Search Results (4,308)

A synthetically accessible library of N-acyl sulfonamides was constructed using a combination of copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and N-acylation of primary sulfonamides. The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable product yields (up to 61%). As a result of the validation process, a 262-member compound library (out of >70K accessible combinations) was prepared. Biological profiling of the synthesized library by differential scanning fluorimetry and enzymatic assays identified several low micromolar inhibitors of human carbonic anhydrase. The interaction of the discovered hits with the biological target was studied by docking and molecular dynamics. Full article

Although the clownfish, Amphiprion ocellaris (A. ocellaris), is a popular ornamental marine fish worldwide, the mechanisms underlying color pattern variation remain unclear. Given that the Platinum-type clownfish, nearly entirely white, has high economic value, understanding the biological mechanism that accounts for the difference between orange and white colors in A. ocellaris is crucial. To investigate these coloration differences, we performed RNA sequencing analysis and identified differentially expressed genes (DEGs) by comparing white and orange skin samples from three A. ocellaris individuals. A total of 76 DEGs were detected, including 56 downregulated and 20 upregulated genes. DEG sequences were annotated using Danio rerio and Stegastus partitus as reference species, selecting the best hit based on the lowest E-value. A protein–protein interaction (PPI) network and Gene Ontology biological process terms were additionally analyzed. Several DEGs previously reported to be associated with pigmentation, including hpdb, cldn11b, sfrp5, slc2a9, slc2a11b, si:ch211-256m1.8, fhl2, rab38, and ttc39b were identified. Based on the functions of these DEGs, it is inferred that leucophores and xanthophores contribute to both white and orange coloration by modulating related genes, including slc2a11b and slc2a9. Additionally, sfrp5, sost, and sp7 genes were identified to interact with each other in the PPI analysis, with sfrp5 and sost being associated with the Wnt signaling pathway, which contributes to melanocyte specification and osteoblast differentiation. Based on these findings, we propose sost and sp7 as candidate genes that might provide insights relevant to extreme white pigmentation phenotypes, such as those observed in Platinum-type clownfish. For a clearer understanding, further studies integrating quantitative genetics and functional analyses are required. Full article

Background: Infections caused by the protozoan Trichomonas vaginalis affect millions of people worldwide and are responsible for one of the most common sexually transmitted diseases. Despite the efficacy of 5-nitroimidazoles like metronidazole, concerns regarding widespread resistance and the absence of viable alternatives for specific patient populations necessitate the development of structurally diverse pharmacological agents. In this study, we investigated the antiparasitic activity of 1,3-thiazolidin-4-one derivatives against T. vaginalis. Methods: Thiazolidines were synthesized via multicomponent reaction (MCR) using one-pot methodology and tested in vitro against the parasite and mammalian cell lines. Results: Seventy percent of the compounds showed more than 80% antiparasitic activity at 100 μM, with compounds 4a, 4b, and 4f exhibiting IC₅₀ ≤ 20 µM. None of the molecules exhibited cytotoxic against Vero CCL-81 and HeLa cells. Evaluation of the structure–activity relationship (SAR) indicates that the substituent at the nitrogen position of the heterocycle may be involved in the antiparasitic effect of these compounds. In silico studies also revealed that the three compounds possess adequate oral bioavailability and do not present mutagenic, tumorigenic or irritating risks. Finally, molecular docking predicted strong interactions of compounds 4a, 4b, and 4f with T. vaginalis enzymes lactate dehydrogenase and purine nucleoside phosphorylase; compound 4f also interacted with methionine Ƴ-lyase. Conclusions: These preliminary results suggest that 1,3-thiazolidin-4-ones are promising scaffolds for developing new trichomonacidal agents. Full article

Background/Objectives: This study compared vestibular evoked myogenic potentials (VEMP) and video head impulse test (vHIT) findings between long-term hearing aid users and non-users with moderately severe to profound sensorineural hearing loss (SNHL) to investigate whether prolonged use of high-power hearing aids has any effect on the functioning of peripheral vestibular organs. Methods: A cross-sectional study was conducted in the audiology clinic of a tertiary care hospital. Using convenience sampling, 67 adults aged 20–64 years who visited for hearing evaluation or hearing aid services were recruited and allocated into hearing aid user and non-user groups. VEMP latency and amplitude and vHIT vestibulo-ocular reflex (VOR) gain values were compared between groups. Multiple linear regression was performed to examine the association between the duration of hearing aid use and vestibular function. Results: No significant group differences were observed for any VEMP or vHIT parameter, except for the latency of P1 of the cVEMP in the left ear. Regression analyses indicated that the duration of hearing aid use was not significantly associated with any vestibular test measure. Conclusions: Long-term use of high-power hearing aids does not appear to be associated with measurable alterations in vestibular function. Nonetheless, longitudinal studies with improved control of confounding variables are recommended to validate these preliminary findings. Full article

Background: Tobramycin is a key therapy for pulmonary exacerbations in children and adolescents with cystic fibrosis (CF), yet its variable pharmacokinetics (PK) combined with narrow therapeutic index necessitates therapeutic drug monitoring (TDM) during clinical care to optimize exposure while minimizing toxicity. Model-informed precision dosing (MIPD) is a potentially powerful tool to support dose individualization in clinical care that leverages population PK models and Bayesian forecasting. Herein, we evaluated the performance of an MIPD initiative at our hospital for once-daily tobramycin in pediatric patients with CF. Methods: Tobramycin practices at a single CF center before (2016–2018) and after (2019–2025) implementation of an MIPD initiative in CF patients < 21 years were evaluated. TDM during the pre-MIPD period used traditional log-linear AUC calculations, while the post-MIPD period used a commercial MIPD software platform integrated within the electronic health record. Outcomes included attainment of the target 24 h area-under-the-curve (AUC₂₄ 80–120 mg·h/L), number of TDM samples and dose adjustments during the first 7 days of treatment, and rates of acute kidney injury (AKI). Results: A total of 114 treatment courses were analyzed (77 pre-MIPD, 37 post-MIPD). Post-MIPD target attainment was 75.7% at TDM1, 89.2% at TDM2, and 100% at TDM3, significantly higher than pre-MIPD at corresponding cycles. The post-MIPD period required fewer TDM samples (4.2 vs. 7.1; p < 0.001) and dose adjustments (0.7 vs. 1.8; p < 0.001) in the first 7 days. AKI incidence remained low and comparable between periods. Conclusions: Implementation of an MIPD initiative for tobramycin in pediatric patients with CF led to the early attainment of therapeutic AUC₂₄ targets while reducing TDM burden and dose adjustments. Full article

This study presents an in silico proof of concept exploring whether deep learning models can perform conditional mitochondrial DNA (mtDNA) sequence prediction across species boundaries. A CNN–BiLSTM model was trained under a leave-one-species-out (LOSO) scheme on complete mitochondrial genomes from 21 vertebrate species, primarily archosaurs. Model behavior was evaluated through multiple complementary tests. Under context-conditioned settings, the model performed next-nucleotide prediction using overlapping 200 bp windows to assemble contiguous 2000 bp fragments for held-out species; the resulting high token-level accuracy (>99%) under teacher forcing is reported as a diagnostic of conditional modeling capacity. To assess leakage-free performance, a two-flank masked-span imputation task was conducted as the primary evaluation, requiring free-running reconstruction of 500 bp interior spans using only distal flanking context; in this setting, the model consistently outperformed nearest-neighbor and demonstrated competitive performance relative to flank-copy baselines. Additional robustness analyses examined sensitivity to window placement, genomic region (coding versus D-loop), and random initialization. Biological plausibility was further assessed by comparing predicted fragments to reconstructed ancestral sequences and against composition-matched null models, where observed identities significantly exceeded null expectations. Using the National Center for Biotechnology Information (NCBI) BLAST web interface, BLASTn species identification was performed solely as a biological plausibility check, recovering the correct species as the top hit in all cases. Although limited by dataset size and the absence of ancient DNA damage modeling, these results demonstrate the feasibility of conditional mtDNA sequence prediction as an initial step toward more advanced generative and evolutionary modeling frameworks. Full article

Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient’s clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis. Full article

This study introduces the Hybrid Hydrological Forecast System (HHFS), a dual-stage, data-driven framework for monthly streamflow forecasting at the Santa Branca outlet in the upper Paraíba do Sul River Basin, Brazil. The system combines two nonlinear regressors, Multi-Layer Perceptron (MLP) and extreme Gradient Boosting (XGB), calibrated through a structured four-step evolutionary procedure in GA₁ (hydrological weighting, dual-regime Ridge fusion, rolling bias correction, and monthly mean–variance adjustment) and a hydro-adaptive probabilistic optimization in GA₂. SHAP-based analysis provides physical interpretability of the learned relations. The regressive stage (GA₁) generates a bias-corrected and climatologically consistent central forecast. After the full four-step optimization, GA₁ achieves robust generalization skill during the independent test period (2020–2023), yielding NSE = 0.77 ± 0.05, KGE = 0.85 ± 0.05, R² = 0.77 ± 0.05, and RMSE = 20.2 ± 3.1 m³ s⁻¹, representing a major improvement over raw MLP/XGB outputs (NSE ≈ 0.5). Time-series, scatter, and seasonal diagnostics confirm accurate reproduction of wet- and dry-season dynamics, absence of low-frequency drift, and preservation of seasonal variance. The probabilistic stage (GA₂) constructs a hydro-adaptive prediction interval whose width (max-min streamflow) and asymmetry evolve with seasonal hydrological regimes. The optimized configuration achieves comparative coverage COV = 0.86 ± 0.00, hit rate p = 0.96 ± 0.04, and relative width r = 2.40 ± 0.15, correctly expanding uncertainty during wet-season peaks and contracting during dry-season recessions. SHAP analysis reveals a coherent predictor hierarchy dominated by streamflow persistence, precipitation structure, temperature extremes, and evapotranspiration, jointly explaining most of the predictive variance. By combining regressive precision, probabilistic realism, and interpretability within a unified evolutionary architecture, the HHFS provides a transparent, physically grounded, and operationally robust tool for reservoir management, drought monitoring, and hydro-climatic early-warning systems in data-limited regions. Full article

Background: In nuclear medicine, numerous cancer types are treated via internal irradiation with radiopharmaceuticals, including low-LET (linear energy transfer) beta-emitting radionuclides like Lu-177. In most cases, such treatments lead to low-dose exposure of organ systems with β-irradiation, which induces only few isolated DSBs (double-strand breaks) in the nuclei of hit cells, the most threatening DNA damage type. That damaging effect contrasts with the clustering of DNA damage and DSBs in nuclei traversed by high-LET particles (α particles, ions, etc.). Methods: After in-solution β-irradiation for 1 h with Lu-177 leading to an absorbed dose of about 100 mGy, we investigated the spatial nano-organization of chromatin at DSB damage sites, of repair proteins and of heterochromatin marks via single-molecule localization microscopy (SMLM) in PBMCs. For evaluation, mathematical approaches were used (Ripley distance frequency statistics, DBScan clustering, persistent homology and similarity measurements). Results: We analyzed, at the nanoscale, the distribution of the DNA damage response (DDR) proteins γH2AX, 53BP1, MRE11 and pATM in the chromatin regions surrounding a DSB. Furthermore, local changes in spatial H3K9me3 heterochromatin organization were analyzed relative to γH2AX distribution. SMLM measurements of the different fluorescent molecule tags revealed characteristic clustering of the DDR markers around one or two damage foci per PBMC cell nucleus. Ripley distance histograms suggested the concentration of MRE11 molecules inside γH2AX-clusters, while 53BP1 was present throughout the entire γH2AX clusters. Persistent homology comparisons for 53BP1, MRE11 and γH2AX by Jaccard index calculation revealed significant topological similarities for each of these markers. Since the heterochromatin organization of cell nuclei determines the identity of cell nuclei and correlates to genome activity, it also influences DNA repair. Therefore, the histone H3 tri methyl mark H3K9me3 was analyzed for its topology. In contrast to typical results obtained through photon irradiation, where γH2AX and H3K9me3 markers were well separated, the results obtained here also showed a close spatial proximity (“co-localization”) in many cases (minimum distance of markers = marker size), even with the strictest co-localization distance threshold (20 nm) for γH2AX and H3K9me3. The data support the results from the literature where only one DSB induced by low-dose low LET irradiation (<100 mGy) can remain without heterochromatin relaxation for subsequent repair. Full article

Currently, with the widespread popularization of e-commerce systems, enterprises have increasingly high requirements for the timeliness of order fulfillment. It has become particularly critical to enhance the operational efficiency of heterogeneous robotic “goods-to-person” (G2P) systems in book e-commerce fulfillment, reduce enterprise operational costs, and achieve highly efficient, low-carbon, and sustainable warehouse management. Therefore, this study focuses on determining the optimal storage location assignment strategy and order batching method. By comprehensively considering the characteristics of book e-commerce, such as small-batch, high-frequency orders and diverse SKU requirements, as well as existing system issues including uncoordinated storage assignment and order processing, and differences in the operational efficiency of heterogeneous robots, this study proposes a joint optimization framework for storage location assignment and order batching centered on a multi-objective model. The framework integrates the time costs of robot picking operations, SKU turnover rates, and inter-commodity correlations, introduces the STCSPBC storage strategy to optimize storage location assignment, and designs the SA-ANS algorithm to solve the storage assignment problem. Meanwhile, order batching optimization is based on dynamic inventory data, and the S-O Greedy algorithm is adopted to find solutions with lower picking costs. This achieves the joint optimization of storage location assignment and order batching, improves the system’s picking efficiency, reduces operational costs, and realizes green and sustainable management. Finally, validation via a spatiotemporal network model shows that the proposed joint optimization framework outperforms existing benchmark methods, achieving a 45.73% improvement in average order hit rate, a 48.79% reduction in total movement distance, a 46.59% decrease in operation time, and a 24.04% reduction in conflict frequency. Full article

About 16% of typhoons making landfall in China strike Hainan Island, where near-surface extreme winds in dense urban areas exhibit a strong spatiotemporal heterogeneity that is difficult to capture with current observations and mesoscale models. Focusing on Haikou during Super Typhoon Yagi (2024)—the strongest autumn typhoon to hit China since 1949—we developed a multiscale ERA5–WRF–PALM framework to conduct 30 m resolution large-eddy simulations. PALM results are in reasonable agreement with most of the five automatic weather stations, while performance is weaker at the most sheltered park site. Mean near-surface wind speeds increased by 20–50% relative to normal conditions, showing a coastal–urban gradient: maps of weighted cumulative exposure to strong winds (≥Beaufort force 8) show much longer and more intense events along open coasts than within built-up urban cores. Urban morphology exerted nonlinear effects: wind speeds followed a U-shaped relation with both the open-space ratio and mean building height, with suppression zones at ~0.5–0.7 openness and ~20–40 m height, while clusters of super-tall buildings induced Venturi-like acceleration of 2–3 m s⁻¹. Spatiotemporal analysis revealed banded swaths of high winds, with open areas and islands sustaining longer, broader extremes, and dense street grids experiencing shorter, localized events. Methodologically, this study provides a rare, systematically evaluated application of a multiscale ERA5–WRF–PALM framework to a real typhoon case at 30 m resolution in a tropical coastal city. These findings clarify typhoon–city interactions, quantify morphological regulation of extreme winds, and support risk assessment, urban planning, and wind-resilient design in coastal megacities. Full article

The production of heavy gauge quenched and tempered steel plates requires alloying strategies that ensure adequate hardenability and microstructural uniformity under limited cooling rates. Molybdenum (Mo) and nickel (Ni) are key elements in this context, as they influence both hot-working behavior and phase transformation kinetics. This study investigates the effect of Mo (0.25–0.50 wt%) and Ni (0–1.00 wt%) additions on static recrystallization and transformation behavior using laboratory thermomechanical simulations representative of thick plate rolling conditions. Multipass and double-hit torsion tests were performed to determine the non-recrystallization temperature (Tnr) and quantify softening kinetics, while dilatometry was employed to construct Continuous Cooling Transformation (CCT) diagrams and assess hardenability. Results indicate that Mo significantly increases Tnr and delays recrystallization through a solute drag mechanism, whereas Ni exerts a minor but measurable effect, likely associated with stacking fault energy rather than classical solute drag. Both elements reduce ferrite and bainite transformation temperatures, enhancing hardenability; however, Mo alone cannot suppress ferrite formation at practical cooling rates, requiring combined Mo–Ni additions to achieve fully martensitic microstructures. These findings provide insight into alloy design for thick plate applications and highlight the limitations of existing predictive models for Ni-containing steels. Full article

Data prefetching is essential for modern file storage systems operating in large-scale cloud and data-intensive environments, where high performance increasingly depends on intelligent, adaptive mechanisms. Traditional rule-based methods and recently proposed machine learning-based techniques often struggle to cope with the complex and rapidly evolving data access patterns characteristic of big-data workloads. In this paper, we introduce an online, streaming machine learning (SML) approach for predictive data prefetching that retrieves useful data into the cache ahead of time. We present a novel online training framework that extracts features in real time and continuously updates streaming ML models to learn and adapt from large and dynamic access streams. Building on this framework, we design new SML-driven prefetching algorithms that decide when, how, and what data to prefetch into the cache with minimal overhead. Extensive experiments using production traces from Huawei Technologies Inc. and Google workloads from the SNIA IOTTA repository demonstrate that our intelligent policies consistently deliver the highest byte hits among competing approaches, achieving 97% prefetch byte precision and reducing data access latency by up to 2.8 times. These results show that streaming ML can deliver immediate performance gains and offers a scalable foundation for future adaptive storage systems. Full article

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N′-disubstituted diamines as promising antichagasic agents and gain insight into the mechanism of action. Methods: The library was evaluated for activity against the T. cruzi amastigote stage and trypanocidal efficacy. In addition, selected compounds were tested as potential polyamine transport inhibitors, and a fluorescent analog was employed to investigate compound internalization. Results: Five compounds exhibited potent activity (pIC₅₀ > 6.0), particularly those with short aliphatic linkers (3–6 carbon atoms), suggesting a structure–activity relationship favouring shorter chains. Mechanistic studies showed that compound 3c strongly inhibited polyamine transport, a vital pathway in T. cruzi, though this was not a universal mechanism among active hits, indicating the potential for multiple targets. A fluorescent analog confirmed intracellular uptake in amastigotes but lacked antiparasitic activity, likely due to disrupted pharmacophoric features. Importantly, none of the compounds demonstrated trypanocidal activity in long-term assays, and some showed cytotoxicity, particularly in the benzyloxy-substituted series. Conclusions: These findings position N,N′-disubstituted diamines as a viable scaffold for Chagas disease drug discovery. However, further optimization is required to enhance selectivity, achieve trypanocidal effects, and better understand the underlying mechanisms of action. Full article

Spina bifida (SB) is a congenital malformation of the central nervous system (CNS), resulting from incomplete closure of the neural tube (NT) during early embryogenesis. Myelomeningocele (MMC), the most severe form of SB, leads to progressive neurological, orthopedic, and urological dysfunctions due to both NT developmental failure and secondary intrauterine injury (“two-hit hypothesis”). Prenatal repair of MMC has progressed considerably since the Management of Myelomeningocele Study (MOMS, 2011) trial, which showed that open fetal surgery can decrease the need for shunting and improve motor function, although it carries significant maternal risks. To address these limitations, minimally invasive techniques have been developed, with the goal of achieving similar benefits for the fetus while reducing maternal morbidity. Recent research has shifted toward regenerative strategies, integrating mesenchymal stem cells (MSCs), bioengineered scaffolds, and cell-derived products to move beyond mere mechanical protection toward true NT repair. Preclinical studies in rodent and ovine models have shown that amniotic- and placenta-derived MSCs exert neuroprotective and immunomodulatory paracrine effects, promoting angiogenesis, modulating inflammation, and supporting tissue regeneration. Minimally invasive, cell-based interventions such as Transamniotic Stem Cell Therapy (TRASCET), in preclinical rodent models, offer the possibility of very early treatment without hysterotomy, although translation remains limited by the lack of large-animal validation and long-term safety data. In parallel, advances in biomaterials, nanostructured scaffolds, and exosome-based therapies reinforce a regenerative paradigm that may improve neurological outcomes and quality of life in affected children. Ongoing translational studies are essential to optimize these approaches and define their safety and efficacy in clinical settings. This review provides an integrated overview of embryological mechanisms, diagnostic strategies, and prenatal therapeutic advances in SB treatment, with emphasis on prenatal repair, fetal surgery and emerging regenerative approaches. Full article