Ultraviolet (UV) exposure induces cross-linked pyrimidine dimers in nucleic acids, primarily forming cyclobutane pyrimidine dimers and 6–4 pyrimidine–pyrimidone adducts. These photoproducts exist in multiple isomeric forms, and various dimeric combinations involving thymine, cytosine, and uracil have been documented since the 1960s. Mass spectrometry (MS) has been pivotal in identifying these species, although condensed-phase spectroscopy remains essential for full structural elucidation. This study integrates MS with gas-phase infrared (IR) spectroscopy to obtain vibrational spectra (800–1900 cm–1) of UV-induced photoproducts from mono- and dinucleotides. Following nanoelectrospray ionization and in-source collision-induced dissociation, fragment ions─commonly used in tandem MS experiments to identify the photoproducts─are embedded in superfluid helium clusters at 0.37 K to measure high-resolution IR action spectra. These spectra are then compared with density functional theory-calculated spectra of various candidate isomers to facilitate structural assignment without reference standards. This combined approach enables detailed characterization of complex, low-abundance biomolecules beyond the reach of conventional MS.

Introduction

Despite the high prevalence of chronic low back pain (cLBP), its underlying mechanisms remain poorly understood. Addressing modifiable psychosocial resources and health behaviours such as physical activity offers a promising avenue for reducing the impact of cLBP. Furthermore, although the relationship between physical activity and pain is theorised as a within-person process, previous research has primarily focused on between-person differences. In this article, we present the protocol for the prospective observational study PRIA (Psychologie und Rückengesundheit im Alltag), which is part of a larger interdisciplinary research consortium investigating preventive, diagnostic and therapeutic aspects of cLBP. Drawing on theories from health and pain psychology, the outlined study examines the interplay between different dimensions of cLBP and back health, physical activity and their psychosocial determinants within individuals in their everyday lives.

Methods and analysis

This prospective longitudinal study combines online questionnaires with ecological momentary assessment of health behaviours, cognitions, affect, social support and pain using a smartphone-based app (movisensXS) and continuous measurement of physical activity by accelerometry (movisens Move 4). Parameters will be recorded at baseline (T0), daily for the following 14 days (five times per day at 09:00, 12:00, 15:00, 18:00 and 21:00, resulting in up to 70 measurement occasions), 3 and 6 months later (T1 and T2). A total of 230 participants (115 individuals with cLBP and 115 without cLBP) aged 18–64 years will be enrolled. The associations between cLBP and the measured parameters will be examined using multilevel models.

Ethics and dissemination

The university’s ethics committee at the MSB Medical School Berlin approved the study on 8 March 2021 (approval number MSB-2021/59, amendment approved on 10 November 2023, amendment number MSB-2023/145). Ethical approval for the FOR 5177 initial screening was granted by Charité – Universitätsmedizin Berlin (EA1/058/21). All participants provided written informed consent. The results of this research will be published in peer-reviewed international journals, presented at national and international conferences, and reported to the German Research Foundation.

Trial registration number

DRKS00032978.

Quite frequently, it is the progression of initial crystallographic fragment screening hits into more potent binders to their target, which constitutes the major bottleneck in many academic compound or drug development projects. While high quality starting points are critical to the success of a drug development project, it is equally important to have accessible pathways for further compound development. Here, we present two crystallographic fragment screening campaigns using a 96 fragment sub-selection of the European Fragment Screening Library (EFSL) provided by EU-OPENSCREEN. The two campaigns against the targets endothiapepsin and the NS2B–NS3 Zika protease, yielded hit rates of 31% and 18%, respectively. Further, we present how within the framework of the EU-OPENSCREEN European Research Infrastructure Consortium (ERIC) fast identification of follow-up compounds can be realized. With just one round of testing related compounds from the European Chemical Biology Library, two follow-up binders for each of the two targets could be identified proving the feasibility of this approach.

Autoimmune disorders are heterogeneous dynamic conditions characterized by dysregulated immune responses and caused by interruption of tolerogenic circuits. Although immunosuppressive drugs, including biological agents, are effective therapeutic options, several patients do not respond to these treatment or develop resistance mechanisms. Galectins, a family of soluble glycan-binding proteins, play central roles in the modulation of autoimmune inflammation. Galectin-1 (Gal-1), a prototype member of this family, interacts with specific N-acetyllactosamine (LacNAc) ligands present in N- and O-glycans via its conserved carbohydrate recognition domain (CRD). The immunomodulatory activity of Gal-1 involves regulation of T cell effector populations, inducing apoptosis of Th1 and Th17 cells, differentiation of tolerogenic dendritic cells and induction of myeloid-derived suppressor cells. To develop a rational galectin-based therapeutic strategy, we evaluated whether Gal-1 retains its function upon multivalent presentation on nanoparticles. Specifically, we report the design strategy, synthesis and characterization of galectin-1-conjugated glucose-stabilized gold nanoparticles, and compare their activities with unconjugated galectin-1. This formulation offers novel opportunities for treating a variety of autoimmune diseases, as well as chronic inflammatory disorders.

Ionizing radiation damage to biomolecules plays a crucial role in radiotherapy as a cancer treatment. Among these, DNA-binding proteins are of particular interest due to their pivotal roles in shielding DNA and facilitating its repair. Hence, in this study, we present first-ever recorded data of radiation damage to a protein monitored directly with near-ambient pressure (NAP) X-ray photoelectron spectroscopy (XPS) under a water atmosphere. This surface sensitive technique was used to in situ damage and probe gene-V protein (G5P, a model DNA-binding protein) under wet NAP conditions and dry vacuum (UHV) conditions to determine the effect of water on the radiation response. In addition, the X-ray radiation damage to selected pure amino acids and short homopeptides was determined to better understand the variety of damage mechanisms within the complex protein. In dry samples, drastic chemical changes were detected in all biomolecules dominated by fragmentation processes. Here, the breakage of peptide bonds in the peptides and the protein are dominant. Surprisingly, hydration – despite introducing additional indirect damage pathways via water radiolysis – led to a reduction in overall radiation damage. This behaviour was attributed to hydration-dependent changes in reaction rates and respective deexcitation and damaging channels within the molecules and secondary species such as low-energy (LEE), (pre)-hydrated/(pre)-solvated electrons and radical species such as hydroxyl radicals.

Experiences shape preferences. This is particularly the case when they deviate from our expectations and thus elicit prediction errors. Here we show that prediction errors do not only occur in response to actual events – they also arise endogenously in response to merely imagined events. Specifically, people repeatedly chose between different acquaintances and then imagined interacting with them. Our results show that they acquired a preference for acquaintances with whom they had pictured unexpectedly pleasant events. This learning can best be accounted for by a computational model that calculates prediction errors based on these rewarding experiences. Using functional MRI, we show that the prediction error is mediated via striatal activity. This activity, in turn, seems to update preferences about the individuals by updating their cortical representations. Our findings demonstrate that imaginings can violate our own expectations and thus drive endogenous learning by coopting a neural system that implements reinforcement learning.

Domestication has shaped animal vocal behaviour, increasing flexibility and responsiveness to humans. In domestic cats ( Felis catus ), two vocalisations, meows and purrs, have distinct communicative roles. Meows are context-dependent signals primarily directed at humans; purrs are stereotyped, low-frequency sounds produced in affiliative contexts. Vocal individuality, key in mammalian communication, supports social recognition and interaction, but its presence across cats’ call types remains poorly understood. We examined whether cats encode individual identity in meows and purrs, hypothesising that meows might show stronger signatures due to their human-directed nature. We analysed 276 meows from 14 cats and 557 purrs from 21 cats. Both call types carried sufficient individual information, but purrs had significantly higher classification accuracy (84.6%) and encoded more information content (4.47 bit) than meows (63.2%, 2.65 bit). To place individuality in a domestication framework, we compared domestic cat meows with those of five wild relatives: African wildcat, European wildcat, jungle cat, cheetah, and cougar. Domestic cat meows showed greater acoustic dispersion than those of wild cats, reflecting increased vocal plasticity through domestication. These findings demonstrate how domestication has shaped feline vocalisations, with purrs acting as stable identity cues and meows emphasising flexibility over recognisability.

Background

The interconnectedness of human, animal, and environmental health drives emerging threats, such as antimicrobial-resistant pathogens. The widespread use of the same antimicrobials in both human and livestock may play a role in interspecies bacterial transmission by disrupting natural microbial communities and creating an environment favouring resistant bacteria. Pigs and poultry receive high levels of antimicrobials and are reservoirs of multidrug-resistant bacteria, including Streptococcus suis, a zoonotic pig pathogen. S. suis detection in non-porcine hosts, particularly poultry, raises a critical question: is this due to transient spillover or does it represent sustained host jumps and adaptation?

Results

Analysing over 3000 S. suis genomes from a diverse range of hosts—including pigs, wild boar, humans, cats, dogs, cattle, fish, otter, and birds—we identify a multidrug-resistant lineage, distinct from the lineage responsible for most zoonoses, that has undergone multiple host jump events into birds. Unlike transmission to humans, which is exclusively derived through contacts with pigs, we find evidence of S. suis adaptation to birds. This includes phylogenetic persistence, independent acquisition of bird-specific mobile genomic islands, enhanced survival in chicken versus pig blood, and subsequent transmission from poultry to wild birds.

Conclusions

While chickens may not be a source of zoonotic S. suis infections, shared antibiotic usage in pigs and poultry may have promoted host jumps of multidrug-resistant S. suis, leading to onward transmission to wild bird populations. Our results suggest that antibiotic use in livestock production may promote transmission of antimicrobial-resistant bacteria to other hosts, thereby expanding the ecological range of bacterial pathogens.

Information extraction (IE) is a transformative process that converts unstructured text data into a structured format by employing entity and relation extraction (RE) methodologies. Identifying the relation between a pair of entities plays a crucial role within this framework. Despite the availability of various techniques for RE, their efficacy heavily depends on access to labeled data and substantial computational resources. To address these challenges, large language models (LLMs) have emerged as promising solutions; however, they are prone to generating hallucinated responses due to the limitations of their training data. To overcome these shortcomings, this work proposes a retrieval-augmented generation-based relation extraction (RAG4RE) approach to enhance RE performance. We evaluate the effectiveness of RAG4RE using various LLMs. By leveraging established benchmarks such as TACRED, TACREV, Re-TACRED and SemEval RE datasets, we aim to comprehensively assess the efficacy of our methodology. Specifically, we employ prominent LLMs, including Flan T5, Llama2, and Mistral, in our investigation. The results of our work demonstrate that RAG4RE outperforms traditional RE methods based solely on LLMs, with significant improvements observed in the TACRED dataset and its variations. Furthermore, our approach exhibits remarkable performance compared to previous RE methodologies across both TACRED and TACREV datasets, underscoring its efficacy and potential for advancing RE tasks in natural language processing.

Das Konzept der Wissenschaftsskepsis gewann im Zuge der Covid-19 Pandemie an Popularität. Epistemische Unsicherheit und Konflikte, das katastrophische Potenzial nicht-konformen Verhaltens, Polarisierungen in der öffentlichen Debatte, autoritäre Bedrohungen und jene neuartige Akteurskategorie der Wissenschaftsskeptiker:innen, Impfgegner:innen und Corona-Leugner:innen waren Elemente jener Gemengelage, in der Politik, Medien und Teile der Sozialwissenschaften vermehrt den Begriff Wissenschaftsskepsis bemühten. Die Beiträge der vorliegenden Collection nähern sich diesem Konzept durch Analysen an, die (1) auf Semantik fokussieren, womit der Diskurs um Faktizität und ihre Krise bzw. Wissenschaftsskepsis in der politischen Öffentlichkeit gemeint ist, die sich (2) mit Wissen näher auseinandersetzen, was Gegenwissen, Nicht-Wissen und Heterodoxie oder Verschwörung einschließt, und die schließlich (3) das Verhältnis von Wissenschaft und Politik reflektieren. Mit diesen Schwerpunkten zielt die Collection darauf, reflexiv-historisierend die politische Funktion des Begriffs und seine Verwendung, die Entstehung eines Forschungsstrangs und das (vermeintliche) Phänomen als ein empirisches zu beleuchten.

Small animal models are indispensable in cardiopulmonary resuscitation (CPR) research. High-quality CPR, characterized by consistent chest compression rate, depth, and positioning is crucial for survival. However, achieving standardization in manual high-frequency chest compressions in small animal models remains technically challenging. This study evaluated the reproducibility of manual chest compressions and introduced a novel mechanical chest compression device (MCD) designed to improve consistency in rodent experiments. In an in vitro setup, manual compressions were performed by ten participants at target rates ranging from 100 to 260 bpm, guided by a metronome. Compressions performed on a fluid-filled polymer reservoir were analyzed for the compression rate, variability, and time within a ± 10% target range. A color indicator was used to assess the variability of the compression point. A small animal MCD was designed and tested under the same conditions. In vivo, 5 Sprague-Dawley rats underwent 5 min of electrically induced normothermic cardiac arrest followed by 8 min of external chest compressions using the MCD. Obtained data was compared to the in vitro results. A total of 21,650 manual and 20,098 mechanical compressions were analyzed. At 200 bpm, chest compressions using the MCD were significantly more precise (201 ± 1.2 bpm) than manual compressions (218 ± 21 bpm, p  < 0.001) with a significant reduced compression point variability (1.7 ± 0.1 cm 2 vs. 10.8 ± 3.1 cm 2 , p  < 0.001). Manual compressions maintained target rate in 58.8% of time compared to 100% for the MCD. In vivo testing confirmed these findings with chest compressions remaining within the target range 100% of the time and showing minimal rate variability (1.8 ± 1.7 bpm). These results highlight the limitations of manual chest compressions and demonstrate the potential of the MCD to enhance standardization and reproducibility in rodent CPR research.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by widespread molecular changes, many of which remain poorly understood. While AD pathology progresses through specific brain regions, it is unclear whether these regions are affected similarly. Long non-coding RNAs (lncRNAs), emerging as key cellular regulators, remain largely uncharacterized in AD. Understanding how lncRNAs interact with protein-coding genes across brain regions could shed light on AD mechanisms and progression. To investigate this, we performed consensus weighted gene co-expression network analysis on 396 postmortem brain RNA-seq samples using a meta-analytic approach. Our analysis revealed substantial network rewiring in AD, particularly in the temporal cortex compared to the frontal cortex. The temporal cortex exhibited adaptive changes in gene interactions, while the frontal cortex showed a breakdown of healthy correlations—possibly reflecting regional differences in disease progression. We identified 46 protein-coding genes and 27 lncRNAs as key components in the AD network of the temporal cortex. Using known functions of protein-coding genes as reference points, we inferred potential functions for over 100 lncRNAs across both regions. These findings highlight novel lncRNA candidates potentially involved in AD and provide insights into their roles in both healthy and diseased brain states.

Background

Oesophageal cancer (EC) is a common cause of cancer mortality. Evidence on the burden, risk factors and treatment outcomes is limited in low-income and middle-income countries. This study aimed to describe the features of EC cases and determine associated factors among patients attending surgical and oncology clinics in Garissa County Referral Hospital (GCRH).

Methods

We conducted a case–control study in which cases were patients with EC and positive histological confirmation and controls were patients admitted to GCRH for other diseases. Data on exposures were extracted from patient files. Data on tobacco and alcohol use were based on current or past use as documented in the records; hot tea intake referred to habitual consumption. Mixed-effect logistic regression model was used to determine EC-associated factors.

Results

141 cases and 282 controls were recruited. Of the 141 cases, 59 (42%) had cancer in the lower third of the oesophagus, whereas 72 (51%) and 10 (7%) had cancers in the middle and upper thirds, respectively. EC was associated with tobacco use (adjusted OR (AOR), 21.02, 95% CI 5.41 to 81.69), consumption of hot tea (AOR 59.87, 95% CI 5.45 to 657.35), chewing khat (miraa, AOR 9.94, 95% CI 3.59 to 27.52), gastro-oesophageal reflux disease (GERD) (AOR 54.12, 95% CI 24.48 to 119.62), gastritis (AOR 17.89, 95% CI 2.94 to 108.989) and peptic ulcer disease (PUD) (AOR 69.31, 95% CI 14.09 to 340.9). Among the case group, 95 (65%) had surgery or gastrostomy tube placement as treatments for EC.

Conclusion

The study findings highlight modifiable risk factors for EC, including tobacco use, hot tea consumption, chewing miraa, GERD, gastritis and PUD. Targeted screening of high-risk patients may improve early detection and outcomes.

Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1 A187V variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of β1-noradrenergic neurons. This enhanced wake-associated behaviors, including home cage activity, locomotion, exploration, and recognition memory, while reducing slow wave activity (SWA) during non-rapid eye movement (NREM) sleep indicating reduced build-up of sleep pressure during active phases. In a mouse model of Alzheimer’s disease, Adrb1 A187V installation restored physiological REM sleep and again reduced NREM sleep SWA following spontaneous activity. Together, these findings demonstrate the feasibility of prime editing for reprogramming genetic circuits in the brain and reveal beneficial effects of the Adrb1 A187V variant on activity and sleep regulation.

Microglia have been shown to sculpt postnatal circuitry from birth up to adulthood due to their role in both synapse formation, synaptic pruning, and the elimination of weak, redundant synapses. Microglia are differentiated in a sex-dependent manner. In this study, we tested whether sexual differentiation of microglia results in sex-dependent postnatal reorganization of CA1 synaptic connectivity in the hippocampus. The stereological counting of synapses in mice using electron microscopy showed a continuous rise in synapse density until the fourth week, followed by a plateau phase and loss of synapses from the eighth week onwards, with no difference between sexes. This course of alteration in synapse numbers did not differ between sexes. However, selectively, on postnatal day (P) 14 the density of synapses was significantly higher in the female than in the male hippocampus. Higher synapse density in females was paralleled by higher activity of microglia, as indicated by morphological changes, CD68 expression, and proximity of microglia to synaptic sites. In Thy1-GFP mice, consistent with increased synapse numbers, bouton density was also clearly increased in females at P14. At this time point, CD47 expression, the "don't eat me" signal of neurons, was similar in males and females. The decrease in bouton density thereafter in conjunction with increased synapse numbers argues for a role of microglia in the formation of multispine boutons (MSB). Our data in females at P14 support the regulatory role of microglia in synapse density. Sexual differentiation of microglia, however, does not substantially affect long-term synaptic reorganization in the hippocampus.

Aims Iron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials. Methods and results Individual participant data were used from the FAIR-HF (n= 459), CONFIRM-HF (n= 304) and AFFIRM-AHF (n= 1108) trials. These data were re-analysed following as closely as possible the approach taken in the analyses of IRONMAN (n= 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random-effects meta-analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48-0.99; between-trial heterogeneity tau=0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95-2.37], age <69.4 vs. >= 69.4 years) (RRR 0.68 [0.40-1.15]), ischaemic versus non-ischaemic aetiology of HF (RRR 0.73 [0.42-1.33]), transferrin saturation <20% vs. >= 20% (RRR 0.75 [0.40-1.34]), estimated glomerular filtration rate <= 60 versus >60 ml/min/1.73m(2) (RRR 0.97 [0.56-1.68]), haemoglobin <11.8 versus >= 11.8 (RRR 0.95 [0.53-1.60]), ferritin <35 versus >= 35 mu g/L (RRR 1.26 [0.72-2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54-1.56]). Conclusions Treatment of iron-deficient HFrEF patients with intravenous iron - namely with ferric carboxymaltose or ferric derisomaltose - results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present.