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Distinct Nuclear Localization Signals Confer Differential Microtubule Dependence among ZFTA Fusion Oncoproteins

A sequential MAP kinase cascade regulates mechanical signalling

Abstract Plants respond to mechanical stimulations like wind, touching or wounding to safeguard their development and survival. Mitogen Activated Protein Kinases (MAPKs) activation by mechanostimuli was reported 26 years ago, but the upstream regulatory mechanism and function remained unknown. We report that mechanostimulation activates a MAPKKK3/4/5-MKK4/5-MPK3/6 cascade within 60 seconds, leading to induction of ~800 genes, encompassing most of the early touch response. Most genes overlap with touch-responsive genes regulated by CAMTA1/2/3, exposing an interplay between MAPKs and CAMTA transcription factors. Furthermore, loss of MKK4/5 leads to global impairment of touch-regulated protein phosphorylation, demonstrating they are crucial regulators. In contrast, phosphorylation does not clearly affect early activation of the touch-induced jasmonic acid (JA) signalling pathway, nor does loss of JA affect the overall early touch-phosphoproteome. Lastly, loss of MAPKKK3/4/5 and MKK4/5 reduces thigmomorphogenesis, underlining the importance of the identified MAPK cascade for steering plant growth during stress. In summary, we have now identified a MAPKKK3/4/5-MKK4/5-MPK3/6 cascade as a key touch- and wounding signalling pathway in plants.

A Dinucleating Modular Phosphine–Pyridine–Oxazoline Ligand for Cu-Catalyzed Asymmetric Dearomative Propargylic Substitutions

Determinants of mobile money loan disbursements: Evidence from Uganda’s post pandemic digital credit boom

In the aftermath of the COVID-19 pandemic, Uganda witnessed a rapid rise in mobile money usage and digital credit adoption, underscoring the sector’s role in post crisis recovery and financial resilience. Against this backdrop, this paper examines the determinants of mobile money loan disbursements in Uganda a global pioneer in mobile financial innovation, using monthly data from July 2021 to December 2024 and applying the Autoregressive Distributed Lag (ARDL) cointegration framework to capture both long-run relationships and short-run dynamics. Results show a long-run relationship linking average loan disbursements with outstanding loan values and lagged inflation. In the short term, past loan disbursements have a significant impact on current loan values. Behavioural proxies are informative, airtime purchases and timely mobile loan repayments are associated with higher disbursement volumes, consistent with lenders interpreting them as signals of reliability and liquidity. By contrast, higher transaction volumes and fees depress disbursements, underscoring the adverse impact of elevated user costs on credit access. These findings highlight actionable levers for expanding responsible digital credit and deepening inclusion.

Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth

Chlorinated VSLSs Surpass HCFCs in CFC-11-Equivalent Emissions for Ozone Layer Depletion in China

Diuranacyclobutadiene: Evidence of Electron Delocalization in the Actinide–Carbon Ring

Isolation and preliminary characterization of extracellular vesicles from bottlenose dolphin (Tursiops truncatus) and long-finned pilot whale (Globicephala melas) blow

Cetaceans are key sentinel species for environmental health monitoring. Although sampling from free-ranging animals is challenging, the analysis of cetacean blow offers a minimally invasive approach to assess their health status. Extracellular vesicles (EVs) are cell-derived nanostructures present in biological fluids and widely studied as disease biomarkers in humans. Despite the potential for similar uses, EVs have not been studied in cetacean blow to date. This proof-of-concept study aims to assess the feasibility of the isolation and characterization of EVs from blow samples collected from five bottlenose dolphins ( Tursiops truncatus ) kept under human care and from a free ranging specimen of long-finned pilot whale ( Globicephala melas ). EVs were purified from bottlenose dolphin blows by ultracentrifugation (UC) or size exclusion chromatography (SEC) and from the long-finned pilot whale by SEC. Particle concentration and size distribution were assessed by Nanoparticle Tracking Analysis (NTA), morphology by Air-atomic force microscopy (AFM) and protein expression by Western Blotting (WB). NTA revealed a higher mean particle concentration in bottlenose dolphin EVs isolated by UC compared to SEC, while EVs isolated from the long-finned pilot whale presented a lower particle concentration. AFM confirmed the presence of EV-like particles within the typical EV size range in bottlenose dolphin’s EVs obtained both by SEC or UC. All EV samples were positive for CD9 and integrin-β and negative to Calnexin. SEC was more sensitive to detect OmpA, a membrane protein of Gram-negative bacteria, in EVs from both species. Our pilot study demonstrates that EV-like particles are present in cetacean blow and can be isolated and characterized. Future investigations focused on characterizing and quantifying a wider array of EV associated molecules may further the application of blow EV analysis for cetacean health assessments.

Leucyl-tRNA synthetase as a molecular target of isobutanol-mediated growth inhibition in Saccharomyces cerevisiae

Few-atom-thick silver films for enhanced nanoscale nonlinear optics

Abstract The inherently weak nonlinear optical response of bulk materials remains a fundamental limitation in advancing photonic technologies. Nanophotonics addresses this challenge by tailoring the size and morphology of nanostructures to manipulate the optical near field, thus modulating the nonlinear response. Here, we explore a complementary strategy based on engineering the electronic band structure in the mesoscopic regime to enhance optical nonlinearities. Specifically, we demonstrate an increase in second-harmonic generation (SHG) from crystalline silver films as their thickness is reduced down to just a few atomic monolayers. Operating at the boundary between bulk and two-dimensional systems, these ultra-thin films exhibit a pronounced enhancement of SHG with decreasing thickness. This enhancement stems from quantum confinement effects that modify the interaction between electronic states and incident light, which we explain based on quantum-mechanical calculation. Our atomically-thin crystalline silver films provide a new means to overcome the small interaction volumes inherent to nanophotonic platforms, enabling efficient nanoscale nonlinear optics with potential applications in photonics, sensing, and quantum technologies.

Collaborative Pt–Ni Sites Enable CO-Tolerant Hydrocracking for Upcycling Polyolefin Waste

Evaluation of early trabecular changes around implants using fractal analysis and panoramic indices

Early trabecular changes around dental implants may not be adequately captured by conventional panoramic morphometric indices. Fractal analysis has been proposed as a quantitative method for detecting subtle changes in bone microarchitecture. This study aimed to evaluate early peri-implant trabecular structural changes using fractal analysis and panoramic morphometric indices during the unloaded healing period. This retrospective study included 60 single-tooth dental implants. Standardized panoramic radiographs were obtained at baseline and 3 months postoperatively. Mandibular cortical width, panoramic mandibular index, and fractal dimension values were measured in mesial, distal, and apical regions using ImageJ software. As all implants healed submerged and unloaded, periodontal parameters—plaque index, gingival index, bleeding on probing, and probing pocket depth—were recorded from natural teeth in the same quadrant. Baseline and 3-month values were compared using paired t-tests, with statistical significance set at p < 0.05. Fractal dimension values increased significantly in all evaluated regions at 3 months compared with baseline (p < 0.05), indicating measurable early trabecular structural changes. In contrast, mandibular cortical width and panoramic mandibular index showed no significant changes. Among periodontal parameters, only gingival index demonstrated a significant improvement (p < 0.001), reflecting reduced gingival inflammation. Fractal analysis detected early trabecular changes during the 3-month unloaded healing period, whereas conventional panoramic morphometric indices showed no significant change. These findings should be interpreted as indicators of trabecular reorganization rather than direct evidence of osseointegration. Fractal analysis may provide supplementary, non-invasive information during early radiographic follow-up.

Impaired cortical actin dynamics via lanosterol-dependent HMG-CoA reductase downregulation mediates IFN-α-induced mast cell stabilization

A carboxylate switch point controls long-range energy transduction in respiratory Complex I

Abstract Complex I is a highly intricate membrane-bound protein complex that powers the cellular energy metabolism by a long-range ( > 300 Å) proton-coupled electron transfer (PCET) reaction. Here, we investigate the highly debated coupling mechanism of Complex I by probing the charge transfer reaction along its functionally central carboxylate pathway (E-channel). By combining biophysical and site-directed mutagenesis experiments with high-resolution (2.6-2.8 Å) cryo-electron microscopy (cryo-EM) and multiscale simulations, we identify a conserved carboxylate switch point (D79 NuoA ) that mediates proton transfer by establishing a kinetic gate and couples the redox chemistry to proton pumping. We find that mutation of the identified site, as found in patients suffering from severe neurodegenerative disorders, drastically perturbs the charge transfer mechanism, and results in a 20% PCET activity. Our combined findings illustrate mechanistic principles of molecular gates underlying long-range charge transfer reactions, and show how disease mutations perturb the function of conserved switch points in energy transduction.

Unified <i>N</i> -Sulfonylated Urea Catalyzed Enantioselective Dimerization, Arylation, and Amination of Tryptamines: Total Synthesis of Five Pyrroloindoline Alkaloids

Developing a natural language processing system using transformer-based models for adverse drug event detection in electronic health records

Objective To develop a transformer-based natural language processing (NLP) system for detecting adverse drug events (ADEs) from clinical notes in electronic health records (EHRs). Materials and Methods We fine-tuned BERT Short-Formers and Clinical-Longformer using the processed dataset from the 2018 National NLP Clinical Challenges (n2c2) shared task Track 2. Two data processing methods, window-based and split-based approaches, were compared to identify the optimal processing method. Model generalizability was evaluated on a dataset extracted from Vanderbilt University Medical Center (VUMC) EHRs. Results On the n2c2 dataset, the best 5-fold cross-validation AUPRC, micro F1, and macro F1 scores were 0.840 (Clinical-Longformer, 4-chunk split), 0.965 (BioBERT, 15-word window), and 0.852 (Clinical-Longformer, 10-chunk split). On the VUMC dataset, the best AUPRC, micro F1, and macro F1 scores were 0.536 (Clinical-Longformer, 6-chunk split), 0.966 (BERT-base-uncased, 6-chunk split), and 0.762 (Clinical-Longformer, 4-chunk split). Discussion Transformer-based models demonstrated strong performance for ADE detection, with split-based processing generally outperforming window-based methods. Clinical-Longformer combined with a practical split-based approach showed promise for real-world implementation. Beyond token limits, chunk size substantially influenced model performance, even when text length remained within limits. Conclusion Our findings provide practical guidance for developing transformer-based ADE detection systems from clinical notes. The selection of both text preprocessing strategies and model architectures should be guided by note characteristics and practical considerations such as annotation burden.

Clinically observed RASA1 missense mutants exhibit diverse RasGAP protein behaviors in vitro

Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides

Abstract Coccidioides is a dimorphic fungal pathogen that grows as a mold in soil and produces infectious arthroconidia. Inhaled arthroconidia transition to spherules containing endospores in mammalian hosts. How distinct developmental forms of Coccidioides interact with immune cells remains poorly defined. Here, we show that arthroconidia activates TLR2 and induces NLRP3-pyrin inflammasomes in macrophages, while ferroptotic signaling promotes arthroconidia killing. Upon transition to spherules, only ruptured spherules—not intact ones—trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores. A TLR2-NLRP3-pyrin-IL-18 axis in macrophages promotes spherule growth. Endospores activate NLRP3 but not pyrin inflammasomes. Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens, correlating with enhanced neutrophil extracellular trap formation in lung granulomas. Neutrophils respond to spherules through NLRP3-pyrin inflammasomes, GSDMD-GSDME, and MLKL. Together, these findings reveal that Coccidioides morphotypes elicit distinct yet overlapping immune programs, coordinating inflammasome activation and regulated cell death to shape host-pathogen dynamics.

Predicting Internal Versus External Nanoparticle Formation in Zr-Based Metal–Organic Frameworks

Monotherapy or combinations? Intravenous vitamin C in sepsis and septic shock: An umbrella review of 31 systematic reviews

Intravenous (IV) vitamin C has been proposed as an adjuvant therapy in sepsis/septic shock due to its biological plausibility and safety profile, but the proliferation of reviews has not resolved its clinical utility. To synthesize the evidence on IV vitamin C (monotherapy, HAT—hydrocortisone+vitamin C+thiamine—and vitamin C+thiamine) in adults with sepsis/septic shock, prioritizing 28–30-day mortality. Umbrella review of systematic reviews and meta-analyses (MEDLINE/PubMed, Embase, Scopus, and Web of Science, without language restriction). Quality was assessed with AMSTAR 2, overlap with CCA, and when available, TSA and component/network meta-analysis (CINeMA). Certainty of evidence was graded using GRADE with an anchor estimator per outcome and regimen. Thirty-one reviews were included (30 quantitative: 28 SR/MA and 2 component/network MA; 1 qualitative). Combinations (HAT and vitamin C+thiamine) did not reduce mortality; hemodynamic improvements (small decreases in ΔSOFA and vasopressor hours) were modest, did not translate into survival benefits, and were primarily attributable to the corticosteroid. Monotherapy showed a possible mortality benefit signal under specific conditions (initiation ≤24 h, intermediate dose 25–100 mg/kg/day, 3–4-day courses; more pronounced in sepsis than shock), but with low-to-moderate certainty due to heterogeneity, imprecision, publication bias, and very high overlap among reviews. Combination regimens (HAT and vitamin C plus thiamine) did not reduce mortality; hemodynamic improvements were modest, did not translate into survival benefits, and were primarily attributable to the corticosteroid component. For monotherapy, a possible mortality benefit signal was identified under specific conditions (initiation within 24 h, intermediate dose 25–100 mg/kg/day, 3–4-day courses, more pronounced in sepsis than shock), but overall certainty remains low-to-moderate due to heterogeneity, imprecision, publication bias, and very high overlap among reviews. These findings do not support routine use of IV vitamin C in any regimen; for monotherapy, the identified signal warrants rigorous multicenter trials in well-defined clinical scenarios before any recommendation can be made.