Browse Articles

Inhibition of FicD-mediated AMPylation and deAMPylation by isoprenoid diphosphates

FicD regulates Unfolded Protein Response (UPR) through reversible AMPylation and deAMPylation of BiP, an HSP70 chaperone and master regulator of the UPR. FicD activity is regulated by endoplasmic reticulum-stress, catalyzing BiP AMPylation under low stress conditions to hold inactive chaperone in reserve. In stressed cells, FicD deAMPylates BiP, acutely increasing its active pool to assist in protein folding. Variants in UPR machinery, including those in the FicD gene, are linked to hereditary diseases. Despite the known role of FicD in UPR, in-vivo regulation of its activity remains elusive, and identifying metabolites that alter FicD activity could prove useful pharmaceutically. We applied an unbiased high-throughput screening platform, known as Mass spectrometry Integrated with equilibrium Dialysis for the discovery of Allostery Systematically (MIDAS), to identify small molecule metabolites that might regulate FicD activity. MIDAS revealed interactions between FicD and two mevalonate pathway intermediates: geranyl-pyrophosphate and farnesyl-pyrophosphate. Biochemical characterization indicates that both potently inhibit FicD-mediated AMPylation and deAMPylation. The crystal structure of FicD bound to farnesyl-pyrophosphate demonstrates a competitive inhibition mechanism, with the pyrophosphate adopting the alpha and beta phosphate positions of adenosine triphosphate (ATP) and the hydrocarbon chain filling the nucleoside pocket. FicD variants previously appeared as biochemically indistinguishable, yet lead to different human pathologies. We demonstrate farnesyl-pyrophosphate inhibits FicD R374H and FicD R374C variants implicated in causing hereditary spastic paraplegia, but not the FicD R371S variant associated with neonatal diabetes. This study furthers our understanding of FicD inhibitors and distinguishes disease causing variants, providing insight into pharmacological targeting of UPR activity.

Changes of regional brain activity associated with the occurrence and severity of depression in diminished ovarian reserve patients

Bias in the AlphaFold3 prediction of ligand-induced domain motion in enzymes

In many enzymes, movement of domains from open to closed state forms the environment required for catalysis. We have studied ligand-induced domain motion in 82 enzymes by generating ensembles of AlphaFold 3 (AF3) models both with and without the presence of ligands that are known to trigger such motion. It was found that the results heavily depend on the number of apo and holo structures of each enzyme in the Protein Data Bank (PDB). For enzymes with more apo than holo structures, 64.8% of models generated without ligand are closer to the open apo than to the closed holo state. In contrast, for enzymes that have more holo than apo structures in the PDB, 75.5% of AF3 models without any ligand are in the holo conformation, revealing strong memorization. In both cases, adding the ligand has only a moderate impact. However, the impact of ligand is substantial for proteins that have only a few structures in the training set. Ligands are placed with higher accuracy if there are more holo structures with different ligands in the PDB. We have found that nonbinder ligands also generate similar domain motion, and the distributions of the predicted enzyme conformations remain close to those obtained with the native trigger ligands, but with lower ligand pLDDT values. For enzymes with more holo than apo structures in the PDB, AlphaFold2 also generates the majority of models close to the holo state, suggesting the same memorization effects seen for AF3.

Bird-inspired optimization approach using taper-shape transfer function for intrusion detection in IoT networks

Ultrasound-driven mechanophore activation in living plants

This study presents a biocompatible, ultrasound-responsive platform for remotely activating mechanochemical reactions within live plant tissue. Fluorogenic Mechanophore-embedded silica NanoParticles (FMNPs) that are thermally stable were engineered to emit blue fluorescence at 440 nm upon mechanical activation. In Solanum lycopersicum (tomato) leaves, activation was achieved through the synergistic combination of gas vesicles (GVs) and high-frequency focused ultrasound (FUS, 550 kHz), enabling spatially localized and minimally invasive stimulation. Low-frequency ultrasound (25 kHz) triggered activation but caused extensive tissue damage, while high-frequency FUS alone was biocompatible yet insufficient to activate FMNPs. Incorporation of GVs as a cavitation amplifier significantly boosted activation efficiency under mild acoustic conditions without observable tissue disruption. In planta fluorescence imaging confirmed that FMNPs retained their functionality after injection into leaf vasculature, and only the combination of GV and FUS produced a statistically significant fluorescence increase, indicating successful mechanochemical activation. This represents a demonstration of noninvasive and biocompatible ultrasound-induced mechanophore activation in live plants. This modular and noninvasive strategy opens possibilities for programmable release of regulatory and metabolic chemicals, biosensing, and synthetic molecular control in plant systems.

Holistic IoT and cloud-based telemetry architecture for proactive fire monitoring in smart agriculture

From data to decisions: Toward a Biodiversity Monitoring Standards Framework

Achieving the goals of the Kunming–Montreal Global Biodiversity Framework (GBF) requires monitoring systems that can transform heterogeneous observations into consistent, decision-relevant knowledge. Yet current biodiversity data are fragmented, uneven in quality, and seldom comparable across space or time. Existing standards such as Darwin Core, Findable, Accessible, Interoperable, and Reusable (FAIR) and Collective Benefit, Authority to Control, Responsibility, and Ethics (CARE) principles provide important foundations, but they do not connect the full chain from field observation to policy reporting. We introduce the Biodiversity Monitoring Standards Framework (BMSF)—a unifying architecture that links ethical principles, standardized data collection, accredited analytical workflows, and transparent reporting into a single auditable “chain of evidence.” The framework’s novelty lies in its tiered and federated design, enabling national agencies, Indigenous knowledge holders, local communities, and private-sector actors to operate under shared principles while maintaining data sovereignty. By integrating Essential Variables, accredited analytical methods, and open-source implementation pathways, the BMSF allows locally generated data to be aggregated into credible, comparable indicators aligned with GBF targets. Concrete application, such as a national forest-connectivity assessment, demonstrates how the BMSF improves reproducibility, transparency, and policy relevance relative to existing approaches. Implemented generally, this framework would convert fragmented monitoring efforts into a coordinated, scalable system capable of tracking and guiding collective progress toward halting and reversing biodiversity loss.

Impact of pressure on the structural, Raman, superconducting, and normal state resistivity properties of Y5Rh6Sn18 quasi-skutterudite single crystal

Abstract High-pressure (HP) electrical resistivity measurements of superconducting quasi-skutterudite Y 5 Rh 6 Sn 18 single crystals were conducted up to 10.7 GPa using a diamond anvil pressure cell. Additionally, HP synchrotron X-ray powder diffraction (XRPD) studies were performed on Y 5 Rh 6 Sn 18 up to 8 GPa and Sc 5 Rh 6 Sn 18 up to 11.7 GPa, along with HP Raman spectroscopy. At ambient conditions, the Y 5 Rh 6 Sn 18 single crystal shows an onset 3.60 K, which increases to a maximum of 3.94 K at 7.89 GPa. Beyond this pressure, further increases lead to a slight decline in T c . Furthermore, the bad metal nature of the Y 5 Rh 6 Sn 18 single crystal is suppressed by external pressure, with the residual resistivity ratio (RRR) value increasing from 0.77 to 0.92. The activation energy for electric conduction (E a ) decreases from 2.74 meV at 0.62 GPa to 0.39 meV at 10.65 GPa, indicating enhanced metallic behaviour. Additionally, four Raman vibrational modes are observed, which exhibit a smooth blue shift with increasing pressure up to 9.6 GPa, similar to that of its sister compound Sc 5 Rh 6 Sn 18 . Both Y 5 Rh 6 Sn 18 and Sc 5 Rh 6 Sn 18 crystallize in the tetragonal I 4 1 / acd space group. With increasing external pressure up to 7 GPa, these compounds exhibit a smooth reduction in unit-cell volume without any structural phase transitions, as described by a second-order Birch-Murnaghan equation of state. Above 7 GPa, Sc 5 Rh 6 Sn 18 also shows an upturn in both lattice parameters a and c and unit cell volume, while an upturn in only the lattice parameter c (and consequently on unit cell volume) is observed for Y 5 Rh 6 Sn 18 at 7 GPa. The deviation in the lattice parameter at higher pressure in Y 5 Rh 6 Sn 18 seems to correlate with the observed decline in T c with pressure. First-principles calculations under pressure reveal a moderate increase in the density of states (DOS) up to ~ 10 GPa, followed by a slight decrease for higher pressures, a trend which is similar to the observed critical temperature. Furthermore, from theory it is clear that the structure remains stable up to approximately 30 GPa.

Mechanical compliance enhances the impulsive energy absorption of glassy polymer films

From soft tissues to seismic damping systems, mechanical compliance is widely exploited by natural and engineered systems for dissipating energy and averting catastrophic failure. While this principle is well understood under quasi-static conditions, the role of compliance at extreme strain rates is less explored. Here, we integrate laser-ablation-based membrane expansion testing, ultra-high-speed imaging, and mechanical modeling to study the real-time dynamic response of glassy poly(methyl methacrylate) (PMMA) films subjected to impulsive loading at strain rates ranging from 10 6 s − 1 to 10 8 s − 1 . Although PMMA ordinarily exhibits low impact resistance, under these conditions, the films deform and can sustain unexpectedly large biaxial strains without catastrophic failure. By tuning the film thickness, we demonstrate that the increased compliance of thinner films promotes plastic deformation, enabling more effective energy absorption. Our findings suggest strategies for designing lighter, tougher materials for impact mitigation under extreme dynamic loading.

Mapping global bee research with traits and plant-pollinator interaction networks

Abstract Bees sustain key functions in natural ecosystems and agricultural landscapes, yet our understanding of their ecology is typically informed from studies concentrated on a few model taxa. To reveal how this may be biasing our understanding of bee responses and function in the environment we quantify global patterns of research attention across 69,682 bee-related publications to test whether research effort aligns with plant-pollinator network centrality, trait variation, public interest, and socio-economic context. Human managed bees take up most of the research effort; importantly this trend has been increasing over time. Plant–pollinator network centrality is unrelated to research effort; here we reveal genera with high centrality but low research attention as prime candidates for future study. Both pollinator management and sociality have an impact on research effort. Excluding Apis and Bombus (the most traditionally researched genera), managed bee genera are the focus of twice as many papers as wild genera, with the managed share rising over time. Our study reveals and quantifies persistent global research biases and highlights the need for monitoring, risk assessment, and policies that target neglected yet structurally central genera in plant-pollinator interaction networks.

Correction for Yanaka et al., Exploring glycoform-dependent dynamic modulations in human immunoglobulin G via computational and experimental approaches

Trapezius fascia reveals mechanosensory capacity and predominance of nociceptive axons in occipital neuralgia

The role of the tryptophan-rich allosteric network and sodium egress in GPCR activation

The human adenosine A 2A receptor (A 2A R) is a prototypical member of the class A family of G Protein–Coupled Receptors (GPCRs), which are engaged by over one-third of FDA-approved drugs. Here, we used 19 F NMR to simultaneously evaluate functional states from the perspective of a CF 3 -tag on transmembrane helix-6 (TM6) and all 5-fluorotryptophan reporters. Whereas spectra from the TM6 tag reveal a dynamic conformational ensemble, the tryptophan spectra exhibit more discrete ligand-dependent states. These ligand-dependent signatures provide insights into microswitches including a universal toggle switch which interfaces with a sodium binding pocket. Over 560 GPCRs share this toggle switch — sodium pocket cluster, implying a fundamental role in activation. Computational rigidity-theory reveals tryptophan reporters reside along prominent allosteric activation pathways, underscoring their roles in mechanical signal propagation and corroborating NMR observations. Among them, W246 6.48 , associated with the toggle switch, plays a critical role in regulation of allosteric networks spanning the orthosteric pocket and extending via tryptophan-rich pathways through the receptor to the A 2A R-Gβ interface and the nucleotide pocket in G s α. While higher sodium concentrations (~100 mM) predictably stabilize the inactive conformation of the receptor, lower concentrations (below 40 mM) greatly enhanced the presence of the activation ensemble and in particular, the precoupled state, suggesting that the release of sodium from the conserved pocket—either through basal conditions for the apo receptor, or upon binding of the agonist—enables sampling of a precoupled state, ultimately needed to initiate activation and coupling.

Retraction: Pooled prevalence and determinants of modern contraceptive utilization in East Africa: A Multi-country Analysis of recent Demographic and Health Surveys

Indicator-based assessment of social sustainability in urban water management across contrasting governance contexts

A data-driven framework linking the connectome to spatial gene expression gradients inspired by chemoaffinity theory

Understanding how brain-wide neural circuits are genetically wired remains a fundamental question in neuroscience. While Sperry’s chemoaffinity theory [Sperry, Proc. Natl. Acad. Sci. U.S.A. 50 , 703–710 (1963)] posits that molecular gradients provide positional cues for axonal projections, its application has been largely limited to localized sensory systems. Here, we present SPERRFY (Spatial Positional Encoding for Reconstructing Rules of axonal Fiber connectivitY), a data-driven framework that operationalizes Sperry’s theory at the whole-brain scale. By integrating connectomic data with spatial transcriptomic profiles from the Allen Mouse Brain Atlas, SPERRFY infers latent positional gradients that underlie axonal wiring. Using canonical correlation analysis (CCA), we extract top gradient pairs that align with observed neural connectivity patterns, capturing both global (interregional) and local (intraregional) organizational principles. Connectivity reconstruction based on these gradients shows strong predictive performance, and permutation-based null models confirm the biological relevance of the inferred structures. Furthermore, SPERRFY can screen for candidate genes that may contribute to positional wiring information, providing molecular insight into the developmental logic of brain-wide circuitry. Our results extend Sperry’s foundational theory beyond the sensory domain, offering a unified, data-driven framework for understanding genetically encoded connectivity across the entire brain.

Retraction: Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

Evaluation of UV/TiO2/H2O2 photocatalysis for the removal of perfluorinated organic compounds from water

Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy

The neuronal K/Cl cotransporter KCC2 regulates the transmembrane chloride gradient, which controls the efficacy of GABAergic signaling. In mesial temporal lobe epilepsy (mTLE) and other neurological disorders, reduced KCC2 expression or function can result in depolarizing GABA signaling, which is thought to contribute to pathological activity and seizures. Therefore, restoring chloride homeostasis represents a promising therapeutic strategy. We investigated the mechanisms and antiseizure effects of two small molecules, prochlorperazine (PCPZ) and CLP-257, that have been identified as potential KCC2 enhancers. We found that both compounds enhance KCC2 function and clustering in cortical neurons while reducing its membrane diffusion, without altering canonical regulatory phosphorylation. CLP-257 also selectively increased extrasynaptic, but not synaptic, GABA A receptor-mediated currents. Using in vitro recordings from resected brain tissue of patients with drug-resistant mTLE and in vivo recordings from a mouse model, we show that PCPZ and CLP-257 (or its prodrug CLP-290) effectively suppressed spontaneous epileptiform activity in both models. These findings reveal that PCPZ and CLP-257 act as genuine KCC2 enhancers and provide experimental evidence of the therapeutic potential of such compounds for treating drug-resistant mTLE.

Tunneled peripherally inserted central catheter versus non-tunneled and its effects in clinical outcomes: A multicenter randomized clinical trial protocol

Background The use of peripherally inserted central catheters (PICC) has increased due to its benefits, such as greater durability, safety, comfort, and cost-effectiveness. Technological advancements, such as catheter tip navigation systems and the use of ultrasound, have improved its quality. However, complications still occur, including infections and thrombosis, especially in oncology and intensive care patients. Studies indicate that advanced practices, technology, and specialized teams reduce these risks. New techniques, such as tunneled insertion, show potential for reducing complications, but further research with larger samples is needed to validate these findings. Objective To compare the tunneling technique of PICC to non-tunneling insertion technique regarding the incidence of isolated or combined outcomes of catheter-related bloodstream infection, thrombosis, occlusion, and accidental dislodgement in the adult population within a 30-days period. Materials and methods In this randomized, parallel, multicenter clinical trial, 840 patients from three reference hospitals will be assigned to two parallel groups (conventional PICC and tunneled PICC groups) through computer-generated stratified randomization. The conventional group will undergo PICC insertion according to routine practice. In the tunneled PICC group, an additional subcutaneous tunneling procedure will be performed. Patients will be followed until PICC removal for any reason or 30 days after insertion, whichever occurs first. The primary outcome is to assess whether subcutaneous tunneling reduces the rate of isolated or combined adverse events (infection, thrombosis, obstruction, and dislodgement) compared to the conventional method. Discussion Subcutaneous tunneling is a widely used method to reduce complications associated with catheters. However, its application in PICC has not yet been extensively explored, especially in Brazil. A randomized clinical trial is necessary to objectively assess the effects of subcutaneous tunneling in PICC insertion. This protocol aims to provide evidence on the effectiveness of this technique in reducing complications. Trial registration Clinical Trials platform NCT06365528