bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weakening Trend of Luzon Strait Overflow Transport in the Past Two Decades
Authors: Zhu Yaohua , Yao Jingxin , Xu Tengfei , Li Shujiang , Wang Yonggang , Wei Zexun 
Published: April 2022

AbstractThe Luzon Strait overflow is a deep current of dense water flowing persistently into the South China Sea (SCS) from the Pacific. It is the primary driving force of the deep SCS circulation and potentially influenced by ocean mass changes. Limited by the lengths of in situ observations, long‐term changes in the Luzon Strait overflow transport (LSOT) have not been ascertained. Based on 14 years of satellite‐based ocean bottom pressure (OBP) time series, here we provide an evidence of a weakening of the LSOT by −0.43 Sv decade−1 between 2003 and 2016. Moreover, both OBP data and mooring time series reveal a large annual cycle in the LSOT. The weakening trend in the LSOT may profoundly influence the deep SCS circulation, as well as heat and mass fluxes between the SCS and surrounding oceans.
Load‐Balancing Intense Physics Calculations to Embed Regionalized High‐Resolution Cloud Resolving Models in the E3SM and CESM Climate Models
Authors: Peng Liran , Pritchard Michael , Hannah Walter M. , Blossey Peter N. , Worley Patrick H. , Bretherton Christopher S. 
Published: April 2022

AbstractWe design a new strategy to load‐balance high‐intensity sub‐grid atmospheric physics calculations restricted to a small fraction of a global climate simulation's domain. We show why the current parallel load balancing infrastructure of Community Earth System Model (CESM) and Energy Exascale Earth Model (E3SM) cannot efficiently handle this scenario at large core counts. As an example, we study an unusual configuration of the E3SM Multiscale Modeling Framework (MMF) that embeds a binary mixture of two separate cloud‐resolving model grid structures that is attractive for low cloud feedback studies. Less than a third of the planet uses high‐resolution (MMF‐HR; sub‐km horizontal grid spacing) relative to standard low‐resolution (MMF‐LR) cloud superparameterization elsewhere. To enable MMF runs with Multi‐Domain cloud resolving models (CRMs), our load balancing theory predicts the most efficient computational scale as a function of the high‐intensity work's relative overhead and its fractional coverage. The scheme successfully maximizes model throughput and minimizes model cost relative to precursor infrastructure, effectively by devoting the vast majority of the processor pool to operate on the few high‐intensity (and rate‐limiting) high‐resolution (HR) grid columns. Two examples prove the concept, showing that minor artifacts can be introduced near the HR/low‐resolution CRM grid transition boundary on idealized aquaplanets, but are minimal in operationally relevant real‐geography settings. As intended, within the high (low) resolution area, our Multi‐Domain CRM simulations exhibit cloud fraction and shortwave reflection convergent to standard baseline tests that use globally homogenous MMF‐LR and MMF‐HR. We suggest this approach can open up a range of creative multi‐resolution climate experiments without requiring unduly large allocations of computational resources.
The Malawi Active Fault Database: An Onshore‐Offshore Database for Regional Assessment of Seismic Hazard and Tectonic Evolution
Authors: Williams Jack N. , Wedmore Luke N. J. , Scholz Christopher A. , Kolawole Folarin , Wright Lachlan J. M. , Shillington Donna J. , Fagereng Åke , Biggs Juliet , Mdala Hassan , Dulanya Zuze , Mphepo Felix , Chindandali Patrick R. N. , Werner Maximilian J. 
Published: April 2022

AbstractWe present the Malawi Active Fault Database (MAFD), an open‐access (https://doi.org/10.5281/zenodo.5507190) geospatial database of 113 fault traces in Malawi and neighboring Tanzania and Mozambique. Malawi is located within the East African Rift's (EAR) Western Branch where active fault identification is challenging because chronostratigraphic data are rare, and/or faults are buried and so do not have a surface expression. The MAFD therefore includes any fault that has evidence for displacement during Cenozoic East African rifting or is buried beneath the rift valley and is favorably oriented to the regional stresses. To identify such faults, we consider a multidisciplinary data set: high‐resolution digital elevation models, previous geological mapping, field observations, seismic reflection surveys from offshore Lake Malawi, and aeromagnetic and gravity data. The MAFD includes faults throughout Malawi, where seismic risk is increasing because of population growth and its seismically vulnerable building stock. We also investigate the database as a sample of the normal fault population in an incipient continental rift. We cannot reject the null hypothesis that the distribution of fault lengths in the MAFD is described by a power law, which is consistent with Malawi's relatively thick seismogenic layer (30–40 km), low (<8%) regional extensional strain, and regional deformation localization (50%–75%) across relatively long hard‐linked border faults. Cumulatively, we highlight the importance of integrating onshore and offshore geological and geophysical data to develop active fault databases along the EAR and similar continental settings both to understand the regional seismic hazard and tectonic evolution.
1.2 Myr Band of Earth‐Mars Obliquity Modulation on the Evolution of Cold Late Miocene to Warm Early Pliocene Climate
Authors: Qin Jie , Zhang Rui , Kravchinsky Vadim A. , Valet Jean‐Pierre , Sagnotti Leonardo , Li Jianxing , Xu Yong , Anwar Taslima , Yue Leping 
Published: April 2022

AbstractThe climatic transitions during the Miocene‐Pliocene epochs had significant impacts on the worldwide biological diversity and were associated with large turnovers of continental vegetation and fauna. Previous studies have shown that late Miocene cooling and continental aridification which was initiated 7 Ma reversed to warm conditions across the Miocene‐Pliocene Boundary ∼5.3 Ma. Here, we present detailed orbital pacing of Asian monsoon deposits to constrain further the global climate change during this period. We produce high‐resolution magnetic susceptibility records which reveal that the 1.2 Myr obliquity modulation would have been the main driving factor of the cooling and warming that occurred ∼7 and 5.3 Ma, respectively. The Tibetan rise and closures of the Panama and Indonesian seaways enhanced the impact of the 405 Kyr eccentricity cycles to an oscillatory climatic state while the Northern Hemisphere glaciations were increasing from 4 to 2.5 Ma.
Identification of a c-MYB-directed therapeutic for acute myeloid leukemia
Authors: Clesham Katherine , Walf-Vorderwülbecke Vanessa , Gasparoli Luca , Virely Clemence , Cantilena Sandra , Tsakaneli Alexia , Inglott Sarah , Adams Stuart , Samarasinghe Sujith , Bartram Jack , Williams Gareth , de Boer Jasper , Williams Owen 
Published: April 2022

AbstractA significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, we demonstrate that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines throughout the world indicates that it represents a promising candidate for repurposing into AML therapy.
Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN)
Authors: Maschmeyer Georg , Bullinger Lars , Garcia-Vidal Carolina , Herbrecht Raoul , Maertens Johan , Menna Pierantonio , Pagano Livio , Thiebaut-Bertrand Anne , Calandra Thierry 
Published: April 2022

AbstractThe 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.
MRI radiomics independent of clinical baseline characteristics and neoadjuvant treatment modalities predicts response to neoadjuvant therapy in rectal cancer
Authors: Song Maxiaowei , Li Shuai , Wang Hongzhi , Hu Ke , Wang Fengwei , Teng Huajing , Wang Zhi , Liu Jin , Jia Angela Y. , Cai Yong , Li Yongheng , Zhu Xianggao , Geng Jianhao , Zhang Yangzi , Wan XiangBo , Wang Weihu 
Published: April 2022

Abstract
Background
To analyse the performance of multicentre pre-treatment MRI-based radiomics (MBR) signatures combined with clinical baseline characteristics and neoadjuvant treatment modalities to predict complete response to neoadjuvant (chemo)radiotherapy in locally advanced rectal cancer (LARC).

Methods
Baseline MRI and clinical characteristics with neoadjuvant treatment modalities at four centres were collected. Decision tree, support vector machine and five-fold cross-validation were applied for two non-imaging and three radiomics-based models’ development and validation.

Results
We finally included 674 patients. Pre-treatment CEA, T stage, and histologic grade were selected to generate two non-imaging models: C model (clinical baseline characteristics alone) and CT model (clinical baseline characteristics combining neoadjuvant treatment modalities). The prediction performance of both non-imaging models were poor. The MBR signatures comprising 30 selected radiomics features, the MBR signatures combining clinical baseline characteristics (CMBR), and the CMBR incorporating neoadjuvant treatment modalities (CTMBR) all showed good discrimination with mean AUCs of 0.7835, 0.7871 and 0.7916 in validation sets, respectively. The three radiomics-based models had insignificant discrimination in performance.

Conclusions
The performance of the radiomics-based models were superior to the non-imaging models. MBR signatures seemed to reflect LARC’s true nature more accurately than clinical parameters and helped identify patients who can undergo organ preservation strategies.
Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle
Authors: Lu Xue , Gong Yingchao , Hu Wanyu , Mao Yankai , Wang Ting , Sun Zeyu , Su Xiaoling , Fu Guosheng , Wang Yanpeng , Lai Dongwu 
Published: April 2022

AbstractAging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using quantitative morphological analysis, we showed that the mitochondria-endoplasmic reticulum contacts (MERCs) were reduced by half over the lifespan with an early onset of accelerated thickening in the clefts. The ultrastructural changes were further validated by proteomic profiling of the MAM fractions. A combination of subcellular fractionation and quantitative mass spectrometry identified 1306 MAM-enriched proteins in both heart and skeletal muscle, with a catalog of proteins dysregulated with aging. Functional mapping of the MAM proteome suggested several aging signatures to be closely associated with the ER-mitochondria crosstalk, including local metabolic rewiring, calcium homeostasis imbalance, and impaired organelle dynamics and autophagy. Moreover, we identified a subset of highly interconnected proteins in an ER-mitochondria organization network, which were consistently down-regulated with aging. These decreased proteins, including VDAC1, SAMM50, MTX1 and MIC60, were considered as potential contributors to the age-related MAM dysfunction. This study highlights the perturbation in MAM integrity during the striated muscle aging process, and provides a framework for understanding aging biology from the perspective of organelle interactions.
The RBPJ/DAPK3/UBE3A signaling axis induces PBRM1 degradation to modulate the sensitivity of renal cell carcinoma to CDK4/6 inhibitors
Authors: Liu Wentao , Zhang Bin , Zhang Dan , Guo Feng , Ye Kun , Zhu Liang , Jin Xin 
Published: April 2022

AbstractRenal cell carcinoma (RCC) is a kind of malignant tumor originating from the renal tubular epithelium. Approximately 30% of patients with renal cancer are found to have metastasis when first diagnosed. Exploring other effective treatment methods in addition to surgery is an urgent need in the research field of renal cell carcinoma. Polybromo 1 (PBRM1) is the second most mutated gene in RCC, with a mutation rate of ~40%. Notably, the posttranscriptional modification of PBRM1 in RCC is unclear. In this study, we performed unbiased mass spectrometry of PBRM1 and identified ubiquitin-protein ligase E3A (UBE3A), an extensively studied E3 ligase that can bind with PBRM1 and regulate the stability of PBRM1 in renal cancer cells. We further found that RBPJ/DAPK3 modulated the E3 ligase activity of UBE3A by interfering with the PKA phosphorylation of UBE3A. Finally, we demonstrated that the RBPJ/DAPK3/UBE3A/PBRM1/p21 axis contributed to the sensitivity of renal cancer cells to CDK4/6 inhibitors. In addition, in combination with RBPJ inhibitors, CDK4/6 inhibitors showed synergistically enhanced effects on renal cancer cells. In summary, we not only revealed a novel RBPJ/DAPK3/UBE3A/PBRM1/p21 signaling axis but also identified a combination strategy for overcoming the resistance of renal cancer cells to CDK4/6 inhibitors.
CircRPAP2 regulates the alternative splicing of PTK2 by binding to SRSF1 in breast cancer
Authors: Yu Yunhe , Fang Lin 
Published: April 2022

AbstractBreast cancer is the most commonly diagnosed malignant tumor and the second-highest cause of cancer-related deaths in women worldwide. Circular RNAs (circRNAs) are associated with the development of numerous cancers, including breast cancer. Here, we present the first report that circRPAP2 (hsa_circ_0000091) is downregulated in breast cancer tissue samples and cell lines. Furthermore, the expression level of circRPAP2 in breast cancer tissues was correlated with axillary lymph node metastasis and TNM stage. Biological function studies demonstrated that circRPAP2 inhibited the proliferation and migration of breast cancer in vivo and in vitro. The mechanistic evaluation indicated that circRPAP2 can bind to the oncoprotein SRSF1, likely competing with the binding between SRSF1 and PTK2 pre-mRNA, thereby attenuating SRSF1-mediated alternate splicing of PTK2, an effector of SRSF1 oncogenic activity, resulting in the reduction of PTK2 mRNA and protein expression. Overall, our findings suggest that circRPAP2 plays a tumor suppressor role and may serve as a biomarker in breast cancer. In addition, the identification of the circRPAP2/SRSF1/PTK2 axis provides new insights into the pathogenesis of breast cancer and highlights a novel target for the development of oncotherapeutics.
Impaired sense of agency and associated confidence in psychosis
Authors: Krugwasser Amit Regev , Stern Yonatan , Faivre Nathan , Harel Eiran Vadim , Salomon Roy 
Published: April 2022

AbstractThe Sense of Agency (SoA), our sensation of control over our actions, is a fundamental mechanism for delineating the Self from the environment and others. SoA arises from implicit processing of sensorimotor signals as well as explicit higher-level judgments. Psychosis patients suffer from difficulties in the sense of control over their actions and accurate demarcation of the Self. Moreover, it is unclear if they have metacognitive insight into their aberrant abilities. In this pre-registered study, we examined SoA and its associated confidence judgments using an embodied virtual reality paradigm in psychosis patients and controls. Our results show that psychosis patients not only have a severely reduced ability for discriminating their actions but they also do not show proper metacognitive insight into this deficit. Furthermore, an exploratory analysis revealed that the SoA capacities allow for high levels of accuracy in clinical classification of psychosis. These results indicate that SoA and its metacognition are core aspects of the psychotic state and provide possible venues for understanding the underlying mechanisms of psychosis, that may be leveraged for novel clinical purposes.
PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity
Authors: Maskin Carolyn R. , Raman Renuka , Houvras Yariv 
Published: April 2022

AbstractIt is critical to understand the molecular mechanisms governing the regulation of MITF, a lineage specific transcription factor in melanocytes and an oncogene in melanoma. We identified PPP6C, a serine/threonine phosphatase, as a key regulator of MITF in melanoma. PPP6C is the only recurrently mutated serine/threonine phosphatase across all human cancers identified in sequencing studies and the recurrent R264C mutation occurs exclusively in melanoma. Using a zebrafish developmental model system, we demonstrate that PPP6C expression disrupts melanocyte differentiation. Melanocyte disruption was rescued by engineering phosphomimetic mutations at serine residues on MITF. We developed an in vivo MITF promoter assay in zebrafish and studied the effects of PPP6C(R264C) on regulating MITF promoter activity. Expression of PPP6C(R264C) cooperated with oncogenic NRAS(Q61K) to accelerate melanoma initiation in zebrafish, consistent with a gain of function alteration. Using a human melanoma cell line, we examined the requirement for PPP6C in proliferation and MITF expression. We show that genetic inactivation of PPP6C increases MITF and target gene expression, decreases sensitivity to BRAF inhibition, and increases phosphorylated MITF in a BRAF(V600E) mutant melanoma cell line. Our data suggests that PPP6C may be a relevant drug target in melanoma and proposes a mechanism for its action.
Mathematical modelling identifies conditions for maintaining and escaping feedback control in the intestinal epithelium
Authors: Fischer Matthias M. , Herzel Hanspeter , Blüthgen Nils 
Published: April 2022

AbstractThe intestinal epithelium is one of the fastest renewing tissues in mammals. It shows a hierarchical organisation, where intestinal stem cells at the base of crypts give rise to rapidly dividing transit amplifying cells that in turn renew the pool of short-lived differentiated cells. Upon injury and stem-cell loss, cells can also de-differentiate. Tissue homeostasis requires a tightly regulated balance of differentiation and stem cell proliferation, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a two-compartment mathematical model of intestinal epithelium population dynamics that includes a known feedback inhibition of stem cell differentiation by differentiated cells. The model shows that feedback regulation stabilises the number of differentiated cells as these become invariant to changes in their apoptosis rate. Stability of the system is largely independent of feedback strength and shape, but specific thresholds exist which if bypassed cause unbounded growth. When dedifferentiation is added to the model, we find that the system can recover faster after certain external perturbations. However, dedifferentiation makes the system more prone to losing homeostasis. Taken together, our mathematical model shows how a feedback-controlled hierarchical tissue can maintain homeostasis and can be robust to many external perturbations.
Contextual associations represented both in neural networks and human behavior
Authors: Aminoff Elissa M. , Baror Shira , Roginek Eric W. , Leeds Daniel D. 
Published: April 2022

AbstractContextual associations facilitate object recognition in human vision. However, the role of context in artificial vision remains elusive as does the characteristics that humans use to define context. We investigated whether contextually related objects (bicycle-helmet) are represented more similarly in convolutional neural networks (CNNs) used for image understanding than unrelated objects (bicycle-fork). Stimuli were of objects against a white background and consisted of a diverse set of contexts (N = 73). CNN representations of contextually related objects were more similar to one another than to unrelated objects across all CNN layers. Critically, the similarity found in CNNs correlated with human behavior across multiple experiments assessing contextual relatedness, emerging significant only in the later layers. The results demonstrate that context is inherently represented in CNNs as a result of object recognition training, and that the representation in the later layers of the network tap into the contextual regularities that predict human behavior.