bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensified Mussel Farming; Impacts on Nutrient Budgets and Ecology in a Eutrophic Semi‐Enclosed Fjord System
Authors: Maar M. , Larsen J. , Schourup‐Kristensen V. 
Published: January 2023

AbstractCompared to land‐based sources, mussel aquaculture provides food products with a high‐quality protein content and a low carbon footprint. At the same time, mussel cultures store nutrients in their tissue that are removed from the system through harvesting. However, increasingly development of suspended bivalve aquaculture in the coastal zone also comes with a price as the ecological carrying capacity of the ecosystem may be exceeded. The present study aims to support future fjord‐management by estimating the nutrient budgets and ecological impacts of intensified mussel aquaculture in a shallow semi‐enclosed system, the Limfjorden, using 3D ecosystem modeling. Model results showed a net removal of nutrients by suspended mussel cultures at basin scale, whereas at farm scale the efficiency was lower due to increased sediment fluxes. An increase in mussel farming from the current 4 kt‐fresh weight to a future projection of 104 kt‐fresh weight did not exceed the ecological carrying capacity with respect to impacts on sediment chemistry but could cause local declines in benthic bivalve populations. Intense mussel farming provided ecosystem services such as better oxygen conditions and higher Secchi depth together with lower nutrient‐ and chlorophyll a concentrations on basin scale. In addition, there was a redistribution of nutrients, chlorophyll a concentrations, and Secchi depth between sub‐basins in the fjord depending on farming location and intensity. Overall, intensified mussel farming could contribute to the mitigation of eutrophication effects by removing nutrients from land sources and by reducing the local sediment loading.
Comparison of phenomics and cfDNA in a large breast screening population: the Breast Screening and Monitoring Study (BSMS)
Authors: Stebbing Justin , Takis Panteleimon G. , Sands Caroline J. , Maslen Lynn , Lewis Matthew R. , Gleason Kelly , Page Karen , Guttery David , Fernandez-Garcia Daniel , Primrose Lindsay , Shaw Jacqueline A. 
Published: January 2023

AbstractTo assess their roles in breast cancer diagnostics, we aimed to compare plasma cell-free DNA (cfDNA) levels with the circulating metabolome in a large breast screening cohort of women recalled for mammography, including healthy women and women with mammographically detected breast diseases, ductal carcinoma in situ and invasive breast cancer: the Breast Screening and Monitoring Study (BSMS). In 999 women, plasma was analyzed by nuclear magnetic resonance (NMR) and Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and then processed to isolate and quantify total cfDNA. NMR and UPLC-MS results were compared with data for 186 healthy women derived from the AIRWAVE cohort. Results showed no significant differences between groups for all metabolites, whereas invasive cancers had significantly higher plasma cfDNA levels than all other groups. When stratified the supervised OPLS-DA analysis and total cfDNA concentration showed high discrimination accuracy between invasive cancers and the disease/medication-free subjects. Furthermore, comparison of OPLS-DA data for invasive breast cancers with the AIRWAVE cohort showed similar discrimination between breast cancers and healthy controls. This is the first report of agreement between metabolomics and plasma cfDNA levels for discriminating breast cancer from healthy subjects in a true screening population. It also emphasizes the importance of sample standardization. Follow on studies will involve analysis of candidate features in a larger validation series as well as comparing results with serial plasma samples taken at the next routine screening mammography appointment. The findings here help establish the role of plasma analysis in the diagnosis of breast cancer in a large real-world cohort.
The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer
Authors: Yang Xue , Cruz Miguel I. , Nguyen Elizabeth V. , Huang Cheng , Schittenhelm Ralf B. , Luu Jennii , Cowley Karla J. , Shin Sung-Young , Nguyen Lan K. , Lim Kam Sian Terry C. C. , Clark Kimberley C. , Simpson Kaylene J. , Ma Xiuquan , Daly Roger J. 
Published: January 2023

AbstractWe have determined that expression of the pseudokinase NRBP1 positively associates with poor prognosis in triple negative breast cancer (TNBC) and is required for efficient migration, invasion and proliferation of TNBC cells in culture as well as growth of TNBC orthotopic xenografts and experimental metastasis. Application of BioID/MS profiling identified P-Rex1, a known guanine nucleotide exchange factor for Rac1, as a NRBP1 binding partner. Importantly, NRBP1 overexpression enhanced levels of GTP-bound Rac1 and Cdc42 in a P-Rex1-dependent manner, while NRBP1 knockdown reduced their activation. In addition, NRBP1 associated with P-Rex1, Rac1 and Cdc42, suggesting a scaffolding function for this pseudokinase. NRBP1-mediated promotion of cell migration and invasion was P-Rex1-dependent, while constitutively-active Rac1 rescued the effect of NRBP1 knockdown on cell proliferation and invasion. Generation of reactive oxygen species via a NRBP1/P-Rex1 pathway was implicated in these oncogenic roles of NRBP1. Overall, these findings define a new function for NRBP1 and a novel oncogenic signalling pathway in TNBC that may be amenable to therapeutic intervention.
Neural substrates of continuous and discrete inhibitory control
Authors: Howlett Jonathon R. , Park Heekyeong , Paulus Martin P. 
Published: January 2023

AbstractInhibitory control dysfunctions play an important role in psychiatric disorders but the precise nature of these dysfunctions is still not well understood. Advances in computational modeling of real-time motor control using a proportion–integral–derivative (PID) control framework have parsed continuous motor inhibition into a preemptive drive component (signified by theKpparameter) and a reactive damping component (signified by theKdparameter). This investigation examined the relationship between inhibitory control processing during a stop signal task and continuous motor control during a simulated one-dimensional driving task in a transdiagnostic sample of participants. A transdiagnostic psychiatric sample of 492 individuals completed a stop signal task during functional magnetic resonance imaging and a simple behavioral motor control task, which was modeled using the PID framework. We examined associations between theKpandKdparameters and behavioral indices as well as neural activation on the stop signal task. Individuals with higher damping, controlling for a drive, on the driving task exhibited relatively less strategic adjustment after a stop trial (indexed by the difference in go trial reaction time and by stop trial accuracy) on the stop signal task. Individuals with higher damping, controlling for a drive, additionally exhibited increased activity in the frontal and parietal regions as well as the insula and caudate during response inhibition on the stop signal task. The results suggest that computational indices of motor control performance may serve as behavioral markers of the functioning of neural systems involved in inhibitory control.
Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
Authors: Eckardt Jan-Niklas , Stasik Sebastian , Röllig Christoph , Sauer Tim , Scholl Sebastian , Hochhaus Andreas , Crysandt Martina , Brümmendorf Tim H. , Naumann Ralph , Steffen Björn , Kunzmann Volker , Einsele Hermann , Schaich Markus , Burchert Andreas , Neubauer Andreas , Schäfer-Eckart Kerstin , Schliemann Christoph , Krause Stefan W. , Herbst Regina , Hänel Mathias , Hanoun Maher , Kaiser Ulrich , Kaufmann Martin , Rácil Zdenek , Mayer Jiri , Cerqueira Tiago , Kroschinsky Frank , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten , Platzbecker Uwe , Baldus Claudia D. , Schetelig Johannes , Siepmann Timo , Bornhäuser Martin , Middeke Jan Moritz , Thiede Christian 
Published: January 2023

AbstractFunctional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.
In-situ cryo-immune engineering of tumor microenvironment with cold-responsive nanotechnology for cancer immunotherapy
Authors: Ou Wenquan , Stewart Samantha , White Alisa , Kwizera Elyahb A. , Xu Jiangsheng , Fang Yuanzhang , Shamul James G. , Xie Changqing , Nurudeen Suliat , Tirada Nikki P. , Lu Xiongbin , Tkaczuk Katherine H. R. , He Xiaoming 
Published: January 2023

AbstractCancer immunotherapy that deploys the host’s immune system to recognize and attack tumors, is a promising strategy for cancer treatment. However, its efficacy is greatly restricted by the immunosuppressive (i.e., immunologically cold) tumor microenvironment (TME). Here, we report an in-situ cryo-immune engineering (ICIE) strategy for turning the TME from immunologically “cold” into “hot”. In particular, after the ICIE treatment, the ratio of the CD8+ cytotoxic T cells to the immunosuppressive regulatory T cells is increased by more than 100 times in not only the primary tumors with cryosurgery but also distant tumors without freezing. This is achieved by combining cryosurgery that causes “frostbite” of tumor with cold-responsive nanoparticles that not only target tumor but also rapidly release both anticancer drug and PD-L1 silencing siRNA specifically into the cytosol upon cryosurgery. This ICIE treatment leads to potent immunogenic cell death, which promotes maturation of dendritic cells and activation of CD8+ cytotoxic T cells as well as memory T cells to kill not only primary but also distant/metastatic breast tumors in female mice (i.e., the abscopal effect). Collectively, ICIE may enable an efficient and durable way to leverage the immune system for combating cancer and its metastasis.
Element- and enantiomer-selective visualization of molecular motion in real-time
Authors: Mincigrucci R. , Rouxel J. R. , Rossi B. , Principi E. , Bottari C. , Catalini S. , Pelli-Cresi J. S. , Fainozzi D. , Foglia L. , Simoncig A. , Matruglio A. , Kurdi G. , Capotondi F. , Pedersoli E. , Perucchi A. , Piccirilli F. , Gessini A. , Giarola M. , Mariotto G. , Oppermann M. , Mukamel S. , Bencivenga F. , Chergui M. , Masciovecchio C. 
Published: January 2023

AbstractUltrafast optical-domain spectroscopies allow to monitor in real time the motion of nuclei in molecules. Achieving element-selectivity had to await the advent of time resolved X-ray spectroscopy, which is now commonly carried at X-ray free electron lasers. However, detecting light element that are commonly encountered in organic molecules, remained elusive due to the need to work under vacuum. Here, we present an impulsive stimulated Raman scattering (ISRS) pump/carbon K-edge absorption probe investigation, which allowed observation of the low-frequency vibrational modes involving specific selected carbon atoms in the Ibuprofen RS dimer. Remarkably, by controlling the probe light polarization we can preferentially access the enantiomer of the dimer to which the carbon atoms belong.
Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma
Authors: Yu Di , Liang Yingying , Kim Claudia , Jaganathan Anbalagan , Ji Donglei , Han Xinye , Yang Xuelan , Jia Yanjie , Gu Ruirui , Wang Chunyu , Zhang Qiang , Cheung Ka Lung , Zhou Ming-Ming , Zeng Lei 
Published: January 2023

AbstractBRD4-NUT, a driver fusion mutant in rare and highly aggressive NUT carcinoma, acts in aberrant transcription of anti-differentiation genes by recruiting histone acetyltransferase (HAT) p300 and promoting p300-driven histone hyperacetylation and nuclear condensation in chromatin. However, the molecular basis of how BRD4-NUT recruits and activates p300 remains elusive. Here, we report that BRD4-NUT contains two transactivation domains (TADs) in NUT that bind to the TAZ2 domain in p300. Our NMR structures reveal that NUT TADs adopt amphipathic helices when bound to the four-helical bundle TAZ2 domain. The NUT protein forms liquid-like droplets in-vitro that are enhanced by TAZ2 binding in 1:2 stoichiometry. The TAD/TAZ2 bipartite binding in BRD4-NUT/p300 triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin that comprise histone H3 lysine 27 and 18 acetylation and transcription proteins BRD4L/S, CDK9, MED1, and RNA polymerase II. The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT’s bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.
scMoMaT jointly performs single cell mosaic integration and multi-modal bio-marker detection
Authors: Zhang Ziqi , Sun Haoran , Mariappan Ragunathan , Chen Xi , Chen Xinyu , Jain Mika S. , Efremova Mirjana , Teichmann Sarah A. , Rajan Vaibhav , Zhang Xiuwei 
Published: January 2023

AbstractSingle cell data integration methods aim to integrate cells across data batches and modalities, and data integration tasks can be categorized into horizontal, vertical, diagonal, and mosaic integration, where mosaic integration is the most general and challenging case with few methods developed. We propose scMoMaT, a method that is able to integrate single cell multi-omics data under the mosaic integration scenario using matrix tri-factorization. During integration, scMoMaT is also able to uncover the cluster specific bio-markers across modalities. These multi-modal bio-markers are used to interpret and annotate the clusters to cell types. Moreover, scMoMaT can integrate cell batches with unequal cell type compositions. Applying scMoMaT to multiple real and simulated datasets demonstrated these features of scMoMaT and showed that scMoMaT has superior performance compared to existing methods. Specifically, we show that integrated cell embedding combined with learned bio-markers lead to cell type annotations of higher quality or resolution compared to their original annotations.
Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy
Authors: Teymournejad Omid , Li Zhaotao , Beesetty Pavani , Yang Ching , Montgomery Christopher P. 
Published: January 2023

AbstractStaphylococcus aureus infections are a major public health issue, and a vaccine is urgently needed. Despite a considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus. Unlike laboratory mice, humans are exposed to S. aureus throughout life. In the current study, we hypothesized that prior exposure to S. aureus “imprints” the immune response to inhibit vaccine-mediated protection. We established a mouse model in which S. aureus skin and soft tissue infection (SSTI) is followed by vaccination and secondary SSTI. Unlike naïve mice, S. aureus-sensitized mice were incompletely protected against secondary SSTI by vaccination with the inactivated α-hemolysin (Hla) mutant HlaH35L. Inhibition of protection was specific for the HlaH35L vaccine and required hla expression during primary SSTI. Surprisingly, inhibition occurred at the level of vaccine-elicited effector T cells; hla expression during primary infection limited the expansion of T cells and dendritic cells and impaired vaccine-specific T cell responses. Importantly, the T cell-stimulating adjuvant CAF01 rescued inhibition and restored vaccine-mediated protection. Together, these findings identify a potential mechanism for the failure of translation of promising S. aureus vaccines from mouse models to clinical practice and suggest a path forward to prevent these devastating infections.
Prognostic and predictive value of a lncRNA signature in patients with stage II colon cancer
Authors: Qu Ailin , Wang Qian , Chang Qing , Liu Jingkang , Yang Yongmei , Zhang Xin , Zhang Yanli , Zhang Xiaoshi , Wang Hongchun , Zhang Yi 
Published: January 2023

AbstractThe current staging method is inadequate to identify high-risk recurrence patients with stage II colon cancer (CC). Using a systematic and comprehensive-biomarker discovery and validation method, we aimed to construct a lncRNA-based signature to improve the prognostic prediction of stage II CC. We identified 1,377 differently expressed lncRNAs by analyzing 16 paired stage II CC tumor tissue and adjacent normal mucosal tissue from the TCGA dataset. Subsequently, using a univariable and step multivariable Cox regression model, we trained an 11-lncRNA signature in the training cohort (n = 141), which could divide patients into high-risk and low-risk groups (AUC at 3 years = 0.801, 95% CI: 0.724–0.877; AUC at 5 years = 0.801, 95% CI: 0.718–0.885). Significantly, patients in the high-risk group had poorer recurrence-free survival (RFS) compared with the low-risk group (log-rank test, P < 0.001 in the training cohort). This lncRNA-based signature was further confirmed in the validation cohort (P < 0.001). Multivariate Cox regression and stratified survival analyses showed that the prognostic value of this signature was independent of other clinicopathological risk factors (CEA, T stage, and chemotherapy). Time-dependent receiver operating characteristic (ROC) analysis demonstrated that this signature had better prognostic ability than any other clinical risk factors or single lncRNAs (all P < 0.05). A nomogram was constructed for clinical use, which integrated both the lncRNA-based signature and clinical risk factors (CEA and T stage) and performed well in the calibration plots. Altogether, our lncRNA-based signature was an independent prognostic factor and possessed a stronger predictive power compared with the currently used clinicopathological risk factors when predicting the recurrence of patients with stage II CC. Collectively, this lncRNA-based signature might facilitate individualized treatment decisions and postoperative counseling, ultimately contributing to improved survival.
Feasibility of a multigroup Boltzmann–Fokker–Planck solution for electron beam dose calculations
Authors: Naceur Ahmed , Hébert Alain , Romano Paul , Forget Benoit , Chilian Cornelia , Carrier Jean-François 
Published: January 2023

AbstractLegacy nuclear-reactor Boltzmann solvers start clinical deployment as an alternative to Monte Carlo (MC) codes and Fermi–Eyges semiemprical models in radiation oncology treatment planning. Today’s certified clinical solvers are limited to photon beams. In this paper, ELECTR, a state-of-the-art multigroup electron cross sections generation module in NJOY is presented and validated against Lockwood’s calorimetric measurements, EGS-nrc and GEANT-4 for 1–20 MeV unidirectional electron beams. The nuclear-reactor DRAGON-5 solver is upgraded to access the library and solve the Boltzmann–Fokker–Planck (BFP) equation. A variety of heterogeneous radiotherapy and radiosurgery phantom configurations were used for validation purpose. Case studies include a thorax benchmark, that of a typical breast Intra-Operative Radiotherapy and a high-heterogeneity patient-like benchmark. For all beams,$$100\%$$100%of the water voxels satisfied the American Association of Physicists in Medicine accuracy criterion for a BFP-MC dose error below$$2\%$$2%. At least,$$97.0\%$$97.0%of adipose, muscle, bone, lung, tumor and breast voxels satisfied the$$2\%$$2%criterion. The average BFP-MC relative error was about$$0.56\%$$0.56%for all voxels, beams and materials combined. By irradiating homogeneous slabs from$$Z=1$$Z=1(hydrogen) to$$Z=99$$Z=99(einsteinium), we reported performance and defects of the CEPXS mode [US. Sandia National Lab., SAND-89-1685] in ELECTR for the entire periodic table. For all Lockwood’s benchmarks, NJOY-DRAGON dose predictions are within the experimental data precision for$$98\%$$98%of voxels.
Design of an artificial phage-display library based on a new scaffold improved for average stability of the randomized proteins
Authors: Gomes M. , Fleck A. , Degaugue A. , Gourmelon F. , Léger C. , Aumont-Nicaise M. , Mesneau A. , Jean-Jacques H. , Hassaine G. , Urvoas A. , Minard P. , Valerio-Lepiniec M. 
Published: January 2023

AbstractScaffold-based protein libraries are designed to be both diverse and rich in functional/folded proteins. However, introducing an extended diversity while preserving stability of the initial scaffold remains a challenge. Here we developed an original approach to select the ensemble of folded proteins from an initial library. The thermostable CheY protein from Thermotoga maritima was chosen as scaffold. Four loops of CheY were diversified to create a new binding surface. The subset of the library giving rise to folded proteins was first selected using a natural protein partner of the template scaffold. Then, a gene shuffling approach based on a single restriction enzyme was used to recombine DNA sequences encoding these filtrated variants. Taken together, the filtration strategy and the shuffling of the filtrated sequences were shown to enrich the library in folded and stable sequences while maintaining a large diversity in the final library (Lib-Cheytins 2.1). Binders of the Oplophorus luciferase Kaz domain were then selected by phage display from the final library, showing affinities in the μM range. One of the best variants induced a loss of 92% of luminescent activity, suggesting that this Cheytin preferentially binds to the Kaz active site.