julilili42/papers huggingface dataset:
ENLIGHTED phase 3 study: Interim results of efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) in the treatment of low-grade upper tract urothelial cancer (LG UTUC).
2025-06-04

LBA4513 Background: Padeliporfin VTP has demonstrated safety and efficacy for UTUC treatment in a Phase 1 study (NCT03617003). Padeliporfin VTP is a combination product of a drug, padeliporfin administered IV and a optical fiber coupled laser emitting near-infrared light endoluminally to UTUC tumors. We report the interim analysis of efficacy and safety outcomes of Padeliporfin VTP for treatment of LG UTUC in ENLIGHTED, a Phase 3 trial (NCT04620239). Methods: This is an open-label phase 3 study conducted in USA, EU, and Israel. Key inclusion criteria are: up to 2 biopsy-proven LG UTUC with index tumor ≤15mm in the kidney (≤20mm in the ureter) and absence of high-grade cytology. VTP is performed via retrograde upper tract endoscopy under anesthetic and low light conditions, Padeliporfin is injected IV and an optical fiber, 20-40 mm diffuser, is positioned in proximity of the tumor through the scope. After Padeliporfin injection, the laser is activated for 10 min. Patients (Pts) are treated in two phases: Induction (ITP) and Maintenance Treatment Phases (MTP). ITP consists of 1-3 VTPs provided at 4-week intervals until achieving complete response (CR) or treatment failure on Primary Response Evaluation (PRE) visit. Primary endpoint is CR on endoscopic evaluation and negative instrumental cytology at the time of PRE (28 ± 3 days post last treatment) during ITP. Pts achieving CR will proceed to MTP and be followed with endoscopic evaluation every 3 months (mos) with VTP provided for recurrent tumors in the period up to 12 mos. Pts completing MTP, will be followed for additional 48 mos for long-term outcomes. A total of 100 pts are to be enrolled. Results: Interim analysis is defined in the study protocol and conducted mid-way (50% of evaluable pts) into the study with the cut-off date 5 November 2024. CR rate 73%, Partial Response rate 13.5%, Disease Recurrency rate 10.8%, Disease progression rate 2.7%, Overall Response Rate 86.5%. The most frequent TEAEs (Grade 1-2, resolved within few days) were: hematuria 14%, flank pain 10%, procedural pain 6.4%, dysuria 5.2%, UTI 5.2%, abdominal pain 4.7%, vomiting 4.7%, fatigue 4%, nausea 3.5%. Sixteen (9.2%) Grade 3 serious adverse events (SAE) were reported. Grade 3 SAEs related to the VTP treatment were renal colic and flank pain, and resolved within 2 days. Conclusions: Padeliporfin VTP has demonstrated efficacy and safety aligned with previous findings. Recruitment in ENLIGHTED trial is ongoing, with results anticipated to support the approval of a new therapy offering clinical benefits and organ-sparing alternative for pts. Clinical trial information: NCT04620239 .
Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies
2025-06-04

Autosomal recessive cerebellar ataxias (ARCAs) represent over 200 clinically heterogeneous genetic conditions involving degeneration of the cerebellum and associated tracts with resultant impairment of balance and coordination. Advancements in genomic testing have enabled rapid identification of the majority of known recessive disorders, shifting research focus to the development of targeted mechanistic treatments addressing underlying physiological pathways. Molecular classification allows recognition of cellular, biochemical, and genetic targets for high‐effect precision therapy development. ARCAs represent a significant global health burden, requiring establishment of a robust pathway for novel therapeutic discovery through modification of mechanisms of disease pathogenesis and subsequent clinical trial development. ANN NEUROL 2025;98:448–470
Azapeptide-based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity
2025-06-04

The main protease (Mpro) of SARS-CoV-2 plays a crucial role in the replication and pathogenesis of the virus. The relatively high conservation within the Coronaviridae family makes it an attractive therapeutic target for developing broad-spectrum agents to prevent and control SARS-CoV-2 and potentially future coronavirus-associated diseases. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 Mpro inhibitors, leading to several compounds with low nanomolar IC50 values. Examples include 14r (IC50 = 13.3 nM), 14s (IC50 = 30.6 nM), 20a (TPG-25-1, IC50 = 34.7 nM), 20g (IC50 = 30.4 nM), and 20h (IC50 = 31.3 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 Mpro but not the human protease cathepsin L. Several inhibitors, particularly 20a and 20f, exhibit antiviral activity with potencies comparable to nirmatrelvir and were highly potent against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2E166V). An Mpro co-crystal structure with 20a shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anti-coronaviral drugs.
Social inclusion policy effects on democratic satisfaction in Europe: a catalyst of polarization threating the identities of privileged social groups
2025-06-04

This study analyses the influence of inclusive policies on the democratic satisfaction of different social groups. It draws on social identity theory to explain how inclusive policies can contribute to conflicts and polarization in attitudes between social groups. More specifically, inclusive policies aim to improve the rights and social recognition of disadvantaged groups while they reduce the privileges of groups traditionally recognized as superior. Consequently, we expect that democratic institutions (as the providers of these policies) either get support or disproval from the respective social groups for inclusive policies—causing related increases and decreases in the democratic satisfaction of the respective groups. Using longitudinal data from European Social Survey (rounds 1–10) and additional country level data, we test how socially inclusive policies affect differences in democratic satisfaction between disadvantaged and privileged groups in four policy areas: (1) religious freedom, (2) inclusion of migrants, (3) equal treatment of homosexuals, and (4) gender equality. Except for gender equality policies, our findings support our hypothesis: socially inclusive policies lead to less democratic satisfaction for groups traditionally recognized as superior while the democratic satisfaction of formerly disadvantaged groups increases. These changes in democratic satisfaction indicate that inclusive policies lead to gains in equal social recognition (Isothymia) for some but at the same time are considered a threat to privileged social recognition (Megalothymia) by others. With respect to support for (democratic) political institutions inclusive policies are therefore a “double-edged sword” and need to be implemented with care. However, given comparatively strong inclusive policies regarding religious freedom and migrant integration our analyses also indicate convergence in democratic satisfaction between disadvantaged and privileged social groups.
The Netherlands: Political Developments and Data in 2024
2025-06-04

Abstract Following the 2023 national elections, the first half year of 2024 focused on negotiations between four parties from the centre‐right to the radical right, resulting in the formation of the Schoof Cabinet. With an independent former top civil servant as Prime Minister, the new government proposed more stringent migration measures, budgetary discipline, democratic reforms and a long‐term perspective for Dutch farmers, as well as a more open and transparent relationship between Parliament and the Cabinet. This marked the first time in over a century that the Prime Minister was not affiliated with one of the coalition parties. This arrangement paved the way for the most right‐wing government in the Netherlands since the postwar era. In the second half of the year, however, the coalition's fragile nature became evident, as the Cabinet found itself on the brink of collapse on three separate occasions.
Comparing UAV-Based Hyperspectral and Satellite-Based Multispectral Data for Soil Moisture Estimation Using Machine Learning
2025-06-05

Accurate estimation of soil moisture content (SMC) is crucial for effective water management, enabling improved monitoring of water stress and a deeper understanding of hydrological processes. While satellite remote sensing provides broad coverage, its spatial resolution often limits its ability to capture small-scale variations in SMC, especially in landscapes with diverse land-cover types. Unmanned aerial vehicles (UAVs) equipped with hyperspectral sensors offer a promising solution to overcome this limitation. This study compares the effectiveness of Sentinel-2, Landsat-8/9 multispectral data and UAV hyperspectral data (from 339.6 nm to 1028.8 nm with spectral bands) in estimating SMC in a research farm consisting of bare soil, cropland and grassland. A DJI Matrice 100 UAV equipped with a hyperspectral spectrometer collected data on 14 field campaigns, synchronized with satellite overflights. Five machine-learning algorithms including extreme learning machines (ELMs), Gaussian process regression (GPR), partial least squares regression (PLSR), support vector regression (SVR) and artificial neural network (ANN) were used to estimate SMC, focusing on the influence of land cover on the accuracy of SMC estimation. The findings indicated that GPR outperformed the other models when using Landsat-8/9 and hyperspectral photography data, demonstrating a tight correlation with the observed SMC (R2 = 0.64 and 0.89, respectively). For Sentinel-2 data, ELM showed the highest correlation, with an R2 value of 0.46. In addition, a comparative analysis showed that the UAV hyperspectral data outperformed both satellite sources due to better spatial and spectral resolution. In addition, the Landsat-8/9 data outperformed the Sentinel-2 data in terms of SMC estimation accuracy. For the different land-cover types, all types of remote-sensing data showed the highest accuracy for bare soil compared to cropland and grassland. This research highlights the potential of integrating UAV-based spectroscopy and machine-learning techniques as complementary tools to satellite platforms for precise SMC monitoring. The findings contribute to the further development of remote-sensing methods and improve the understanding of SMC dynamics in heterogeneous landscapes, with significant implications for precision agriculture. By enhancing the SMC estimation accuracy at high spatial resolution, this approach can optimize irrigation practices, improve cropping strategies and contribute to sustainable agricultural practices, ultimately enabling better decision-making for farmers and land managers. However, its broader applicability depends on factors such as scalability and performance under different conditions.
The genetic and phenotypic spectrum of GABRB1-related disorders
2025-06-05

Abstract Pathogenic variants in GABAA receptor subunits genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations, and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harboring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all eleven missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits. Gain-of-function (GoF) effects, characterised by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one, and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease including profound intellectual disability, hypotonia, and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus. Seizures were therapy-resistant in all individuals with GoF variants, and in a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterisation of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, though larger prospective studies are needed to confirm these observations.
An efficient discretization to simulate the solution of linear–quadratic stochastic boundary control problem
2025-06-05

Abstract We present a fast, implementable discretization for the Dirichlet boundary control problem associated with the stochastic heat equation and show its space–time convergence with rates. After space–time discretization the discrete optimality conditions involve the discretization of a backward SPDE, whose numerical solution is well known to be costly since it requires the computation of conditional expectations. In this work we give a reformulation of the discrete optimality conditions, which avoids the need to simulate conditional expectations and therefore significantly reduces complexities if compared with regression-based simulation while keeping the same convergence rate.
Advantages of digital twin technology in orthopedic trauma Surgery – Exploring different clinical use cases
2025-06-06

Abstract Digital twin technology offers significant benefits for addressing fracture non-unions in orthopedic trauma surgery, particularly in cases requiring revision surgery. In this study, we developed a clinically applicable digital twin workflow that integrates patient-specific imaging, motion capture, musculoskeletal modeling, and finite element simulation. We applied this workflow to five real patient cases involving different anatomical sites and treatment strategies, including implant modification, augmentative fixation, and corrective osteotomy. Each case was virtually reconstructed to evaluate mechanical conditions before and after revision surgery. The results demonstrated that digital twins can predict improvements in implant stress distribution and fracture strain states, offering valuable insights for optimizing surgical decisions. This work highlights the feasibility of digital twins and their clinical value in supporting individualized revision strategies, laying the foundation for their broader use in trauma care. .
Disentangling representations of retinal images with generative models
2025-06-06

Retinal fundus images play a crucial role in the early detection of eye diseases. However, the impact of technical factors on these images can pose challenges for reliable AI applications in ophthalmology. For example, large fundus cohorts are often confounded by factors such as camera type, bearing the risk of learning shortcuts rather than the causal relationships behind the image generation process. Here, we introduce a population model for retinal fundus images that effectively disentangles patient attributes from camera effects, enabling controllable and highly realistic image generation. To achieve this, we propose a disentanglement loss based on distance correlation. Through qualitative and quantitative analyses, we show that our models encode desired information in disentangled subspaces and enable controllable image generation based on the learned subspaces, demonstrating the effectiveness of our disentanglement loss. The project code is publicly available at https://github.com/berenslab/disentangling-retinal-images.
Transduction of γδ T cells with Baboon envelope pseudotyped lentiviral vector encoding chimeric antigen receptors for translational and clinical applications
2025-06-06

γδ T cells represent a promising cell platform for adoptive cell therapy. Their natural anti-tumor reactivity and HLA-independent target cell recognition make them an attractive platform for allogeneic adoptive immunotherapy clinical interventions. Initial clinical trials exploring allogeneic γδ T-cell therapies have demonstrated encouraging safety profiles. However, their therapeutic efficacy, especially against solid tumors, remains limited. This highlights the need for further optimization of γδ T cell products to improve anti-tumor potency, such as the increased targeting induced by the expression of a chimeric antigen receptors (CAR). However, a critical challenge in the development of CAR-γδ T cell therapies has been optimizing transduction efficiency with standard vector formats allowing for optimal CAR transgene expression that then produces an optimal therapeutic product. Here we present an effective method for enhancing CAR transgene expression in γδ T cells using a Baboon-pseudotyped lentiviral vector (BaEV-LV), comparing it to the conventional vesicular-stomatitis-virus-G protein (VSV-G) LVs. BaEV-LV significantly enhanced the transduction efficiency of γδ T cells with CARs, while conserving the beneficial cell product composition and phenotype of untransduced γδ T cells. The γδ T cells transduced with BaEV-LV CARs demonstrated significantly enhanced cytotoxicity against B7H3-expressing tumor cells in both 2D and 3D in vitro models. Our findings represent a significant advancement in CAR-γδ T cell engineering, offering a promising new avenue for cancer immunotherapy that combines the unique properties of Vγ9Vδ2 T cells with the targeted specificity of CAR technology. This method is compatible with automated closed-system platforms such as the CliniMACS Prodigy ® , facilitating Good Manufacturing Practice (GMP)-compliant production for clinical trials. This feature significantly enhances the translational potential of engineered γδ T cells, paving the way for the development of next-generation γδ T cell-based immunotherapies.
Reactivation of the tRNASer/tRNATyr gene cluster in Arabidopsis thaliana root tips
2025-06-06

Abstract Plants maintain redundant tRNA genes (tDNAs) in their nuclear genomes, but the significance, regulation, and functional roles of these genes remain poorly understood. A cluster of tandemly repeated tDNAs decoding serine and tyrosine (SYY cluster) is located on Arabidopsis (Arabidopsis thaliana) chromosome 1, intersecting constitutive heterochromatin and remaining transcriptionally silenced in most tissues. The natural conditions inducing their transcription remain unknown. Here, we elucidate the tissue-specific expression pattern of this cluster during seedling establishment. Our findings reveal that SYY cluster tRNAs are primarily produced in the root cap columella and adjacent root cap cells. Transcriptional reactivation of the SYY cluster occurs in these tissues despite high DNA methylation levels. Furthermore, we demonstrate that these cells accumulate high levels of a transgenic glycoprotein rich in serine, tyrosine, and proline, and that CRISPR/Cas9 deletion of the SYY cluster alters the accumulation and stability of the glycoprotein in these specific cells. Our work provides pioneering evidence of a developmental and cell-specific expression program for a plant tDNA. We offer insights into the putative role of specialized tDNAs in enhancing glycoprotein biosynthesis in protective tissues of the meristem.
Natural History of Autosomal Recessive IMPG2-Associated Retinal Dystrophy
2025-06-06

Autosomal recessive IMPG2-retinal dystrophy is typically an early onset retinal dystrophy associated with poor visual acuity. Younger patients are more likely to benefit from intervention in future trials due to early macular involvement in most patients.
Combining cognitive behavioral therapy and group training for social skills and cognition to improve negative symptoms in patients with psychotic disorders: a randomized controlled pilot trial
2025-06-06

Patients with psychotic disorders may exhibit negative symptoms and cognitive deficits in addition to delusions and hallucinations. The innovative MOSAIC psychotherapy combines individual cognitive behavioral therapy and group training for social skills and cognition over eight months to improve negative symptoms, social cognition and social functioning. Sixty patients with psychotic disorders participated in a randomized controlled pilot trial comparing MOSAIC with SUPPORT (supportive conversations and pleasant group activities with equal duration and frequency). Statistical analysis revealed no significant differences between MOSAIC and SUPPORT regarding improvement in negative symptoms (p = 0.72, Cohen's d = 0.1). However, pre-post comparisons showed reduction in negative symptoms with medium to large effect sizes within each group. Mean PANSS negative scores decreased by 4.7 ± 5.8 points for MOSAIC (p < 0.001, d = 0.82) and by 4.1 ± 7.7 points for SUPPORT (p = 0.01, d = 0.53). In addition, a significant dose-response relationship with therapy adherence was observed in both groups. The current clinical pilot study showed no superiority of the new therapeutic approach over supportive treatment. Nevertheless, the results add to the empirical evidence that psychotherapeutic treatments with a combination of individual and group sessions can contribute to improvement of negative symptoms.