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Objective: Sporopollenin exine capsules (SpECs) have been used to encapsulate active pharmaceutical agents for oral drug delivery. This study investigated whether fragrance encapsulated within SpECs prolonged perceived fragrance intensity compared with fragrance oil alone. Methods: A double-blind, placebo-controlled, randomized pilot study was conducted (clinical trial number: NCT07383337); ten healthy female participants (mean age 35.4 ± 5.6 years) received fragrance with SpEC-encapsulated fragrance (SpECs) on one wrist and fragrance alone (control) on the contralateral wrist. The fragrance intensity was assessed using a visual analogue scale (0-10) by both the participants and an independent blinded reviewer at baseline and after 2, 4 and 8 h. Paired Wilcoxon signed-rank tests and linear mixed-effects models were used for analysis. In vitro cytotoxicity was assessed using an ATP viability assay in human bronchial epithelial (BEAS-2B) cells exposed to SpECs or raw Lycopodium clavatum spores. Results: There were no significant differences between the formulations at baseline. From 2 h onward, SpECs was associated with significantly a higher fragrance intensity compared with the control for both participant-rated (p = 0.03 at 2 and 4 h; p = 0.005 at 8 h) and reviewer-rated assessments (p = 0.02 at 2 h; p = 0.01 at 4 h; and p = 0.008 at 8 h). Mixed-model analyses suggested a greater decline in intensity for control at 8 h for reviewer-rated assessments. In vitro, raw spores significantly reduced cell viability (as an indicator of potential allergenicity), whereas SpECs did not differ from control. Conclusions: Fragrance encapsulation within SpECs significantly prolongs measured fragrance intensity with no evidence of cytotoxicity. These findings support the potential of SpECs as a safe and effective sustained-release platform for topical fragrance formulations.

Developing photoactive materials with promoted charge separation and interfacial electron transfer represents an effective avenue for enhancing the performance of self-powered photoelectrochemical biosensors (SPECs). In this work, a TiO2/fluorinated covalent organic framework (FCOF) decorated with Pt nanoparticles (TiO2/FCOF/Pt) has been developed as photocathode material for SPECs, in which a target-induced dual steric hindrance effect is also integrated as a sensing mechanism. Due to the hot-electron effect, the Pt nanoparticles act as electron sinks for the formation of a directional electron transfer pathway (TiO2→FCOF→Pt), which suppresses the electron-hole recombination and thus improves the photoresponsive ability of TiO2/FCOF/Pt photocathode. When using CYFRA21-1 as a target analyte, Fe3O4 nanospheres can be immobilized onto the TiO2/FCOF/Pt photocathode via sandwich immunoreactions, yielding a steric effect. Meanwhile, the Fe3O4 nanospheres can also mimic peroxidase-like activity and mediate the precipitation reaction, further magnifying the steric hindrance and attenuation in the open circuit voltage of SPECs. Benefiting from the excellent photoresponsive ability and the dual steric hindrance effect, this developed SPECs has realized the analysis of CYFRA21-1 with satisfactory results. This work not only provides a promising tool for the clinical analysis of lung cancer but also offers an effective strategy to improve the directional electron transfer in heterojunction photosystems.

Sporopollenin Exine Capsules (SpECs) were studied as particle stabilizers in all-aqueous emulsions of polyethylene glycol (PEG) and dextran (Dex) (8 % PEG: 6 % Dex). To investigate the role of particle interactions on stabilization mechanisms, SpECs were derivatized to provide positive charges through amidation, and neutral particles via acetylation. Emulsions with non-derivatized SpECs were stable only at pH 6 and 7 when negative charge was high (around -30 mV). Acetylated SpECs with low charge did not stabilize emulsions, while amidated SpECs stabilized the emulsions at all pH values, independent of the charge. Confocal microscopy showed that emulsion stabilization was most likely obtained through two effects: 1) particle adsorption at the interface through a Pickering-like mechanism, and 2) additional electrostatic repulsion between particles in the continuous phase. Overall, this study revealed diverse mechanisms by which SpECs can stabilize all-aqueous emulsions, highlighting their versatility to be used for specific applications.

Non-communicable diseases (NCDs) have become the leading cause of mortality globally, with a sharp rise in Iran due to lifestyle changes and urbanisation. Although many NCD risk factors are modifiable, limited understanding of their determinants hinders effective prevention. To address this, the Prospective Epidemiological Research Studies in Iran (PERSIAN) Cohort was established in 2014 to study NCDs nationwide. The Sabzevar PERSIAN Cohort Study (SPECS) is the first in northeastern Iran, aiming to investigate environmental and social factors influencing NCDs in a unique regional context. SPECS enrolled 5174 adults (aged 35-70 years) in northeastern Iran between January 2018 and January 2019 through a census and an online registration process. The baseline data collection included demographic verification, informed consent, health questionnaires, anthropometric measurements and biological samples (blood, urine, hair, nails). The annual follow-up began in April 2019, with full reassessments every 5 years over a 15-year period. The data is gathered via an active and passive follow-up, supported by trained staff and registry linkages. Of the 5174 participants, 4241 (81%) remained in the study. Among the cohort, 54.5% were female, with a mean age of 50.5 years. The majority were married (93.5%), and nearly half had at least high-school education (46.5%) and moderate socioeconomic status (49.4%). Drug abuse history (smoking/drugs) was reported by about 15% of the sample. The mean body mass index was 26.9 kg/m², and the average blood pressure was higher in males (118.1/74.0 mm Hg) than in females (111.5/70.2 mm Hg). The common conditions included hypertension (22.8%), kidney stones (22.4%), fatty liver (15.4%) and diabetes (13.8%). Cancer had the highest treatment rate (100%), while fatty liver had the lowest (70.1%). Stroke had the highest mean age of onset (51.2 years), and epilepsy the lowest (23.7 years). All health data were self-reported. SPECS, part of the national PERSIAN cohort initiative, is the only adult NCD-focused study in Khorasan Razavi. Its 15-year follow-up aims to generate region-specific insights into the incidence of NCDs and their risk factors. The ethnically homogeneous sample enhances statistical power, and the findings may inform culturally tailored health policies. While self-reported data have limitations due to bias, high initial participation and access to free healthcare support long-term engagement, especially among lower-income groups.

Exploration of signal amplification strategy is an important link during the development of self-powered photoelectrochemical biosensors (SPECs). Herein, we develop a dual-electrode-cooperating signal amplification mode by transferring the released component of Z-scheme heterojunction onto opposite photoelectrode, and integrate it with DNA entropy-driven amplification design for ultrasensitive SPECs bioanalysis. Specifically, microRNA-155, the model analyte triggers the entropy-driven DNA circuit to release large amounts of output DNAs, which can competitively hybridize with the partial complementary DNA double strand between TiO2 nanospheres and Sb2S3/Au photoanode for initiating the release of TiO2 nanospheres. In this case, the formed Z-scheme heterojunction on photoanode will suffer destruction, generating a positive shift of photoanode potential and thus a decrease in the open circuit voltage (EOCV) of SPECs. Meanwhile, the DNA on the surfaces of these liberated TiO2 nanospheres can further hybridize with the hairpin DNA anchored on CuO/Cu2O photocathode, leading to the formation of type-II heterojunction and the negative shift of photocathode potential. Therefore, an additional decrease in the EOCV of SPECs can be realized for cascading signal amplification. This work adds a new member to the family of signal amplification strategies from dual-electrode-cooperating perspective, which will attract more attentions in the field of SPECs and even other fuel cells-based biosensor.

Enterococcus faecium, a member of the ESKAPE pathogens, has become a significant clinical threat due to its rapidly increasing resistance to frontline antibiotics. This gram-positive bacterium has developed multidrug resistance through prolonged exposure to hospital environments, posing serious risks to immunocompromised patients. The present study aimed to identify novel therapeutic targets from the E. faecium genome and to explore the potential of marine natural products as anti-quorum sensing agents. A comprehensive subtractive proteomics pipeline incorporating non-human homology, essentiality, subcellular localization, druggability, and pathway uniqueness identified the accessory gene regulator A protein (AgrA) as a key target involved in quorum sensing, biofilm formation, and virulence. Following structural quality assessment, a hierarchy-based virtual screening of MNPs from the CMNPD and SPECS natural product libraries was carried out to identify potential AgrA inhibitors. The virtual screening workflow shortlisted three promising MNPs (CMNPD6428, CMNPD30814, and SPECS AE-765) with favourable binding affinities and pharmacokinetic properties. Docking scores ranged from - 7.46 to - 8.01 kcal/mol, and MM/GBSA binding free energy calculations (≤ - 50 kcal/mol) further supported their strong interactions. Pharmacokinetic evaluation indicated acceptable safety profiles. Density functional theory analysis confirmed the chemical stability and reactivity of the compounds through HOMO-LUMO energy gap assessment. Finally, 500 ns molecular dynamics simulations and principal component analysis-based free energy landscape mapping validated the structural stability and sustained binding of the identified MNPs within the AgrA binding pocket. Overall, this study highlights three promising MNPs as potential anti-quorum sensing leads against E. faecium, offering a foundation for future therapeutic development.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Decreased glucose metabolism and ATP levels are well-established early biomarkers of AD. Recent studies indicate that the activation of phosphoglycerate kinase 1 (PGK1), a critical enzyme in the glycolytic pathway, promotes glucose metabolism and ATP production, thus offering potential therapeutic benefits for AD. However, two significant gaps persist: The expression pattern of PGK1 across different brain cell types remains unclear, and the structural diversity of known PGK1 activators is limited, restricting comprehensive investigation. In this study, we show that PGK1 exhibits high expression in neurons in the brain, and that reduced PGK1 expression is evident in both AβO-induced SH-SY5Y cells and 3×Tg-AD mice. PGK1 overexpression mitigates AβO-induced damage by enhancing glycolysis. Through surface plasmon resonance and molecular dynamics simulations, we identify compound L03 (Specs ID: AT-051/43421517) as a novel PGK1 activator. Pretreatment with compound L03 protects against AβO-induced glycolytic dysfunction in SH-SY5Y cells. Furthermore, administration of compound L03 ameliorates cognitive deficits, Aβ deposition, and Tau hyperphosphorylation in 3×Tg-AD mice. Our findings highlight PGK1 as a crucial regulator of neuronal bioenergetics in AD and position compound L03 as a promising PGK1 activator for restoring glycolytic function.

Physical exercise (PE) benefits both physical fitness and cognitive function. As a major source of myokines, skeletal muscle links PE to brain health. Irisin, cleaved from FNDC5, is a PE-induced myokine that crosses the blood-brain barrier and is also expressed in neurons, suggesting complex roles in the central nervous system. In this study, mice were subjected to 4 weeks of treadmill exercise (15  m/min, 30  min/day, 3  days/week). PE reduced anxiety‑like behaviors in open field and elevated plus maze tests and upregulated FNDC5/irisin in the amygdala. Amygdalar FNDC5/irisin knockdown abolished the anxiolytic effects of PE, while local overexpression recapitulated them. Mechanistically, FNDC5/irisin suppressed amygdalar neuronal excitability and excitatory synaptic transmission through astrocytic glutamate transporter‑1 (GLT1). Based on the GLT1‑FNDC5 binding interface, we identified the small molecule AG‑205/36953163 (AG205, SPECS library ID: 36953163). Intraperitoneal administration of AG‑205 (1  mg·kg-1·d-1, 3  days) exerted significant anxiolytic effects. Our findings reveal that FNDC5/irisin in the amygdala mediates the anxiolytic effects of PE via direct neural regulation, offering a potential target for anxiety‑related disorders.

Objectives: Individuals under community supervision (e.g., probation and parole) have high rates of illicit substance use (ISU) and substance use disorders (SUDs), increasing their risk for numerous health issues, including HIV transmission. While SUD treatment can reduce substance use and HIV transmission risk, gaps remain in our understanding of its receipt among community-supervised individuals at risk for HIV. Methods: Using baseline data from the Southern Pre-Exposure Prophylaxis Study (SPECS), we examined the prevalence and demographic characteristics associated with SUD treatment receipt among community-supervised individuals at risk for HIV. Two participant subsets from SPECS were analyzed: those with a history of ISU (n = 346) and, among these participants, those specifically reporting a history of illicit opioid use (IOU; n = 211). Results: A high prevalence of SUD treatment receipt was found among participants reporting ISU (58.7%) and IOU (73.9%). Among participants with a history of ISU, Black non-Hispanic individuals had a significantly lower prevalence of treatment receipt than White non-Hispanic individuals (aPR = 0.68, 95% CI: 0.51, 0.90, p = 0.007). Among participants reporting IOU, White non-Hispanic individuals were 2.7 (95% CI: 1.2, 6.3) times more likely to receive medication for an SUD than individuals of any other race or ethnicity. Conclusions: Study findings highlight missed opportunities to engage people on community supervision who are at risk for HIV in evidence-based SUD care. Targeted efforts are needed to promote the adoption of medications for opioid use disorders (MOUDs) among individuals under community supervision, particularly for racially minoritized populations.

The KRAS G12D mutation is commonly found in pancreatic cancer and is integral to the cell signaling pathway, making it a critical target for drug development. Structure-based virtual screening (SBVS) is a conventional strategy for discovering new inhibitors and expanding the chemical space against KRAS G12D. However, the SBVS efforts needed to be evaluated and benchmarked. Herein, in the first stage of the study, we evaluated two popular docking tools (FRED and AutoDock Vina) utilizing DeepCoy decoys-using DEKOIS 2.0 parameters-against KRAS G12D. Furthermore, re-scoring performance of the docking outcome via two popular pretrained machine learning scoring functions (ML SFs), such as CNN-Score and RF-Score-VS v2 were explored. While FRED exhibited the best screening performance based on pROC-AUC value, both tools showed high early enrichment indicated by EF 1%. Interestingly, both FRED and AutoDock Vina displayed superior performance to re-scoring using the ML SFs. This highlights the target-specific nature of the screening performance. In the second stage, accordingly, a VS effort was performed using FRED on specs world diversity database. Selected hits identified as potential KRAS G12D binders, were subjected to cell viability assays against the pancreatic cancer cell line PANC-1. Molecule (CP3) exhibited a promising antiproliferative activity with IC50 value of 1.95 µM. Subsequently, molecular dynamics (MD) simulation and MM-GBSA calculations rationalized its postulated binding towards KRAS G12D. This study provides an example of how to conduct an in-depth benchmarking approach for KRAS G12D and offering an evaluated SBVS protocol for it.

The ecdysone receptor (EcR/USP) plays a vital role in regulating molting and metamorphosis in insects, rendering it an attractive green target for developing novel insect growth regulators (IGRs). In this study, the ligand pharmacophore model S1&S2 and the Combine active pockets were constructed on the basis of the two different ligand-binding pockets of Lepidoptera EcR. A multi-level virtual screening of the SPECS database was performed, using pesticide-likeness rule and molecular docking, to obtain 13 screening compounds. Then, a novel experimental method was established to evaluate Plutella xylostella EcR/USP-LBD binding to ligand molecules using the Surface Plasmon Resonance (SPR) technique. The binding assays demonstrated that compounds VS-13, VS-16, VS-17, VS-18, and VS-19 exhibited comparable or superior efficacy to the commercial insecticide methoxyfenozide. Notably, VS-13 showed the highest binding activity, with a Kd of 0.2 ± 0.03 μM, similar to Ponesterone A (PonA, Kd = 0.1 ± 0.01 μM). Furthermore, molecular docking studies revealed that, in addition to three important residues (Asn503, Tyr407, and Thr342), Trp525 and Met379 are also key residues in stable the ligand-receptor interactions. These findings provide an effective strategy to design and discovery novel non-ecdysteroid analogs targeting lepidopteran insects.

Nocardiosis can lead to disseminated disease and affect various physiological systems, most commonly the skin, lungs, and central nervous system. Nocardia farcinica is unique among other Nocardia species due to its high pathogenicity and antibiotic resistance, and it is more likely to cause brain abscesses and other widespread infections affecting multiple organs. Therefore, new treatment targets are urgently needed to combat the multidrug-resistant nosocomial pathogen N. farcinica. This study aims to prioritize candidate inhibitors using structural bioinformatics and identify prospective therapeutic targets involved in the distinct metabolic pathways of N. farcinica, along with high-throughput virtual screening to identify potential drug compounds. The alpha/beta hydrolase fold domain-containing protein has been identified as a promising target for therapeutic development. Virtual screening of the CMNPD, MNPD, Seaweed, and Specs chemical libraries identified five promising candidates based on their ADME properties and binding affinities. Among these, MNPD738 was inferred as a potent inhibitor due to its stability throughout the molecular dynamics simulation and low binding free energy. These putative therapeutic targets will aid in the development of effective drugs that inhibit the metabolic pathways unique to pathogens. The identified drug targets and lead compounds may contribute to the development of effective therapies for combating drug-resistant N. farcinica infections. Future research should focus on experimental validation of the identified compounds and further exploration of the mechanism underlying N. farcinica pathogenicity.

To assess the patterns and severity of different refractive errors in children aged 3 to 5 years presenting with established amblyopia in a tertiary care eye centre in Pakistan. A cross-sectional study was conducted at a tertiary care eye center involving 178 children (aged 3-5 years). The study specifically included only those with refractive amblyopia; children with strabismic or sensory deprivation amblyopia were excluded. From each participant, only the amblyopic eye (or the eye with the worse visual acuity in bilateral cases) was analyzed to ensure statistical independence. All participants underwent a comprehensive ophthalmic examination, including cycloplegic refraction (using 1% cyclopentolate) and dilated fundus evaluation. Refractive errors were classified according to MEPEDS criteria, and data was analyzed using SPSS version 24.0. Among the 178 amblyopic eyes, astigmatism (53.4%) was common, particularly myopic astigmatism (n = 28, 15.7%) and hyperopic astigmatism (n = 27, 15.2%). Females were more likely to have myopia or astigmatism, whereas males were more likely to have hyperopia or astigmatism which may indicate some gender-specific patterns in amblyopia. Hyperopia was mostly low to moderate, while moderate astigmatism was more common than high astigmatism. These differences were also statistically significant (p < 0.001). Amblyopes with myopic astigmatism (n = 28, 15.7%) and hyperopic astigmatism (n = 27, 15.2%) exhibited the poorest visual acuity (mean LogMAR VA 1.05 &#xb1; 0.49 and 0.96 &#xb1; 0.46). Astigmatic refractive errors are more likely associated with greater amblyopia severity, and even lower thresholds of refractive error have the potential to cause amblyopia. By establishing these amblyogenic patterns, our study provides the surveillance data essential for early intervention. These findings advocate for preschool screening to prevent irreversible vision loss, directly advancing the WHO SPECS 2030 goal of people-centered eye care.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in the base excision repair (BER) pathway, and its aberrant overexpression is closely associated with poor prognosis, enhanced invasiveness, and therapeutic resistance in multiple cancers, making it an attractive anticancer drug target. In this study, a systematic structure-based virtual screening workflow was established using the crystal structure of the APE1 endonuclease active pocket (PDB ID: 7TC2) to screen approximately 1.529&#xa0;million small molecules collected from the DrugBank, TargetMol, Specs, and ChemDiv databases. Through multi-step filtering involving drug-likeness evaluation, molecular docking, interaction fingerprint (IFP) screening, conformational strain energy assessment, and MM/GBSA binding free energy calculations, a set of candidate compounds with predicted affinity toward APE1 was identified. Representative hit compounds from different databases were further subjected to binding mode analysis and 100 ns molecular dynamics simulations. Computational analyses suggested that these candidate compounds were able to maintain hydrogen-bonding and hydrophobic interactions with key residues in the APE1 active site. Among them, DB02187 and T9286 exhibited more favorable computational performance than the reference ligand in multiple dimensions, including complex stability, per-residue energy contribution, and free energy landscape profiles. In contrast, although HIT107168463 exhibited favorable static binding energy, it showed relatively poor dynamic stability. Overall, DB02187 and T9286 displayed favorable predicted binding features and may represent candidate scaffolds for future experimental validation and lead optimization.

The phosphatidylinositol 3-kinase (PI3K) pathway is a vital intracellular signaling cascade that plays a key role in cancer cell survival, angiogenesis, and metastasis. Consequently, PI3K has been a primary target for therapeutic inhibition in the treatment of various malignancies. Accumulating studies indicate that targeting multiple isoforms of PI3K may enhance antitumor activity. The advancement of pan-PI3K inhibitors for cancer treatment offers a promising research and development opportunity. This study introduces a machine learning-based virtual screening (VS) method that combines a Na&#xef;ve Bayesian classification model employing molecular fingerprints and descriptors, alongside a pharmacophore model and consensus scoring-based molecular docking, to discover new pan-PI3K inhibitors. The VS method was validated for its strong predictive accuracy by successfully identifying the commercially available pan-PI3K inhibitor copanlisib. The hybrid VS strategy was applied to the SPECS database, leading to the discovery of several promising PI3K inhibitor compounds. The machine learning-based VS approach is expected to offer meaningful insights and a practical framework for discovering novel PI3K inhibitors.

The rise of multidrug-resistant (MDR) Pseudomonas aeruginosa poses a significant threat in clinical settings due to its intricate antimicrobial resistance mechanism, biofilm formation, quorum sensing, and efflux pump-mediated antibiotic tolerance capability. The progressive decline in the efficacy of conventional antibiotics necessitates the development of new treatment strategies. Disrupting the Quorum sensing, a pivotal regulator of virulence and biofilm-associated resistance presents a promising anti-virulence strategy. An integrated Subtractive genomics and in silico drug discovery approach was applied to the complete proteome of P. aeruginosa JJPA01, excluding paralogous, human homologous, and non-essential proteins to identify virulence-associated targets. 27 pathogen-specific pathway proteins were identified, with pqsH (WP_003090354.1), a key monooxygenase in the PQS quorum-sensing system. Potential inhibitors for pqsH were identified using High-Throughput Virtual Screening (HTVS) on natural compounds from the COCONUT, CMNPD, MNPD, Seaweed, and Specs databases. The docking study identified five compounds with the best binding affinities, ranging from -&#xa0;6.6 to -&#xa0;7.7&#xa0;kcal/mol. However, only CNP0000215 and CNP0007440 exhibited higher binding affinity to the pqsH protein than the cofactor Flavine Adenine Dinucleotide. With its established role in Antimicrobial Resistance and Virulence, pqsH has been selected as a therapeutic target and CNP0000215 as a promising PQS inhibitor to disrupt biofilm formation and combat antimicrobial resistance. These findings lay the groundwork for the strategic design of novel anti-therapeutics offering a promising strategy to inhibit persistent infections and resistance mechanisms in P. aeruginosa.