bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models
Authors: Mitsukawa Kayo , Terada Michiko , Yamada Ryuji , Monjo Taku , Hiyoshi Tetsuaki , Nakakariya Masanori , Kajita Yuichi , Ando Tatsuya , Koike Tatsuki , Kimura Haruhide 
Published: September 2024

AbstractNarcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.
Biomechanical evaluation of an experimental internal ring fixator (RingFix) for stabilization of pelvic ring injuries on an osteoporotic bone model
Authors: Arand Charlotte , Hartung Christian , Mehler Dorothea , Gercek Erol , Wollstädter Jochen , Wagner Daniel , Rommens Pol M. 
Published: September 2024

AbstractDuring the last decades, effective pain reduction and early mobilization were identified as the central priorities in therapy of insufficiency fractures of the pelvis. For operative treatment minimally-invasive stabilization techniques are favored. While there is consensus on the significance of sufficient dorsal stabilization the role of additional fixation of the anterior fracture component stays under discussion. Within the present study we developed an internal ring fixator system (RingFix) with the question whether an in-itself-closed construct can improve stability of the entire ring structure. RingFix was evaluated on an osteoporotic bone model with a standardized FFP IIIc fracture within an established biomechanical setup regarding its primary stabilization potential. Further, it was compared to transiliac–transsacral screw fixation with and without stabilization of the anterior fracture component. The transiliac–transsacral fixation with separate screw fixation of the anterior fracture showed significantly higher stability than the RingFix and the transiliac–transsacral screw fixation without anterior stabilization. Our results show that stabilization of the anterior fracture component relevantly improves the stability of the entire ring construct. As a bridging stabilizer, RingFix shows biomechanical advantages over an isolated dorsal fracture fixation, but inferior results than direct stabilization of the single fracture components.
mTORC1 pathway activity biases cell fate choice
Authors: Wang Yuntao , Papayova Monika , Warren Eleanor , Pears Catherine J. 
Published: September 2024

AbstractPluripotent stem cells can differentiate into distinct cell types but the intracellular pathways controlling cell fate choice are not well understood. The social amoeba Dictyostelium discoideum is a simplified system to study choice preference as proliferating amoebae enter a developmental cycle upon starvation and differentiate into two major cell types, stalk and spores, organised in a multicellular fruiting body. Factors such as acidic vesicle pH predispose amoebae to one fate. Here we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway has a role in cell fate bias in Dictyostelium. Inhibiting the mTORC1 pathway activity by disruption of Rheb (activator Ras homolog enriched in brain), or treatment with the mTORC1 inhibitor rapamycin prior to development, biases cells to a spore cell fate. Conversely activation of the pathway favours stalk cell differentiation. The Set1 histone methyltransferase, responsible for histone H3 lysine4 methylation, in Dictyostelium cells regulates transcription at the onset of development. Disruption of Set1 leads to high mTORC1 pathway activity and stalk cell predisposition. The ability of the mTORC1 pathway to regulate cell fate bias of cells undergoing differentiation offers a potential target to increase the efficiency of stem cell differentiation into a particular cell type.
Pregnancy-related changes in the canine serum N-glycosylation pattern studied by Rapifluor HILIC-UPLC-FLR-MS
Authors: Ramström Margareta , Lavén Martin , Amini Ahmad , Holst Bodil Ström 
Published: September 2024

AbstractCanine reproduction differs from that of many other domestic animals, and increased knowledge on biochemical changes during canine pregnancy is important for investigations of infertility or subfertility. The total glycosylation pattern, i.e., the glycome, of body fluids reflects cellular status in health and disease. The aim of the present pilot study was to investigate pregnancy-related changes of the serum N-glycome in bitches. A method based on Rapifluor HILIC-UPLC-FLR-MS was optimized and applied for analysis and quantification of N-glycans in canine serum. Serum samples from six pregnant and five non-pregnant bitches, collected at four well-defined time points, were included. The levels of sialylated and galactosylated complex glycans were significantly elevated in serum from pregnant bitches, consistent with previous reports on human pregnancy. The levels of fucosylated and agalactosylated glycans decreased significantly in pregnant dogs. In non-pregnant dogs, the glycosylation pattern did not change during the cycle. Pregnancy is an inflammatory state, but our findings during canine pregnancy are quite the opposite to changes that have previously been described for dogs with a known parasitic infection. Evaluation of the canine glycome may thus be valuable in studies of canine pregnancy, possibly differing inflammatory changes related to pregnancy to those caused by an infection.
Self-supervised learning of wrist-worn daily living accelerometer data improves the automated detection of gait in older adults
Authors: Brand Yonatan E. , Kluge Felix , Palmerini Luca , Paraschiv-Ionescu Anisoara , Becker Clemens , Cereatti Andrea , Maetzler Walter , Sharrack Basil , Vereijken Beatrix , Yarnall Alison J. , Rochester Lynn , Del Din Silvia , Muller Arne , Buchman Aron S. , Hausdorff Jeffrey M. , Perlman Or 
Published: September 2024

AbstractProgressive gait impairment is common among aging adults. Remote phenotyping of gait during daily living has the potential to quantify gait alterations and evaluate the effects of interventions that may prevent disability in the aging population. Here, we developed ElderNet, a self-supervised learning model for gait detection from wrist-worn accelerometer data. Validation involved two diverse cohorts, including over 1000 participants without gait labels, as well as 83 participants with labeled data: older adults with Parkinson's disease, proximal femoral fracture, chronic obstructive pulmonary disease, congestive heart failure, and healthy adults. ElderNet presented high accuracy (96.43 ± 2.27), specificity (98.87 ± 2.15), recall (82.32 ± 11.37), precision (86.69 ± 17.61), and F1 score (82.92 ± 13.39). The suggested method yielded superior performance compared to two state-of-the-art gait detection algorithms, with improved accuracy and F1 score (p < 0.05). In an initial evaluation of construct validity, ElderNet identified differences in estimated daily walking durations across cohorts with different clinical characteristics, such as mobility disability (p < 0.001) and parkinsonism (p < 0.001). The proposed self-supervised method has the potential to serve as a valuable tool for remote phenotyping of gait function during daily living in aging adults, even among those with gait impairments.
A hybrid residue based sequential encoding mechanism with XGBoost improved ensemble model for identifying 5-hydroxymethylcytosine modifications
Authors: Uddin Islam , Awan Hamid Hussain , Khalid Majdi , Khan Salman , Akbar Shahid , Sarker Mahidur R. , Abdolrasol Maher G. M. , Alghamdi Thamer A. H. 
Published: September 2024

AbstractRNA modifications play an important role in actively controlling recently created formation in cellular regulation mechanisms, which link them to gene expression and protein. The RNA modifications have numerous alterations, presenting broad glimpses of RNA’s operations and character. The modification process by the TET enzyme oxidation is the crucial change associated with cytosine hydroxymethylation. The effect of CR is an alteration in specific biochemical ways of the organism, such as gene expression and epigenetic alterations. Traditional laboratory systems that identify 5-hydroxymethylcytosine (5hmC) samples are expensive and time-consuming compared to other methods. To address this challenge, the paper proposed XGB5hmC, a machine learning algorithm based on a robust gradient boosting algorithm (XGBoost), with different residue based formulation methods to identify 5hmC samples. Their results were amalgamated, and six different frequency residue based encoding features were fused to form a hybrid vector in order to enhance model discrimination capabilities. In addition, the proposed model incorporates SHAP (Shapley Additive Explanations) based feature selection to demonstrate model interpretability by highlighting the high contributory features. Among the applied machine learning algorithms, the XGBoost ensemble model using the tenfold cross-validation test achieved improved results than existing state-of-the-art models. Our model reported an accuracy of 89.97%, sensitivity of 87.78%, specificity of 94.45%, F1-score of 0.8934%, and MCC of 0.8764%. This study highlights the potential to provide valuable insights for enhancing medical assessment and treatment protocols, representing a significant advancement in RNA modification analysis.
Using the online version of the Trier Social Stress Test to investigate the effect of acute stress on functional lateralization
Authors: Pfeifer Lena Sophie , Heyers Katrin , Wolf Oliver T. , Stockhorst Ursula , Güntürkün Onur , Merz Christian J. , Ocklenburg Sebastian 
Published: September 2024

AbstractHow stress affects functional hemispheric asymmetries is relevant because stress represents a risk factor for the development of mental disorders and various mental disorders are associated with atypical lateralization. Using three lateralization tasks, we investigated whether functional hemispheric asymmetries in the form of hemispheric dominance for language (verbal dichotic listening task), emotion processing (emotional dichotic listening task), and visuo-spatial attention (line bisection task) were affected by acute stress in healthy adults. One hundred twenty right-handed men and women performed these lateralization tasks in randomized order after exposure to a mild online stressor (i.e., an online variant of the Trier Social Stress Test (TSST), TSST-OL) and a non-stressful online control task (friendly TSST-OL, fTSST-OL) in a within-subjects design. Importantly, the verbal and the emotional dichotic listening tasks were presented online whereas the line bisection task was completed in paper–pencil form. During these tasks, we found the expected hemispheric asymmetries, indicating that online versions of both the verbal and the emotional dichotic listening task can be used to measure functional hemispheric asymmetries in language and emotion processing remotely. Even though subjective and physiological markers confirmed the success of the online stress manipulation, replicating previous studies, we found no stress-induced effect on functional hemispheric asymmetries. Thus, in healthy participants, functional hemispheric asymmetries do not seem to change flexibly in response to acute stress.
Glycomics of cervicovaginal fluid from women at risk of preterm birth reveals immuno-regulatory epitopes that are hallmarks of cancer and viral glycosylation
Authors: Wu Gang , Grassi Paola , Molina Belen Gimeno , MacIntyre David A. , Sykes Lynne , Bennett Phillip R. , Dell Anne , Haslam Stuart M. 
Published: September 2024

AbstractDuring pregnancy the immune system needs to maintain immune tolerance of the foetus while also responding to infection, which can cause premature activation of the inflammatory pathways leading to the onset of labour and preterm birth. The vaginal microbiome is an important modifier of preterm birth risk, with Lactobacillus dominance during pregnancy associated with term delivery while high microbial diversity is associated with an increased risk of preterm birth. Glycans on glycoproteins along the lower female reproductive tract are fundamental to microbiota-host interactions and the mediation of inflammatory responses. However, the specific glycan epitopes involved in these processes are not well understood. To address this, we conducted glycomic analyses of cervicovaginal fluid (CVF) from 36 pregnant women at high risk of preterm birth and 4 non-pregnant women. Our analysis of N- and O-glycans revealed a rich CVF glycome. While O-glycans were shown to be the main carriers of ABO blood group epitopes, the main features of N-glycans were the presence of abundant paucimannose and high mannose glycans, and a remarkable diversity of complex bi-, tri-, and tetra-antennary glycans decorated with fucose and sialic acid. We identified immuno-regulatory epitopes, such as Lewis antigens, and found that fucosylation was negatively correlated to pro-inflammatory factors, such as IL-1β, MMP-8, C3a and C5a, while glycans with only sialylated antennae were mainly positively correlated to those. Similarly, paucimannose glycans showed a positive correlation to pro-inflammatory factors. We revealed a high abundance of glycans which have previously been identified as hallmarks of cancer and viral glycosylation, such as Man8 and Man9 high mannose glycans. Although each pregnant woman had a unique glycomic profile, longitudinal studies showed that the main glycosylation features were consistent throughout pregnancy in women who delivered at term, whereas women who experienced extreme preterm birth exhibited sharp changes in the CVF glycome shortly before delivery. These findings shed light on the processes underlying the role of glycosylation in maintaining a healthy vaginal microbiome and associated host immune responses. In addition, these discoveries facilitate our understanding of the lower female reproductive tract which has broad implications for women’s health.
High levels of tumor cell-intrinsic STING signaling are associated with increased infiltration of CD8+ T cells in dMMR/MSI-H gastric cancer
Authors: Kanoda Ryo , Nakajima Shotaro , Fukai Satoshi , Saito Motonobu , Saito Katsuharu , Suzuki Hiroya , Kikuchi Tomohiro , Nirei Azuma , Okayama Hirokazu , Mimura Kosaku , Hanayama Hiroyuki , Sakamoto Wataru , Momma Tomoyuki , Saze Zenichiro , Kono Koji 
Published: September 2024

AbstractMismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (−)] GC. The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS–STING was highly expressed in dMMR GC compared to pMMR/EBV (−) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8+ tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (−). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment.
Inference through innovation processes tested in the authorship attribution task
Authors: Tani Raffaelli Giulio , Lalli Margherita , Tria Francesca 
Published: September 2024

AbstractUrn models for innovation capture fundamental empirical laws shared by several real-world processes. The so-called urn model with triggering includes, as particular cases, the urn representation of the two-parameter Poisson-Dirichlet process and the Dirichlet process, seminal in Bayesian non-parametric inference. In this work, we leverage this connection to introduce a general approach for quantifying closeness between symbolic sequences and test it within the framework of the authorship attribution problem. The method demonstrates high accuracy when compared to other related methods in different scenarios, featuring a substantial gain in computational efficiency and theoretical transparency. Beyond the practical convenience, this work demonstrates how the recently established connection between urn models and non-parametric Bayesian inference can pave the way for designing more efficient inference methods. In particular, the hybrid approach that we propose allows us to relax the exchangeability hypothesis, which can be particularly relevant for systems exhibiting complex correlation patterns and non-stationary dynamics.
Wie beeinflusst eine gute medikamentöse Krankheitskontrolle den Verlauf und die orthopädische Therapie entzündlich-rheumatischer Erkrankungen?
Authors: Gaulke Ralph 
Published: September 2024

ZUSAMMENFASSUNGDie Inzidenz der entzündlich-rheumatischen Erkrankungen und insbesondere der rheumatoiden Arthritis steigt weltweit. Durch den Einsatz von Biologika und Januskinase-Inhibitoren kann der Krankheitsverlauf in der Schwere deutlich abgemildert werden. Durch diese bessere Kontrolle der Erkrankung sind gelenkerhaltende Operationen länger möglich als in der Vergangenheit. Da die Gelenkzerstörung unter dieser Therapie zwar langsamer, aber aufgrund fehlender oder nur geringer Schmerzen häufig unbemerkt verläuft, ist die ganze Aufmerksamkeit der Patienten und behandelnden Ärzte gefordert, um die Chancen für gelenkerhaltende Eingriffe nicht ungenutzt verstreichen zu lassen. Die Beurteilung der Krankheitsaktivität sollte sowohl anamnestisch, klinisch, laborchemisch als auch durch die bildgebende Diagnostik erfolgen. Die Intervalle zur Nachuntersuchung sind individuell festzulegen und hängen maßgeblich von der individuellen Krankheitsaktivität ab. Schwellungen der Sehnenscheiden und Gelenke, welche unter wirksamer Basistherapie auftreten, sollten unbedingt abgeklärt werden, um einerseits keine Infektionen zu übersehen und andererseits Gelenkschäden durch die entzündlich-rheumatische Aktivität so gering wie möglich zu halten.
Neurologische Defizite bei rheumatoider Arthritis
Authors: Biehl Christoph , Biehl Lotta , Biehl Madita 
Published: September 2024

ZUSAMMENFASSUNGNeurologische Defizite kommen bei Erkrankungen des rheumatischen Formenkreises nicht primär vor, sondern sind zumeist Folge einer arthritischen oder periartikulären Veränderung. Diese treten häufiger auf als es auf den ersten Blick scheint. Am häufigsten ist eine Neurologie des N. medianus. Eine sorgfältige Anamnese und systematische Untersuchung sind für die Diagnose unerlässlich.
Design of an X-band high efficiency coaxial relativistic backward wave oscillator with permanent magnetic package
Authors: Yang Kaiqi , Zhou Fugui , Zhang Dian , Jin Zhenxing , Xiang Yujie , Wang Tengfang , Zhang Wei 
Published: September 2024

Relativistic backward wave oscillators (RBWOs) have the characteristics of high power and high repetition rate. Reducing the magnetic field strength and the weight of the external permanent magnet (PM) is a significant development direction of RBWOs. In previous research, an X-band RBWO enclosed with a PM has achieved a power efficiency of 50%. However, the PM used in these papers requires a magnetic field magnitude of over 0.68 T, which leads to a weight exceeding 400 kg. The RBWO designed in this paper operates in coaxial TM01 mode, and the radial distance between its cathode and the surface of the slow wave structures reaches 7 mm. Under the condition of a low magnetic field, this design can provide a wide electron beam channel to avoid the rubbing of the electron beam envelope on the inner and outer conductors. Particle-in-cell simulation results have demonstrated that this RBWO achieves an output microwave power of 3 GW with a power efficiency of 50% enclosed in a PM with a magnetic field strength of 0.43 T and a weight of 74 kg.
Soft-carbon-tuned hard carbon anode for ultrahigh-rate sodium storage
Authors: Dai Hongjin , Cao Yufang , Sun Jingyu 
Published: September 2024

Abstract
High-rate hard carbon anode is critical for achieving fast-charging sodium-ion batteries, whereas the limited ion/electron kinetics caused by unexpected surface defects and unsatisfactory conductivity greatly limits rate capability. Herein, a coconut shell-derived soft-carbon-tuned hard carbon (SHC) with low surface area (4.7 m2 g−1) was prepared. With SHCs as bricks, a high conductivity single-walled carbon nanotube (SWNT)-bonded hard carbon film was constructed. The pitch-derived soft carbon formed on SHCs can effectively decrease the surface defects and simultaneously induce optimized disordered graphite domains into carbon matrix, enabling high Na+ reversibility and ionic/electronic conductivity. The crosslinked SWNTs in-between can provide continuous ion/charge transport ‘highways’, thus ensuring rapid ion/electron kinetics. As a result, such a self-supporting carbon anode exhibits remarkable rate performance (330 mAh g−1 at 0.1 C and 272 mAh g−1 at 5 C), superior initial Coulombic efficiency of 95.2% and outstanding cycling stability.