bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial interactions of immune cells as potential predictors to efficacy of toripalimab plus chemotherapy in locally advanced or metastatic pancreatic ductal adenocarcinoma: a phase Ib/II trial
Authors: Cheng Ke , Li Xiaoying , Lv Wanrui , Zhao Gang , Zhou Ruihan , Chang Chen , Yang Heqi , Li Ruizhen , Li Zhiping , Chen Ye , Yi Cheng , Yan Ouying , Xiao Chaoxin , Zhang Yi , Xiong Junjie , Huang Zixin , Shao Weikang , You Xin , Guo Wenhao , He Du , Ling Wenwu , Wang Rui , Tian Bole , Zhao Chengjian , Cao Dan 
Published: November 2024

AbstractAdvanced pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Immunotherapy alone offers limited efficacy, but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects. This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel (GnP) regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers (ChiCTR2000032293). The primary endpoints were safety and overall survival (OS). The secondary outcomes were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune-related biomarkers including programmed death-ligand 1 (PD-L1) expression, genetic status, cytokine levels, and spatial features of the tumor immune microenviroment (TIME) were investigated. Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported. Among the 72 patients, the median OS was 8.9 months, 12-month OS rate was 31.9%, with median PFS of 5.6 months, ORR of 33.3%, and DCR of 90.3%. Higher PD-L1 expression, without liver metastases were associated with higher ORR, however these factors could not effectively distinguish responders and non-responders. Importantly, dendritic cells - T helper cells - cytotoxic T lymphocytes (DC-Th-CTL) enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay, with an area under the curve value of 0.8. Overall, GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population, and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.
Decreased prefrontal glutamatergic function is associated with a reduced astrocyte-related gene expression in treatment-resistant depression
Authors: Wada Masataka , Nakajima Shinichiro , Honda Shiori , Takano Mayuko , Taniguchi Keita , Homma Saki , Ueda Risako , Tobari Yui , Mimura Yu , Fujii Shinya , Mimura Masaru , Noda Yoshihiro 
Published: November 2024

AbstractGlutamatergic dysfunction is involved in the pathophysiology of treatment-resistant depression (TRD). However, few physiological studies have evaluated its pathophysiology in vivo in individuals with TRD. Transcranial magnetic stimulation-electroencephalography (TMS-EEG) techniques can assess intracortical facilitation (ICF), which reflects glutamatergic neurophysiological function in specific cortical regions. The objectives of this study were (1) to compare glutamatergic receptor-mediated function as indexed with ICF TMS-EEG in the dorsolateral prefrontal cortex (DLPFC) between participants with TRD and healthy controls (HCs) and (2) to explore the relationships between cell-specific gene expression levels and the group difference in glutamatergic neural propagation using virtual histology approach. Sixty participants with TRD and thirty HCs were examined with ICF TMS-EEG measure (80 single-pulse TMS and paired-pulse ICF) in the left DLPFC. Both sensor and source-level ICF measures were computed to compare them between the TRD and HC groups. Furthermore, we conducted spatial correlation analyses interregionally between ICF glutamatergic activity and cell-specific gene expression levels employing the Allen Human Brain Atlas dataset. DLPFC-ICF at the sensor level was not significantly different between the two groups, whereas DLPFC-ICF at the source level was reduced in the TRD group compared with the HC group (p = 0.026). Moreover, the reduced ICF signal propagation of TRD correlated with astrocyte-specific gene expression level (p < 0.0001). The glutamatergic neural activities indexed by ICF in the left DLPFC were decreased in participants with TRD. Additionally, a relative reduction in glutamatergic signal propagation originating from the DLPFC in TRD may be associated with astrocytic abnormality.
Spatiotemporal functions of leukemia inhibitory factor in embryo attachment and implantation chamber formation
Authors: Aikawa Shizu , Hiraoka Takehiro , Matsuo Mitsunori , Fukui Yamato , Fujita Hidetoshi , Saito-Fujita Tomoko , Shimizu-Hirota Ryoko , Takeda Norihiko , Hiratsuka Daiki , He Xueting , Ishizawa Chihiro , Iida Rei , Akaeda Shun , Harada Miyuki , Wada-Hiraike Osamu , Ikawa Masahito , Osuga Yutaka , Hirota Yasushi 
Published: November 2024

AbstractEmbryo implantation is crucial for successful pregnancy, requiring appropriate uterine responses to implantation-competent blastocysts. Molecular communication at the maternal–fetal junction governs this process. Leukemia inhibitory factor (Lif) plays a pivotal role in implantation across species. Lif is abundantly expressed in the glandular epithelium during blastocyst-receptive phase and is induced in the stroma surrounding attached blastocysts. While diminished Lif expression leads to infertility, its influence on peri-implantation uteri remains unclear. Therefore, we investigated the role of Lif in uterine physiology using its uterine-specific knockout (uKO) and uterine epithelial-specific KO (eKO) in mice. Lif eKO and uKO mice displayed infertility owing to failed embryo attachment. Recombinant Lif supplementation rescued the reproductive phenotype of Lif eKO mice, but not Lif uKO mice; however, recombinant Lif injection rescued embryo attachment in Lif uKO mice. RNA-seq analysis indicated that Lif governs uterine epithelial genes, but not embryonic genes, to facilitate embryo attachment via activating nuclear Stat3. Concordantly, three-dimensional imaging of the uterine epithelium revealed that luminal closure and crypt formation are regulated by the uterine Lif–Stat3 axis as well as the presence of blastocysts. Collectively, our findings shed light on previously unknown mechanism on how Lif influences uterine functions molecularly and physiologically during early pregnancy.
Universal salt-assisted assembly of MXene from suspension on polymer substrates
Authors: Zhao Liang , Bi Lingyi , Hu Jiayue , Gao Guanhui , Zhang Danzhen , Li Yun , Flynn Aidan , Zhang Teng , Wang Ruocun , Cheng Xuemei M. , Liu Ling , Gogotsi Yury , Li Bo 
Published: November 2024

AbstractTwo-dimensional carbides and nitrides, known as MXenes, are promising for water-processable coatings due to their excellent electrical, thermal, and optical properties. However, depositing hydrophilic MXene nanosheets onto inert or hydrophobic polymer surfaces requires plasma treatment or chemical modification. This study demonstrates a universal salt-assisted assembly method that produces ultra-thin, uniform MXene coatings with exceptional mechanical stability and washability on various polymers, including high-performance polymers for extreme temperatures. The salt in the Ti3C2Tx colloidal suspension reduces surface charges, enabling electrostatically hydrophobized MXene deposition on polymers. A library of salts was used to optimize assembly kinetics and coating morphology. A 170 nm MXene coating can reduce radiation temperature by ~200 °C on a 300 °C PEEK substrate, while the coating on Kevlar fabric provides comfort in extreme conditions, including outer space and polar regions.
The Acrasis kona genome and developmental transcriptomes reveal deep origins of eukaryotic multicellular pathways
Authors: Sheikh Sanea , Fu Cheng-Jie , Brown Matthew W. , Baldauf Sandra L. 
Published: November 2024

AbstractAcrasids are amoebae with the capacity to form multicellular fruiting bodies in a process known as aggregative multicellularity (AGM). This makes acrasids the only known example of multicellularity among the earliest branches of eukaryotes (the former Excavata). Here, we report the Acrasis kona genome sequence plus transcriptomes from pre-, mid- and post-developmental stages. The genome is rich in novelty and genes with strong signatures of horizontal transfer, and multigene families encode nearly half of the amoeba’s predicted proteome. Development in A. kona appears molecularly simple relative to the AGM model, Dictyostelium discoideum. However, the acrasid also differs from the dictyostelid in that it does not appear to be starving during development. Instead, developing A. kona appears to be very metabolically active, does not induce autophagy and does not up-regulate its proteasomal genes. Together, these observations strongly suggest that starvation is not essential for AGM development. Nonetheless, development in the two amoebae appears to employ remarkably similar pathways for signaling, motility and, potentially, construction of an extracellular matrix surrounding the developing cell mass. Much of this similarity is also shared with animal development, suggesting that much of the basic tool kit for multicellular development arose early in eukaryote evolution.
Streptolysin O accelerates the conversion of plasminogen to plasmin
Authors: Tang Di , Khakzad Hamed , Hjortswang Elisabeth , Malmström Lars , Ekström Simon , Happonen Lotta , Malmström Johan 
Published: November 2024

AbstractGroup A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity.
Features of membrane protein sequence direct post-translational insertion
Authors: Kalinin Ilya A. , Peled-Zehavi Hadas , Barshap Alon B. D. , Tamari Shai A. , Weiss Yarden , Nevo Reinat , Fluman Nir 
Published: November 2024

AbstractThe proper folding of multispanning membrane proteins (MPs) hinges on the accurate insertion of their transmembrane helices (TMs) into the membrane. Predominantly, TMs are inserted during protein translation, via a conserved mechanism centered around the Sec translocon. Our study reveals that the C-terminal TMs (cTMs) of numerous MPs across various organisms bypass this cotranslational route, necessitating an alternative posttranslational insertion strategy. We demonstrate that evolution has refined the hydrophilicity and length of the C-terminal tails of these proteins to optimize cTM insertion. Alterations in the C-tail sequence disrupt cTM insertion in both E. coli and human, leading to protein defects, loss of function, and genetic diseases. In E. coli, we identify YidC, a member of the widespread Oxa1 family, as the insertase facilitating cTMs insertion, with C-tail mutations disrupting the productive interaction of cTMs with YidC. Thus, MP sequences are fine-tuned for effective collaboration with the cellular biogenesis machinery, ensuring proper membrane protein folding.
Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53
Authors: Wendrich Kim , Gallant Kai , Recknagel Sarah , Petroulia Stavroula , Kazi Nafizul Haque , Hane Jan André , Führer Siska , Bezstarosti Karel , O’Dea Rachel , Demmers Jeroen , Gersch Malte 
Published: November 2024

AbstractUbiquitin-specific proteases (USPs) represent the largest class of human deubiquitinases (DUBs) and comprise its phylogenetically most distant members USP53 and USP54, which are annotated as catalytically inactive pseudoenzymes. Conspicuously, mutations within the USP domain of USP53 cause progressive familial intrahepatic cholestasis. Here, we report the discovery that USP53 and USP54 are active DUBs with high specificity for K63-linked polyubiquitin. We demonstrate how USP53 mutations abrogate catalytic activity, implicating loss of DUB activity in USP53-mediated pathology. Depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Assays with substrate-bound polyubiquitin reveal that USP54 cleaves within K63-linked chains, whereas USP53 can en bloc deubiquitinate substrate proteins in a K63-linkage-dependent manner. Biochemical and structural analyses uncover underlying K63-specific S2 ubiquitin-binding sites within their catalytic domains. Collectively, our work revises the annotation of USP53 and USP54, provides reagents and a mechanistic framework to investigate K63-linked polyubiquitin decoding and establishes K63-linkage-directed deubiquitination as a new DUB activity.
The yeast genome is globally accessible in living cells
Authors: Prajapati Hemant K. , Eriksson Peter R. , Elizalde Paul A. , Coey Christopher T. , Xu Zhuwei , Clark David J. 
Published: November 2024

Abstract
Eukaryotic genomes are packaged into chromatin, which is composed of condensed filaments of regularly spaced nucleosomes, resembling beads on a string. The nucleosome contains ~147 bp of DNA wrapped almost twice around a central core histone octamer. The packaging of DNA into chromatin represents a challenge to transcription factors and other proteins requiring access to their binding sites. Consequently, control of DNA accessibility is thought to play a key role in gene regulation. Here we measure DNA accessibility genome wide in living budding yeast cells by inducible expression of DNA methyltransferases. We find that the genome is globally accessible in living cells, unlike in isolated nuclei, where DNA accessibility is severely restricted. Gene bodies are methylated at only slightly slower rates than promoters, indicating that yeast chromatin is highly dynamic in vivo. In contrast, silenced loci and centromeres are strongly protected. Global shifts in nucleosome positions occur in cells as they are depleted of ATP-dependent chromatin remodelers, suggesting that nucleosome dynamics result from competition among these enzymes. We conclude that chromatin is in a state of continuous flux in living cells, but static in nuclei, suggesting that DNA packaging in yeast is not generally repressive.
Intrusion detection in software defined network using deep learning approaches
Authors: Ataa M. Sami , Sanad Eman E. , El-khoribi Reda A. 
Published: November 2024

AbstractEnsuring robust network security is crucial in the context of Software-Defined Networking(SDN). Which, becomes a multi-billion dollar industry, and it’s deployed in many data centers nowadays. The new technology provides network programmability, network centralized control, and a global view of the network. But, unfortunately, it comes with new vulnerabilities, and new attack vectors compared to the traditional network. SDN network cybersecurity became a trending research topic due to the hype of Machine Learning (ML) when a group of Machine Learning(ML) techniques called Deep Learning(DL) started to take shape in the setting of SDN networks. This paper focuses on developing advanced Deep Learning(DL) models to address the inherent new attack vectors. In this paper, we have built and compared two models that can be used for building a complete Intrusion Detection System(IDS) solution, one using a hybrid CNN-LSTM architecture and the other using Transformer encoder-only architecture. We specifically target the SDN controller where it represents a crucial point. We utilized the InSDN dataset for training and testing our models, this dataset captures real-world traffic within the SDN environment. For evaluation, we have used accuracy, precision, recall, and F1 Score. Our experiment results show that the Transformer model with 48 features achieves the highest accuracy at 99.02%, while the CNN-LSTM model achieves 99.01%. We have reduced the features to 6 and 4, which gave us varying impacts on the models’ performance. We have merged 4 poorly represented attacks in one class, which enhanced the accuracy by a significant score. Additionally, we investigate binary classification by merging all attack types into a single class, as a result, the accuracy increased for both models. The CNN-LSTM model achieves the best results with an accuracy of 99.19% for 6 feature sets, this enhances the state-of-the-art results.
Panax ginseng nanoemulsion for counteracting male infertility via modulating sex hormones and oxidative stress in a rat model
Authors: El-Shimi Basma I. , Mohareb Rafat M. , Ahmed Hanaa H. , Abohashem Rehab S. , Mahmoud Khaled F. , Hanna Demiana H. 
Published: November 2024

AbstractThis study end to develop nanoemulsions of Panax ginseng dry extract and to evaluate the potential impact of these nanoemulsions versus free Panax ginseng dry extract and Vit.E in recovering male infertility induced in rats. Nanoemulsions of Panax ginseng dry extract were prepared by oil in water method. The designed samples were characterized by TEM, zeta sizer, FTIR, and TGA. The in vitro study included DPPH assay to estimate the free radical scavenging activity of the suggested treatments. The in vivo study included 100 adult male Wistar rats which were assigned into 10 equal groups; five groups of young rats weighting (150–200 g) and five groups of aged rats weighting (350–400 g). Group I, negative control. Group II, bisphenol-A (BPA). Group III, BPA+ Panax ginseng dry extract nanoemulsion. Group IV, BPA+ free Panax ginseng dry extract. Group V, BPA +Vit.E. After 40 days, serum total testosterone, free testosterone, MDA, 8-OHdG and AGEs were estimated. Besides, the histological investigation of testicular tissue sections was performed. TEM imaging of Panax ginseng dry extract nanoemulsions indicated spherical shape with diameter range from 2 to 50 nm, and the size distribution was in the range from 62 to 123 d.nm. The zeta potential of the designed nanoemulsions was -32.8 to -38.9 mV. FTIR spectra revealed the common active groups in the prepared nanoemulsions. The thermal stability of the nanoemulsions was up to 207 ºC. The in vitro results of DPPH assay showed % inhibition of DPPH free radical for Panax ginseng nanoemulsions samples was 49.38% (for young-treated group Sample A) and 72.28% (for aged-treated group Sample B), while for free Panax ginseng dry extract samples was 30.27% (for young-treated group Sample C) and 56.76% (for aged-treated group Sample D), for Vit.E samples was 32.36% (for young-treated group Sample E) and 36.39% (for aged-treated group Sample F).Thus the nanoemulsions exhibit free radicals scavenging activity more than free Panax ginseng dry extract and Vit.E. The in vivo findings elucidated that Panax ginseng dry extract nanoemulsions and Vit.E successfully revers the progressive insult of BPA on male fertility by significantly enhance total testosterone (2.87±0.318) and free testosterone (1.63±0.033) serum levels, and significantly decrease MDA (2.77±0.018), 8-OHdG (6.76±0.174) and AGEs (92.60±1.701) serum levels. Interestingly, the most promising outcomes were recorded upon the treatment with Panax ginseng dry extract nanoemulsions. In conclusion the developed Panax ginseng dry extract nanoemulsion could be used as a promising strategy in improving potential male infertility defects by rescuing male sex hormones, neutralizing oxidative stress and retrieving the structural organization of the testes.
Bladder image stitching algorithm for navigation and referencing using a standard cystoscope
Authors: Li Ming , Varble Nicole A. , Gurram Sandeep , Long Dilara , Valera Vladimir , Gopal Nikhil , Bakhutashvili Ivane , Reed Sheridan , Pritchard William F. , Karanian John W. , Xu Sheng , Wood Bradford J. 
Published: November 2024

AbstractTo aid in the diagnosis, monitoring, and surveillance of bladder carcinoma, this study aimed to develop and test an algorithm that creates a referenceable bladder map rendered from standard cystoscopy videos without the need for specialized equipment. A vision-based algorithm was developed to generate 2D bladder maps from individual video frames, by sequentially stitching image frames based on matching surface features, and subsequently localize and track frames during reevaluation. The algorithm was developed and calibrated in a 2D model and 3D anthropomorphic bladder phantom. The performance was evaluated in vivo in swine and with retrospective clinical cystoscopy video. Results showed that the algorithm was capable of capturing and stitching intravesical images with different sweeping patterns. Between 93% and 99% of frames had sufficient features for bladder map generation. Upon reevaluation, the cystoscope accurately localized a frame within 4.5 s. In swine, a virtual mucosal surface map was generated that matched the explant anatomy. A surface map could be generated based on archived patient cystoscopy images. This tool could aid recording and referencing pathologic findings and biopsy or treatment locations for subsequent procedures and may have utility in patients with metachronous bladder cancer and in low-resource settings.
A comparison of lower body gait kinematics and kinetics between Theia3D markerless and marker-based models in healthy subjects and clinical patients
Authors: D’Souza Sonia , Siebert Tobias , Fohanno Vincent 
Published: November 2024

AbstractThree-dimensional (3D) marker-based motion capture is the current gold standard to assess and monitor pathological gait in a clinical setting. However, 3D markerless motion capture based on pose estimation is advancing into the field of gait analysis. This study aims at evaluating the lower-body 3D gait kinematics and kinetics from synchronously recorded Theia3D markerless and CAST marker-based systems. Twelve healthy individuals and 34 clinical patients aged 8–61 years walked at self-selected speed over a 13 m long walkway. Similarity between models was statistically analysed using inter-trial variability, root mean square error, Pearson’s correlation coefficient and Statistical Parametric Mapping. Inter-trial variability was on average higher for clinical patients in both models. Overall, the markerless system demonstrated similar gait patterns although hip and knee rotations were non-comparable. Pelvic anterior tilt was significantly underestimated. Significant differences especially in peak values at specific phases of the gait cycle were observed across all planes for all joints (more so for clinical patients than healthy subjects) as well as in the sagittal powers of the hip, knee and ankle. Theia3D markerless system offers great potential in gait analysis. This study brings awareness to potential clinical users and researchers where they can have confidence, as well as areas where caution should be exercised.