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Abstract Drug discovery often involves targeting specific members within a family of similar proteins. For example, pyruvate dehydrogenase kinase (PDHK) exists as four isozymes, which exhibit varying expression patterns across multiple tissues. Different PDHK isozymes have been implicated in conditions such as cancer, heart failure, and diabetes, suggesting that targeting them with inhibitors may offer therapeutic benefits. However, simultaneous inhibition of all four PDHK isozymes has the potential to be counterproductive, or poorly tolerated, highlighting a need for isoform-selective PDHK inhibitors. Despite multiple prior reports of PDHK inhibitors, identifying isoform-specific inhibitors for each PDHK isozyme has proven elusive. In this work, we propose a comprehensive framework that combines a machine learning-based prediction method and biochemical testing to screen a library of novel and previously reported compounds, thereby identifying selective inhibitors for PDHK isozymes. Initially, a coupled tensor matrix completion (CTMC) approach is employed to predict compound-target interaction (CTI) and pinpoint target-specific inhibitors. Subsequently, biochemical testing is performed to validate the predicted CTIs. Utilizing this approach, we successfully identified five novel PDHK1-specific inhibitors, underscoring the reliability of this approach as a screening method in the early stages of drug discovery and hit identification.

Abstract White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1’s function during differentiation. These findings underscore PATZ1’s regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.

Abstract Despite the variety in sequencing platforms, mappers, and variant callers, no single pipeline is optimal across the entire human genome. Therefore, developers, clinicians, and researchers need to make tradeoffs when designing pipelines for their application. Currently, assessing such tradeoffs relies on intuition about how a certain pipeline will perform in a given genomic context. We present StratoMod, which addresses this problem using an interpretable machine-learning classifier to predict germline variant calling errors in a data-driven manner. We show StratoMod can precisely predict recall using Hifi or Illumina and leverage StratoMod’s interpretability to measure contributions from difficult-to-map and homopolymer regions for each respective outcome. Furthermore, we use Statomod to assess the effect of mismapping on predicted recall using linear vs. graph-based references, and identify the hard-to-map regions where graph-based methods excelled and by how much. For these we utilize our draft benchmark based on the Q100 HG002 assembly, which contains previously-inaccessible difficult regions. Furthermore, StratoMod presents a new method of predicting clinically relevant variants likely to be missed, which is an improvement over current pipelines which only filter variants likely to be false. We anticipate this being useful for performing precise risk-reward analyses when designing variant calling pipelines.

Abstract Mucopolysaccharidoses are inherited metabolic disorders caused by the deficiency in lysosomal enzymes required to break down glycosaminoglycans. Accumulation of glycosaminoglycans leads to progressive, systemic degenerative disease. The central nervous system is particularly affected, resulting in developmental delays, neurological regression, and early mortality. Current treatments fail to adequately address neurological defects. Here we explore the potential of human induced pluripotent stem cell (hiPSC)-derived microglia progenitors as a one-time, allogeneic off-the-shelf cell therapy for several mucopolysaccharidoses (MPS). We show that hiPSC-derived microglia progenitors, possessing normal levels of lysosomal enzymes, can deliver functional enzymes into four subtypes of MPS knockout cell lines through mannose-6-phosphate receptor-mediated endocytosis in vitro. Additionally, our findings indicate that a single administration of hiPSC-derived microglia progenitors can reduce toxic glycosaminoglycan accumulation and prevent behavioral deficits in two different animal models of MPS. Durable efficacy is observed for eight months after transplantation. These results suggest a potential avenue for treating MPS with hiPSC-derived microglia progenitors.

BackgroundThe posttranslational modification of cellular macromolecules by glycosylation is considered to contribute to disease pathogenesis in autoimmune and inflammatory conditions. In a subgroup of patients with common variable immunodeficiency (CVID), the occurrence of such complications is associated with an expansion of naïve-like CD21low B cells during a chronic type 1 immune activation. The glycosylation pattern of B cells in CVID patients has not been addressed to date.ObjectiveThe objective of this study was to examine the surface glycome of B cells in patients with CVID and associated immune dysregulation.MethodsWe performed surface lectin staining on B cells from peripheral blood and tonsils, both ex vivo and after in vitro stimulation. Additionally, we examined the expression of glycosylation-related genes by RNAseq in naïve-like CD21low B cells ex vivo, as well as in naïve CD21pos B cells from healthy controls after in vitro stimulation.ResultsUnlike CD21pos B cells, naïve-like CD21low B cells from CVID patients and CD21low B cells from healthy controls exhibited a unique glycosylation pattern with high levels of α2,6 sialic acids and fucose. This hypersialylation and hyperfucosylation were particularly induced by activation with anti-IgM and interferon-γ (IFN-γ). Transcriptome analysis suggested that naïve-like CD21low B cells possess a comprehensively reorganised glycosylation machinery, with anti-IgM/IFN-γ having the potential to initiate these changes in vitro.ConclusionCD21low B cells are hypersialylated and hyperfucosylated. This may implicate altered lectin-ligand interactions on the cell surface potentially affecting the CD21low B-cell function. These glycome changes appear to be driven by the prominent type I immune response in complicated CVID patients. A better understanding of how altered glycosylation influences immune cell function could lead to new therapeutic strategies.

Category: Trauma; Basic Sciences/Biologics Introduction/Purpose: A variable pitch locking screw is intended to provide interfragmentary compression combined with fixed angle stability of locking plate constructs. The objective of this study was to compare variable pitch locking screws with standard locking screws in bicortical fixation scenarios in cadaver bone, by assessing: (1) interfragmentary compression and plate-bone compression; and (2) construct biomechanical stability. Methods: Nine matched pairs of fresh-frozen cadaveric specimens were used to compare variable pitch locking screws and standard locking screws. First, interfragmentary compression and plate-bone compression associated with insertion of single bicortical screws at increasing levels of torque were measured in distal tibiae having a simulated longitudinal fracture. Second, fibulae were osteotomized to create a stable fracture pattern, fixed with five-screw plated constructs, and tested in either cyclic axial and torsional loading or four-point bending. Results: Interfragmentary and plate-bone compression forces were significantly higher with variable pitch locking screws compared to standard locking screws (p =0.002 & p=0.028, respectively). The amount of compression was variable across specimens. In cyclic loading of fibula constructs, no significant differences were detected in construct axial displacement or angular displacement. In four-point bending, no differences were detected in maximum force or bending stiffness. Conclusion: Variable pitch locking screws can produce high interfragmentary compression between cortices, along with moderate plate-bone compression. In a stable bicortical fixation scenario under external loading, construct stability was similar to normal locking screws.

Background The COVID-19 pandemic posed severe challenges to delivery of services at Primary Care level and for achieving follow-up of patients with chronic diseases.Objectives We analysed data from the PRICOV-19 study to explore determinants of active follow-up for chronic disease patients in seven Central and Eastern European (CEE) countries during the pandemic.Methods Pricov-19 was a cross-sectional study conducted within PC (Primary Care) practices in 37 European countries. We analysed data from 7 CEE countries (Bulgaria, Czech Republic, Hungary, Poland, Moldova, Romania, Ukraine) collected between November 2020 and December 2021. Practices were recruited through random or convenience sampling and participation of practices was voluntary. We performed descriptive statistics to identify the level of follow-up of chronic disease and what health system and practice-specific factors were associated with better follow-up. We used logistic regression and meta-analysis techniques to explore associations and heterogeneity between countries.Results 67.8% out of 978 practices reported actively following up chronic patients. Positive associations were found between active follow-up and such as having more GPs (aOR = 1.18, p-value = 0.005), an above-average chronic patient population (aOR = 3.13, p-value = 0.006), adequate government support (aOR = 2.35, p-value = 0.001), and GPs having time for guideline reading (aOR = 0.008, p-value = 1.71).Conclusions Patient follow-up, was influenced by different health system and practice-specific factors. The implications suggest the need for government support to enhance PC practice organisation during crises and solutions to decrease GP workload and provide tailored care for patients with chronic disease.

Abstract This study investigates the possibility of increasing the radiation efficiency of printed antennas and arrays by suppressing their inherent surface waves using a metasurface made of quad-split rings (QSR). A symmetrical resonant microstrip dipole and a four-element series-fed dipole array printed on an infinite grounded dielectric layer (layer thickness: 0.2 mm; relative permittivity: 9.4; tanδ: 0.0005) were simulated with FEKO 2022 software. Conducted at 100–116 GHz, the numerical results revealed extremely low radiation efficiencies of approximately 31% and 40% for the studied dipole and dipole array, respectively, which resulted from the presence of surface waves in the dielectric. However, placing only one QSR near each dipole arm triggered an increase in radiation efficiency by 2.5 times (up to 75%). The use of a metasurface in the form of two small QSR arrays triggered a pronounced improvement in radiation efficiency, reaching 93.6% and 95.8% for the studied dipole and dipole array, respectively. Analysis of the electric field distribution images showed that this enhancement resulted from surface wave suppression.

Abstract Background Tension band wire fixation (TBW) is a well-described method for treating displaced olecranon fractures. Further surgery is often needed due to wound breakdown or prominent hardware. An all-suture technique has recently been described as an alternative to TBW but radiographic and clinical outcome are not well established. The aim of this single-center retrospective cohort study was to evaluate outcome after treatment with all-suture technique for simple displaced olecranon fractures. Methods A retrospective review of olecranon fractures in patients (> 18 years) treated for displaced olecranon fractures with tension band suture fixation (TBSF) between February and August 2019 was performed in our facility. Primary outcome was revision surgery, which was assessed four years after surgery. Clinical and radiographical follow-up was performed at two weeks, six weeks, three months and six months to assess union rate, fracture displacement, range of motion (ROM), Quick-DASH and Oxford Elbow Score. Results A total of 24 patients were included. Median age was 64 years [IQR:39–73], 9 patients were male and median ASA score was 2 [IQR:1–2]. 15 fractures were Mayo type 2 A and 9 type 2B with minor comminution. At four-year follow-up, three patients had died. None of the remaining 21 patients had undergone revision surgery. At six months, the median Quick-DASH and Oxford Elbow Score were 2.3 [IQR:0-4.5] and 47 [IQR:46–48], respectively. Median elbow extension and flexion deficits were 0° [IQR:0-2.25] and 0° [IQR:0–0], respectively. Radiographic union was achieved in all patients. In two cases radiographic loss of reduction and malunion was observed but both patients were asymptomatic and had no functional deficits. One patient refractured the elbow due to a second trauma and was reoperated. Conclusions TBSF is a promising technique for Mayo type 2 A and 2B fractures with minor comminution. There were no revision surgeries within the first four years. We found good functional outcomes and a high union rate.

Abstract The value of luxury goods, particularly investment-grade gemstones, is influenced by their origin and authenticity, often resulting in differences worth millions of dollars. Traditional methods for determining gemstone origin and detecting treatments involve subjective visual inspections and a range of advanced analytical techniques. However, these approaches can be time-consuming, prone to inconsistencies, and lack automation. Here, we propose GEMTELLIGENCE, a novel deep learning approach enabling streamlined and consistent origin determination of gemstone origin and detection of treatments. GEMTELLIGENCE leverages convolutional and attention-based neural networks that combine the multi-modal heterogeneous data collected from multiple instruments. The algorithm attains predictive performance comparable to expensive laser-ablation inductively-coupled-plasma mass-spectrometry analysis and expert visual examination, while using input data from relatively inexpensive analytical methods. Our methodology represents an advancement in gemstone analysis, greatly enhancing automation and robustness throughout the analytical process pipeline.

Abstract Consensus holds that pottery technology came to Central Europe from the Northern Balkans with independent pottery traditions existing concurrently in Eastern Europe. An unusual grass-tempered pottery dating back to around 5800 cal BC found in lake sediments at Santovka, Slovakia, predated the earliest known Neolithic pottery in the region (~ 5500 cal BC), suggesting unexplored narratives of pottery introduction. Analyses of the pottery’s technology, origin, and grass temper shedding light on ceramic traditions' spread can unveil mobility patterns and community lifestyles. Our findings indicate a non-local provenance, low temperature firing, Festuca sp. grass temper and unique rectangular or cylindrical vessel shapes which align with Eastern European hunter-gatherer practices. Moreover, the pottery style and technology have no analogies in the contemporary Danubian pottery traditions and have more similarities to those of the Eastern traditions. The pottery's raw materials likely originated from distant areas, indicating extensive territorial access for its creators. Our findings imply late Mesolithic hunter-gatherers as the probable artisans and with implications for the site's significance in the late Mesolithic landscape.

Abstract Natural selection can drive organisms to strikingly similar adaptive solutions, but the underlying molecular mechanisms often remain unknown. Several amphibians have independently evolved highly adhesive skin secretions (glues) that support a highly effective antipredator defence mechanism. Here we demonstrate that the glue of the Madagascan tomato frog, Dyscophus guineti, relies on two interacting proteins: a highly derived member of a widespread glycoprotein family and a galectin. Identification of homologous proteins in other amphibians reveals that these proteins attained a function in skin long before glues evolved. Yet, major elevations in their expression, besides structural changes in the glycoprotein (increasing its structural disorder and glycosylation), caused the independent rise of glues in at least two frog lineages. Besides providing a model for the chemical functioning of animal adhesive secretions, our findings highlight how recruiting ancient molecular templates may facilitate the recurrent evolution of functional innovations.

Switches & crossings (S&Cs) are vital assets as they allow for increased railway capacity by introducing flexibility and connectivity in railway networks. At the same time, this makes them critical since they can cause costly delays and disruptions if they are not well maintained. This motivates studies to improve maintenance strategies of S&Cs, considering both the life-cycle costs (LCC) of the assets and socio-economic transportation costs for passengers and freight customers. In this paper, the interdependence between deterioration mechanisms, maintenance activities, and expected LCC (including transportation costs) is investigated using a combination of mechanical and econometric modelling. The interrelation between the degradation of contact geometry and track settlement is analysed using simulations of dynamic vehicle–turnout interaction. Long-term mechanical degradation of the S&C is simulated for different maintenance strategies that correspond to different timing of the associated maintenance measures (crossing repair welding and tamping). This provides the basis for analysing the interdependence between preventive and corrective activities using econometric modelling. Based on a case study of a common type of S&Cs in the Swedish infrastructure, the impact of different maintenance strategies on LCC and transportation costs is analysed. Opportunities and challenges in the development of more socio-economically effective maintenance strategies of S&Cs are discussed.

Open ecosystems occur all around the world in various forms including temperate and tropical grasslands, savannas, shrublands, heathlands, among others. They are home to unique biodiversity, provide key ecosystem services and sustain traditional livelihoods of nearly two billion people. In the face of ongoing climate change, practitioners aiming to restore open ecosystems need the support of the scientific community more than ever. The aim of this Special Issue (SI) is to provide an attention-grabbing collection of high-quality publications addressing the growing challenges of open ecosystems restoration. The SI contains 14 papers that fill various, often interdisciplinary knowledge gaps. Three papers deal with the challenges of identifying the right target states, including the genetic composition of constituting plant species, for restoration under changing environmental conditions and competing stakeholder interests. Five papers advance our understanding on the appropriate timing and methodological toolkit to actively ignite re-assembly of the target plant communities, while two papers focus on situations where spontaneous processes can still also be relied on. The interaction of open ecosystems health and recovery with higher trophic levels, particularly grazers, is also discussed in three papers. Finally, a review paper systematically identifies further knowledge gaps, such as the role of soil microbes in grassland recovery and makes clear guidelines how to fill them. Due to the variety of topics and the rigorous content, this SI provides strong support for open ecosystems restoration policy and practice under the UN Decade on Ecosystem Restoration and beyond.

Common ragweed - Ambrosia artemisiifolia L. (Asteraceae) is an invasive plant species in Europe native to North America. Most of the records of known eriophyid mites on different ragweed species are from their native range. Our field experiments in Slovakia, 2016-2023, aimed to identify specific species feeding on common ragweed. We searched for symptomatic plants and collected growing tips, which were then preserved in 70% ethanol for further study. A recently described species of eriophyid mite, Aceria artemisiifoliae Vidović & Petanović (Acari: Eriophyoidea), was found in western and eastern Slovakia. This is the first record of the species in Slovakia and the second record in the world. It remains unclear whether this species is invasive like Ambrosia, and whether it could be used as a potential biological control agent.

The thymus plays a pivotal role in generating a highly-diverse repertoire of T lymphocytes while preventing autoimmunity. Thymus seeding progenitors (TSPs) are a heterogeneous group of multipotent progenitors that migrate to the thymus via CCR7 and CCR9 receptors. While NOTCH guides thymus progenitors toward T cell fate, the absence or disruption of NOTCH signaling renders the thymus microenvironment permissive to other cell fates. Following T cell commitment, developing T cells undergo multiple selection checkpoints by engaging with the extracellular matrix, and interacting with thymic epithelial cells (TECs) and other immune subsets across the different compartments of the thymus. The different selection checkpoints assess the T cell receptor (TCR) performance, with failure resulting in either repurposing (agonist selection), or cell death. Additionally, environmental cues such as inflammation and endocrine signaling induce acute thymus atrophy, contributing to the demise of most developing T cells during thymic selection. We discuss the occurrence of acute thymus atrophy in response to systemic inflammation. The thymus demonstrates high plasticity, shaping inflammation by abrogating T cell development and undergoing profound structural changes, and facilitating regeneration and restoration of T cell development once inflammation is resolved. Despite the challenges, thymic selection ensures a highly diverse T cell repertoire capable of discerning between self and non-self antigens, ultimately egressing to secondary lymphoid organs where they complete their maturation and exert their functions.

Abstract Far-UVC light in the wavelength range of 200–230 nm has attracted renewed interest because of its safety for human exposure and effectiveness in inactivating pathogens. Here we present a compact solid-state far-UVC laser source based on second-harmonic generation (SHG) using a low-cost commercially-available blue laser diode pump. Leveraging the high intensity of light in a nanophotonic waveguide and heterogeneous integration, our approach achieves Cherenkov phase-matching across a bonded interface consisting of a silicon nitride (SiN) waveguide and a beta barium borate (BBO) nonlinear crystal. Through systematic investigations of waveguide dimensions and pump power, we analyze the dependencies of Cherenkov emission angle, conversion efficiency, and output power. Experimental results confirm the feasibility of generating far-UVC, paving the way for mass production in a compact form factor. This solid-state far-UVC laser source shows significant potential for applications in human-safe disinfection, non-line-of-sight free-space communication, and deep-UV Raman spectroscopy.

Abstract Background The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies. Methods A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted. Results A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak). Conclusions This consensus provides practical recommendations to support a clinician’s decision making in the management of tSCI polytrauma patients.

Rail transport is expected to become a key component in the development of a long-term sustainable transport system. The planning, construction, operation, and maintenance of railway infrastructure are crucial in this effort. Hence, it is essential to ascertain that the railway infrastructure withstands and is adapted to extreme weather conditions and climate change. This study focuses on evaluating climate adaptation measures for lateral track buckling in Sweden. Through a literature review and interview with an expert at Swedish Transport Administration, it is highlighted that the maintenance status of railway infrastructure plays a significant role in the occurrence of lateral track buckling. According to the expert, inadequate track maintenance is the primary cause of lateral track buckling rather than weather variables like air temperature. The interview also clarifies that the chain of events related to the handling of track buckling is mainly initiated by the observation of a discrete lateral irregularity by a train driver, whereupon the train dispatcher at the traffic management center stops traffic until the location in the track has been inspected by a track entrepreneur. During the inspection, up to half of the observed cases of track buckling turn out to be false.

Abstract The essential G1-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G1-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2BS14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2BS14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.

Abstract Impaired cerebrovascular function contributes to the genesis of age‐related cognitive decline. In this study, the hypothesis is tested that impairments in neurovascular coupling (NVC) responses and brain network function predict cognitive dysfunction in older adults. Cerebromicrovascular and working memory function of healthy young (n = 21, 33.2±7.0 years) and aged (n = 30, 75.9±6.9 years) participants are assessed. To determine NVC responses and functional connectivity (FC) during a working memory (n‐back) paradigm, oxy‐ and deoxyhemoglobin concentration changes from the frontal cortex using functional near‐infrared spectroscopy are recorded. NVC responses are significantly impaired during the 2‐back task in aged participants, while the frontal networks are characterized by higher local and global connection strength, and dynamic FC (p < 0.05). Both impaired NVC and increased FC correlate with age‐related decline in accuracy during the 2‐back task. These findings suggest that task‐related brain states in older adults require stronger functional connections to compensate for the attenuated NVC responses associated with working memory load.

Abstract Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and their implications for histopathological parameters and prognosis in TGCT using a data-driven explorative approach. Pre-surgery serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) and prolactin were measured in a retrospective multicenter TGCT cohort (n = 518). Clusters of patients were defined by latent class analysis. Clinical, pathologic and survival parameters were compared between the clusters by statistical hypothesis testing, Random Forest modeling and Peto-Peto test. Cancer tissue expression of sex hormone-related genes was explored in the publicly available TCGA cohort (n = 149). We included 354 patients with pure seminoma and 164 patients with non-seminomatous germ cell tumors (NSGCT), with a median age of 36 years. Three hormonal clusters were defined: ‘neutral’ (n = 228) with normal sex hormone homeostasis, ‘testicle’ (n = 91) with elevated T and E2, low pituitary hormones, and finally ‘pituitary’ subset (n = 103) with increased FSH and LH paralleled by low-to-normal levels of the gonadal hormones. Relapse-free survival in the hormonal subsets was comparable (p = 0.64). Cancer tissue expression of luteinizing hormone- and follicle-stimulating hormone-coding genes was significantly higher in seminomas, while genes of T and E2 biosynthesis enzymes were strongly upregulated in NSGCT. Substantial percentages of TGCT patients are at increased risk of sex hormone dysfunction at primary diagnosis before orchiectomy. TGCT may directly influence systemic hormonal homeostasis by in-situ synthesis of sex hormones.

Abstract Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand‐dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF‐κB and type‐I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis‐regulatory regions including enhancers. LXRα‐deficient macrophages present fewer binding of p65 NF‐κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo‐MHC‐IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα‐dependent transcriptional cis‐activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.

IntroductionSchool-aged children experience crucial developmental changes in white matter (WM) in adolescence. The human immunodeficiency virus (HIV) affects neurodevelopment. Children living with perinatally acquired HIV (CPHIVs) demonstrate hearing and neurocognitive impairments when compared to their uninfected peers (CHUUs), but investigations into the central auditory system (CAS) WM integrity are lacking. The integration of the CAS and other brain areas is facilitated by WM fibers whose integrity may be affected in the presence of HIV, contributing to neurocognitive impairments.MethodsWe used diffusion tensor imaging (DTI) tractography to map the microstructural integrity of WM between CAS regions, including the lateral lemniscus and acoustic radiation, as well as between CAS regions and non-auditory regions of 11-year-old CPHIVs. We further employed a DTI-based graph theoretical framework to investigate the nodal strength and efficiency of the CAS and other brain regions in the structural brain network of the same population. Finally, we investigated associations between WM microstructural integrity outcomes and neurocognitive outcomes related to auditory and language processing. We hypothesized that compared to the CHUU group, the CPHIV group would have lower microstructural in the CAS and related regions.ResultsOur analyses showed higher mean diffusivity (MD), a marker of axonal maturation, in the lateral lemniscus and acoustic radiations, as well as WM between the CAS and non-auditory regions predominantly in frontotemporal areas. Most affected WM connections also showed higher axial and radial diffusivity (AD and RD, respectively). There were no differences in the nodal properties of the CAS regions between groups. The MD of frontotemporal and subcortical WM-connected CAS regions, including the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and internal capsule showed negative associations with sequential processing in the CPHIV group but not in the CHUU group.DiscussionThe current results point to reduced axonal maturation in WM, marked by higher MD, AD, and RD, within and from the CAS. Furthermore, alterations in WM integrity were associated with sequential processing, a neurocognitive marker of auditory working memory. Our results provide insights into the microstructural integrity of the CAS and related WM in the presence of HIV and link these alterations to auditory working memory.

Background: To retrospectively investigate scatter radiation (SCR) exposure among staff in the endourology operating theatre. Methods: During surgeries under fluoroscopic guidance, five professional groups (urological surgeon [US], surgical nurse [SN], assistant surgical nurse [ASN], anaesthetist [A], and anaesthesia care [AC]) wore real-time dosimeters (Philips DoseAware System) on their head and chest over lead aprons between July 2023 and February 2024. The SCR data were analysed and correlated with procedural and patient factors. Results: In total, 249 procedures were performed, including 86 retrograde intrarenal surgeries and 10 percutaneous nephrolithotomies. Median SCR exposure was 38.81, 17.20, 7.71, 11.58, 0.63, 0.23, 0.12, and 0.15 Microsievert (µSv) for US chest (USC), US head (USH), SN chest (SNC), SN head (SNH), A chest (AC), AC chest (ACC), ASN chest (ASNC), and ASN head (ASNH), respectively. There was a significant correlation between DAP and SCR doses detected by USC, USH, SNC, SNH, AC, and ACC dosimeters (p < 0.05). The median chest-to-eye conversion factor (CECF) was 2.11 for the US and 0.71 for the SN. Conclusions: This study, using real-time dosimetry, is among the first to assess staff occupational SCR exposure in endourology. It highlights a substantial SCR exposure, indicating an occupational health hazard that warrants further investigation.

Tauopathies, a group of neurodegenerative disorders, are characterized by the abnormal aggregation of microtubule-associated Tau proteins in neurons and glial cells. The process of Tau proteins transitioning from soluble, intrinsically disordered monomers to disease-associated aggregates is still unclear. Investigating these molecular mechanisms requires the reconstitution of such processes in cellular and in vitro models using recombinant proteins at high purity and yield. However, the production of phase-separating or aggregation-prone recombinant proteins like Tau’s hydrophobic-rich domains or disease mutation-carrying variants on a large scale is highly challenging due to their limited solubility. To overcome this challenge, we have developed an improved strategy for expressing and purifying recombinant Tau proteins using the major ampullate spidroin-derived solubility tag (MaSp-NT*). This approach involves using NT* as a fusion tag to enhance the solubility and stability of expressed proteins by forming micelle-like particles within the cytosol of E. coli cells. We found that fusion with the NT* tag significantly increased the solubility and yield of highly hydrophobic and/or aggregation-prone Tau constructs. Our purification method for NT* fusion proteins yielded up to twenty-fold higher amounts than proteins purified using our novel tandem-tag (6xHis-SUMO-Tau-Heparin) purification system. This enhanced expression and yield were demonstrated with full-length Tau (hT40/Tau441), its particularly aggregation-prone repeat domain (Tau-MTBR), and Frontotemporal dementia (FTD)-associated mutant (Tau-P301L). These advancements offer promising avenues for the production of large quantities of Tau proteins suitable for in vitro experimental techniques such as nuclear magnetic resonance (NMR) spectroscopy without the need for a boiling step, bringing us closer to effective treatments for tauopathies.

Evaluation approaches are needed to ensure the development of effective design support. These approaches help developers ensure that their design support possesses the general design support characteristics necessary to enable designers to achieve their desired outcomes. Consequently, evaluating design support based on these characteristics ensures that the design support fulfils its intended purpose.

Introduction: Post-traumatic hypopituitarism (PTHP) is a significant, but often neglected consequence of traumatic brain injury (TBI). Research question: We aimed to provide a comprehensive overview of epidemiology, pathophysiology, clinical features and diagnostic approaches of PTHP. Materials and methods: MEDLINE, EMBASE, Cochrane Library and Web of Science were searched. 45 articles of human studies evaluating acute endocrine changes following mild, moderate and severe TBI were selected. Results: Severity of TBI seems to be the most important risk factor of PTHP. Adrenal insufficiency (AI) was present in 10% of TBI patients (prevalence can be as high as 50% after severe TBI), and hypocortisolemia is a predictor of mortality and long-term hypopituitarism. Suppression of the thyroid axis in 2–33% of TBI patients may be an independent predictor of adverse neurological outcome, as well. 9–36% of patients with severe TBI exhibit decreased function of the somatotrophic axis with a divergent effect on the central nervous system. Arginine-Vasopressin (AVP) deficiency is present in 15–51% of patients, associated with increased mortality and unfavorable outcome. Due to shear and injury of the stalk hyperprolactinemia is relatively common (2–50%), but it bears little clinical significance. Sex hormone levels remain within normal values. Discussion and conclusion: PTHP occurs frequently after TBI, affecting various axis and determining patients’ outcome. However, evidence is scarce regarding exact epidemiology, diagnosis, and effective clinical application of hormone substitution. Future studies are needed to identify patients at-risk, determine the optimal timing for endocrine testing, and refine diagnostic and treatment approaches to improve outcome.

AbstractBackground The shortage of family physicians is a considerable challenge in Hungary. The number of vacant practices is increasing and the rural and deprived areas are more affected.Objectives This study aimed to investigate medical students’ attitudes towards rural family medicine.Methods The current study used a cross-sectional design with a self-administered questionnaire. Each of the four Hungarian medical universities was represented by their medical students from December 2019 to April 2020.Results The response rate was 67.3% (n = 465/691). Only 5% of the participants plan to be a family doctor, 5% of the students plan to work in rural areas. On a 5-point Likert scale (1 = ‘surely not’, 5 = ‘surely yes’), half of the participants answered 1 or 2 to choose rural medical work, while 17.5% answered 4 or 5. There was a significant relationship between rural working plans and rural origin (OR = 1.97; p = 0.024), and the plan to work in family practice (OR = 4.90; p

Abstract Senior executives have a major role in leading corporations both strategically and operationally. In large corporations, the executive team is leading through their respective organizations, ensuring that corporate strategy is executed efficiently and effectively. In addition, executive management plays the key role in shaping the culture and the values of the corporation. There exists a wealth of research conducted on executive management team dynamics and the success factors related to their performance. This study examines how diversity in executive management impacts the perceived innovativeness of companies. We compare the most innovative companies and the largest players in the bioeconomy. Currently, the bioeconomy has received a lot of attention as it is considered one of the industries associated with solving global societal and environmental challenges. However, it is not perceived as highly innovative and is considered to be lacking in diversity among senior executive teams. This study adds to the body of knowledge connecting innovation, diversity, and corporate leadership and highlights similarities and differences from diversity perspective related to the companies investigated.

AbstractLaryngeal sarcoidosis is a rare condition, particularly in the pediatric population. Acute airway intervention may be required in severe cases, but guidelines to support the therapeutic strategy are absent. Moreover, evidence regarding systemic therapy is scarce. This encouraged us to report the result of airway management and systemic methotrexate at a one-year follow-up in a child with severe laryngeal sarcoidosis. A 14-year-old Caucasian female presented with dyspnea, dysphagia, and hoarseness. Fiberoptic laryngoscopy revealed profound swelling of the epiglottis and the arytenoid regions. Laryngeal sarcoidosis was suspected, and direct laryngoscopy, including biopsies, cold steel debulking, and intralesional corticosteroid injections, was performed to secure the airway. Histology was compatible with sarcoidosis, and long-term therapy with methotrexate was prescribed. At one-year follow-up, the patient was asymptomatic, and fiberoptic laryngoscopy demonstrated a near complete remission.

Heterogeneous nuclear ribonucleoproteins (hnRNP) function in RNA processing, have RNA-recognition motifs (RRMs) and intrinsically disordered, low-complexity domains (LCDs). While RRMs are drivers of RNA binding, there is only limited knowledge about the RNA interaction by the LCD of some hnRNPs. Here, we show that the LCD of hnRNPA2 interacts with RNA via an embedded Tyr/Gly-rich region which is a disordered RNA-binding motif. RNA binding is maintained upon mutating tyrosine residues to phenylalanines, but abrogated by mutating to alanines, thus we term the RNA-binding region ‘F/YGG motif’. The F/YGG motif can bind a broad range of structured (e.g. tRNA) and disordered (e.g. polyA) RNAs, but not rRNA. As the F/YGG otif can also interact with DNA, we consider it a general nucleic acid-binding motif. hnRNPA2 LCD can form dense droplets, by liquid–liquid phase separation (LLPS). Their formation is inhibited by RNA binding, which is mitigated by salt and 1,6-hexanediol, suggesting that both electrostatic and hydrophobic interactions feature in the F/YGG motif. The D290V mutant also binds RNA, which interferes with both LLPS and aggregation thereof. We found homologous regions in a broad range of RNA- and DNA-binding proteins in the human proteome, suggesting that the F/YGG motif is a general nucleic acid-interaction motif.

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1–dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.

IntroductionMild traumatic brain injury (mTBI) and hypertension synergize to induce persistent disruption of the blood–brain barrier (BBB), neuroinflammation and cognitive decline. However, the underlying mechanisms are not known. Cerebral production of Cyclophilin A (CyPA) is induced in hypertension and after TBI, and it was demonstrated to activate the nuclear factor-κB (NF-kB)- matrix-metalloproteinase-9 (MMP-9) pathway in cerebral vessels leading to BBB disruption.MethodsTo test the role of CyPA in mTBI- and hypertension-induced BBB disruption we induced mTBI in normotensive and spontaneously hypertensive rats (SHR), then the animals were treated with cyclosporine A (a specific inhibitor of CyPA production) or vehicle for 7 days. We assessed BBB permeability and integrity, cerebral expression and activity of the CyPA-NF-kB-MMP-9 pathway, extravasation of fibrin and neuroinflammation.ResultsWe found that mild TBI induced BBB disruption and upregulation of the CyPA-NF-kB-MMP-9 pathway in hypertension, which were prevented by blocking CyPA. Cyclosporine treatment and preservation of BBB function prevented accumulation of blood-derived fibrin in the brain parenchyma of hypertensive rats after mTBI and reversed increased neuroinflammation.DiscussionWe propose that mTBI and hypertension interact to promote BBB disruption via the CyPA-NF-kB-MMP-9 pathway, and inhibition of cyclophilin production after mTBI may exert neuroprotection and improve cognitive function in hypertensive patients.

Grasslands are ubiquitous globally, and their conservation and restoration are critical to combat both the biodiversity and climate crises. There is increasing interest in implementing effective multifunctional grassland restoration to restore biodiversity concomitant with above- and belowground carbon sequestration, delivery of carbon credits and/or integration with land dedicated to solar panels. Other common multifunctional restoration considerations include improved forage value, erosion control, water management, pollinator services, and wildlife habitat provisioning. In addition, many grasslands are global biodiversity hotspots. Nonetheless, relative to their impact, and as compared to forests, the importance of preservation, conservation, and restoration of grasslands has been widely overlooked due to their subtle physiognomy and underappreciated contributions to human and planetary well-being. Ultimately, the global success of carbon sequestration will depend on more complete and effective grassland ecosystem restoration. In this review, supported by examples from across the Western world, we call for more strenuous and unified development of best practices for grassland restoration in three areas of concern: initial site conditions and site preparation; implementation of restoration measures and management; and social context and sustainability. For each area, we identify the primary challenges to grassland restoration and highlight case studies with proven results to derive successful and generalizable solutions.

Performing a minimally invasive surgery comes with a significant advantage regarding rehabilitating the patient after the operation. But it also causes difficulties, mainly for the surgeon or expert who performs the surgical intervention, since only visual information is available and they cannot use their tactile senses during keyhole surgeries. This is the case with laparoscopic hysterectomy since some organs are also difficult to distinguish based on visual information, making laparoscope-based hysterectomy challenging. In this paper, we propose a solution based on semantic segmentation, which can create pixel-accurate predictions of surgical images and differentiate the uterine arteries, ureters, and nerves. We trained three binary semantic segmentation models based on the U-Net architecture with the EfficientNet-b3 encoder; then, we developed two ensemble techniques that enhanced the segmentation performance. Our pixel-wise ensemble examines the segmentation map of the binary networks on the lowest level of pixels. The other algorithm developed is a region-based ensemble technique that takes this examination to a higher level and makes the ensemble based on every connected component detected by the binary segmentation networks. We also introduced and trained a classic multi-class semantic segmentation model as a reference and compared it to the ensemble-based approaches. We used 586 manually annotated images from 38 surgical videos for this research and published this dataset.

Abstract Objectives The Veterans Administration (VA) Mobility Screening and Solutions Tool (VA MSST) was developed to screen a patient’s safe mobility level ‘in the moment’ and provide clinical decision support related to the use of safe patient handling and mobility (SPHM) equipment. This evidence-based flowchart tool is a common language tool that enables any healthcare worker at any time to accurately measure and communicate patient mobility and transfer equipment needs across disciplines and settings. Methods The VA MSST has four levels and differentiates between the need for powered and non-powered equipment depending on the patient’s independence. Subject matter experts wrote scenarios for interrater reliability and validity testing. The initial VA MSST draft iteration was reviewed by 163 VA staff (mostly physical therapists and occupational therapists) amongst simulation scenarios and provided content validity, and additional insight and suggestions. Revisions were made to create the final VA MSST which was evaluated by over 200 healthcare workers from varied disciplines (including medical doctors, advanced practice registered nurses, registered nurses, licensed practical nurses, certified nursing assistants, occupational therapists, physical therapists, speech therapists, radiology and ultrasound technicians, etc.). An instruction video and eighteen scenario videos were embedded in an online survey. The survey intended to demonstrate the interrater reliability and validity (concurrent and construct) of the VA MSST. Over 500 VA staff (raters) received a survey invitation via email. Results Raters (N = 230) from multiple disciplines and healthcare settings independently screened patient mobility status for each of 18 scenarios using the VA MSST. The raters were diverse in their age and years of experience. The estimated interrater reliability (IRR) for VA MSST was excellent and statistically significant with an estimated Krippendorff’s alpha (ICC (C, k)) of 0.998 [95% CI: 0.996–0.999]. Eighty-two percent of raters reported that overall VA MSST instructions were clear or very clear and understandable. VA MSST ratings made by technicians and nursing assistants group correlated strongly (r = 0.99, p

Abstract Background Chronic radiation-associated dysphagia (C-RAD) is considered to be one of the most severe functional impairments in head and neck cancer survivors treated with radiation (RT) or chemoradiation (CRT). Given the major impact of these late toxicities on patients’ health and quality of life, there is a strong need for evidence-based dysphagia management. Although studies report the benefit of strengthening exercises, transference of changes in muscle strength to changes in swallowing function often remains limited. Therefore, combining isolated strengthening exercises with functional training in patients with C-RAD may lead to greater functional gains. Methods This 3-arm multicenter randomized trial aims to compare the efficacy and possible detraining effects of mere strengthening exercises (group 1) with a combination of strengthening exercises and functional swallowing therapy (group 2) and non-invasive brain stimulation added to that combination (group 3) in 105 patients with C-RAD. Patients will be evaluated before and during therapy and 4 weeks after the last therapy session by means of swallowing-related and strength measures and quality of life questionnaires. Discussion Overall, this innovative RCT is expected to provide new insights into the rehabilitation of C-RAD to optimize post-treatment swallowing function. Trial registration International Standard Randomized Controlled Trials Number (ISRCTN) registry ID ISRCTN57028065. Registration was accepted on 15 July 2021.