs, respectively, using semiempirical simulations. This structure increases the oscillator integration density significantly, enabling complex tasks with a large number of oscillators. Moreover, it can enhance the computational speed of neural networks due to its rapid switching speed.

Causal impact analysis of weir opening on cyanobacterial blooms and water quality in the Yeongsan River, Korea: A bayesian structural time-series analysis and median difference test.

The construction of weirs in Korea's Four Major Rivers Project has led to an increase in cyanobacterial blooms, posing environmental challenges. To address this, the government began opening weirs in 2017. However, interpreting experimental results has proven to be complex due to the multifaceted nature of blooms. This study aimed to assess the impact of opening the Juksan Weir on cyanobacterial blooms and water quality in the Yeongsan River. Using a median difference test (MDT) and causal impact analysis (CIA) with Bayesian structural time-series (BSTS) models, changes in cyanobacterial cell density (Cyano) and chlorophyll a concentration (Chl-a) before (January 2013 to June 2017) and after (July 2017 to December 2021) the weir-opening event were analyzed. The MDT revealed no significant change in Cyano post-weir opening (p = 0.267), but Chl-a significantly increased by 48.1 % (p < 0.01). As a result of CIA, Cyano decreased, albeit statistically insignificantly (p = 0.454), while Chl-a increased by 59.0 % (p < 0.01). These findings contradict the expectation that Cyano decrease due to the increased flow velocity resulting from weir opening. The absence of changes in Cyano and the increase in Chl-a can be attributed to several factors, including the constrained and inadequate duration of full weir opening combined with conducive conditions for the proliferation of other algae such as diatoms and green algae. These findings suggest that the effectiveness of weir opening in controlling Cyano may have been compromised by factors influencing the overall aquatic ecosystem dynamics. Further analysis revealed that factors such as elevated water temperatures (≥ 30 °C) and reduced flow rates (< 37 m3/s) contributed to the flourishing of cyanobacteria, whose concentrations exceeded 10,000 cells/mL. In analyzing causal relationships in environmental management, especially when there are complex causal interactions, the application of MDT and CIA provides valuable insights.