Search Results (79)

Human-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) have been shown to be useful for the development of cell-based regenerative strategies and for modelling drug discovery. However, stem cell-derived HLCs are not identical in nature to primary human hepatocytes (PHHs), which could affect the cell phenotype and, potentially, model reliability. Therefore, we employed the in-depth gene expression profiling of HLCs and other important and relevant cell types, which led to the identification of clear similarities and differences between them at the transcriptional level. Through gene set enrichment analysis, we identified that genes that are critical for immune signalling pathways become downregulated upon HLC differentiation. Our analysis also found that TAV.HLCs exhibit a mild gene signature characteristic of acute lymphoblastic leukaemia, but not other selected cancers. Importantly, HLCs present significant similarity to PHHs, making them genuinely valuable for modelling human liver biology in vitro and for the development of prototype cell-based therapies for pre-clinical testing. Full article

Diabetes mellitus, especially type 2 diabetes mellitus (T2DM), is a major health problem worldwide and has become a leading cause of mortality. As a common complication of patients with T2DM, cardiac autonomic dysfunction (including sympathetic overactivation and reduced vagal tone) is associated with a higher risk of arrhythmia-related sudden cardiac death. Our previous study found that T2DM-elevated hydrogen peroxide (H₂O₂) levels in atrioventricular ganglion (AVG) neurons contribute to the decrease in cardiac vagal function and ventricular arrhythmogenesis through inhibition of N-type Ca²⁺ channels (Ca_v2.2). In the present study, treatment with exogenous H₂O₂ in differentiated NG108-15 cells increased REST expression and decreased Ca_v2.2-α expression. Adenoviral catalase gene transfection into the AVG neurons significantly reduced the REST levels elevated by a high-fat diet plus streptozotocin-induced T2DM. Lentiviral REST shRNA transfection markedly increased Ca_v2.2-α expression in the AVG neurons from T2DM rats. REST shRNA also activated N-type Ca²⁺ channels and increased cell excitability of AVG neurons in T2DM rats. Additionally, REST shRNA markedly improved cardiac vagal activation in T2DM rats. The present study suggests that the H₂O₂-REST-Ca_v2.2 channel signaling axis could be a potential therapeutic target to normalize cardiac vagal dysfunction and its related cardiac complications in T2DM. Full article

Assisted reproductive technology (ART)such as in vitro embryo culture (IVC), is widely used in human infertility treatments; however, its long-term effects on the cardiac health of offspring remain unclear. This study aimed to determine whether the effects of IVC on cardiac metabolism and associated signaling pathways persist after birth into adolescence. Embryos were either transferred to an intermediate ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) with methionine supplementation (IVCHS+M) for 6 days after mating. Naturally mated (NM) ewes were used as controls. Protein expression and hormone concentrations in the left ventricle (LV) were analyzed using Western blot and LC-MS/MS analyses, respectively. IVC was associated with sex-specific alterations in cardiac mitochondria, with males exhibiting reduced mitochondrial abundance. Cardiac protein expression of oxidative phosphorylation (OXPHOS) complexes 1 and 4 was reduced by IVC. Additionally, IVC reduced protein expression of PDK-4 and Mn-SOD in the IVCHS+M group, which may impact energy efficiency and defense against oxidative stress. These changes may predispose IVC offspring to cardiac oxidative stress and mitochondrial dysfunction, particularly in males. This study provides insights into the sex-dependent effects of IVC on cardiac health, emphasizing the importance of evaluating long-term cardiovascular risks associated with IVC protocols. Full article

Effective thermal management is essential for the safe and efficient operation of lithium-ion battery packs, particularly in compact, airflow-sensitive applications such as drones. This study presents a comprehensive thermal analysis of a 16-cell lithium-ion battery pack by exploring seven geometric configurations under airflow speeds ranging from 0 to 15 m/s and integrating nano-carbon-based phase change materials (PCMs) to enhance heat dissipation. A Computational Fluid Dynamics (CFD) approach was employed using Ansys Discovery and Workbench 2024 R1 to simulate airflow and heat transfer processes with high spatial resolution. Using high-fidelity 3D simulations, we found that the trapezoidal wide-base configuration, combined with a 5-inlet and 1-outlet airflow design, achieved the most balanced cooling performance across all speed regimes. This configuration maintained battery temperatures within the optimal operating range (∼45 °C) in both low- and high-speed airflow conditions, with a maximum temperature reduction of up to 8.3 °C compared to the standard square configuration. Additionally, PCM integration extended the thermal regulation duration to approximately 12.5 min, effectively buffering thermal spikes during peak loads. These findings underscore the critical role of CFD-driven geometric optimization and advanced material integration in designing high-efficiency, compact cooling systems for energy-dense battery applications in drones and portable electronics. Full article

The rapid development of UAV-LiDAR and data processing capabilities is likely to enable accurate individual-tree inventories in the near future, requiring few on-ground calibration measurements. Using data collected from 20 radiata pine trials dispersed across New Zealand, the objective of this study was to determine the accuracy of high-density UAV-LiDAR for the prediction of tree diameter and volume, under a range of data calibration scenarios. Using all measurements for the calibration (a range of 335–4703 tree measurements across the 20 sites), accurate random forest models for each of the 20 sites were created from a diverse range of LiDAR metrics that characterised the horizontal and vertical structures of the canopy. Averaged across the 20 sites, predictions had a mean R² and relative RMSE (rRMSE) of, respectively, 0.713 and 9.699% for the tree diameter and 0.746 and 19.57% for the tree volume. Reductions in the numbers of calibration trees per trial had little effect on model accuracy until only 300 trees/site were used; however, accurate, unbiased predictions were still possible using as few as 100 trees/site. More generally, applicable random forest models for both tree dimensions were constructed by collating all of the data and tested using leave-one-site-out cross-validation to determine the accuracy of the model predictions when calibration measurements were not available. The predictions using this approach were reasonable but less accurate and more biased than with the use of calibration data, with a mean R² and rRMSE of, respectively, 0.631 and 15.12% for the tree diameter and 0.631 and 35.6% for the volume. Our research aims to facilitate the transition from a plot-based to tree-level inventory in plantation forests and contribute to the future development of a generalised model that could accurately predict tree dimensions from UAV-LiDAR, relying on minimal field measurements. Full article

Human milk-derived extracellular vesicles (HMEVs) are key components in breast milk, promoting infant health and development. Maternal conditions could affect HMEV cargo; however, the impact of SARS-CoV-2 infection on HMEVs remains unknown. This study investigated the influence of SARS-CoV-2 infection during pregnancy on postpartum HMEV molecules. The median duration from SARS-CoV-2 test positivity to milk collection was 3 months. After defatting and casein micelle disaggregation, HMEVs were isolated from milk samples of nine mothers with prenatal SARS-CoV-2 and six controls by sequential centrifugation, ultrafiltration, and qEV-size exclusion chromatography. The presence of HMEV was confirmed via transmission electron microscopy. Nanoparticle tracking analysis demonstrated particle diameters of <200 nm and yields of >1 × 10¹¹ particles per mL of milk. Western immunoblots detected ALIX, CD9, and HSP70, supporting the presence of HMEVs in the isolates. Cargo from thousands of HMEVs were analyzed using a multi-omics approach, including proteomics and microRNA sequencing, and predicted that mothers with prenatal SARS-CoV-2 infection produced HMEVs with enhanced functionalities involving metabolic reprogramming, mucosal tissue development, and immunomodulation. Our findings suggest that SARS-CoV-2 infection during pregnancy boosts mucosal site-specific functions of HMEVs, potentially protecting infants against viral infections. Further prospective studies should be pursued to reevaluate the short- and long-term benefits of breastfeeding in the post-COVID era. Full article

Aeromonas species are enteropathogens that cause gastroenteritis with a unique three-peak infection pattern related to patient age. The contributions of individual Aeromonas species to age-related infections remain unknown. Multi-locus sequence typing (MLST) was performed to determine the species of Aeromonas strains from Australian patients with gastroenteritis. Public database searches were conducted to collect strains of enteric Aeromonas species, identified by either MLST or whole genome sequencing with known patient age. Violin plot analysis was performed to assess Aeromonas infection distribution across patients of different ages. Generalized additive model (GAM) analysis was employed to investigate the relationship between Aeromonas species and patient age. A total of 266 strains of seven Aeromonas species met the selection criteria, which were used for analyses. The violin plots revealed distinct patterns among individual Aeromonas species in relation to patient age. The GAM analyses identified a significant association between Aeromonas species and patient age (p = 0.009). Aeromonas veronii (153 strains) showed the highest probability of infection in most ages, particularly among young adults. Aeromonas caviae (59 strains) is more common in young children and adults over 60 years of age. The probability of infection for Aeromonas hydrophila (34 strains) and Aeromonas dhakensis (9 strains) was generally low, there was a slight increase in individuals aged 50–60 for A. hydrophila and over 60 years for A. dhakensis. These findings provide novel evidence of the varied contributions of different Aeromonas species to human enteric infections related to patient age, offering valuable insights for epidemiology and clinical management. Full article

Background: Bispecific antibodies represent a promising class of biologics for cancer treatment. However, their dual specificity and complex structure pose challenges in the engineering process, often resulting in molecules with good functional but poor physicochemical properties. Method: To overcome limitations in the properties of an anti-5T4 x anti-CD3 (α5T4 x αCD3) DART molecule, a phage-display method was developed, which succeeded in simultaneously engineering cross-reactivity to the cynomolgus 5T4 ortholog, improving thermostability and the elevating expression level. Results: This approach generated multiple DART molecules that exhibited significant improvements in all three properties. The lead DART molecule demonstrated potent in vitro and in vivo anti-tumor activity. Although its clearance in human FcRn-transgenic mice was comparable to that of the parental molecule, faster clearance was observed in cynomolgus monkeys. The lead α5T4 x αCD3 DART molecule displayed no evidence of off-target binding or polyspecificity, suggesting that the increased affinity for the target may account for its accelerated clearance in cynomolgus monkeys. Conclusions: This may reflect target-mediated drug disposition (TMDD), a potential limitation of targeting 5T4, despite its limited expression in healthy tissues. Full article

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims. Full article

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013–2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic. Full article

A diagnostic investigation into an outbreak of fatal respiratory disease among young goats in Iowa, USA revealed bronchitis lesions of unknown etiology and secondary bacterial bronchopneumonia. Hypothesis-free metagenomics identified a previously unreported picornavirus (USA/IA26017/2023), and further phylogenetic analysis classified USA/IA26017/2023 as an aphthovirus related to bovine rhinitis B virus. Viral nucleic acid was localized to lesions of bronchitis using in situ hybridization. This marks the first report of a picornavirus putatively causing respiratory disease in goats and highlights the potential for cross-species transmission of aphthoviruses. Full article

Stellar and black hole feedback heat and disperse surrounding cold gas clouds, launching gas flows off circumnuclear and galactic disks, producing a dynamic interstellar medium. On large scales bordering the cosmic web, feedback drives enriched gas out of galaxies and groups, seeding the intergalactic medium with heavy elements. In this way, feedback shapes galaxy evolution by shutting down star formation and ultimately curtailing the growth of structure after the peak at redshift 2–3. To understand the complex interplay between gravity and feedback, we must resolve both the key physics within galaxies and map the impact of these processes over large scales, out into the cosmic web. The Advanced X-ray Imaging Satellite (AXIS) is a proposed X-ray probe mission for the 2030s with arcsecond spatial resolution, large effective area, and low background. AXIS will untangle the interactions of winds, radiation, jets, and supernovae with the surrounding interstellar medium across the wide range of mass scales and large volumes driving galaxy evolution and trace the establishment of feedback back to the main event at cosmic noon. This white paper is part of a series commissioned for the AXIS Probe mission concept; additional AXIS white papers can be found at the AXIS website. Full article

Although seatbelt use is known to reduce motor vehicle occupant crash injury and death, rear-seated adult occupants are less likely to use restraints. This study examines risk and protective factors associated with injury severity in front- and rear-seated adults involved in a motor vehicle crash in New York State. The Crash Outcome Data Evaluation System (CODES) (2016–2017) was used to examine injury severity in front- and rear-seated occupants aged 18 years or older (N = 958,704) involved in a motor vehicle crash. CODES uses probabilistic linkage of New York State hospitalization, emergency department, and police and motorist crash reports. Multivariable logistic regression models with MI analyze employed SAS 9.4. Odds ratios are reported as OR with 95% CI. The mortality rate was approximately 1.5 times higher for rear-seated than front-seated occupants (136.60 vs. 92.45 per 100,000), with rear-seated occupants more frequently unrestrained than front-seated occupants (15.28% vs. 1.70%, p < 0.0001). In adjusted analyses that did not include restraint status, serious injury/death was higher in rear-seated compared to front-seated occupants (OR:1.272, 1.146–1.412), but lower once restraint use was added (OR: 0.851, 0.771–0.939). Unrestrained rear-seated occupants exhibited higher serious injury/death than restrained front-seated occupants. Unrestrained teens aged 18–19 years old exhibit mortality per 100,000 occupants that is more similar to that of the oldest two age groups than to other young and middle-aged adults. Speeding, a drinking driver, and older vehicles were among the independent predictors of serious injury/death. Unrestrained rear-seated adult occupants exhibit higher severe injury/death than restrained front-seated occupants. When restrained, rear-seated occupants are less likely to be seriously injured than restrained front-seated occupants. Full article

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications. Full article