Search Results (1,583)

Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants. Here we demonstrate the clinical utility of epigenetic signatures in prioritizing variants of uncertain significance in genes associated with developmental delay (DD) and intellectual disability (ID). Methods: Genome sequencing was performed in a male with developmental delay. He was found to have VUSs in both PHF6 and DDB1 genes, linked with Börjeson–Forssman–Lehmann syndrome (BFLS) and White–Kernohan syndrome (WHIKERS), respectively. These two disorders share a similar phenotype but have distinct inheritance patterns and molecular pathogenic mechanisms. DNA methylation profiling (DNAm) of whole blood was performed using the clinically validated EpiSign assay. Results: The proband’s methylation profile demonstrated a strong correlation with the BFLS methylation signature, supporting the PHF6 variant as a likely cause of his neurodevelopmental disorder. Conclusions: Epigenetic testing for disorders with distinct methylation patterns can provide diagnostic utility when a patient presents with variants of uncertain significance in genes associated with developmental delay. Epigenetic signatures can also guide genetic counselling and family planning. Full article

Nosocomial infections caused by ESKAPE pathogens represent a significant burden to global health. These pathogens may exhibit multidrug resistance (MDR) mechanisms, of which mechanisms such as efflux pumps and biofilm formation are gaining significant importance. Multidrug resistance mechanisms in ESKAPE pathogens have led to an increase in the effective costs in health care and a higher risk of mortality in hospitalized patients. These pathogens utilize antimicrobial efflux pump mechanisms and bacterial biofilm-forming capabilities to escape the bactericidal action of antimicrobials. ESKAPE bacteria forming colonies demonstrate increased expression of efflux pump-encoding genes. Efflux pumps not only expel antimicrobial agents but also contribute to biofilm formation by bacteria through (1) transport of molecules and transcription factors involved in biofilm quorum sensing, (2) bacterial fimbriae structure transport for biofilm adhesion to surfaces, and (3) regulation of a transmembrane gradient to survive the difficult conditions of biofilm microenvironments. The synergistic role of these mechanisms complicates treatment outcomes. Given the mechanistic link between biofilms and efflux pumps, therapeutic strategies should focus on targeting anti-biofilm mechanisms alongside efflux pump inactivation with efflux pump inhibitors. This review explores the molecular interplay between efflux pumps and biofilm formation, emphasizing potential therapeutic strategies such as efflux pump inhibitors (EPIs) and biofilm-targeting agents. Full article

In this work, we demonstrate high-efficiency 385 nm AlGaN-based near-ultraviolet micro light emitting diode (NUV-Micro LED) arrays. The epi structure is prepared using a novel AlN-inserted superlattice electrical blocking layer which enhances hole spreading in the p-type region significantly. The NUV-Micro LED arrays in this work comprise 228 chips in parallel with wavelengths at 385 nm, and each single chip size is 15 × 30 μm². Compared with conventional bulk AlGaN-based EBL structures, the NUV-Micro LED arrays that implemented the new hole spreading enhanced superlattice electrical blocking layer (HSESL-EBL) structure proposed in this work had a remarkable increase in light output power (LOP) at current density, increasing the range down from 0.02 A/cm² to as high as 97 A/cm². The array’s light output power is increased up to 1540% at the lowest current density 0.02 A/cm², and up to 58% at the highest current density 97 A/cm², measured under room temperature (RT); consequently, the WPE is increased from 13.4% to a maximum of 30.18%. This AlN-inserted HESEL-EBL design significantly enhances both the lateral expansion efficiency and the hole injection efficiency into the multi quantum well (MQW) in the arrays, improving the concentration distribution of the holes in MQW while maintaining good suppression of electron leakage. The array’s efficiency droop has also been greatly reduced. Full article

Proanthocyanidins are a subclass of flavonoids formed through a poorly understood polymerization process that forms chains of 3–30 catechins and epi-catechins. Proanthocyanidins serve as UV protectants and antifeedants that accumulate in diverse plant species, including the lotus. To identify candidate genes underlying proanthocyanidin synthesis and polymerization, we generated and functionally annotated transcriptomes from seedpods and seed epicarps of two lotus cultivars, “Guoqing Hong” and “Space Lotus”, which accumulate markedly divergent proanthocyanidin levels across the immature, near-mature, and mature developmental stages. Our transcriptome analysis was based on a total of 262.29 GB of raw data. We aligned the transcriptome data with the lotus genome and obtained an alignment efficiency that ranged from 91.74% to 96.44%. Based on the alignment results, we discovered 4774 new genes and functionally annotated 3232 genes. A total of 14,994 differentially expressed genes (DEGs) were identified from two-by-two comparisons of transcript libraries. We found 61 DEGs in the same developmental stage in the same tissue of different species. Comparative transcriptome analysis of seedpods and seed epicarps from two cultivars identified 14,994 differentially expressed genes (DEGs), of which 10 were functionally associated with proanthocyanidin synthesis and 9 were possibly implicated in the polymerization reactions. We independently quantified the expression of the candidate genes using qRT-PCR. Significant differences in the expression of candidate genes in different tissues and periods of lotus species are consistent with particular genes contributing to the polymerization of catechins and epi-catechins into proanthocyanidins in lotus seedpods and seed epicarps. Full article

Background: Exocrine pancreatic insufficiency (EPI or PEI) may be prevalent in as many as 3 of 10 people with diabetes due to exocrine pancreatic function being reduced as early as the time of diagnosis. EPI can be treated with pancreatic enzyme replacement therapy (PERT), but the symptom burden of EPI remains high and improved screening and diagnosis methods are needed. Methods: An online survey (n = 324) evaluated the gastrointestinal symptom experiences of people with (n = 155) and without (n = 169) EPI using a novel symptom tool, the Exocrine Pancreatic Insufficiency Symptom Score (EPI/PEI-SS). A large sub-group (n = 120) of people with diabetes with EPI (Type 1, n = 14, Type 2, n = 20) or without EPI (Type 1, n = 78; Type 2; n = 6) was characterized and compared to those without diabetes (n = 204) in a sub-analysis of the larger EPI/PEI-SS study. Results: The symptom burden of EPI is similar, irrespective of diabetes. Like those without diabetes, people with type 1 diabetes with EPI had a statistically significant (p < 0.001) higher mean score (range 0–225) on the EPI/PEI-SS (100.86, SD: 48.92) than people with T1D without EPI (31.59, SD: 28.25), distinct from other GI conditions (p < 0.001). Similar patterns occurred in those with T2D. Conclusions: High EPI/PEI-SS scores seem to distinguish between likely EPI and other GI conditions among people with diabetes, and the EPI/PEI-SS should be further studied as a possible screening method for EPI at a population level. It should also be evaluated as a tool to aid individuals with diabetes in tracking changes to EPI symptoms over time based on PERT titration. Full article

Background/Objectives: Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) vary both in European countries and in other geographical regions. The aim of our retrospective study was to present the genetic variants identified in a group of 48 CF patients from the Moldova region (Romania), as well as to establish genotype–phenotype correlations. Methods: Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or those in whom no mutation was detected, CFTR gene sequencing (NGS) was performed. Results: The compound heterozygous genotype was identified in 26 (54.16%) of the patients (with one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by G542X (6.25%, 6/96). Several new variants were also identified that had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). Phenotypic manifestations in patients with CFTR class I, II, III and VII variants (homozygous and compound heterozygous) were more severe compared to those in patients with CFTR class IV, V and VI mutations, with the data obtained being consistent with those in the literature. Respiratory tract involvement was present in 77.08% of the patients, being more frequent in patients with the compound heterozygous genotype compared to the homozygous F508del genotype. Most patients had exocrine pancreatic insufficiency (EPI) (85.41%). Gastrointestinal manifestations included hepatocytolysis (66.66%) and biliary cirrhosis (0.41%). Meconium ileus was detected in 18.75% of patients, all with a compound heterozygous genotype. Conclusions: We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis. Full article

Accurate in vitro models of intestinal permeability are essential for predicting oral drug absorption. Standard models like Caco-2 cells have well-known limitations, including lack of segment-specific physiology, but are widely used. Emerging models such as organoid-derived monolayers and microphysiological systems (MPS) offer enhanced physiological relevance but require comparative validation. We performed a head-to-head evaluation of Caco-2 cells, human jejunal (J2) and duodenal (D109) enteroid-derived cells, and EpiIntestinal^TM tissues cultured on either static Transwell and flow-based MPS platforms. We assessed tissue morphology, barrier function (TEER, dextran leakage), and permeability of three model small molecules (caffeine, propranolol, and indomethacin), integrating the data into a physiologically based gut absorption model (PECAT) to predict human oral bioavailability. J2 and D109 cells demonstrated more physiologically relevant morphology and higher TEER than Caco-2 cells, while the EpiIntestinal^TM model exhibited thicker and more uneven tissue structures with lower TEER and higher passive permeability. MPS cultures offered modest improvements in epithelial architecture but introduced greater variability, especially with enteroid-derived cells. Predictions of human fraction absorbed (F_abs) were most accurate when using static Caco-2 data with segment-specific corrections based on enteroid-derived values, highlighting the utility of combining traditional and advanced in vitro gut models to optimize predictive performance for F_abs. While MPS and enteroid-based systems provide physiological advantages, standard static models remain robust and predictive when used with in silico modeling. Our findings support the need for further refinement of enteroid-MPS integration and advocate for standardized benchmarking across gut model systems to improve translational relevance in drug development and regulatory reviews. Full article

This study aimed to quantitatively and qualitatively evaluate the content of carnosic acid (CA), 12-O-methyl-carnosic acid (12MCA), carnosol (CS), rosmanol (RO) and 7-O-methyl-epi-rosmanol (7MER) in 61 Lamiaceae plants growing in Greece, using ¹H-qNMR spectroscopy as a simple, rapid and direct method without sample deterioration. For this purpose, methanol extracts from 18 genera (e.g., Salvia, Mentha, Melissa, Ocimum) were analyzed using isolated and fully characterized metabolites, previously identified by our group, as standards. At least one of the target compounds was detected in 22 species, predominantly belonging to the genus Salvia. Notably, 7MER and RO were not detected in any extract. CA, CS and 12MCA were exclusively found in Salvia species, with S. somalensis, S. officinalis and S. fruticosa emerging as the richest sources of these diterpenes. Among them, S. somalensis showed the highest concentration of CA (>30 mg/g), while 12MCA was most abundant in S. microphylla. These results highlight Salvia as the most promising genus for the accumulation of bioactive abietane-type diterpenes. The implementation of ¹H-qNMR for such chemical profiling provides a reliable approach toward the phytochemical standardization of plant extracts, supporting their further use in nutraceutical or pharmaceutical formulations. Full article

Deep learning-based super-resolution (SR) frameworks are widely used in remote sensing applications. However, existing SR models still face limitations, particularly in recovering contours, fine features, and textures, as well as in effectively integrating channel information. To address these challenges, this study introduces a novel residual model named OARN (Optimized Attention Residual Network) specifically designed to enhance the visual quality of low-resolution images. The network operates on the Y channel of the YCbCr color space and integrates LKA (Large Kernel Attention) and OCM (Optimized Convolutional Module) blocks. These components can restore large-scale spatial relationships and refine textures and contours, improving feature reconstruction without significantly increasing computational complexity. The performance of OARN was evaluated using satellite images from WorldView-2, GaoFen-2, and Microsoft Virtual Earth. Evaluation was conducted using objective quality metrics, such as Peak Signal-to-Noise Ratio (PSNR), Structural Similarity Index Measure (SSIM), Edge Preservation Index (EPI), and Perceptual Image Patch Similarity (LPIPS), demonstrating superior results compared to state-of-the-art methods in both objective measurements and subjective visual perception. Moreover, OARN achieves this performance while maintaining computational efficiency, offering a balanced trade-off between processing time and reconstruction quality. Full article

Background: Percutaneous electrolysis (PE) is a minimally invasive procedure that utilizes galvanic current delivered through a needle. PE is increasingly employed for musculoskeletal disorders, despite the scarcity of scientific evidence supporting its use. The aim of this systematic review is to synthesize the existing evidence and explore the applications of PE in rehabilitation. Methods: In line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted across the PubMed, Web of Science, Scopus, and PEDro databases from inception to July 2025. The search strategy employed the term “Percutaneous Electrolysis” without applying additional filters or time restrictions, ensuring a comprehensive search. Cited references from screened articles were also evaluated for potential inclusion. Studies were included if they met the following criteria: peer-reviewed articles, intervention-based research, relevance to the topic, and publication in English. Results: Of the 181 papers retrieved, 143 were excluded for various reasons, leaving 38 studies. The evidence suggests that PE appears effective in reducing pain and improving function, particularly when combined with exercises such as eccentric training or stretching, though inconsistencies in protocols and patient characteristics, along with unclear mechanisms, show that it warrants further investigation. Conclusions: In conclusion, while PE emerges as a promising therapeutic strategy for musculoskeletal disorders, its full integration into rehabilitation practice necessitates further rigorous research to standardize treatment protocols, elucidate the underlying mechanism, and validate its cost-effectiveness. These steps are essential to establish PE as a robust and evidence-based option within the field of rehabilitation. Full article

Consider an evolving epidemic in which each person is either (S) susceptible and healthy; (E) exposed, contagious but asymptomatic; (I) infected, symptomatic, and quarantined; or (R) recovered, healthy, and susceptible. The inference problem, given (i) who is showing symptoms (I) and who is not (S, E, R) and (ii) the distribution of meetings among people each day, is to predict the number of infected people (state I) in future days (e.g., 1 through 20 days out into the future) for the purpose of planning resources (e.g., needles, medicine, staffing) and policy responses (e.g., masking). Each prediction horizon has different uses. For example, staffing may require forecasts of only a few days, while logistics (i.e., which supplies to order) may require a two- or three-week horizon. Our algorithm and system EpiInfer is a non-Markovian approach to forecasting infection rates. It is non-Markovian because it looks at infection rates over the past several days in order to make predictions about the future. In addition, it makes use of the following information: (i) the distribution of the number of meetings per person and (ii) the transition probabilities between states and uses those estimates to forecast future infection rates. In both simulated and real data, EpiInfer performs better than the standard (in epidemiology) differential equation approaches as well as general-purpose neural network approaches. Compared to ARIMA, EpiInfer is better starting with 6-day forecasts, while ARIMA is better for shorter forecast horizons. In fact, our operational recommendation would be to use ARIMA (1,1,1) for short predictions (5 days or less) and then EpiInfer thereafter. Doing so would reduce relative Root Mean Squared Error (RMSE) over any state of the art method by up to a factor of 4. Predictions of this accuracy could be useful for people, supply, and policy planning. Full article

The depletion of global fish stocks poses a major challenge to sustainable development, particularly in economies where marine resources are critical to livelihoods and food security. In this study, the relationship between economic development and the sustainability of fish stocks is examined using the Environmental Kuznets Curve (EKC). We use panel data from 32 economies between 2002 and 2020 and analyze the fish stock status indicator (EPI_FSS) from the Environmental Performance Index, which captures the proportion of national catches from overfished or collapsed stocks. Using a dynamic panel approach and the generalized method of moments (GMM), we investigate how the human development index (HDI) and other socio-economic factors influence changes in the state of fish stocks. Our results show a statistically significant inverted-U-shaped (∩-shaped) relationship between the HDI and the state of fish stocks, suggesting that the deterioration of fish stocks increases at lower levels of development, but improves beyond a certain threshold. In addition, higher levels of foreign direct investment (FDI), education, and research and development (R&D) spending are associated with better outcomes for fish stocks. These results suggest that while early economic growth may put pressure on marine resources, sustained investment in human capital, innovation, and global integration is critical to promoting long-term marine sustainability. Full article

Post-traumatic stress disorder (PTSD) has traditionally been viewed as a psychiatric disorder of fear, memory, and emotional regulation. However, growing evidence implicates systemic and neuroinflammation as key contributors. Individuals with PTSD often exhibit elevated blood levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and C-reactive protein, indicating immune dysregulation. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis marked by reduced cortisol levels impair the body’s ability to regulate inflammation, allowing persistent immune activation. Circulating cytokines cross a weakened blood–brain barrier and activate microglia, which release additional inflammatory mediators. This neuroinflammatory loop can damage brain circuits critical to emotion processing including the hippocampus, amygdala, and prefrontal cortex, and disrupt neurotransmitter systems like serotonin and glutamate, potentially explaining PTSD symptoms such as hyperarousal and persistent fear memories. Rodent models of PTSD show similar inflammatory profiles, reinforcing the role of neuroinflammation in disease pathology. Bromo-epi-androsterone (BEA), a synthetic analog of dehydroepiandrosterone (DHEA), has shown potent anti-inflammatory effects in clinical trials, significantly reducing IL-1β, IL-6, and TNF-α. By modulating immune activity, BEA represents a promising candidate for mitigating neuroinflammation and its downstream effects in PTSD. These findings support the rationale for initiating clinical trials of BEA as a novel therapeutic intervention for PTSD. Full article

Background/Objectives: The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. Food and Drug Administration were quantified using the human-derived sublingual HO-1-u-1 and buccal EpiOral™ in vitro tissue models. Methods: Epithelial barrier properties were monitored using propranolol and Lucifer Yellow as prototypic transcellular and paracellular markers. APIs were dissolved in artificial saliva, pH 6.7, and transepithelial flux from the apical to the basolateral compartment was quantified using HPLC. Results: Apparent permeability coefficients (Papp) calculated for these APIs in the sublingual HO-1-u-1 tissue model varied from Papp = 2.72 ± 0.06 × 10⁻⁵ cm/s for asenapine to Papp = 6.21 ± 2.60 × 10⁻⁵ cm/s for naloxone. In contrast, the buccal EpiOral™ tissue model demonstrated greater discrimination power in terms of permeation properties for the same APIs, with values ranging from Papp = 3.31 ± 0.83 × 10⁻⁷ cm/s for acyclovir to Papp = 2.56 ± 0.68 × 10⁻⁵ cm/s for sufentanil. The tissue-associated dose fraction recovered at the end of the transport experiment was significantly increased in the buccal EpiOral™ tissue model, reaching up to 8.5% for sufentanil. Conclusions: Experimental permeation data collected for selected APIs in FDA-approved oral cavity products will serve as a training set to aid the development of predictive computational models for improving algorithms that describe drug absorption from the oral cavity. Following a robust in vitro–in vivo correlation analysis, it is expected that such innovative in silico modeling strategies will the accelerate development of generic oral cavity products by facilitating the utility of model-integrated evidence to support decision making in generic drug development and regulatory approval. Full article

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents. Full article