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METTL3-mediated m6A modification stabilizes circCDK6 to promote cervical cancer tumorigenesis via the miR-449a/CDK6 axis

Unusual terminational effect on atomic ripple of Ti3C2Tx MXenes

Correction: Effect of exercise preconditioning on myocardial content of Sphingosine1-phosphate and its mechanism in rats after exhaustive exercise

Hot niches, cold niches, and the clone within

Econometric assessment of seasonal volatility and predictive uncertainty in Albania’s hydropower-dependent electricity market

The genomic basis of adaptive leaf variation in the Galápagos giant daisies

Abstract Scalesia (Asteraceae) is the largest endemic plant genus of the Galápagos archipelago and an example of adaptive radiation. While Scalesia species are highly varied in habit and morphology, most remarkable is their variety of leaf shapes, especially in the differential presence of leaf lobing/serration, a derived trait that evolved multiple times as a likely adaptation to the islands’ hot and dry equatorial climate. Using population-level genomic data from 396 individuals representing all 15 recognized Scalesia species, we characterize this young radiation (around 1 million years ago), and reveal that their substantial morphological divergence and ecological specialization are primarily based on shared genetic variation. To further elucidate the repeated adaptive evolution of leaf lobing in Scalesia , we integrate genomic and leaf morphometric data, with transcriptomes from different developmental stages, and conclude that leaf lobing evolved through diversifying selection. Natural selection occurs independently on different regulators in the pathway controlling development of adaxial-abaxial leaf polarity, highlighting the importance of the founder populations’ high genetic diversity maintained via allopolyploidy. Finally, our findings have implications for the conservation of Scalesia ’s threatened biodiversity, as unexpectedly high intra-specific genetic structure and long-term isolation among populations indicate widespread nascent speciation.

Bayesian reanalysis of early remdesivir for the treatment of COVID-19 in outpatients with high risk of progression to severe disease

Background Though Bayesian methods are flexible, intuitive, and readily incorporated into clinical decision-making, with particular utility when prior information is available, they remain underutilized in the analysis of clinical trials. Methods In PINETREE, a Phase 3 randomized controlled trial (RCT) of remdesivir (RDV) for the treatment of outpatients with COVID-19 at high risk of severe disease, the primary outcome of COVID-19–related hospitalization or all-cause death was reanalyzed using a range of reference and data-driven priors. Posterior probability distributions were used to calculate the probability that the estimated hazard ratio (HR) was below a range of clinically meaningful specified thresholds and to estimate the treatment effect and its 95% credible interval (CrI). Results Under a minimally informative prior, the posterior probability of an estimated HR less than 1 for COVID-19–related hospitalization or all-cause death was 1 with a posterior median HR 0.13 and 95% CrI 0.02–0.47, recovering the frequentist estimates. Moreover, estimated posterior probability distributions, posterior median HRs, and 95% CrIs were robust across a range of both reference and data-driven prior choices, indicating the strength of the trial data. Lastly, using priors that incorporate historical RCT data, precision of the estimated posterior median HR and 95% CrI was improved over naïve, frequentist estimates. Conclusions In a Bayesian reanalysis of the PINETREE trial, there was a 98.9% or greater probability that treatment with RDV reduced the risk of COVID-19–related hospitalization or all-cause death across all prior probability distributions.

<i>GRK5</i> polymorphism turns up the volume on PAR1

Applications of artificial intelligence in mechanical engineering for the field of upper limb exoskeletons

Chirality-selective optical transport of nanoparticles in the evanescent field of a nanofibre

Epidemiology and care management of Paroxysmal Nocturnal Hemoglobinuria (PNH) in a real-world setting in France: Description from the French National Hospitalization Database

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem-cell disease causing anemia, aplasia and thromboses, affecting ~1/80,000 patients in France. Treatment mainly involves C5 inhibitors (C5i) and iterative red-blood-cell transfusions. Recent real-world French data on PNH epidemiology and management are scarce in the era of complement inhibitors. This study described PNH epidemiology, patients’ characteristics, and C5i use. Methods This was a non-interventional claims study using secondary data from the French national hospital database. Patients with a hospital diagnosis of PNH (ICD-10 code D59.5) over 2018–2022 were selected, after exclusion of those with other C5i-treated diseases. A subgroup of C5i initiators was followed from initiation to last hospitalization, to describe C5i treatment patterns. Results The study included 897 patients: 496 (55.3%) receiving a C5i and 218 (24.3%) initiating treatment over 2018–2022. In 2022, 725 PNH patients were identified (prevalence ~1/94,000). Mean (SD) age was 52.1 (21.1) and 45.7 (19.4) years overall and among C5i initiators, respectively. C5i initiators had 20.9 (6.9) dispensations annually. Most patients initiated with eculizumab (n = 196, 89.9%), and almost half of them (n = 80, 40.8%) switched to ravulizumab. Conclusion PNH prevalence was ~ 1/94,000. Most patients initiated eculizumab, with 40.8% switching to ravulizumab.

Predicting development of pediatric chronic immune thrombocytopenia at disease onset using a statistical risk model

Abstract Immune thrombocytopenia (ITP) is associated with a variable and unpredictable clinical course in children, including a spectrum of bleeding and systemic symptoms in the months following diagnosis. Although many children will have spontaneous resolution of the disease prior to 1 year, up to 30% will go on to develop chronic disease. The known predictors for developing chronic ITP are limited, making clinical management and guidance during this early course of disease highly challenging. In addition, the pathophysiology of immune dysregulation in ITP is complex, with multiple variables likely contributing to the development of chronic disease. We aimed to create a statistical model to predict the development of chronic ITP. Using a retrospective training cohort of 611 children with ITP from 2 institutions and 2 validation cohorts comprised of 161 children, we developed and validated a multivariable logistic regression model and found that age; sex; immunoglobulin G (IgG), IgA, and IgM levels; presenting platelet count; presenting lymphocyte count; known secondary cause at diagnosis; and direct antiglobulin test positivity were useful in predicting chronic ITP. The external validations demonstrated consistent discriminative performance and clinical utility. The model is available for use at https://opal.shinyapps.io/citp-rm/. A chronicity prediction tool for use at the time of ITP diagnosis will better equip hematologists to counsel patients and families and engage in appropriate treatment strategies for individual patients earlier in their course.

Electric vehicles can ride to the grid’s rescue

Kinetics, kinematics, and performance modeling of two arm swing techniques in the swimming kick-start

Abstract This experimental study investigated the effect of two arm swing techniques on kinematic and kinetic variables during the swimming kick-start. Twelve elite male swimmers performed starts using forward and butterfly arm swing techniques. Kinematic and kinetic data were collected using a Kistler Performance Analysis System. Data were analyzed for variables calculated from ground reaction force (GRF) and block, above the water, and underwater performance. The results revealed that work, power, and most of the force parameters measured higher values for the butterfly arm swing technique ( p  &lt; 0.05). The butterfly arm swing was also advantageous regarding resultant underwater and vertical take-off velocities ( p  &lt; 0.05). The butterfly arm swing technique demonstrated a significant correlation ( p  &lt; 0.05) between the 15 m swimming time trial and additional parameters, including take-off horizontal velocity, power, force on the block, entry distance, and performance at 5, 7.5, and 10 m of swimming. Regression analysis indicated the combination of different predictors of the time to 15 m, including some GRF metrics, and above the water and underwater parameters for both types of arm swing. The butterfly arm swing produced a significantly shorter start time over the distance from 7.5 m to 15 m than the forward arm swing ( p  &lt; 0.05). However, this is not necessarily related to the early phase of the start because no significant differences between analyzed dives were found at the 5 m time ( p  = 0.056).

Cryo-EM structures of higher order Gephyrin oligomers reveal principles of inhibitory postsynaptic scaffold organization

Abstract Gephyrin, the principal scaffolding protein of inhibitory postsynaptic densities, clusters glycine and GABA A receptors via multivalent interactions. It features structured N and C terminal domains connected by an intrinsically disordered linker. Although the structural and functional properties of its terminal domains are well characterized, the mechanism by which full-length gephyrin organizes into higher-order complexes remains unresolved. Here, we combine biochemical reconstitution, cryo-electron microscopy, and mutational analyses to elucidate the structural logic of gephyrin oligomerization. We demonstrate that gephyrin adopts a stable dimeric assembly which constitutes the basic unit for both linear and oblique tetramers as well as linear hexameric arrangements. High resolution structures reveal a critical segment of the flexible linker that adopts two distinct conformations, one of which occludes the receptor-binding site. This segment harbors key phosphorylation sites, suggesting a regulatory control mechanism. Our findings redefine the architecture of inhibitory postsynaptic sites and reconcile gephyrin oligomerization models with published in-situ postsynaptic densities characterized by cryo-electron tomography.

Renal coccidiosis in black skimmers in North America reveals an uncharacterized Eimeria lineage (Apicomplexa: Eimeriidae)

Black skimmers ( Rynchops niger niger ) are New World coastal seabirds that breed along the Gulf of Mexico, southern Atlantic and Pacific coasts of the United States. Black skimmer populations are declining in North America, and little is known about health and diseases of this species. An outbreak of mortality causing the death of approximately 160 juvenile black skimmers occurred in the West Galveston and East Matagorda Bay populations during the 2022 and 2023 breeding seasons. Necropsy, histopathology, and molecular genetic methods were utilized to investigate the cause of morbidity in six chicks that died or were euthanized. The main gross findings included bilateral renomegaly with multiple pale tan foci. Characteristic histologic findings were granulomatous nephritis and cloacitis with intralesional coccidia. Various developmental stages including immature gamonts, microgamonts, macrogamonts, and oocysts were present extracellularly and in the cytoplasm of epithelial cells of distal tubules, medullary collecting ducts, ureters, and cloacal epithelium. A few oocysts were in the cytoplasm of multinucleated giant cells. Additionally, schizonts were observed in the small intestine of one case. Genetic analysis of partial 18S rRNA gene revealed a previously uncharacterized Eimeria lineage affecting kidney and cloaca and another Eimeria lineage affecting the small intestine. To the best of our knowledge, this is the first report of Eimeria infection in the genus Rynchops . The significance of renal and intestinal coccidiosis in black skimmers is unknown; however, in the present work it appeared to cause morbidity and likely contributed to the recent mortality outbreak.

Does minimal residual disease matter in t(11;14) myeloma?

Garcinia derived adsorbents for efficient ammonium removal from wastewater in fixed bed column systems

Abstract Ammonium contamination in wastewater poses serious risks to aquatic environments and requires efficient continuous treatment strategies. This study evaluates a Garcinia-derived biosorbent for NH 4 + removal in a laboratory-scale fixed-bed column and quantitatively examines the influence of flow rate, influent concentration, and bed height on dynamic adsorption behavior. Breakthrough and exhaustion were defined at C t /C o  = 0.05 and C t /C o  = 0.95, respectively. Decreasing the flow rate from 2.0 to 0.5 mL min −1 increased the Thomas capacity from 10.5 to 18.5 mg g −1 and extended breakthrough time from &lt; 100 to ~ 240 min. Increasing bed height from 5 to 20 cm enhanced q max from 12.0 to 23.5 mg g −1 . Model validation using the Thomas and Yoon–Nelson equations showed good agreement with experimental data (R 2  = 0.89–0.99, RMSE = 0.021–0.065, MAE = 0.018–0.054). The mass transfer zone (MTZ) length and empty bed contact time (EBCT) were estimated to provide additional insight into column hydrodynamics. The results demonstrate the potential applicability of Garcinia-based biosorbent for laboratory-scale continuous ammonium removal and provide useful operational insights for fixed-bed adsorption systems.

Activation mechanism of the full-length histidine kinase LvrB from pathogenic Leptospira

Abstract Pathogenic Leptospira modulate their virulence via the Lvr signaling system, with the histidine kinase LvrB being a central element. LvrB is a prototype of Rec-controlled histidine kinases, which are frequently found in bacterial two-component systems, and yet whose regulatory mechanisms remain largely unknown. Here, we report full-length structures of LvrB in different states uncovering its mechanism of activation. Kinase-inactive LvrB is a symmetric homodimer, with its catalytic domains rigidly clasped onto the central helical domain. Phosphorylation of the N-terminal Rec domains induces coiled-coil formation of the central αS helices thereby breaking symmetry through liberation of the catalytic domains into a dynamic, auto-phosphorylation competent state. We further identified LvrB’s downstream effector partner LvrC, an anti-σ factor that reprograms the transcription of hundreds of virulence genes. Our findings set a mechanistic paradigm for Rec-controlled histidine kinases enabling the design of virulence inhibitors.

Seasonality and mobility: An Integrative framework for reconstructing Kura-Araxes pastoral systems at Maxta I, Nakhchivan

The Kura-Araxes Culture (3500–2500 BCE) is often depicted as a homogeneous pastoralist horizon, yet its internal economic and mobility strategies remain poorly understood. This study for the first time introduces an integrative framework for reconstructing site-specific pastoral practices through a detailed case study of Maxta I (Nakhchivan). It represents the first study in the Kura-Araxes context and more broadly in the Caucasus to combine zooarchaeology, Zooarchaeology by Mass Spectrometry (ZooMS), stable isotope analysis, and settlement data. This multi-method approach offers a comprehensive view of livestock management, seasonal movement, and socio-economic organisation. The results reveal a seasonally flexible agro-pastoral system that blends permanent settlement features with structured herd mobility, birthing seasons, and possible targeted secondary product exploitation strategies for fleece. Rather than adhering to a binary model of nomadic versus sedentary lifeways, Maxta I demonstrates how Kura-Araxes communities dynamically adapted to diverse ecological and social landscapes. This research challenges assumptions of cultural uniformity and establishes a new comparative model for understanding the diversity of pastoral strategies across Southwest Asia.