Search Results (43,992)

Numerous scientific studies highlight the crucial role of common genetic and epigenetic factors in the development and progression of cancer. To deepen our understanding of how different VEGFR and epigenetic pathways interact in carcinogenesis, the current review examines novel therapeutic agents that target various molecular mechanisms involved in this complex disease. Growing evidence from scientific studies suggests that VEGFR and epigenetic signaling pathways contribute to complex pathophysiological changes in cancer. Therefore, simultaneously targeting VEGFR and epigenetic factors, such as sirtuins, by developing dual inhibitors could provide more individualized therapeutic approaches with safer and more effective outcomes. In this context, Computer-Aided Drug Design (CADD) offers a comprehensive suite of bioinformatic, chemoinformatic, and chemometric approaches to design novel chemotypes of epigenetic dual-target inhibitors. This facilitates the efficient discovery of new drug candidates, enabling innovative treatments for these multifactorial diseases. The review also explores the detailed anticancer mechanisms by which VEGFR, SIRT, and dual-target inhibitors modify metastatic and tumorigenic properties, affect the tumor microenvironment, and regulate the immune response. Full article

Introduction: Extranodal extension (ENE) is a well-established adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC), associated with reduced survival and the need for intensified therapy. Nutritional status—commonly assessed using the Prognostic Nutritional Index (PNI) and Body Mass Index (BMI)—also influences outcomes in HNSCC. However, whether or not ENE correlates with nutritional status has not been previously investigated. Methods: We conducted a retrospective cohort study of 109 treatment-naïve HNSCC patients with pathologically confirmed nodal metastases who underwent primary tumor resection and neck dissection between 2014 and 2025 at a national tertiary center. ENE status was determined histologically. Nutritional status was evaluated using BMI, PNI, serum albumin, and percentage of weight loss at diagnosis. Statistical analyses included t-tests, Chi-square tests, ANOVA, Cox regression, Kaplan–Meier survival analysis, and Full Factorial General Linear Models. Results: ENE was present in 54.1% of patients and significantly reduced overall survival (Kaplan–Meier p = 0.006; Cox regression RR = 1.927, p = 0.008). No significant differences in BMI, PNI, weight loss, or serum albumin were observed between ENE-positive and ENE-negative groups. ENE prevalence varied significantly by tumor origin (p = 0.018), being highest in hypopharyngeal cancers (75.8%) and lowest in oral cavity tumors (25.0%). ENE status was independent of tobacco use, alcohol abuse, and all nutritional markers across TNM 8/9 subgroups. Conclusions: ENE is a strong prognostic marker in HNSCC, appearing to be independent of nutritional status. The demonstrated heterogeneity of ENE prevalence among tumor subsites supports the need for individualized management approaches. Full article

To comprehensively assess the emissions of flue gas pollutants from municipal solid waste incineration (MSWI) in China and their socioeconomic driving factors, this study employs a bottom-up approach to develop an integrated carbon and air pollutant emission inventory for 1016 MSWI plants in 2024. We apply a Random Forest (RF) model to analyze the underlying drivers. Results indicate that for air pollutants, NO_x has the highest emissions, whereas mercury (Hg) and dioxins (polychlorinated dibenzo-p-dioxins and dibenzofurans, PCDD/Fs) are identified as priority control pollutants due to their high toxicity. Spatially, emissions display a distinct “high in the east, low in the west” pattern, concentrated in eastern coastal provinces, with characteristic pollutants being prominent in specific regions. Meanwhile, among greenhouse gases (GHGs), CO₂ dominates mass emissions, while N₂O exhibits significant global warming potential. Driver analysis reveals that Gross Domestic Product (GDP) and MSWI treatment capacity are key common drivers, showing stable positive and negative contributions, respectively. The number of invention patent applications is specifically and strongly associated with NO_x and heavy metal emissions. This study provides a national-scale integrated quantification of MSWI emissions and a quantitative analysis of their driving mechanisms using RF, offering a critical data foundation and scientific basis for supporting synergistic pollution and carbon reduction. Full article

Cibotium barometz (L.) J. Sm., a medicinally significant fern in traditional Chinese medicine, is little explored at the genomic level regarding its bioactive compounds. Using an integrated approach combining Illumina and PacBio sequencing technologies, we profiled its root, rachis, and pinna transcriptomes, identifying 12,718, 21,341, and 11,441 unigenes, respectively. Our analysis systematically characterized the transcriptional features of transcription factors (TFs), simple sequence repeats (SSRs), long non-coding RNAs (lncRNAs), and differentially expressed genes (DEGs). Enrichment analyses highlighted the roles of highly expressed unigenes in secondary metabolism. Seventeen key enzymes involved in polysaccharide biosynthesis showed tissue-specific expression patterns. Notably, total polysaccharide content correlated positively with UDP-arabinose 4-epimerase (UXE) expression but negatively with phosphoglucomutase (PGM) and 3,5-epimerase/4-reductase (UER1). Flavonoid accumulation inversely correlated with chalcone synthase (CHS) expression. Two lignin pathways (H-lignin and G-lignin) were characterized, with phenylalanine ammonia-lyase (PAL), cinnamate-4-hydroxylase (C4H), and cinnamyl alcohol dehydrogenase (CAD) as key genes. The absence of ferulate-5-hydroxylase (F5H) explains the undetected S-lignin pathway. Regulatory network analysis revealed positive correlations between PAL expression and NAC72/NAC78/WRKY35 and C4H expression and WRKY65/WRKY69/WRKY71, while a negative correlation was revealed between flavonoid 3′,5′-hydroxylase (F3′5′H) and MYB3R4. This study provides comprehensive transcriptomic insights into C. barometz bioactive compound biosynthesis, serving as a foundation for mechanistic research. Full article

To implement a successful strawberry (Fragaria × ananassa) farming, fungal diseases must be detected in a timely manner so that informed crop protection decisions can be made. While field scouting is an option, it is manual and labor intensive. Scouting is also inaccurate and reduces efficiency due to micro-climatic lighting and field clutter, among other factors. StrawberryDualNet is a framework that supports Integrated Pest Management and automates symptom surveillance. We present dual-path CNN–Transformer fusion design that integrates two branches: a dynamic multi-scale convolution and a lightweight transformer. The former is able to capture fine-grained morphological lesion textures, while the latter captures overall contextual patterns. The two representations are fused through a learnable gating mechanism to decrease visual uncertainty amongst differing symptoms. We used a stratified five-fold cross-validation to evaluate the framework among five economically significant pathogens. Our approach significantly outperformed other automated scouting baselines, achieving 95.1% accuracy and 95.3% precision, respectively, and it is successful for Anthracnose, Gray Mold, Powdery Mildew, Rhizopus Rot, and Black Spot. The model is also scaled down compared to others (0.04 M parameters; 0.72 MB, 13–20× smaller than MobileNetV2/ShuffleNetV2) and is thus able to be deployed on devices that are lacking computational resources. For edge feasibility, we assessed reduced-precision inference; 16-bit floating point quantization preserved baseline performance at 83 FPS, whereas 8-bit integer quantization caused notable accuracy degradation. Overall, the proposed local–global fusion design provides an accurate, interpretable, and scalable tool for real-time disease phenotyping in precision horticulture. Full article

The objective of this study was to explore the effect of the assembly sequences of wall materials on the structure and properties of Antarctic krill peptide (AKP)-loaded ovalbumin (OVA)–chitosan (CS) nanoparticles (NPs). Two AKP-loaded NPs (CS/OVA-AKP and OVA/CS-AKP) were prepared by changing the sequences of OVA and CS. The results confirmed that CS/OVA-AKP had a smaller particle size (291 nm vs. 320 nm), lower polydispersity index (0.233 vs. 0.282), higher absolute zeta potential (34.4 mV vs. 32.1 mV), and higher encapsulation efficiency (81.6% vs. 75.4%) than OVA/CS-AKP. X-ray diffraction analysis confirmed that AKP was encapsulated in an amorphous state within the NPs. Fourier transform infrared spectroscopy and three-dimensional (3D) fluorescence spectroscopy revealed that electrostatic interactions, hydrogen bonding, and hydrophobic interactions were the primary driving forces for nanoparticle formation, with CS/OVA-AKP demonstrating a stronger OVA fluorescence quenching effect. Compared with OVA/CS-AKP, CS/OVA-AKP exhibited better redispersibility, and CS/OVA-AKP showed greater stability under various environmental factors (thermal treatment, salt concentration, pH, and storage time). During simulated gastrointestinal digestion, CS/OVA-AKP effectively protected AKP from gastric degradation and showed a higher AKP release rate in simulated intestinal fluid (61.1%) than OVA/CS-AKP (53.0%). The release followed the Korsmeyer–Peppas model, with OVA/CS-AKP exhibiting non-Fickian diffusion (n = 0.7500), and CS/OVA-AKP approached Case II transport (n = 0.9889), indicating erosion-controlled release behavior. CS/OVA-AKP also demonstrated higher hypoglycemic activity, with inhibition rates of 41.1%, 37.5%, and 36.1% for α-glucosidase, α-amylase, and DPP-IV, respectively. These findings underscore the important influence of wall-material assembly sequences on the structure and properties of AKP-loaded NPs, offering valuable insights for the development of bioactive peptide delivery systems. Full article

This paper addresses the critical challenge of semantic segmentation for remote sensing images (RSIs) under extremely limited labeled data. A high-quality initial model is paramount for downstream semi-supervised or weakly supervised learning paradigms, as it mitigates error propagation from the outset. We conducted a systematic investigation into self-supervised pretraining to serve this precise need. Within the low-label regime, we identify and tackle two pivotal factors limiting performance: (1) the domain shift between large-scale pretraining data and specific target tasks, and (2) the deficiency in local feature learning caused by large-window masking in visual foundation model (VFM) pretraining. To resolve these issues, we first benchmark various pretraining strategies, demonstrating that a two-phase General-Purpose Pretraining (GPPT) followed by Domain-Adaptive Pretraining (DAPT) framework is optimal, significantly outperforming both single-phase methods and the existing two-phase paradigm initialized from ImageNet. Subsequently, we propose an Edge-Guided Masked Image Modeling (EGMIM) method for the DAPT phase, which explicitly integrates edge priors to guide the masking and reconstruction process, thereby enhancing the model’s capability to capture fine-grained local structures. Extensive experiments on four RSI benchmarks validate the effectiveness of our approach, showing consistent and substantial gains, particularly in extreme low-label scenarios. Beyond empirical results, we provide in-depth mechanistic analyses to explain the synergistic roles of GPPT and DAPT. Full article

Background: Vesicourethral anastomotic stricture (VUAS) remains a clinically relevant complication following radical prostatectomy, with important implications for postoperative urinary function. Minimally invasive approaches may offer technical advantages; however, their impact on stricture formation in patients with microangiopathic risk factors remains incompletely defined. Objective: We aimed to compare the incidence of vesicourethral anastomotic stricture following open radical prostatectomy (ORP) and laparoscopic radical prostatectomy (LRP) in patients with microangiopathic comorbidities and to explore clinical and perioperative factors associated with stricture development. Materials and Methods: A retrospective two-centre cohort study was conducted including 115 patients who underwent radical prostatectomy for clinically localized prostate cancer between 2022 and 2024. All patients had at least one microangiopathic risk factor (diabetes mellitus, hypertension, or coronary artery disease). Seventy-two patients underwent ORP and forty-three underwent LRP. VUAS was defined by obstructive symptoms with endoscopic confirmation requiring intervention within 12 months postoperatively. Univariate analyses and exploratory logistic regression models were performed to assess factors associated with stricture formation. Results: Vesicourethral anastomotic stricture occurred in 21 patients (18.3%). The crude incidence of VUAS was lower after LRP compared with ORP (9.3% vs. 23.6%); however, this difference did not reach statistical significance. Patients who developed VUAS had a significantly higher body mass index, longer operative time, and greater intraoperative blood loss. In exploratory multivariable analyses, body mass index and operative duration were consistently associated with increased odds of stricture, whereas the effect of surgical approach was unstable and imprecise due to limited event numbers. Conclusions: In patients with microangiopathic risk factors, laparoscopic radical prostatectomy was associated with a lower crude incidence of vesicourethral anastomotic stricture compared with open surgery; however, this association was not robust after adjustment. Perioperative and technical factors appear to play a more prominent role in anastomotic healing than surgical approach alone. These findings highlight the importance of optimizing intraoperative conditions to reduce postoperative stricture risk. Full article

Autophagy plays a key role in the development and homeostasis of the cochlear organ. Alterations in the autophagic pathways have been associated with damage to auditory cell types and hearing impairment caused by an array of factors like age, ototoxicity, exposure to high levels of noise, or genetic mutations. Cochlear damage frequently entails mitochondrial dysfunction, impaired mitophagy and the accumulation of high concentrations of free radicals. This review summarizes the observations made to date on the autophagic function in response to cochlear damage and the results of either activating or inhibiting these processes. The data demonstrate that autophagic activity is cell context-dependent and varies according to the cochlear cell type, the toxic agent, its levels and the length and timing of its administration; other factors that influence the autophagic response may be external to the auditory system or related to epigenetic changes or the expression of genetic variants. Modulation of the autophagic status has an effect on auditory cell loss and the progression to hearing impairment and this approach has thus become a promising avenue towards the protection of the hearing function. Nonetheless, this is no easy task and it will require the identification of reliable biomarkers to evaluate the dynamics of autophagic activity as well as the development of specific autophagy modulators that do not exert toxicity. Full article

Background/Objectives: Dementia represents a complex syndrome in which biological, psychological, social, and cultural dimensions intersect. While its clinical features are well documented, less is known about how lived experiences, caregiving contexts, and cultural beliefs shape the trajectory of illness. This study explored clinical, behavioral, and socio-cultural dimensions related to the quality of life of people living with dementia from an anthropological perspective, focusing on the interaction between comorbidities, cognition, lifestyle, and caregiving environments as reported by their informal caregivers. Methods: We conducted a single-center, observational cross-sectional study including 73 family caregivers of patients with clinically diagnosed dementia who accessed care at the Neurology–Psychiatry Department of the C.F.2 Clinical Hospital (Bucharest, Romania) between November 2023 and April 2024. Caregivers provided socio-demographic, behavioral, lifestyle, and cultural information using a newly developed anthropological questionnaire. Descriptive and exploratory inferential analyses were performed to examine relationships between cognitive performance, comorbidities, lifestyle factors, and socio-cultural variables. Results: People with dementia had a mean age of 79.2 ± 7.5 years (range 66–95) and were predominantly female (71.2%). Multimorbidity was common, averaging 2.22 ± 1.03 chronic conditions, mainly neurological (84.9%) and cardiovascular (68.5%). The mean BMI was 26.1 ± 3.8 kg/m². Cognitive impairment was substantial (MMSE mean 11.47 ± 7), with descriptively lower scores among older individuals and those with lower education or income, although inferential tests were underpowered. Appetite and sleep disturbances were frequent and tended to co-occur with lower activity levels. Disclosure of diagnosis occurred in 74% of cases; reactions varied widely, ranging from acceptance to denial, confusion, anxiety, and sadness. Family responses likewise reflected a heterogeneous and often ambivalent adjustment process. Cultural beliefs and spirituality played a salient role in shaping explanatory models and coping strategies, with many caregivers attributing importance to religious practices and, to a lesser extent, alternative treatments. Conclusions: In this Romanian cohort, dementia was shaped not only by age-related multimorbidity and cognitive decline but also by caregiving practices, socioeconomic constraints and culturally grounded interpretations of illness. These findings highlight the relevance of integrative approaches to dementia care that consider medical, behavioral, and socio-cultural dimensions and that incorporate caregiver perspectives to improve the quality of life of both patients and families. Full article

In forensic pathology, accurately estimating the time since injury is essential. Current histological and imaging approaches commonly miss subtle temporal changes, especially in deaths occurring within hours of injury. This review discusses the timing of neuroinflammation after traumatic brain injury and emphasizes possible markers for estimating the time of injury in forensic cases. Promising markers include microglial activation (allograft inflammatory factor 1 and transmembrane protein 119, detectable within 10 min to 2 h), β-amyloid precursor protein accumulation (20–35 min), high-mobility group box 1 translocation (2–6 h), cytokine fluctuations (IL-1β and TNF-α peak between 4 and 24 h, IL-6 shows delayed, extended elevation), sequential leukocyte infiltration (neutrophils from 2 to 48 h, lymphocytes after 3–5 days), blood–brain barrier breakdown markers such as fibrinogen and IgG leakage, loss of tight junction proteins (2–3 h), matrix metalloproteinase-9 activity (peaking at 24–48 h), and reactive astrocytosis with increased glial fibrillary acidic protein levels (from 12 to 24 h onward). The association between injury severity and inflammation is influenced by factors such as age, genetics (e.g., APOE ε4), coexisting conditions, and preexisting inflammation, which reduce the reliability of individual markers. A multiparametric approach may offer the best prospects to improve the accuracy of post-traumatic and post-mortem interval assessment in medicolegal cases. Full article

Caprylic acid (CA) fractionation of serum is a simple and cost-effective method of producing high-quality immunoglobulins. While standardised procedures exist for CA purification of IgG for various animals, no published protocol exists for baboon IgG. This study aimed to optimise an efficient protocol for purifying IgG from baboon serum using CA through a stepwise one-factor-at-a-time (OFAT) approach. The effects of serum pH, CA concentration, stirring time and intensity, dialysis buffer, and lyophilisation were evaluated based on the protein content, with SDS-PAGE profiles and albumin–globulin ratios distinguishing IgG from residual albumin. Serum at pH 5.0 with 7% CA (v/v) produced the highest yield, minimising albumin while maximising IgG content. Lower pH (4.0–4.5) and CA (5–6%) reduced protein content, while a higher pH (5.5–6.0) and CA (8–15%) increased protein, but with elevated albumin and contaminants. Stirring serum vigorously at 1200 rpm for 60 min provided effective precipitation of non-IgG proteins. Lower intensities and shorter times resulted in higher albumin and residual proteins, while excessive stirring caused protein denaturation. Dialysis buffer composition had little impact, while lyophilisation significantly enhanced IgG concentration. The optimal protocol involved serum at pH 5.0, 7% CA (v/v), vigorous stirring (1200 rpm) for 60 min, and dialysis against sodium phosphate buffer (pH 7.4) followed by lyophilisation. The resulting IgG enrichment and purity were comparable to commercial-grade products. This study thus established optimal conditions for the purification of baboon IgG with CA, which could be used to support research in this animal model of immunology. Full article

With renewable integration and zero-carbon microgrids achieving 100% penetration, converter-dominated systems exhibit millisecond-timescale transient synchronization, which challenges existing physical cognitive methods and cognitive methodology with the synchronous generator (SG). In this paper, in order to quantificationally analyze the transient synchronization, a unified framework has been proposed that combines the generalized participation factor (GPF) method and basin of attraction (BOA) boundary analysis using the manifold approach. According to the GPF and BOA analyses, the fourth-order models are essential for accurate stability quantification, with synchronization controls (PLL, VSG, and droop control) contributing greater than 70% to transient dynamics versus about 20% from power-balance interactions. Further, the dynamic security region (DSR) is redefined by two typologies. Type 1 DSR maps stability in active-power injection space, and Type 2 DSR (generalized DSR) delineates limits in the controllable parameter space. The estimation procedures are proposed for these two types of DSRs by the BOA method. Finally, electromagnetic transient simulations and critical clearing time validation are employed for fidelity verification of models and estimation approaches. To sum up, the proposed novel framework enables systematic DSR estimations for renewable-rich power systems, empowering grid operators to optimize converter-controllable parameters and system operation conditions. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

Background/Objectives: Dementia-related cognitive impairments and staffing shortages in nursing homes challenge the possibilities for individually tailored recreational activities, raising the question of how the physical and social environment might be leveraged to stimulate engagement through response facilitation, a form of vicarious incentive motivation grounded in Social Cognitive Theory. This study examines in which social contexts observing others’ recreational activities can effectively engage residents with moderate to advanced dementia. Methods: A qualitative, scenario-based multiple case study was conducted in four nursing homes (n = 21), using fly-on-the-wall observations, narratives, and three experimentally embedded social contexts (individual, dyadic, group) around familiar leisure activities. Behavioural engagement, mood, and agitation were assessed with validated observational scales (e.g., OERS and MEDLO), complemented by wearable sensor data (HR/PR, HRV/PRV, SCL, and temperature) and video for contextualised interpretation. Results: Across scenarios, non-participating residents showed limited behavioural responses in individual and dyadic settings, while group activities more frequently elicited both observable engagement and physiological markers consistent with attention or cognitive engagement. Observational and physiological data frequently diverged, which may indicate cognitive or emotional engagement even when overt participation or affect remained minimal or appeared negative. Conclusions: Response facilitation appears most likely in structured group activities if supported by explicit social scaffolding, rather than in individual or dyadic constellations alone. Reliance on behavioural observation or environmental design in isolation risks underestimating engagement; multimodal, context-sensitive approaches are recommended to better harness social mechanisms for meaningful participation in dementia care. Future research should integrate contextual factors with physiological measurements and observations as well as further explore patterns of inactivity to distinguish disengagement from subtle forms of cognitive engagement. Full article