Search Results (505)

The Barcelona Raman LIDAR (brl) will provide continuous monitoring of the aerosol extinction profile along the line of sight of the Cherenkov Telescope Array Observatory (Cherenkov Telescope Array Observatory (CTAO)). It will be located at its Northern site (Northern site of the Cherenkov Telescope Array Observatory (CTAO-N)) on the Observatorio del Roque de Los Muchachos. This article presents the performance of the pathfinder Barcelona Raman LIDAR (pbrl), a prototype instrument for the final brl. Power budget simulations were carried out for the pbrl operating under various conditions, including clear nights, moon conditions, and dust intrusions. The LIDAR PreProcessing (LIDAR PreProcessing software (LPP)) software suite is presented, which includes several new statistical methods for background subtraction, signal gluing, ground layer and cloud detection and inversion, based on two elastic and one Raman lines. Preliminary test campaigns were conducted, first close to Barcelona and later at CTAO-N, albeit during moonlit nights only. The pbrl, under these non-optimal conditions, achieves maximum ranges up to about 35 km, range resolution of about 50 m for strongly absorbing dust layers, and 500 m for optically thin clouds with the Raman channel only, leading to similar resolutions for the LIDAR ratios and Ångström exponents. Given the reasonable agreement between the extinction coefficients obtained from the Raman and elastic lines independently, an accuracy of aerosol optical depth retrieval in the order of 0.05 can be assumed with the current setup. The results show that the pbrl can provide valuable scientific results on aerosol characteristics and structure, although not all performance requirements could be validated under the conditions found at the two test sites. Several moderate hardware improvements are planned for its final upgraded version, such as gated Photomultiplier Tubes (PMTs) for the elastic channels and a reduced-power laser with a higher repetition rate, to ensure that the data acquisition system is not saturated and therefore not affected by residual ringing. Full article

The human genome is widely transcribed, with part of these transcribed regions producing stably expressed protein-coding or non-coding RNAs. Long intergenic non-coding RNAs (lincRNAs) are significantly differentially expressed in various cell lines and tissues. However, the influence of their transcription events remains unclear. In this study, we constructed a human genomic interaction network and found frequent interactions between lincRNA genes and protein-coding genes that are highly related to the occupancy of RNA polymerase II on the lincRNA gene. Interestingly, in the human genome interaction networks, the degree of lincRNA genes was significantly higher than that of protein-coding genes. The promoter regions of the protein-coding genes interacting with the lincRNA genes are enriched with R-loop structures, indicating that lincRNA may influence the target genes through R-loop structures. These promoters were enriched in more transcription factor binding sites. Furthermore, the whole network and sub-network could be utilized to explore potential biomarkers of leukemia. We found that zinc finger protein 668 (ZNF668), eosinophil granule ontogeny transcript (EGOT), and glutamate metabotropic receptor 7 (GRM7) could serve as novel biomarkers for acute myeloid leukemia (LMAL). Pasireotide acetate (CAS No. 396091-76-2) represents a potential drug for LMAL patients. These results suggested that potential biomarkers and corresponding drugs for cancer could be identified based on lincRNA–promoter network/sub-network topological parameters. Full article

High-risk neuroblastoma remains a clinically challenging pediatric cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group of patients includes surgery and intensive chemotherapy that involves combinations of the tubulin inhibitor vincristine with several other chemotherapeutics. Unfortunately, unresponsiveness to therapy and relapse are common, with tumors often displaying resistance to vincristine. Recently, we characterized a novel set of tubulin inhibitors that are distinct from vincristine and bind within the colchicine binding site present on tubulin monomers. Colchicine binding site inhibitors (CBSIs) have gained traction as improved chemotherapeutics due to their potential to overcome tubulin inhibitor-induced resistance. In this study, we investigate the functional impact of CBSI treatment on multiple neuroblastoma cell lines, including those that are vincristine-resistant. We demonstrate that our newly developed compounds are effective at disrupting cell division in non-resistant and resistant cells and have cellular activity against vincristine-resistant cell lines. Interestingly, we find that vincristine-resistant cell lines differ in their ability to undergo apoptotic cell death in response to CBSI treatment. Taken together, these findings provide a solid foundation to further investigate the utility of CBSIs for neuroblastoma treatment, while highlighting the distinct resistance mechanisms that can emerge in these childhood cancers. Full article

HIV/AIDS and Mycobacterial tuberculosis (Mtb) are the leading cause of deaths worldwide. Thus, better medicaments are required to manage these diseases. Quinolines have shown great potential due to their broad spectrum of biological activity. Thus, quinoline–1,2,3-triazole–aniline hybrids were synthesised in moderate to good yields. Compounds 11g (IC₅₀ = 0.388 µM), 11h (IC₅₀ = 0.01032 µM) and 11i (IC₅₀ = 0.167 µM) exhibited the most promising in vitro activities against the wild-type HIV-1 subtype B, with 11h being 9-fold more active than AZT (IC₅₀ = 0.0909 µM), the reference drug. Furthermore, compound 11h displayed moderate activity, with a MIC₉₀ of 88μM against Mtb’s H37Rv strain. Cytotoxicity studies on TZM-bl cell lines revealed that most of the tested compounds were generally non-cytotoxic; the selectivity index (SI) for 11h, the front runner, is >2472. Molecular docking studies revealed that 11h interacted with Phe112, Tyr108, Glu283 and Trp86 amino acid residues in the active site of HIV-1. DFT studies revealed that 11h has the ability to donate and accept electrons to and from available orbitals. The predicted ADMET studies showed that these compounds possess drug-likeness, and 11h has the potential for further optimisation as an anti-HIV-1 agent. Full article

CRISPR-Cas9 genome editing is a versatile platform for studying and treating various diseases. Homology-directed repair (HDR) with DNA donor templates serves as the primary pathway for gene correction in therapeutic applications, but its efficiency remains a significant challenge. This study investigates strategies to enhance gene correction efficiency using a T-shaped lipo-xenopeptide (XP)-based Cas9 RNP/ssDNA delivery system combined with various HDR enhancers. Nu7441, a known DNA-PKcs inhibitor, was found to be most effective in enhancing HDR-mediated gene correction. An over 10-fold increase in HDR efficiency was achieved by Nu7441 in HeLa-eGFPd2 cells, with a peak HDR efficiency of 53% at a 5 nM RNP concentration and up to 61% efficiency confirmed by Sanger sequencing. Surprisingly, the total gene editing efficiency including non-homologous end joining (NHEJ) was also improved. For example, Nu7441 boosted exon skipping via NHEJ-mediated splice site destruction by 30-fold in a DMD reporter cell model. Nu7441 modulated the cell cycle by reducing cells in the G1 phase and extending the S and G2/M phases without compromising cellular uptake or endosomal escape. The enhancement in genome editing by Nu7441 was widely applicable across several cell lines, several Cas9 RNP/ssDNA carriers (LAF-XPs), and also Cas9 mRNA/sgRNA/ssDNA polyplexes. These findings highlight a novel and counterintuitive role for Nu7441 as an enhancer of both HDR and total gene editing efficiency, presenting a promising strategy for Cas9 RNP-based gene therapy. Full article

Gene-edited cattle overexpressing natural resistance-associated macrophage 1 (NRAMP1) have demonstrated enhanced resistance to tuberculosis (TB). However, introducing synthetic sequences and selection markers may pose potential risks. The endogenous editing of target gene promoters could effectively mitigate these risks. To date, no available mutation sites in the bovine NRAMP1 promoter have been identified to enhance host resistance to TB. In this study, we identified a unique mutation editing site, designated as 2SP, within the bovine NRAMP1 promoter, using bioinformatics analysis and dual luciferase assays. The mutation at the 2SP site specifically increased NRAMP1 promoter activity by 2.3-fold after Mycobacterium tuberculosis H37Ra infection, without modifying promoter activity in non-infected groups. By using base editing techniques, an endogenously edited THP-1 cell line with a mutation at the homologous region of the 2SP site was generated, without introducing screening markers. In H37Ra infection experiments, the edited THP-1 cells specifically upregulated NRAMP1 expression and significantly inhibited H37Ra proliferation, while maintaining baseline NRAMP1 expression levels in the absence of infection. In this research, we identified a novel mutation site and provided a fundamental reference for the development of gene-edited cattle with enhanced resistance to TB. Full article

The synthesis of (E)-1-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-3-phenyl-2-propen-1-one derivatives was carried out in two steps, using benzylic chloride derivatives as starting material. The structural determination of intermediates and final products was performed by spectroscopic methods: infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry (IR, NMR, and MS). In vitro evaluation of cytotoxic activity on adherent and non-adherent cells showed that triazole chalcones exhibited significant activity against three of the five cell lines studied: non-Hodgkin lymphoma U937, glioblastoma multiform tumor T98G, and gallbladder cancer cells Gb-d1. In contrast, the cytotoxic activity observed for cervical cancer HeLa and gallbladder adenocarcinoma G-415 was considerably lower. Additionally, in the cell lines where activity was observed, some compounds demonstrated an In vitro inhibitory effect superior to that of the control, paclitaxel. Molecular docking studies revealed specific interactions between the synthesized ligands and therapeutic targets in various cell lines. In U937 cells, compounds 4a and 4c exhibited significant inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, correlating with their biological activity. This effect was attributed to favorable interactions with key residues in the binding site. In T98G cells, compounds 4r and 4w showed affinity for transglutaminase 2 (TG2) protein, driven by their ability to form hydrophobic interactions. In Gb-d1 cells, compounds 4l and 4p exhibited favorable interactions with mitogen-activated protein kinase (MEK) protein, similar to those observed with the known inhibitor selumetinib. In HeLa cells, compounds 4h and 4g showed activity against dihydrofolate reductase (DHFR) protein, driven by hydrogen bonding interactions and favorable aromatic ring orientations. On the other hand, compounds 4b and 4t exhibited no activity, likely due to unfavorable interactions related to halogen substitutions in the aromatic rings. Full article

Objectives: This study aimed to histologically evaluate, in humans, the orientation of collagen fibers around screw-less, Morse taper, hemispherical base abutments. Methods: This study was designed as an observational, case–control, clinical trial to evaluate the histological orientation of collagen fibers around implants. Biopsies of the peri-implant tissue were performed 8 (group A, control) or 16 (group B, test) weeks of implant uncovering, and histologically analyzed under optical microscope using Hematoxylin and Eosin, Masson, and Picro Sirius histochemical staining and a scanning electron microscope. Results: Eight patients were enrolled in this study and 16 biopsies were performed. All the biopsies were correctly analyzed. The histological examination of cross-sectional portions of the tissue taken 8 weeks after implant uncovering showed the almost complete absence of epithelial lining, while the connective tissue bundles in the superficial portion showed a lower circular pattern. The histochemical cross-section examination of the tissue taken 16 weeks after implant uncovering showed the partial presence of non-keratinizing epithelial lining at the implant site and the collagen bundles showed a greater organization, with a circumferential course around the abutment. At 8 weeks, the final histological analysis showed an average height of 1.01 mm for the keratinized epithelium, 0.83 mm for the non-keratinized epithelium, and 1.39 mm for the connective tissue. While, at 16 weeks, the values were 1.20 mm, 0.48 mm, and 1.11 mm, respectively. No statistically significant differences were found between the groups (p > 0.05). Conclusions: Histologically, there were not any differences in the height and profile of the gingiva between 8 and 16 weeks of healing after prosthesis delivery. Greater organization of the collagen fibers with a circumferential course around the abutment was found in the test group (16 weeks) compared with the control group (8 weeks). Full article

Background/Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory disease characterized by chronic sterile uni- or multifocal osteomyelitis. The treatment of CNO is mostly empirical and the outcome of the disease has not yet been standardized. The aims of this study were to correlate clinically active lesions with radiological signs of inflammation and to evaluate the outcomes in terms of symptoms and radiological signs with Whole Body Magnetic Resonance Imaging (WB-MRI) based on the treatment line used. Methods: A retrospective, observational cohort study of 20 CNO patients, recruited from a single tertiary center in southern Italy, was conducted. Patients included in the study were treated based on the “step-up” approach and were guided by the “treat-to-target” strategy as well as by the response to therapy. The outcome measure was stratified into four different groups, defined by a “Delphy consensus”, depending on the symptoms and the presence of bone lesions in WB-MRI, compared with the therapy carried out. Results: Pain was the most common presenting symptom of the disease. Only 15% of our patients reported long-term complications. WB-MRI was performed for each patient both at diagnosis and during follow-up. At onset, the site most affected by the disease was the tibia. All patients who reached a 5-year follow-up (30%, n = 6) achieved a complete disease remission. Conclusions: The standardized “step-up” treatment approach in our cohort proved effective in disease management with disease control or remission in nearly 90% of patients at one year from diagnosis. Full article

A series of novel hydrazones bearing diphenylamine and 5-oxopyrrolidine moieties, along with benzene and naphthalene rings substituted with hydroxy, alkoxy, or carboxylic groups, were synthesized. Their anticancer activity was evaluated in vitro using both 2D (MTT and ‘wound healing’ assays) and 3D (cell spheroid) models against human melanoma IGR39 cells, the triple-negative breast cancer cell line MDA-MB-231, and pancreatic carcinoma Panc-1 cell line. Compounds 8 (2-hydroxybenzylidene derivative) and 12 (2-hydroxynaphthalenylmethylene derivative) demonstrated the highest cytotoxicity in both 2D and 3D assays, while compounds 4 (2,5-dimethoxybenzylidene derivative) and 6 (2,4,6-trimethoxybenzylidene derivative) were most effective at inhibiting cell migration. Notably, all compounds exhibited lower activity against the Panc-1 cancer cell line in a cell monolayer, but the effects on spheroid cell viability in 3D models were comparable across all tested cancer cell lines. Molecular docking studies of the most active hydrazones suggested that these compounds may act as multikinase inhibitors. In particular, 2-hydroxynaphthalenylmethylene derivative 12 showed high binding affinity values (−11.174 and −11.471 kcal/mol) to the active sites of two key protein kinases—a non-receptor TK (SCR) and STPK (BRAF)—simultaneously. Full article

Beta attenuation monitors (BAMs) are widely used for the regulatory monitoring of fine particulate matter (PM_2.5) and fence line monitoring of industrial sites. The elemental analysis of BAM filter tapes potentially could enable additional source PM_2.5 attribution. However, the chemical characterization of the glass fiber filters is hindered by high background metal values. A sample preparation method was developed using the ultrasonic extraction of particulate matter from BAM filter spots in nitric acid and the analysis of metals by inductively coupled plasma–mass spectrometry (ICP-MS) and scanning electron microscopy–energy-dispersive X-ray spectroscopy (SEM-EDS). To demonstrate the utility of this method, BAM filter spots were analyzed from wildfire smoke periods in the San Francisco Bay Area in California in Fall 2023 and indicated elevated levels of chromium compared to a non-wildfire period in Spring 2023. The SEM-EDS of the BAM tape was used to probe individual particulate morphology, but it only detected Fe and Ba at levels above the blank media. The ultrasonic extraction method of BAM filter spots could be used in future wildfire smoke events to extend the characterization of beta attenuation monitor filters in PM_2.5 monitoring. Full article

Histone H3 trimethylated at lysine 4 (H3K4me3) is an histone mark associated with transcriptionally active genes. H3K4me3 has two types of distribution: a sharp distribution of approximately 500 bp and a broad H3K4me3 domain that may extend 4 kb and longer through the gene body. Most transcribed genes have a narrow H3K4me3 configuration, whereas genes involved in cell identity and tumor suppression have a broad arrangement in normal cells. In cancer cells, genes that promote cancer possess a broad H3K4me3 domain. In this study, we performed H3K4me3 chromatin immunoprecipitation sequencing to determine the genes with narrow and broad H3K4me3 configurations in normal colon epithelial cells and three colon cancer cell lines. The analysis revealed that genes involved in cell adhesion and nervous system development had an H3K4me3 peak next to their transcription start site in normal cells but not in colon cancer cells. Genes coding for long non-coding RNA (lncRNA) were differentially marked with a broad H3K4me3 domain in normal colon versus colon cancer cells (FENDRR in normal colon; ELFN1-AS1 in colon cancer). Identifying the genes that are silenced or activated, particularly in colon cancer, provides a list of actionable targets for designing effective treatments for this prevalent human disease. Full article

Amazonian fruits are a source of bioactive compounds, among which phenolic compounds, flavonoids, and carotenes stand out. These compounds play a crucial role in restoring oxidative balance, consequently reducing the proliferation of cancer cells. However, the content of these metabolites and their biological properties may vary significantly depending on the geographical location and the environmental conditions where plants grow. This research assessed the content of metabolites, free radical scavenging capacity, and hemolytic and antiproliferative effects of the hydro-methanolic extracts of the Amazonian fruits Theobroma grandiflorum and Mauritia flexuosa. The results revealed that the extracts derived from the seeds of Theobroma grandiflorum sourced from the Balcanes experimental farm and the pulp of Mauritia flexuosa harvested in Florencia exhibited higher contents compared to other analyzed sites: Total phenolic content (TPC) (619.41 ± 12.05 and 285.75 ± 10.06 mg GAE/100 g FW), Total flavonoid content (TFC) (569.09 ± 4.51 and 223.21 ± 3.92 mg CAT/100 g FW), and Total carotenoid content (TCC) (25.12 ± 0.16 and 48.00 ± 0.28 mg eq β-carotene/100 g FW), respectively. Also, these samples demonstrated superior scavenging capacities for the ABTS and DPPH radicals, while the peel of Mauritia flexuosa exhibited the highest scavenging capacity for the oxygen radical (526.23 ± 2.08 µmol Trolox.g⁻¹). The hemolytic effect shows dose-dependent responses with IC50 values of 27.73 μg/mL for the Balcanes seeds and 1.27 μg/mL for the Florencia pulp. Furthermore, it was observed that treatment with the fruit-derived extracts effectively reduced the number of viable human colorectal cancer cells, using SW480 ATCC cell line, demonstrating a non-dose-dependent behavior compared to the control cells. Full article

(1) Background: There are many cases of human disease caused by the hepatitis A virus contamination of aquatic products, so the development of the rapid detection of hepatitis A virus in aquatic products is crucial. (2) Methods: In this study, we developed three visual loop-mediated isothermal amplification methods for the rapid and intuitive detection of hepatitis A virus in aquatic products. New specific LAMP primers were designed for the HAV-specific VP1 protein shell. (1) HNB dye was added to the LAMP reaction system. After the reaction, the color of the reaction mixture changed from violet to sky blue, showing a positive result. (2) Cresol red dye was added to the LAMP reaction system, and a positive result was indicated by orange, while a negative result was indicated by purple. (3) By labeling FIP with biotin and LF with 6-FAM, the amplified product simultaneously contained biotin and 6-FAM, which bound to the anti-biotin antibody on the gold nanoparticles on the lateral flow dipstick (LFD). Subsequently, biotin was further combined with the anti-fam antibody on the T-line of the test strip to form a positive test result. (3) Results: The three visual LAMP methods were highly specific for HAV. The sensitivity of the visual assay was 2.59 × 10⁰ copies/μL. The positive detection ratio for 155 bivalve shellfish samples was 8.39%, which was the same as that for RT-qPCR. The three visual LAMP methods established in our work have better sensitivity than the international gold standard, and their operation is simple and requires less time. (4) Conclusions: The results can be obtained by eye color comparison and lateral flow dipsticks. Without the use of large-scale instrumentation, the sensitivity is the same as that of RT-qPCR. The test strips are lightweight, small in size, and easy to carry; they are suitable for emergency detection, on-site monitoring, field sampling, or remote farms and other non-laboratory environments for rapid identification. Full article

Reproductive interactions between species could have negative effects on the fitness of the species involved, which can have important ecological and evolutionary consequences, such as population declines (including local extinction) or character divergence. Here, we report the courtship and attempted mating between two congeneric species of fireflies endemic to Mexico. The interactions involved males of the synchronous firefly Photinus palaciosi and females of the much larger, non-synchronous P. extensus. In the study site, the population density of P. palaciosi is much higher than that of P. extensus. Observations of marked P. extensus females throughout most of the mating season showed that 37.8% of their interactions with males were with P. palaciosi males. Although interspecific interactions were usually of shorter length, they frequently consumed a significant portion of the nightly mate-locating/courting period. These interspecific interactions are probably facilitated by the similarities in the mate location and courtship behavior of both species, which also share female brachyptery (elytra and wing reduction that makes females unable to fly). The simplest hypothesis to explain our behavioral observations is that P. palaciosi males mistakenly courted P. extensus females. The available evidence suggests that the operational sex ratio (OSR) of P. palaciosi is male-biased, as it seems to be the case in all synchronous fireflies studied to date. We hypothesize that the intense male competition for mates resulting from a male-biased OSR explains, at least in part, the “indiscriminate” sexual responses of P. palaciosi males. Another still not studied factor that could contribute to the frequent interspecific sexual interactions observed is the degree of similitude of the mating signals. The relatively high frequency of interspecific interactions and the significant amount of time invested in many of them (relative to the duration of the nightly mating period) indicate that the study of the potential fitness costs (and benefits?) of these interactions is a promising line of research. Full article