julilili42/papers huggingface dataset:
Method comparison and overview of refractive measurements in children: implications for myopia management
2024-03-01

Objective This study investigated the agreement between objective wavefront-based refraction and subjective refraction in myopic children. It also assessed the impact of cyclopentolate and refraction levels on the agreement. Methods A total of 84 eyes of myopic children aged 6–13 years were included in the analysis. Non-cycloplegic and cycloplegic objective wavefront-based refraction were determined and cycloplegic subjective refraction was performed for each participant. The data were converted into spherical equivalent, J 0 and J 45 , and Bland-Altman plots were used to analyse the agreement between methods. Results Linear functions were used to determine the dependency between the central myopic refractive error and the difference between the method of refraction (=bias). The influence of central myopia was not clinically relevant when analysing the agreement between wavefront results with and without cyclopentolate (comparison 1). The bias for wavefront-based minus subjective spherical equivalent refraction (comparison 2) was ≤−0.50 D (95% limits of agreement −0.010 D to −1.00 D) for myopia of −4.55 D and higher when cycloplegia was used (p&lt;0.05). When no cyclopentolate was used for the wavefront-based refraction (comparison 3), the bias of −0.50 D (95% limits of agreement −0.020 D to −0.97 D) was already reached at a myopic error of −2.97 D. Both astigmatic components showed no clinically relevant bias. Conclusion The spherical equivalent, measured without cycloplegic agents, led to more myopic measurements when wavefront-based refraction was used. The observed bias increased with the amount of myopic refractive error for comparisons 2 and 3, which needs to be considered when interpreting wavefront-refraction data. Trial registration number NCT05288335 .
361 Sexual health and quality of life after molecular-based adjuvant treatment in the randomised PORTEC-4a trial
2024-03-01

<h3>Introduction/Background</h3> The PORTEC-4a trial was the first to introduce molecular factors for adjuvant treatment allocation in women with early-stage high-intermediate risk endometrial cancer (HIR-EC). Here, we investigated health-related quality of life (HRQL) and sexual well-being between treatment arms. <h3>Methodology</h3> Patients with HIR-EC were randomised (2:1) between individualised treatment based on a molecular-integrated risk profile or vaginal brachytherapy (VBT), figure 1A. HRQL and sexual outcomes were assessed (EORTC-QLQ C30 and EN24) at baseline, after treatment and 6-monthly after randomisation up to two years after randomisation and compared with age-matched normative data. A linear mixed model was used and a 2-sided p&lt;0.01 was considered statistically significant. <h3>Results</h3> From 2012 to 2021, 563 evaluable patients were included, 367 in the intervention-arm and 196 in the standard arm, figure 1A. Median age was 69. Both treatment groups reported similar quality of life (p=0.17) and physical (p=0.62) and role functioning (p=0.05) scores over time, which were all better than those of the age-matched normative data. In addition, no differences in emotional (p=0.37) and social (p=0.94) functioning were observed between the two arms. At baseline, 72.9% and 74.6% (p=0.76) of patients in the intervention and standard arm, respectively, indicated to not be sexually active. Sexual activity slightly increased over time to 38.5% in the intervention group vs 33.9% in the standard arm (p=0.47) at two years after randomisation. Most frequently given reasons for not being sexually active were either sex not being important or medical issues of their partner or themselves. No differences in sexual and vaginal problems were observed between treatment arms (p=0.83). All PORTEC-4a trial patients reported slightly higher sexual activity scores than an aged-matched normative population, figure 1C. <h3>Conclusion</h3> Individualised treatment in the molecular arm of the PORTEC-4a trial led to a significant reduction in use of adjuvant treatment, with similar HRQL and sexual well-being. <h3>Disclosures</h3> No disclosures.
A revised model for Neogene Zagros foreland sedimentation in the Lurestan arc based on new geochemical data
2024-03-01

Abstract The Zagros foreland basin is an important sedimentary archive for the tectonic and paleoclimatic evolution of the Zagros Mountains and the entire Neotethyan Arabia–Iran collision zone. By combining new geochemical high‐resolution whole rock XRF data with clay mineralogy and soluble salt geochemistry we propose an evolution of the sedimentary environment in the Lurestan arc from the Serravallian to the early Pleistocene, closing a gap in understanding the complex exhumation history of the central Zagros mountain belt. An increase in ultramafic sedimentary input indicates a shift from provenance 1 to provenance 2 by ophiolite exhumation at ca.10 Ma in the Imbricated Zagros north of the Lurestan arc. Our data further indicates that the sedimentary environment of parts of the Lahbari Mb within the Lurestan arc represents a piedmont deposition of fine‐grained alluvial fans and siltstones with aeolian contribution deposited under hyper‐arid climate conditions. These represent provenance shift 3 and were likely sourced from evaporites of the underlying Gachsaran Fm and fluvial deposits of the Lower Aghajari Mb (provenance 1 and provenance 2), uplifted by the Mountain Front Flexure at around 5.6 Ma. Combining XRF whole rock data with clay mineral data refines formation conditions of the clay minerals in the foreland basin such as palygorskite, which is revealed to be authigenic in origin in the Lower Aghajari Mb. as a function of varying Mg‐content due to variations of erosion of the ultramafic and mafic rocks in the Imbricate Zagros belt. Palygorskite in the Lahbari Member is likely both inherited from the Neogene Gachsaran evaporites as well as of authigenic origin.
Suzanne Labin: socialist, anti-communist and ‘Globalist’
2024-03-01

Abstract This article follows the transnational career of Suzanne Labin, a French socialist and anti-communist professional, in order to analyse the roles and agencies of individuals while the global connectivity of anti-communist actors was growing during the ‘long 1960s’ (approximately 1955–1980). Retrospective analysis, as well as accounts from contemporaries, describes this period as a time of multi-polarisation and globalisation. I will chart Labin’s path from anti-Stalinist circles in France to conservative circles in the US, to finally becoming the first and only female permanent member of the global anti-communist umbrella organisation, the World Anti-Communist League (WACL), chairing its French chapter in 1972. An analysis of Labin’s seemingly ambiguous alliances as a socialist with anti-communist and right-wing organisations will shed light on the particularities of international anti-communism during the ‘long 1960s’ on three levels. First, it will show the dynamics between anti-communist networks and actors on national, transatlantic and global levels, especially their contact points. Second, it will underline the diversity of anti-communism and its capacity to integrate several (even contradictory) ideologemes. Third, by following Labin’s global anti-communist engagement within the WACL and her cosmopolitan lifestyle, this article will argue that anti-communist actors were actively involved in the process of globalisation during the ‘long 1960s’.
The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance
2024-03-02

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These mechanisms are essential for viral replication, because missing functions cannot be compensated by the virus. However, this assumption needs experimental proof. Here we compared the HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities in SARS-CoV-2. During serial passage of δ-B1.617.2 adaptation to all DAAs occurred, while the inhibitory capacity of ZMN was not altered. Known single nucleotide polymorphisms (SNPs) responsible for partial resistances were found for RDV, NTV and PAX. Additionally, the high mutagenic potential of MPV was confirmed and decreased drug efficacies were found for the first time. Reduced DAA efficacy did not alter the inhibitory potential of ZMN. These results show that ZMN confers a high barrier towards the development of viral resistance and has the potential to act against partially DAA-insensitive viruses.
Consequences of Amyloid‐β Deficiency for the Liver
2024-03-02

Abstract The hepatic content of amyloid beta (Aβ) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aβ deficiency in the liver. This is especially relevant in view of recent advances in anti‐Aβ therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aβ in transgenic AD mice immunized with Aβ antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP‐KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha‐actin, and collagen type I. Aβ absence in APP‐KO and deficiency in immunized mice lead to strong activation of transforming growth factor‐β (TGFβ), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial‐mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aβ42 in transgenic AD mice and neprilysin inhibitor LBQ657‐treated wild‐type mice protect the liver against carbon tetrachloride (CCl 4 )‐induced injury. Transcriptomic analysis of CCl 4 ‐treated transgenic AD mouse livers uncovers the regulatory effects of Aβ42 on mitochondrial function, lipid metabolism, and its onco‐suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aβ as an indispensable regulator of cell–cell interactions in healthy liver and a powerful protector against liver fibrosis.
Siderophore piracy enables the nasal commensalStaphylococcus lugdunensisto antagonize the pathogenStaphylococcus aureus
2024-03-02

Abstract Bacterial pathogens such as Staphylococcus aureus colonize body surfaces of part of the human population, which represents a critical risk factor for skin disorders and invasive infections. However, such pathogens do not belong to the human core microbiomes – beneficial ‘commensal’ bacteria can often prevent the persistence of certain pathogens – using molecular strategies that are only superficially understood. We recently reported that the commensal bacterium Staphylococcus lugdunensis produces the novel antibiotic lugdunin, which eradicates S. aureus from nasal microbiomes of hospitalized patients. However, it has remained unclear if S. lugdunensis may affect S. aureus carriage in the general population and how S. lugdunensis carriage could be promoted to enhance its S. aureus -eliminating capacity. We could cultivate S. lugdunensis from the noses of 6.3% of healthy human volunteers. In addition, S. lugdunensis DNA could be identified in metagenomes of many culture-negative nasal samples indicating that cultivation success depends on a specific bacterial threshold density. Healthy S. lugdunensis carriers had a 5.2-fold lower propensity to be colonized by S. aureus indicating that lugdunin can eliminate S. aureus also in healthy humans. S. lugdunensis -positive microbiomes were dominated by either Staphylococcus epidermidis , Corynebacterium species, or Dolosigranulum pigrum . These and further bacterial commensals, whose abundance was positively associated with S. lugdunensis , promoted S. lugdunensis growth in co-culture. Such mutualistic interactions depended on the production of iron-scavenging siderophores by supporting commensals, and on the capacity of S. lugdunensis to import siderophores. These findings underscore the importance of microbiome homeostasis for eliminating pathogen colonization. Elucidating mechanisms that drive microbiome interactions will become crucial for microbiome-precision editing approaches.
Blocking TGF-β- and Epithelial-to-Mesenchymal Transition (EMT)-mediated activation of brain pericytes in glioblastoma impacts tumor angiogenesis
2024-03-02

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM displays excessive and unfunctional vascularization which may, among others, be a reason for its devastating prognosis. Pericytes have been identified as the major component of the irregular vessel structure in GBM. In vitro data suggest an epithelial-to-mesenchymal transition (EMT)-like activation of glioma-associated pericytes (GA-Peris), stimulated by GBM-secreted TGF-β, to be involved in the formation of a chaotic and dysfunctional tumor vasculature. This study investigated whether TGF-β impacts pericyte functions in vivo via the induction of the EMT transcription factor SLUG and whether this is associated with the development of GBM-associated vascular abnormalities. Upon prohibiting the TGF-β-/SLUG-mediated EMT induction in GA-Peris, the number of PDGFRβ and αSMA positive pericytes was significantly reduced, regardless of whether TGF-β secretion by GBM cells was blocked or whether SLUG was specifically knocked out in GA-Peris. The reduced amount of PDGFRβ+ or αSMA+ pericytes observed under those conditions correlated with a lower vessel density and fewer vascular abnormalities. Our data provide evidence that the SLUG-mediated modulation of pericyte activity is induced by GBM-secreted TGF-β and that activated pericytes are key contributors in neo-angiogenic processes. We suggest that a pathologically altered activation of GA-Peris in the tumor microenvironment is responsible for the unstructured tumor vasculature. There is emerging evidence that vessel normalization alleviates tumor hypoxia, reduces tumor-associated edema and improves drug delivery. Therefore, avoiding the generation of an unstructured and non-functional tumor vasculature during tumor recurrence might be a promising treatment approach for GBM and identifies pericytes as a potential novel therapeutic target.
Protein hydrolysates from buffalo cheese whey: production and characterisation for food supplementation
2024-03-03

Summary The objective of this study was to obtain protein hydrolysates from buffalo cheese whey proteins and characterise them. Degrees of hydrolysis ranged between 10% and 16% depending on processing time. The hydrolysate obtained after 12 h showed a low water activity value (&lt;0.4), and the lowest moisture content (4.88% w/w), besides demonstrating better solubility, and enhanced emulsion stability. The hydrolysate obtained after an 18‐h process exhibited higher foam production capacity. In vitro, protein digestibility values of the hydrolysates ranged from 25% to 27% (w/w). Prolonging the hydrolysis (18 h) of the buffalo whey proteins with Flavourzyme resulted in a greater release of amino acids. The hydrolysate obtained after a 12‐h process exhibited the best techno‐functional characteristics (moisture, oil holding capacity, and emulsion stability), while the 18‐h showed the highest levels of branched‐chain amino acids. The characteristics of these hydrolysates enable their use in the production of supplements, providing another strategy for bubaline whey utilisation.
Desmoid Fibromatosis Fused With a Lipoma in the Upper Arm
2024-03-03

Lipoma, the most common mesenchymal tumor, often appears as a slow-growing mass in the musculoskeletal system (MSK). While generally non-invasive, their location can cause symptoms. Desmoid fibromatosis (DF), a rare and locally aggressive neoplasm, poses challenges in MSK system diagnosis and management due to its infiltrative nature. Despite lacking metastatic potential, DF has a high recurrence rate, classifying it as "intermediate, locally aggressive" in the WHO classification. Collaborative efforts among orthopedic surgeons, radiologists, and pathologists are crucial for accurate diagnosis and treatment planning for all tumors of the MSK system. This case report presents the first documented example of a DF within a lipoma, highlighting the challenges of diagnosing and treating musculoskeletal tumors.
Regulated cell death‐amplified sonodynamic anti‐tumor immune nanotherapeutics
2024-03-04

Abstract Nanomedicine‐assisted sonodynamic therapy (SDT) has emerged as one of the most promising cancer therapies due to its unique advantages of high penetration, non‐radiation, and excellent oxidative stress effect, but has always suffered from the self‐protection mechanism and apoptosis resistance characteristics of evolutionarily mutated cancer cells. Regulated cell death (RCD) has received increasing attention in precision cancer treatments because of its significant role in synergistically sensitizing apoptosis and reversing the immunosuppressive microenvironment during SDT nanomedicine‐triggered immunogenic cell death. Herein, paradigmatic research of RCD‐augmented sonodynamic tumor immunotherapeutics are typically introduced, such as autophagy blockade, ferroptosis targeting, pyroptosis induction, necroptosis initiation, cuproptosis actuation, PANoptosis trigger, and the coordinated anti‐tumor mechanisms are discussed in detail. Multiple analysis focusing on the currently unsolved problems and future development prospects of RCD‐based SDT nano‐oncology medicine are also discussed and prospected to further strengthen and expand the scope of its therapeutic applications.
IGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype
2024-03-04

Human skeletal muscle models are highly valuable to study how exercise prevents type 2 diabetes without invasive biopsies. Current models did not fully recapitulate the function of skeletal muscle especially during exercise. By supplementing insulin-like growth factor 1 (IGF1), the authors developed a functional human skeletal muscle model characterized by inducible contractility and increased oxidative and insulin-sensitive metabolism. The novel protocol overcomes the limitations of previous standards and enables investigation of exercise on a molecular level.
Machine Learning-Based Virtual Screening of Antibacterial Agents against Methicillin-Susceptible and Resistant Staphylococcus aureus
2024-03-04

The application of computer-aided drug discovery (CADD) approaches has enabled the discovery of new antimicrobial therapeutic agents in the past. The high prevalence of methicillin-resistant<i>Staphylococcus aureus</i>(MRSA) strains promoted this pathogen to a high-priority pathogen for drug development. In this sense, modern CADD techniques can be valuable tools for the search for new antimicrobial agents. We employed a combination of a series of machine learning (ML) techniques to select and evaluate potential compounds with antibacterial activity against methicillin-susceptible <i>S. aureus</i> (MSSA) and MRSA strains. In the present study, we describe the antibacterial activity of six compounds against MSSA and MRSA reference (American Type Culture Collection (ATCC)) strains as well as two clinical strains of MRSA. These compounds showed minimal inhibitory concentrations (MIC) in the range from 12.5 to 200 μM against the different bacterial strains evaluated. Our results constitute relevant proven ML-workflow models to distinctively screen for novel MRSA antibiotics.
Sildenafil delays bone remodeling of fractured femora in aged mice by reducing the number and activity of osteoclasts within the callus tissue
2024-03-04

The elderly exhibit a reduced healing capacity after fracture, which is often associated with delayed or failed bone healing. This is due to a plethora of factors, such as an impaired bone vascular system and delayed angiogenesis. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil exerts pro-angiogenic and pro-osteogenic effects. Hence, we herein investigated in aged mice whether sildenafil can improve fracture healing. For this purpose, 40 aged CD-1 mice (16-18 months) were daily treated with 5 mg/kg body weight sildenafil (n = 20) or vehicle (control, n = 20) by oral gavage. The callus tissue of their femora was analyzed at 2 and 5 weeks after fracture by X-ray, biomechanics, micro-computed tomography (μCT), histology, immunohistochemistry as well as Western blotting. These analyses revealed a significantly increased bone volume and higher ratio of callus to femoral bone diameter in sildenafil-treated mice at 5 weeks after fracture when compared to controls. This was associated with a reduced number and activity of osteoclasts at 2 weeks after fracture, most likely caused by an increased expression of osteoprotegerin (OPG). Taken together, these findings indicate that sildenafil does not improve fracture healing in the elderly but delays the process of bone remodeling most likely by reducing the number and activity of osteoclasts within the callus tissue.
Systematic classification of phage receptor-binding proteins predicts surface glycopolymer structure inStaphylococcuspathogens
2024-03-04

Summary Wall teichoic acids (WTAs) are major surface polymers of staphylococcal pathogens and commensals, whose variable structure governs interaction with host receptors, immunoglobulins, and bacteriophages. The ribitol phosphate (RboP) WTA type contributes to virulence, for instance in Staphylococcus aureus , but we lack comprehensive knowledge of WTA types and cognate phages. We developed a computational pipeline to identify the receptor-binding proteins (RBPs) in 335 Staphylococcus phage genomes, yielding multiple distinct RBP clusters. Notably, many phages had two separate RBPs with in part different WTA preferences. RBP representatives differed in specificity for RboP WTA glycosylation types, recapitulating the specificity of the corresponding phage. Based on these results, we created a publicly available bioinformatic tool to predict phage host specificity based on RBP similarity. The RboP WTA specific Φ13-RBP also revealed that the presence of RboP WTA on non-aureus staphylococci is more common than previously thought. Our approach facilitates the characterization of opportunistic Staphylococcus pathogens according to WTA types, which has major implications for phage-mediated interspecies horizontal gene transfer and future phage therapies.