julilili42/papers huggingface dataset:
Application of the grading system for “nociplastic pain” in chronic primary and chronic secondary pain conditions: a field study
2024-08-26

Abstract The concept “nociplastic pain” has been developed for patients with features of nociceptive system sensitization that are not explained as nociceptive or neuropathic. Here, we tested how well the recently published grading system differentiates between chronic primary and secondary pain conditions. We recruited patients with fibromyalgia (FMS, n = 41), complex regional pain syndrome (CRPS, n = 11), osteoarthritis (OA, n = 21), or peripheral nerve injury (PNI, n = 8). We used clinical history, pain drawings, quantitative sensory testing (QST), and questionnaires to classify their pains as possibly or probably “nociplastic.” All patients with chronic primary pain exhibited widespread/regional pain not explainable by either nociceptive or neuropathic mechanisms. Widespread pain occurred in 12 patients with OA but was identified as nociceptive in 11 of 12. Regional pain occurred in 4 patients with PNI but was identified as neuropathic in 3 of 4. At this step, the grading system had 100% sensitivity and 93% specificity. Clinical evidence for pain hypersensitivity by QST, and history of hypersensitivity and mental comorbidities did not differentiate between chronic primary pain (QST: 36/52 = 69%, history: 43/52 = 83%) and secondary pain conditions (QST: 20/29 = 69%, history: 24/29 83%). Based on these data, specificity remained excellent (93%), but sensitivity dropped substantially (60%) due to lacking evidence for pain hypersensitivity in many patients with FMS. This low sensitivity suggests that the published grading system is not suitable for screening purposes. We suggest structural and content modifications to improve sensitivity, including placement of patient history before clinical examination and addition of a high tender point count as evidence for widespread pain hypersensitivity.
Subcutaneous foslevodopa in akinetic crisis. A case report from the neurological intensive care unit
2024-08-26

Introduction Akinetic crisis is a severe deterioration of motor performance occurring in syndromes with pre- or postsynaptic dopaminergic deficit, necessitating effective dopamine replacement therapy. The subcutaneously applicable levodopa derivative foslevodopa represents a new therapeutic option for patients with advanced Parkinson’s disease as a continuous therapy. However, its potential role as a parenteral treatment option for akinetic crisis has not been investigated, yet. The case A 78 year-old patient who had developed akinetic-rigid symptomatology in the context of normal pressure hydrocephalus was admitted to our intensive care unit after experiencing an acute exacerbation of akinesia in the context of pulmonary infection. Off-label administration of subcutaneous foslevodopa was initiated after repeated failures to insert a gastric tube for enteral application of levodopa and contraindications against amantadine and apomorphine. Results Following the administration of a subcutaneous test dose, continuous application of foslevodopa via a B. Braun syringe pump was gradually increased to 0.3 mL/h during the daytime and 0.15 mL/h at night, corresponding to a levodopa equivalent dosage of 1,020 mg/d. This was accompanied by an improvement of the MDS-UPDRS III score from 85 points to 59 points after 72 h. Discussion Treatment of an akinetic crisis with subcutaneous foslevodopa in an intensive care unit setting has proven to be safe and effective in a patient with acute akinesia associated with dopamine-sensitive hydrocephalus. Due to the pathophysiological distinction from Parkinson’s disease, there may be differences in therapeutic response and side effects. Nevertheless, the method used here can serve as a protocol basis for the treatment of akinetic crises with foslevodopa in general and as a starting point for further research.
Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial
2024-08-26

Background In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor μ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Objective Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor μ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. Methods We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months’ follow-up. Results Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. Conclusion The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. Clinical Trial Registration ClinicalTrials.gov , identifier [NCT05005780].
Staphylococcus aureus Stress Response to Bicarbonate Depletion
2024-08-26

Bicarbonate and CO2 are essential substrates for carboxylation reactions in bacterial central metabolism. In Staphylococcus aureus, the bicarbonate transporter, MpsABC (membrane potential-generating system) is the only carbon concentrating system. An mpsABC deletion mutant can hardly grow in ambient air. In this study, we investigated the changes that occur in S. aureus when it suffers from CO2/bicarbonate deficiency. Electron microscopy revealed that ΔmpsABC has a twofold thicker cell wall thickness compared to the parent strain. The mutant was also substantially inert to cell lysis induced by lysostaphin and the non-ionic surfactant Triton X-100. Mass spectrometry analysis of muropeptides revealed the incorporation of alanine into the pentaglycine interpeptide bridge, which explains the mutant’s lysostaphin resistance. Flow cytometry analysis of wall teichoic acid (WTA) glycosylation patterns revealed a significantly lower α-glycosylated and higher ß-glycosylated WTA, explaining the mutant’s increased resistance towards Triton X-100. Comparative transcriptome analysis showed altered gene expression profiles. Autolysin-encoding genes such as sceD, a lytic transglycosylase encoding gene, were upregulated, like in vancomycin-intermediate S. aureus mutants (VISA). Genes related to cell wall-anchored proteins, secreted proteins, transporters, and toxins were downregulated. Overall, we demonstrate that bicarbonate deficiency is a stress response that causes changes in cell wall composition and global gene expression resulting in increased resilience to cell wall lytic enzymes and detergents.
iVAC-XS15-CLL01: personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients undergoing BTK-inhibitor-based regimens
2024-08-26

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton’s tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured “peptide warehouse” based on the patient’s individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.
Systematic Characterization of Transport Regulation inEscherichia coliacross defined environmental cues
2024-08-26

Abstract Transport of small molecules across the bacterial cell envelope is essential to ensure nutrient uptake and protect bacteria from toxic compounds. Due to its decisive role, transport is controlled by complex regulatory networks, knowledge of which – in particular across external cues – remains poorly understood. Here we investigate transcriptional regulation of seven prominent transport genes in Escherichia coli across 94 defined chemical cues, and simultaneously map the contributions of the key regulators MarA, SoxS and Rob to promoter activity. One third of all tested compounds triggered transcriptional changes, the vast majority of which previously unknown. Importantly, we exposed main drivers of transport control in E. coli , e.g. bacteriostatic, but not bactericidal, antibiotics trigger expression of efflux pumps, and that Rob contributes to ∼1/3 of all measured transcriptional changes, thereby emerging as a more prominent transport regulator than previously thought. We showcase the potential of our resource by elucidating the molecular mechanism of antibiotic antagonisms with widely consumed caffeine in E. coli . Altogether, our resource capitalizes on providing a quantitative overview of transport determinants across environments, and brings perspective to long-term prevailing concepts in the field.
Deep-rooted Indian Middle Palaeolithic: Terminal Middle Pleistocene lithic assemblage from Retlapalle, Andhra Pradesh, India
2024-08-27

The Indian Middle Palaeolithic has been recognized as crucial evidence for understanding the complex behavioural dynamics of hominins and is also seen as a behavioural marker of early Homo sapiens in the region. Recent research has pushed back the timeline of the Middle Palaeolithic to the Middle Pleistocene epoch, indicating a potential in-situ emergence from the earlier Late Acheulian culture. The long-lasting Middle Palaeolithic culture in India evolve over multiple glacial-interglacial cycle, showing signs of behavioural resilience to bigger climatic upheaval like ~74 ka Toba super-eruption. This has added to the complexity of our understanding of the Middle Palaeolithic in the region and emphasizes the need for further research. This study focuses upon the investigation of Middle Palaeolithic artefacts found in the Retlapalle area within the upper Gundlakamma river basin, Andhra Pradesh. The dating of the artefact-bearing layer was carried out using the p-IR-IRSL method, which revealed a burial age of 139±17 thousand years. The Retlapalle assemblage is characterized by a diverse range of Levallois core reductions, various retouched artefacts, with a dominance of pointed tools, and a few blade components. The study provides a valuable addition to the existing body of data concerning Palaeolithic sites dating back to the Middle Pleistocene, a period that remains relatively underexplored.
Unveiling the Opportunities of Unexplored Use of Cover Crop in Mediterranean Agriculture through Systematic Review and Meta-Analysis
2024-08-27

Cover crops are multifunctional, and contribute to improving soil properties and reducing environmental impact compared to no-cover crops, thus could provide multiple soil, agricultural, and environmental benefits, and they are recognized as a valid strategy for the achievement of sustainable agriculture. However, cover crops’ impacts on subsequent cash crops and soil characteristics are dependent on several factors, such as pedoclimatic conditions, cover crop species, agricultural practices, method of termination, and irrigation management. The fact that cover crops are never applied as a single practice in the real agricultural sector, but are instead combined with other factors or agricultural practices, deeply affects their performance, but the scientific literature nevertheless keeps considering the use of cover crops alone. Moreover, the potential outcomes of cover crops that encompass other factors or agricultural practices affecting soil quality, weed control, and cash crops are still unclear. Additionally, cover crops are still poorly use in the Mediterranean type of climate. Therefore, this study reviewed the scientific literature to identify the most relevant factors or agricultural practices driving cover crops’ performance, and to outline future fields of investigation looking towards promising sustainable agriculture in Mediterranean areas with a view to minimizing the competition for soil water with the cropping systems and to reduce soil degradation. Furthermore, the investigation includes multiple factors or agricultural practices that better represent the real farming system, contributing to a comprehensive understanding of their interactions with cover crops, and suggests alternative strategies for reducing yield gap while seeking to achieve agricultural sustainability.
Two Models for the Orbital Modulation of Gamma Rays in Cyg X-3
2024-08-27

Abstract We model the currently available γ -ray data on Cyg X-3 from the Fermi Large Area Telescope. Thanks to Cyg X-3’s very strong γ -ray activity during 2018–2021, the data quality has significantly improved. We study the strong orbital modulation of the γ -rays observed at high γ -ray fluxes. The modulation, as found earlier, is well modeled by anisotropic Compton scattering of the donor blackbody emission by relativistic electrons in a jet strongly misaligned with respect to the orbital axis. We confirm that this model fits well both the average γ -ray modulation light curve and the spectrum. However, we find that if the jet were aligned with the spin axis of a rotating black hole, it would undergo geodetic precession with a period of ∼50 yr. However, its presence is ruled out by both the γ -ray and radio data. Therefore, we consider an alternative model in which the average jet direction is aligned, but it is bent outside the orbit owing to the thrust of the donor stellar wind, and thus precesses at the orbital period. The γ -ray modulation then appears as a result of the variable Doppler boosting of synchrotron self-Compton jet emission. This model also fits the data well. However, the fitted bending angle is much larger than the theoretical one based on the binary and wind parameters as currently known. Thus, both models disagree with important aspects of our current theoretical understanding of the system. We discuss possible ways to find the correct model.
Monotone Arc Diagrams with few Biarcs
2024-08-27

We show that every planar graph has a monotone topological 2-page book embedding where at most (4n-10)/5 (of potentially 3n-6) edges cross the spine, and every edge crosses the spine at most once; such an edge is called a biarc. We can also guarantee that all edges that cross the spine cross it in the same direction (e.g., from bottom to top). For planar 3-trees we can further improve the bound to (3n-9)/4, and for so-called Kleetopes we obtain a bound of at most (n-8)/3 edges that cross the spine. The bound for Kleetopes is tight, even if the drawing is not required to be monotone. A Kleetope is a plane triangulation that is derived from another plane triangulation T by inserting a new vertex v_f into each face f of T and then connecting v_f to the three vertices of f.
Introducing the Inventory of Creative Activities for Young Adolescents: An Adaption and Validation Study
2024-08-27

The measurement of everyday creative activities has been a widely applied measure of creativity in adult samples in order to investigate the relationship with creative potential and creative achievements. Despite the importance of creative activities for the development of achievements the assessment mostly focuses on adults. In the study at hand, we develop a questionnaire for adolescents and provide results regarding its structural, convergent, and predictive validity in a sample of n = 423 talented students from sixth and seventh grade. We show structural validity of the theoretically derived factor structure including six content domains (e.g., literature, handicrafts, etc.) Furthermore, we provide proof of convergent validity given the correlation of creative activities with divergent thinking as well as predictive validity regarding creative achievements. We discuss the findings in the light of previous studies including adult samples and summarize recommendations for the application of the measurement of creative activities in gifted students as well as in more general student populations.
Myotis daubentonii is able to catch small fish
2024-08-28

(Uploaded by Plazi for the Bat Literature Project) We experimentally showed that Daubenton's bat (Myotis daubentonii), a Palearctic vespertilionid species hunting for insects floating on or flying close to water surfaces, can take a small fish for prey if the fish penetrates a smooth water surface. The bat in our experiments was able to lift small fish and other big prey items out of the water by using its large feet. The bat readily fed on the fish we offered.
Elongation of Very Long-Chain Fatty Acids (ELOVL) in Atopic Dermatitis and the Cutaneous Adverse Effect AGEP of Drugs
2024-08-28

Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin’s stratum corneum. Palmitic acid and stearic acid, along with C16-ceramide and 2-hydroxy C16-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier. Ceramides originate from cellular sphingolipid/ceramide metabolism, comprising a well-orchestrated network of enzymes involving various ELOVLs and CerSs in the de novo ceramide synthesis and neutral and acid CERase in degradation. Contrasting changes in long-chain ceramides and very long-chain ceramides in AD can be more clearly explained by the compartmentalization of ceramide synthesis. According to our hypothesis, the origin of increased C16-ceramide and 2-hydroxy C16-ceramide is located in the lysosome. Conversely, the decreased ultra-long-chain and very long-chain ceramides are the result of impaired ELOVL fatty acid elongation. The suggested model’s key elements include the lysosomal aCERase, which has pH-dependent long-chain C16-ceramide synthase activity (revaCERase); the NADPH-activated step-in enzyme ELOVL6 for fatty acid elongation; and the coincidence of impaired ELOVL fatty acid elongation and an elevated lysosomal pH, which is considered to be the trigger for the altered ceramide biosynthesis in the lysosome. To maintain the ELOVL6 fatty acid elongation and the supply of NADPH and ATP to the cell, the polyunsaturated PPARG activator linoleic acid is considered to be one of the most suitable compounds. In the event that the increase in lysosomal pH is triggered by lysosomotropic compounds, compounds that disrupt the transmembrane proton gradient or force the breakdown of lysosomal proton pumps, non-HLA-classified AGEP may result.
Survivorship program including long‐term toxicities and quality‐of‐life development over 10 years in a randomized trial in operable stage III non‐small‐cell lung cancer (ESPATUE)
2024-08-28

Abstract Over 40% stage‐III non‐small‐cell lung cancer (NSCLC) patients (pts) experience 5‐year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality‐of‐life (QoL) in the further long‐term follow‐up. Therefore, we invited pts from our randomized phase‐III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow‐up imaging, laboratory parameters, cardio‐pulmonary investigations, long‐term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long‐term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1‐year follow‐up. This is the first comprehensive SSP of very late survival follow‐up reported in stage‐III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.
The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding
2024-08-28

The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun <i>et al.</i> 2012, <i>J. Am. Chem. Soc.</i> 134 (28), 11322-11325; Hurley <i>et al.</i> 2015, <i>ACS Med. Chem. Lett.</i> 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated. Using microbiological and biochemical assays in combination with fluorescence microscopy, we provide evidence that DCAP interacts with undecaprenyl pyrophosphate-coupled cell envelope precursors, thereby blocking peptidoglycan biosynthesis and impairing cell division site organization. Our work discloses a concise model for the mode of action of DCAP which involves the binding to a specific target molecule to exert pleiotropic effects on cell wall biosynthetic and divisome machineries.