Collisionless shocks are ubiquitous in space plasmas throughout the Universe and are widely believed to be primary sites of cosmic ray acceleration1,2. The prevailing mechanism, diffusive shock acceleration, requires particles to repeatedly cross the shock front, gaining energy with each crossing. The maximum achievable energy is fundamentally constrained by the Hillas criterion, which relates the physical scale of the accelerator to the maximum particle energy3. However, the scarcity of direct observational constraints for acceleration sites limits our ability to predict maximum particle energies across most astrophysical systems. Here, using data from the Juno spacecraft of NASA, we show the direct evidence of relativistic electron acceleration (≥1 MeV) upstream of the bow shock of Jupiter, powered by a large-scale foreshock transient4,5. Leveraging these and complementary Solar System observations, we propose a universal scaling law for the Hillas limit that empirically connects the observable size of a transient to maximum particle energy. Applying this scaling to various environments, from planetary bow shocks6 to protostellar jets7 and supernova remnants8, yields a simple model of maximum obtainable particle energies ranging from MeV scales up to about tens of GeV, and about tens of TeV, respectively, providing an observationally grounded method for constraining maximum cosmic ray energies at astrophysical shocks9,10.
Jupiter, a rapidly rotating gas giant, features over 20 atmospheric jet streams that penetrate thousands of kilometers into the planet. This work discusses recent progress, identifies key uncertainties regarding the jets’ driving and dissipating mechanisms, and suggests future research avenues.
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Accurate knowledge of the electrical and thermal conductivities and structural properties of hydrogen-helium mixtures under thermodynamic conditions within and beyond the immiscibility range is very important to predict the thermal evolution and internal structure of gas giant planets like Jupiter and Saturn. Here, we propose a novel method to determine the immiscibility boundary accurately without the need for free energy calculations, while providing consistent insights into structural and transport properties of mixtures. We show with direct large-scale ab initio simulations that the insulator-metal transition (IMT) of the hydrogen subsystem is strongly affected by an admixture with a small fraction of helium and occurs at temperatures significantly higher than those of pure hydrogen. At pressures below 150 GPa, the IMT boundary is not related anymore to the H2 subsystem dissociation, the system remains insulating even after the full dissociation of H2 molecules and its transition to an atomic H-He mixture. The offset of the IMT in the H-He mixture relative to the dissociation region in the hydrogen subsystem and the significant reduction of static electrical and thermal conductivity by a factor between two and a few thousand relative to pure hydrogen found in mixtures have consequences for Jupiter and Saturn's thermal evolution, internal structure, and dynamo action, affecting a large fraction of the interior of both planets.
Atherosclerosis is recognized as a chronic inflammatory disease, with high-sensitivity C-reactive protein (hs-CRP) serving as a biomarker of cardiovascular risk that persists despite optimal control of traditional risk factors. Landmark trials, like JUPITER (Justification for the Use of Statins in Prevention) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy), demonstrate the effect of lipid-lowering medications on inflammation. This can have further implications for comprehensive cardiovascular risk reduction. Statins lower hs-CRP alongside low-density lipoprotein cholesterol (LDL-C), with greater effects from high-intensity regimens. Nonstatin medications have variable effects; for example, the addition of ezetimibe to statin therapy enhances hs-CRP reduction. Bempedoic acid exerts direct anti-inflammatory effects, producing significant hs-CRP lowering. Omega-3 fatty acids also demonstrate favorable effects on inflammatory markers. However, fibrates offer only marginal benefits, and PCSK9 inhibitors (Proprotein Convertase Subtilisin/Kexin type 9) have minimal impact. Residual inflammatory risk persists despite LDL-C control, supporting dual-target strategies. The evidence supports therapeutic strategies targeting both lipid and inflammatory pathways, with hs-CRP serving as a complementary marker to refine cardiovascular risk stratification and guide treatment intensification in primary and secondary prevention. Future studies should evaluate inflammation-targeted adjunctive therapies to address discordance between lipid control and residual inflammatory risk.
In low- and middle-income nations, abortion ranks among the top five causes of maternal mortality. It is associated to a pregnancy and childbirth-related complications. Despite this, there are few scientific researches focusing on predicting abortion and its determinants in East African countries. Therefore, this study aimed to predict abortion and its determinants among women of reproductive-age in East African countries. Community-based cross-sectional study design was used from eleven East African countries DHS dataset spanning 2015 to 2023. The study participants were all reproductive age women who were selected using a two-stage stratified sampling technique. The machine-learning algorithms were applied to predict abortion and its determinants using Python, particularly Jupiter notebook in Google colab. Data cleaning, one-hot encoding, data splitting, and ten-fold cross-validation were performed. Ten machine learning algorithms and SHAP were used to select and interpret the best model. From the total of 372,053 reproductive age women in East Africa, 12.2% participants perform abortion. Random forest was found the best model for training data with 91% of an AUC and 86% of accuracy. According to SHAPE analysis, women who have been never in union, women whose age 15-19 years, women whose age 20-24 years, women from Ethiopia, and women who not used any method were the top four features of abortion. This study identified that random forest classifier was emerged as the best-performing model to predict abortion among women reproductive age in East African countries. Marital status, marital status, age, country, Contraceptive use by method type, and living children plus current pregnancy were key determinant of abortion in East African countries. Governments and health systems should provide access to comprehensive family planning services, reproductive health education, and maternal health support.
We review the key observations and theories relevant to the origin and evolution of the Galilean satellites. Key observations include: the potentially undifferentiated nature of Callisto; the increasing ice fraction with semi-major axis; the present-day existence of the Laplace resonance; the potential resurfacing of Ganymede mid-way through its evolution; and the metal-enriched nature of Jupiter's envelope. The most widely accepted theory for the formation of the satellites is the so-called "starved disk" model, although newer alternatives including decretion disks and pebble accretion have also been proposed. Models that allow slow satellite formation in a cold disk are preferred, based on the density progression and Callisto's apparent differentiation state. Major model uncertainties include the angular momentum distribution of the material infalling to the circumplanetary disk, the source of the solids, and the thermal and viscosity structure of the disk. We identify six outstanding questions, some of which will be answered by JUICE, Europa Clipper and Tianwen-4. A major difficulty in answering some questions is overprinting of primordial characteristics by later events.
Habitability of rocky planets relies on the budgets of life-essential elements (LEEs) in their building blocks. The provenance and geochemistry of the planetesimals that supplied the LEEs to Earth remain debated. Traditional models argue LEE delivery via outer Solar System chondrites, but their 2 to 4 million-year (Myr) accretion ages preclude them as the first feedstock. To investigate the initial LEE distribution, we reconstructed the phosphorus-nitrogen (P-N) budget of the iron meteorite parent bodies (IMPBs), which accreted <1 Myr of Solar System formation. High-pressure-temperature experiments of P-N partitioning between solid and liquid alloys combined with geochemical models reveal higher P/N ratios in outer Solar System IMPBs than in inner ones-a trend reversed in chondrites. This evolution reflects early refractory schreibersite delivery to the outer disk, later curtailed by Jupiter's growth. Further modeling in combination with previous elemental and isotopic data on volatile LEEs suggests that both early and later inner Solar System planetesimals are chief contributors to Earth's LEE inventory.
Genetically encoded sensors and actuators have advanced the ability to observe and manipulate cellular activity, yet few non-invasive strategies enable cells to directly couple their intracellular states to user-defined outputs. We promote a bioluminescent activity-dependent (BLADe) platform that facilitates programmable feedback through genetically encoded light generation. Using calcium (Ca2+) flux as a model, we engineered a Ca2+-dependent luciferase that functions as an activity-gated light source capable of photoactivating light-sensing actuators. As an initial demonstration of the versatility of this platform we present two separate use cases in neurons. In the first application, the presence of luciferin triggers Ca2+ dependent local illumination that provides activity dependent gene expression by activating a light-sensitive transcription factor. In the second application, neuronal activity-driven Ca2+ fluctuations via locally generated bioluminescence control neural dynamics through opsin activation in single cells, populations and intact tissue. BLADe can be expanded to couple any signal that bioluminescent enzymes can be engineered to detect with the wide variety of photosensing actuators. This modular strategy of coupling an activity dependent light emitter to a light sensing actuator offers, in principle, a generalizable framework for state dependent cell-autonomous control across biological systems.
CD8+ T cells responding to chronic infections are functionally and spatially heterogeneous. In this issue of Immunity, Shen et al. and Geng et al. demonstrate that the transcription factors KLF2 and KLF3 have integrated but opposing roles in regulating tissue residency and terminal exhaustion.
Disease-associated RNAs are increasingly recognized as promising therapeutic targets for small-molecule intervention. While DNA-encoded libraries (DELs) have long been established for protein ligand discovery, recent studies have demonstrated their feasibility for identifying RNA-binding small molecules. To further advance RNA-targeted ligand discovery, a diverse, solid-phase DEL enriched in privileged RNA-binding scaffolds was constructed and applied to identify ligands of r(G4C2)exp, a toxic RNA repeat expansion implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). DEL selection outcomes were analyzed through large-scale molecular docking integrated with physicochemical and structure-activity relationship (SAR) analyses. Correlations were observed between docking predictions and experimental enrichment trends, supporting lead identification. The lead compound was subsequently optimized based on rational design, resulting in analogues with enhanced binding affinity and bioactivity. These findings demonstrate that RNA ligand identification can be effectively achieved by combining DNA-encoded library technology with computational approaches for rational design and analysis and highlight a broadly adaptable platform for RNA-targeted small-molecule discovery.
Population pharmacokinetic (PK) models can be combined with Bayesian estimation to optimize dosing regimens. The impact of sample collection time on the accuracy and precision of Bayesian predictions was evaluated. Data from adult and pediatric patients were used to develop a cefepime population PK model for Bayesian prior use. Holdout data were used for model evaluation. Clinical dosing regimens in the latter cohort were used to conduct optimal sample-time analysis. The accuracy and precision of the Bayesian predictions were assessed as a function of infusion duration and the differences between the observed and optimal sampling times. Analyses were conducted using Pmetrics for R. An allometrically scaled 2-compartment model was fitted (n = 71 patients, 685 observations). In the holdout group (n = 116 patients, 203 observations), the posterior Bayesian fit was acceptable (R2 = 0.923; relative bias -3%; median absolute error, 11.2%; F20, 72%; and F30, 86%). Mid-interval sampling was the optimal 1-sample design for 11/16 regimens. In the 2-sample design, a peak (8/16 regimens) and trough (9/16 regimens) approach was frequently optimal. The 2-sample design yields a lower Bayesian risk of misclassification. For 0.5-hour infusions, Bayesian predictions were similarly accurate but significantly more imprecise when samples were collected >2 hour away from the optimal time versus within ±1 hour of the optimal time (ΔRMSE: 8.98 mg/L, 95% CI: 3.61-15.7 mg/L). For 3 hours infusions, no significant differences in the accuracy or imprecision of the Bayesian predictions were noted. The nonparametric cefepime population PK model fit as a Bayesian prior in the holdout group. The optimal timing of PK sample collection varied according to regimen type and infusion duration. The precision of Bayesian estimates was lower for 0.5-hour infusions when samples were collected further from the model-predicted regimen-specific optimal collection times.
This study examined the effects of resistance training (RT) and supraphysiological nandrolone decanoate (ND) administration on hippocampal neurogenesis, neurotrophic signaling, and behavior. Forty 3-month-old male C57BL/6 J mice were randomized to RT or sedentary (SED) conditions. Each group was further divided into sham (S) or ND (38 mg·kg-1·wk.-1) treatment groups. All interventions lasted 7 wk. Adult hippocampal neurogenesis was quantified in the dentate gyrus using BrdU+/NeuN+ immunolabeling. Hippocampal expression of brain-derived neurotrophic factor (BDNF), androgen receptor (AR), estrogen receptor-β (ER-β), insulin-like growth factor-1 (IGF-1), and irisin was assessed by western blot analyses. No significant exercise × treatment interactions were observed for any of the behavior measures. When collapsed across treatments, RT exhibited a greater number of open-arm entries (p = 0.006) and reduced average latency times (p = 0.002) than SED. ND administration did not alter behavioral outcomes. RT (p = 0.001) and ND (p = 0.032) each independently increased hippocampal BrdU+/NeuN+ cell numbers, with no additive effects. AR expression for SED-S was significantly lower (p's < 0.05) than all other groups and IGF-1 expression for RT-S was significantly greater (p's < 0.05) than all other groups. Main effects revealed that RT and ND resulted in significant elevations in AR, ER-β and BDNF expressions. In conclusion, RT enhanced hippocampal plasticity and behavioral performance, whereas supraphysiological ND administration produced distinct molecular changes without conferring additive behavioral or neuroplastic benefit.
High expression of prostate-specific membrane antigen (PSMA) is observed in advanced prostate cancer, supplying a promising target for precision therapeutic interventions. Despite its efficacy in metastatic castration-resistant disease, cabazitaxel (CTX) is limited by severe systemic toxicity and a narrow therapeutic index, underscoring the urgent demand for tumor-selective delivery systems. A novel PSMA-targeted dextran-based conjugate, Dextran-CTX-GLA-EuK, was synthesized via click chemistry by conjugating CTX, γ-linolenic acid (GLA), and a Glu-urea-Lys (EuK) PSMA-targeting ligand to bifunctionalized dextran. Critical in vitro and in vivo PSMA blocking experiments (using the PSMA inhibitor 2-PMPA) were performed to validate its targeting specificity. A thorough myelosuppression study was performed in murine models to evaluate the systemic hematological safety profile. The biodistribution profile and in vivo antitumor efficacy of the conjugate were evaluated in murine xenograft models. The conjugate Dextran-CTX-GLA-EuK exhibited favorable physicochemical properties, high water solubility, and strong PSMA-binding affinity. In vitro and in vivo PSMA blocking experiments conclusively verifying its PSMA-mediated specific cellular internalization and tumor accumulation. In PSMA-overexpressing xenograft models, the conjugate demonstrated selective tumor enrichment, with intratumoral CTX levels up to 98.3-fold higher than those of parent CTX, while reducing exposure in normal tissues. Dextran-CTX-GLA-EuK exerted prominent dose-dependent tumor growth inhibition, attaining a 96.6% suppression rate at a 10 mg/kg dosage in PC-3/PSMA tumors and prolonging the survival of 22Rv1 tumor-bearing mice. Importantly, comprehensive myelosuppression assays revealed that the conjugate only induced a transient reduction in white blood cell and neutrophil counts (which rapidly recovered to baseline) without impairing bone marrow hematopoietic function; unlike CTX, the conjugate did not cause significant weight loss, organ toxicity, or hematological abnormalities in tumor-bearing mice. These findings demonstrate that Dextran-CTX-GLA-EuK synergizes active targeting with dextran-based delivery, enhancing antitumor efficacy while abolishing dose-limiting toxicities. This strategy offers a clinically translatable approach for PSMA-directed therapy in prostate cancer.
Association of the TNF-like cytokine 1A (TL1A) with Death Receptor 3 (DR3) triggers a signaling cascade in T cells that results in the increased AP-1- and NF-κB-mediated expression of inflammation-promoting gene products. Dysregulation of TL1A/DR3 signaling is a major contributor to many autoimmune diseases, cancers, and other conditions yet there is a dearth of small molecule regulators of this pathway. Here we report a cell-based high throughput screen of 8000 compounds of compounds that yielded 12 antagonists but no agonists of this pathway.
The relative efficacy and safety of oral P2Y purinergic receptor 12 (P2Y12) inhibitors (clopidogrel, ticagrelor, or prasugrel) after percutaneous coronary intervention (PCI) are not well defined. To assess the efficacy and safety of oral P2Y12 inhibitors in patients who underwent PCI. PubMed and Embase were searched until November 15, 2025, for randomized clinical trials comparing at least 2 of the 3 agents. Data were abstracted by 2 independent authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Random-effects odds ratios (ORs) and 95% confidence intervals were calculated. Data were analyzed in December 2025. The primary efficacy outcome was major adverse cardiovascular events (MACE), while the primary safety outcome was major bleeding. The primary analysis compared prasugrel and ticagrelor in reference to clopidogrel using a mixed treatment comparison meta-analysis. Data were analyzed from 15 randomized clinical trials that included 48 904 patients (mean [SD] age, 63.2 [4.21] years; 13 330 female patients [27.3%]). Compared with clopidogrel, there was a lower risk of MACE (OR, 0.80; 95% CI, 0.69-0.93) driven by lower myocardial infarction (OR, 0.71; 95% CI, 0.62-0.82) and stent thrombosis (OR, 0.48; 95% CI, 0.37-0.62) with prasugrel. MACE was not reduced with ticagrelor compared with clopidogrel, although there was lower stent thrombosis (OR, 0.73; 95% CI, 0.59-0.91). Furthermore, there was lower risk of MACE with prasugrel compared to ticagrelor (OR, 0.83; 95% CI, 0.70-0.98) driven by lower myocardial infarction (OR, 0.78; 95% CI, 0.65-0.94) and stent thrombosis (OR, 0.66; 95% CI, 0.49-0.88). There was a higher risk of major bleeding with ticagrelor vs clopidogrel (OR, 1.24; 95% CI, 1.01-1.52) driven by higher intracranial hemorrhage (OR, 1.89; 95% CI, 1.08-3.33). Prasugrel ranked first, followed by ticagrelor and clopidogrel, for MACE, myocardial infarction, and stent thrombosis. In this systematic review and meta-analysis of 15 randomized clinical trials in patients who underwent PCI, prasugrel provided the optimal balance between efficacy and safety compared with ticagrelor and clopidogrel.
Long COVID is increasingly associated with persistent neurological symptoms. Bioinformatic analysis identified multiple predicted miR-29c-3p binding sites in the 3'-UTR of Ten-Eleven-Translocation 3 (TET3). Luciferase reporter assays demonstrated that the miR-29c-3p is likely to bind an 8 base pair (bp) sequence within the 3'-UTR of TET3, supporting TET3 as a direct regulatory target. In vivo, an inverse relationship between miR-29c-3p and TET3 expression was observed in virus-positive midbrains from K18-hACE2 mice, while virus-negative and mock-infected midbrains showed no significant changes. The observation that only virus-positive brains showed decreased miR-29c-3p supports an alternative hypothesis that low base levels of miR-29c-3p expression may predispose the brain to viral neuro-invasion. Overall, miR-29c-3p > TET3 signaling emerges as a potential regulator of SARS-CoV-2-induced neurological consequences that warrants further investigation.
Adeno-associated virus (AAV) capsids are important gene therapy vectors, allowing for the one-time treatment of monogenetic disorders, with durable gene expression lasting for years. However, despite the clinical success of AAV usage, low transduction efficiencies require high dosage to achieve therapeutic efficacy, resulting in prohibitive costs and rare, but life-threatening immune responses. One key knowledge gap is how the capsids traffic to the nucleus following endocytosis. Here, we identify a direct interaction between AAV2 and actin filaments. Our results show that AAV2 bundles multiple actin filaments in a highly periodic hexagonal lattice. Therefore, we propose that AAV2 is the founding member of a new class of actin binding proteins, the actin bundling viruses (ABVs). Using cryogenic electron microscopy, we determined the structure of AAV2-actin filaments, identified the interaction interfaces, and engineered capsid variants that no longer bundle actin. Together, our results suggest that the AAV2-actin interaction may be responsible for trapping capsids and mediating peri-nuclear accumulation. Overall, this interaction expands the current understanding of AAV2 biology and offers new directions for capsid engineering.
Newer methicillin-resistant antimicrobials are needed to address the rising prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative (MRCONS) infections. We describe two contrasting, recalcitrant staphylococcal infections successfully managed using early transition to the oral benzoquinolizine antibiotic alalevonadifloxacin, highlighting its utility in complex clinical settings. Two high-severity cases of staphylococcal infections are presented. Patient 1, a 58-year-old metastatic lung and orthopedic implant infection on hemodialysis, developed catheter-associated MRSA sepsis with bacteremia, endocarditis, and metastatic lung and orthopedic implant infection. Patient 2, a 41-year-old male with a prior craniotomy, presented with a chronic cranial wound infection due to methicillin-resistant Staphylococcus hominis (MRCONS) originating from an infected ex vivo bone flap. Both patients initially received intravenous therapy and were transitioned to oral alalevonadifloxacin upon availability of susceptibility data. Levonadifloxacin susceptibility testing showed an MIC of 2 µg/mL for MRSA and 0.047 µg/mL for MRCONS-SCV. Patient 1 received 7 weeks of oral therapy aligned with POET recommendation for endocarditis, while Patient 2 completed 8 weeks of oral therapy consistent with OVIVA-based management of osteomyelitis. Despite significant challenges, both patients demonstrated rapid clinical improvement, resolution of infection, and no relapse during follow-up. These cases support oral alalevonadifloxacin as an effective and safe step-down option for complex MRSA and MRCONS infections, including endocarditis, osteomyelitis and meningitis. Alalevonadifloxacin (prodrug of levonadifloxacin) offers a promising oral treatment option when conventional agents are not suitable.
With the continuous rise in antibiotic resistance, novel methods that can reveal currently unknown antibiotic resistance mechanisms are essential to prepare and inform health responses and novel antibiotic discovery campaigns. Here, we built a library of species representative of the genus Mycobacterium and determined their antibiotic resistance profiles, allowing for the first time systematic multispecies comparisons. Analyzing antibiotic resistance in the context of other closely related yet diverse organisms revealed species with truly exceptional traits as well as general principles underpinning antibiotic resistance. Among these, we reveal that intrabacterial accumulation of antibiotics does not correlate with their potency at the species level. Our data also reveals that rifamycin resistance in mycobacteria is dominantly caused by antibiotic modification, contrary to what has been observed in Mycobacterium tuberculosis. Our data provides a solid starting point for the exploration of novel determinants of antibiotic resistance. We illustrate the utility of this species-level approach to discovery of novel traits by characterizing a previously unrecognized rifamycin-inactivating enzyme group that is present in a wide range of bacterial genera.