Search Results (1,390)

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

This study investigates the use of a Random Forest (RF), an artificial intelligence (AI) model, to estimate the planetary boundary layer height (PBLH) over Central Amazonia from climatic elements data collected during the GoAmazon experiment, held in 2014 and 2015, as it is a key metric for air quality, weather forecasting, and climate modeling. The novelty of this study lies in estimating PBLH using only surface-based meteorological observations. This approach is validated against remote sensing measurements (e.g., LIDAR, ceilometer, and wind profilers), which are seldom available in the Amazon region. The dataset includes various meteorological features, though substantial missing data for the latent heat flux (LE) and net radiation (Rn) measurements posed challenges. We addressed these gaps through different data-cleaning strategies, such as feature exclusion, row removal, and imputation techniques, assessing their impact on model performance using the Root Mean Square Error (RMSE), Mean Absolute Error (MAE), and $r^2$ metrics. The best-performing strategy achieved an RMSE of 375.9 m. In addition to the RF model, we benchmarked its performance against Linear Regression, Support Vector Regression, LightGBM, XGBoost, and a Deep Neural Network. While all models showed moderate correlation with observed PBLH, the RF model outperformed all others with statistically significant differences confirmed by paired t-tests. SHAP (SHapley Additive exPlanations) values were used to enhance model interpretability, revealing hour of the day, air temperature, and relative humidity as the most influential predictors for PBLH, underscoring their critical role in atmospheric dynamics in Central Amazonia. Despite these optimizations, the model underestimates the PBLH values—by an average of 197 m, particularly in the spring and early summer austral seasons when atmospheric conditions are more variable. These findings emphasize the importance of robust data preprocessing and higtextight the potential of ML models for improving PBLH estimation in data-scarce tropical environments. Full article

The Fernald Feed Materials Production Center (FMPC), located in Fernald, Ohio, USA, released radon (Rn) as a byproduct of the processing of uranium materials during the years from 1951 to 1989. Rn is a colorless, odorless gas that emits charged alpha radiation that interacts with cells in the lung and trachea-bronchial tree, leading to DNA damage, mutations, and tumor initiation. The purpose of this project was to use evidence collected by the Fernald Dosimetry Reconstruction Project and other sources to estimate the outdoor Rn exposure to individuals in the community immediately surrounding the FMPC during the years of plant operation. Using previously tabulated source terms, diffusion and meteorological data, and self-reported detailed residential histories, we estimated radon exposure for approximately 9300 persons who lived at more than 14,000 addresses. The results indicated that a portion of the population cohort experiences mean annual Rn exposure exceeding the U.S. Environmental Protection Agency (EPA) action limit of 4 pCiL⁻¹. These exposure estimates support the analysis of the incidence of lung cancer in the Fernald Community Cohort (FCC). Full article

High nighttime temperature (HNT) due to asymmetric diurnal warming threatens wheat productivity. This study evaluated the effect of HNT on wheat phenology, physiology, and yield through field and controlled environment experiments in Central Queensland, Australia. Two wheat genotypes, Faraday and AVT#6, were assessed under three sowing dates—1 May (Early), 15 June (Mid), and 1 August (Late)—within the recommended sowing window for the region. In a parallel growth chamber study, the plants were exposed to two nighttime temperature regimes, of 15 °C (normal) and 20 °C (high), with consistent daytime conditions from booting to maturity. Late sowing resulted in shortened vegetative growth and grain filling periods and increased exposure to HNT during the reproductive phase. This resulted in elevated floret sterility, lower grain weight, and up to 40% yield loss. AVT#6 exhibited greater sensitivity to HNT despite maturing earlier. Leaf gas exchange analysis revealed increased nighttime respiration (Rn) and reduced assimilation (A), resulting in higher Rn/A ratio for late-sown crops. The results from controlled environment chambers resembled trends of the field experiment, producing lower grain yield and biomass under HNT. Cumulative nighttime hours above 20 °C correlated more strongly with yield losses than daytime heat. These findings highlight the need for HNT-tolerant genotypes and optimized sowing schedules under future climate scenarios. Full article

This study investigates the seasonal dynamics of energy balance, evapotranspiration (ET), and Net Ecosystem Production (NEP) in the Dengkou desert ecosystem of Inner Mongolia, China. Using eddy covariance and meteorological data from 2019 to 2022, the research focuses on understanding how these processes interact in one of the world’s most water-limited environments. This arid research area received an average of 109.35 mm per annum precipitation over the studied period, classifying the region as a typical arid ecosystem. Seasonal patterns were observed in daily air temperature, with extremes ranging from −20.6 °C to 29.6 °C. Temporal variations in sensible heat flux (H), latent heat flux (LE), and net radiation (Rn) peaked during summer season. The average ground heat flux (G) was mostly positive throughout the observation period, indicating heat transmission from atmosphere to soil, but showed negative values during the winter season. The energy balance ratio for the studied period was in the range of 0.61 to 0.80, indicating challenges in achieving energy closure and ecological shifts. ET exhibited two annual peaks influenced by vegetation growth and climate change, with annual ET exceeding annual precipitation, except in 2021. Net ecosystem production (NEP) from 2019 to 2020 revealed that the Dengkou desert were a net source of carbon, indicating the carbon loss from the ecosystem. In 2021, the Dengkou ecosystem shifted to become a net carbon sink, effectively sequestrating carbon. However, this was sharply reversed in 2022, resulting in a significant net release of carbon. The study findings highlight the complex interactions between energy balance components, ET, and NEP in desert ecosystems, providing insights into sustainable water management and carbon neutrality strategies in arid regions under climate change effect. Full article

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies. Full article

Prolonged inundations are altering coastal forest ecosystems of the southeastern US, causing extensive tree die-offs and the development of ghost forests. This hydrological stressor also alters carbon fluxes, threatening the stability of coastal carbon sinks. This study was conducted to investigate the interactions between hydrological drivers and ecosystem responses by analyzing daily eddy covariance flux data from a wetland forest in North Carolina, USA, spanning 2009–2019. We analyzed temporal patterns of net ecosystem exchange (NEE), gross primary productivity (GPP), and ecosystem respiration (RE) under both flooded and non-flooded conditions and evaluated their relationships with observed tree mortality. Generalized Additive Modeling (GAM) revealed that groundwater table depth (GWT), leaf area index (LAI), NEE, and net radiation (Rn) were key predictors of mortality transitions (R² = 0.98). Elevated GWT induces root anoxia; declining LAI reduces productivity; elevated NEE signals physiological breakdown; and higher Rn may amplify evapotranspiration stress. Receiver Operating Characteristic (ROC) analysis revealed critical early warning thresholds for tree mortality: GWT = 2.23 cm, LAI = 2.99, NEE = 1.27 g C m⁻² d⁻¹, and Rn = 167.54 W m⁻². These values offer a basis for forecasting forest mortality risk and guiding early warning systems. Our findings highlight the dominant role of hydrological variability in ecosystem degradation and offer a threshold-based framework for early detection of mortality risks. This approach provides insights into managing coastal forest resilience amid accelerating sea level rise. Full article

The Complementary Relationship (CR) principle of evapotranspiration provides an efficient approach for estimating actual evapotranspiration (ET_a), owing to its simplified computation and effectiveness in utilizing meteorological factors. Accurate estimation of actual evapotranspiration (ET_a) is crucial for understanding surface energy and water cycles, especially in permafrost regions. This study aims to evaluate the applicability of two Complementary Relationship (CR)-based methods—Bouchet’s in 1963 and Brutsaert’s in 2015—for estimating ETa on the Qinghai–Tibetan Plateau (QTP), using observations from Eddy Covariance (EC) systems. The potential evapotranspiration (ET_p) was calculated using the Penman equation with two wind functions: the Rome wind function and the Monin–Obukhov Similarity Theory (MOST). The comparison revealed that Bouchet’s method underestimated ET_a during frozen soil periods and overestimated it during thawed periods. In contrast, Brutsaert’s method combined with the MOST yielded the lowest RMSE values (0.67–0.70 mm/day) and the highest correlation coefficients (r > 0.85), indicating superior performance. Sensitivity analysis showed that net radiation (Rn) had the strongest influence on ET_a, with a daily sensitivity coefficient of up to 1.35. This study highlights the improved accuracy and reliability of Brutsaert’s CR method in cold alpine environments, underscoring the importance of considering freeze–thaw dynamics in ET modeling. Future research should incorporate seasonal calibration of key parameters (e.g., ε) to further reduce uncertainty. Full article

Antibody-mediated autoimmune diseases are common, can involve any organ system, and pose a large burden for patients and healthcare systems. Most antibody-mediated diseases are mediated by IgG antibodies. Selective targeting of pathogenic antibodies is an attractive treatment option which has already proven to be effective in antibody-positive generalized myasthenia gravis, maternal-fetal alloimmune cytopenias, and immune thrombocytopenic purpura. Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder mediated by pathogenic antibodies mainly of the IgG class with no approved therapy. Current treatment includes non-specific immunosuppression with corticosteroids, rituximab, and other immunosuppressive agents. With most therapies, time to response can be delayed and transfusions may be needed. Neonatal Fc receptor (FcRN) therapies provide rapid and sustained reduction of pathogenic IgG levels providing potential for fast, effective therapy in antibody-mediated autoimmune diseases including warm autoimmune hemolytic anemia. This review focuses on the emerging role of FcRn inhibition in autoimmune hematologic diseases, and their therapeutic potential in wAIHA. Full article

It is demonstrated that neuromorphic materials designed for computational tasks can be effectively implemented by drawing an analogy with trigger-based systems built upon classical binary elements. Among the most promising approaches in this context are systems that perform computations based on the Residue Number System (RNS). A specific implementation of a trigger-based adder employing the proposed methodology is presented and tested through simulation modeling. This adder utilizes the representation of natural numbers as elements of a subtraction ring modulo P, where P is the product of Mersenne prime numbers. This configuration enables component-wise, independent execution of arithmetic operations. It is further shown that analogous trigger-based systems can be realized using recurrent neural network analogs, particularly those implemented with neuromorphic materials. The study emphasizes that it is possible to construct a neural network, especially one based on neuromorphic substrates, that can perform logical operations equivalent to those executed by conventional binary circuitry. A key challenge in the proposed approach lies in implementing an operation analogous to the carry mechanism employed in classical binary adders. An algorithm addressing this issue is proposed, based on the transition from computations modulo P to computations modulo 2P. Full article

The C-terminus of the BoNT/A heavy chain (BoNT/AHC) mediates binding to its receptor, SV2, a critical step for toxicity. Antibody inhibition of this interaction enhances neuronal survival. We previously identified a functional anti-BoNT/AHC nanobody, HM. To extend its in vivo half-life, we designed and prepared two Fc-optimized nanoparticles, HM-Fc5 and HM-Fc6. Structural modeling (homology/docking) of the HM Fv-AHC complex predicted that HM engages key AHC residues (Tyr¹¹⁵⁵, Phe¹¹⁶⁰, Ile¹¹⁶¹, Val¹¹⁸⁴, Asn¹¹⁸⁸, Lys¹¹⁸⁹, Glu¹¹⁹⁰), which overlap with the SV2 binding site. This suggests HM’s protective mechanism involves blocking toxin-receptor binding and cellular entry. HM-Fc5 and HM-Fc6 retained the stability and function of the parental HM antibody while exhibiting prolonged in vivo half-life. These optimized nanobodies offer economical candidates potentially enabling longer dosing intervals, beneficial for prophylaxis or chronic disease treatment. Significance Statement: The purpose of the study is to design and prepare two Fc optimized nanoparticles, HM-Fc5 and HM-Fc6, and predict the key residues involved in the interaction between HMs and AHC. The experimental results showed that HM-Fc5 and HM-Fc6 have the same stability as the parent HM antibody but have a longer half-life in vivo. The key residues Tyr¹¹⁵⁵, Phe¹¹⁶⁰, Ile¹¹⁶¹, Val¹¹⁸⁴, Asn¹¹⁸⁸, Lys¹¹⁸⁹, and Glu¹¹⁹⁰ overlap with the SV2 binding site. Our experimental results indicate that these nanobody candidates are not only more economical and convenient, but may also have longer dosing intervals, providing strong evidence and reference for prolonging the in vivo half-life of nanomaterials. Full article

Seed germination and early seedling growth are pivotal stages that define crop establishment and yield potential. Conventional agrochemicals used to improve these processes often raise environmental concerns, highlighting the need for sustainable alternatives. In this study, we demonstrated that water treated with cylindrical dielectric barrier discharge (c-DBD) plasma, enriched with nitric oxide (NO) and reactive nitrogen species (RNS), markedly enhanced onion (Allium cepa) seed germination and seedling vigor. The plasma-treated water (PTW) promoted rapid imbibition, broke dormancy, and accelerated germination rates beyond 98%. Seedlings irrigated with PTW exhibited significantly increased biomass, root and shoot length, chlorophyll content, and antioxidant enzyme activities, accompanied by reduced lipid peroxidation. Transcriptomic profiling revealed that PTW orchestrated a multifaceted regulatory network by upregulating gibberellin biosynthesis genes (GA3OX1/2), suppressing abscisic acid signaling components (ABI5), and activating phenylpropanoid metabolic pathways (PAL, 4CL) and antioxidant defense genes (RBOH1, SOD). These molecular changes coincided with elevated NO₂⁻ and NO₃⁻ levels and finely tuned hydrogen peroxide dynamics, underpinning redox signaling crucial for seed activation and stress resilience. Our findings establish plasma-generated NO-enriched water as an innovative, eco-friendly technology that leverages redox and hormone crosstalk to stimulate germination and early growth, offering promising applications in sustainable agriculture. Full article

Phage therapy shows promise as an adjunct to antibiotics for treating Staphylococcus aureus infections. We previously reported a combined flucloxacillin/two-phage cocktail treatment selected for resistance to podovirus phage 66 in a rodent model of methicillin-susceptible S. aureus (MSSA) endocarditis. Here we show that resistant clones harbor mutations in tarS, which encodes a glycosyltransferase essential for β-GlcNAcylation of wall teichoic acid (WTA). This WTA modification has been described in vitro as critical for podoviruses adsorption. Transcriptomics confirmed continued tarS expression in resistant clones, supporting a loss-of-function mechanism. Accordingly, phage 66 binding and killing were restored by WT tarS complementation. In addition, we investigated the counterintuitive innate susceptibility to phage 66 of the tarM + Laus102 strain used in the endocarditis model. We show that it likely results from a significant lower tarM expression, in contrast to the innate resistant strain RN4220. Our findings demonstrate that tarS-mediated WTA β-GlcNAcylation is critical for podovirus infection also in vivo and identify tarM transcriptional defect as a new mechanism of podoviruses susceptibility in S. aureus. Moreover, and since tarS disruption has been previously shown to enhance β-lactam susceptibility, our results support the development of combined podovirus/antibiotic strategies for the management of MRSA infections. Full article

Plants are constantly exposed to environmental stressors such as drought, salinity, and extreme temperatures, which threaten their growth and productivity. To counter these challenges, they employ complex molecular defense systems, including epigenetic modifications that regulate gene expression without altering the underlying DNA sequence. This review comprehensively examines the emerging roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as central signaling molecules orchestrating epigenetic changes in response to abiotic stress. In addition, biotic factors such as pathogen infection and microbial interactions are considered for their ability to trigger ROS/RNS generation and epigenetic remodeling. It explores how ROS and RNS influence DNA methylation, histone modifications, and small RNA pathways, thereby modulating chromatin structure and stress-responsive gene expression. Mechanistic insights into redox-mediated regulation of DNA methyltransferases, histone acetyltransferases, and microRNA expression are discussed in the context of plant stress resilience. The review also highlights cutting-edge epigenomic technologies such as whole-genome bisulfite sequencing (WGBS), chromatin immunoprecipitation sequencing (ChIP-seq), and small RNA sequencing, which are enabling precise mapping of stress-induced epigenetic landscapes. By integrating redox biology with epigenetics, this work provides a novel framework for engineering climate-resilient crops through the targeted manipulation of stress-responsive epigenomic signatures. Full article

Mineral waters from two tectonically active mountain systems within the Alpine-Himalayan orogenic belt, the Pamir and the Greater Caucasus (Elbrus region), were analyzed for ²²²Rn activity and ²³⁸U concentrations to establish correlations with geological conditions, physicochemical characteristics of water, and to assess the potential health risk associated with ²³⁸U and ²²²Rn. It was found that in mineral waters of the Pamir, the concentrations of ²³⁸U (0.004–13.3 µg/L) and activity of ²²²Rn (8–130 Bq/L) are higher than in the Elbrus area: 0.04–3.74 µg/L and 6–33 Bq/L, respectively. Results indicate that uranium mobility in water is strongly influenced by T, pH, and Eh, but is less affected by the age of host rocks or springs′ elevation, whereas radon activity in waters depends on the age of rocks, spring elevation, ²³⁸U content, and values of δ¹⁸O and δ²H in water. This study reveals fundamental geological distinctions governing uranium and radon sources in the mineral waters of these regions. Isotopic evidence (²²²Rn and ³He/⁴He) demonstrates crustal radon sources prevail in Pamir, whereas the Elbrus system suggests mantle-derived components. The U concentrations do not exceed 30 µg/L, and most water samples (94%) showed ²²²Rn activities below 100 Bq/L, complying with the drinking water exposure limits recommended by the World Health Organization and European Union Directive. However, in intermountain depressions of the Pamirs, at low absolute elevations (~2300 m), radon concentrations in water can increase significantly, which requires special attention and study. Full article