Search Results (2,209)

Drones have long been explored by commercial and military users for supply. While several systems offering small payloads in drone delivery have seen operational use, large-scale supply drones have yet to be adopted. A range of setbacks cause this, including technological and operational challenges that hinder their adoption. Here, we evaluate these challenges from a conceptual modelling perspective and forecast their applicability once these barriers are overcome. This study uses technology trend modelling and bibliometric activity mapping methodologies to predict the applicability of specific technologies that are currently identified as operational challenges. Specifically for supply drones, we model trends in technological improvements of battery technology and aircraft control, and project its focus on landing zone autonomy and powertrain. The prediction also focuses on the current state of hybrid power and higher levels of automation required for landing zone operations. These models are validated through several published case studies of small delivery drones and then applied to assess the feasibility and constraints of larger supply drones. A case study involving the conceptual design of a supply drone large enough to move a shipping container is presented to illustrate the critical technologies required to transition large supply drones from concept to operational reality. Key technologies required for large-scale supply drones have yet to build up a critical mass of research activity, particularly on landing zone autonomy and powertrain. Moreover, additional constraints beyond technological and operational challenges could include limitations in autonomy, certification hurdles, regulatory complexity, and the need for greater social trust and acceptance. Full article

Rationale: Radium-223 dichloride (²²³RaCl₂) is an FDA-approved alpha-emitting radiopharmaceutical that targets bone metastases in metastatic castration-resistant prostate cancer (mCRPC). This study investigates the therapeutic and immunological effects of combining ²²³RaCl₂ with immune checkpoint inhibitors (ICIs) in a clinically relevant, immunocompetent murine model of prostate cancer bone metastasis. Methods: Luciferase-expressing MyC-CaP prostate cancer cells were implanted intratibially into FVB mice to establish bone metastases. Mice were treated with escalating doses of ²²³RaCl₂ (0.04–0.27 µCi) alone or a single dose combined with anti-CTLA-4 and anti-PD-L1 ICIs. Tumor growth was monitored using bioluminescence imaging. Micro-CT, alpha camera imaging, histology, and qPCR were used to assess bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression. Ex vivo biodistribution and blood analyses quantified tissue uptake and toxicity. Results: Escalating doses of ²²³RaCl₂ did not significantly inhibit tumor growth or improve survival. Biodistribution and imaging showed preferential localization of ²²³RaCl₂ to tumor-adjacent bone, with minimal signal in isolated tumor tissue. Immunohistochemistry revealed increased CD4⁺ and CD8α⁺ T-cell infiltration in regions of high γH2AX expression, indicating localized immune modulation. However, combination therapy with ICIs did not enhance tumor control or immune infiltration beyond monotherapy. qPCR demonstrated significant upregulation of Mhc1 only in the combination group, suggesting localized immune activation. Toxicity profiles remained acceptable. Conclusions: ²²³RaCl₂ localizes primarily to bone surfaces, limiting direct cytotoxic and immunomodulatory effects within the tumor microenvironment. While combination with ICIs did not improve efficacy, these findings provide a platform for studying spatial dose distribution and support future development of tumor-targeted alpha therapies to potentiate immunotherapy in mCRPC. Full article

We develop and evaluate a deep contextual bandit framework for multivariate off-policy evaluation within a controlled simulation-based validation setting. Using real covariate distributions from the Adult, Boston Housing, and Wine Quality datasets, we construct synthetic treatment assignments and multivariate potential outcomes to enable rigorous benchmarking under known data-generating processes. We compare CNN-LSTM, LSTM, and Feed-forward Neural Network (FNN) architectures as nonlinear action-value estimators. To examine representation learning under structured dependence, an $AR\left(1\right)$ feature augmentation scheme is employed, while multivariate outcomes are standardized using empirical copula transformations to preserve cross-dimensional dependence. Policy values are estimated using Stabilized Importance Sampling (SIPS) and doubly robust (DR) estimators with bootstrap inference. Although the decision problem is strictly one-step, empirical results indicate that CNN-LSTM architectures provide competitive action-value calibration under temporal augmentation. Across all datasets, the DR estimator demonstrates substantially lower variance and greater stability than SIPS, consistent with its theoretical variance-reduction properties. Diagnostic analyses—including propensity overlap assessment, cumulative oracle regret (with oracle values known by construction), calibration evaluation, and sensitivity analysis—support the reliability of the proposed evaluation framework. Overall, the results demonstrate that combining copula-normalized multivariate outcomes with doubly robust off-policy evaluation yields a statistically principled and variance-efficient approach for offline policy learning in high-dimensional simulated environments. Full article

(1) Background: Bioactive peptides from marine and plant sources show neuroprotective potential, yet how their combination ratios affect memory regulation via the gut–brain axis remains unclear. This study investigated the effects of different ratios of marine peptide QMDDQ (Glutamine-Methionine-Aspartate-Aspartate-Glutamine) and plant peptide AGLPM (Alanine-Glycine-Leucine-Proline-Methionine) on scopolamine-induced memory impairment in mice. (2) Methods: Cognitive function was assessed using the Morris water maze and novel object recognition tests. Nissl staining, microplate-based assays for acetylcholine (ACh) content and acetylcholinesterase (AChE) activity, Western blotting for neurotrophic factors, LC-MS/MS-based intestinal peptide profiling, and HPLC-based brain amino acid analysis were performed. (3) Results: The 1:1 ratio most effectively restored learning and memory, regulated hippocampal cholinergic function, mitigated neuronal damage, and elevated BDNF, NGF, and NTF-3 expression. In the gut, peptides were hydrolyzed into glutamate- and proline-rich fragments, which influenced brain amino acid balance by elevating glutamate and proline levels while reducing NH₃-related signaling. (4) Conclusions: These results highlight the ratio-dependent efficacy of QMDDQ-AGLPM combinations and provide evidence for a gut peptide remodeling-brain metabolic link relevant to cognitive impairment. Full article

Background/Objectives: Patient-level predictors of treatment response after genicular artery embolization (GAE) for knee osteoarthritis (OA) are poorly understood. We evaluated clinical, serum, and imaging biomarkers for their ability to predict achievement of the minimally clinically important difference (MCID) for WOMAC pain and stiffness subscales following GAE. Methods: Data from a prospective single-arm clinical trial of 25 patients who underwent GAE for symptomatic knee OA was retrospectively analyzed. Candidate predictors included sex, age, BMI, contralateral Kellgren–Lawrence (KL) scores, and baseline values for serum IL-1Ra, serum VEGF, and total bone marrow edema scores on MRI using the MOAKS methodology. The primary outcomes were the frequency of achieving the MCID in WOMAC pain and WOMAC stiffness at 1, 3, and 12 months, modeled as an ordinal outcome (0–3). Ordinal logistic regression models were constructed. Variance inflation factors (VIFs) were assessed to detect multicollinearity, and leave-one-out cross-validation was performed to evaluate model robustness. Results: All candidate predictors were successfully incorporated into regression models, with no evidence of multicollinearity by VIF analysis. Lower contralateral KL scores (OR: 0.087 [0.012–0.618], p = 0.0146) and higher BMI (OR: 1.383 [1.001–1.910], p = 0.049) were significantly associated with achievement of the MCID for WOMAC pain, although significance for BMI was borderline. Lower baseline serum IL-1Ra levels (OR: 0.122 [0.018–0.816], p = 0.030) were significantly associated with achievement of the MCID for WOMAC stiffness. The remaining clinical, serum, and imaging biomarkers were not significantly associated with MCID achievement. Conclusions: In this exploratory analysis, specific baseline clinical and serum factors were associated with achievement of clinically meaningful improvements in pain and stiffness. Analysis of larger cohorts will help clarify ideal demographic-, biomarker- and imaging-based patient selection strategies that can improve prediction of treatment response and guide clinical decision-making in GAE for knee OA. Full article

Pesticides are essential for modern agriculture but raise concerns about potential neurodevelopmental consequences, leading to bans in some countries. This study aimed to investigate the long-term effects of prenatal exposure to chlorpyrifos (CPF) on behavior and DNA methylation, considering genetic susceptibility via the apolipoprotein E (APOE) genotype. Pregnant mice—C57BL/6J and those carrying human APOE ε3 or ε4 alleles—were orally exposed to 0 or 1 mg/kg/day of CPF from gestational day 12 to 18. Adult offspring underwent light and dark and Morris water maze tests to assess anxiety-like behavior and spatial learning and memory. Then, hippocampal samples were collected to assess DNA methylation. Results indicated that body weight was lower in females and CPF-treated mice. C57BL/6J males spent less time in the light compartment, worsened by CPF. In contrast, within APOE genotype ε4 carriers spent more time in the light compartment, with CPF increasing male activity. Moreover, long-term retention was impaired in both male and female apoE4 mice prenatally exposed to CPF. DNA methylation analysis revealed sex-dependent differences, with hypomethylation in the CPF-treated male hippocampus. These findings highlight how pesticides and genetic factors interact, affecting neurobehavioral development, and explore the potential impact of CPF on DNA methylation. Full article

Background and Clinical Significance: Non-bacterial thrombotic endocarditis (NBTE), historically termed marantic endocarditis, is a severe manifestation of cancer-associated hypercoagulability characterized by sterile valvular vegetations and a high risk of systemic embolization. While direct oral anticoagulants (DOACs) have become the standard of care for cancer-associated venous thromboembolism (CAT), their efficacy in preventing high-shear arterial thrombosis in NBTE has been contested. Emerging data suggest that DOACs may fail to halt vegetation growth in active malignancy, necessitating a reversion to heparin-based therapies. Case Presentation: A 47-year-old female with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) presented with progressive dyspnea and digital ischemia despite strict adherence to therapeutic anticoagulation with rivaroxaban for a prior pulmonary embolism. Echocardiography showed large vegetations on all three cusps of the aortic valve, confirming NBTE. Computed tomography revealed extensive tumor progression. The therapeutic strategy involved an immediate switch from rivaroxaban to therapeutic low-molecular-weight heparin (LMWH) and the initiation of dual targeted therapy with selpercatinib and tepotinib. Serial transesophageal echocardiography documented regression within two weeks and eventual complete resolution of the valvular vegetations after eight weeks, occurring in tandem with a rapid radiological response of the tumor. Conclusions: Upon diagnosis of NBTE, a rapid oncologic work-up is warranted, as ongoing tumor progression is highly likely. This case questions the appropriateness of direct oral anticoagulants in patients with NBTE and active, progressive malignancy. Full article

Teacher preparation is an emotional as well as a cognitive process in which pre-service teachers must develop both reflective judgment and the emotional resilience needed for demanding instructional contexts. This study examined how university-based supervisors enacted the relational spaces of the University-Based Coaching Framework (UBCF) and how these enactments shaped pre-service teachers’ emotional and reflective development. Drawing on qualitative analysis of coaching discourse among three supervisor-pre-service teacher pairs, the comparative case study identifies distinct coaching identities that emerged from supervisors’ patterned relational moves. These identities corresponded to varying intensities of UBCF space enactment and produced differential pathways through a reflective-motional cycle connecting appraisal, coping, and reappraisal. Findings demonstrate that supervisors’ relational stance functions as both cognitive scaffolding and as an emotional regulator. By conceptualizing UBCF-based coaching as an interactional process that integrates relational attunement with reflective challenge, this study contributes new insight into how emotional and cognitive dimensions of supervision jointly support teacher knowledge development and early professional resilience. Full article

Theological studies of the Anglophone crisis in Cameroon have centred upon the question of secession. Those opposed to the creation of an independent (freedomland) Anglophone state (Ambazonia) draw extensively on the work of Emmanuel Katongole and Stanley Hauerwas, whose outright opposition to the nation state has shaped a number of African theologians. This essay engages the voices of Anglophone young people caught up in the crisis and brings them into dialogue with these professional theologians. Full article

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social deficits, repetitive behaviors, and heightened anxiety. Despite extensive research, effective interventions targeting core symptoms remain limited. Gami-Guibitang (GBT), a traditional herbal formula, has been clinically prescribed for anxiety-related symptoms and cognitive complaints, yet its effects on ASD-associated behavioral and molecular abnormalities have not been fully elucidated. Objective: This study aimed to evaluate the anxiolytic and neuroregulatory effects of GBT in a valproic acid (VPA)-induced ASD mouse model, focusing on behavioral outcomes and hippocampal synaptic protein expression. Methods: Pregnant C57BL/6N mice received a single intraperitoneal injection of VPA (500 mg/kg) at embryonic day 12.5. Male offspring were administered GBT (150 mg/kg, p.o.) twice daily for 4 weeks from postnatal day 21 (PND 21). These mice were behaviorally evaluated by the open-field test, elevated plus maze, marble-burying test, Y-maze, three-chamber social interaction test, and Morris water maze. Western blot analysis was conducted to examine hippocampal expression of phosphorylated and total CREB and GluR1, PI3K/Akt signaling components, as well as GABRA1 and GABRB1. Results: VPA-exposed offspring exhibited increased anxiety-like behaviors, altered repetitive behaviors, dysregulated exploratory activity, and impaired spatial learning, and reduced spontaneous alternation performance in the Y-maze. GBT reduced anxiety-like behaviors in the elevated plus maze and marble burying tests, partially improved spatial learning acquisition in the Morris water maze, and normalized excessive locomotor activity, without significantly affecting short-term working memory performance. At the molecular level, GBT significantly attenuated VPA-induced hyperphosphorylation of CREB, GluR1, PI3K, and Akt, indicating suppression of aberrant synaptic signaling rather than global enhancement. In addition, GBT increased GABRA1 expression toward control levels and enhanced GABRB1 expression beyond baseline, suggesting selective modulation of GABAergic receptor subunit composition rather than simple normalization. Conclusions: These findings provide preclinical evidence that GBT alleviates anxiety-like behavior and modulates hippocampal synaptic signaling disrupted by prenatal VPA exposure. By attenuating aberrant excitatory signaling and selectively regulating GABAergic receptor balance, GBT may represent a multi-target herbal candidate for modulating ASD-associated emotional dysregulation and domain-specific cognitive dysfunction, rather than acting as a broad cognitive enhancer. Full article

Background: SARS-CoV-2 vaccination is crucial for protecting against severe COVID-19 disease; however, patients with haematological malignancies (HM) respond poorly to vaccination due to immunosuppression driven by chemotherapy, targeted cell depletion, and immune dysregulation. We sought to define novel biomarkers that predict effective vaccination in patients with HM. Methods: HM patients and healthy controls received SARS-CoV-2 vaccines and were followed for six months post-vaccination. Virus-specific humoral and cellular immune responses were analysed in serum and whole blood pre- and post-vaccination, and serum proteomics was analysed pre-vaccination to identify potential biomarkers for vaccine response. Results: HM patients displayed delayed antibody seroconversion, and 37.5% failed to seroconvert. Baseline proteomic and cellular immune profiles revealed that T-cell-associated chemokines CXCL13 and CRTAM were differentially expressed, with decreased levels seen in vaccine non-responders. Vaccine response was also associated with a reduced frequency of circulating monocytes, greater numbers of B-cells, and a trend toward greater numbers of CD4+ helper cell phenotypes, including T peripheral helper cells pre-vaccination. In vitro generation of COVID-19-specific T-cells from a subset of participants trended towards increased cytotoxic CD4+ and CD8+ T-cell activity in seroconverters and dysfunctional COVID-19-specific T-cell responses in non-seroconverters. Conclusions: These results suggest that HM patients have impaired T-cell immunity, and non-responders may be identified by low levels of serum CXCL13 and CRTAM. This allows for the identification of at-risk patients who would benefit from alternative COVID-19 prophylaxis strategies. Full article

Addressing climate change necessitates coordinated efforts across multiple sectors, with agriculture representing a significant source of greenhouse gas (GHG) emissions. This requires sophisticated mitigation strategies at the farm level. Digital decision support tools (DSTs) tailored for this purpose play a crucial role in accelerating farm-level decarbonization. Ensuring the reliability and accuracy of these DSTs mandates thorough model robustness validation. This study validates a farm-level GHG accounting and decarbonization DST using Sobol and Morris global sensitivity analyses to evaluate output robustness and to identify key input parameters critical for reliable mitigation planning. Both sensitivity analysis methods provide a comprehensive assessment of the tool’s robustness and highlight parameters most influencing farm-level GHG emission outcomes. Results show consistent outcomes across sensitivity approaches, reinforcing confidence in the tool’s application for emission reduction planning. The sensitivity analysis results indicate that the tool delivers reliable outcomes across various sensitivity analysis methods, thereby enhancing confidence in its suitability for decarbonization planning. Furthermore, the findings of this study provide a methodological foundation for future advancements and expanded use within the agriculture sector. This supports the DST’s effectiveness in prioritizing mitigation strategies and planning emission reduction pathways at the farm scale, while providing a transparent template to guide future tool improvements and broader agricultural applications. Full article

We present a comprehensive framework for estimating heterogeneous treatment effects and evaluating decision-making policies in high-dimensional settings. Our approach combines nonlinear manifold learning techniques—UMAP, t-SNE, and Isomap—with a Causal Conditional Deep Network (CCDN) to model complex nonlinear interactions among covariates, treatments, and outcomes. Within this framework, we assess five treatment assignment policies—Greedy, Thompson Sampling, Epsilon-Greedy, Random, and a novel LLM-guided Thompson policy—across simulated and real-world datasets, including Adult, Wine Quality, and Boston Housing. Empirical results reveal a fundamental trade-off: exploitative policies like Greedy minimize cumulative regret but underperform in recovering heterogeneous treatment effects, whereas exploratory policies, particularly Random and LLM-Thompson, achieve a lower Conditional Average Treatment Effect Root Mean Squared Error (CATE RMSE) by providing broader coverage of the action–covariate space. Notably, LLM-Thompson consistently delivers strong performance across noisy, real-world datasets, highlighting the advantage of uncertainty-aware exploration in capturing treatment heterogeneity. Overall, the framework demonstrates that integrating manifold-informed deep networks with principled exploration strategies enhances both policy optimization and individualized treatment effect estimation in high-dimensional, complex environments. Full article

Background/Objectives: Unpredictable chronic mild stress exposure is a primary driver of cognitive decline, largely mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation and subsequent oxidative neurotoxicity. In traditional Thai medicine, the AYW-KK-04 formulation—a complex polyherbal remedy—has long been utilized as a “Ya Aayu-Wattana” to restore vitality and elemental balance, yet its neurobiological mechanisms remain poorly understood. This study aimed to evaluate the adaptogenic and neuroprotective potential of AYW-KK-04 against cognitive impairment. Methods: Unpredictable Chronic Mild Stress (UCMS)-induced cognitive impairment in a ICR mouse model. Total phenolic and flavonoid contents and antioxidant capacity (ABTS assay) of AYW-KK-04 were determined. Behavioral assessments using Y-maze test, novel object recognition test (NORT), and Morris Water Maze (MWM) test. BDNF, CREB, Nrf and Keap1 mRNA gene expression, SOD and CAT enzymatic activity and lipid peroxidation assay were investigated to clarify the mechanisms of action. Moreover, HPLC chromatography was studied to quantify the active compounds of the AYW-KK-04 formulation. Results: It demonstrated that oral administration of AYW-KK-04 significantly reversed UCMS-induced memory deficits. At the molecular level, AYW-KK-04 effectively upregulated BDNF and CREB mRNA expression in the frontal cortex and hippocampus, suggesting a restoration of synaptic plasticity. Simultaneously, the formulation activated the Nrf2/Keap1 signaling pathway, leading to enhanced SOD and CAT enzymatic activities and a marked reduction in MDA-mediated lipid peroxidation. HPLC analysis confirmed the presence and consistency of key bioactive constituents. Conclusions: These findings suggest that the adaptogenic properties of AYW-KK-04 arise from its dual capacity to reinforce neurotrophic support and bolster the endogenous antioxidant shield, providing a mechanistic support for the traditional use of AYW-KK-04 as an adaptogenic formulation and highlighting its potential as a multi-target intervention for stress-related cognitive dysfunction. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies. The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings. This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies. The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS. Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators. From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function. Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies. Full article