bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Concise Empirical Formula for the Field‐Aligned Distribution of Auroral Kilometeric Radiation Based on Arase Satellite and Van Allen Probes
Authors: Zhang Sai , Liu Si , Li Wentao , He Yihua , Yang Qiwu , Xiao Fuliang , Kumamoto Atsushi , Miyoshi Yoshizumi , Nakamura Yosuke , Tsuchiya Fuminori , Kasahara Yoshiya , Shinohara Iku 
Published: April 2021

AbstractAuroral kilometric radiations (AKR) are strong radio emission phenomena, and can produce significant acceleration or scattering of radiation belt electrons. The variation of AKR wave amplitude with the latitude (λ) has not been reported so far owing to lack of measurements. Here, using observations of the Arase satellite and Van Allen Probes from March 23, 2017 to July 31, 2019, we present the first statistical study on the AKR electric field amplitude (Et) in the radiation belts for |λ| = 0° − 40° and L‐shell L = 3.0–6.2. Results (totally 14,770 samples) show that Et can be described by a concise formula: Et(λ) = E0  exp(ξ sin |λ|), decreasing with decreasing latitude. Fitting parameters E0 and ξ are limited in the ranges: E0 = 0.054–0.340 mV/m and ξ = 3.0–4.2. Wave amplitudes are greater (smaller) under intense (weak) geomagnetic conditions. This study helps to better quantify the gyroresonance between AKR and radiation belt electrons.
Individualized plasticity autograft mimic with efficient bioactivity inducing osteogenesis
Authors: Wei Yan , Zhu Guixin , Zhao Zifan , Yin Chengcheng , Zhao Qin , Xu Hudi , Wang Jinyang , Zhang Jinglun , Zhang Xiaoxin , Zhang Yufeng , Xia Haibin 
Published: April 2021

AbstractMineralized tissue regeneration is an important and challenging part of the field of tissue engineering and regeneration. At present, autograft harvest procedures may cause secondary trauma to patients, while bone scaffold materials lack osteogenic activity, resulting in a limited application. Loaded with osteogenic induction growth factor can improve the osteoinductive performance of bone graft, but the explosive release of growth factor may also cause side effects. In this study, we innovatively used platelet-rich fibrin (PRF)-modified bone scaffolds (Bio-Oss®) to replace autograft, and used cytokine (BMP-2) to enhance osteogenesis. Encouragingly, this mixture, which we named “Autograft Mimic (AGM)”, has multiple functions and advantages. (1) The fiber network provided by PRF binds the entire bone scaffold together, thereby shaping the bone grafts and maintaining the space of the defect area. (2) The sustained release of BMP-2 from bone graft promoted bone regeneration continuously. (3) AGM recruited bone marrow mesenchymal stem cells (BMSCs) and promote their proliferation, migration, and osteogenic differentiation. Thus, AGM developed in this study can improve osteogenesis, and provide new guidance for the development of clinical bone grafts.
Nutrient supplementation experiments with saltern microbial communities implicate utilization of DNA as a source of phosphorus
Authors: Hua Zhengshuang , Ouellette Matthew , Makkay Andrea M , Papke R Thane , Zhaxybayeva Olga 
Published: April 2021

Abstract
All environments including hypersaline ones harbor measurable concentrations of dissolved extracellular DNA (eDNA) that can be utilized by microbes as a nutrient. However, it remains poorly understood which eDNA components are used, and who in a community utilizes it. For this study, we incubated a saltern microbial community with combinations of carbon, nitrogen, phosphorus, and DNA, and tracked the community response in each microcosm treatment via 16S rRNA and rpoB gene sequencing. We show that microbial communities used DNA only as a phosphorus source, and provision of other sources of carbon and nitrogen was needed to exhibit a substantial growth. The taxonomic composition of eDNA in the water column changed with the availability of inorganic phosphorus or supplied DNA, hinting at preferential uptake of eDNA from specific organismal sources. Especially favored for growth was eDNA from the most abundant taxa, suggesting some haloarchaea prefer eDNA from closely related taxa. The preferential eDNA consumption and differential growth under various nutrient availability regimes were associated with substantial shifts in the taxonomic composition and diversity of microcosm communities. Therefore, we conjecture that in salterns the microbial community assembly is driven by the available resources, including eDNA.
HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
Authors: Konte Bettina , Walters James T. R. , Rujescu Dan , Legge Sophie E. , Pardiñas Antonio F. , Cohen Dan , Pirmohamed Munir , Tiihonen Jari , Hartmann Annette M. , Bogers Jan P. , van der Weide Jan , van der Weide Karen , Putkonen Anu , Repo-Tiihonen Eila , Hallikainen Tero , Silva Ed , Ingimarsson Oddur , Sigurdsson Engilbert , Kennedy James L. , Sullivan Patrick F. , Rietschel Marcella , Breen Gerome , Stefansson Hreinn , Stefansson Kari , Collier David A. , O’Donovan Michael C. , Giegling Ina 
Published: April 2021

AbstractThe atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer
Authors: Khan Mairah T. , Irlam-Jones Joely J. , Pereira Ronnie Rodrigues , Lane Brian , Valentine Helen R. , Aragaki Kai , Dyrskjøt Lars , McConkey David J. , Hoskin Peter J. , Choudhury Ananya , West Catharine M. L. 
Published: April 2021

AbstractBackgroundmiRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.MethodsTaqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation.ResultsA 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403,p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95,p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92,p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82,p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033).ConclusionA 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling
Authors: Hong Nanchao , Zhang Erge , Xie Huilin , Jin Lihui , Zhang Qi , Lu Yanan , Chen Alex F. , Yu Yongguo , Zhou Bin , Chen Sun , Yu Yu , Sun Kun 
Published: April 2021

AbstractCardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with Sox7 haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple Sox7 conditional loss-of-function mice models were generated to explore the role of Sox7 in atrioventricular cushion development. Sox7 deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in Sox7 deficiency atrioventricular cushions. Mechanistically, Sox7 deficiency reduced the expressions of Bmp2 in atrioventricular canal myocardium and Wnt4 in endocardium, and Sox7 binds to Wnt4 and Bmp2 directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by Sox7 deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify Sox7 as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4–Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.
Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles
Authors: Bai Lin , Wang Yafei , Huo Jia , Li Shuai , Wen Ya , Liu Qi , Yang Jing , Liu Yaling , Li Rui 
Published: April 2021

Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1G93A cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1G93A mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1G93A mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1G93A mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.
TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7
Authors: Hu Jia , Ding Xueliang , Tian Shaobo , Chu Yanan , Liu Zhibo , Li Yuqin , Li Xiaoqiong , Wang Guobin , Wang Lin , Wang Zheng 
Published: April 2021

AbstractThe biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome–lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.
Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status
Authors: Kumar Dinesh , Patel Saket Awadesbhai , Hassan Md. Khurshidul , Mohapatra Nachiketa , Pattanaik Niharika , Dixit Manjusha 
Published: April 2021

AbstractIQGAP2, a member of the IQGAP family, functions as a tumor suppressor in most of the cancers. Unlike IQGAP1 and IQGAP3, which function as oncogenes in breast cancer, the role of IQGAP2 is still unexplored. Here we report a reduced expression of IQGAP2, which was associated with lymph node positivity, lymphovascular invasion, and higher age in breast cancer patients. We found an inverse correlation of IQGAP2 expression levels with oncogenic properties of breast cancer cell lines in estrogen receptor (ER) independent manner. IQGAP2 expression enhanced apoptosis via reactive oxygen species (ROS)-P38-p53 pathway and reduced epithelial–mesenchymal transition (EMT) in a MEK-ERK-dependent manner. IQGAP2-IQGAP1 ratio correlated negatively with phospho-ERK levels in breast cancer patients. Pull-down assay showed interaction of IQGAP1 and IQGAP2. IQGAP2 overexpression rescued, IQGAP1-mediated ERK activation, suggesting the possibility of IQGAP1 sequestration by IQGAP2. IQGAP2 depletion, in a tumor xenograft model, increased tumor volume, tumor weight, and phospho-ERK expression. Overall, our findings suggest that IQGAP2 is negatively associated with proliferative and metastatic abilities of breast cancer cells. Suppression of IQGAP1-mediated ERK activation is a possible route via which IQGAP2 restricts oncogenic properties of breast cancer cells. Our study highlights the candidature of IQGAP2 as a potent target for therapeutic intervention.
mTORC1 mediates fiber type-specific regulation of protein synthesis and muscle size during denervation
Authors: You Jae-Sung , Kim Kookjoo , Steinert Nathaniel D. , Chen Jie , Hornberger Troy A. 
Published: April 2021

AbstractSkeletal muscle denervation occurs in diverse conditions and causes severe muscle atrophy. Signaling by mammalian target of rapamycin complex 1 (mTORC1) plays a central role in the maintenance of skeletal muscle mass by regulating net protein balance; yet, its role in denervation-induced atrophy is unclear. In this study, by using skeletal muscle-specific and inducible raptor knockout mice, we demonstrate that signaling through mTORC1 is activated during denervation and plays an essential role in mitigating the atrophy of non-type IIB muscle fibers. Measurements of protein synthesis rates of individual fibers suggest that denervation increases protein synthesis specifically in non-type IIB muscle fibers and that mTORC1 is required for this event. Furthermore, denervation induced a more pronounced increase in the level of phosphorylated ribosomal S6 protein in non-type IIB muscle fibers than in type IIB muscle fibers. Collectively, our results unveil a novel role for mTORC1 in mediating a fiber type-specific regulation of muscle size and protein synthesis during denervation.
What people really change after genetic testing (GT) performed in private labs: results from an Italian study
Authors: Oliveri Serena , Cincidda Clizia , Ongaro Giulia , Cutica Ilaria , Gorini Alessandra , Spinella Francesca , Fiorentino Francesco , Baldi Marina , Pravettoni Gabriella 
Published: April 2021

AbstractDespite the widespread diffusion of direct-to-consumer genetic testing (GT), it is still unclear whether people who learn about their genetic susceptibility to a clinical condition change their behaviors, and the psychological factors involved. The aim of the present study is to investigate long-term changes in health-related choices, individual tendencies and risk attitudes in an Italian sample of GT users. In the context of the Mind the Risk study, which investigated a sample of Italian adults who underwent GT in a private laboratory, 99 clients participated in the follow up assessment. They completed a self-administered questionnaire investigating: (a) clinical history and motivation for testing, (b) lifestyle and risk behaviors, (c) individual tendencies toward health, and (d) risk-taking attitude and risk tolerance. Such variables were measured at three different time-points: T0—before GT, T1—at 6 months after genetic results, and T2—at 1 year from results. Results showed that, at baseline, participants who stated they intended to modify their behavior after GT results, effectively did so over time. This result held both for participants who received a positive or negative test result. In general, a healthier diet was the most frequently observed long-term behavioral change. As regards psychological variables, a risk-taking attitude and risk tolerance did not seem to affect the decision to change the lifestyle. Finally, we found an overall reduction in anxiety and worry over health over time, but also a reduction in the motivation for health promotion and prevention, health esteem, and positive expectations for their health in the future.
Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis
Authors: Webb Bryn D. , Hotchkiss Hilary , Prasun Pankaj , Gelb Bruce D. , Satlin Lisa 
Published: April 2021

AbstractKCNJ16encodes Kir5.1 and acts in combination with Kir4.1, encoded byKCNJ10, to form an inwardly rectifying K+channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+handling. Previous work has shown thatKcnj16−/−mice and SSKcnj16−/−rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants inKCNJ16by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.
How the west was won: genetic reconstruction of rapid wolf recolonization into Germany’s anthropogenic landscapes
Authors: Jarausch Anne , Harms Verena , Kluth Gesa , Reinhardt Ilka , Nowak Carsten 
Published: April 2021

AbstractFollowing massive persecution and eradication, strict legal protection facilitated a successful reestablishment of wolf packs in Germany, which has been ongoing since 2000. Here, we describe this recolonization process by mitochondrial DNA control-region sequencing, microsatellite genotyping and sex identification based on 1341 mostly non-invasively collected samples. We reconstructed the genealogy of German wolf packs between 2005 and 2015 to provide information on trends in genetic diversity, dispersal patterns and pack dynamics during the early expansion process. Our results indicate signs of a founder effect at the start of the recolonization. Genetic diversity in German wolves is moderate compared to other European wolf populations. Although dispersal among packs is male-biased in the sense that females are more philopatric, dispersal distances are similar between males and females once only dispersers are accounted for. Breeding with close relatives is regular and none of the six male wolves originating from the Italian/Alpine population reproduced. However, moderate genetic diversity and inbreeding levels of the recolonizing population are preserved by high sociality, dispersal among packs and several immigration events. Our results demonstrate an ongoing, rapid and natural wolf population expansion in an intensively used cultural landscape in Central Europe.
The white matter is a pro-differentiative niche for glioblastoma
Authors: Brooks Lucy J. , Clements Melanie P. , Burden Jemima J. , Kocher Daniela , Richards Luca , Devesa Sara Castro , Zakka Leila , Woodberry Megan , Ellis Michael , Jaunmuktane Zane , Brandner Sebastian , Morrison Gillian , Pollard Steven M. , Dirks Peter B. , Marguerat Samuel , Parrinello Simona 
Published: April 2021

AbstractGlioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C
Authors: Moradi Shoeib , Stankovic Sanda , O’Connor Geraldine M. , Pymm Phillip , MacLachlan Bruce J. , Faoro Camilla , Retière Christelle , Sullivan Lucy C. , Saunders Philippa M. , Widjaja Jacqueline , Cox-Livingstone Shea , Rossjohn Jamie , Brooks Andrew G. , Vivian Julian P. 
Published: April 2021

AbstractThe closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.