bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis
Authors: Lei Yunxuan , Guo Xin , Luo Yanping , Niu Xiaoyin , Xi Yebin , Xiao Lianbo , He Dongyi , Bian Yanqin , Zhang Yong , Wang Li , Peng Xiaochun , Wang Zhaojun , Chen Guangjie 
Published: January 2024

AbstractMast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.
Neoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial
Authors: Lin Jian-Xian , Tang Yi-Hui , Zheng Hua-Long , Ye Kai , Cai Jian-Chun , Cai Li-Sheng , Lin Wei , Xie Jian-Wei , Wang Jia-Bin , Lu Jun , Chen Qi-Yue , Cao Long-Long , Zheng Chao-Hui , Li Ping , Huang Chang-Ming 
Published: January 2024

AbstractProspective evidence regarding the combination of programmed cell death (PD)−1 and angiogenesis inhibitors in treating locally advanced gastric cancer (LAGC) is limited. In this multicenter, randomized, phase 2 trial (NCT04195828), patients with gastric adenocarcinoma (clinical T2-4N + M0) were randomly assigned (1:1) to receive neoadjuvant camrelizumab and apatinib combined with nab-paclitaxel plus S-1 (CA-SAP) or chemotherapy SAP alone (SAP) for 3 cycles. The primary endpoint was the major pathological response (MPR), defined as <10% residual tumor cells in resection specimens. Secondary endpoints included R0 resection rate, radiologic response, safety, overall survival, and progression-free survival. The modified intention-to-treat population was analyzed (CA-SAP [n = 51] versus SAP [n = 53]). The trial has met pre-specified endpoints. CA-SAP was associated with a significantly higher MPR rate (33.3%) than SAP (17.0%, P = 0.044). The CA-SAP group had a significantly higher objective response rate (66.0% versus 43.4%, P = 0.017) and R0 resection rate (94.1% versus 81.1%, P = 0.042) than the SAP group. Nonsurgical grade 3-4 adverse events were observed in 17 patients (33.3%) in the CA-SAP group and 14 (26.4%) in the SAP group. Survival results were not reported due to immature data. Camrelizumab and apatinib combined with chemotherapy as a neoadjuvant regimen was tolerable and associated with favorable responses for LAGC.
IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity
Authors: Landoni Elisa , Woodcock Mark G. , Barragan Gabriel , Casirati Gabriele , Cinella Vincenzo , Stucchi Simone , Flick Leah M. , Withers Tracy A. , Hudson Hanna , Casorati Giulia , Dellabona Paolo , Genovese Pietro , Savoldo Barbara , Metelitsa Leonid S. , Dotti Gianpietro 
Published: January 2024

AbstractHuman natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy, and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 show enhanced antitumor activity in leukemia and neuroblastoma tumor models, persist long-term in vivo and conserve the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.
Initial-site characterization of hydrogen migration following strong-field double-ionization of ethanol
Authors: Severt Travis , Weckwerth Eleanor , Kaderiya Balram , Feizollah Peyman , Jochim Bethany , Borne Kurtis , Ziaee Farzaneh , P Kanaka Raju , Carnes Kevin D. , Dantus Marcos , Rolles Daniel , Rudenko Artem , Wells Eric , Ben-Itzhak Itzik 
Published: January 2024

AbstractAn essential problem in photochemistry is understanding the coupling of electronic and nuclear dynamics in molecules, which manifests in processes such as hydrogen migration. Measurements of hydrogen migration in molecules that have more than two equivalent hydrogen sites, however, produce data that is difficult to compare with calculations because the initial hydrogen site is unknown. We demonstrate that coincidence ion-imaging measurements of a few deuterium-tagged isotopologues of ethanol can determine the contribution of each initial-site composition to hydrogen-rich fragments following strong-field double ionization. These site-specific probabilities produce benchmarks for calculations and answer outstanding questions about photofragmentation of ethanol dications; e.g., establishing that the central two hydrogen atoms are 15 times more likely to abstract the hydroxyl proton than a methyl-group proton to form H$${}_{3}^{+}$$3+and that hydrogen scrambling, involving the exchange of hydrogen between different sites, is important in H2O+formation. The technique extends to dynamic variables and could, in principle, be applied to larger non-cyclic hydrocarbons.
TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress
Authors: Jeong Eutteum , Willett Rose , Rissone Alberto , La Spina Martina , Puertollano Rosa 
Published: January 2024

AbstractLysosomes have emerged as critical regulators of cellular homeostasis. Here we show that the lysosomal protein TMEM55B contributes to restore cellular homeostasis in response to oxidative stress by three different mechanisms: (1) TMEM55B mediates NEDD4-dependent PLEKHM1 ubiquitination, causing PLEKHM1 proteasomal degradation and halting autophagosome/lysosome fusion; (2) TMEM55B promotes recruitment of components of the ESCRT machinery to lysosomal membranes to stimulate lysosomal repair; and (3) TMEM55B sequesters the FLCN/FNIP complex to facilitate translocation of the transcription factor TFE3 to the nucleus, allowing expression of transcriptional programs that enable cellular adaptation to stress. Knockout oftmem55genes in zebrafish embryos increases their susceptibility to oxidative stress, causing early death oftmem55-KO animals in response to arsenite toxicity. Altogether, our work identifies a role for TMEM55B as a molecular sensor that coordinates autophagosome degradation, lysosomal repair, and activation of stress responses.
Deep learning-driven fragment ion series classification enables highly precise and sensitive de novo peptide sequencing
Authors: Klaproth-Andrade Daniela , Hingerl Johannes , Bruns Yanik , Smith Nicholas H. , Träuble Jakob , Wilhelm Mathias , Gagneur Julien 
Published: January 2024

AbstractUnlike for DNA and RNA, accurate and high-throughput sequencing methods for proteins are lacking, hindering the utility of proteomics in applications where the sequences are unknown including variant calling, neoepitope identification, and metaproteomics. We introduce Spectralis, a de novo peptide sequencing method for tandem mass spectrometry. Spectralis leverages several innovations including a convolutional neural network layer connecting peaks in spectra spaced by amino acid masses, proposing fragment ion series classification as a pivotal task for de novo peptide sequencing, and a peptide-spectrum confidence score. On spectra for which database search provided a ground truth, Spectralis surpassed 40% sensitivity at 90% precision, nearly doubling state-of-the-art sensitivity. Application to unidentified spectra confirmed its superiority and showcased its applicability to variant calling. Altogether, these algorithmic innovations and the substantial sensitivity increase in the high-precision range constitute an important step toward broadly applicable peptide sequencing.
Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences
Authors: Fu Cong , He Ling , Xu Hui , Zhang Zongpeng , Chang Xin , Dang Yanfeng , Dong Xiu-Qin , Wang Chun-Jiang 
Published: January 2024

AbstractChiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.
Multiplexed multicolor antiviral assay amenable for high-throughput research
Authors: Li Li-Hsin , Chiu Winston , Huang Yun-An , Rasulova Madina , Vercruysse Thomas , Thibaut Hendrik Jan , ter Horst Sebastiaan , Rocha-Pereira Joana , Vanhoof Greet , Borrenberghs Doortje , Goethals Olivia , Kaptein Suzanne J. F. , Leyssen Pieter , Neyts Johan , Dallmeier Kai 
Published: January 2024

AbstractTo curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once, as demonstrated by using three distantly related orthoflaviviruses: dengue, Japanese encephalitis and yellow fever virus. Each virus is tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high-content imaging. Specific antisera and small-molecule inhibitors are employed to validate that multiplexing approach yields comparable inhibition profiles to single-virus infection assays. To facilitate downstream analysis, a kernel is developed to deconvolute and reduce the multidimensional quantitative data to three cartesian coordinates. The methodology is applicable to viruses from different families as exemplified by co-infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery of broader-spectrum antivirals, as shown in a pilot screen of approximately 1200 drug-like small-molecules.
Discrete symmetries tested at 10−4 precision using linear polarization of photons from positronium annihilations
Authors: Moskal Paweł , Czerwiński Eryk , Raj Juhi , Bass Steven D. , Beyene Ermias Y. , Chug Neha , Coussat Aurélien , Curceanu Catalina , Dadgar Meysam , Das Manish , Dulski Kamil , Gajos Aleksander , Gorgol Marek , Hiesmayr Beatrix C. , Jasińska Bożena , Kacprzak Krzysztof , Kaplanoglu Tevfik , Kapłon Łukasz , Klimaszewski Konrad , Konieczka Paweł , Korcyl Grzegorz , Kozik Tomasz , Krzemień Wojciech , Kumar Deepak , Moyo Simbarashe , Mryka Wiktor , Niedźwiecki Szymon , Parzych Szymon , del Río Elena Pérez , Raczyński Lech , Sharma Sushil , Choudhary Shivani , Shopa Roman Y. , Silarski Michał , Skurzok Magdalena , Stępień Ewa Ł. , Tanty Pooja , Ardebili Faranak Tayefi , Ardebili Keyvan Tayefi , Eliyan Kavya Valsan , Wiślicki Wojciech 
Published: January 2024

AbstractDiscrete symmetries play an important role in particle physics with violation of CP connected to the matter-antimatter imbalance in the Universe. We report the most precise test of P, T and CP invariance in decays of ortho-positronium, performed with methodology involving polarization of photons from these decays. Positronium, the simplest bound state of an electron and positron, is of recent interest with discrepancies reported between measured hyperfine energy structure and theory at the level of 10−4 signaling a need for better understanding of the positronium system at this level. We test discrete symmetries using photon polarizations determined via Compton scattering in the dedicated J-PET tomograph on an event-by-event basis and without the need to control the spin of the positronium with an external magnetic field, in contrast to previous experiments. Our result is consistent with QED expectations at the level of 0.0007 and one standard deviation.
KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo
Authors: Najumudeen Arafath K. , Fey Sigrid K. , Millett Laura M. , Ford Catriona A. , Gilroy Kathryn , Gunduz Nuray , Ridgway Rachel A. , Anderson Eve , Strathdee Douglas , Clark William , Nixon Colin , Morton Jennifer P. , Campbell Andrew D. , Sansom Owen J. 
Published: January 2024

AbstractOncogenicKRASmutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence ofKRASallelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele inKRASmutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-typeKrasin the context of oncogenicKras. Deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-typeKrasupon tumour initiation, progression and therapeutic response inKrasmutant CRC.
Mapping nucleosome-resolution chromatin organization and enhancer-promoter loops in plants using Micro-C-XL
Authors: Sun Linhua , Zhou Jingru , Xu Xiao , Liu Yi , Ma Ni , Liu Yutong , Nie Wenchao , Zou Ling , Deng Xing Wang , He Hang 
Published: January 2024

AbstractAlthough chromatin organizations in plants have been dissected at the scales of compartments and topologically associating domain (TAD)-like domains, there remains a gap in resolving fine-scale structures. Here, we use Micro-C-XL, a high-throughput chromosome conformation capture (Hi-C)-based technology that involves micrococcal nuclease (instead of restriction enzymes) and long cross-linkers, to dissect single nucleosome-resolution chromatin organization in Arabidopsis. Insulation analysis reveals more than 14,000 boundaries, which mostly include chromatin accessibility, epigenetic modifications, and transcription factors. Micro-C-XL reveals associations between RNA Pols and local chromatin organizations, suggesting that gene transcription substantially contributes to the establishment of local chromatin domains. By perturbing Pol II both genetically and chemically at the gene level, we confirm its function in regulating chromatin organization. Visible loops and stripes are assigned to super-enhancers and their targeted genes, thus providing direct insights for the identification and mechanistic analysis of distal CREs and their working modes in plants. We further investigate possible factors regulating these chromatin loops. Subsequently, we expand Micro-C-XL to soybean and rice. In summary, we use Micro-C-XL for analyses of plants, which reveal fine-scale chromatin organization and enhancer-promoter loops and provide insights regarding three-dimensional genomes in plants.
Gene regulation and speciation in a migratory divide between songbirds
Authors: Louder Matthew I. M. , Justen Hannah , Kimmitt Abigail A. , Lawley Koedi S. , Turner Leslie M. , Dickman J. David , Delmore Kira E. 
Published: January 2024

AbstractBehavioral variation abounds in nature. This variation is important for adaptation and speciation, but its molecular basis remains elusive. Here, we use a hybrid zone between two subspecies of songbirds that differ in migration – an ecologically important and taxonomically widespread behavior---to gain insight into this topic. We measure gene expression in five brain regions. Differential expression between migratory states was dominated by circadian genes in all brain regions. The remaining patterns were largely brain-region specific. For example, expression differences between the subspecies that interact with migratory state likely help maintain reproductive isolation in this system and were documented in only three brain regions. Contrary to existing work on regulatory mechanisms underlying species-specific traits, two lines of evidence suggest that trans- (vs. cis) regulatory changes underlie these patterns – no evidence for allele-specific expression in hybrids and minimal associations between genomic differentiation and expression differences. Additional work with hybrids shows expression levels were often distinct (transgressive) from parental forms. Behavioral contrasts and functional enrichment analyses allowed us to connect these patterns to mitonuclear incompatibilities and compensatory responses to stress that could exacerbate selection on hybrids and contribute to speciation.
A plant cell death-inducing protein from litchi interacts with Peronophythora litchii pectate lyase and enhances plant resistance
Authors: Li Wen , Li Peng , Deng Yizhen , Situ Junjian , He Zhuoyuan , Zhou Wenzhe , Li Minhui , Xi Pinggen , Liang Xiangxiu , Kong Guanghui , Jiang Zide 
Published: January 2024

AbstractCell wall degrading enzymes, including pectate lyases (PeLs), released by plant pathogens, break down protective barriers and/or activate host immunity. The direct interactions between PeLs and plant immune-related proteins remain unclear. We identify two PeLs, PlPeL1 and PlPeL1-like, critical for full virulence of Peronophythora litchii on litchi (Litchi chinensis). These proteins enhance plant susceptibility to oomycete pathogens in a PeL enzymatic activity-dependent manner. However, LcPIP1, a plant immune regulator secreted by litchi, binds to PlPeL1/PlPeL1-like, and attenuates PlPeL1/PlPeL1-like induced plant susceptibility to Phytophthora capsici. LcPIP1 also induces cell death and various immune responses in Nicotiana benthamiana. Conserved in plants, LcPIP1 homologs bear a conserved “VDMASG” motif and exhibit immunity-inducing activity. Furthermore, SERK3 interacts with LcPIP1 and is required for LcPIP1-induced cell death. NbPIP1 participates in immune responses triggered by the PAMP protein INF1. In summary, our study reveals the dual roles of PlPeL1/PlPeL1-like in plant-pathogen interactions: enhancing pathogen virulence through PeL enzymatic activity while also being targeted by LcPIP1, thus enhancing plant immunity.
Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use
Authors: Worthmann Anna , Ridder Julius , Piel Sharlaine Y. L. , Evangelakos Ioannis , Musfeldt Melina , Voß Hannah , O’Farrell Marie , Fischer Alexander W. , Adak Sangeeta , Sundd Monica , Siffeti Hasibullah , Haumann Friederike , Kloth Katja , Bierhals Tatjana , Heine Markus , Pertzborn Paul , Pauly Mira , Scholz Julia-Josefine , Kundu Suman , Fuh Marceline M. , Neu Axel , Tödter Klaus , Hempel Maja , Knippschild Uwe , Semenkovich Clay F. , Schlüter Hartmut , Heeren Joerg , Scheja Ludger , Kubisch Christian , Schlein Christian 
Published: January 2024

AbstractDietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids – a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.
Mosaic: in-memory computing and routing for small-world spike-based neuromorphic systems
Authors: Dalgaty Thomas , Moro Filippo , Demirağ Yiğit , De Pra Alessio , Indiveri Giacomo , Vianello Elisa , Payvand Melika 
Published: January 2024

AbstractThe brain’s connectivity is locally dense and globally sparse, forming a small-world graph—a principle prevalent in the evolution of various species, suggesting a universal solution for efficient information routing. However, current artificial neural network circuit architectures do not fully embrace small-world neural network models. Here, we present the neuromorphic Mosaic: a non-von Neumann systolic architecture employing distributed memristors for in-memory computing and in-memory routing, efficiently implementing small-world graph topologies for Spiking Neural Networks (SNNs). We’ve designed, fabricated, and experimentally demonstrated the Mosaic’s building blocks, using integrated memristors with 130 nm CMOS technology. We show that thanks to enforcing locality in the connectivity, routing efficiency of Mosaic is at least one order of magnitude higher than other SNN hardware platforms. This is while Mosaic achieves a competitive accuracy in a variety of edge benchmarks. Mosaic offers a scalable approach for edge systems based on distributed spike-based computing and in-memory routing.