Miracle-dz/UniFAR-FTUs huggingface dataset:
Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229

Palladium nanoparticles (PdNPs) are increasingly being used in medical and biological applications due to their unique physical and chemical properties. Recent evidence suggests that these nanoparticles can act as both a pro-oxidant and as an antioxidant. Melatonin (MLT), which also shows pro- and antioxidant properties, can enhance the efficacy of chemotherapeutic agents when combined with anticancer drugs. Nevertheless, studies regarding the molecular mechanisms underlying the anticancer effects of PdNPs and MLT in cancer cells are still lacking. Therefore, we aimed to investigate the potential toxicological and molecular mechanisms of PdNPs, MLT, and the combination of PdNPs with MLT in A549 lung epithelial adenocarcinoma cells. We evaluated cell viability, cell proliferation, cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in cells treated with different concentrations of PdNPs and MLT. PdNPs and MLT induced cytotoxicity, which was confirmed by leakage of lactate dehydrogenase, increased intracellular protease, and reduced membrane integrity. Oxidative stress increased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl content (PCC), lipid hydroperoxide (LHP), and 8-isoprostane. Combining PdNPs with MLT elevated the levels of mitochondrial dysfunction by decreasing mitochondrial membrane potential (MMP), ATP content, mitochondrial number, and expression levels of the main regulators of mitochondrial biogenesis. Additionally, PdNPs and MLT induced apoptosis and oxidative DNA damage due to accumulation of 4-hydroxynonenal (HNE), 8-oxo-2′-deoxyguanosine (8-OhdG), and 8-hydroxyguanosine (8-OHG). Finally, PdNPs and MLT increased mitochondrially mediated stress and apoptosis, which was confirmed by the increased expression levels of apoptotic genes. To our knowledge, this is the first study demonstrating the effects of combining PdNPs and MLT in human lung cancer cells. These findings provide valuable insights into the molecular mechanisms involved in PdNP- and MLT-induced toxicity, and it may be that this combination therapy could be a potential effective therapeutic approach. This combination effect provides information to support the clinical evaluation of PdNPs and MLT as a suitable agents for lung cancer treatment, and the combined effect provides therapeutic value, as non-toxic concentrations of PdNPs and MLT are more effective, better tolerated, and show less adverse effects. Finally, this study suggests that MLT could be used as a supplement in nano-mediated combination therapies used to treat lung cancer.
Detection and Analysis of Uncharged Particles Using Consumer-grade CCDs

Abstract In the current climate of increased global terrorism, the threat of a radiological incident is becoming more realistic than ever, and as such, the necessity of early-warning detection is paramount to national security. To assist with this need, we have investigated the detection of uncharged particle emissions from radiological sources using charged-coupled devices (CCDs), which are contained within a variety of products, including consumer cellphones and traffic cameras. Because the CCD is intrinsically sensitive to charge accumulation as a result of linear energy transfer by the incident particles, each event can be counted and quantified using video-image processing and an estimated energy band assessed by the properties of the pixels. In an effort to make this process applicable to the widest possible range of CCDs available, this experiment was conducted using low-quality CCDs contained within consumer-grade, budget web cameras. Within a 239Pu-Be neutron howitzer, particles were detected using several camera models: Gigaware X76, Z76 and Logitech C170, C270. Particle detection events were counted by post-processing with Matlab, and an efficiency for each CCD was determined relative to both a theoretical flux model and a calibrated 3He tube detector. The relative detection efficiencies for the cameras tested fell within the range 14–18% and showed a linear correlation between incident energy and pixel response.
Epidemiology, histopathology and aetiology of olive anthracnose caused by Colletotrichum acutatum and C. gloeosporioides in Portugal

Anthracnose is an important disease affecting mature olive fruits, causing significant yield losses, and poor fruit and oil quality. In Portugal, high anthracnose incidence was recorded during 2003-2007 with 41% of 908 orchards surveyed displaying disease symptoms. In another 14% of the orchards, the pathogen was recorded in symptomless plants. Disease severity was on average 36%, frequently reaching 100%. In Portugal, anthracnose is endemic to neglected orchards of susceptible cultivars, but under favourable conditions it can also severely affect less susceptible cultivars. Pathogens were genetically heterogeneous, with Colletotrichum acutatum genetic group A2 as the most frequent (80%), followed by group A4 (12%) and group A5 along with C. gloeosporioides (3-4%), while groups A3 and A6 of C. acutatum were sporadic. Important geographic variations were observed in the frequencies of these populations, accompanied by year-to-year populational shifts. Epidemiology and histopathology studies showed the presence of the pathogens on vegetative organs year-round, particularly on olive leaves and branches, and on weeds. These represent inoculum reservoirs where secondary conidiation occurs, and conidia are then dispersed by spring rains reaching flowers and young fruits or by autumn rains reaching pre-mature fruits. Unripe fruits were colonized without showing symptoms up to penetration of the cuticle, but further colonization and symptom production was completed only as fruits matured. These findings challenge current control practices, particularly the timing of fungicide treatment, and contribute to improved disease management.
Evaluating Success Factors of a Medication Adherence Tracker Pilot Program in Improving Part D Medication Adherence Metrics in a Medicare Advantage Plan: Importance of Provider Engagement

BACKGROUND: Health plans and providers can increase quality by improving adherence to chronic disease medications included in star ratings among Medicare Advantage Part D (MAPD) plan enrollees. Research is needed to evaluate effective means of collaboration between health plans and providers. The Medication Adherence Tracker (MAT) is a health plan initiative to help primary care providers use outreach to improve their patients’ adherence. OBJECTIVE: To quantify the contribution of structural and process factors on the success of a health plan-initiated tracking system in improving chronic disease medication adherence over 6 months. METHODS: The MAT quality improvement initiative was carried out in South Texas from June to December 2016. Health plan pharmacists used claims data to identify MAPD enrollees at risk of nonadherence to triple-weighted star medications: renin-angiotensin system antagonists, oral diabetes medications, and statins. Actionable reports were delivered biweekly to each provider, either by fax or in person, by embedded health plan nurses. Multivariable regression was used to evaluate sociodemographic and clinical factors as well as the role of provider outreach in increasing paid pharmacy claims and medication adherence as measured by proportion of days covered (PDC) > 0.8. RESULTS: Of 3,542 patients in 5 Texas physician-organized delivery system groups whose 67 providers received tracking reports from June through December 2016, 1,901 (54%) patients had more than 1 related prescription, and 3,064 (87%) received provider outreach on at least 1 prescription. 2,493 (70%) had at least 1 paid pharmacy claim. Provider outreach was associated with greater likelihood of paid prescription claims (relative risk [RR] = 4.59, 95% CI = 3.74-5.62) and greater year-end adherence (PDC > 0.8, RR = 1.86, 95% CI = 1.63-2.12) in multivariable predictive models. 95% CIs for age, gender, low-income subsidy eligibility, and number of prescriptions did not exclude the null value. CONCLUSIONS: Provider engagement is critical to effective health plan-provider partnerships to overcome barriers, change behavior, and improve chronic disease care quality and population outcomes.
Endoscopic endonasal open reduction for fractures of the frontal process of the maxilla

Objective This study was performed to evaluate the clinical efficacy of endoscopic endonasal open reduction of fractures of the frontal process of the maxilla (FFPM). Methods We performed a retrospective study of patients who underwent endoscopic endonasal open reduction of FFPM from December 2013 to October 2018. The preoperative assessment included nasal endoscopy, computed tomography imaging, and three-dimensional craniofacial reconstruction. The clinical results were evaluated with a visual analog scale at 2 days and 1 year postoperatively. Results Thirty-two patients (25 male, 7 female) with an average age of 39 years were included in the study. All patients successfully underwent a surgical operation via the endoscopic endonasal approach with a nasal mucosal incision, and the nasal deformities were corrected. At the 1-year follow-up, six (18.8%) and 26 (81.2%) patients were somewhat satisfied and very satisfied with the aesthetic result, respectively, and five (15.6%) and 27 (84.4%) were somewhat satisfied and very satisfied with the functional result, respectively. Conclusion Endoscopic endonasal open reduction can be considered a reliable method for anatomical reduction of FFPM. This technology provides a viable choice for the treatment of FFPM.
Impacts des défoliations de la processionnaire du pin (Thaumetopoea pityocampa) sur la croissance du pin maritime (Pinus pinaster)

Parmi les perturbations attendues des ecosystemes forestiers dans le cadre du changement climatique, les degâts causes par les insectes ravageurs devraient augmenter en raison notamment de la hausse des temperatures. Ces dommages devraient reduire la capacite des forets a stocker du carbone, et donc a attenuer les causes du changement climatique. Plus specifiquement, il est predit que l’augmentation des pullulations d’insectes defoliateurs conduise a une diminution importante de la productivite des forets mais leur impact reel est difficile a quantifier et a comprendre. L’objectif general de ce travail a donc ete d’ameliorer nos connaissances sur l’impact d’une defoliation sur la croissance d’arbres d’âges contrastes et soumis a differentes contraintes environnementales. Dans un premier temps, ce travail a permis de quantifier la relation entre l’intensite de defoliation de la processionnaire du pin et la perte de production du pin maritime. Une meta-analyse nous a permis de synthetiser les resultats de l’ensemble des 45 etudes publiees a ce jour sur le sujet. Par la suite, profitant d’une pullulation exceptionnelle de processionnaire du pin pendant l’hiver 2009-2010, nous avons experimentalement teste l’effet de defoliations variant de 25 a 100% en interaction avec l’âge des peuplements de pin maritime. Nous concluons que les pertes de production sont proportionnelles a l’intensite de defoliation et augmentent avec l’âge de l’arbre.L’evolution du climat etant susceptible de favoriser la combinaison de differents stress, nous nous sommes egalement interesses aux effets cumules de la defoliation et du stress hydrique sur la croissance de l’arbre. Notre etude revele que la defoliation et le stress hydrique ont des effets additifs sur la croissance du pin maritime. Nos resultats confirment la complexite de la reponse eco-physiologique de l’arbre a la defoliation. L’etude des reserves carbonees et azotees nous a permis d’explorer les possibles mecanismes sous-jacents a l’effet d’une defoliation. Plus qu’une simple diminution de la fixation carbonee par alteration de l’appareil photosynthetique, nous proposons que la defoliation affecte la croissance via des processus de limitation en ressources carbonees et azotees. Les reserves carbonees n’etant affectees qu’en debut de saison, nous emettons l’hypothese d’une limitation azotee de l’arbre apres defoliation. Ainsi, la defoliation et le stress hydrique pourraient diminuer conjointement la disponibilite en eau et en ressources minerales, ce qui expliquerait leurs effets additifs sur la croissance de l’arbre.
Expression of lamin C2 in mammalian oocytes

Lamin C2 (LMN C2) is a short product of the lamin a gene. It is a germ cell-specific lamin and has been extensively studied in male germ cells. In this study, we focussed on the expression and localization of LMN C2 in fully-grown germinal vesicle (GV) oocytes. We detected LMN C2 in the fully-grown germinal vesicle oocytes of various mammalian species with confirmation done by immunoblotting the wild type and Lmnc2 gene deleted testes. Expression of LMN C2 tagged with GFP showed localization of LMN C2 to the nuclear membrane of the oocyte. Moreover, the LMN C2 protein notably disappeared after nuclear envelope breakdown (NEBD) and the expression of LMN C2 was significantly reduced in the oocytes from aged females and ceased altogether during meiotic maturation. These results provide new insights regarding LMN C2 expression in the oocytes of various mammalian species.
Reliability testing of the Matching Assessment using Photographs of Scars App

The Matching Assessment using Photographs with Scars assessment tool, published in 2005, enables accurate relocation and reassessment of scars. While used in Australia, uptake has been hampered by its paper manual format. With electronic records and increasing use of smart devices in health, here we report the development of the Matching Assessment using Photographs with Scars manual into a mobile application format: ClinMAPSTM Pro. At the time of development, no other digital scar assessment applications were available. For clinical validation, the digitized Matching Assessment using Photographs with Scars module within ClinMAPSTM Pro was used for intra‐ and inter‐rater reliability testing. Convenience sampling was utilized to recruit burns patients representing 44 scars, based on predetermined power calculations. Three therapists, one experienced and two novice, acted as the assessors. Each therapist assessed preselected scars with the digitized Matching Assessment using Photographs with Scars. Re‐assessment of the same scar sites occurred 3 to 7 days later. Inter‐rater reliability testing scores of the new electronic assessment application showed fair to moderate agreement (combined Fleiss Kappa = 0.38‐0.49, P < .0001). Intra‐rater reliability scores between initial and repeat measures showed moderate to almost perfect agreement (Cohen's Kappa = 0.43‐0.90, P < .0001). It was noted that for an experienced rater, intra‐rater agreement demonstrated substantial to almost perfect agreement. Intraclass correlation coefficients calculated to allow for comparison between other published scar assessment tools demonstrated excellent reliability for all scar assessment parameters for both intra‐ (=0.76‐0.91) and inter‐ (=0.76‐0.98) reliability. Notably, reliability testing results confirm its intra‐ and inter‐rater reliability. Our findings validate this novel concept for digitization of the previously paper‐based scar assessment manual and prove that the Matching Assessment using Photographs with Scars within the ClinMAPSTM Pro application is now readily available for clinicians and researchers internationally.
Peptides containing the PCNA interacting motif APIM bind to the β-clamp and inhibit bacterial growth and mutagenesis

Abstract In the fight against antimicrobial resistance, the bacterial DNA sliding clamp, β-clamp, is a promising drug target for inhibition of DNA replication and translesion synthesis. The β-clamp and its eukaryotic homolog, PCNA, share a C-terminal hydrophobic pocket where all the DNA polymerases bind. Here we report that cell penetrating peptides containing the PCNA-interacting motif APIM (APIM-peptides) inhibit bacterial growth at low concentrations in vitro, and in vivo in a bacterial skin infection model in mice. Surface plasmon resonance analysis and computer modeling suggest that APIM bind to the hydrophobic pocket on the β-clamp, and accordingly, we find that APIM-peptides inhibit bacterial DNA replication. Interestingly, at sub-lethal concentrations, APIM-peptides have anti-mutagenic activities, and this activity is increased after SOS induction. Our results show that although the sequence homology between the β-clamp and PCNA are modest, the presence of similar polymerase binding pockets in the DNA clamps allows for binding of the eukaryotic binding motif APIM to the bacterial β-clamp. Importantly, because APIM-peptides display both anti-mutagenic and growth inhibitory properties, they may have clinical potential both in combination with other antibiotics and as single agents.
Endogenously-Activated Ultrasmall-in-Nano Therapeutics: Assessment on 3D Head and Neck Squamous Cell Carcinomas

Negative or positive HPV-associated Head and Neck Squamous Cell Carcinomas (HNSCCs) are high recurrence neoplasms usually resulting in a poor prognosis, mainly due to metastasis formation. Despite the low overall patient survival rate and the severe side effects, the treatment of choice is still cisplatin-based chemotherapy. Here, we report a straightforward protocol for the production of high throughput 3D models of negative or positive HPV-associated HNSCCs, together with their employment in the therapeutic evaluation of gold ultrasmall-in-nano architectures comprising an endogenously-activatable cisplatin prodrug. Beyond enhancing the biosafety of cisplatin, our approach paves the way for the establishment of synergistic co-therapies for HNSCCs based on excretable noble metals.
De Novo Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma

These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis. The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming. Significance: These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.
Biological and Computational Studies for Dual Cholinesterases Inhibitory Effect of Zerumbone

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) mediate the degradation of acetylcholine (ACh), a primary neurotransmitter in the brain. Cholinergic deficiency occurs during the progression of Alzheimer’s disease (AD), resulting in widespread cognitive dysfunction and decline. We evaluated the potential effect of a natural cholinesterase inhibitor, zerumbone, using in vitro target enzyme assays, as well as in silico docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) simulation. Zerumbone showed a predominant cholinesterase inhibitory property with IC50 values of 2.74 ± 0.48 µM and 4.12 ± 0.42 µM for AChE and BChE, respectively; however, the modes of inhibition were different. Computational docking simulation indicated that Van der Waals interactions between zerumbone and both the cholinesterases were the main forces responsible for its inhibitory effects. Furthermore, zerumbone showed the best physicochemical properties for both bioavailability and blood–brain barrier (BBB) permeability. Together, in the present study, zerumbone was clearly identified as a unique dual AChE and BChE inhibitor with high permeability across the BBB, suggesting a strong potential for its physiological benefits and/or pharmacological efficacy in the prevention of AD.
Enhancing the Cellular Uptake and Antibacterial Activity of Rifampicin through Encapsulation in Mesoporous Silica Nanoparticles

An urgent demand exists for the development of novel delivery systems that efficiently transport antibacterial agents across cellular membranes for the eradication of intracellular pathogens. In this study, the clinically relevant poorly water-soluble antibiotic, rifampicin, was confined within mesoporous silica nanoparticles (MSN) to investigate their ability to serve as an efficacious nanocarrier system against small colony variants of Staphylococcus aureus (SCV S. aureus) hosted within Caco-2 cells. The surface chemistry and particle size of MSN were varied through modifications during synthesis, where 40 nm particles with high silanol group densities promoted enhanced cellular uptake. Extensive biophysical analysis was performed, using quartz crystal microbalance with dissipation (QCM-D) and total internal reflection fluorescence (TIRF) microscopy, to elucidate the mechanism of MSN adsorption onto semi-native supported lipid bilayers (snSLB) and, thus, uncover potential cellular uptake mechanisms of MSN into Caco-2 cells. Such studies revealed that MSN with reduced silanol group densities were prone to greater particle aggregation on snSLB, which was expected to restrict endocytosis. MSN adsorption and uptake into Caco-2 cells correlated well with antibacterial efficacy against SCV S. aureus, with 40 nm hydrophilic particles triggering a ~2.5-log greater reduction in colony forming units, compared to the pure rifampicin. Thus, this study provides evidence for the potential to design silica nanocarrier systems with controlled surface chemistries that can be used to re-sensitise intracellular bacteria to antibiotics by delivering them to the site of infection.