bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drag‐Based CME Modeling With Heliospheric Images Incorporating Frontal Deformation: ELEvoHI 2.0
Authors: Hinterreiter Jürgen , Amerstorfer Tanja , Temmer Manuela , Reiss Martin A. , Weiss Andreas J. , Möstl Christian , Barnard Luke A. , Pomoell Jens , Bauer Maike , Amerstorfer Ute V. 
Published: September 2021

AbstractThe evolution and propagation of coronal mass ejections (CMEs) in interplanetary space is still not well understood. As a consequence, accurate arrival time and arrival speed forecasts are an unsolved problem in space weather research. In this study, we present the ELlipse Evolution model based on HI observations (ELEvoHI) and introduce a deformable front to this model. ELEvoHI relies on heliospheric imagers (HI) observations to obtain the kinematics of a CME. With the newly developed deformable front, the model is able to react to the ambient solar wind conditions during the entire propagation and along the whole front of the CME. To get an estimate of the ambient solar wind conditions, we make use of three different models: Heliospheric Upwind eXtrapolation model (HUX), Heliospheric Upwind eXtrapolation with time dependence model (HUXt), and EUropean Heliospheric FORecasting Information Asset (EUHFORIA). We test the deformable front on a CME first observed in STEREO‐A/HI on February 3, 2010 14:49 UT. For this case study, the deformable front provides better estimates of the arrival time and arrival speed than the original version of ELEvoHI using an elliptical front. The new implementation enables us to study the parameters influencing the propagation of the CME not only for the apex, but for the entire front. The evolution of the CME front, especially at the flanks, is highly dependent on the ambient solar wind model used. An additional advantage of the new implementation is given by the possibility to provide estimates of the CME mass.
Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes
Authors: Kang Hyeon-Ji , Min Byong-Keol , Choi Won-Il , Jeon Jae-Han , Kim Dong Wook , Park Sungmi , Lee Yun-Kyung , Kim Hwa-jin , Byeon Ju-Eun , Go Younghoon , Ham Hye Jin , Jeon Yong Hyun , Kim Mi-Jin , Lee Jung Yi , Wende Adam R. , Choi Sung Hee , Harris Robert A. , Lee In-Kyu 
Published: September 2021

AbstractObesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity.
Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling
Authors: Ren Yinghui , Cao Limin , Wang Limin , Zheng Sijia , Zhang Qicheng , Guo Xueru , Li Xueqin , Chen Mengmeng , Wu Xiang , Furlong Fiona , Meng Zhaowei , Xu Ke 
Published: September 2021

AbstractTumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial–mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs’ effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.
ZGRF1 promotes end resection of DNA homologous recombination via forming complex with BRCA1/EXO1
Authors: Yan Shuang , Song Man , Ping Jie , Lai Shu-ting , Cao Xiao-yu , Bai Chen-Jun , Xie Da-Fei , Guan Hua , Gao Shan-shan , Zhou Ping-Kun 
Published: September 2021

AbstractTo maintain genomic stability, the mammalian cells has evolved a coordinated response to DNA damage, including activation of DNA repair and cell cycle checkpoint processes. Exonuclease 1 (EXO1)-dependent excision of DNA ends is important for the initiation of homologous recombination (HR) repair of DNA breaks, which is thought to play a key role in activating the ATR-CHK1 pathway to induce G2/M cell cycle arrest. But the mechanism is still not fully understood. Here, we report that ZGRF1 forms complexes with EXO1 as well as other repair proteins and promotes DNA repair through HR. ZGRF1 is recruited to DNA damage sites in a MDC1-RNF8-BRCA1 dependent manner. Furthermore, ZGRF1 is important for the recruitment of RPA2 to DNA damage sites and the following ATR-CHK1 mediated G2/M checkpoint in response to irradiation. ZGRF1 null cells show increased sensitivity to many DNA-damaging agents, especially PARPi and irradiation. Collectively,our findings identify ZGRF1 as a novel regulator of DNA end resection and G2/M checkpoint. ZGRF1 is a potential target of radiation and PARPi cancer therapy.
The functions and potential roles of extracellular vesicle noncoding RNAs in gynecological malignancies
Authors: Si Lulu , Bai Jing , Fu Hanlin , Qiu Haifeng , Guo Ruixia 
Published: September 2021

AbstractExtracellular vesicles (EVs) are small membranous vesicles secreted by multiple kinds of cells and are widely present in human body fluids. EVs containing various constituents can transfer functional molecules from donor cells to recipient cells, thereby mediating intercellular communication. Noncoding RNAs (ncRNAs) are a type of RNA transcript with limited protein-coding capacity, that have been confirmed to be enriched in EVs in recent years. EV ncRNAs have become a hot topic because of their crucial regulating effect in disease progression, especially in cancer development. In this review, we summarized the biological functions of EV ncRNAs in the occurrence and progression of gynecological malignancies. In addition, we reviewed their potential applications in the diagnosis and treatment of gynecological malignancies.
sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension
Authors: Vogel Julia , Boehme Philip , Homann Susanne , Boehm Mario , Schütt Katharina Andrea , Boden Katharina , Balitzki Jakob , Hüser Jörg , Dinh Wilfried , Truebel Hubert , Sandner Peter , Mondritzki Thomas 
Published: September 2021

AbstractTherapy-resistant hypertension is a serious medical problem, causing end-organ damage, stroke, and heart failure if untreated. Since the standard of care fails in resistant hypertension patients, there is still a substantial unmet medical need for effective therapies. Active stimulation of soluble guanylyl cyclase via novel soluble guanylyl cyclase stimulators might provide an effective treatment option. To test this hypothesis, we established a new experimental dog model and investigated the effects of the soluble guanylyl cyclase-stimulator BAY 41-2272. In beagle dogs, a resistant hypertension phenotype was established by combining unilateral renal wrapping with the occlusion of the renal artery in the contralateral kidney. The most frequently used antihypertensive drugs were administered orally, either alone or in combination, and their acute effect on telemetric measured blood pressure was assessed and compared with that of BAY 41-2272. The chosen disease stimulus led to a moderate and stable increase in blood pressure. Even high doses of standard-of-care antihypertensives only slightly decreased blood pressure. In contrast, the administration of the soluble guanylyl cyclase stimulator BAY 41-2272 as standalone therapy led to a dose-dependent reduction in blood pressure (−14.1 ± 1.8 mmHg). Moreover, BAY 41-2272 could also further decrease blood pressure in addition to a triple combination of standard-of-care antihypertensives (−28.6 ± 13.2 mmHg). BAY 41-2272 was highly efficient as a standalone treatment in resistant hypertension but was also effective in addition to standard-of-care treatment. These data strongly suggest that soluble guanylyl cyclase stimulators might provide an effective pharmacologic therapy for patients with resistant hypertension.
Liquid condensation of reprogramming factor KLF4 with DNA provides a mechanism for chromatin organization
Authors: Sharma Rajesh , Choi Kyoung-Jae , Quan My Diem , Sharma Sonum , Sankaran Banumathi , Park Hyekyung , LaGrone Anel , Kim Jean J. , MacKenzie Kevin R. , Ferreon Allan Chris M. , Kim Choel , Ferreon Josephine C. 
Published: September 2021

AbstractExpression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid–liquid condensation of the isolated KLF4 DNA binding domain with a DNA fragment from the NANOG proximal promoter is enhanced by CpG methylation of a KLF4 cognate binding site. We propose KLF4-mediated condensation as one mechanism for selectively organizing and re-organizing the genome based on the local sequence and epigenetic state.
A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression
Authors: Liu Jing , Ottaviani Daniela , Sefta Meriem , Desbrousses Céline , Chapeaublanc Elodie , Aschero Rosario , Sirab Nanor , Lubieniecki Fabiana , Lamas Gabriela , Tonon Laurie , Dehainault Catherine , Hua Clément , Fréneaux Paul , Reichman Sacha , Karboul Narjesse , Biton Anne , Mirabal-Ortega Liliana , Larcher Magalie , Brulard Céline , Arrufat Sandrine , Nicolas André , Elarouci Nabila , Popova Tatiana , Némati Fariba , Decaudin Didier , Gentien David , Baulande Sylvain , Mariani Odette , Dufour Florent , Guibert Sylvain , Vallot Céline , Rouic Livia Lumbroso-Le , Matet Alexandre , Desjardins Laurence , Pascual-Pasto Guillem , Suñol Mariona , Catala-Mora Jaume , Llano Genoveva Correa , Couturier Jérôme , Barillot Emmanuel , Schaiquevich Paula , Gauthier-Villars Marion , Stoppa-Lyonnet Dominique , Golmard Lisa , Houdayer Claude , Brisse Hervé , Bernard-Pierrot Isabelle , Letouzé Eric , Viari Alain , Saule Simon , Sastre-Garau Xavier , Doz François , Carcaboso Angel M. , Cassoux Nathalie , Pouponnot Celio , Goureau Olivier , Chantada Guillermo , de Reyniès Aurélien , Aerts Isabelle , Radvanyi François 
Published: September 2021

AbstractRetinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.
A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
Authors: Wang Lin , Li Jingzheng , Zhou Hu , Zhang Weidao , Gao Jing , Zheng Ping 
Published: September 2021

AbstractRPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment.
Rad27 and Exo1 function in different excision pathways for mismatch repair in Saccharomyces cerevisiae
Authors: Calil Felipe A. , Li Bin-Zhong , Torres Kendall A. , Nguyen Katarina , Bowen Nikki , Putnam Christopher D. , Kolodner Richard D. 
Published: September 2021

AbstractEukaryotic DNA Mismatch Repair (MMR) involves redundant exonuclease 1 (Exo1)-dependent and Exo1-independent pathways, of which the Exo1-independent pathway(s) is not well understood. The exo1Δ440-702 mutation, which deletes the MutS Homolog 2 (Msh2) and MutL Homolog 1 (Mlh1) interacting peptides (SHIP and MIP boxes, respectively), eliminates the Exo1 MMR functions but is not lethal in combination with rad27Δ mutations. Analyzing the effect of different combinations of the exo1Δ440-702 mutation, a rad27Δ mutation and the pms1-A99V mutation, which inactivates an Exo1-independent MMR pathway, demonstrated that each of these mutations inactivates a different MMR pathway. Furthermore, it was possible to reconstitute a Rad27- and Msh2-Msh6-dependent MMR reaction in vitro using a mispaired DNA substrate and other MMR proteins. Our results demonstrate Rad27 defines an Exo1-independent eukaryotic MMR pathway that is redundant with at least two other MMR pathways.
Molecular basis for PICS-mediated piRNA biogenesis and cell division
Authors: Wang Xiaoyang , Zeng Chenming , Liao Shanhui , Zhu Zhongliang , Zhang Jiahai , Tu Xiaoming , Yao Xuebiao , Feng Xuezhu , Guang Shouhong , Xu Chao 
Published: September 2021

AbstractBy incorporating two mutually exclusive factors, PID-1 and TOST-1, C. elegans PICS complex plays important roles in piRNA biogenesis, chromosome segregation and cell division. We firstly map the interaction network between PICS subunits, then uncover the mechanisms underlying the interactions between PICS subunits by solving several complex structures, including those of TOFU-6/PICS-1, ERH-2/PICS-1, and ERH-2/TOST-1. Our biochemical experiment also demonstrates that PICS exists as an octamer consisting of two copies of each subunit. Combining structural analyses with mutagenesis experiments, we identify interfacial residues of PICS subunits that are critical for maintaining intact PICS complex in vitro. Furthermore, using genetics, cell biology and imaging experiments, we find that those mutants impairing the in vitro interaction network within PICS, also lead to dysfunction of PICS in vivo, including mislocalization of PICS, and reduced levels of piRNAs or aberrant chromosome segregation and cell division. Therefore, our work provides structural insights into understanding the PICS-mediated piRNA biogenesis and cell division.
Influence of storms on the emission of pollutants from sewage into waters
Authors: Suchowska-Kisielewicz Monika , Nowogoński Ireneusz 
Published: September 2021

AbstractDuring heavy precipitation, chemical and biological pollutants from urban and agricultural areas enter the waters from storm overflows as a result of infiltration and inflow, as well as via uncontrolled outflows from water treatment plants. Infiltration and inflow of rainwater into sewers is an especially popular and major worldwide problem. Climate forecasts indicate changes in climatic conditions towards an increase in the intensity and frequency of torrential rainfalls. It may therefore be assumed that the negative impact of rainwater on water quality will increase. This article attempts to address the question of the impact of pollution from wastewater introduced into water during rainy weather to the receiver. The assessment of the impact of rainfalls on a receiver was carried out on the basis of a simulation of pollution loads from sewage introduced into a river by storm overflows based on data from monitoring the amount of rainfall and simulating the operation of storm overflows using Environmental Protection Agency Storm Water Management Model (EPA SWMM). The obtained results were compared with the pollutant loads discharged at the same time from the sewage treatment plant (STP). In addition, the article assesses possible improvement solutions to reduce the negative impact of storm overflows on water.
A pilot study shows the positive effects of continuous airway pressure for treating hypernasal speech in children with infantile-onset Pompe disease
Authors: Zeng Yin-Ting , Liu Wen-Yu , Torng Pao-Chuan , Hwu Wuh-Liang , Lee Ni-Chung , Lin Chun-Yi , Chien Yin-Hsiu 
Published: September 2021

AbstractChildren with infantile-onset Pompe disease (IOPD) demonstrate hypernasality. This study aimed to evaluate whether continuous positive airway pressure (CPAP) training may reduce hypernasality in children with IOPD. Five children with IOPD were enrolled in a single-subject experimental design of type A-B-A′. The intervention comprised an 8-week, 6-day-per-week regimen of CPAP training at home. Participants continued traditional speech therapy once per week throughout the 24-week study duration. The outcome measurements included the degree of hypernasality (DH), the percentage of consonants correct (PCC), and the speech intelligibility score (SIS). C-statistic analysis with an α of 0.05 was used along with visual analysis to assess speech changes. Three patients completed the study. During the CPAP training phase, the DH, PCC, and SIS were significantly improved compared with the baseline (p < 0.05). At the follow-up phase, both DH and SIS were improved compared with the baseline (p < 0.05), but the PCC had returned to the baseline level. CPAP training demonstrated effectiveness in reducing nasal sounds in IOPD patients. Further studies training younger children with normal hearing may help elucidate the persistence of the effects in children with IOPD.
A risk model for detecting clinically significant prostate cancer based on bi-parametric magnetic resonance imaging in a Japanese cohort
Authors: Sakaguchi Kazushige , Hayashida Michikata , Tanaka Naoto , Oka Suguru , Urakami Shinji 
Published: September 2021

AbstractSelective identification of men with clinically significant prostate cancer (sPC) is a pivotal issue. Development of a risk model for detecting sPC based on the prostate imaging reporting and data system (PI-RADS) for bi-parametric magnetic resonance imaging (bpMRI) and clinical parameters in a Japanese cohort is expected to prove beneficial. We retrospectively analyzed clinical parameters and bpMRI findings from 773 biopsy-naïve patients between January 2011 and December 2016. A risk model was established using multivariate logistic regression analysis and presented on a nomogram. Discrimination of the risk model was compared using the area under the receiver operating characteristic curve. Statistical differences between the predictive model and clinical parameters were analyzed using DeLong test. sPC was detected in 343 men (44.3%). Multivariate logistic regression analysis to predict sPC revealed age (P = 0.002), log prostate-specific antigen (P < 0.001), prostate volume (P < 0.001) and PI-RADS scores (P < 0.001) as significant contributors to the model. Area under the curve was higher for the risk model (0.862), than for age (0.646), log prostate-specific antigen (0.652), prostate volume (0.697) or imaging score (0.822). DeLong test results also showed that the novel risk model performed significantly better than those parameters (P < 0.05). This novel risk model performed significantly better compared with PI-RADS scores and other parameters alone, and is thus expected to prove beneficial in making decisions regarding biopsy on suspicion of sPC.