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Abstract We study tetraquarks in large N QCD with heavy quarks, in the domain where non-relativistic quantum mechanics offers an adequate approximation. Within the regime of validity of the Born-Oppenheimer approximation, we systematically study and explicitly construct tetraquark states. At leading order in the 1/N expansion, the bound spectrum consists of free mesons, while the 1/N corrections give rise to a Born-Oppenheimer potential that can bind the mesons into tetraquarks. We find two different types of tetraquarks, each endowed with distinct color-spatial wavefunctions. These states arise in the presence of an O $$ \mathcal{O} $$ (N) mass hierarchy between the quarks and the antiquarks. We provide a quantitative argument indicating that only for such a hierarchy is the ground state of the system a tetraquark. We discuss what the extrapolation of our results to realistic values of the parameters may imply for the QCD tetraquark states.

Abstract Background Invasive blood pressure measurement is the in-hospital gold standard to guide hemodynamic management and consecutively cerebral perfusion pressure in patients with traumatic brain injury (TBI). Its prehospital use is controversial since it may delay further care. The primary aim of this study was to test the hypothesis that patients with severe traumatic brain injury who receive prehospital arterial cannulation, compared to those with in-hospital cannulation, do not have a prolonged time between on-scene arrival and first computed tomography (CT) of the head by more than ten minutes. Methods This retrospective study included patients 18 years and older with isolated severe TBI and prehospital induction of emergency anaesthesia who received treatment in the resuscitation room of the University Hospital of Graz between January 1st, 2015, and December 31st, 2022. A Wilcoxon rank-sum test was used to test for non-inferiority (margin = ten minutes) of the time interval between on-scene arrival and first head CT. Results We included data of 181 patients in the final analysis. Prehospital arterial line insertion was performed in 87 patients (48%). Median (25–75th percentile) durations between on-scene arrival and first head CT were 73 (61–92) min for prehospital arterial cannulation and 75 (60–93) min for arterial cannulation in the resuscitation room. Prehospital arterial line insertion was significantly non-inferior within a margin of ten minutes with a median difference of 1 min (95% CI − 6 to 7, p = 0.003). Conclusion Time-interval between on-scene arrival and first head CT in patients with isolated severe traumatic brain injury who received prehospital arterial cannulation was not prolonged compared to those with in-hospital cannulation. This supports early out-of-hospital arterial cannulation performed by experienced providers.

Background: During the post-World War II occupation of Austria, approximately 20,000–30,000 ‘children born of war’ (CBOW), also called occupation children were born through intimate contacts between Austrian women and occupation soldiers. Research on other CBOW populations indicates that CBOW mostly grow up under difficult conditions, sometimes with strong long-term mental health consequences.Objective: To examine whether comparable psychosocial consequences can be found in Austrian occupation children (AOC), a first quantitative study was carried out.Method: Child maltreatment, post-traumatic stress disorder, depression and somatization, and general life satisfaction were assessed in a sample of 98 AOC using self-report instruments. Results were compared to a sample of German occupation children (GOC; N = 146).Results: High prevalence of above threshold full (10.2%) and partial (14.3%) PTSD, somatic (16.3%) and depressive (11.1%) symptomatology were found in AOC. They were at high risk of child maltreatment (e.g. emotional abuse: 53.6%), which was associated with current symptomatology. Notably, AOC tended to report high levels of general life satisfaction. No differences were found between GOC and AOC.Conclusions: Findings highlight the complex and long-term effects of developmental conditions and childhood maltreatment on mental health of CBOW, even decades later. Findings of high life satisfaction provide evidence of resilience and maturation processes across the lifespan.

BackgroundLoiasis is a disease of relevance in endemic populations and there has been advocacy for its inclusion on the World Health Organization's neglected tropical diseases list. As loiasis-related healthcare-seeking behaviors and related costs are unknown, we aimed to evaluate these aspects in a population residing in an endemic region in Gabon.MethodsData were collected during a community-based, cross-sectional study assessing the disease burden due to loiasis. Diagnostics for microfilaremia were performed and a history of eyeworm was obtained. In addition, a standardized questionnaire about type of healthcare resources and frequency of use, as well as respective associated costs was administered to each participant. Loiasis related healthcare-seeking behaviors were evaluated, and the associated monetary burden was estimated as a secondary outcome of the study.FindingsIndividuals diagnosed with loiasis more frequently reported any healthcare-seeking (OR 1.52 (95%CI: 1.21-1.91)), self-medicating (OR 1.62 (1.26-2.08)), inability to work (OR 1.86 (1.47-2.35)), and consulting with traditional healers (logOdds 1.03 (0.52-1.53)), compared to loiasis negative individuals. The most frequently reported treatment for the eyeworm was traditional herbs. The estimated healthcare associated costs, per positive individual, was US-$ 58 (95% CI: 21-101) per year, which would correspond to 3.5% of the reported mean household income. Extrapolation to the rural population of Gabon (n = 204,000), resulted in an annual monetary burden estimate of US-$ 3,206,000 (1,150,000-5,577,000).InterpretationLoiasis patients have demonstrated healthcare needs, often consulted traditional healers, and used traditional treatments for disease specific symptoms. Further, loiasis seems to be associated with substantial direct and indirect costs for individuals and thus may cause a relevant economic burden for endemic populations and economies of affected countries.

Abstract ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.

Abstract Eukaryotic gene regulation and pre-mRNA transcription depend on the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II. Due to its highly repetitive, intrinsically disordered sequence, the CTD enables clustering and phase separation of Pol II. The molecular interactions that drive CTD phase separation and Pol II clustering are unclear. Here, we show that multivalent interactions involving tyrosine impart temperature- and concentration-dependent self-coacervation of the CTD. NMR spectroscopy, molecular ensemble calculations and all-atom molecular dynamics simulations demonstrate the presence of diverse tyrosine-engaging interactions, including tyrosine-proline contacts, in condensed states of human CTD and other low-complexity proteins. We further show that the network of multivalent interactions involving tyrosine is responsible for the co-recruitment of the human Mediator complex and CTD during phase separation. Our work advances the understanding of the driving forces of CTD phase separation and thus provides the basis to better understand CTD-mediated Pol II clustering in eukaryotic gene transcription.

Abstract Background Breastfeeding provides the optimal nutrition for infants and offers numerous benefits for both mother and child. The World Health Organisation recommends exclusive breastfeeding during the first 6 months of life and the introduction of complementary feeding between the fifth and seventh months of life. There is a discrepancy between breastfeeding recommendations and the actual duration of breastfeeding. The aim of this study was to analyse breastfeeding behaviour in primiparous women in order to be able to provide support for mothers. Methods In this prospective, questionnaire-based study conducted between 2020 and 2022, primiparous women were asked to complete three questionnaires at three defined survey time points (routine prepartum presentation, postpartum hospitalization, completed sixth month of life). Results A total of 140 women were included and returned all three questionnaires. Fifty-eight percent performed breastfeeding exclusively at least until their baby had reached the age of 6 months, whereas 20% already stopped within the first 6 months. The main reasons given for early cessation were insufficient milk supply and inadequate infant weight gain. A comprehensive level of prepartum knowledge had a significant positive effect on participants’ sense of confidence with breastfeeding. Sociodemographic factors such as age and educational level were also associated with breastfeeding behaviour, but significant corresponding differences in the duration of breastfeeding were not observed. Women with postpartum midwifery care breastfed significantly longer (p

BackgroundThe parasitic disease loiasis is associated with significant morbidity and mortality. Individuals with hyper-microfilaremia (greater than 20,000 microfilariae per mL of blood) may suffer from serious treatment-related or spontaneous adverse events. Diagnosing loiasis remains complex and primarily relies on direct parasite detection. In this study, we analyzed the performance of various diagnostic tests and the influence of parasitological and clinical factors on test outcomes in samples from individuals living in an endemic region.MethodsData and samples were collected from rural Gabon. Loiasis was defined as either detectable microfilaremia, or a positive history of eyeworm as assessed by the RAPLOA questionnaire. Diagnostic testing included a quantitative PCR (qPCR) for detection of Loa loa DNA in blood samples, an in-house crude L. loa antigen IgG ELISA, and a rapid test for antibodies against the Ll-SXP-1 antigen (RDT). Sensitivity and specificity were determined for each test and factors potentially influencing outcomes were evaluated in an exploratory analysis.ResultsELISA, RDT and qPCR results were available for 99.8%, 78.5%, and 100% of the 1,232 participants, respectively. The ELISA and RDT had only modest diagnostic accuracy. qPCR was specific for L. loa microfilaremia and Cycle threshold values correlated with microfilarial density. Anti-L. loa IgG levels were highest in occult loiasis, and antibody levels correlated inversely with L. loa microfilarial density as did RDT line intensities. Only 84.6% and 16.7% of hyper-microfilaremic individuals tested positive by ELISA (11/13) and RDT (2/12), respectively.ConclusionNone of the tests demonstrated high sensitivity and specificity for loiasis. Indirect diagnostic assays were characterized by low specificity. Additionally, hyper-microfilaremic individuals often tested negative by RDT and ELISA, indicating that these tests are not suitable for individual case management in endemic populations.

The European research area exhibits considerable opacity and fragmentation in food safety research funding and organizational structures, impeding the exploitation of existing research potential across European countries. Given that food safety is inherently linked to the societal challenges of our time, identifying and removing existing barriers to research funding in this area is crucial. Towards investigating this matter, interviews were conducted with funding bodies from six European countries to assess key issues related to research funding in general and food safety in particular. Funding experts were then invited to a workshop to jointly discuss the challenges identified and explore strategies to address them. Evaluation of the food safety research funding situation in selected European countries revealed both convergences and significant differences among national funding bodies. Engaging with funding experts provided invaluable insights into the issues encountered with research funding, such as inadequate call management staff or insufficient research funds, culminating in a set of recommendations for action to remedy the situation.

Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to be recognized by the BBSome.

ABSTRACT The BBSome is a complex of eight Bardet-Biedl Syndrome (BBS) proteins that removes signaling receptors from cilia. The GTPase ARL6/BBS3 recruits the BBSome to the ciliary membrane where the BBSome–ARL6 GTP complex ferries G protein-coupled receptors (GPCRs) across the transition zone, a diffusion barrier at the base of cilia. Here, we find that the BBSome undergoes a conformational change upon recruitment to membranes by ARL6 GTP . Modeling the binding of the BBSome to membranes and to the GPCR Smoothened (SMO) reveals that the amphipathic helix 8 of SMO must be released from the membrane for SMO to be recognized by the BBSome. Underscoring the functional importance of amphipathic helix extraction in TZ crossing, we find that exchanging the amphipathic helix of ARL6 for one that embeds deeper into the membrane blocks BBSome-mediated exit of GPCRs from cilia. We propose that the rigid curvature and dense lipid packing of the transition zone reject asymmetric insertions in the inner leaflet and that the BBSome licenses transition zone crossing by extracting bulky amphipathic helices from the inner leaflet.

The frequency of clinically relevant transmitted drug resistance mutations (DRMs) against drugs used for 2-drug regimens was 15.6%, but only 2% were not eligible for 1 or more 2-drug regimens. More than 50% of patients harboring any clinically relevant DRMs were found to be part of genetic transmission clusters.

The frequency of clinically relevant transmitted drug resistance mutations (DRMs) against drugs used for 2-drug regimens was 15.6%, but only 2% were not eligible for 1 or more 2-drug regimens. More than 50% of patients harboring any clinically relevant DRMs were found to be part of genetic transmission clusters.

The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.

IntroductionThe European research landscape suffers widely from fragmentation and little cross-border research collaboration. Efforts are underway to bring the European Research Area to a higher level of performance and capacity in cutting-edge science, with high anticipations for the promotion of multidisciplinary research infrastructures of transnational engagement. A European distributed research infrastructure active in this framework is METROFOOD-RI, committed to promoting metrology in food and nutrition with particular focus on measurement research related to agrifood systems.MethodsFor research infrastructures, streamlining resources among partner organizations and establishing priorities around specific topics is critical for ensuring smooth operation. Similarly, METROFOOD-RI faced the challenge of exploring its strategic direction and research priorities as revealed in its first Strategic Research and Innovation Agenda (SRIA). This report details how the internal process of topic identification and prioritization progressed within the METROFOOD-RI SRIA and what obstacles were encountered along the way. A dual-track strategy was taken for locating future SRIA topics, applying a top-down and bottom-up approach, followed by internal consultation with METROFOOD-RI experts. The topic prioritization drew on a vote among the METROFOOD-RI Management Committee employing a custom-designed numerical rating scale questionnaire. Based on the maximum scores obtained for each topic, appropriate thresholds were introduced for classifying individual topics into high, medium, low, and very low priority ones.ResultsA total of 80 topics categorized into eight major clusters of challenges were located as potential SRIA candidates. Upon prioritization, 9 topics of very high priority and 16 topics of medium priority were identified as key research thematic areas of the newly developed SRIA.DiscussionAs a strategic framework, the SRIA occupies a central position and sets not only the scientific focus of the research infrastructure in the coming years, but also contributes to realizing the full potential and excellence of METROFOOD-RI, selectively expanding the existing portfolio and thus contributing to maximum efficiency and sustainability. It is anticipated that the lessons learned by METROFOOD-RI and its experiences shared are a valuable stimulus and guide for those who are taking on the challenge of setting-up a SRIA and are looking for edifying and constructive information on how to do so.

Abstract Finite density effects can destabilize the metastable vacua in relaxion models. Focusing on stars as nucleation seeds, we derive the conditions that lead to the formation and runaway of a relaxion bubble of a lower energy minimum than in vacuum. The resulting late-time phase transition in the universe allows us to set new constraints on the parameter space of relaxion models. We also find that similar instabilities can be triggered by the large electromagnetic fields around rotating neutron stars.

Abstract Protein kinases play an important role in cellular signaling pathways and their dysregulation leads to multiple diseases, making kinases prime drug targets. While more than 500 human protein kinases are known to collectively mediate phosphorylation of over 290,000 S/T/Y sites, the activities have been characterized only for a minor, intensively studied subset. To systematically address this discrepancy, we developed a human kinase array in Saccharomyces cerevisiae as a simple readout tool to systematically assess kinase activities. For this array, we expressed 266 human kinases in four different S. cerevisiae strains and profiled ectopic growth as a proxy for kinase activity across 33 conditions. More than half of the kinases showed an activity‐dependent phenotype across many conditions and in more than one strain. We then employed the kinase array to identify the kinase(s) that can modulate protein–protein interactions (PPIs). Two characterized, phosphorylation‐dependent PPIs with unknown kinase–substrate relationships were analyzed in a phospho‐yeast two‐hybrid assay. CK2α1 and SGK2 kinases can abrogate the interaction between the spliceosomal proteins AAR2 and PRPF8, and NEK6 kinase was found to mediate the estrogen receptor (ERα) interaction with 14‐3‐3 proteins. The human kinase yeast array can thus be used for a variety of kinase activity‐dependent readouts.

Abstract Bioprinting is increasingly used to create complex tissue constructs for an array of research applications, and there are also increasing efforts to print tissues for transplantation. Bioprinting may also prove valuable in the context of drug screening for personalized medicine for treatment of diseases such as cancer. However, the rapidly expanding bioprinting research field is currently limited by access to bioprinters. To increase the availability of bioprinting technologies we present here an open source extrusion bioprinter based on the E3D motion system and tool changer to enable high-resolution multimaterial bioprinting. As proof of concept, the bioprinter is used to create collagen constructs using freeform reversible embedding of suspended hydrogels (FRESH) methodology, as well as multimaterial constructs composed of distinct sections of laminin and collagen. Data is presented demonstrating that the bioprinted constructs support growth of cells either seeded onto printed constructs or included in the bioink prior to bioprinting. This open source bioprinter is easily adapted for different bioprinting applications, and additional tools can be incorporated to increase the capabilities of the system.