Active Complex Research Articles

Complexity of CO2 Activation and Reaction on Surfaces in Relation to Heterogeneous Catalysis: A Review and Perspective

Complexity of CO2 Activation and Reaction on Surfaces in Relation to Heterogeneous Catalysis: A Review and Perspective

Differences in EEG complexity of cognitive activities among subtypes of schizophrenia

IntroductionThe neural mechanisms that underpin cognitive impairments in patients with schizophrenia remain unclear. Previous studies have typically treated patients as a homogeneous group, despite the existence of distinct symptom presentations between deficit and non-deficit subtypes. This approach has been found to be inadequate, necessitating separate investigation.MethodsThis study was conducted at Daizhuang Hospital in Jining City, China, from January 2022 to October 2023. The study sample comprised 30 healthy controls, 19 patients with deficit schizophrenia, and 19 patients with non-deficit schizophrenia, all aged between 18 and 45 years. Cognitive abilities were evaluated using a change detection task. The NeuroScan EEG/ERP System, comprising 64 channels and utilising standard 10-20 electrode placements, was employed to record EEG signals. The multiscale entropy and sample entropy of the EEG signals were calculated.ResultsThe healthy controls demonstrated superior task performance compared to both the non-deficit (p < 0.001) and deficit groups(p < 0.001). Significant differences in multiscale entropy between the three groups were observed at multiple electrode sites. In the task state, there are significant differences in the sample entropy of the β frequency band among the three groups of subjects. Under simple conditions of difficulty, the performance of the healthy controls exhibited a positive correlation with alpha band sample entropy(r = 0.372) and a negative correlation with beta band sample entropy (r = -0.411). Deficit patients demonstrated positive correlations with alpha band sample entropy (r = 0.370), whereas non-deficit patients exhibited negative correlations with both alpha and beta band sample entropy (r = -0.451, r = -0.362). Under difficult conditions of difficulty, the performance of healthy controls demonstrated a positive correlation with beta band sample entropy (r = 0.486). Deficit patients exhibited a positive correlation with alpha band sample entropy (r = 0.351), while non-deficit patients demonstrated a negative correlation with beta band sample entropy (r = -0.331).ConclusionThe results of this study indicate that cognitive impairment in specific subtypes of schizophrenia may have distinct physiological underpinnings, underscoring the need for further investigation.

RING dimerisation drives higher-order organisation of SINA/SIAH E3 ubiquitin ligases.

RING-type E3 ubiquitin ligases promote ubiquitylation by stabilising an active complex between a ubiquitin-loaded E2-conjugating enzyme and a protein substrate. To fulfil this function, the E3 ubiquitin-protein ligase SIAH1 and other SINA/SIAH subfamily RING-type E3 ligases employ an N-terminal catalytic RING domain and a C-terminal substrate-binding domain (SBD), separated by two zinc fingers. Here, we present the first crystal structure of the RING domain of human SIAH1, together with an adjacent zinc finger, revealing a potential RING dimer, which was validated in solution using static light scattering. RING dimerisation contributes to the E3 ligase activity of SIAH1 both in vitro and in cells. Moreover, as the RING domain is the second element, after the SBD, to independently favour homodimerisation within SINA/SIAH E3 ligases, we propose that alternating RING:RING and SBD:SBD interactions organise multiple copies of a SINA/SIAH protein into a higher-order homomultimer. In line with this hypothesis, fluorescently tagged full-length human SIAH1, human SIAH2 and fruit fly SINA show cytoplasmic clusters in human cells, whereas their distribution becomes more diffuse when RING dimerisation is disabled. The wild-type (WT) form of SIAH1, but not its RING dimerisation mutant, colocalises with aggregated synphilin-1A under proteasomal inhibition, suggesting that SIAH1 multimerisation might contribute to its reported preference for aggregated or multimeric substrates.

A COMPLEXITY-BASED EXAMINATION OF VARIATIONS IN BRAIN ACTIVITY BETWEEN INDIVIDUALS WITH INTELLECTUAL AND DEVELOPMENTAL DISORDERS (IDD) AND HEALTHY CONTROLS DURING REST AND EXTERNAL STIMULATION PERIODS

Investigating the disparities in brain activity between healthy individuals and those with intellectual and developmental disorders (IDD) is pivotal in biomedical research. In this study, we delved into these differences by employing a complexity-based analysis of electroencephalogram (EEG) signals. Specifically, we computed the fractal dimension (FD), approximate entropy, and sample entropy (SampEn) of EEG signals for both control (healthy) subjects and IDD individuals during rest and stimulation with music. Our findings revealed that IDD subjects exhibited higher complexity in both rest and stimulation scenarios compared to control subjects, indicative of heightened brain activity complexity among IDD individuals. This analysis not only sheds light on the variations in brain activity associated with IDD, but also underscores its potential applicability in assessing brain activity alterations across various disorders compared to healthy counterparts.

Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex

The aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a transcriptionally active complex with aryl hydrocarbon receptor nuclear translocator (ARNT), for DNA binding and initiation of gene expression programs that include cellular detoxification pathways and immune responses. Here, we examine the molecular mechanisms governing AHR’s high-affinity binding and activation by a diverse group of ligands. Crystal structures of the AHR-ARNT-DNA complexes, bound with each of six established AHR ligands, including Tapinarof, 6-formylindolo[3,2-b]carbazole (FICZ), benzo[a]pyrene (BaP), β-naphthoflavone (BNF), Indigo and Indirubin, reveal an unconventional mode of subunit assembly with intimate association between the PAS-B domains of AHR and ARNT. AHR’s PAS-B domain utilizes eight conserved residues whose dynamic rearrangements account for the ability to bind to ligands through hydrophobic and π-π interactions. Our findings further reveal the structural underpinnings of a ligand-driven activation mechanism, whereby a segment of the AHR protein undergoes a structural transition from chaperone engagement to ARNT heterodimer stabilization, to generate the transcriptionally competent assembly. Our results provide key information for the future development of AHR-targeting drugs.

Versatile New Lanthanide Complexes Containing Organic Ligand Derived From Vitamin B6 as Potential Tyrosinase Inhibitors: Synthesis, Characterizations, and Structure Activity Investigations

ABSTRACTThe synthesis, characterizations, and tyrosinase enzyme inhibition experiments on eight novel lanthanide metal complexes (1–8) are reported. A multidonor versatile ligand L was prepared from the condensation reaction of picolinohydrazide with pyridoxal. The synthesized complexes were analyzed using FT‐IR and UV‐vis spectroscopies, elemental (CHN) analysis, and single‐crystal X‐ray diffraction analysis. These complexes exhibited significant tyrosinase enzyme inhibition with IC50 values in the range of 9.67 ± 0.17–21.88 ± 0.57 μM. The molecular docking results of the most active complex (2) correlate well with in vitro observations.

Hyperparameter Tuning of Random Forest using Social Group Optimization Algorithm for Credit Card Fraud Detection in Banking Data

As the adoption of credit cards continues to expand alongside advancements in e-commerce, the frequency and complexity of fraudulent activities have also grown, posing significant challenges for the financial sector. Detecting fraudulent transactions within highly imbalanced datasets remains a critical issue in ensuring secure banking operations. This study explores a robust approach RF_SGO to credit card fraud detection by combining pre-processing techniques such as Synthetic Minority Oversampling Technique (SMOTE) and class weight adjustment with Random Forest (RF) models optimized using the Social Group Optimization (SGO) algorithm. Additionally, the study utilizes Random Forest's feature importance mechanism to identify the most influential features contributing to fraud detection, enhancing interpretability and decision-making. Our methodology evaluates RF_SGO across three datasets: the original European cardholders' imbalanced dataset, a class-weight-adjusted dataset, and a SMOTE-enhanced dataset. Model performance is measured using key metrics, including Accuracy, Precision, Recall, F1-Score, and ROC-AUC. The RF_SGO model demonstrated superior performance, with the SMOTE-enhanced variant achieving the highest ROC-AUC (0.98) and Recall (0.88), effectively balancing sensitivity and specificity. The class-weighted RF_SGO achieved the highest Precision (0.96), making it ideal for minimizing false positives. Furthermore, the feature importance analysis identified key predictors of fraudulent behavior, providing actionable insights for financial institutions. Comparisons with traditional machine learning algorithms (e.g., Logistic Regression, Decision Trees, and SVM) and advanced models (e.g., XGBoost, CatBoost, and deep learning) highlight RF_SGO's ability to outperform in precision-recall trade-offs and overall classification effectiveness. This study underscores the significance of incorporating hyperparameter tuning, feature importance analysis, and data balancing strategies to improve fraud detection. The proposed RF_SGO framework offers a scalable and efficient solution for financial institutions to mitigate fraud, ensuring more reliable and secure transaction systems.

Unraveling the depth-dependent causal dynamics of methanogenesis and methanotrophy in a high-latitude fen peatland

Abstract The dynamics of methane (CH4) cycling in high-latitude peatlands through different pathways of methanogenesis and methanotrophy are still poorly understood due to the spatiotemporal complexity of microbial activities and biogeochemical processes. Additionally, long-term in situ measurements within soil columns are limited and associated with large uncertainties in microbial substrates (e.g., dissolved organic carbon, acetate, hydrogen). To better understand CH4 cycling dynamics, we first applied an advanced biogeochemical model, ecosys, to explicitly simulate methanogenesis, methanotrophy, and CH4 transport in a high-latitude fen (within the Stordalen Mire, northern Sweden). Next, to explore the vertical heterogeneity in CH4 cycling, we applied the PCMCI/PCMCI+ causal detection framework with a bootstrap aggregation method to the modeling results, characterizing causal relationships among regulating factors (e.g., temperature, microbial biomass, soil substrate concentrations) through acetoclastic methanogenesis, hydrogenotrophic methanogenesis, and methanotrophy, across three depth intervals (0-10 cm, 10-20 cm, 20-30 cm). Our results indicate that temperature, microbial biomass, and methanogenesis and methanotrophy substrates exhibit significant vertical variations within the soil column. Soil temperature demonstrates strong causal relationships with both biomass and substrate concentrations at the shallower depth (0-10 cm), while these causal relationships decrease significantly at the deeper depth within the two methanogenesis pathways. In contrast, soil substrate concentrations show significantly greater causal relationships with depth, suggesting the substantial influence of substrates on CH4 cycling. CH4 production is found to peak in August, while CH4 oxidation peaks predominantly in October, showing a lag response between production and oxidation. Overall, this research provides important insights into the causal mechanisms modulating CH4 cycling across different depths, which will improve carbon cycling predictions, and guide the future field measurement strategies.

Complexes of Cd(II) with Nicotinamide, Nitrate, and Oxalate as Mixed Ligands: Synthesis, Characterization, and Biological Activity

Three complexes of Cd(II), [Cd(NA)₂(NO₃)₂(H₂O)₂] (1), [Cd(NA)₂(NO₃)₂(H₂O)₂]·2NA (2), and [Cd(ox)(NA)(H₂O)]·H₂O (3) (NA = nicotinamide, ox = oxalate) were synthesized and characterized. Complexes (1) and (2) are mononuclear, while complex (3) is a bidimensional polymeric coordination compound, with oxalate anions bridging metal ions in two different ways: µ₂ bis-bidentate chelating manner and µ₄ bis-bidentate bis-monodentate manner. The stereochemistry of Cd(II) in compounds (1) and (3) is a distorted pentagonal bipyramid, while in compound (2) it is a regular octahedron. Complexes (1) and (2) demonstrated significant activity against Enterococcus faecalis and Escherichia coli, showcasing their potential as effective antibacterial agents and inhibitors of microbial adhesion. The complexes were characterized by means of single-crystal X-ray diffraction, elemental analysis, FTIR (all complexes), 1H NMR, 13C NMR, fluorescence spectroscopy, and antimicrobial activity (complexes (1) and (2)).

Профессионально важные качества психологов в современных зарубежных исследованиях

<p style="text-align: justify;">The article presents an analysis of modern foreign publications devoted to the study of professionally important personal qualities of psychologists, education psychologists and psychologists-consultants. Research has shown the complexity of the professional activity of a psychologist involving the solution of significant psychological issues, often not having clear work patterns. The key tasks that tackle psychologists are outlined: development and implementation of primary and secondary interventions, monitoring of educational and behavioral difficulties, counselling participants of educational environment, development and evaluation of psychological support programs, research activities, continuous improvement and validation of qualifications, work with critical situations. An attempt was made to analyze various approaches in the understanding of foreign researchers of the problem of professional identity. Professional identity is dynamic and variable, formed throughout life, unites emotional-will, value-semantic, personal features, begins with the choice of profession and continues throughout the professional life. The methods of diagnostics of professionally important personal qualities of psychologists developed by foreign researchers are described.</p>

Three-dimensional standard electrocardiogram: A first approach based on precordial leads.

Traditional electrocardiography (ECG) is limited to two-dimensional (2D) representations, which restricts its ability to capture the full complexity of cardiac electrical activity. We propose a novel three-dimensional (3D) ECG methodology directly derived from standard 2D recordings, providing enhanced spatial insights without requiring additional hardware modifications. Additionally, we introduce a new formulation, which we term "almost-curvature", to optimize the detection of variations in acute ischemic states, which is one of the leading causes of mortality and exhibits sensitivity issues in diagnosis using traditional ECG methods. To introduce the methodology for developing 3D ECG and evaluate its diagnostic utility in detecting morphological changes associated with acute myocardial ischemia through perimeter, curvature, and almost-curvature metrics. We developed a methodology based on spherical-to-Cartesian coordinate transformations applied to standard ECG data from the PhysioNet database. For validation, we utilized datasets from patients with induced myocardial ischemia. We extracted perimeter, curvature, and almost-curvature metrics from both 3D and 2D ECG and compared them across different ischemic states. From method implementation to clinical validation, we used clustering analyses and statistical tests such as Anderson-Darling, Kolmogorov-Smirnov, Mantel, Shapiro-Wilk, Wilcoxon, and the Permutation test. Statistical analysis revealed a correlation between the plane presenting standard deflections in the 3D ECG and the plane displaying the novel loops generated by our methodology. The almost-curvature metric demonstrated an enhanced capacity to detect variations between ischemic states, surpassing the diagnostic performance of traditional curvature metrics. While 2D analyses showed a reduction in curvature and perimeter during ischemia progression, 3D ECG analysis revealed an increase in these metrics, underscoring its ability to capture morphological changes that may be overlooked by conventional methods. 3D ECG analysis shows potential to enhance the detection of ischemic alterations, offering a more detailed spatial representation of cardiac electrical activity compared to traditional methods. By leveraging spherical-to-Cartesian transformations, our methodology integrates temporal and voltage dynamics into a unified framework, potentially revealing subtle morphological changes associated with ischemia. Although the methodology remains in its early developmental stage and requires further refinement, its promising diagnostic utility suggests it could significantly enhance cardiac diagnostics. Further studies are essential to validate its clinical applicability and address current limitations.

Ingested house dust mite favors sensitization to egg white in mice independently of its proteinase activity.

It is well-documented that house dust mite (HDM) exposure can cause tissue damage and activate innate immune responses. However, its role in promoting gastrointestinal sensitization and allergenicity to food proteins has been relatively unexplored. This study investigates the immunostimulatory effects of HDM in a murine model of oral sensitization to egg white (EW) in the absence of exogenous adjuvants. Additionally, we examined a proteolytically inactivated form of HDM (iHDM) to assess the contribution of HDM protease activity to its adjuvant potential. Both HDM and iHDM enhanced allergic responses to EW proteins via the oral route, evidenced by mast cell degranulation in the intestinal tract upon EW challenge. Notably, only iHDM induced detectable concentrations of serum EW-specific IgE and IgG1 antibodies. Whereas HDM increased intestinal expression of genes encoding tight junction proteins and Th2-inducing alarmins to a greater extent than iHDM, active proteinases were not required for its adjuvant activity, as iHDM preferentially promoted Th2 responses in intestinal lymphoid tissues. These findings suggest that ingestion of environmental dust may contribute to food allergy development and highlight the complex and context-dependent nature of the adjuvant activity of HDM.

The use of biologically active substances of peptide nature in medicine

One of the promising directions in preventive medicine in the region is the use of biologically active additives (dietary supplements). Such complexes are concentrated sources of various biologically active substances, such as vitamins, minerals, amino acids, extracts of medicinal plants and others. Numerous studies demonstrate that a number of components of biologically active nutrient complexes are able to have a positive effect on the mental state of a person, affecting various mechanisms underlying mental functions. This review is devoted to the consideration of the main mechanisms of action of biologically active additives, ensuring their beneficial effect on human mental health.

De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.

Key Role of Phosphorylation in Small Heat Shock Protein Regulation via Oligomeric Disaggregation and Functional Activation.

Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins share a conserved α-crystallin domain (ACD) critical for their chaperone function, with flexible N- and C-terminal extensions that facilitate oligomer formation. Phosphorylation, a key post-translational modification (PTM), plays a dynamic role in regulating sHSP structure, oligomeric state, stability, and chaperone function. Unlike other PTMs such as deamidation, oxidation, and glycation-which are often linked to protein destabilization-phosphorylation generally induces structural transitions that enhance sHSP activity. Specifically, phosphorylation promotes the disaggregation of sHSP oligomers into smaller, more active complexes, thereby increasing their efficiency. This disaggregation mechanism is crucial for protecting cells from stress-induced damage, including apoptosis, inflammation, and other forms of cellular dysfunction. This review explores the role of phosphorylation in modulating the function of sHSPs, particularly HSPB1, HSPB4, and HSPB5, and discusses how these modifications influence their protective functions in cellular stress responses.

Molecular Sensing of Chiral Carboxylic Acid Enantiomers Using CD Inductions in the Visible Light Region.

The reaction between a chiral carboxylic acid molecule and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride in the presence of a mild base generates a chiroptically active metal complex displaying strong circular dichroism (CD) signals in the visible light region, a highly sought-after goal in the optical sensing realm. The molecular recognition process is complete within a few minutes and can be used for fast chiroptical determination of the enantiomeric composition and concentration of carboxylic acid samples. This method is operationally simple and broadly applicable to a large variety of structures including important drugs, natural products, amino acids, and hydroxy acids. All components needed are commercially available, and this optical sensing assay can be readily adapted by any laboratory interested in chirality analysis and high-throughput experimentation.

Controlling Catalyst Speciation to Achieve Room Temperature Pd‐Catalyzed Aminations with Aryl and Heteroaryl Chlorides

The amination of aryl halides with palladium catalysts (Buchwald‐Hartwig amination) is a widely used transformation in synthetic and drug discovery chemistry. In this report, we demonstrate that a monometallic 2‐phosphinoimidazole Pd catalyst exhibits comparable or enhanced reactivity when compared to all ligands screened for room temperature amination of aryl chlorides with secondary amines. The di‐tert‐butylphosphine derivative showed extremely high reactivity while the di‐isopropyl variant led to almost complete loss of catalytic activity. Computational and experimental mechanistic and kinetic studies indicate that a monometallic Pd structure rather than a bimetallic Pd structure is key to fast catalysis. The di‐tert‐butylphosphine ligand has fast catalysis because it thermodynamically disfavors the formation of a much less active bimetallic Pd complex. A wide substrate scope is demonstrated for the arylation of secondary amines with aryl chlorides using our new catalyst system.

Open Science at the University of Toronto

Objective: The impetus for this project is to begin to understand open science practices and obstacles at the XXX. This project uses open-ended questions to understand the ways in which university-affiliated individuals learn about, think about, and interact with open science. The goal of this study is to showcase the complexity and diversity of activity and challenges in this domain to help determine how best to move open science forward. Methods: From March to October 2022, 45 semi-structured interviews were conducted with faculty, graduate students, librarians and administrative staff. Interviews were conducted and recorded using Zoom and the audio was transcribed using otter.ai. As part of a commitment to open science practices, a data management plan was created and with participant consent, 26 transcripts were uploaded to Dataverse. Data analysis used structured coding and thematic development to investigate responses. Results: The core finding of this study is that there is no singular status of open science at XXX. The qualitative findings reflect a diversity of opinions, practices and relationships to open science. Conclusion: For open science practices and scholarship to have longevity, there must be systemic changes to adopt more open activities. XXX is well positioned to guide the transition and harness open principles to move into the future.

Electrophysiological Signatures of Alpha Coma.

Recent research on quantitative EEG in coma has proposed several metrics correlating with consciousness level. However, the heterogeneous nature of coma can challenge the generalizability of these measures. This study investigates alpha-coma, an electroclinical pattern characterized by a widespread, nonreactive alpha rhythm often linked to poor outcomes. The aim was to quantify the electrophysiological features of alpha-coma and compare them to the alpha rhythm in awake controls, seeking clearer insights into quantitative EEG analysis in comatose states. Fourteen alpha-coma patients were retrospectively selected from University Hospitals of Geneva and age-matched with 14 healthy control subjects from an open-source dataset. EEG data were preprocessed and analyzed to extract power spectra, spectral decay (aperiodic activity), sample entropy, and functional connectivity. Alpha-coma patients did not differ in alpha power but exhibited significantly higher levels of spectral decay (p < 0.001), suggesting a convergence toward an inhibitory state. Sample entropy was significantly higher in alpha-coma patients (p = 0.01), indicating an increase in the cortical complexity in alpha-coma compared with healthy subjects. Alpha-coma shows increased aperiodic activity and EEG complexity, despite similar alpha power and clustering coefficient. The increased aperiodic activity aligns with findings in other comatose patients, including those sedated or with subcortical dysfunction. However, the increased entropy contradicts existing literature, suggesting that alpha-coma may represent a state of widespread cortical dysfunction likely resulting from nonhierarchical, turbulent brain activity. This indicates that the loss of consciousness does not guarantee consistent cortical measures across the whole spectrum of EEG patterns.

Structural basis of THC analog activity at the Cannabinoid 1 receptor

Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.