Browse Articles

Discovery and development of an oral analgesic targeting the α2B adrenoceptor

Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/hypotension and bradycardia. Here, we report that ( Z )-1-(3-ethyl-5-fluorobenzo[ d ] thiazol-2(3 H )-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified α2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the α2A-dependent pain inhibitory pathway. Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and nonhuman primates without cardiovascular effects. Mice with genetic loss of the α2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the α2B adrenoceptor is a promising target for nonopioid analgesics through the activation of the α2A-dependent descending pathway.

Correction: Maternal adiposity moderates associations between dietary, serum, and human milk n-3 and n-6 PUFA

Protracted circum-continent subduction: A mechanism for craton destruction and a rationale for craton longevity

The evolution of continents is shaped by the growth and destruction of long-lived cratons, which serve as their stable cores. Processes for craton destruction are controversial because most invoked mechanisms occur frequently throughout Earth history, making the preservation of cratons for billions of years problematic. Here, we address this issue by presenting a crustal-scale analytical signal-amplitude model obtained from high-resolution airborne and shipborne magnetic data across cratons within East Asia. Magmatic, magnetic, and basin-history constraints show that the eastern North China craton experienced focused weakening, thickening, and catastrophic destruction of its mantle lithosphere due to a unique combination of circum-craton subduction and subsequent collision since the Paleozoic. By contrast, the adjacent South China craton was not impacted in this way, and thus, its mantle root was spared from destruction. The long-term survival of cratons may stem from the infrequent occurrence of sustained circum-cratonic subduction or collisional processes capable of destabilizing their lithospheric roots.

Global, regional, and national burden of nonrheumatic calcific aortic valve disease based on GBD study 2021

Hide-and-Seek genome editing reveals that Gephyrin is required for axo-axonic synapse assembly

The visualization and manipulation of proteins in neurons is widely used to deduce their functions. While every experimental approach has limitations, the concurrent knock-in and knockout of two different proteins can be especially challenging. To this end, we developed Hide-and-Seek genome editing, which allows the simultaneous visualization and knockout of proteins in neurons using Adeno-associated viral vectors and the CRISPR/Cas9 system. We demonstrate the efficacy and flexibility of this method for rapid, efficient, and simultaneous knock-in and knockout of proteins in vitro and in vivo, at the synapse, axon initial segment (AIS), nucleus, and mitochondria. Using Hide-and-Seek, we show that the scaffolding protein Gephyrin is required for the proper assembly of axo-axonic synapses at the AIS.

Long-read sequencing uncovers key regulatory genes involved in the differentiation of preadipocytes of Chinese red steppe cattle

20E-induced <i>Kr-h1</i> expression facilitates developmental transitions depending on chromosome accessibility of <i>BR-C</i> enhancers

Transcription factors and histone modification-mediated chromatin accessibility coordinately regulate spatiotemporal expression of genes that control growth and development. It is well documented that juvenile hormone-activated Kr-h1 antagonizes 20-hydroxyecdysone (20E)-induced expression of the pupal specifier BR-C to sustain larval status in holometabolous insects. Here, we revealed that during the larval–prepupal transition in Drosophila melanogaster , the 20E-activated Kr-h1-BR-C axis is a prerequisite for wing disc morphogenesis. Mechanistically, 20E-EcR/USP-Met-Tai directly activates Kr-h1 that upregulates BR-C expression via the positive Kr-h1 binding sites (PKBS) in the BR-C enhancers. Furthermore, we showed that 20E-induced H3K27 acetylation increases chromatin accessibility of the PKBS-containing enhancers, facilitating the maximum of BR-C expression that promotes developmental transitions. Collectively, in response to different hormone stimuli, a single transcription factor either negatively or positively regulates the expression of the same target gene depending on chromatin accessibility of its different enhancer regions, thus manipulating distinct developmental events.

A multi strategy bidirectional RRT* algorithm for efficient mobile robot path planning

Controlling transient and coupled diffusion with pseudoconformal mapping

Diffusion in physical, chemical, and biological systems often occurs under transient conditions and involves coupling across multiple physical fields, challenging conventional control methods limited to steady-state, single-field settings. Here, we present a general geometric framework for regulating diffusion in time-dependent and multiphysics-coupled environments based on pseudoconformal mapping. This method preserves material isotropy and ensures smooth interface matching, enabling robust and flexible modulation of diffusion governed by Fick’s second law and beyond. We apply this framework to radiative–conductive, advective–conductive, and thermoelectric systems, achieving precise spatial and temporal control of temperature, flux, and voltage distributions. The proposed strategy is validated through simulations and experiments, demonstrating its broad applicability and scalability. Our findings provide a geometry-driven paradigm to programmable diffusion control, with potential impact across thermal management, energy conversion, and biomedical transport systems.

Machine learning-assisted quantitative metabolomics of West African patients with advanced breast cancer

Dipole-induced transition in 3 dimensions

The Kosterlitz–Thouless and the Hexatic phase transitions are celebrated examples of dipole (vortex, dislocation) induced transitions in condensed matter physics. For very clear reasons, these important “topological” transitions are restricted to 2-dimensions. Here, we present a genuine dipole-induced transition in the 3-dimensional response of (athermal) amorphous solids to applied strain. Similarly to the existence of a hexatic phase between normal solid and fluid, we identify an intermediate phase between a phase of normal elastic response at high pressure, and fluid matter at zero pressure. The mechanical response in the intermediate phase is accompanied by plasticity that is generically associated with “nonaffine” quadrupolar events seen in the resulting displacement field. Gradients of the quadrupolar fields act as dipole charges that screen elasticity, breaking both translational and chiral symmetries. We highlight angular correlations that exhibit diverging correlation lengths at this transition and determine the critical scaling exponents.

Underwater image enhancement using hybrid transformers and evolutionary particle swarm optimization

Evaluating plant growth–defense trade-offs by modeling the interaction between primary and secondary metabolism

Understanding the molecular mechanisms behind plant response to stress can enhance breeding strategies and help us design crop varieties with improved stress tolerance, yield, and quality. To investigate resource redistribution from growth- to defense-related processes in an essential tuber crop, potato, here we generate a large-scale compartmentalized genome-scale metabolic model (GEM), potato-GEM. Apart from a large-scale reconstruction of primary metabolism, the model includes the full known potato secondary metabolism, spanning over 566 reactions that facilitate the biosynthesis of 182 distinct potato secondary metabolites. Constraint-based modeling identifies that the activation of the largest amount of secondary (defense) pathways occurs at a decrease of the relative growth rate of potato leaf, due to the costs incurred by defense. We then obtain transcriptomics data from experiments exposing potato leaves to two biotic stress scenarios, a herbivore and a viral pathogen, and apply them as constraints to produce condition-specific models. We show that these models recapitulate experimentally observed decreases in relative growth rates under treatment as well as changes in metabolite levels between treatments, enabling us to pinpoint the metabolic rewiring underlying growth–defense trade-offs. Potato-GEM thus presents a useful resource to study and broaden our understanding of potato and general plant defense responses under stress conditions.

Valorizing alum sludge waste augmented ferrite as a sustainable magnetic pathway for treating Indigo carmine effluent

Abstract One of the guiding sustainability principles is centered on mitigating the waste streams through the industrial ecology manner. On this regard, this research examines the conversion of dewatered alum sludge (AS) waste derived from water-works plants to be and innovative, magnetic and inexpensive nanoadsorbent. Alum sludge (AS) is calcined at 400 °C and mixed with zinc ferrite (F-Zn) that is prepared by simple co-precipitation route and signified with its high chemical stability, harmfulness as well as good magnetic properties that makes them a candidate as reusable adsorbent. The composite is mixed at varied proportions and labeled as AS400 (F-Zn/AS400 (1:1), F-Zn/AS400 (2:1) and F-Zn/AS400 (1:2). Such materials are thereby checked for their composition, structure and physical–chemical characterized through X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, Energy dispersive X-ray Spectroscopy, vibrating sample magnetometer, and Brunauer–Emmett–Teller. Then, the composites are applied for anionic dye so-called Indigo carmine (IC) adsorption through a comparative manner. The operating parameters are examined and the experimental results revealed that the isotherm time for all adsorbents is corresponding to 2 h using 0.5 g/L of the applied materials dose. Also, the aqueous medium pH is checked and the point of zero charge is evaluated and confirmed the IC removal was successful in an acidic medium (pH 2.0). The temperature influence verified the process is exothermic in nature. Kinetic modeling is evaluated and the results are well fitted with the pseudo-second order model. Various isotherm models are applied and the data is fitting the Langmuir isotherm model. The presence of ferrite improves the AS400 capacity from to 12.57 to 29.42 mg/g.

Reduction of TRAF3 by heterozygosity or aging impacts B cell function

TNF receptor-associated factor 3 (TRAF3) is a signaling adaptor protein that is ubiquitously expressed but has highly distinct cell type–specific functions. TRAF3 plays critical roles in restraint of B lymphocyte activation, differentiation, and homeostatic survival. Consistent with such roles, loss-of-function mutations in TRAF3 have long been found in various human B cell malignancies. Mice lacking TRAF3 specifically in B cells have autoimmune manifestations, lymphadenopathy, and increased incidence of B cell lymphomas. More recently, human patients with germline TRAF3 mutations leading to haploinsufficiency have been reported; the phenotypes of these patients show striking similarities with those of mice with TRAF3-deficient B cells. This raises the important knowledge gap of how relative quantity of TRAF3 protein regulates B cells. To address this question, we investigated the effect of decreased B cell TRAF3 using mice whose B cells are heterozygous for loss of Traf3 . Traf3 +/− B cells displayed multiple functional abnormalities, to an extent intermediate between Traf3 +/+ and Traf3 −/− B cells, indicating a striking dose–response of B cells to relative quantities of TRAF3. Additionally, B cell TRAF3 protein—but not transcript—was reduced in B cells from normal aged mice and humans, consistent with increased occurrence of both B cell hyperactivity and B cell malignancies in older populations. Treatment of aged mice with a proteasome inhibitor restored the level of B cell TRAF3, suggesting age-related chronic signaling through receptors that lead to TRAF3 degradation. Thus, relative levels of B cell TRAF3 protein have important biological impacts on B cell function.

Research on motion tracking and impact force detection of flying objects

Quantitative and sensitive sequencing of somatic mutations induced by a maize transposon

Cells accumulate mutations throughout development, contributing to cancer, aging, and evolution. Quantitative data on the abundance of de novo mutations within plants or animals are limited, as new mutations are often rare within a tissue and fall below the limits of current sequencing depths and error rates. Here, we show that mutations induced by the maize Mutator (Mu) transposon can be reliably quantified down to a detection limit of 1 part in 16,000. We measured the abundance of millions of de novo Mu insertions across four tissue types. Within a tissue, the distribution of de novo Mu allele frequencies was highly reproducible between plants, showing that, despite the stochastic nature of mutation, repeated statistical patterns of mutation abundance emerge. In contrast, there were significant differences in the allele frequency distribution between tissues. At the extremes, root was dominated by a small number of highly abundant de novo insertions, while endosperm was characterized by thousands of insertions at low allele frequencies. Finally, we used the measured pollen allele frequencies to reinterpret a classic genetic experiment, showing that evidence for late Mu activity in pollen is better explained by cell division statistics. These results provide insight into the complexity of mutation accumulation in multicellular organisms and a system to interrogate the factors that shape mutation abundance.

Multicomponent synthesis of pyrano-pyrazolo-pyridones by a bimetallic cobalt-cadmium magnetic catalyst

Fluid flow generates bacterial conjugation hot spots by increasing the rate of shear-driven cell–cell encounters

Conjugation accelerates bacterial evolution by enabling bacteria to acquire genes horizontally from their neighbors. Plasmid donors must physically encounter and connect with recipients to allow plasmid transfer, and different environments are characterized by vastly different encounter rates between cells, based on mechanisms ranging from simple diffusion to fluid flow. However, how the environment affects the conjugation rate by setting the encounter rate has been largely neglected, mostly because existing experimental setups do not allow for direct control over cell encounters. Here, we describe the results of conjugation experiments in Escherichia coli in which we systematically varied the magnitude of shear flow using a cone-and-plate rheometer to control the encounter rate. We found that the conjugation rate increases with shear until it peaks at an optimal shear rate ( γ ˙ = 1 × 10 2 s − 1 ), reaching a conjugation rate fivefold higher than the baseline set by diffusion-driven encounters. This optimum marks the transition from a regime in which shear promotes conjugation by increasing the rate of cell–cell encounters to a regime in which shear disrupts conjugation. Regions of high fluid shear are widespread in aquatic systems, in the gut of host organisms, and in soil, and our results indicate that these regions could be hot spots of bacterial conjugation in the environment.

CPS1-promoted the progression of lung adenocarcinoma via suppressing ammonia induced the activation of ROS/AMPK/P53/LKB1 signaling pathway