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.

Edition of three “deluxe” (or “elaborate”) horoscopes for births in the second and third centuries CE, one probably dated to the reign of Gallus. Each offers indirect reflections of astrological interpretation of the horoscopic data, including the classification of planets, zodiac signs, their parts, and of additional objects such as the cardinal points and paranatel lonta. A checklist collects the other original horoscopes belonging to this type.

This article discusses the role that algorithmic thinking and management play in health care and the kind of exclusions this might create. We argue that evidence-based medicine relies on research and data to create pathways for patient journeys. Coupled with data-based algorithmic prediction tools in health care, they establish what could be called health care algorithmics-a mode of management of healthcare that produces forms of algorithmic governmentality. Relying on a critical posthumanist perspective, we show how healthcare algorithmics is contingent on the way authority over bodies is produced and how predictive health care algorithms can reproduce inequalities of the worlds from which they are made, centreing possible futures on existing normativities regulated through algorithmic biopower. In contrast to that, we explore posthuman speculative ethics as a way to challenge understanding of 'ethics' and 'care' in healthcare algorithmics. We suggest some possible avenues towards working speculative ethics into health care while still being critically attentive to algorithmic modes of management and prediction in health care.

The generalized Langevin equation (GLE) is a useful framework for analyzing and modeling the dynamics of many-body systems in terms of low-dimensional reaction coordinates, where the specific form of the GLE depends on the choice of projection formalism. We compare parameters derived from different GLE formulations using molecular dynamics (MD) simulations of the dihedral angle dynamics of butane in water. Our analysis reveals non-negligible non-Gaussian contributions of the orthogonal force in all GLEs, being most significant for the Mori-GLE, where all non-linearities are relegated to the orthogonal force. By using the orthogonal-force trajectory extracted from MD simulations to perform simulations of the GLE, we show that the non-Gaussianity and higher-than-two-point autocorrelations of the orthogonal force are relevant for accurately reproducing the dihedral-angle distribution and dynamics. We find that the accuracy of GLE simulations depends significantly on the chosen GLE formalism. Surprisingly, the Mori-GLE offers the most accurate framework for capturing the dihedral angle dynamics as judged by comparing barrier-crossing times calculated from different GLE formulations, provided an accurate non-Gaussian orthogonal-force trajectory with the correct higher-than-two-point autocorrelations is used.

Immune monitoring of patients on a single-cell level is becoming increasingly important in various diseases. Due to the often very limited availability of human specimens and our increased understanding of the immune systems there is an increasing demand to analyze as many markers as possible simultaneously in one panel. Full spectrum flow cytometry is emerging as a powerful tool for immune monitoring since 5-laser instruments enable characterization of 40 parameters or more in a single sample. Nevertheless, even if only machines with fewer lasers are available, development of novel fluorophore families enables increasing panel sizes. Here, we demonstrate that careful panel design enables the use of 31-color panels on a 3-laser Cytek (R) Aurora cytometer for analyzing human peripheral blood leukocytes, without the need for custom configuration and using only commercially available fluorochromes. The panel presented here should serve as an example of a 31-fluorochrome combination that can be resolved on a 3-laser full spectrum cytometer and that can be adapted to comprise other (and possibly more) markers of interest depending on the research focus.

Atopic dermatitis (AD) is a chronic skin disease with a prevalence of 10%–20% in children and 1%–3% in adults.1 We investigated the expression patterns of interleukin (IL)-1α, IL-1β and IL-18 in AD and their interplay with the expression of profilaggrin, loricrin and claudin-1.

We performed analyses by RT-qPCR and immunohistochemistry using skin samples from AD patients (n = 6) and healthy controls (HC) (n = 6), but also human skin explants (n = 4–8). Non-atopic, HCs were defined as having no personal or family history of allergic diseases, no personal history of chronic systemic or skin diseases and a serum total IgE that was ≤2 SD of age-dependent norms. SCORAD and three item severity scores were used to evaluate the severity of AD. Punch biopsies were obtained from forearm of six AD patients and six HC. Innate immune responses derived from keratinocytes are important initiators of skin inflammation, for example after skin irritation.2 The role of IL-1 cytokines including IL-1α, IL-1β and IL-18 in skin inflammation has been established for a long time.3 We observed enhanced IL-1α and IL-1β positive cells in lesional—compared to non-lesional skin (Figure 1a,b). Also, IL-1β- and IL-18-positive cells were upregulated in lesional AD compared to HC (Figure 1b,c).

Synaptic vesicle (SV) fusion is not only tightly coordinated but also happens at a millisecond timescale. Competing models for fusion initiation and propagation suggest tight docking and hemifusion of SVs or localized lipid rearrangements leading to tip-like membrane contacts. Yet, a direct nanoscale examination of the full SV fusion sequence has been lacking. Here, we establish a workflow for timed in situ cryo-electron tomography of optogenetically stimulated mouse neurons to capture the complete SV fusion sequence – from SV recruitment to fusion pore formation, opening and collapse – with near-native structural preservation. Notably, tethered SVs directly undergo fusion initiation via stalk formation, without preceding tight docking or SV flattening. The plasma membrane forms a minimal dimple during fusion initiation, contradicting preceding models that invoke strong membrane bending prior to fusion. In addition, we observe filaments linking fusing SVs to adjacent SVs, indicating a physical link between fusion and SV resupply.

Termites are a lineage of social cockroaches abundant in tropical ecosystems where they are key decomposers of organic matter. Despite their ecological significance, only a handful of reference-quality termite genomes have been sequenced, which is insufficient to unravel the genetic mechanisms that have contributed to their ecological success. Here, we perform sequencing and hybrid assembly of 45 taxonomically and ecologically diverse termites and two cockroaches, resulting in haplotype-merged genome assemblies of 47 species, 22 of which were near-chromosome level. Next, we examine the link between termite dietary evolution and major genomic events. We find that Termitidae, which include ~80% of described termite species, have larger genomes with more genes and a higher proportion of transposons than other termites. Our analyses identify a gene number expansion early in the evolution of Termitidae, including an expansion of the repertoire of CAZymes, the genes involved in lignocellulose degradation. Notably, this expansion of genomes and gene repertoires coincided with the origin of soil-feeding in Termitidae and remained unchanged in lineages that secondarily reverted to a wood-based diet. Overall, our sequencing effort multiplies the number of available termite genomes by six and provides insights into the genome evolution of an ancient lineage of social insects.