Activation Loop Research Articles

On the Existence of Long-period Decayless Oscillations in Short Active Region Loops

Abstract Decayless kink oscillations, characterized by their lack of decay in amplitude, have been detected in coronal loops of varying scales in active regions, the quiet Sun, and coronal holes. Short-period (<50 s) decayless oscillations have been detected in short loops (< 50 Mm) within active regions. Nevertheless, long-period decayless oscillations in these loops remain relatively unexplored and crucial for understanding the wave modes and excitation mechanisms of decayless oscillations. We present the statistical analysis of decayless oscillations from two active regions observed by the Extreme Ultraviolet Imager onboard Solar Orbiter. The average loop length and period of the detected oscillations are 19 Mm and 151 s, respectively. We find 82 long-period and 23 short-period oscillations in these loops. We do not obtain a significant correlation between loop length and period. We discuss the possibility of different wave modes in short loops, although standing waves cannot be excluded from possible wave modes. Furthermore, a different branch exists for active region short loops in the loop length versus period relation, similar to decayless waves in short loops in the quiet Sun and coronal holes. The magnetic fields derived from MHD seismology, based on standing kink modes, show lower values for multiple oscillations compared to previous estimates for long loops in active regions. Additionally, the comparison of period distributions in short loops across different coronal regions indicates that different excitation mechanisms may trigger short-period kink oscillations in active regions compared to the quiet Sun and coronal holes.

A Virtual Synchronous Generator Control Strategy Based on Transient Damping Compensation and Virtual Inertia Adaptation

To mitigate the challenges posed by transient oscillations and steady-state deviations in the traditional virtual synchronous generator (TVSG) that is subjected to active power and grid frequency disturbances, a VSG control strategy based on Transient Damping Compensation and Virtual Inertia Adaptation is presented. Initially, a closed-loop small-signal model for the grid-connected active power loop (APL) of the TVSG is constructed, which highlights the contradiction between the dynamic and static characteristics of TVSG output power through the analysis of root locus distribution trends. Secondly, a VSG control strategy based on Transient Damping Compensation (TDC) is proposed. The influence of APL system parameters introduced by TDC on system stability is qualitatively analyzed based on pole distribution trends and frequency response, and a comprehensive parameter design scheme is presented. In addition, based on the TDC algorithm, an improved virtual inertia adaptive strategy utilizing the Inverse Square Root Unit (ISRU) approach is designed, and the tuning range of parameters is provided. Finally, simulations and experiments verify that the proposed strategy exhibits superior active response performance and transient oscillation suppression capabilities, effectively eliminating active steady-state deviations caused by frequency disturbances in the power grid.

Chemokine CXCL12 Activates CXC Receptor 4 Metastasis Signaling Through the Upregulation of a CXCL12/CXCR4/MDMX (MDM4) Axis.

The metastasis-promoting G-protein-coupled receptor CXC Receptor 4 (CXCR4) is activated by the chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF-1). The CXCL12/CXCR4 pathway in cancer promotes metastasis but the molecular details of how this pathway cross-talks with oncogenes are understudied. An oncogene pathway known to promote breast cancer metastasis in MDA-MB-231 xenografts is that of Mouse Double Minute 2 and 4 (MDM2 and MDM4, also known as MDMX). MDM2 and MDMX promote circulating tumor cell (CTC) formation and metastasis, and positively correlate with a high expression of CXCR4. Interestingly, this MDMX-associated upregulation of CXCR4 is only observed in cells grown in the tumor microenvironment (TME), but not in MDA-MB-231 cells grown in a tissue culture dish. This suggested a cross-talk signaling factor from the TME which was predicted to be CXCL12 and, as such, we asked if the exogenous addition of the cell non-autonomous CXCL12 ligand would recapitulate the MDMX-dependent upregulation of CXCR4. We used MDA-MB-231 cells and isolated CTCs, with and without MDMX knockdown, plus the exogenous addition of CXCL12 to determine if MDMX-dependent upregulation of CXCR4 could be recapitulated outside of the TME context. We added exogenous CXCL12 to the culture medium used for growth of MDA-MB-231 cells and isogenic cell lines engineered for MDM2 or MDMX depletion. We carried out immunoblotting, and quantitative RT-PCR to compare the expression of CXCR4, MDM2, MDMX, and AKT activation. We carried out Boyden chamber and wound healing assays to assess the influence of MDMX and CXCL12 on the cells' migration capacity. The addition of the CXCL12 chemokine to the medium increased the CXCR4 cellular protein level and activated the PI3K/AKT signaling pathway. Surprisingly, we observed that the addition of CXCL12 mediated the upregulation of MDM2 and MDMX at the protein, but not at the mRNA, level. A reduction in MDMX, but not MDM2, diminished both the CXCL12-mediated CXCR4 and MDM2 upregulation. Moreover, a reduction in both MDM2 and MDMX hindered the ability of the added CXCL12 to promote Boyden chamber-assessed cell migration. The upregulation of MDMX by CXCL12 was mediated, at least in part, by a step upstream of the proteasome pathway because CXCL12 did not increase protein stability after cycloheximide treatment, or when the proteasome pathway was blocked. These data demonstrate a positive feed-forward activation loop between the CXCL12/CXCR4 pathway and the MDM2/MDMX pathway. As such, MDMX expression in tumor cells may be upregulated in the primary tumor microenvironment by CXCL12 expression. Furthermore, CXCL12/CXCR4 metastatic signaling may be upregulated by the MDM2/MDMX axis. Our findings highlight a novel positive regulatory loop between CXCL12/CXCR4 signaling and MDMX to promote metastasis.

131 and 304 Å Emission Variability Increases Hours Prior to Solar Flare Onset

Abstract Thermal changes in coronal loops are well studied, both in quiescent active regions and in flaring scenarios. However, relatively little attention has been paid to loop emission in the hours before the onset of a solar flare; here, we present the findings of a study of over 50 off-limb flares of Geostationary Operational Environmental Satellite class C5.0 and above. We investigated the integrated emission variability for Solar Dynamics Observatory Atmospheric Imaging Assembly channels 131, 171, 193, and 304 Å for 6 hr before each flare and compared these quantities to the same time range and channels above active regions without proximal flaring. We find significantly increased emission variability in the 2–3 hr before flare onset, particularly for the 131 and 304 channels. This finding suggests a potential new flare prediction methodology. The emission trends between the channels are not consistently well correlated, suggesting a somewhat chaotic thermal environment within the coronal portion of the loops that disturbs the commonly observed heating and cooling cycles of quiescent active region loops. We present our approach and the resulting statistics and discuss the implications for heating sources in these preflaring active regions.

Enhancing Seasonal Performance of Heat Pumps integrated into Building Ventilation Systems using a Multi-Stage Volume Enlarger: a Comparative Study across European Regions

The buildings sector is one of the largest energy consumers in the EU, accounting for approximately 40% of final energy consumption and around 36% of greenhouse gas emissions. European governments are implementing various measures to reduce these figures. One effective approach to lowering energy consumption is to enhance the energy efficiency of HVAC systems in buildings. Extending the control range of heat pumps can significantly improve their seasonal energy efficiency, thereby reducing carbon dioxide emissions and enhancing building sustainability. Modern heat pump capacity control commonly involves a variable-speed compressor and an electronic expansion valve. In this study, the authors introduce an additional control component—variable volume in the active loop of the heat pump.The paper evaluates the performance of a variable-volume heat pump integrated into a ventilation system across different European regions (Vilnius, Helsinki, and Milan). A comparison is made between the conventional control approach, which uses a compressor and expansion valve, and an enhanced control method that incorporates an additional device to regulate the heat pump circuit volume. Based on data from prior experiments—specifically, the dependencies of the heat pump heat output and efficiency on compressor speed, expansion valve position, and circuit volume—a control algorithm was developed with Matlab to simulate heat pump performance in a ventilation system over a typical meteorological year for each city.Key findings highlight that the use of additional volume control in the heat pump loop significantly extends the unit’s operational time compared to conventional control methods. Specifically, operational time increased from several percent to as much as 69.97% across the regions analysed, positively impacting seasonal performance. These results underscore the critical importance of optimizing heat pump control strategies, as they not only enhance energy efficiency but also contribute to reducing reliance on auxiliary heating and lowering overall carbon emissions. Furthermore, despite these advantages, the study notes a significant limitation: the current lack of commercially available tools for implementing dynamic volume adjustment in heat pumps, which presents challenges for practical application in the field.

Temporal evolution of axially standing kink motions in solar coronal slabs: An eigenfunction expansion approach

We aim to provide more insights into the applicability of the much-studied discrete leaky modes (DLMs) in classic analyses to solar coronal seismology. Under linear ideal pressureless magnetohydrodynamics (MHD), we examined 2D axial fundamental kink motions that arise when localized velocity exciters impact some symmetric slab equilibria. Continuous structuring is allowed. A 1D initial value problem (IVP) is formulated in conjunction with an eigenvalue problem (EVP) for laterally open systems, with no strict boundary conditions (BCs) at infinity. The IVP is solved by eigenfunction expansion, allowing a clear distinction between the contributions from proper eigenmodes and improper continuum eigenmodes. Example solutions are offered for parameters typical of active region loops. Our solutions show that the system evolves toward long periodicities due to proper eigenmodes (on the order of the axial time), whereas the interference of the improper continuum may lead to short periodicities initially (on the order of the lateral time). Specializing to the slab axis, we demonstrate that the proper contribution strengthens with the density contrast, but may occasionally be stronger for less steep density profiles. Short periodicities are not guaranteed in the improper contribution, the details of the initial exciter being key. When identifiable, these periodicities tend to agree with the oscillation frequencies expected for DLMs, despite the differences in the BCs between our EVP and classic analyses. The eigenfunction expansion approach enables all qualitative features to be interpreted as the interplay between the initial exciter and some response function, the latter being determined solely by the equilibria. Classic theories for DLMs can find seismological applications, with time-dependent studies offering additional ways for constraining initial exciters.

Water and chloride as allosteric inhibitors in WNK kinase osmosensing.

Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2). Here, we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride-binding site are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here, we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.

Water and chloride as allosteric inhibitors in WNK kinase osmosensing

Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2). Here, we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride-binding site are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here, we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.

Machine Intelligence-Accelerated Optimization of All-Temperature Aqueous Electrolyte for Stable Zn-Ion Batteries

Rechargeable aqueous batteries are the leading candidate to meet the surging demand for safe and low-cost energy storage systems. To achieve their development, the optimization of aqueous electrolyte for wide electrochemical stability window (ESW) and stable electrolyte/electrode interfaces is crucial. However, the selection of salts and solvents is critical to dictate the ultimate performance of Zn-ion batteries. Conventional approach requires trial-and-error optimization experiments, which is time-consuming and laborious. Herein, we show an integrated workflow that combines robotics and machine learning to accelerate the optimization of all temperature stable aqueous electrolyte with programmable ESW, ionic conductivity, and electrolyte/electrode interface stability. First, an automated pipetting robot is commanded to prepare 557 electrolyte mixtures using 2 salts (ZnCl2 and Zn(OTf)2) and 2 solvents (water and methanol). After equilibration/stabilization at 30 °C, the solubility of the electrolyte mixtures is evaluated to train a support-vector machine classifier. Next, through active learning loops with data augmentation, 60 electrolyte solutions are prepared/evaluated, establishing an artificial neural network prediction model. The achieved model is capable of two main functions: (1) predicting the electrochemical performance of an electrolyte solution based on its formulation, and (2) conducting multi-objective optimization on electrolytes to identify stable electrolytes with high Coulombic efficiency, rate performance, and interfacial stability. The model-suggested electrolyte with wide ESW, high conductivity, and stable electrolyte/electrode interfaces deliver ultrahigh cyclic stability in Zn||Zn symmetric cells, as well as outstanding capacity retention, fast charge/discharge capability, and excellent efficiency in full cells. The fusion of robotics-accelerated experimentation, machine intelligence, and simulation tools facility the discovery of electrolytes that involve time-intensive experiments and multi-dimensional design spaces.

Delving into Macrolide Binding Affinities and Associated Structural Modulations in Erythromycin Esterase C: Insights into the Venus Flytrap Mechanism.

Since their inception in antibacterial therapy, macrolide-based antibiotics have significantly shaped the evolutionary pathways of pathogenic bacteria, driving them to develop diverse antimicrobial resistance (AMR) mechanisms. Among these, macrolide esterase, commonly referred to as erythromycin esterase, emerged as a critical defense mechanism, enabling bacteria to detoxify macrolides by hydrolyzing the macrolactone ring within the bacterial cell. In this study, we delve into the intricate interactions and conformational dynamics of erythromycin esterase C (EreC), a key member of the Ere enzyme family. We have focused on three FDA-approved and widely prescribed macrolides─erythromycin, clarithromycin, and azithromycin─by employing classical molecular dynamics, absolute binding free energy calculations, and 2D well-tempered metadynamics simulations to explore their interactions with EreC. To estimate the absolute binding free energies, we have used the recently developed and robust "Streamlined Alchemical Free Energy Perturbation (SAFEP)" protocol. The results from our molecular dynamics simulations and advanced analyses portrayed the crucial role of hydrophobic interactions within the macrolide binding cleft of EreC, along with the significant influence of the minor lobe in facilitating overall structural fluctuation. In silico alanine scanning identified top three hydrophobic residues, i.e., PHE248, MET333, and PHE344, responsible for macrolide binding inside that cleft. According to the free energy calculations, azithromycin and clarithromycin showed greater binding affinities toward EreC than the parent macrolide erythromycin. Moreover, 2D metadynamics simulations along with graph theory-based eigenvector centrality analyses revealed a metastable "semiopen" state during the hypothesized "active loop closure" of the EreC protein triggered by subtle conformational changes of an important histidine residue, HIS289, upon macrolide capture, drawing a fascinating parallel to the renowned "Venus flytrap" mechanism.

PRC1 and CTCF-Mediated Transition from Poised to Active Chromatin Loops Drives Bivalent Gene Activation.

Polycomb Repressive Complex 1 (PRC1) and CCCTC-binding factor (CTCF) are critical regulators of 3D chromatin architecture that influence cellular transcriptional programs. Spatial chromatin structures comprise conserved compartments, topologically associating domains (TADs), and dynamic, cell-type-specific chromatin loops. Although the role of CTCF in chromatin organization is well-known, the involvement of PRC1 is less understood. In this study, we identified an unexpected, essential role for the canonical Pcgf2-containing PRC1 complex (cPRC1.2), a known transcriptional repressor, in activating bivalent genes during differentiation. Our Hi-C analysis revealed that cPRC1.2 forms chromatin loops at bivalent promoters, rendering them silent yet poised for activation. Using mouse embryonic stem cells (ESCs) with CRISPR/Cas9-mediated gene editing, we found that the loss of Pcgf2, though not affecting the global level of H2AK119ub1, disrupts these cPRC1.2 loops in ESCs and impairs the transcriptional induction of crucial target genes necessary for neuronal differentiation. Furthermore, we identified CTCF enrichment at cPRC1.2 loop anchors and at Polycomb group (PcG) bodies, nuclear foci with concentrated PRC1 and its tethered chromatin domains, suggesting that PRC1 and CTCF cooperatively shape chromatin loop structures. Through virtual 4C and other genomic analyses, we discovered that establishing neuronal progenitor cell (NPC) identity involves a switch from cPRC1.2-mediated chromatin loops to CTCF-mediated active loops, enabling the expression of critical lineage-specific factors. This study uncovers a novel mechanism by which pre-formed PRC1 and CTCF loops at lineage-specific genes maintain a poised state for subsequent gene activation, advancing our understanding of the role of chromatin architecture in controlling cell fate transitions.

Active learning for the design of polycrystalline textures using conditional normalizing flows

Generative modeling has opened new avenues for solving previously intractable materials design problems. However, these new opportunities are accompanied by a drastic increase in the required amount of training data. This is in stark juxtaposition to the high expense and difficulty in curating such large materials datasets. In this work, we propose a novel framework for integrating generative models within an active learning loop. This enables the training of generative models with datasets significantly smaller than what has previously been demonstrated, providing a direct route for their application in data constrained environments. The functionality of this framework is then demonstrated by addressing the challenge of designing polycrystalline textures associated with target anisotropic mechanical properties. The developed protocol exhibited a cost reduction between 14 to 18 times over a randomly sampled experimental design.

Effect of Coupling Impedance on Stability Assessment of Grid-Forming Converters Under Various Grid Conditions

The phenomenon of frequency coupling is widely observed in grid-forming (GFM) converters due to the presence of asymmetrical controls and nonlinear blocks. However, the factors influencing frequency coupling have not been thoroughly explored. This paper introduces a systematic small-signal impedance model of GFM converters that intuitively reflects the factors affecting frequency coupling and provides a detailed analysis of how coupling impedance affects stability. It is demonstrated that the influencing factors of coupling impedance are an active power loop and reactive power loop. Specifically, the active power loop influences coupling impedance characteristics near the fundamental frequency, while the reactive power loop impacts the entire frequency range. This paper first reveals that the reactive power loop has a more pronounced effect on frequency coupling than the active power loop. Additionally, the variation in the steady-state operating points also affects the degree of frequency coupling of the GFM converters, primarily affecting the coupling impedance characteristics beyond the fundamental frequency, and the low operating points tend to affect system stability adversely. Finally, simulation results validate the accuracy of the mathematical model and theoretical analysis.

The Conformational Space of the SARS-CoV-2 Main Protease Active Site Loops Is Determined by Ligand Binding and Interprotomer Allostery.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and is, therefore, an important drug target. Here, we investigate two flexible loops in Mpro that play a role in catalysis. Using all-atom molecular dynamics simulations, we analyze the structural ensemble of Mpro in an apo state and substrate-bound state. We find that the flexible loops can adopt open, intermediate (partly open), and closed conformations in solution, which differs from the partially closed state observed in crystal structures of Mpro. When the loops are in closed or intermediate states, the catalytic residues are more likely to be in close proximity, which is crucial for catalysis. Additionally, we find that substrate binding to one protomer of the homodimer increases the frequency of intermediate states in the bound protomer while also affecting the structural propensity of the apo protomer's flexible loops. Using dynamic network analysis, we identify multiple allosteric pathways connecting the two active sites of the homodimer. Common to these pathways is an allosteric hotspot involving the N-terminus, a critical region that comprises part of the binding pocket. Taken together, the results of our simulation study provide detailed insight into the relationships between the flexible loops and substrate binding in a prime drug target for COVID-19.

Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation.

Somatic alterations in the oncogenic kinase AKT1 have been identified in a broad spectrum of solid tumours. The most common AKT1 alteration replaces Glu17 with Lys (E17K) in the regulatory pleckstrin homology domain1, resulting in constitutive membrane localization and activation of oncogenic signalling. In clinical studies, pan-AKT inhibitors have been found to cause dose-limiting hyperglycaemia2-6, which has motivated the search for mutant-selective inhibitors. We exploited the E17K mutation to design allosteric, lysine-targeted salicylaldehyde inhibitors with selectivity for AKT1 (E17K) over wild-type AKT paralogues, a major challenge given the presence of three conserved lysines near the allosteric site. Crystallographic analysis of the covalent inhibitor complex unexpectedly revealed an adventitious tetrahedral zinc ion that coordinates two proximal cysteines in the kinase activation loop while simultaneously engaging the E17K-imine conjugate. The salicylaldimine complex with AKT1 (E17K), but not that with wild-type AKT1, recruits endogenous Zn2+ in cells, resulting in sustained inhibition. A salicylaldehyde-based inhibitor was efficacious in AKT1 (E17K) tumour xenograft models at doses that did not induce hyperglycaemia. Our study demonstrates the potential to achieve exquisite residence-time-based selectivity for AKT1 (E17K) by targeting the mutant lysine together with Zn2+ chelation by the resulting salicylaldimine adduct.

Study on improved control strategy of virtual synchronous generator

Virtual synchronous generator (VSG) control technology for photovoltaic, energy storage, wind power, and other new energy to provide flexibility in the grid interface characteristics, is conducive to improving the stability of the power system, and has been widely considered by many scholars. Firstly, an improved VSG control method is proposed through simulation and analysis, which realizes the complete decoupling of the frequency response time constant and the inertia quantity of the active power control loop and reduces the complexity of the parameter design of the VSG system. Secondly, to avoid the frequent action of the VSG system caused by small-scale frequency change perturbation, this study proposes a VSG frequency optimization control method for VSG frequency control with rated angular velocity ωset feedforward composed of multivariate factors when considering a primary frequency regulation dead zone. Thirdly, the impact of VSG parameter design on the system is investigated through the system response characteristics of power scheduling, primary frequency regulation at the grid connection, and the small-signal dynamic characterization of the improved VSG. Finally, Simulation and experimental verification yielded an active power overshoot of 7% and a maximum frequency deviation of 0.17 Hz for the improved system. The improved control method resulted in an improvement of 0.1 s in the frequency response time and a reduction of 0.15 Hz in the oscillation amplitude. The response speed of the improved control method is much better, while the oscillation amplitude is reduced to meet the grid's regulation requirements. The simulation and experimental analysis verify the feasibility of the improved VSG control method.

Multiple ligands simultaneous molecular docking and dynamics approach to study the synergetic inhibitory of curcumin analogs on ErbB4 tyrosine phosphorylation

Background and purpose: Lapatinib (FMM) and 5-fluorouracil (5-FU) are anticancer drugs employed in a combination approach. FMM inhibits tyrosine phosphorylation of ErbB4 while 5-FU inhibits cell proliferation. This research aimed to investigate the potential of two compounds, namely (1E,4E)-1,5-bis (4-hydroxyphenyl) penta-1,4-dien-3-one (AC01) and (1E,4E)-1,5-bis (3,4-dihydroxy phenyl) penta-1,4-dien-3-one (AC02), both as individual inhibitors and combination partners with FMM, targeting ErbB4 inhibition. AC01 and AC02 were combined with FMM, which targets ErbB4. The combination of 5-FU with FMM served as a reference in this study. Experimental approach: The research utilized computational simulation methods such as single and multiple ligands simultaneously docking and dynamics. Data analysis was performed using AutoDockTools and gmx_MMPBSA. Findings/Results: Single docking results indicated that 5-FU exhibited the lowest binding affinity, while FMM demonstrated the highest. Simultaneous docking of AC01 and AC02 paired with FMM revealed their binding positions overlapping with the FMM-5-FU workspace. The FMM-AC01 and FMM-AC02 complexes exhibited slightly weaker binding affinities compared to FMM-5-FU. In combination with FMM, AC01 and AC02 occupied the ErbB4 activation loop, whereas 5-FU was outside the activation loop. Furthermore, in their interaction with ErbB4, AC02 exhibited slightly stronger binding than AC01, as confirmed by the average binding free energy calculations from molecular dynamics simulations. Conclusion and implications: In conclusion, computational simulations indicated that both AC01 and AC02 have the potential to act as anticancer candidates, demonstrating ErbB4 inhibitory potential both as individual agents and in synergy with FMM.

KATANA - water activation facility at JSI TRIGA, Part II: First experiments

Water as a primary coolant will play an important role in the performance of fusion reactors, as after being irradiated and activated, it causes an ionising radiation field throughout the facility. In direct support of ITER, the KATANA irradiation facility, which utilises a closed-water activation loop and serves as a well-defined and stable high-energy γ and neutron source, was commissioned in 2024 at the TRIGA Mark II research reactor at the Jožef Stefan Institute in Slovenia.A series of first experiments using the KATANA irradiation facility were performed to determine the operational characteristics of the KATANA, i.e. characterisation of the neutron flux within the irradiation component, dose rate measurements, spectrum characterisation of the activated water, and response to a change in reactor power & flow rate. The KATANA facility demonstrated the desired operational characteristics in terms of high and stable water flow rates and high activity values of the observed isotopes 16N, 17N and 19O, which is essential for minimising the experimental uncertainties.The first experiments performed at KATANA provided in-depth knowledge into the operation and capabilities of the facility and essential data to serve as a basis for further, more detailed/benchmark experiments.

Leishmania donovani adenylosuccinate synthetase requires IMP for dimerization and organization of the active site.

Adenylosuccinate synthetase (AdSS), which catalyses the GTP-dependent conversion of inosine monophosphate (IMP) and aspartic acid to succinyl-AMP, plays a major role in purine biosynthesis. In some bacterial AdSS, it is implicated that IMP binding is important to organize the active site, but in certain plant AdSS, GTP performs this role. Here, we report that in Leishmania donovani AdSS, IMP binding favoured dimerization, induced greater conformational change and improved the protein stability more than GTP binding. IMP binding, which resulted in a network of hydrogen bonds, stabilized the conformation of active site loops and brought the switch loop to a closed conformation, which then facilitated GTP binding. Our results provide a basis for designing better inhibitors of leishmanial AdSS.

Multi-iteration active learning for the composition design of potassium–sodium niobate ceramics with enhanced piezoelectric coefficient

The piezoelectricity of piezoceramics considerably depends on the doped compositions. However, the conventional trial-and-error approach to composition design is time-consuming and inefficient when searching for high-performance piezoceramics with various dopants. In this study, we introduce a data-driven framework to accelerate the design and discovery of lead-free (K,Na)NbO3 (KNN) materials with enhanced piezoelectric performance. The proposed framework integrates machine learning with feature engineering, surrogate-based optimisation, and experimentation in an active learning loop. Using feature engineering techniques, we demonstrated that the piezoelectric coefficient d33 of KNN materials can be predicted based on a set of elemental and atomic properties. We evaluated six machine learning models and found that support vector regression with a radial basis function kernel achieved high accuracy in predicting the d33 values of KNN ceramics. After three iterations of experimentation and optimisation, we identified an optimal composition with a relatively high d33 of ∼353 pC/N from thousands of possible compositions using a pure exploitation strategy. This study demonstrates an efficient and systematic approach to the composition design of KNN-based piezoceramics, which can be applied to investigate the diverse functional properties of other materials.