bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Oceanic Memory Effects in the Barents Sea in the Seasonal Linkage Between the Winter and Summer Arctic Oscillation
Authors: Hoshi Ryosuke , Takahashi Hiroshi G. 
Published: November 2021

AbstractWe investigated the mechanism of inter‐seasonal linkage between the winter Arctic Oscillation (AO) and the subsequent summer AO. Our focus was the collapse of the linkage in the late 1980s, associated with substantial sea ice loss in the Arctic. Because atmospheric circulation itself does not have long‐lasting memory effects from winter to summer, the seasonal persistency of sea ice and sea surface temperature (SST) anomalies are likely to contribute to the inter‐seasonal linkage. In the early significant‐linkage period prior to 1990, the winter AO signal was maintained in the sea ice and SST anomalies over the Barents Sea during inter‐seasonal periods. The surface anomalies then influenced the summer atmospheric circulation by exciting the Rossby wave propagation. However, in the recent poor‐linkage period after 1990, sea ice loss in the Barents Sea and Northern Hemisphere was significant. In addition, the seasonal persistency of sea ice and SST anomalies over the Barents Sea were less significant, and the winter AO signal was not maintained beyond a given season. Thus, the oceanic memory effects of the Barents Sea were reduced and might not have been associated with the recent inter‐seasonal linkage.
Understanding the Non‐Linear Response of Summer Evapotranspiration to Clouds in a Temperate Forest Under the Impact of Vegetation Water Content
Authors: Wang Yipu , Li Rui , Hu Jiheng , Fu Yuyun , Duan Jiawei , Cheng Yuanxi , Song Binbin 
Published: November 2021

AbstractUnderstanding the cloud impact on forest evapotranspiration (ET) is crucial for studying the interaction of vegetation‐cloud‐atmosphere. Combining long‐term (2003–2010) satellite passive microwave observations and in‐situ measurements, a non‐linear response of canopy‐scale ET to cloud increase was found at a temperate forest in Northeast China. As cloud increased, an initial enhancement (4%–10%) in ET occurred under less cloudy sky, while a significant reduction (>20%) in ET occurred under more cloudy sky. The phenomenon existed under both high and low vegetation water content (VWC) indicated by satellite microwave emissivity difference vegetation index (EDVI). Analysis showed that this was the combined effect from the enhancement (5%–30%) in evaporative fraction (EF) and the reduction (5%–50%) in net radiation under cloud increase. Decoupling analysis based on coefficients (ρ) of path analysis model showed that enhanced EF (ρ > 0.61) rather than radiation (ρ < 0.47) dominated the ET enhancement under less cloudy sky, while the control of reduced radiation became stronger (ρ > 0.63) and could not be compensated by increased EF (ρ < 0.48) under more cloudy sky. EF enhancement under clouds was strongly correlated with the decline in canopy resistance (Rs) which was dominated by vapor pressure deficit (VPD). Higher VWC increased ET via reducing Rs and enlarging EF. This positive effect of VWC was more noticeable under less cloudy sky. Associated mechanisms could be related to the dynamic controls of plant physiology and environmental conditions induced by VWC and clouds. This study highlighted the dynamic effect of clouds and VWC on forest ET and improved our knowledge of vegetation‐cloud interactions.
Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage
Authors: Sun Lizhong , He Libang , Wu Wei , Luo Li , Han Mingyue , Liu Yifang , Shi Shijie , Zhong Kaijing , Yang Jiaojiao , Li Jiyao 
Published: November 2021

AbstractUnrestrained inflammation is harmful to tissue repair and regeneration. Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation. Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function, but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions. In this study, we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation (early pulpitis as the model) with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo. Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide (E. coli LPS) with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways. Moreover, nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects, attenuating inflammatory conditions in the early stage. Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage, which widens the potential cell types for inflammation regulation.
Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers
Authors: Li Yi , Guo Wei , Li Xiuqin , Zhang Jianguo , Sun Moyi , Tang Zhangui , Ran Wei , Yang Kai , Huang Guilin , Li Longjiang 
Published: November 2021

AbstractThe first gene therapy product, recombinant adenovirus human p53 (rAd-p53), has been approved by CFDA since 2013. During these years, most of the clinical trials and the relevant basic research were carried out by Chinese oncologists. Gendicine was proved to be a safe and promising gene therapy drug for patients who suffered from head and neck squamous cell carcinoma (HNSCC). The basic therapeutic theories of gene therapy were totally different from the traditional ones, such as surgeries or radio- and chemotherapy, and the evaluation of treatment outcomes should also be changed simultaneously. However, there still existed a lot of misunderstandings about gene therapy, which resulted in improper administration, insufficient dosage calculation, and treatment cycles, and the treatment outcomes were unsatisfactory, especially for inexperienced oncologists or hospitals. Therefore, we will provide some practical guidance here on the gene therapy of rAd-p53 based on our previous research and experience, which focused on the basic theories and clinical issues, to answer the questions arising during the clinical of gene therapy and to accelerate the development of gene therapy for the benefit of patients bearing malignant tumors.
MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis
Authors: Weissman Ran , Diamond Eli L. , Haroche Julien , Durham Benjamin H. , Cohen Fleur , Buthorn Justin , Amoura Zahir , Emile Jean-François , Mazor Roei D. , Shomron Noam , Abdel-Wahab Omar I. , Shpilberg Ofer , Hershkovitz-Rokah Oshrat 
Published: November 2021

AbstractErdheim–Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAFV600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
Authors: Park Jun Young , Lee Dongsoo , Lee Jang Jae , Gim Jungsoo , Gunasekaran Tamil Iniyan , Choi Kyu Yeong , Kang Sarang , Do Ah Ra , Jo Jinyeon , Park Juhong , Park Kyungtaek , Li Donghe , Lee Sanghun , Kim Hoowon , Dhanasingh Immanuel , Ghosh Suparna , Keum Seula , Choi Jee Hye , Song Gyun Jee , Sael Lee , Rhee Sangmyung , Lovestone Simon , Kim Eunae , Moon Seung Hwan , Kim Byeong C. , Kim SangYun , Saykin Andrew J. , Nho Kwangsik , Lee Sung Haeng , Farrer Lindsay A. , Jun Gyungah R. , Won Sungho , Lee Kun Ho ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2021

AbstractEstablished genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
Activated naïve γδ T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia
Authors: Chang Yu-Cheng , Chiang Yi-Hao , Hsu Kate , Chuang Chih-Kuang , Kao Chen-Wei , Chang Yi-Fang , Chang Ming-Chih , Lim Ken-Hong , Cheng Hung-I , Hsu Yen-Ning , Chen Caleb G. 
Published: November 2021

AbstractTyrosine kinase inhibitors (TKIs) that target BCR-ABL are the frontline treatments in chronic myeloid leukemia (CML). Growing evidence has shown that TKIs also enhance immunity. Since gamma-delta T (γδT) cells possess the potent anticancer capability, here we investigated the potential involvement of γδT cells in TKI treatments for CML. We characterized γδT cells isolated from chronic-phase CML patients before and during TKI treatments. γδT expression increased significantly in CML patients who achieved major molecular response (MMR) and deep molecular response (DMR). Their Vδ2 subset of γδT also expanded, and increased expression of activating molecules, namely IFN-γ, perforin, and CD107a, as well as γδT cytotoxicity. Mechanistically, TKIs augmented the efflux of isopentenyl pyrophosphate (IPP) from CML cells, which stimulated IFN-γ production and γδT expansion. Notably, the size of the IFN-γ+ naïve γδT population in TKI-treated CML patients was strongly correlated with their rates to reach DMR and with the duration on DMR. Statistical analysis suggests that a cutoff of 7.5% IFN-γ+ naïve subpopulation of γδT in CML patients could serve as a determinant for MR4.0 sustainability. Our results highlight γδT cells as a positive regulator for TKI responses in CML patients.
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib
Authors: Zhuo Jianyong , Lu Di , Lin Zuyuan , Yang Xinyu , Yang Modan , Wang Jianguo , Tao Yaoye , Wen Xue , Li Huihui , Lian Zhengxing , Cen Beini , Dong Siyi , Wei Xuyong , Xie Haiyang , Zheng Shusen , Shen Youqing , Xu Xiao 
Published: November 2021

AbstractCytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials
Authors: Wu Dan-Ya , Li Xinxin , Sun Qiao-Ran , Dou Cheng-Li , Xu Tian , He Hainan , Luo Han , Fu Haitao , Bu Guo-Wei , Luo Bingbing , Zhang Xia , Ma Bin-Guang , Peng Cheng , Miao Yi-Liang 
Published: November 2021

AbstractNuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.
Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity
Authors: Hadjitheodorou Amalia , Bell George R. R. , Ellett Felix , Shastry Shashank , Irimia Daniel , Collins Sean R. , Theriot Julie A. 
Published: November 2021

AbstractTo migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to ‘listen’ to receptor inputs and respond to directional reprogramming.
Nanoscale π-conjugated ladders
Authors: Meißner Stefanie A. , Eder Theresa , Keller Tristan J. , Hofmeister David A. , Spicher Sebastian , Jester Stefan-S. , Vogelsang Jan , Grimme Stefan , Lupton John M. , Höger Sigurd 
Published: November 2021

AbstractIt is challenging to increase the rigidity of a macromolecule while maintaining solubility. Established strategies rely on templating by dendrons, or by encapsulation in macrocycles, and exploit supramolecular arrangements with limited robustness. Covalently bonded structures have entailed intramolecular coupling of units to resemble the structure of an alternating tread ladder with rungs composed of a covalent bond. We introduce a versatile concept of rigidification in which two rigid-rod polymer chains are repeatedly covalently associated along their contour by stiff molecular connectors. This approach yields almost perfect ladder structures with two well-defined π-conjugated rails and discretely spaced nanoscale rungs, easily visualized by scanning tunnelling microscopy. The enhancement of molecular rigidity is confirmed by the fluorescence depolarization dynamics and complemented by molecular-dynamics simulations. The covalent templating of the rods leads to self-rigidification that gives rise to intramolecular electronic coupling, enhancing excitonic coherence. The molecules are characterized by unprecedented excitonic mobility, giving rise to excitonic interactions on length scales exceeding 100 nm. Such interactions lead to deterministic single-photon emission from these giant rigid macromolecules, with potential implications for energy conversion in optoelectronic devices.
scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies
Authors: Schmid Katharina T. , Höllbacher Barbara , Cruceanu Cristiana , Böttcher Anika , Lickert Heiko , Binder Elisabeth B. , Theis Fabian J. , Heinig Matthias 
Published: November 2021

AbstractSingle cell RNA-seq has revolutionized transcriptomics by providing cell type resolution for differential gene expression and expression quantitative trait loci (eQTL) analyses. However, efficient power analysis methods for single cell data and inter-individual comparisons are lacking. Here, we present scPower; a statistical framework for the design and power analysis of multi-sample single cell transcriptomic experiments. We modelled the relationship between sample size, the number of cells per individual, sequencing depth, and the power of detecting differentially expressed genes within cell types. We systematically evaluated these optimal parameter combinations for several single cell profiling platforms, and generated broad recommendations. In general, shallow sequencing of high numbers of cells leads to higher overall power than deep sequencing of fewer cells. The model, including priors, is implemented as an R package and is accessible as a web tool. scPower is a highly customizable tool that experimentalists can use to quickly compare a multitude of experimental designs and optimize for a limited budget.
Organ-specific genome diversity of replication-competent SARS-CoV-2
Authors: Van Cleemput Jolien , van Snippenberg Willem , Lambrechts Laurens , Dendooven Amélie , D’Onofrio Valentino , Couck Liesbeth , Trypsteen Wim , Vanrusselt Jan , Theuns Sebastiaan , Vereecke Nick , van den Bosch Thierry P. P. , Lammens Martin , Driessen Ann , Achten Ruth , Bracke Ken R. , Van den Broeck Wim , Von der Thüsen Jan , Nauwynck Hans , Van Dorpe Jo , Gerlo Sarah , Maes Piet , Cox Janneke , Vandekerckhove Linos 
Published: November 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not always confined to the respiratory system, as it impacts people on a broad clinical spectrum from asymptomatic to severe systemic manifestations resulting in death. Further, accumulation of intra-host single nucleotide variants during prolonged SARS-CoV-2 infection may lead to emergence of variants of concern (VOCs). Still, information on virus infectivity and intra-host evolution across organs is sparse. We report a detailed virological analysis of thirteen postmortem coronavirus disease 2019 (COVID-19) cases that provides proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of immunocompromised patients, including heart, kidney, liver, and spleen (NCT04366882). In parallel, we identify organ-specific SARS-CoV-2 genome diversity and mutations of concern N501Y, T1027I, and Y453F, while the patient had died long before reported emergence of VOCs. These mutations appear in multiple organs and replicate in Vero E6 cells, highlighting their infectivity. Finally, we show two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma. Our results provide insights about the pathogenesis and intra-host evolution of SARS-CoV-2 and show that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients, even when respiratory symptoms cease.
Two-input protein logic gate for computation in living cells
Authors: Vishweshwaraiah Yashavantha L. , Chen Jiaxing , Chirasani Venkat R. , Tabdanov Erdem D. , Dokholyan Nikolay V. 
Published: November 2021

AbstractAdvances in protein design have brought us within reach of developing a nanoscale programming language, in which molecules serve as operands and their conformational states function as logic gates with precise input and output behaviors. Combining these nanoscale computing agents into larger molecules and molecular complexes will allow us to write and execute “code”. Here, in an important step toward this goal, we report an engineered, single protein design that is allosterically regulated to function as a ‘two-input logic OR gate’. Our system is based on chemo- and optogenetic regulation of focal adhesion kinase. In the engineered FAK, all of FAK domain architecture is retained and key intramolecular interactions between the kinase and the FERM domains are externally controlled through a rapamycin-inducible uniRapR module in the kinase domain and a light-inducible LOV2 module in the FERM domain. Orthogonal regulation of protein function was possible using the chemo- and optogenetic switches. We demonstrate that dynamic FAK activation profoundly increased cell multiaxial complexity in the fibrous extracellular matrix microenvironment and decreased cell motility. This work provides proof-of-principle for fine multimodal control of protein function and paves the way for construction of complex nanoscale computing agents.