julilili42/papers huggingface dataset:
CTNI-85. FINAL RESULTS FROM N2M2/NOA-20
2024-11-01

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.
High-dimensional Bayesian likelihood normalisation for CRESST's background model
2024-11-01

Abstract Using CaWO 4 crystals as cryogenic calorimeters, the CRESST experiment searches for nuclear recoils caused by the scattering of potential Dark Matter particles. A reliable identification of a potential signal crucially depends on an accurate background model. In this work, we introduce an improved normalisation method for CRESST's model of electromagnetic backgrounds, which is an important technical step towards developing a more accurate background model. Spectral templates based on Geant4 simulations are normalised via a Bayesian likelihood fit to experimental background data. Contrary to our previous work, no explicit assumption of partial secular equilibrium is required a priori, which results in a more robust and versatile applicability. This new method also naturally considers the correlation between all background components. Due to these purely technical improvements, the presented method has the potential to explain up to 82.7 % of the experimental background within [1 keV,40 keV], an improvement of at most 18.6 % compared to our previous method. The actual value is subject to ongoing validations of the included physics.
Deficits in or Preservation of Basic Number Processing in Parkinson's Disease? A Registered Report
2024-11-01

ABSTRACT Neurodegenerative diseases such as Parkinson's disease (PD) have a huge impact on patients, caregivers, and the health care system. Until now, diagnosis of mild cognitive impairments in PD has been established based on domain‐general functions such as executive functions, attention, or working memory. However, specific numerical deficits observed in clinical practice have not yet been systematically investigated. PD‐immanent deterioration of domain‐general functions and domain‐specific numerical areas suggests mechanisms of both primary and secondary dyscalculia. The current study systematically investigated basic number processing performance in PD patients for the first time, targeting domain‐specific cognitive representations of numerosity and the influence of domain‐general factors. The overall sample consisted of patients with a diagnosis of PD, according to consensus guidelines, and healthy controls. PD patients were stratified into patients with normal cognition (PD‐NC) or mild cognitive impairment (level I‐PD‐MCI based on cognitive screening). Basic number processing was assessed using transcoding, number line estimation, and (non‐) symbolic number magnitude comparison tasks. Discriminant analysis was employed to assess whether basic number processing tasks can differentiate between a healthy control group and both PD groups. All participants were subjected to a comprehensive numerical and a neuropsychological test battery, as well as sociodemographic and clinical measures. Results indicate a profile of preserved (verbal representation) and impaired (magnitude representation, place × value activation) function in PD‐MCI, hinting at basal ganglia dysfunction affecting numerical cognition in PD. Numerical deficits could not be explained by domain‐general cognitive impairments, so that future research needs to incorporate domain‐specific tasks of sufficient difficulty.
Measuring Cognitive Ability in Children and Adolescents
2024-11-01

Abstract: Working memory capacity (WMC) measures for children are unsatisfying in terms of lack of operational continuity with measures for adolescents and adults. Thus, we developed and validated a multivariate WMC test battery that uses WMC paradigms that can be applied from 1st grade onwards. In Study 1, we developed child-contextualized WMC tests and investigated their psychometric properties (including gender differences) in N = 343 1st graders. In Study 2, we juxtaposed child-contextualized and decontextualized instantiations of our tasks in N = 379 5th–10th graders. Child-contextualized tests were essentially equivalent to structurally identical, decontextualized WMC tests, and the battery correlated strongly with a multivariate measure of fluid intelligence. Across studies, we found support for good psychometric properties of the tests. The battery bridges the gap between child-specific and decontextualized WMC tests, is applicable for all ability levels, can be adapted easily in terms of difficulty and length.
Religious Coexistence in the Dutch Republic and France in the Seventeenth Century: Legal Systems, Sacred Spaces, and Minority Resilience in Utrecht and Nîmes
2024-11-01

Abstract This article examines religious coexistence and survival tactics of the religious minority groups in the Dutch Republic and the Kingdom of France, comparing Utrecht’s Catholics and Nîmois Huguenots in three respects: legal systems, battles over sacred spaces, and minority resilience. The distinct legal systems in the two countries – the Union of Utrecht and the Edict of Nantes – shaped two different forms of religious diversity in Utrecht and Nîmes, that is, de facto and de jure coexistence. Under these divergent legal settings, both Catholics and Protestants in the two cities similarly asserted their presence in the urban space and sought to practice their faith publicly. However, the minorities’ tactics in the conflicts over sacred spaces and the extent of physical violence in those battles differed significantly. While facing challenging circumstances in the last quarter of the seventeenth century, both minority groups demonstrated a remarkable resilience, mobilizing various survival tactics. They constantly negotiated the detailed conditions of coexistence with the dominant faith, attempting to carve out their own positions within their local, precarious environment.
Immune cell distributions in the blood of healthy individuals at high genetic risk of Parkinson’s disease
2024-11-02

Abstract The immune system likely plays a key role in Parkinson’s disease (PD) pathophysiology. Thus, we investigated whether immune cell compositions are already altered in healthy individuals at high genetic risk for PD. We quantified 92 immune cell subtypes in the blood of 442 individuals using multicolor flow cytometry. Polygenic risk scores (PGS) for PD were calculated based on genome-wide significant SNPs (n = 87) from a large genome-wide association study (n = 1,530,403). Linear regression analyses did not reveal significant associations between PGS and any immune cell subtype (FDR = 0.05). Nominally significant associations were observed for NKG2C+ B cells (p = 0.026) in the overall sample. Older participants at increased genetic PD risk also showed a higher proportion of myeloid dendritic cells (p = 0.019) and CD27+CD4+ memory T cells (p = 0.043). Several immune cells were nominally statistically associated in women only. These findings suggest that major alterations of immune cells only occur later in the progression of PD.
AI-enabled conversational agent increases engagement with cognitive-behavioral therapy: A randomized controlled trial
2024-11-02

Abstract Timely support after referral to mental healthcare is crucial, yet patients often face prolonged wait times without intervention. Digital mental health interventions offer scalable solutions, but many struggle to achieve acceptable patient engagement. Tailoring and personalizing materials to individual needs is paramount for driving engagement, a task that generative artificial intelligence AI (genAI) is potentially able to achieve. To examine this promise, we conducted a randomized controlled trial using a genAI-enabled therapy app, Limbic Care, which delivers personalized cognitive behavioral therapy (CBT) materials, against PDF workbooks delivering static CBT content, as commonly used in standard care. Adults with elevated symptoms of anxiety or depression (N = 540) were randomly assigned to the app or control group for six weeks. The app group exhibited a threefold increase in engagement (2.4 times higher usage frequency, 3.8 times longer usage durations). While both groups showed similar overall symptom improvement, participants who engaged with the app’s clinical personalization capabilities experienced significantly greater reductions in anxiety symptoms and enhanced well-being than those who engaged with the standard CBT materials. Importantly, the app was safe, with no increase in adverse events compared to standard care. Our findings suggest that genAI-enabled therapy apps can safely enhance patient engagement and improve clinical outcomes through clinically personalized interventions.
Unraveling the role of PBK in glioblastoma: from molecular mechanisms to therapeutic targets
2024-11-02

Background: This study investigates the gene expression characteristics of glioma-initiating cells (GIC), an important subgroup of glioblastoma (GBM), after knockdown of PBK (PDZ-binding kinase). Differentially expressed genes (DEGs) between PBK knockdown GIC and control groups were screened through bioinformatics methods. The authors analyzed the mechanisms and roles of these DEGs in GBM tumorigenesis and patient prognosis. Methods: Microarray data (GSE53800) were obtained from the Gene Expression Omnibus (GEO) database, selecting 18 GIC cell line samples with or without PBK knockdown. Each control and knockdown group contained three samples. DEGs were screened using R software. GO enrichment analysis, KEGG pathway analysis, PPI network analysis, and hub gene identification were conducted to explore DEG mechanisms. Western blot analysis was also performed to detect EIF4E protein expression, one of the key hub genes, after PBK knockdown in the HS683 glioma cell line. Results: A total of 175 upregulated and 145 downregulated genes were identified. GO analysis showed that DEGs were mainly enriched in the positive regulation of cell proliferation, cell adhesion, and angiogenesis. KEGG pathway analysis revealed that DEGs were mainly involved in neuroactive ligand-receptor interactions, calcium signaling, and HIF-1 signaling pathways. Western blot results indicated that EIF4E was downregulated after PBK knockdown. Conclusion: A group of genes, such as EIF4E, were closely associated with PBK expression and functions. These findings may provide insight into the molecular mechanism of PBK in GBM.
The spliceosomal component GAMETOPHYTIC FACTOR 1 (GFA1) regulates a key photoperiodic switch
2024-11-03

Abstract Plants have evolved sophisticated mechanisms to perceive and interpret daytime in order to flower at an optimal time point. Here we show that the spliceosomal component GAMETOPHYTIC FACTOR 1 ( GFA1 ) constitutes a previously unrecognized key photoperiodic switch, that is essential for flowering in long days. We show that gfa1 hypomorphic ( gfa1 hyp ) plants fail to initiate flowering in long-days (LD), which correlates with ectopic activation of the short-day (SD) flowering repressor ARABIDOPSIS THALIANA CENTRORADIALIS (ATC) . Accordingly, flowering is restored upon inactivation of ATC in gfa1 hyp mutants. A novel tissue-specific in-planta splice assay and comprehensive RNAseq profiling of gfa1 hyp mutants indicate that GFA1 mediated pre-mRNA splicing is substrate specific, as previously suggested for GFA1 orthologs. Furthermore, we show that gfa1 hyp mutants accumulate nonsense transcripts of the photoreceptor components PHYB and RRC1 , suggesting inappropriate photoreceptor signaling as a potential cause for the ectopic activation of the SD characteristic profile in gfa1 hyp . In fact, known downstream targets of the phytochrome system such as RS31, SR34a, SRp30 accumulate reduced amounts of light-dependent splice isoforms. Together, our data reveal a link between spliceosome composition and long-day flowering, based on complex transcriptional readouts in response to day length.
Apheresis therapies in MOGAD: a retrospective study of 117 therapeutic interventions in 571 attacks
2024-11-04

Background Incomplete attack remission is the main cause of disability in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Apheresis therapies such as plasma exchange and immunoadsorption are widely used in neuroimmunology. Data on apheresis outcomes in MOGAD attacks remain limited. Methods We retrospectively evaluated all apheresis treated attacks occurring in patients with MOGAD between 2008 and 2023 at 18 Neuromyelitis Optica Study Group centres. Treatment response was categorised as complete, partial or no remission. Preattack and follow-up Expanded Disability Status Scale (EDSS) and visual Functional System Scores (FSS) were used to calculate absolute outcomes (ΔEDSS/Δvisual FSS). Predictors of complete remission were analysed using a generalised linear mixed model. Results Apheresis was used for 117/571 (20.5%) attacks in 85/209 (40.7%) patients. Attacks with simultaneous optic neuritis and myelitis were treated more often with apheresis (42.4%, n=14) than isolated myelitis (25.2%, n=35), cerebral manifestation (21.0%, n=17) or isolated optic neuritis (17.6%, n=51). Apheresis was initiated as first-line therapy in 12% (4.5 (IQR 0–11) days after attack onset), second-line therapy in 62% (15 (IQR 6.75–31) days) and third-line therapy in 26% (30 (IQR 19–42) days). Complete remission was achieved in 21%, partial remission in 70% and no remission in 9% of patients. First-line apheresis (OR 2.5, p=0.040) and concomitant disease-modifying therapy (OR 1.5, p=0.011) were associated with complete remission. Both parameters were also associated with a favourable ΔEDSS. No differences in outcomes were observed between the apheresis types. Conclusion Apheresis is frequently used in MOGAD attacks. An early start as first-line therapy and concomitant disease-modifying therapy predict full attack recovery.
Ecto-NOX Disulfide-Thiol Exchanger 2 (ENOX2/tNOX) Is a Potential Prognostic Marker in Primary Malignant Melanoma and May Serve as a Therapeutic Target
2024-11-04

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) ENOX2 RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib. We discovered that high ENOX2 expression is associated with decreased overall (OS), disease-specific (DSS) and metastasis-free survival (MFS) in primary melanoma (PM) and a reduction in electronic tumor-infiltrating lymphocytes (eTILs). A gradual rise in ENOX2 expression was found with an increase in malignant potential from benign nevi (BNs) via PMs to melanoma metastases (MMs), as well as with an increasing tumor thickness and stage. These results highlight the important role of ENOX2 in cancer growth, progression and metastasis. The ENOX2 expression was not limited to malignant cell lines but could also be found in keratinocytes, fibroblasts and melanocytes. The viability of melanoma cell lines could be inhibited by PXD. A reduced induction of phospho-AKT under PXD could prevent the development of acquired BRAFi resistance. In conclusion, ENOX2 may serve as a potential prognostic marker and therapeutic target in malignant melanoma.
StreptomeDB 4.0: a comprehensive database of streptomycetes natural products enriched with protein interactions and interactive spectral visualization
2024-11-05

Abstract Streptomycetes remain an important bacterial source of natural products (NPs) with significant therapeutic promise, particularly in the fight against antimicrobial resistance. Herein, we present StreptomeDB 4.0, a substantial update of the database that includes expanded content and several new features. Currently, StreptomeDB 4.0 contains over 8500 NPs originating from ∼3900 streptomycetes, manually annotated from ∼7600 PubMed-indexed peer-reviewed articles. The database was enhanced by two in-house developments: (i) automated literature-mined NP–protein relationships (hyperlinked to the CPRiL web server) and (ii) pharmacophore-based NP–protein interactions (predicted with the ePharmaLib dataset). Moreover, genome mining was supplemented through hyperlinks to the widely used antiSMASH database. To facilitate NP structural dereplication, interactive visualization tools were implemented, namely the JSpecView applet and plotly.js charting library for predicted nuclear magnetic resonance and mass spectrometry spectral data, respectively. Furthermore, both the backend database and the frontend web interface were redesigned, and several software packages, including PostgreSQL and Django, were updated to the latest versions. Overall, this comprehensive database serves as a vital resource for researchers seeking to delve into the metabolic intricacies of streptomycetes and discover novel therapeutics, notably antimicrobial agents. StreptomeDB is publicly accessible at https://www.pharmbioinf.uni-freiburg.de/streptomedb.
Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β‐Lactam Antibiotics
2024-11-05

Abstract Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci.
Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice
2024-11-05

Background: Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform phosphodiesterase 10A (PDE10A) might be a target for analgesic therapy. Methods: In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors. Results: PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD, 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (two-way ANOVA, group, F[1,18] = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund’s adjuvant (F[1,14] = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920. Conclusions: Collectively, the data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.
De Se Modal Illusions
2024-11-05

Abstract Research on personal identity often relies on imaginary cases and tends to theorize about our nature from the first‐person perspective. In this paper, I argue that a problem arises when we combine the two methods and assess imaginary cases from the first‐person perspective. The problem is that the link between de se imagination and modality is broken. De se imagination regularly gives rise to de se modal illusions. De se modal illusions come in two varieties: there are de se illusions of possibility and de se illusions of impossibility. I present a systematic account of the two types of illusion. I further make the case that the proposed account is compatible with maintaining a general link between imaginability and possibility. I apply the account to two concrete cases and use it to undercut the motivation behind a central theory of personal ontology, Dualism, and a central account of personal persistence, Lockeanism.