Scientific Reports

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.

QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath's flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.

Abstract Polycyclic aromatic compounds (PACs) are known due to their mutagenic activity. Among them, 2-nitrobenzanthrone (2-NBA) and 3-nitrobenzanthrone (3-NBA) are considered as two of the most potent mutagens found in atmospheric particles. In the present study 2-NBA, 3-NBA and selected PAHs and Nitro-PAHs were determined in fine particle samples (PM 2.5) collected in a bus station and an outdoor site. The fuel used by buses was a diesel-biodiesel (96:4) blend and light-duty vehicles run with any ethanol-to-gasoline proportion. The concentrations of 2-NBA and 3-NBA were, on average, under 14.8 µg g −1 and 4.39 µg g −1 , respectively. In order to access the main sources and formation routes of these compounds, we performed ternary correlations and multivariate statistical analyses. The main sources for the studied compounds in the bus station were diesel/biodiesel exhaust followed by floor resuspension. In the coastal site, vehicular emission, photochemical formation and wood combustion were the main sources for 2-NBA and 3-NBA as well as the other PACs. Incremental lifetime cancer risk (ILCR) were calculated for both places, which presented low values, showing low cancer risk incidence although the ILCR values for the bus station were around 2.5 times higher than the ILCR from the coastal site.

Abstract A large body of literature is available on wound healing in humans. Nonetheless, a standardized ex vivo wound model without disruption of the dermal compartment has not been put forward with compelling justification. Here, we present a novel wound model based on application of negative pressure and its effects for epidermal regeneration and immune cell behaviour. Importantly, the basement membrane remained intact after blister roof removal and keratinocytes were absent in the wounded area. Upon six days of culture, the wound was covered with one to three-cell thick K14 + Ki67 + keratinocyte layers, indicating that proliferation and migration were involved in wound closure. After eight to twelve days, a multi-layered epidermis was formed expressing epidermal differentiation markers (K10, filaggrin, DSG-1, CDSN). Investigations about immune cell-specific manners revealed more T cells in the blister roof epidermis compared to normal epidermis. We identified several cell populations in blister roof epidermis and suction blister fluid that are absent in normal epidermis which correlated with their decrease in the dermis, indicating a dermal efflux upon negative pressure. Together, our model recapitulates the main features of epithelial wound regeneration, and can be applied for testing wound healing therapies and investigating underlying mechanisms.

We report on solid-state mesoscopic heterojunction solar cells employing nanoparticles (NPs) of methyl ammonium lead iodide (CH(3)NH(3))PbI(3) as light harvesters. The perovskite NPs were produced by reaction of methylammonium iodide with PbI(2) and deposited onto a submicron-thick mesoscopic TiO(2) film, whose pores were infiltrated with the hole-conductor spiro-MeOTAD. Illumination with standard AM-1.5 sunlight generated large photocurrents (J(SC)) exceeding 17 mA/cm(2), an open circuit photovoltage (V(OC)) of 0.888 V and a fill factor (FF) of 0.62 yielding a power conversion efficiency (PCE) of 9.7%, the highest reported to date for such cells. Femto second laser studies combined with photo-induced absorption measurements showed charge separation to proceed via hole injection from the excited (CH(3)NH(3))PbI(3) NPs into the spiro-MeOTAD followed by electron transfer to the mesoscopic TiO(2) film. The use of a solid hole conductor dramatically improved the device stability compared to (CH(3)NH(3))PbI(3) -sensitized liquid junction cells.

Community detection is often used to understand the structure of large and complex networks. One of the most popular algorithms for uncovering community structure is the so-called Louvain algorithm. We show that this algorithm has a major defect that largely went unnoticed until now: the Louvain algorithm may yield arbitrarily badly connected communities. In the worst case, communities may even be disconnected, especially when running the algorithm iteratively. In our experimental analysis, we observe that up to 25% of the communities are badly connected and up to 16% are disconnected. To address this problem, we introduce the Leiden algorithm. We prove that the Leiden algorithm yields communities that are guaranteed to be connected. In addition, we prove that, when the Leiden algorithm is applied iteratively, it converges to a partition in which all subsets of all communities are locally optimally assigned. Furthermore, by relying on a fast local move approach, the Leiden algorithm runs faster than the Louvain algorithm. We demonstrate the performance of the Leiden algorithm for several benchmark and real-world networks. We find that the Leiden algorithm is faster than the Louvain algorithm and uncovers better partitions, in addition to providing explicit guarantees.

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

Abstract Effective pulpectomy of maxillary primary molars depends on a clear understanding of their complex internal root canal anatomy, yet high-resolution data on the second mesiobuccal (MB2) canal in the primary dentition remain scarce. Using micro-computed tomography (micro-CT; SkyScan 1172; 13.61 μm isotropic voxel size), the three-dimensional root and canal morphology of 60 extracted maxillary primary molars were charaterized, focusing on the prevalence, location, and morphometry of the MB2 canal, along with inter-orifice distances, canal diameters, and dentin wall thickness. Three-rooted molars predominated (83.3%). An MB2 canal was present in 43.3% of mesiobuccal roots and, when present, was consistently located palatal to the main mesiobuccal (MB1) canal, originating predominantly in the coronal third. Long-oval and oval cross-sections together accounted for almost all canals. The MB1–MB2 inter-orifice distance was the shortest of any canal pair (mean 1.12 mm), and buccolingual diameters exceeded mesiodistal diameters in the mesiobuccal, MB2, and distobuccal roots but not the palatal root. Apical dentin was thinnest in the palatal roots (0.10 mm). Maxillary primary molars therefore combine a frequently overlooked MB2 canal with thin apical walls. These findings may help clinicians plan access cavities, select instruments, and perform conservative apical preparation during pulpectomy procedures.

Abstract Corneal diseases are among the leading causes of blindness, and transplantation may be the only treatment option. Studies providing a comprehensive economic analysis of the corneal tissue processing chain, from procurement to release for transplantation by eye banks, are scarce. This study aimed to estimate the cost of preparing donated corneal tissue for transplantation at an Eye Bank. We performed a cost analysis using the Time-Driven Activity-Based Costing (TDABC) method based on data from the stages of corneal tissue preparation. The study population consisted of data from corneal donors collected in 2023. The median cost per donor was estimated at USD 454.65. Supplies (43%), human resources (32%), and operational costs (23%) were the costliest components. Multiple regression analysis identified predictors influencing costs. This study highlighted critical stages in the process and resource consumption. Investing in domestic pharmaceutical production, improving interinstitutional communication, training healthcare professionals, and providing logistical support may reduce costs and contribute to the management and sustainability of Eye Banks.

Abstract Accurate detection and depth perception of pavement targets from close-range remote sensing observations are important for intelligent road monitoring and transportation infrastructure assessment. However, existing stereo matching methods often produce unstable disparity estimates in weak-texture and low-height pavement regions, such as manhole covers and speed bumps, where the disparity distribution is easily affected by matching ambiguity and image noise. To address this issue, a detection-guided disparity post-processing strategy named Detection-Aware Disparity Refinement (DADR) is proposed. A custom pavement dataset containing approximately 3000 annotated images is first constructed from a binocular vision-based remote sensing platform, covering five pavement target categories, including manhole covers, speed bumps, road damage, storm drains, and iron plates. YOLOv11 is employed to detect target regions, while FoundationStereo is used to generate initial disparity maps from calibrated stereo images. Instead of modifying the stereo matching network, the proposed method performs a rule-based post-processing operation that combines detection bounding boxes, a local ground-reference disparity, and confidence-weighted fusion to stabilize the disparity representation within detected target regions. Experimental results show that the YOLOv11 detector achieves a Precision of 0.89, a Recall of 0.88, and an mAP@50 of 0.895, and compares favourably with other one-stage detectors trained under the same protocol. Visual analysis with magnified regions of interest shows that the proposed strategy produces more spatially coherent disparity responses for weak-texture pavement targets, and an ablation study identifies the local ground reference and the adaptive confidence weighting as the main contributing components. Quantitative evaluation indicates that the within-region disparity standard deviation decreases from 3.81 px to 1.25 px after refinement. Because no independent depth ground truth is available, this result is reported as improved local disparity consistency rather than improved absolute depth accuracy. The proposed approach offers a lightweight, detector-agnostic disparity stabilization strategy for low-height pavement targets in close-range remote sensing scenarios and provides useful geometric cues for subsequent road-condition assessment, while its reliance on a locally planar ground reference and on detector reliability is discussed as a limitation.

Abstract Magnesium silver oxide nanostructures were synthesized via a straightforward co-precipitation method and characterized using various analytical techniques. The morphological analysis revealed a 2D/3D sheet hierarchical architecture decorated with ultrafine spherical nanoparticles, providing distinctive characteristics include large specific surface area and high porous network that may facilitate enhanced interaction with microbial cells. The nanohybrid showed remarkable antimicrobial activity against Proteus vulgaris with an inhibition zone diameter of 20 mm as well as moderate antibacterial activity against Bacillus subtilis and Staphylococcus aureus with inhibition zone diameters of 14.33 and 11.67 mm, respectively. In contrast, no detectable antibacterial activity was observed against Escherichia coli . The Mg/Ag₂O nanostructure also demonstrated pronounced antifungal activity against Aspergillus fumigatus and Candida albicans producing inhibition zones of 10.50 and 12 mm, respectively. Moreover, the nanostructure exhibited remarkable adulticidal efficacy against Culex pipiens at a concentration of 300 ppm. In biomedical field, Mg/Ag₂O nanocomposite revealed strong antioxidant and anticancer activities achieving an IC₅₀ value of 2.80 ± 0.37 µg/mL and a maximum inhibition rate of 99.05%, highlighting its promising potential for diverse biomedical applications.

Protein arginine N-methyltransferase 4 (PRMT4) has been a novel target to discover anticancer drugs, and PRMT4 inhibitors offer a promising option for the treatment of colorectal cancer. In this work, a series of natural flavanones were evaluated for their inhibitory activity against PRMT4. Among them, Lespedezaflavanone H was a potent and selective PRMT4 inhibitor with an IC 50 value of 1.73 µM. Lespedezaflavanone H was predicted to form hydrogen bonds with ASN-265 and ARG-267 of PRMT4, as revealed by molecular docking. Chemical descriptors and molecular electrostatic potential analysis of Lespedezaflavanone H were deeply investigated. Molecular dynamics simulations demonstrated that the complex between PRMT4 and Lespedezaflavanone H maintained a stable binding mode. Importantly, Lespedezaflavanone H inhibited the proliferation of colorectal cancer cell lines RKO, SW620, COLO 205, and LS180 with IC 50 values of 3.93, 2.32, 5.68, and 11.26 µM, respectively. To the best of our knowledge, this is the first report that Lespedezaflavanone H acts as a PRMT4 inhibitor and exhibits antiproliferative activity against colorectal cancer cells.