The gold(III) starting material [Au(damp-κC1,N)Cl2] (Hdamp = 2-(dimethylaminomethyl)benzene) reacts with the thiourea-type ligands 3,3-diethyl-1-benzoylthiourea (HL1) or N-(3,3-diethylamino-thiocarbonyl)-N′-(2-hydroxyphenyl)benzamidine (H2L2) under formation of the gold(III) cations [Au(damp-κC1,N)(L1-κS,O)]+ (1) and [Au(Hdamp-κC1)(L2-κS,N,O)]+ (2). The products have been isolated in crystalline form as their PF6− salts and studied by X-ray diffraction and spectroscopic methods. The preservation of the gold(III) oxidation state and the square-planar coordination spheres in the products is most probably due to the formation of chelate rings by the incoming ligands and the presence of the Au–C bond to the phenyl rings of the damp− or Hdamp ligands.

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC50 0.03–0.46 μM 1a–g; IC50 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations.

Thyroid diseases in horses are rare and pose challenges for veterinarians due to the complexity of clinical and diagnostic approaches. This retrospective case series describes cases of equine thyroid disease in a referral hospital population. Files of horses examined for suspected thyroid disease at an equine university clinic between 2009 and 2024 were reviewed. Data from nine horses examined for suspected thyroid disease, including signalment, clinical presentation, laboratory results, imaging findings, fine needle aspirates, biopsies, diagnoses, and treatments, were summarised. Diagnoses included thyroid adenoma (n = 6), multiple thyroid cysts (possibly thyroid adenoma (n = 1)), non-thyroidal illness syndrome (NTIS, n = 1), and iodine deficiency goitre (n = 1). Diagnostic modalities varied, with, besides manual palpation performed in every patient, basal thyroid hormone measurement and ultrasonography being the most common. Low serum iodine concentrations were noted in four horses, yet iodine supplementation was inconsistently applied. Hemithyroidectomy was performed in four horses, enabling histopathological diagnosis (three out of four). Despite being rare, thyroid diseases in horses require consistent and thorough diagnostic approaches, including imaging, laboratory, and histopathological examinations. Improved screening tools and research could enhance the diagnostic accuracy and management of equine thyroid disorders.

Congenital patellar luxation (PL) and cranial cruciate ligament rupture (CCLR) are among the most prevalent hereditary musculoskeletal disorders in dogs. Despite their frequency, the microstructural alterations in the stifle joint capsule associated with these conditions remain poorly understood. This study aimed to characterize histomorphological changes in the joint capsule of dogs affected by PL and/or CCLR. Capsule samples were collected from dogs undergoing corrective surgery for PL or CCLR, while control tissue was obtained from dogs with unrelated orthopedic conditions. Histological evaluation assessed capsule thickness, the organization of its layers (stratum fibrosum, stratum subsynoviale, and stratum synoviale), synovial cell number, and villous or plicae formation. Associations with disease type, chronicity, sex, age, breed, and weight were analyzed. Dogs with PL and CCLR exhibited increased superficial synovial cell layers compared to controls, whereas chronic cases showed reduced villous formation (SEF = 2.46). Absence or marked reduction of the stratum subsynoviale correlated with PL and prolonged lameness. In PL cases, the stratum synoviale was frequently absent, whereas CCLR cases exhibited an increase in overall capsular thickness. These findings reveal distinct histomorphological remodeling in PL and CCLR, suggesting that chronic instability drives degenerative changes. Understanding these alterations may aid in early diagnosis, improve treatment strategies, and inform breeding programs targeting joint stability in predisposed breeds.

Amino acid (AA) metabolism and the adaptation of muscles to increased physical performance are interdependent. This field study examined changes in plasma amino acid (PAA) concentrations and two metabolites (ammonia and urea) before and after cross-country (CC) competitions throughout an entire eventing season and their associations with performance outcomes in eventing horses. Twenty horses from nine different Warmblood breeds were evaluated between two and seven times across 14 international eventing competitions over a 23-week period. A total of 55 rides were sampled. Blood samples were collected at four time points: before the start (TP0), 10 min after completion of the CC ride (TP1), 30 min post-CC (TP2), and the next morning (TP3). A mixed ANOVA revealed significant effects (p < 0.05) of calendar week on PAA concentrations for asparagine, ornithine, and proline. Correlations between CC scores and PAA concentrations were observed for 4 of the 25 measured parameters. TP0 leucine concentrations and TP2 histidine concentrations correlated negatively with CC penalty score, whereas TP1 proline concentrations and TP3 alanine concentrations correlated positively with CC penalty score. These results indicate that higher plasma leucine concentrations may contribute to improved performance in eventing horses. Additionally, alanine and proline show potential as performance-related diagnostic biomarkers.

The chromatin remodelling proteins DAXX and ATRX are key regulators of genome stability and epigenetic processes. Alterations in their expression have been associated with tumour stage and prognostic outcomes in various human cancer types, whereas their role in veterinary oncology has received little investigation to date. We analysed canine prostate and urinary bladder samples, including 18 prostate carcinomas (12 adenocarcinomas and 6 prostatic urothelial carcinomas), 10 non-malignant prostate tissues, 22 urinary bladder carcinomas, and 6 non-malignant bladder tissues. Nuclear expression of DAXX and ATRX was assessed using fully quantitative digital immunohistochemistry. Overall, DAXX exhibited consistently higher expression than ATRX across benign and malignant samples from the prostate and bladder. DAXX and ATRX expression demonstrated a positive correlation across all samples (ρ = 0.553, p < 0.05), suggesting coordinated regulation. They displayed organ-specific expression patterns: prostate carcinomas showed increased expression of DAXX compared with non-malignant prostate tissues (p < 0.05). In contrast, in the bladder, expression of DAXX and ATRX declined with increasing tumour grade (p < 0.05). Our findings provide new insights into the potential of DAXX and ATRX as biomarkers, offering new insights into their clinical relevance in dogs.

Background/Objectives: Antimicrobial resistance (AMR) threatens global public health. This systematic review and meta-analysis, as part of the “ENVIRE” project (interventions to control the dynamics of antimicrobial resistance from chickens through the environment), assesses the prevalence of phenotypic and genotypic resistance, including extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases, carbapenemases, colistin, and fluoroquinolone resistance, in broiler chickens and their environment. Methods: The analysis covers the years 2002–2022, focusing on Escherichia (E.) coli, Klebsiella spp., Enterobacter spp., and Citrobacter spp. in fecal, meat, environmental, and other-than-feces samples from observational studies published in PubMed and Web of Science. Quality assessment was performed using the Alberta Heritage Foundation criteria. Results: Data from 170 studies, conducted in Europe, North Africa, and North America, were included. The most frequently studied resistance was to beta-lactam, with focus on ESBL-producing and AmpC beta-lactamase isolates. The pooled prevalence of ESBL-resistant E. coli observed in meat samples at 41% and in fecal samples at 38% demonstrated significant heterogeneity between the studies. The negative binomial regression analysis of prevalence data revealed significantly higher ESBL-producing E. coli rates in European meat samples compared to North African samples. Conclusions: This systematic review revealed substantial variation in prevalence and emphasizes the need for standardized surveillance systems and robust study designs.

The number of structurally investigated cyclopentadienyl (Cp−) complexes of technetium is limited in contrast to the situation with its heavier homolog, rhenium. Although this could be attributed to the radioactivity of all isotopes of the radioelement, there are also clear chemical differences to analogous compounds of the other group seven elements, manganese and rhenium. Technetium Cp− compounds are known with the metal in the oxidation states “+1” to “+7”, with a clear dominance of Tc(I) carbonyls and nitrosyls. Corresponding carbonyl complexes also play a significant role in the development of 99mTc-based radiopharmaceuticals with the aromatic ring as an ideal position for the attachment of biomarkers. In this paper, the present status of the synthetic and structural chemistry of technetium with Cp− ligands is discussed, together with recent developments in the corresponding 99mTc labeling chemistry.

Mental pain is commonly defined as an experience situated on a continuum between cognitive appraisal of the painful event and the affective disposition of the person experiencing it. Drawing on ethnographic material and interviews on severe psychiatric disorders in Bali and Java, I will try to understand what mental pain does to the person experiencing it, as well as to their immediate environment. To answer this question, I will first describe the salient attributes of mental pain as they emerged during my conversations with outpatients and observations of their milieu. These were a challenged “realness” of the experience of mental pain, its ability to take hold of one’s subjective experience, an elusive and relational quality, and a perceived ambiguous and indeterminate temporal dimension. Moreover, I will describe the uncertainties of people navigating a severe psychiatric disorder (health, sanative, social, and behavioral uncertainties), and I will suggest that the salient attributes of mental pain contribute to the makeup of these uncertainties. Finally, this article illustrates that the interrelated nature of mental pain and experienced uncertainties can inform certain illness behaviors, particularly instances of self-isolation.

AbstractWe performed whole-genome sequencing of three multidrug-resistant KPC-producing Klebsiella pneumoniae isolates recovered from patients in a tertiary-care hospital in Abu Dhabi, UAE, and conducted a comparative genomic analysis with previously reported blaKPC−2-positive isolates from the region. The study aimed to characterize acquired antimicrobial resistance genes (ARGs), assess their phylogenetic context, and analyze the plasmids carrying blaKPC−2. Between 2017 and 2018, 162 carbapenem-resistant K. pneumoniae (CRKP) isolates were collected from four tertiary care hospitals in Abu Dhabi. Antibiotic susceptibility was determined using the Vitek2 system, and PCR was used to detect carbapenemase genes. Whole-genome sequencing was performed for the three blaKPC-2-positive isolates using Illumina NovaSeq, and assemblies were generated with SPAdes 3.9. PlasmidSPAdes and PLACNETw were used to reconstruct blaKPC-2-carrying plasmids, which were then compared with plasmids described in earlier UAE reports. The three K. pneumoniae isolates belonged to sequence types ST11, ST20, and ST231, respectively. All harbored the blaKPC−2 gene on IncFII-type plasmids of varying sizes. Our comparative analysis demonstrated variability in the genetic platforms carrying blaKPC−2, with two transposons (Tn1721a and Tn4401b) identified as the main structures associated with this gene in UAE isolates. Conclusions: Our findings highlight the diversity of genetic platforms carrying blaKPC-2 in the UAE, particularly the frequent association with IncFII plasmids and their potential role in the dissemination of antimicrobial resistance. Although blaKPC-2 is a globally widespread carbapenemase gene, it has been rarely reported in the United Arab Emirates (UAE). To date, only two studies describing blaKPC-2-carrying Klebsiella pneumoniae isolates have been published from the region—in 2015 and 2019. Our study presents a comprehensive genomic analysis of blaKPC-2-positive isolates collected in 2017–2018 from tertiary care hospitals in the UAE. Compared to previous reports, this study employed advanced bioinformatics tools and conducted deep genomic surveillance, including resistome, plasmidome, transposon mapping, and phylogenetic comparisons with public genomes. We identified distinct genetic platforms carrying blaKPC-2, notably the association with IncFII plasmids and the continued presence of the Tn4401b transposon. Although blaKPC-2 is present in the UAE, it remains underreported, likely due to limited regional sequencing efforts. This study provides essential baseline genomic data and a comparative framework to support ongoing and future surveillance of antimicrobial resistance in the Gulf region.

Introduction

Biologic therapies, such as vedolizumab (VDZ) and ustekinumab (UST), offer effective treatment options for inflammatory bowel disease. In spite of limited evidence, it is common practice to escalate the dosing regimen if clinical symptoms or biomarkers give suspicion of loss of response. This study aims to determine whether model-informed precision dosing (MIPD) can provide equal efficacy and possibly superior cost-effectiveness compared with symptom-based management.

Methods and analysis

This study is an unblinded, randomised controlled trial, conducted at six centres in Denmark. A total of 166 patients diagnosed with Crohn’s disease or ulcerative colitis who have been on stable VDZ or UST therapy for at least 3 months will be enrolled. Participants will be randomised to receive either continued symptom and biomarker-based dosing (control group) or dosing guided by therapeutic drug monitor using pharmacokinetic (PK) models together with PK-pharmacodynamic targets (=MIPD; intervention group). The primary endpoint is the fraction of patients in steroid-free remission at the end of the observation period. Secondary endpoints include mucosal healing, clinical remission, biochemical disease control, PK assessment and cost-effectiveness.

Ethics and dissemination

The trial has been approved by the Danish Medicines Agency and The Medical Research Ethics Committee. No study-related procedures will take place before patients have signed written informed consent. Results will be published in peer-reviewed journals and presented at international conferences.

Trial registration numbers

EUCT, 2024-517123-39-00; NCT06788340 .

Russian leadership for decades has been skeptical of the US-centric world, considering it both a threat to Russia’s sovereignty and the great power status. At the same time, the main goal of Russia appears to be less making Russia the new global leader and more creating a multipolar world with numerous power centers engaging in various alliances and conflicts. The war in Ukraine, due to the commitment of the Western nations and the US to support this country, is currently perceived in Moscow as a way to coming closer to this multipolar world. Whether this perception has changed under Donald Trump, is doubtful.

The efficient design of (C)­sp 3 -rich molecular scaffolds with defined exit vectors is central to expanding drug-like chemical space. Here, we report a boron-enabled strategy for the synthesis of polysubstituted housanes from nonsymmetrical dienes. A geminal diboron system ensures site-, regio-, and diastereoselectivity in an energy transfer-catalyzed [2 + 2] cycloaddition of nonsymmetrical dienes while also facilitating the mild generation of a cyclobutyl anion that triggers a stereospecific intramolecular annulation via conjugate addition, delivering complex housanes, with three defined exit vectors, in just two steps. Systematic derivatization across all substituents demonstrates the breadth of chemical diversification, while mechanistic and density functional theory (DFT) computational studies reveal the stereoelectronic origins of diastereoselectivity and the counterintuitive electrophile-driven reactivity of the housane framework. This work establishes housanes as stable, derivatizable, and structurally rigid fragments that provide multidirectional exit vectors, offering a powerful platform for the exploration of three-dimensional (3D) chemical space in medicinal chemistry.

Cortisol, a key biomarker of hypothalamus–pituitary–adrenal (HPA) axis activity, is central to early stress regulation and neurodevelopment. While prior studies have linked maternal and infant cortisol to child outcomes, less is known about their synchrony during early infancy, a time of rapid neuroendocrine development. In this longitudinal study, we examined cortisol coupling and the correlation with maternal adverse childhood experiences (ACEs) in 305 mother–infant dyads from São Paulo, Brazil. Salivary cortisol was collected at ~ 1 month (32.3 days) and 6 months postpartum. We assessed intra- and interindividual cortisol dynamics and coupling using bivariate latent change score modeling. Maternal and infant cortisol were positively correlated at baseline (r = 0.319, p < 0.001) and at 6 months (r = 0.208, p = 0.003), suggesting early attunement that diminishes over time. Mothers and infants showed negative self-feedback, where higher baseline cortisol predicted smaller changes (mothers: B = -0.654; infants: B = -0.615; both p < 0.001). Maternal ACEs predicted elevated maternal cortisol at baseline (B = 0.126, p = 0.026) but did not affect the rate of change. These findings reveal early HPA synchrony and gradual decoupling, and highlight the lasting effects of maternal adversity on postpartum stress physiology.

Sensory attenuation is the phenomenon that self-produced stimulations are suppressed compared to externally generated ones, both at the subjective and electrophysiological level. Despite the extensive literature on this phenomenon, it remains unclear whether electrophysiological attenuations are consistent across senses and whether they do reflect subjective attenuations of perceived intensity for self-produced sensations. Therefore, the aim of the present study is twofold: first we aimed to collect behavioural and electrophysiological measures of sensory attenuation in a controlled virtual reality setup, both in the auditory and somatosensory domain. Secondly, we correlated behavioural and electrophysiological indices of sensory attenuation to formally test whether the suppression for potentials evoked by self-generated stimulations reflects the sensory suppression revealed by behavioural measures. A total of 28 participants were included to compare the intensity of a first stimulation, which was self-generated or externally administered, to a second stimulation, which was administered at rest with varying intensity. The stimulations could be either electrical pulses at the fingertip or auditory clicks. Participants were also required to undergo a control task in which no stimulation was administered. The behavioural results indicate a reduced perceived intensity for self-produced compared to externally administered stimuli for the auditory domain. In contrast, no such difference was observed for the somatosensory domain. EEG results revealed suppression of the P2 for the auditory modality and the P200 in the somatosensory modality. Furthermore, a positive correlation between the P2 suppression and subjective intensity attenuation was found for the auditory modality. Together, our results suggest that electrophysiological suppression at mid-latency components reflect the perceived subjective attenuation of self-produced stimulation. This relationship, however, might be dependent on the sensory domain.

Effective pain management in animal models is crucial for maintaining ethical and scientific integrity. However, commonly used analgesics may affect immune responses and disturb signaling pathways, thereby potentially confounding the experimental outcomes. In mouse colitis models, opioids and non-steroidal anti-inflammatory drugs have been shown to interfere with the immune response and the activation of the central regulator of inflammation, the transcription factor nuclear factor kappa B (NF-κB). Here, we propose a tailored pipeline for the identification and the validation of analgesics with minimal off-target effects. This approach combines protein-centered relation extraction using deep language models and distant supervision via the Protein-Centered Association Extraction with Deep Language (PEDL + ) together with an in vivo experimental validation with a NF-κB reporter mouse model that enables unambiguous visualization of direct NF-κB activity across different tissues. Our findings indicate that commonly used analgesics, such as tramadol and acetaminophen, not only interfere with immune cell recruitment and NF-κB activation but also skew the differentiation of epithelial stem cells into goblet cells, affecting epithelial functions even after short exposures. Conversely, the analgesics selected by our PEDL + -based workflow, such as piritramide, demonstrated no significant interference with NF-κB signaling. To validate our findings in vivo , we treated our NF-κB reporter mice with the analgesics selected by our computational pipeline. Amantadine demonstrated the least impact on the inflammatory responses and NF-κB activation. We then predicted and identified the signaling pathways that are impacted by amantadine treatment. In summary, our proposed pipeline facilitates a shift from one-size-fits-all analgesics to a precision medicine approach that considers the unique molecular interactions associated with each model.

China's embrace of open-source AI appears to contradict its centralized “cyber sovereignty” doctrine. This article analyses China's open-source AI strategy through a four-layer framework (physical, logical, application, societal), revealing how openness is repurposed to serve state-centric goals: achieving technological self-reliance, controlling applications and data, and steering innovation toward state-defined priorities. Globally, the strategy functions as asymmetric competition, countering U.S. tech dominance through the narrative of “AI democratization,” while shaping industry standards and subtly promoting China's vision of digital governance across the world.

This review summarizes key virological parameters of SARS-CoV-2, the clinical spectrum of COVID-19, antiviral options, resistance, and the evolution of SARS-CoV-2 during the first four years of the pandemic. It draws on evidence that has been continuously updated throughout the pandemic by the interdisciplinary working group ‘SARS-CoV-2 Diagnostics and Evolution’ at Robert Koch Institute (RKI), Germany’s national public health institute. We describe basic SARS-CoV-2 characteristics and highlight notable virus variants from 2020 to mid-2023. During this period, the nationwide collection of SARS-CoV-2 genomes provided a substantial resource for monitoring viral lineage frequencies and mutations. We summarize this dataset to underscore the importance of virological surveillance in the context of public health and pandemic preparedness.

Introduction: Calf health is still giving cause for concern, even though best management practices have been known for a long time. This qualitative study aimed to gain insights into the adoption of veterinary recommendations by farmers of large dairy herds to improve the health of calves in Saxony, Germany.

Methods: In the first year of study, nine large dairy farms were visited twice to assess data on calves’ health after assessing the perception of farmers regarding major calves’ diseases. Then, farmers and study veterinarians discussed the results and agreed on three to five measures per farm. Stages of change according to the transtheoretical model, as well as barriers and motivators, were assessed for the following year.

Results: The perception of farmers and the prevalence assessed by study veterinarians correlated moderately. However, the farmers assessed calves’ health better than the comparison with reference data indicated. In total, farmers implemented 15 of 36 recommendations within 1 year (42%). Barriers hindering the implementation were related to concerns that the team would or could not comply, the belief in the effectiveness of measures as well as the old buildings. Recommendations that needed constant changes in management were less likely to be implemented. Especially offering roughage and water to the calves—a measure mostly suggested by the study team—were seldom implemented or were given up before the study ended. However, factors mentioned positively were necessity and simplicity of recommendations.

Discussion: This study indicates that farmers are, in general, willing to adopt measures to improve the health of calves. However, staff shortage and the motivation of team members played a crucial role in these large dairy farms. Moreover, constant feedback and evaluation of success are needed to encourage farmers to maintain those measures that need constant action.