julilili42/papers huggingface dataset:
Exploration of fluorinated peptoid-based histone deacetylase inhibitors as dual-stage antiplasmodial agents
2025-06-24

In this study, we investigated the antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of Plasmodium falciparum, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound 1h emerged as the most potent derivative, showing strong activity against both P. falciparum strains (Pf 3D7 and Dd2 IC50: 0.010 μM) and against P. berghei liver stages (Pb EEF IC50: 0.74 μM), while lacking activity against mature gametocytes. Compound 1b was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.019 μM; Pf Dd2 IC50: 0.023 μM; Pb EEF IC50: 2.25 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2389; SIHepG2/Dd2: 1973) and notable activity against mature gametocytes (IC50: 1.70 μM). Compared to our previous hit compound MAHA-022, both 1b and 1h exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds 1b and 1h represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.
Genome Mining Leads to the Discovery of Kasichelins A–D, Unusual β-Alanine- and β-Aminoisobutyric Acid-Containing Siderophores from Streptomyces
2025-06-24

Genome mining of a <i>Streptomyces</i> strain collected in Tanzania revealed its potential to produce a novel siderophore. Heterologous expression of the corresponding biosynthetic gene cluster (BGC) in <i>S. coelicolor</i> M512 resulted in the production of kasichelin A, a new metal-chelating molecule featuring a phenolate oxazoline and a hydroxamate moiety as iron-binding ligands connected via a β-aminoisobutyric acid (BAIBA) linker. Further analysis of the heterologous producer and subsequent optimization of the culture conditions for the wild-type strain led to the isolation of three additional congeners, kasichelins B, C, and D. Marfey's analysis of kasichelin C, the most abundant congener, established its absolute configuration as 2<i>R</i>,7<i>R</i>,10<i>S</i>,11<i>R.</i> Notably, kasichelin C was found to be identical to L-654,040, a partially characterized compound previously described in the patent literature. The iron-binding properties of the kasichelins were evaluated using the chrome azurol S (CAS) assay, UV/vis spectroscopy, and electrospray ionization-mass spectrometry (ESI-MS). All four kasichelins exhibit comparable iron(III)-binding affinities and surpass deferoxamine in their ability to sequester the metal, despite natural variations in their ligands and linker structures. The biosynthetic origin of the unusual BAIBA moiety presents an intriguing direction for future research.
PET-based immunomapping of intratumoral CD4 + cells to monitor acquired resistance to checkpoint inhibitors
2025-06-25

CD4 + T cells are crucial in shaping response and resistance to immunotherapy. To enhance our understanding of their multifaceted functions, we developed copper-64–radiolabeled nanobodies targeting the human CD4 receptor ( 64 Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice, 64 Cu-CD4-Nb1 specifically accumulated in different orthotopic tumors, correlating with histological CD4 + cell densities. Based on intratumoral CD4 + cell distribution patterns within the core and periphery, we distinguished responders to combined αPD-1/4-1BB antibodies early on-treatment. CD4-PET identified resistance to αPD-1 monotherapy, which was mitigated by adding regulatory T cell–depleting α4-1BB antibodies. Patients with early-stage non–small cell lung cancer who relapsed after neoadjuvant αPD-L1 therapy revealed low CD4 + T cell densities in the tumor core. In human and mouse tumor tissues, regulatory T cells correlated with CD4 + cell densities. Thus, visualizing the spatial distribution patterns of CD4 + cells by PET offers mechanistic insights into CD4-mediated therapy efficacy, with great potential for guiding combinatorial immunotherapies in patients with cancer.
High Seroprevalence of Hepatitis E Virus Among Patients With Hepatitis B and Those With Hepatitis of Unknown Etiology in Central Vietnam
2025-06-25

Abstract Background Hepatitis E virus (HEV) is a significant cause of acute viral hepatitis, particularly in regions with poor sanitation. Co-infection with hepatitis B virus (HBV) is common in high-risk populations, such as individuals with chronic liver disease, but data on HEV prevalence in patients living with HBV in Southeast Asia are limited. This study investigates HEV seroprevalence among patients with HBV and those with hepatitis of unknown etiology (HUE) in central Vietnam Method Blood samples from 587 patients with HBV and 158 individuals with HUE were collected and analyzed for anti-HEV immunoglobulin G (IgG) and immunoglobulin M antibodies by enzyme-linked immunosorbent assay. HEV RNA was detected using reverse transcriptase-polymerase chain reaction, and HBV viral load was quantified via real-time polymerase chain reaction. Results The overall anti-HEV IgG seroprevalence was 26% in patients with HBV and 36% in those with HUE. Although patients with liver cirrhosis and hepatocellular carcinoma exhibited higher rates of anti-HEV IgG seropositivity, these differences were not statistically significant. Among patients with HBV, the seroprevalence was highest in those with liver cirrhosis and hepatocellular carcinoma (46%), whereas the lowest (24%) was found in patients with symptomatic chronic hepatitis B. Only 1 (0.1%) tested positive for anti-HEV immunoglobulin M, and no HEV RNA positivity was detected. Furthermore, biochemical laboratory parameters in patients with liver diseases were not found to be associated with anti-HEV seropositivity. Conclusions Anti-HEV IgG seroprevalence was relatively high among patients with chronic liver disease, including those with HBV. However, no association was observed between HEV exposure and liver disease progression. HEV is not a common cause of hepatitis in Central Vietnam.
ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution
2025-06-25

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ + pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.
Existing health disparities in congenital heart disease: the path forward to achieving health equity—A scientific statement of the European Association of Preventive Cardiology of the ESC
2025-06-25

Abstract There is increasing recognition that social determinants of health affect outcomes in individuals with congenital heart disease and cause health disparities. This scientific statement from the European Association of Preventive Cardiology of the European Society of Cardiology provides an outline of the existing disparities from a global perspective in this population. We review the current knowledge on racial and ethnic patterns and the role of deprivation status, food insecurity, built environment, financial strain, psychological health and parental distress and education and literacy in creating inequities. Finally, we provide future directions for policy, research, and clinical practice in achieving health equity in the congenital heart disease population.
Presence of Different Ceramide Species Modulates Barrier Function and Structure of Stratum Corneum Lipid Membranes: Insights from Molecular Dynamics Simulations
2025-06-25

Ceramides, as major components of the human stratum corneum's (SC) lipid matrix, are considered crucial for regulating the skin's barrier function against the ingress of exogenous substances as well as to prevent water loss through the skin. Multiple clinical and experimental studies found different classes of ceramide species to affect the skin barrier nonuniformly, with some ceramides being associated with an impaired skin barrier, such as ceramide NS, while others are associated with a healthy, unimpaired skin, e.g., ceramide NP. This study investigates how the presence of these two ceramide classes in an SC lipid bilayer membrane influences the water permeability as well as the structure of the bilayer using molecular dynamics (MD) simulations. To this end, simulated membranes comprising free fatty acids, cholesterol, as well as either ceramide NS or ceramide NP were systematically compared in regard to differences in the membrane structure and water permeability, as well as to results found in the literature. The simulation found ceramide NP-containing membranes to have a significantly lower water permeability than ceramide NS-containing systems, with the permeability values of NP-based systems being almost half of those of the NS-based systems. Furthermore, the simulation also showed significant structural differences between the two systems in terms of headgroup conformation and lipid positioning in the membrane, hinting toward the molecular mechanisms underpinning the differences in permeability of the two systems. In conclusion, the MD simulation was able to reproduce effects of the presence of different ceramide species in the membrane that are consistent with experimental as well as clinical studies on skin barrier function and drug delivery and validate previous simulation-based investigations into SC lipid bilayer permeability.
The prevalence of prolonged grief disorder according to the international classification of diseases 11: a scoping review
2025-06-25

Abstract Background The eleventh revision of the International Classification of Diseases (ICD-11) introduces Prolonged Grief Disorder (PGD) as a new diagnostic category. This paper summarizes methodological approaches and prevalence estimates of studies on PGD in ICD-11. Methods This review follows the JBI Manual of Evidence Synthesis and PRISMA-ScR guidelines. We searched MEDLINE, Embase, Web of Science, and PsycINFO (2011–2024), along with grey literature sources (Web of Science, Science.gov, NDLTD Global ETD Search). Included studies were cross-sectional or longitudinal, evaluating PGD prevalence using ICD-11 criteria. Two reviewers (KN, SK) independently screened studies, with a third (SG) resolving disagreements. Methodological quality was not assessed. Data extraction covered bibliographic details, study period, location, sample characteristics, diagnostic tools, algorithms, and prevalence. Results Of 124 screened records, 35 studies were included in a qualitative synthesis. Seven main study categories emerged, primarily bereaved adults and representative national samples. Of 46 study samples, 24 were from Europe, followed by North America ( n = 10) and Asia ( n = 5), with none from South America. The PG-13 was the most commonly used tool, often omitting and raising ICD-11 PGD criteria simultaneously. ICD-11 PGD prevalence ranged from 1.5 to 15.3% in bereaved adults and 9.9–11.4% in national samples. Conclusions Findings reveal heterogeneous study populations but limited geographic diversity. Standardized PGD assessments aligned with ICD-11 criteria, using tools specifically designed for ICD-11, along with detailed sample reporting, are needed to improve study comparability and consistency of prevalence. Important gaps by geographical and demographic groups remain.
Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance
2025-06-25

Abstract IκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ’s function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses Cxcl9 , Cxcl10 , and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8 + T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.
In silico & in vitro approaches suggest osteoclastogenesis induction underlying fractures in Entrectinib-treated children
2025-06-25

Abstract Entrectinib, a potent, CNS-active, TRK and ROS1 inhibitor is associated with occurrence of bone fractures, particularly in pediatric patients. We embarked on computer-guided and experimental investigations to identify the underlying mechanism that should help safe dosing of children receiving this drug. An artificial intelligence (AI)-based approach was used to allow for hypothesis generation regarding drug effects in a clinical setting and mechanistic insights on safety and efficacy. This was followed by confirmatory in vitro studies using human bone cell cultures. The AI-based hypothesis suggested an effect via inhibition of TRK and JAK2, as molecular targets of Entrectinib, underlying the fractures. Subsequent experiments using human bone cells showed that Entrectinib reduced markers of osteoblastic- and mineralization-activity. Conversely, Entrectinib had stimulating effects on osteoclast function indicative of bone resorption. 3D osteoblast-osteoclast cultures revealed reduced stiffness after Entrectinib treatment and this was pronounced in the absence of 17β-estradiol, characteristic for juvenile bone. Pathway analysis revealed inhibition of bone growth regulators TGF-β and BMP which is suggested to underlie the in silico-proposed JAK2 effect. Pre-treatment with Vitamin D led to partially restored osteoblast function in vitro, while osteoclast function was suppressed. These experiments suggest an on-target effect of Entrectinib underlying increased fractures particularly in children with developing bones, offering potential mitigation strategies if these observations can be confirmed with data from ongoing clinical trials.
Computational Discovery and Optimization of a Potent, Selective, and Drug-like Scaffold for p38α Inhibition
2025-06-25

Mitogen-activated protein kinase 14 (MAPK14), commonly known as p38α, is a stress-activated kinase involved in various physiological and pathological processes, including inflammation, cancer, and neurodegenerative diseases. Despite extensive research and numerous clinical trials, the development of selective p38α inhibitors with consistent clinical efficacy has remained a challenge due to cellular adaptability, compensatory signaling pathways, and dose-dependent toxicities. In this study, we report the identification and optimization of a novel p38α inhibitor scaffold through an integrated virtual screening and structure-based drug discovery approach. Using ESSENCE-Dock, a consensus virtual screening method combining multiple molecular docking algorithms, we identified several promising hit compounds, from which Compound 24 emerged as the most potent candidate (IC50 = 26.2 nM). Subsequent optimization efforts leveraging consensus fingerprint similarity and Butina clustering led to the discovery of structurally related analogs with enhanced potency, including Compounds 28, 47, 48, 50, and 53, all exhibiting IC50 values below 10 nM. MolSHAP-based SAR analysis highlighted key R-group contributions to potency, while synthetic routes enabled efficient scaffold diversification. Molecular dynamics simulations confirmed stable binding interactions with key residues, and KINOMEscanTM profiling showed high selectivity for Compound 26. ADME profiling demonstrated favorable drug-like properties, including high plasma stability (&gt;120 min) and good solubility. A NanoBRET assay further confirmed potent intracellular target engagement of p38α by Compound 26, with 71.4% inhibition at 10 nM, supporting its suitability for further development. Notably, the core scaffold is structurally distinct from previously reported p38α inhibitors, underscoring its novelty. This study underscores the utility of advanced virtual screening and structure-guided optimization in discovering novel and selective p38α inhibitors with potential relevance to inflammatory and neurodegenerative diseases.
Probing leptophobic dark sector with a pseudoscalar portal in the NA64 experiment at CERN
2025-06-25

A bstract We propose the possibility of discovering a light pseudoscalar particle a , axion-like particle (ALP), interacting mainly with quarks using the electron and photon scattering reaction chain e + Z → e + γ + Z ; γ + Z → a + Z on nuclei in the NA64 experiment at the CERN SPS. We consider the mixing of ALP with light pseudoscalar mesons P = π , η , η ′ with taking into account of the ALP mass explicitly breaking the Peccei-Quinn symmetry. It could open invisible channels of ALP decaying into dark fermion matter by analogy with P mesons decays. New bounds on the coupling strengths of the ALP with quarks and of pseudoscalar mesons with dark fermions are obtained by using existing upper bounds on invisible decay modes of P s including those recently derived by NA64. We also study a scenario when the a plays the role of a messenger in the communication between our world and the dark sector. New upper limits on axion couplings with quarks and its mixing parameters with π , η , η ′ mesons are established.
Manuscript Sinai Greek 1338
2025-06-25

Abstract This study introduces and analyzes Manuscript Sinai Greek 1338, preserved at the Monastery of Saint Catherine in Sinai. This 13th-century bilingual lexicon contains Greek word entries paired with Arabic translations. Previously unidentified in academic research, the manuscript is revealed to be part of the tradition of Cyril’s Lexicon. The manuscript spans 149 folios and includes approximately 2,500 Greek entries alongside Arabic translations. It is a learning resource aimed at Arabic-speaking monks to help them understand and chant Greek liturgical texts. The interlinear format and additional pedagogical content, like grammatical notes and Byzantine musical notation, suggest its use as both a linguistic and liturgical guide. My analysis identifies the manuscript’s affiliation with Recension v. The manuscript also preserves practical examples of Byzantine chant in a bilingual format, with Greek texts marked for pronunciation and melody. It stands out as a rich resource that bridges Greek heritage and the Arabic-speaking Orthodox tradition.
Plasma Proteomics Reveals Distinct Signatures in Occult and Microfilaremic Loa loa Infections
2025-06-25

Abstract Background Loiasis, caused by the filarial nematode Loa loa, imposes a significant disease burden in endemic regions in West and Central Africa. Manifestations include adult worms in soft tissue (e.g., the conjunctiva of the eye) and microfilaria in peripheral blood, with clinical presentations ranging from asymptomatic infections to life-threatening organ involvement. Diagnosis remains challenging due to variable microfilaria counts, frequent amicrofilaremic occult infections, and unreliable serological tests. The untargeted plasma proteome reflects broad (patho-)physiological responses, providing valuable insights into the host and disease. Methods Applying high-throughput plasma proteomics, we investigated the host responses of 274 patients with different L. loa disease states, including occult loiasis (n = 148), microfilaremia (n = 42), or both (n = 84), compared to 136 L. loa–negative controls. Differentially abundant proteins between L. loa–infected individuals and negative controls were validated using targeted proteomics. Results Five proteins (IGHG3, IGHG4, ACTBL2, LCP1, and IGLV9-49) were elevated in infected individuals compared to healthy controls. IGHG3, IGHG4, ACTB, and LCP1 increased from L. loa negative over individuals with history of eye worm migration to microfilaremic patients, indicating a comparatively pronounced proteomic host response to microfilaria in the blood. Sixty-three proteins differed depending on self-reported symptoms. The proteomic signatures enabled accurate classification of individuals with occult loiasis (area under the receiver operating characteristic curve [AUROC] = 0.73) and microfilaremia (AUROC = 0.84) by a random forest machine learning model. Conclusions Overall, infection with Loa loa alters the host plasma proteome, exhibiting distinct host responses in different infection states and allowing for molecular disease classification of this highly neglected parasitic disease.
Augmented reality in pelvic surgery: using an AR-headset as intraoperative radiation-free navigation tool
2025-06-26

Abstract Purpose The incidence of acetabular and pelvic fractures is rising significantly. Pelvic ring fractures rank as the sixth most common fractures in adults, with the majority occurring in the elderly. Due to complications related to surgical approaches, with rates of up to 31%, there is an increasing demand for minimally invasive surgical techniques. Augmented Reality (AR) has the potential to facilitate spatial orientation by a sophisticated user interface. The aim of this study was to develop an AR-based, radiation-free navigation system for pelvic fractures. Methods The Microsoft® HoloLens 2 was used as the AR headset. The Unity® game engine was used for programming. Pelvic models from Sawbones® served as the model. Segmentation was performed using Slicer3D by Slicer Corporation. The symphysis and both anterior superior iliac spines were defined as anatomical reference points. Ten pelvic models were used for testing. A preoperatively defined drill trajectory was displayed to the surgeon. A total of 20 S1 screws and 19 S2 screws were placed using only AR navigation without visual access to the pelvic model. Screw placement was controlled using CT. Results The matching process took an average of 3 min and 28 s. 18 out of 20 (90%) S1 screws and 3 out of 20 (15%) S2 screws were placed correctly. In most cases, no perforation occurred. The mean procedure time was 7 min for S1 screws and 5 min for S2 screws. Conclusion Proper drilling was achieved by displaying the trajectories via AR, particularly for S1 screws, where a slightly wider drilling corridor was aimed for compared to S2 screws. No registration scan was necessary with our matching method. No intraoperative radiation was required.