bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders
Authors: Arnsten Amy F. T. , Ishizawa Yumiko , Xie Zhongcong 
Published: April 2023

AbstractNeuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from “long-COVID” or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC) that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are especially vulnerable to kynurenic acid inflammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual neuromodulation, with cAMP magnification of calcium signaling in spines, which opens nearby potassium channels to rapidly weaken connectivity and reduce neuronal firing. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to prevent loss of firing. However, the production of GCPII inflammatory signaling reduces mGluR3 actions and markedly diminishes dlPFC network firing. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network firing and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the locus coeruleus and amygdala, and by having anti-inflammatory actions in the immune system. This information is particularly timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the treatment of cognitive deficits from long-COVID.
Viral vectored vaccines: design, development, preventive and therapeutic applications in human diseases
Authors: Wang Shen , Liang Bo , Wang Weiqi , Li Ling , Feng Na , Zhao Yongkun , Wang Tiecheng , Yan Feihu , Yang Songtao , Xia Xianzhu 
Published: April 2023

AbstractHuman diseases, particularly infectious diseases and cancers, pose unprecedented challenges to public health security and the global economy. The development and distribution of novel prophylactic and therapeutic vaccines are the prioritized countermeasures of human disease. Among all vaccine platforms, viral vector vaccines offer distinguished advantages and represent prominent choices for pathogens that have hampered control efforts based on conventional vaccine approaches. Currently, viral vector vaccines remain one of the best strategies for induction of robust humoral and cellular immunity against human diseases. Numerous viruses of different families and origins, including vesicular stomatitis virus, rabies virus, parainfluenza virus, measles virus, Newcastle disease virus, influenza virus, adenovirus and poxvirus, are deemed to be prominent viral vectors that differ in structural characteristics, design strategy, antigen presentation capability, immunogenicity and protective efficacy. This review summarized the overall profile of the design strategies, progress in advance and steps taken to address barriers to the deployment of these viral vector vaccines, simultaneously highlighting their potential for mucosal delivery, therapeutic application in cancer as well as other key aspects concerning the rational application of these viral vector vaccines. Appropriate and accurate technological advances in viral vector vaccines would consolidate their position as a leading approach to accelerate breakthroughs in novel vaccines and facilitate a rapid response to public health emergencies.
Cdc2-like kinases: structure, biological function and therapeutic targets for diseases
Authors: Song Mengqiu , Pang Luping , Zhang Mengmeng , Qu Yingzi , Laster Kyle Vaughn , Dong Zigang 
Published: April 2023

AbstractThe CLKs (Cdc2-like kinases) belong to the dual-specificity protein kinase family and play crucial roles in regulating transcript splicing via the phosphorylation of SR proteins (SRSF1–12), catalyzing spliceosome molecular machinery, and modulating the activities or expression of non-splicing proteins. The dysregulation of these processes is linked with various diseases, including neurodegenerative diseases, Duchenne muscular dystrophy, inflammatory diseases, viral replication, and cancer. Thus, CLKs have been considered as potential therapeutic targets, and significant efforts have been exerted to discover potent CLKs inhibitors. In particular, clinical trials aiming to assess the activities of the small molecules Lorecivivint on knee Osteoarthritis patients, and Cirtuvivint and Silmitasertib in different advanced tumors have been investigated for therapeutic usage. In this review, we comprehensively documented the structure and biological functions of CLKs in various human diseases and summarized the significance of related inhibitors in therapeutics. Our discussion highlights the most recent CLKs research, paving the way for the clinical treatment of various human diseases.
Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells
Authors: Sung Hye Kyoung , Murugathasan Mayoorey , Abdul-Sater Ali A. , Sweeney Gary 
Published: April 2023

AbstractIron overload is associated with various pathological changes which contribute to metabolic syndrome, many of which have been proposed to occur via damaging tissue through an excessive amount of reactive oxygen species (ROS) production. In this study, we established a model of iron overload in L6 skeletal muscle cells and observed that iron enhanced cytochrome c release from depolarized mitochondria, assayed by immunofluorescent colocalization of cytochrome c with Tom20 and the use of JC-1, respectively. This subsequently elevated apoptosis, determined via use of a caspase-3/7 activatable fluorescent probe and western blotting for cleaved caspase-3. Using CellROX deep red and mBBr, we observed that iron increased generation of reactive oxygen species (ROS), and that pretreatment with the superoxide dismutase mimetic MnTBAP reduced ROS production and attenuated iron-induced intrinsic apoptosis and cell death. Furthermore, using MitoSox Red we observed that iron enhanced mROS and the mitochondria-targeted anti-oxidant SKQ1 reduced iron-induced ROS generation and cell death. Western blotting for LC3-II and P62 levels as well as immunofluorescent detection of autophagy flux with LC3B and P62 co-localization indicated that iron acutely (2–8 h) activated and later (12–24 h) attenuated autophagic flux. We used autophagy-deficient cell models generated by overexpressing a dominant-negative Atg5 mutant or CRISPR-mediated ATG7 knock out to test the functional significance of autophagy and observed that autophagy-deficiency exacerbated iron-induced ROS production and apoptosis. In conclusion, our study showed that high iron levels promoted ROS production, blunted the self-protective autophagy response and led to cell death in L6 skeletal muscle cells.
Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization
Authors: Zhou Xun , Chen Hui , Hu Yan , Ma Xiaoyan , Li Jinqing , Shi Yingfeng , Tao Min , Wang Yi , Zhong Qin , Yan Danying , Zhuang Shougang , Liu Na 
Published: April 2023

AbstractLong-term follow-up data indicates that 1/4 patients with acute kidney injury (AKI) will develop to chronic kidney disease (CKD). Our previous studies have demonstrated that enhancer of zeste homolog 2 (EZH2) played an important role in AKI and CKD. However, the role and mechanisms of EZH2 in AKI-to-CKD transition are still unclear. Here, we demonstrated EZH2 and H3K27me3 highly upregulated in kidney from patients with ANCA-associated glomerulonephritis, and expressed positively with fibrotic lesion and negatively with renal function. Conditional EZH2 deletion or pharmacological inhibition with 3-DZNeP significantly improved renal function and attenuated pathological lesion in ischemia/reperfusion (I/R) or folic acid (FA) mice models (two models of AKI-to-CKD transition). Mechanistically, we used CUT & Tag technology to verify that EZH2 binding to the PTEN promoter and regulating its transcription, thus regulating its downstream signaling pathways. Genetic or pharmacological depletion of EZH2 upregulated PTEN expression and suppressed the phosphorylation of EGFR and its downstream signaling ERK1/2 and STAT3, consequently alleviating the partial epithelial-mesenchymal transition (EMT), G2/M arrest, and the aberrant secretion of profibrogenic and proinflammatory factors in vivo and vitro experiments. In addition, EZH2 promoted the EMT program induced loss of renal tubular epithelial cell transporters (OAT1, ATPase, and AQP1), and blockade of EZH2 prevented it. We further co-cultured macrophages with the medium of human renal tubular epithelial cells treated with H2O2 and found macrophages transferred to M2 phenotype, and EZH2 could regulate M2 macrophage polarization through STAT6 and PI3K/AKT pathways. These results were further verified in two mice models. Thus, targeted inhibition of EZH2 might be a novel therapy for ameliorating renal fibrosis after acute kidney injury by counteracting partial EMT and blockade of M2 macrophage polarization.
Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures
Authors: Melin Esbjörn , Andersson My , Gøtzsche Casper R. , Wickham Jenny , Huang Yuzhe , Szczygiel Julia Alicja , Boender Arnie , Christiansen Søren H. , Pinborg Lars , Woldbye David P. D. , Kokaia Merab 
Published: April 2023

AbstractGene therapy with AAV vectors carrying genes for neuropeptide Y and its receptor Y2 has been shown to inhibit seizures in multiple animal models of epilepsy. It is however unknown how the AAV serotype or the sequence order of these two transgenes in the expression cassette affects the actual parenchymal gene expression levels and the seizure-suppressant efficacy. To address these questions, we compared three viral vector serotypes (AAV1, AAV2 and AAV8) and two transgene sequence orders (NPY-IRES-Y2 and Y2-IRES-NPY) in a rat model of acutely induced seizures. Wistar male rats were injected bilaterally with viral vectors and 3 weeks later acute seizures were induced by a subcutaneous injection of kainate. The latency until 1st motor seizure, time spent in motor seizure and latency to status epilepticus were measured to evaluate the seizure-suppressing efficacy of these vectors compared to an empty cassette control vector. Based on the results, the effect of the AAV1-NPY-IRES-Y2 vector was further investigated by in vitro electrophysiology, and its ability to achieve transgene overexpression in resected human hippocampal tissue was evaluated. The AAV1-NPY-IRES-Y2 proved to be better to any other serotype or gene sequence considering both transgene expression and ability to suppress induced seizures in rats. The vector also demonstrated transgene-induced decrease of glutamate release from excitatory neuron terminals and significantly increased both NPY and Y2 expression in resected human hippocampal tissue from patients with drug-resistant temporal lobe epilepsy. These results validate the feasibility of NPY/Y2 receptor gene therapy as a therapeutic opportunity in focal epilepsies.
Chasing the spin gap through the phase diagram of a frustrated Mott insulator
Authors: Pustogow A. , Kawasugi Y. , Sakurakoji H. , Tajima N. 
Published: April 2023

AbstractThe quest for entangled spin excitations has stimulated intense research on frustrated magnetic systems. For almost two decades, the triangular-lattice Mott insulator κ-(BEDT-TTF)2Cu2(CN)3 has been one of the hottest candidates for a gapless quantum spin liquid with itinerant spinons. Very recently, however, this scenario was overturned as electron-spin-resonance (ESR) studies unveiled a spin gap, calling for reevaluation of the magnetic ground state. Here we achieve a precise mapping of this spin-gapped phase through the Mott transition by ultrahigh-resolution strain tuning. Our transport experiments reveal a reentrance of charge localization below T⋆ = 6 K associated with a gap size of 30–50 K. The negative slope of the insulator-metal boundary, dT⋆/dp < 0, evidences the low-entropy nature of the spin-singlet ground state. By tuning the enigmatic ‘6K anomaly’ through the phase diagram of κ-(BEDT-TTF)2Cu2(CN)3, we identify it as the transition to a valence-bond-solid phase, in agreement with previous thermal expansion and magnetic resonance studies. This spin-gapped insulating state persists at T → 0 until unconventional superconductivity and metallic transport proliferate.
Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers
Authors: ter Brugge Petra , Moser Sarah C. , Bièche Ivan , Kristel Petra , Ibadioune Sabrina , Eeckhoutte Alexandre , de Bruijn Roebi , van der Burg Eline , Lutz Catrin , Annunziato Stefano , de Ruiter Julian , Masliah Planchon Julien , Vacher Sophie , Courtois Laura , El-Botty Rania , Dahmani Ahmed , Montaudon Elodie , Morisset Ludivine , Sourd Laura , Huguet Léa , Derrien Heloise , Nemati Fariba , Chateau-Joubert Sophie , Larcher Thibaut , Salomon Anne , Decaudin Didier , Reyal Fabien , Coussy Florence , Popova Tatiana , Wesseling Jelle , Stern Marc-Henri , Jonkers Jos , Marangoni Elisabetta 
Published: April 2023

AbstractThe high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.
Testing electron–phonon coupling for the superconductivity in kagome metal CsV3Sb5
Authors: Zhong Yigui , Li Shaozhi , Liu Hongxiong , Dong Yuyang , Aido Kohei , Arai Yosuke , Li Haoxiang , Zhang Weilu , Shi Youguo , Wang Ziqiang , Shin Shik , Lee H. N. , Miao H. , Kondo Takeshi , Okazaki Kozo 
Published: April 2023

AbstractIn crystalline materials, electron-phonon coupling (EPC) is a ubiquitous many-body interaction that drives conventional Bardeen-Cooper-Schrieffer superconductivity. Recently, in a new kagome metal CsV3Sb5, superconductivity that possibly intertwines with time-reversal and spatial symmetry-breaking orders is observed. Density functional theory calculations predicted weak EPC strength, λ, supporting an unconventional pairing mechanism in CsV3Sb5. However, experimental determination of λ is still missing, hindering a microscopic understanding of the intertwined ground state of CsV3Sb5. Here, using 7-eV laser-based angle-resolved photoemission spectroscopy and Eliashberg function analysis, we determine an intermediate λ=0.45–0.6 atT = 6 K for both Sb 5pand V 3delectronic bands, which can support a conventional superconducting transition temperature on the same magnitude of experimental value in CsV3Sb5. Remarkably, the EPC on the V 3d-band enhances to λ~0.75 as the superconducting transition temperature elevated to 4.4 K in Cs(V0.93Nb0.07)3Sb5. Our results provide an important clue to understand the pairing mechanism in the kagome superconductor CsV3Sb5.
Year-round utilization of sea ice-associated carbon in Arctic ecosystems
Authors: Koch Chelsea W. , Brown Thomas A. , Amiraux Rémi , Ruiz-Gonzalez Carla , MacCorquodale Maryam , Yunda-Guarin Gustavo A. , Kohlbach Doreen , Loseto Lisa L. , Rosenberg Bruno , Hussey Nigel E. , Ferguson Steve H. , Yurkowski David J. 
Published: April 2023

AbstractSea ice primary production is considered a valuable energy source for Arctic marine food webs, yet the extent remains unclear through existing methods. Here we quantify ice algal carbon signatures using unique lipid biomarkers in over 2300 samples from 155 species including invertebrates, fish, seabirds, and marine mammals collected across the Arctic shelves. Ice algal carbon signatures were present within 96% of the organisms investigated, collected year-round from January to December, suggesting continuous utilization of this resource despite its lower proportion to pelagic production. These results emphasize the importance of benthic retention of ice algal carbon that is available to consumers year-round. Finally, we suggest that shifts in the phenology, distribution and biomass of sea ice primary production anticipated with declining seasonal sea ice will disrupt sympagic-pelagic-benthic coupling and consequently the structure and the functioning of the food web which is critical for Indigenous Peoples, commercial fisheries, and global biodiversity.
Crystal structure of a highly conserved enteroviral 5′ cloverleaf RNA replication element
Authors: Das Naba K. , Hollmann Nele M. , Vogt Jeff , Sevdalis Spiridon E. , Banna Hasan A. , Ojha Manju , Koirala Deepak 
Published: April 2023

AbstractThe extreme 5′-end of the enterovirus RNA genome contains a conserved cloverleaf-like domain that recruits 3CD and PCBP proteins required for initiating genome replication. Here, we report the crystal structure at 1.9 Å resolution of this domain from the CVB3 genome in complex with an antibody chaperone. The RNA folds into an antiparallel H-type four-way junction comprising four subdomains with co-axially stacked sA-sD and sB-sC helices. Long-range interactions between a conserved A40 in the sC-loop and Py-Py helix within the sD subdomain organize near-parallel orientations of the sA-sB and sC-sD helices. Our NMR studies confirm that these long-range interactions occur in solution and without the chaperone. The phylogenetic analyses indicate that our crystal structure represents a conserved architecture of enteroviral cloverleaf-like domains, including the A40 and Py-Py interactions. The protein binding studies further suggest that the H-shape architecture provides a ready-made platform to recruit 3CD and PCBP2 for viral replication.
Intermittent fasting modulates the intestinal microbiota and improves obesity and host energy metabolism
Authors: Hu Xiangwei , Xia Kai , Dai Minhui , Han Xiaofeng , Yuan Peng , Liu Jia , Liu Shiwei , Jia Fuhuai , Chen Jiayu , Jiang Fangfang , Yu Jieyao , Yang Huanming , Wang Jian , Xu Xun , Jin Xin , Kristiansen Karsten , Xiao Liang , Chen Wei , Han Mo , Duan Shenglin 
Published: April 2023

Abstract
Intermittent fasting (IF) is a promising paradigm for weight loss which has been shown to modulate the gut microbiota based on 16S rRNA gene amplicon sequencing. Here, 72 Chinese volunteers with a wide range of body mass index (BMI) participated in a three-week IF program during which an average loss of 3.67 kg body weight accompanied with improved clinical parameters was observed irrespective of initial anthropometric and gut microbiota status. Fecal samples were collected before and after the intervention and subjected to shotgun metagenomic sequencing. De novo assembly yielded 2934 metagenome-assembled genomes (MAGs). Profiling revealed significant enrichment of Parabacteroides distasonis and Bacteroides thetaiotaomicron after the intervention, with inverse correlations between their relative abundances and parameters related to obesity and atherosclerotic cardiovascular diseases (ASCVD). MAGs enriched after the intervention showed high richness and diversity of carbohydrate-active enzymes, with an increased relative abundances of genes related to succinate production and glutamate fermentation.
Identifying breast cancer patients at risk of relapse despite pathological complete response after neoadjuvant therapy
Authors: Huober Jens , van Mackelenbergh Marion , Schneeweiss Andreas , Seither Fenja , Blohmer Jens-Uwe , Denkert Carsten , Tesch Hans , Hanusch Claus , Salat Christoph , Rhiem Kerstin , Solbach Christine , Fasching Peter A. , Jackisch Christian , Reinisch Mattea , Lederer Bianca , Mehta Keyur , Link Theresa , Nekljudova Valentina , Loibl Sibylle , Untch Michael 
Published: April 2023

AbstractThis retrospective pooled analysis aims to identify factors predicting relapse despite a pathologic complete response (pCR) in patients with breast cancer (BC). 2066 patients with a pCR from five neoadjuvant GBG/AGO-B trials fulfill the inclusion criteria of this analysis. Primary endpoint is disease-free survival (DFS); secondary endpoints is distant DFS (DDFS) and overall survival (OS). After a median follow-up of 57.6 months, DFS is significantly worse for patients with positive lymph nodes (cN+ vs cN0 hazard ratio [HR] 1.94, 95%CI 1.48–2.54; p < 0.001). In patients with triple-negative tumors, lobular histology (lobular vs other HR 3.55, 95%CI 1.53–8.23; p = 0.003), and clinical nodal involvement (cN+ vs cN0 HR 2.45, 95%CI 1.59–3.79; p < 0.001) predict a higher risk of DFS events. Patients with HER2-positive cT3/4 tumors have a significantly higher risk of relapse (cT3/4 vs cT1 HR 2.07, 95%CI 1.06–4.03; p = 0.033). Initial tumor load and histological type predict relapse in patients with a pCR.
High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease
Authors: Im K. W. , Huppert L. A. , Malevanchik L. , Rugo H. S. , Combes A. J. , Campbell M. J. , Krummel M. F. , Melisko M. E. 
Published: April 2023

AbstractLeptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8+ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of Tregs than patients without LMD. Interestingly, the frequency of partially exhausted CD8+ T cells (CD38hiTIM3lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8+ T cells, which may offer an important therapeutic target.