bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer
Authors: Cheng Lin , Zhou Shichao , Zhou Shaoqing , Shi Kaixuan , Cheng Yan , Cai Mei-Chun , Ye Kaiyan , Lin Lifeng , Zhang Zhenfeng , Jia Chenqiang , Xiang Huaijiang , Zang Jingyu , Zhang Meiying , Yin Xia , Li Ying , Di Wen , Zhuang Guanglei , Tan Li 
Published: July 2022

Abstract

Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/CDK13 covalent inhibitors. In this study, we used an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitors ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional reprogramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T-cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12.

Significance:
This study dissects the specific roles of CDK12 and CDK13 in ovarian cancer and develops a CDK12/CDK13 inhibitor that impairs both tumor and immune cells, which could guide future CDK12 inhibitor development.
Cell–Cell Interactions Drive Metastasis of Circulating Tumor Microemboli
Authors: Tao Jianxin , Zhu Lei , Yakoub Mina , Reißfelder Christoph , Loges Sonja , Schölch Sebastian 
Published: July 2022

Abstract
Circulating tumor cells are the cellular mediators of distant metastasis in solid malignancies. Their metastatic potential can be augmented by clustering with other tumor cells or nonmalignant cells, forming circulating tumor microemboli (CTM). Cell–cell interactions are key regulators within CTM that convey enhanced metastatic properties, including improved cell survival, immune evasion, and effective extravasation into distant organs. However, the cellular and molecular mechanism of CTM formation, as well as the biology of interactions between tumor cells and immune cells, platelets, and stromal cells in the circulation, remains to be determined. Here, we review the current literature on cell–cell interactions in homotypic and heterotypic CTM and provide perspectives on therapeutic strategies to attenuate CTM-mediated metastasis by targeting cell–cell interactions.
Menthol Cigarette Smoking Trends among United States Adults, 2003–2019
Authors: Seaman Elizabeth L. , Corcy Nalini , Chang Joanne T. , Chomenko Dana , Hartman Anne M. , Kittner Deirdre Lawrence , Reyes-Guzman Carolyn M. 
Published: July 2022

AbstractBackground:Smoking is declining, except among current menthol cigarette smokers. This study examines menthol cigarette smoking in the United States.Methods:Cross-sectional data from 35,279 self-respondent current adult smokers who selected menthol cigarettes as their usual type, across the 2003, 2006–2007, 2010–2011, 2014–2015, and 2018–2019 waves of the nationally-representative Tobacco Use Supplement to the Current Population Survey, were analyzed in SAS/SUDAAN. Menthol cigarette smoking among current smokers was assessed by sex, age, race/ethnicity, employment, geography, and educational attainment. Linear contrasts were used to assess trends.Results:Overall cigarette smoking (12.6% in 2018–2019 from 17.3% in 2003) and menthol cigarette smoking (4.0% in 2018–2019 from 4.7% in 2003) in the population decreased in 2018–2019 from 2003 (both P &lt; 0.001). Using predicted marginals, adjusted by demographics, menthol smoking among current smokers increased to 33.8% in 2018–2019 from 27.9% in 2003 (P &lt; 0.001). Among current smoking adults, increases in menthol smoking were observed among non-Hispanic Black persons (76.8% in 2018–2019 from 73.0% in 2003), young adults (37.7% in 2018–2019 from 31.7% in 2003), and women (39.6% in 2018–2019 from 32.1% in 2003).Conclusions:Smoking and menthol smoking in the population has decreased, yet menthol smoking among current smokers increased from 2003 to 2018–2019. Young adult, female, and non-Hispanic Black current smokers were more likely to use menthol cigarettes than their counterparts; these differences have persisted.Impact:Increased menthol smoking among current smokers, notably young adults, women, and non-Hispanic Black individuals, highlights the need for targeted tobacco control interventions for these health disparity populations.
Coping with habitat disturbance: camera-traps reveal cathemerality of Prolemur simus in the community-managed area of Tsaratanana, eastern Madagascar
Authors: Nazim Aleksandra , Reuillon Laurine , Randrianarijaona Avotra , Roullet Delphine , Donati Giuseppe 
Published: July 2022

Abstract
This study provides new findings on the flexible activity of Prolemur simus in an anthropogenically modified habitat in the rural commune of Tsaratanana, eastern Madagascar. Based on camera-trap data, we compared the temporal distribution of activity of one group of lemurs between the forest edge and the forest core. We also investigated the possible influence of nocturnal luminosity on the activity cycle. The analysis was conducted using Kernel Density estimates and the R package OVERLAP. The distribution across the 24-h cycle confirmed that Prolemur simus is cathemeral in the wild. The lemurs displayed three peaks of activity: one during the night and two coinciding with morning and evening twilights. The highest proportions of nocturnal activity occurred at the forest edge and at low moon luminosity suggesting a possible anti-predator and/or human-avoidance strategy. The flexible activity of Prolemur simus may contribute to the tolerance of this Critically Endangered species to anthropogenic disturbance.
Mortal Mistakes
Authors: Christie Lars 
Published: July 2022

Abstract
What are the justifications for and constraints on the use of force in self-defense? In his book The Morality of Defensive Force, Jonathan Quong presents the moral status account to address this and other fundamental questions. According to the moral status account, moral liability to defensive harm is triggered by treating others with less respect than they are due. At the same time, Quong rejects the relevance of culpability to the morality of defensive harming. In this article I argue that this rejection of culpability is unfounded and that Quong fails to establish his account as superior to the culpability account of liability to defensive harm.
Against the Worse Than Nothing Account of Harm: A Reply to Immerman
Authors: Johansson Jens , Risberg Olle 
Published: July 2022

Abstract
The counterfactual comparative account of harm (cca) faces well-known problems concerning preemption and omission. In a recent article in this journal, Daniel Immerman proposes a novel variant of cca, which he calls the worse than nothing account (wtna). According to Immerman, wtna nicely handles the preemption and omission problems. We seek to show, however, that wtna is not an acceptable account of harm. In particular, while wtna deals better than cca with some cases that involve preemption and omission, it has implausible implications in other similar cases – cases that, moreover, pose no problems for cca.
Une histoire intellectuelle de la tripartition notion, concept, idée selon les dictionnaires philosophiques
Authors: Roux Sophie 
Published: July 2022

Résumé
Cet article esquisse une généalogie du privilège que le terme concept a acquis en français par rapport à notion et à idée en se fondant non seulement sur les ouvrages des philosophes, mais sur des dictionnaires de langue philosophique. Il comprend quatre parties chronologiques. Après avoir étudié l’introduction des termes concept, notion, idée dans la langue philosophique, la première partie répertorie leurs usages dans les dictionnaires scolastiques du SVIIe siècle. La deuxième montre que Descartes a imposé idée en donnant de ce terme une acception large et que les dictionnaires post-cartésiens la reprenne. La troisième établit que Kant a, contre cette acception large, introduit une distinction entre Begriff et Idee, mais que, initialement, les dictionnaires français refusèrent cette distinction. La quatrième et dernière partie est consacrée à un XXe siècle marqué par l’idéalisme allemand et l’analyse logique : aussi différentes qu’aient été ces deux traditions, elles ont été d’accord pour consacrer la prééminence du terme concept.
Decadal Variability of Rainfall in Senegal: Beyond the Total Seasonal Amount
Authors: Badji Aïssatou , Mohino Elsa , Diakhaté Moussa , Mignot Juliette , Gaye Amadou Thierno 
Published: July 2022

Abstract
Rainfall characteristics are crucial in monsoon regions, in particular for agriculture. Crop yields indeed depend on the rainfall seasonal amounts, but also on other rainfall characteristics such as the onset of the rainy season or the distribution of rainy days. In the Sahel region, while the average amount of seasonal rainfall has been shown to be marked by strong decadal variability, the modulation of rainfall characteristics has received less attention in the literature so far. In this study, we show that the frequency of light, heavy, and extreme rainfall events and the mean intensity of rainfall events in Senegal exhibit a marked decadal variability over the 1918–2000 period, strongly similar to that of the mean seasonal rainfall. The decadal modulations of these events show a strong and positive link with the Atlantic multidecadal variability (AMV). Indeed, positive sea surface temperature anomalies over the North Atlantic and Mediterranean related to a warm AMV phase are associated with negative sea level pressure anomalies over the northern Atlantic and a northward shift of the intertropical convergence zone. We also find that the onset and cessation dates as well as the length of the rainy season show relatively less decadal variability, which is more related to the interdecadal Pacific oscillation (IPO), a positive phase of the latter leading to a late onset, an early cessation, and an overall shorter rainy season in Senegal.
Role of the Climatological North Pacific High in the North Tropical Atlantic–ENSO Connection
Authors: Park Jae-Heung , Kug Jong-Seong , Yang Young-Min , Oh Hyoeun , Zhao Jiuwei , Wu Yikai 
Published: July 2022

Abstract
Observational and climate model analysis showed that the anomalous sea surface temperature in the north tropical Atlantic (NTA) in boreal spring can trigger El Niño–Southern Oscillation (ENSO) in the subsequent winter. Similarly, the climate models participating in phase 5 of the Coupled Model Intercomparison Project (CMIP5) are known to reasonably simulate the NTA effect. Nevertheless, the strengths of the NTA effect on ENSO among the climate models are also diverse. In this light, we revisited the possible causes that contributed to the different NTA effects on ENSO in the CMIP5 climate models. We found that the strength of the NTA triggering ENSO in the climate model tended to be proportional to the intensity of the climatological subtropical North Pacific high system in boreal spring. The stronger climatological subtropical North Pacific high accompanied enhanced trade wind, precipitation reduction, and cold sea surface temperature over the subtropics. Under these conditions, the moist static energy feedback process, also known as the moist enthalpy advection mechanism, effectively operated around the Pacific intertropical convergence zone. That is, the NTA-induced signals in the subtropical North Pacific readily intruded into the deep tropical Pacific with the aid of the feedback processes, leading to an ENSO event. Consistent with the CMIP5 analysis results, the observed NTA effect on ENSO became stronger during the decades when the climatological North Pacific subtropical high intensified, underpinning the importance of climatology in the subtropical North Pacific in the NTA–ENSO connection.
Large-Amplitude Internal Wave Transformation into Shallow Water
Authors: Sinnett Gregory , Ramp Steven R. , Yang Yiing J. , Chang Ming-Huei , Jan Sen , Davis Kristen A. 
Published: July 2022

Abstract
Large-amplitude internal solitary wave (ISW) shoaling, breaking, and run-up was tracked continuously by a dense and rapidly sampling array spanning depths from 500 m to shore near Dongsha Atoll in the South China Sea. Incident ISW amplitudes ranged between 78 and 146 m with propagation speeds between 1.40 and 2.38 m s−1. The ratio between wave amplitude and a critical amplitude A0 controlled breaking type and was related to wave speed cp and depth. Fissioning ISWs generated larger trailing elevation waves when the thermocline was deep and evolved into onshore propagating bores in depths near 100 m. Collapsing ISWs contained significant mixing and little upslope bore propagation. Bores contained significant onshore near-bottom kinetic and potential energy flux and significant offshore rundown and relaxation phases before and after the bore front passage, respectively. Bores on the shallow forereef drove bottom temperature variation in excess of 10°C and near-bottom cross-shore currents in excess of 0.4 m s−1. Bores decelerated upslope, consistent with upslope two-layer gravity current theory, though run-up extent Xr was offshore of the predicted gravity current location. Background stratification affected the bore run-up, with Xr farther offshore when the Korteweg–de Vries nonlinearity coefficient α was negative. Fronts associated with the shoaling local internal tide, but equal in magnitude to the soliton-generated bores, were observed onshore of 20-m depth.
Vortex Sheet Sensitivity to Low-Level Vertical Shear and Airmass Temperature Perturbation
Authors: Houston Adam L. , Limpert George 
Published: July 2022

Abstract
A theoretical, numerical-modeling-based examination of the sensitivity of vortex sheets along airmass boundaries to the following three characteristics is presented: 1) boundary-normal component of the vertical wind shear, 2) boundary-parallel component of the vertical wind shear, and 3) temperature perturbation within the parent air mass of the boundary. The overall aim of this work is to advance understanding of the sensitivity of micro-α- to meso-γ-scale vortex generation along airmass boundaries to the ambient environment. Density currents are simulated in a 2D domain that does not allow baroclinic generation of near-surface vertical vorticity (ζns) with parameterized latent heating for convection initiated at the associated airmass boundary and Coriolis turned on. Despite the absence of baroclinically generated ζns, with Coriolis turned on and without any boundary-parallel shear, ζns more than two orders of magnitude larger than planetary vorticity is generated along the boundary and located within the cold air. The magnitude of ζns is found to increase with increasing boundary-normal shear with statistically significant intra-experiment separations. Near-surface vertical vorticity ζns is found to scale inversely with boundary-parallel shear with a transition to negative leading-edge ζns in several of the larger boundary-normal shear simulations. An inverse and statistically significant relationship is found between ζns and the temperature perturbation within the parent air mass of the boundary (Δθ), and is a direct consequence of the dependence of boundary propagation speed on Δθ.

Significance Statement
Research presented in this article aims to contribute to an improved understanding of the environmental controls on the generation of small-scale vortices along airmass boundaries. Vertical shear, both along and across an airmass boundary, as well as temperature of the air mass on the cool side of an airmass boundary are found to regulate the magnitude of near-surface vertical vorticity available to small-scale vortices.
Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1
Authors: Janssen Maike , Schmidt Christina , Bruch Peter-Martin , Blank Maximilian F. , Rohde Christian , Waclawiczek Alexander , Heid Daniel , Renders Simon , Göllner Stefanie , Vierbaum Lisa , Besenbeck Birgit , Herbst Sophie A. , Knoll Mareike , Kolb Carolin , Przybylla Adriana , Weidenauer Katharina , Ludwig Anne Kathrin , Fabre Margarete , Gu Muxin , Schlenk Richard F. , Stölzel Friedrich , Bornhäuser Martin , Röllig Christoph , Platzbecker Uwe , Baldus Claudia , Serve Hubert , Sauer Tim , Raffel Simon , Pabst Caroline , Vassiliou George , Vick Binje , Jeremias Irmela , Trumpp Andreas , Krijgsveld Jeroen , Müller-Tidow Carsten , Dietrich Sascha 
Published: July 2022

Abstract
BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Therefore, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 antileukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited the highest synergy with venetoclax in FLT3 wild-type AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine–resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wild-type signaling in specimens with low in vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation. Gilteritinib and venetoclax were active in an FLT3 wild-type AML patient-derived xenograft model with TP53 mutation and reduced leukemic burden in 4 patients with FLT3 wild-type AML receiving venetoclax-gilteritinib off label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation. Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML.
MicroRNA-205-5p plays a suppressive role in the high-fat diet-induced atrial fibrosis through regulation of the EHMT2/IGFBP3 axis
Authors: Xiao Zezhou , Xie Yu , Huang Fangze , Yang Jie , Liu Ximao , Lin Xuefeng , Zhu Peng , Zheng Shaoyi 
Published: July 2022

AbstractObjectiveMicroRNAs (miRNAs) targeting has been revealed to be an appealing strategy for the treatment and management of atrial fibrillation (AF). In this research, we aimed to explore the mechanisms of miR-205-5p in reducing the high-fat diet (HFD)-induced atrial fibrosis through the EHMT2/IGFBP3 axis.MethodsExpression levels of miR-205-5p, IGFBP3 and EHMT2 were determined in AF patients, cell fibrosis models and mouse atrial fibrosis models. Luciferase activity and RIP assays were performed to detect the binding between miR-205-5p and EHMT2, and ChIP assays were implemented to detect the enrichment of H3K9me2 and H3K4me3 in the promoter region of IGFBP3 in cells. The related experiments focusing on the inflammatory response, atrial fibrosis, mitochondrial damage, and metabolic abnormalities were performed to figure out the roles of miR-205-5p, IGFBP3, and EHMT2 in cell and mouse atrial fibrosis models.ResultsLow expression levels of miR-205-5p and IGFBP3 and a high expression of EHMT2 were found in AF patients, cell fibrosis models and mouse atrial fibrosis models. Upregulation of miR-205-5p reduced the expression of TGF-β1, α-SMA, Col III and other fibrosis-related proteins. miR-205-5p overexpression targeted EHMT2 to regulate the methylation of H3 histones to promote IGFBP3 expression, which in turn affected the fibrosis of atrial muscle cells. In HFD-induced atrial fibrosis mice, upregulated miR-205-5p or elevated IGFBP3 alleviated atrial fibrosis, mitochondrial damage, and metabolic abnormalities.ConclusionThis study suggests that miR-205-5p attenuates HFD-induced atrial fibrosis via modulating the EHMT2/IGFBP3 axis.Graphical AbstractmiR-205-5p alleviates high-fat diet-induced atrial fibrosis in mice via EHMT2/IGFBP3.
Marker-controlled watershed with deep edge emphasis and optimized H-minima transform for automatic segmentation of densely cultivated 3D cell nuclei
Authors: Kaseva Tuomas , Omidali Bahareh , Hippeläinen Eero , Mäkelä Teemu , Wilppu Ulla , Sofiev Alexey , Merivaara Arto , Yliperttula Marjo , Savolainen Sauli , Salli Eero 
Published: July 2022

AbstractBackgroundThe segmentation of 3D cell nuclei is essential in many tasks, such as targeted molecular radiotherapies (MRT) for metastatic tumours, toxicity screening, and the observation of proliferating cells. In recent years, one popular method for automatic segmentation of nuclei has been deep learning enhanced marker-controlled watershed transform. In this method, convolutional neural networks (CNNs) have been used to create nuclei masks and markers, and the watershed algorithm for the instance segmentation. We studied whether this method could be improved for the segmentation of densely cultivated 3D nuclei via developing multiple system configurations in which we studied the effect of edge emphasizing CNNs, and optimized H-minima transform for mask and marker generation, respectively.ResultsThe dataset used for training and evaluation consisted of twelve in vitro cultivated densely packed 3D human carcinoma cell spheroids imaged using a confocal microscope. With this dataset, the evaluation was performed using a cross-validation scheme. In addition, four independent datasets were used for evaluation. The datasets were resampled near isotropic for our experiments. The baseline deep learning enhanced marker-controlled watershed obtained an average of 0.69 Panoptic Quality (PQ) and 0.66 Aggregated Jaccard Index (AJI) over the twelve spheroids. Using a system configuration, which was otherwise the same but used 3D-based edge emphasizing CNNs and optimized H-minima transform, the scores increased to 0.76 and 0.77, respectively. When using the independent datasets for evaluation, the best performing system configuration was shown to outperform or equal the baseline and a set of well-known cell segmentation approaches.ConclusionsThe use of edge emphasizing U-Nets and optimized H-minima transform can improve the marker-controlled watershed transform for segmentation of densely cultivated 3D cell nuclei. A novel dataset of twelve spheroids was introduced to the public.