bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influences of Polydisperse Sea Spray Size Distributions on Model Predictions of Air‐Sea Heat Fluxes
Authors: Peng Tianze , Richter David 
Published: June 2020

AbstractQuantifying the influence of sea spray on air‐sea fluxes under high‐wind conditions is challenging due to a variety of factors. Among existing models, the so‐called bulk air‐sea flux model is commonly used in meteorological applications due to its simplicity, which often involves strong but untested assumptions on spray‐mediated heat fluxes and feedback effects. For example, a common assumption is to treat each droplet size as an independent contribution; that is, it does not interact with other sizes. Thus, the interactions between different size classes of spray are often neglected. In this study, we focus on the polydispersity of the spray size distribution and investigate the appropriateness of assuming an independent contribution from different spray size classes. We implement direct numerical simulations (DNS) with Lagrangian tracking of spray droplets. Based on DNS results, the bulk spray model fails to capture the interactions between different sizes that are observed directly from the droplet and feedback statistics in DNS. Thus, assuming independent contributions from spray droplets results in significant overestimates on the total heat fluxes. We further test different representative sizes of a spray size distribution. We find that the volume‐weighted representative size is capable of predicting the droplet‐modified temperature and humidity fields and generally captures the vertical profiles of spray‐mediated and interfacial heat fluxes. The results indicate that the computation of spray‐mediated fluxes can be simplified in large‐scale parameterizations.
Development of a Data Assimilation Method Using Vibration Equation for Large‐Eddy Simulations of Turbulent Boundary Layer Flows
Authors: Nakayama Hiromasa , Takemi Tetsuya 
Published: June 2020

AbstractIn order to improve the simulation accuracy, it is effective to use a data assimilation technique which is capable of reproducing more realistic simulated states by incorporating observational data into simulation models. One of the simplest ones among data assimilation techniques is a Newtonian relaxation‐type nudging method which has been widely used in mesoscale meteorological models. In this study, we proposed a data assimilation method using a vibration equation which can incorporate turbulence winds toward target mean winds while maintaining small‐scale turbulent fluctuations as a different approach from the conventional nudging method. First, we conducted test simulations in which nudging is applied in a basic turbulent boundary layer (TBL) flow toward a target one. It is shown that the basic TBL flow can be reasonably nudged toward the target one while maintaining the turbulent fluctuations well when prescribing the natural frequency in the vibration equation smaller than the spectral peak frequency in the TBL flow. Then, we applied the proposed nudging method by incorporating data obtained from meteorological observations located in the actual city of Kyoto. The mean wind velocity profiles were reasonably nudged toward the target observed profile and the turbulence statistics were also favorably maintained. It is concluded that the data assimilation method using the vibration equation successfully nudges toward the target mean winds while maintaining small‐scale turbulent fluctuations well.
Focusing of Fast Magnetosonic Waves in the Dayside Magnetosphere
Authors: Leonovich A. S. , Kozlov D. A. 
Published: June 2020

AbstractThe spatial structure of ultra‐low‐frequency (ULF) fast magnetosonic (FMS) waves is calculated in the dayside magnetosphere. A balanced model is developed of a dipole magnetosphere with a plasma rotating in the azimuthal direction. The magnetopause is in the form of a smooth transition layer. It is shown that the largest‐scale FMS eigen harmonics are either weakly unstable or neutrally stable. The calculations show that the eigen oscillation amplitudes increase greatly from the magnetopause into the magnetosphere. Presumably, the dayside magnetosphere plays the role of a sort of focusing lens for ULF FMS waves. Hence, one can expect a significant increase in the magnetosonic oscillation amplitudes in the inner part of the magnetosphere when the FMS oscillations (determining the magnetopause eigen oscillation amplitudes) are amplified in the magnetosheath.
Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing
Authors: Davi Frédéric , Langerak Anton W. , de Septenville Anne Langlois , Kolijn P. Martijn , Hengeveld Paul J. , Chatzidimitriou Anastasia , Bonfiglio Silvia , Sutton Lesley-Ann , Rosenquist Richard , Ghia Paolo , Stamatopoulos Kostas ,   on behalf of ERIC, the European Research Initiative on CLL, and the EuroClonality-NGS Working Group
Published: June 2020

AbstractTwenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.
Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice
Authors: Borges Kleiton Silva , Pignatti Emanuele , Leng Sining , Kariyawasam Dulanjalee , Ruiz-Babot Gerard , Ramalho Fernando Silva , Taketo Makoto Mark , Carlone Diana L. , Breault David T. 
Published: June 2020

AbstractAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized theCyp11b2(AS)Cremouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation,Trp53deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation orTrp53deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation ofStarandCyp11b1and upregulation ofEzh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.
Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal
Authors: Chai Tin Fan , Manu Kanjoormana Aryan , Casey Patrick J. , Wang Mei 
Published: June 2020

AbstractCancer stem cells possess the capacity for self-renewal and resistance to chemotherapy. It is therefore crucial to understand the molecular regulators of stemness in the quest to develop effective cancer therapies. TAZ is a transcription activator that promotes stem cell functions in post-development mammalian cells; suppression of TAZ activity reduces or eliminates cancer stemness in select cancers. Isoprenylcysteine carboxylmethyltransferase (ICMT) is the unique enzyme of the last step of posttranslational prenylation processing pathway that modifies several oncogenic proteins, including RAS. We found that suppression of ICMT results in reduced self-renewal/stemness in KRAS-driven pancreatic and breast cancer cells. Silencing of ICMT led to significant reduction of TAZ protein levels and loss of self-renewal ability, which could be reversed by overexpressing mutant KRAS, demonstrating the functional impact of ICMT modification on the ability of KRAS to control TAZ stability and function. Contrary to expectation, YAP protein levels appear to be much less susceptible than TAZ to the regulation by ICMT and KRAS, and YAP is less consequential in regulating stemness characteristics in these cells. Further, we found that the ICMT-dependent KRAS regulation of TAZ was mediated through RAF, but not PI3K, signaling. Functionally, we demonstrate that a signaling cascade from ICMT modification of KRAS to TAZ protein stability supports cancer cell self-renewal abilities in both in vitro and in vivo settings. In addition, studies using the proof-of-concept small molecule inhibitors of ICMT confirmed its role in regulating TAZ and self-renewal, demonstrating the potential utility of targeting ICMT to control aggressive KRAS-driven cancers.
Noncoding RNAs: the shot callers in tumor immune escape
Authors: Liu Lei , Wang Qin , Qiu Zhilin , Kang Yujuan , Liu Jiena , Ning Shipeng , Yin Yanling , Pang Da , Xu Shouping 
Published: June 2020

AbstractImmunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.
Therapeutic siRNA: state of the art
Authors: Hu Bo , Zhong Liping , Weng Yuhua , Peng Ling , Huang Yuanyu , Zhao Yongxiang , Liang Xing-Jie 
Published: June 2020

ABSTRACTRNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)–siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.
Ischemic damage may play an important role in spinal cord injury during dancing
Authors: Tong An-Ni , Zhang Jun-Wei , Zhou Hong-Jun , Tang He-Hu , Bai Jin-Zhu , Wang Fang-Yong , Lv Zhen , Chen Shi-Zheng , Liu Shu-Jia , Liu Jie-Sheng , Hong Yi 
Published: June 2020

Abstract
Study design
Retrospective analysis.

Setting
China Rehabilitation Research Center, Beijing, China.

Objective
To explore possible mechanisms underlying spinal cord injury (SCI) in children caused by hyperextension of the spine while dancing.

Methods
The clinical records of 88 children with SCI (mean age, 5.97 years; age range, 4–10 years) admitted to our hospital from January 1989 to October 2019 were retrospectively reviewed. Computed tomography and magnetic resonance imaging were performed on the day of injury. The time from injury to development of paralysis, as well as post-injury activities were surveyed, while abnormal patterns on images, the range of the involved vertebrae, and the extents of edema and atrophy were assessed.

Results
Among the 88 patients, 6 (6.8%) were unable to move immediately after SCI, while paralysis occurred in 42, 23, and 17 patients at <30, 30–60, and >60 min after SCI, respectively. The neurological level of injury of 84 patients was between T4 and T12. On sagittal T2-weighted images (T2WIs), the longitudinal range of spinal cord edema was more than one vertebral body in 65 patients, while spinal cord atrophy below T8 was found in 40 patients. On axial T2WIs, although three patients had none, long T2 signals were found in the central gray matter of seven patients. Meanwhile, necrosis of the central area combined with the peripheral white matter was observed in 57 patients, while three patients had total involvement on a cross section.

Conclusion
Ischemia-related damage, rather than direct trauma to the spinal cord, may play an important role in SCI due to spinal hyperextension during dancing.
Linking depressive symptom dimensions to cerebellar subregion volumes in later life
Authors: Bogoian Hannah R. , King Tricia Z. , Turner Jessica A. , Semmel Eric S. , Dotson Vonetta M. 
Published: June 2020

AbstractThe present study examined the relationship between subthreshold depressive symptoms and gray matter volume in subregions of the posterior cerebellum. Structural magnetic resonance imaging data from 38 adults aged 51 to 80 years were analyzed along with participants’ responses to the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms, and lack of positive affect were calculated, and multiple regression analyses were used to examine the relationship between symptom dimensions and cerebellar volumes. Greater total depressive symptoms and greater somatic symptoms of depression were significantly related to larger volumes of vermis VI, a region within the salience network, which is altered in depression. Exploratory analyses revealed that higher scores on the lack of positive affect subscale were related to larger vermis VIII volumes. These results support that depressive symptom profiles have unique relationships within the cerebellum that may be important as the field move towards targeted treatment approaches for depression.
Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults
Authors: Rovira Paula , Sánchez-Mora Cristina , Pagerols Mireia , Richarte Vanesa , Corrales Montserrat , Fadeuilhe Christian , Vilar-Ribó Laura , Arribas Lorena , Shireby Gemma , Hannon Eilis , Mill Jonathan , Casas Miquel , Ramos-Quiroga Josep Antoni , Soler Artigas María , Ribasés Marta 
Published: June 2020

AbstractAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.
YBX1 mediates autophagy by targeting p110β and decreasing the sensitivity to cisplatin in NSCLC
Authors: Cui Yanwei , Li Fengzhou , Xie Qiang , Zhao Shilei , Guo Tao , Guo Ping , Hu Sheng , Hao Jiaojiao , Tian Chunfang , Yu Wendan , Li Zhuoshi , Fang Lei , Zhao Lei , Chen Manyu , Wu Taihua , Gu Chundong 
Published: June 2020

AbstractY-box binding protein 1 (YBX1) is involved in the development of multiple types of tumors. However, the relationship between YBX1 and autophagy in non-small cell lung cancer (NSCLC) remains unclear. In this study, we analyzed the expression and clinical significance of YBX1 and markers of autophagy (LC3I/II) in NSCLC and examined their roles in regulating sensitivity to cisplatin in NSCLC. The retrospective analysis of patients with NSCLC indicated that YBX1 was positively correlated with autophagy. Increased levels of YBX1 or autophagy also observed in NSCLC cells compared with those in 16HBE cells. Compared to the controls, the knockdown of YBX1 expression suppressed autophagy, increased drug sensitivity and promoted apoptosis in response to cisplatin in NSCLC cells by targeting the p110β promoter and inhibiting p110β/Vps34/beclin1 signaling pathways. We also demonstrated in an in vivo study that the overexpressed YBX1 effectively increased NSCLC growth and progression and decreased the sensitivity to cisplatin by inducing autophagy in a xenograft tumor model, and these effects were concomitant with the increasing of p110β and beclin1 expression. Collectively, these results show that YBX1 plays an essential role in autophagy in NSCLC.
Delivering genome sequencing for rapid genetic diagnosis in critically ill children: parent and professional views, experiences and challenges
Authors: Hill Melissa , Hammond Jennifer , Lewis Celine , Mellis Rhiannon , Clement Emma , Chitty Lyn S. 
Published: June 2020

AbstractRapid genomic sequencing (RGS) is increasingly being used in the care of critically ill children. Here we describe a qualitative study exploring parent and professional perspectives around the usefulness of this test, the potential for unintended harms and the challenges for delivering a wider clinical service. The Rapid Paediatric Sequencing (RaPS) study offered trio RGS for diagnosis of critically ill children with a likely monogenic disorder. Main and actionable secondary findings were reported. Semi-structured interviews were conducted with parents of children offered RGS (n = 11) and professionals (genetic clinicians, non-genetic clinicians, scientists and consenters) (n = 19) by telephone (parents n = 10/professionals n = 1) or face-to-face (parents n = 1/professionals n = 18). We found that participants held largely positive views about RGS, describing clinical and emotional benefits from the opportunity to obtain a rapid diagnosis. Parental stress surrounding their child’s illness complicates decision making. Parental concerns are heightened when offered RGS and while waiting for results. The importance of multidisciplinary team working to enable efficient delivery of a rapid service was emphasised. Our findings give insight into the perceived value of RGS for critically ill children. Careful pre-test counselling is needed to support informed parental decision making. Many parents would benefit from additional support while waiting for results. Education of mainstream clinicians is required to facilitate clinical implementation.
Non-cooperative 4E-BP2 folding with exchange between eIF4E-binding and binding-incompatible states tunes cap-dependent translation inhibition
Authors: Dawson Jennifer E. , Bah Alaji , Zhang Zhenfu , Vernon Robert M. , Lin Hong , Chong P. Andrew , Vanama Manasvi , Sonenberg Nahum , Gradinaru Claudiu C. , Forman-Kay Julie D. 
Published: June 2020

AbstractPhosphorylation of intrinsically disordered eIF4E binding proteins (4E-BPs) regulates cap-dependent translation by weakening their ability to compete with eIF4G for eIF4E binding within the translation initiation complex. We previously showed that phosphorylation of T37 and T46 in 4E-BP2 induces folding of a four-stranded beta-fold domain, partially sequestering the canonical eIF4E-binding helix. The C-terminal intrinsically disordered region (C-IDR), remaining disordered after phosphorylation, contains the secondary eIF4E-binding site and three other phospho-sites, whose mechanisms in inhibiting binding are not understood. Here we report that the domain is non-cooperatively folded, with exchange between beta strands and helical conformations. C-IDR phosphorylation shifts the conformational equilibrium, controlling access to eIF4E binding sites. The hairpin turns formed by pT37/pT46 are remarkably stable and function as transplantable units for phospho-regulation of stability. These results demonstrate how non-cooperative folding and conformational exchange leads to graded inhibition of 4E-BP2:eIF4E binding, shifting 4E-BP2 into an eIF4E binding-incompatible conformation and regulating translation initiation.