julilili42/papers huggingface dataset:
Modulation of Maximum Pitch in the Speech of Caregivers Addressing Their 18- to 24-Month-Old Children Corresponds to Objects Vertical Position
2025-10-01

There are close relationships between vertical positions in space and auditory experiences of fundamental frequency (F0), which even very young children seem to use. Like adults, they associate higher or rising F0 values with upper positions in space and vice versa for lower or falling F0 values. Here, we tested whether caregivers’ speech capitalizes on these associations to guide the attention of very young children (18 to 24 months). Together with their child, caregivers saw four different objects (in the corners of a computer screen). Caregivers produced standardized sentences (e.g., “Look at the hat.”). We observed a significantly increased maximum F0 (but no differences in mean or minimum F0) at the onset of the utterance when the to be named object appeared at an upper position compared to the same object at a lower position. Furthermore, exploratory analyses of F0 dynamics of caregivers’ utterances indicated that the higher F0 maximum was part of a more prominent F0 increase for objects appearing at an upper compared to a lower position. Adults without a child present and less experience in interacting with children did not show systematic pitch modulation when addressing an imagined child in the same study set-up. Thus, caregivers appear to systematically modulate F0 dynamics to provide an effective language environment when they are interacting with their child.
Mitochondrial genomes of Middle Pleistocene horses from the open-air site complex of Schöningen
2025-10-01

Abstract Deep-time palaeogenomics offers rare insights into macroevolutionary events for both extant and extinct species. Aside from a Middle Pleistocene genome from North American permafrost (780–560 ka) and a number of Late Pleistocene specimens, most ancient horse DNA studies have focused on tracing the origins of domestication and subsequent periods. Here we present mitochondrial genomes from two Equus mosbachensis specimens from Schöningen, Germany, a Middle Pleistocene archaeological site complex with direct and repeated evidence of hominin–horse interactions on the shore of a palaeolake. Using petrous bone sampling, targeted enrichment and damage-aware and polarization-free mitochondrial DNA reconstruction methods, we extend the range of genome recovery in open-air sites to ~300,000 years ago. Phylogenetic analyses position these mitochondrial DNAs in two distinct, deeply divergent lineages, basal to both previously sequenced ancient Eurasian specimens and all modern-day horses. The Schöningen horse mitochondrial DNA data reveal a previously unrecognized diversification event within the clade, ultimately giving rise to modern-day horses, that is molecularly dated to ~570 ka and provides genetic support for the morphological species assignment. By extending the recoverable limits of ancient DNA from Middle Pleistocene open-air sites, our molecular findings bridge a temporal and geographic gap, providing insights on early evolutionary events within the genus Equus .
FTIR Analysis of Experimental Adhesives: Investigating Spectral Reproducibility, Chemometric Approaches, and Archaeological Applications
2025-10-01

<title>Abstract</title> Reflectance-mode Fourier transform infrared (FTIR) spectroscopy is increasingly employed in archaeological residue studies, offering a non-destructive means to investigate Paleolithic adhesive technologies. This study evaluates the reproducibility and comparability of reflectance-mode FTIR spectra collected from experimental adhesives on flint substrates, analyzed across an eight-year interval using two different FTIR instruments. A comprehensive suite of natural resins, gums, glues, and admixtures was assessed to examine spectral variability introduced by instrument configuration, sample orientation, and residue composition. To evaluate classification accuracy and interpretive consistency, both analyst-defined and ingredient-defined grouping strategies were applied to processed spectra. Chemometric methods including Principal Component Analysis (PCA) and Hierarchical Clustering Analysis (HCA) were used to investigate compositional trends and clustering, supplemented by a blind validation set of pure adhesives. While key chemical features were preserved across instruments after standardized processing, minor spectral differences introduced variability in chemometric clustering. In contrast, analyst-based groupings following a Kramers-Kronig transformation remained largely consistent across instruments and sample conditions. The results highlight the value of integrating visual inspection with chemometric tools and underscore the importance of tailored preprocessing strategies, transparent classification criteria and realistic experimental references. Reflectance-mode FTIR, when paired with reproducible workflows and robust interpretive strategies, offers a promising approach for identifying archaeological adhesive residues, particularly in contexts where destructive sampling is limited.
The Diverse Neuromuscular Spectrum of VPS13A Disease
2025-10-01

ABSTRACT Objective VPS13A disease (chorea‐acanthocytosis) is a rare neurodegenerative disorder caused by biallelic variants in VPS13A, typically presenting with hyperkinetic movement disorders, while neuromuscular signs are often mild. The aim of the project was to investigate the frequency and severity of neuromuscular impairment in VPS13A disease. Methods We systematically assessed the neuromuscular involvement in six patients with VPS13A disease. Our evaluation included genetic and clinical data, blood tests, electrophysiological studies, muscle MRI, and tissue samples from muscle and nerve. Results Age at clinical onset was 14 to 38 years (median: 37.5). Age at onset of paresis was 27 to 29 years (median: 29). Initial symptoms included seizures (5/6), hyperkinesia (2/6), and muscle weakness (1/6). Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6). Nine VPS13A variants were detected, including a novel copy‐neutral inversion. Phosphocreatine kinase was elevated in all cases (498–12,420 U/L; median of highest values: 2230 U/L). Nerve conduction studies revealed sensorimotor axonal neuropathy. Electromyography showed chronic neurogenic changes with high amplitudes, polyphasic potentials, and reduced interference patterns (6/6). Muscle MRI displayed fatty atrophy, most prominently in the calves (5/5). Muscle histology indicated neurogenic and myopathic changes. Electron microscopy of mitochondria and respiratory chain analysis showed no specific pathological findings. Interpretation Our findings emphasize the underrecognized neuromuscular spectrum in VPS13A disease, ranging from subclinical signs to severe paresis and sometimes preceding the hyperkinesia that gave rise to the historical term of chorea‐acanthocytosis. A comprehensive understanding of the phenotype is crucial for early diagnosis and appropriate management of VPS13A disease.
Fluctuations in the optimal sensorimotor mu-rhythm phase associated with high corticospinal excitability during TMS-EEG
2025-10-01

Our findings confirm that mu-phase and mu-power modulate corticospinal excitability. Individual inter-session variability and within-session fluctuations limit the generalizability of fixed-phase targeting. Future closed-loop TMS protocols may benefit from real-time adaptive algorithms to optimize stimulation efficacy.
An Analytic Element Method solution for simulating multiple steady-state groundwater contamination scenarios
2025-10-01

This paper presents a new Analytic Element Method (AEM) model for a 2D reactive transport problem. The AEM approach offers domain complexity due to superposition of multiple boundary conditions, while minimizing computational efforts, being a grid-free method. For the solution development, transformations of the advection-dispersion-reaction (ADR) equation are applied resulting in an equivalent mathematical problem governed by the modified Helmholtz equation. A solution (infinite series of Mathieu functions) derived for circular source elements provides the steady-state concentration distribution of two compounds undergoing an instantaneous and binary reaction in uniform flow. The solution is verified with an absolute error of the order 10<sup>-7</sup> mg/l and a relative error of order 10<sup>-4</sup> along boundary conditions. A sensitivity analysis identifies source strength and utilization factor of the reactants as parameters with the strongest impact on the plume length. The practicality of the developed AEM model is illustrated using different conceptual scenarios in which multiple source elements are superimposed as co- and counter interacting sources. Additionally, the method of images is applied using the same solution for representing the vertically oriented domain. These highlight the potential of the developed model for simulating a variety of practical conditions, such as irregular source geometries with or without continuity with unrestricted domain extent and minimal computational effort. Further, three field sites are briefly evaluated to present the applicability of the model.
Lenvatinib after progression on pemigatinib and futibatinib in FGFR2 fusion-positive biliary tract cancer with an acquired kinase point mutation
2025-10-01

Abstract Biliary tract cancers (BTC) represent a heterogeneous group of malignancies with a poor prognosis and rising incidence. Oncogenic FGFR2 fusions are one of several actionable molecular alterations. In this context, selective FGFR tyrosine kinase inhibitors have demonstrated promising and durable response rates and are now approved and included in clinical guidelines. However, secondary kinase mutations frequently arise over time, leading to resistance against these drugs. We present the case of a 41-year-old male patient with metastatic BTC who underwent molecular analysis after disease progression to various established chemotherapy combinations. Testing identified an oncogenic FGFR2 fusion (FGFR2::BICC1). The patient was treated with pemigatinib for 14 months. Upon disease progression, the resistance-associated FGFR2 p. E565A variant was detected in a follow-up biopsy. Treatment was switched to futibatinib, resulting in rapid disease progression. Lacking other therapeutic options, the patient was treated with lenvatinib, supported by previously published data suggesting a potential benefit in similar settings. The treatment was well tolerated, with only a mild increase in transaminases, and the patient remained on treatment with noteworthy effects for 15 months to date. With a growing incidence of BTC and growing use of targeted therapies for FGFR2 alterations, the emergence of secondary resistance-causing point mutations following treatment with approved inhibitors is becoming increasingly challenging. Beyond selective inhibitors, lenvatinib may represent a viable therapeutic option.
Is the Development of Hypo-Gammaglobulinemia Associated with Better Treatment Response in Patients with Rheumatoid Arthritis Using Rituximab?
2025-10-01

Objectives: To determine the frequency of development of hypogammaglobulinemia in rheumatoid arthritis (RA) patients receiving rituximab (RTX) and to examine the relation between the development of hypogammaglobulinemia and RTX treatment response. Methods: The data of 165 RA patients who applied to our outpatient clinic between January 2010 and June 2021, and who received at least 2 courses of RTX with an interval of 6 months, were retrospectively evaluated. The demographic, clinical, and laboratory data, as well as treatment characteristics, were collected. Results: Of 165 patients, 35 (21.2%) developed hypogammaglobulinemia. In the multivariable analysis examining the risk factors for the development of hypogammaglobulinemia in RA patients receiving RTX, it was determined that having pre-treatment IgG value below 10.5 g/l (OR= 4.24 (95% CI 1.69–10.66) and the increase in the number of RTX courses (OR= 1.1 (95% CI 1.01–1.22) were independently associated risk factors. During their follow-up, patients who developed hypogammaglobulinemia and those who did not were compared. No difference was observed between DAS28-ESR levels, but CRP levels were significantly lower in the group that developed hypogammaglobulinemia. Conclusions: In this study, there was no difference in DAS28-ESR levels between patients with and without hypogammaglobulinemia, although a difference was observed in acute phase reactants, which are more objective parameters. This may be due to subjective parameters in DAS28-ESR scoring or other concomitant conditions such as fibromyalgia. Therefore, additional objective findings or methods may guide the evaluation of treatment response.
Diffuse Continuum Emission and Large Extended Sources at MeV Energies
2025-10-01

Abstract Future <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>γ</mml:mi> </mml:math> -ray survey instruments, such as COSI , newASTROGAM and AMEGO-X , will significantly improve previous and current all-sky surveys at MeV energies. In this paper we discuss the continuum emission from the Milky Way, two prominent large extended sources, the Fermi bubbles and Loop I, and the extragalactic <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>γ</mml:mi> </mml:math> -ray background. We highlight the importance of measurements in the MeV to GeV energy range for understanding CR production and propagation in the Galaxy, for the determination of the nature of the Fermi bubbles and Loop I, and for exploring the origin of the extragalactic <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>γ</mml:mi> </mml:math> -ray background.
P11.29.B WHOLE-BRAIN RADIATION THERAPY WITH DOSE ESCALATION ON MULTIPLE METASTASES, WITH AND WITHOUT HIPPOCAMPAL AVOIDANCE (HIPPORAD TRIAL)
2025-10-01

Abstract BACKGROUND The HIPPORAD trial investigated a novel method of whole brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) with and without hippocampal avoidance in patients with multiple brain metastases. MATERIAL AND METHODS This was a prospective, multicenter, randomized, double-blind phase II clinical trial (DRKS00004598), conducted across 13 German centers. Patients with 4 to 10 brain metastases (≥5 mm in size) were randomly assigned (1: 1) to receive either hippocampal avoidance WBRT with SIB (HA-WBRT+SIB, Arm A) or standard WBRT with SIB without hippocampal sparing (Arm B). Treatment comprised WBRT with 30 Gy combined with SIB of 51 Gy directed at the metastases (42 Gy for lesions in the brainstem or surgical cavities), administered over 12 daily fractions. The primary outcome was the change in neurocognitive performance in the Verbal Learning and Memory Test (VLMT), assessed three months post-therapy. Secondary endpoints included neurocognitive function at 9 and 18 months, emotional wellbeing, quality of life, and oncological efficacy. RESULTS Between 02.08.2016-07.09.2021, 170 patients were enrolled and 136 randomized: 67 to HA-WBRT+SIB and 69 to WBRT+SIB. At the three-month evaluation, 38 patients in Arm A and 42 in Arm B were alive, treated per protocol, and included in the primary analysis. No significant difference in overall learning ability was observed between groups (p = 0.83). Both arms experienced a decline in VLMT scores at three months. At the nine-month mark, cognitive scores improved, with Arm A trending more favorably than Arm B. Notably, depression rates were significantly lower in the HA-WBRT+SIB group at both 3 (p = 0.047) and 18 months (p = 0.048). Arm A also exhibited a trend towards lower anxiety and higher emotional functioning. One year after treatment, the rate of distant intracranial progression was 22% in both groups, whereas local progression occurred in 4% of patients in Arm A and 12% in Arm B. Time to hippocampal metastases did not differ significantly (p = 0.98). Median overall survival was 9.1 months in the HA-WBRT+SIB arm und 6.6 months in the WBRT+SIB arm (p = 0.44). Neurological mortality at one year was 4% in arm A and 12% in arm B. Serious adverse events related to treatment were observed in 3% of Arm A patients and 6% of Arm B patients. CONCLUSION This is the first randomized trial to prove feasibility of HA-WBRT+SIB and suggest that it may reduce depressive symptoms in patients with multiple brain metastases. Verbal memory performance showed no significant difference, although patients receiving HA-WBRT+SIB exhibited a trend toward better recovery. HA-WBRT+SIB was well tolerated, maintained strong intracranial control, and was associated with very low neurological mortality.
P05.19.A CLINICAL OUTCOME OF BIOMARKER-GUIDED THERAPIES IN ADULT NEURO-ONCOLOGY PATIENTS: AN UPDATE FROM THE TÜBINGEN MOLECULAR TUMOR BOARD COHORT
2025-10-01

Abstract BACKGROUND Molecular profiling and target decision in the Molecular Tumor Board (MTB), within structured networks such as the Centers for Personalized Medicine (CPM), have broadened therapeutic options for neuro-oncology patients. Here, we provide an updated analysis of the Tübingen MTB cohort for adult patients with advanced tumors in the nervous system. MATERIAL AND METHODS The Tübingen MTB cohort is an ongoing observational study (NCT03503149) focusing on precision oncology in patients with advanced tumors. Upon enrollment, patients undergo comprehensive molecular profiling, and targeted therapy recommendations are recommended through interdisciplinary discussions in the MTB. RESULTS This report includes follow-up data on neuro-oncology patients up to the cutoff date of June 30, 2024. Of 1,088 patients enrolled, 854 were presented at the MTB (78.5%). Molecularly guided therapy was recommended for 773 of 854 patients (90.5%), with prioritization based on evidence levels. Treatment was initiated in 155 of 773 patients (20.1%). Among these, progression-free survival (PFS) data were available for 134 patients, of whom 47 (35.1%) achieved a PFS2/PFS1 ratio &amp;gt;1.3. CONCLUSION The CPM and MTB workflows have become an integral part of routine clinical practice and demonstrate clinical benefit in approximately one-third of treated patients.
P02.12.A DISTINCT MODULATION OF METABOLISM AND GLIOMA-ASSOCIATED MICROENVIRONMENT BY DEXAMETHASONE AND BEVACIZUMAB
2025-10-01

Abstract BACKGROUND Glioblastomas are aggressive primary tumors of the central nervous system with limited registered therapeutic options. Peritumoral vasogenic or treatment-associated edema —commonly observed after radiation or immunotherapy—poses a significant clinical burden in glioblastoma patients. Dexamethasone (DEXA), a synthetic glucocorticoid, is commonly used in clinical practice in these situations, though its immunosuppressive effects may counteract immunotherapeutic strategies. Bevacizumab (BEV), an anti-VEGF antibody, is increasingly utilized in clinical practice to address therapy-induced edema. In this study, we investigated the differential effects of DEXA and BEV on tumor metabolism and the glioma-associated microenvironment in experimental models. MATERIAL AND METHODS We performed ex vivo proton nuclear magnetic resonance (1H-NMR) spectroscopy-based metabolomics on glioma long-term cell lines upon treatment with DEXA or BEV to assess metabolic changes. Cytokine-release profiles were analyzed by ELISA. Microenvironmental modulation was further examined using co-culture systems and a syngeneic orthotopic glioma mouse model with immune profiling by flow cytometry and immunohistochemistry. RESULTS Comparison of DEXA and BEV treated glioma long-term cell lines revealed changes in abundance of distinct metabolites involved in energy and amino acid metabolism (e.g. lactate, alanine). DEXA and BEV elicited distinct cytokine-release profiles in glioma long-term cell lines. In vivo, BEV treatment led to a reduced presence of regulatory T cells (CD4+FOXP3+) and an increased proportion of activated T cells (CD4+GzmB+) in the tumor microenvironment as compared to DEXA. CONCLUSION DEXA and BEV exert distinct effects on glioma metabolism and immune microenvironmental composition. These molecular insights could inform clinical strategies for managing treatment-associated cerebral edema in clinical trials investigating immunotherapeutic approaches.
P02.13.B MAGNETIC NAVIGATION OF IMMUNOBOTS TO ORTHOTOPIC EXPERIMENTAL GLIOMA MODULATES THE GLIOMA-ASSOCIATED MICROENVIRONMENT
2025-10-01

Abstract BACKGROUND Glioblastomas are primary tumors of the central nervous system with a poor prognosis. They are characterized by deep infiltration into the surrounding brain parenchyma and an immunosuppressive tumor microenvironment, both of which pose significant challenges to current therapeutic strategies. Various cellular carriers—such as neural stem cells, mesenchymal stem cells, and bone marrow-derived hematopoietic progenitor cells (HPCs)—have been investigated for targeted delivery, and they indeed home to intracerebral gliomas even after intravenous administration. However, their migration cannot be externally controlled. Mobile microrobots are emerging tools capable of operating at the cellular scale and being steered wirelessly, potentially enabling access to otherwise inaccessible tumor regions. In this study, we explore a novel strategy utilizing such microrobots. MATERIAL AND METHODS We developed immunobots by loading autologous macrophages with Janus silica particles (~500 nm in diameter), which were half-coated with a 60 nm FePt nanofilm for magnetic guidance and functionalized with bacterial lipopolysaccharide (LPS) to induce an anti-tumorigenic macrophage phenotype. We evaluated their in vivo tolerability and therapeutic efficacy in the syngeneic, immunocompetent SMA560/VM/Dk glioma mouse model. Post-treatment effects were assessed by flow cytometry and immunohistochemistry. RESULTS Direct injection of immunobots into the striatum of VM/Dk mice was well tolerated, with no signs of autoinflammation. Intratumoral administration into orthotopic SMA560 gliomas led to modulation of the tumor microenvironment, including enhanced infiltration of T cells. Furthermore, intravenous administration of immunobots followed by magnetic guidance using a permanent magnet array successfully directed them to the tumor site and induced local immunomodulatory effects. CONCLUSION Our study demonstrates that magnetically guided microrobots based on autologous bone-marrow-derived macrophages enable the modulation of the glioma-associated tumor microenvironment.