bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained RNA virome diversity in Antarctic penguins and their ticks
Authors: Wille Michelle , Harvey Erin , Shi Mang , Gonzalez-Acuña Daniel , Holmes Edward C , Hurt Aeron C 
Published: April 2020

Abstract
Despite its isolation and extreme climate, Antarctica is home to diverse fauna and associated microorganisms. It has been proposed that the most iconic Antarctic animal, the penguin, experiences low pathogen pressure, accounting for their disease susceptibility in foreign environments. There is, however, a limited understanding of virome diversity in Antarctic species, the extent of in situ virus evolution, or how it relates to that in other geographic regions. To assess whether penguins have limited microbial diversity we determined the RNA viromes of three species of penguins and their ticks sampled on the Antarctic peninsula. Using total RNA sequencing we identified 107 viral species, comprising likely penguin associated viruses (n = 13), penguin diet and microbiome associated viruses (n = 82), and tick viruses (n = 8), two of which may have the potential to infect penguins. Notably, the level of virome diversity revealed in penguins is comparable to that seen in Australian waterbirds, including many of the same viral families. These data run counter to the idea that penguins are subject to lower pathogen pressure. The repeated detection of specific viruses in Antarctic penguins also suggests that rather than being simply spill-over hosts, these animals may act as key virus reservoirs.
A validated composite organ and hematologic response model for early assessment of treatment outcomes in light chain amyloidosis
Authors: Sidana Surbhi , Milani Paolo , Binder Moritz , Basset Marco , Tandon Nidhi , Foli Andrea , Dispenzieri Angela , Gertz Morie A. , Hayman Suzanne R. , Buadi Francis K. , Lacy Martha Q. , Kapoor Prashant , Leung Nelson , Rajkumar S. Vincent , Merlini Giampaolo , Palladini Giovanni , Kumar Shaji K. 
Published: April 2020

AbstractNewly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo:n = 473; validation cohort, Pavia:n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months,p < 0.001 [Mayo] and 87 vs. 23 months,p < 0.001 [Pavia]. In conclusion, we developed a model that can assess multiple organs concurrently, and integrate both HR and OR assessments to determine early clinical benefit with treatment, which may be used as a surrogate end-point in trials and to compare outcomes with different therapies.
The association between unexpected weight loss and cancer diagnosis in primary care: a matched cohort analysis of 65,000 presentations
Authors: Nicholson Brian D. , Hamilton Willie , Koshiaris Constantinos , Oke Jason L. , Hobbs F. D. Richard , Aveyard Paul 
Published: April 2020

Abstract
Background
We aimed to understand the time period of cancer diagnosis and the cancer types detected in primary care patients with unexpected weight loss (UWL) to inform cancer guidelines.

Methods
This retrospective matched cohort study used cancer registry linked electronic health records from the UK’s Clinical Practice Research Datalink from between 2000 and 2014. Univariable and multivariable time-to-event analyses examined the association between UWL, and all cancers combined, cancer site and stage.

Results
In all, 63,973 patients had UWL recorded, of whom 1375 (2.2%) were diagnosed with cancer within 2 years (days-to-diagnosis: mean 181; median 80). Men with UWL (HR 3.28 (2.88–3.73)) and women (1.87 (1.68–2.08)) were more likely than comparators to be diagnosed with cancer within 3 months. The association was greatest in men aged ≥50 years and women ≥70 years. The commonest cancers were pancreas, cancer of unknown primary, gastro-oesophageal, lymphoma, hepatobiliary, lung, bowel and renal-tract. The majority were late-stage, but there was some evidence of association with stage II and stage III cancers. In the 3–24 months after presenting with UWL, cancer diagnosis was less likely than in comparators.

Conclusion
UWL recorded in primary care is associated with a broad range of cancer sites of early and late-stage.
MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling
Authors: Jiang Ke , Yao Gang , Hu Lulu , Yan Yumei , Liu Jia , Shi Ji , Chang Youwei , Zhang Ye , Liang Dapeng , Shen Dachuan , Zhang Guirong , Meng Songshu , Piao Haozhe 
Published: April 2020

AbstractMps one binder 2 (MOB2) regulates the NDR kinase family, however, whether and how it is implicated in cancer remain unknown. Here we show that MOB2 functions as a tumor suppressor in glioblastoma (GBM). Analysis of MOB2 expression in glioma patient specimens and bioinformatic analyses of public datasets revealed that MOB2 was downregulated at both mRNA and protein levels in GBM. Ectopic MOB2 expression suppressed, while depletion of MOB2 enhanced, the malignant phenotypes of GBM cells, such as clonogenic growth, anoikis resistance, and formation of focal adhesions, migration, and invasion. Moreover, depletion of MOB2 increased, while overexpression of MOB2 decreased, GBM cell metastasis in a chick chorioallantoic membrane model. Overexpression of MOB2-mediated antitumor effects were further confirmed in mouse xenograft models. Mechanistically, MOB2 negatively regulated the FAK/Akt pathway involving integrin. Notably, MOB2 interacted with and promoted PKA signaling in a cAMP-dependent manner. Furthermore, the cAMP activator Forskolin increased, while the PKA inhibitor H89 decreased, MOB2 expression in GBM cells. Functionally, MOB2 contributed to the cAMP/PKA signaling-regulated inactivation of FAK/Akt pathway and inhibition of GBM cell migration and invasion. Collectively, these findings suggest a role of MOB2 as a tumor suppressor in GBM via regulation of FAK/Akt signaling. Additionally, we uncover MOB2 as a novel regulator in cAMP/PKA signaling. Given that small compounds targeting FAK and cAMP pathway have been tested in clinical trials, we suggest that interference with MOB2 expression and function may support a theoretical and therapeutic basis for applications of these compounds.
Recent trends in vision impairment certifications in England and Wales
Authors: Rahman Farzana , Zekite Antra , Bunce Catey , Jayaram Hari , Flanagan Declan 
Published: April 2020

Abstract
Background
The Certificate of Visual Impairment (CVI) provides essential data for preventable sight loss indicators as part of the Public Health Outcomes Framework (PHOF) published annually by the Department of Health. Trends in CVI certification rates can provide information on the effectiveness of current services and treatments and may be used to guide allocation of resources, and is the only such indicator within ophthalmology. This study aimed to compare recent trends in new vision impairment certifications in 2017/18 against prior baseline data in England and document trends in new certifications in Wales.

Methods
PHOF data from 2010/11 and 2017/18 were examined with respect to preventable sight loss indicators: age-related macular degeneration (AMD) (Indicator E12a), glaucoma (Indicator E12b), diabetic eye disease (Indicator E12c) as well as the total numbers of certifications (Indicator E12d).

Results
In 2017/18, the rate of new CVI certifications was 41 per 100,000 population which has reduced from 43/100,000 in 2010/11 in England. Certifications for AMD reduced from 132/100,000 in 2010/11 to 107/100,000 in 2017–18. Certifications for glaucoma have remained stable at 13/100,000 in 2017/8. Certifications for diabetic eye disease have declined from 4/100,000 in 2010/11 to 3/ 100,000 in 2017/18. The number of vision impaired individuals that each Clinical Commissioning Group (CCG) has to support varies from 8 to 82 per 100,000 population.

Conclusions
There has been a significant decrease in the rate of all CVI certifications particularly from AMD and diabetic retinopathy. However, maintaining this will require changes in the way care is delivered as the elderly population, which is at greatest risk of preventable sight loss, is projected to increase by 50% over the next 20 years. Inherited retinal diseases are now the leading cause of sight loss in the working age population. CVI data demonstrate the need for CCGs to tailor their investment in ophthalmic services to the needs of their specific patient populations. It is important that all ophthalmologists continue to provide accurate CVI data in order to help support the future equitable allocation of adequate resources to reduce avoidable vision loss.
Large spatial extension of the zero-energy Yu–Shiba–Rusinov state in a magnetic field
Authors: Scherübl Zoltán , Fülöp Gergő , Moca Cătălin Paşcu , Gramich Jörg , Baumgartner Andreas , Makk Péter , Elalaily Tosson , Schönenberger Christian , Nygård Jesper , Zaránd Gergely , Csonka Szabolcs 
Published: April 2020

AbstractVarious promising qubit concepts have been put forward recently based on engineered superconductor subgap states like Andreev bound states, Majorana zero modes or the Yu-Shiba-Rusinov (Shiba) states. The coupling of these subgap states via a superconductor strongly depends on their spatial extension and is an essential next step for future quantum technologies. Here we investigate the spatial extension of a Shiba state in a semiconductor quantum dot coupled to a superconductor. With detailed transport measurements and numerical renormalization group calculations we find a remarkable more than 50 nm extension of the zero energy Shiba state, much larger than the one observed in very recent scanning tunneling microscopy measurements. Moreover, we demonstrate that its spatial extension increases substantially in a magnetic field.
Minimum epistasis interpolation for sequence-function relationships
Authors: Zhou Juannan , McCandlish David M. 
Published: April 2020

AbstractMassively parallel phenotyping assays have provided unprecedented insight into how multiple mutations combine to determine biological function. While such assays can measure phenotypes for thousands to millions of genotypes in a single experiment, in practice these measurements are not exhaustive, so that there is a need for techniques to impute values for genotypes whose phenotypes have not been directly assayed. Here, we present an imputation method based on inferring the least epistatic possible sequence-function relationship compatible with the data. In particular, we infer the reconstruction where mutational effects change as little as possible across adjacent genetic backgrounds. The resulting models can capture complex higher-order genetic interactions near the data, but approach additivity where data is sparse or absent. We apply the method to high-throughput transcription factor binding assays and use it to explore a fitness landscape for protein G.
Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity
Authors: Bywater Megan J. , Burkhart Deborah L. , Straube Jasmin , Sabò Arianna , Pendino Vera , Hudson James E. , Quaife-Ryan Gregory A. , Porrello Enzo R. , Rae James , Parton Robert G. , Kress Theresia R. , Amati Bruno , Littlewood Trevor D. , Evan Gerard I. , Wilson Catherine H. 
Published: April 2020

AbstractIt is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies.
Nanosecond-time-scale delayed fluorescence molecule for deep-blue OLEDs with small efficiency rolloff
Authors: Kim Jong Uk , Park In Seob , Chan Chin-Yiu , Tanaka Masaki , Tsuchiya Youichi , Nakanotani Hajime , Adachi Chihaya 
Published: April 2020

AbstractAromatic organic deep-blue emitters that exhibit thermally activated delayed fluorescence (TADF) can harvest all excitons in electrically generated singlets and triplets as light emission. However, blue TADF emitters generally have long exciton lifetimes, leading to severe efficiency decrease, i.e., rolloff, at high current density and luminance by exciton annihilations in organic light-emitting diodes (OLEDs). Here, we report a deep-blue TADF emitter employing simple molecular design, in which an activation energy as well as spin–orbit coupling between excited states with different spin multiplicities, were simultaneously controlled. An extremely fast exciton lifetime of 750 ns was realized in a donor–acceptor-type molecular structure without heavy metal elements. An OLED utilizing this TADF emitter displayed deep-blue electroluminescence (EL) with CIE chromaticity coordinates of (0.14, 0.18) and a high maximum EL quantum efficiency of 20.7%. Further, the high maximum efficiency were retained to be 20.2% and 17.4% even at high luminance.
Full activation pattern mapping by simultaneous deep brain stimulation and fMRI with graphene fiber electrodes
Authors: Zhao Siyuan , Li Gen , Tong Chuanjun , Chen Wenjing , Wang Puxin , Dai Jiankun , Fu Xuefeng , Xu Zheng , Liu Xiaojun , Lu Linlin , Liang Zhifeng , Duan Xiaojie 
Published: April 2020

AbstractSimultaneous deep brain stimulation (DBS) and functional magnetic resonance imaging (fMRI) constitutes a powerful tool for elucidating brain functional connectivity, and exploring neuromodulatory mechanisms of DBS therapies. Previous DBS-fMRI studies could not provide full activation pattern maps due to poor MRI compatibility of the DBS electrodes, which caused obstruction of large brain areas on MRI scans. Here, we fabricate graphene fiber (GF) electrodes with high charge-injection-capacity and little-to-no MRI artifact at 9.4T. DBS-fMRI with GF electrodes at the subthalamic nucleus (STN) in Parkinsonian rats reveal robust blood-oxygenation-level-dependent responses along the basal ganglia-thalamocortical network in a frequency-dependent manner, with responses from some regions not previously detectable. This full map indicates that STN-DBS modulates both motor and non-motor pathways, possibly through orthodromic and antidromic signal propagation. With the capability for full, unbiased activation pattern mapping, DBS-fMRI using GF electrodes can provide important insights into DBS therapeutic mechanisms in various neurological disorders.
Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas
Authors: Daniels Jay , Doukas Peter G. , Escala Maria E. Martinez , Ringbloom Kimberly G. , Shih David J. H. , Yang Jingyi , Tegtmeyer Kyle , Park Joonhee , Thomas Jane J. , Selli Mehmet E. , Altunbulakli Can , Gowthaman Ragul , Mo Samuel H. , Jothishankar Balaji , Pease David R. , Pro Barbara , Abdulla Farah R. , Shea Christopher , Sahni Nidhi , Gru Alejandro A. , Pierce Brian G. , Louissaint Abner , Guitart Joan , Choi Jaehyuk 
Published: April 2020

AbstractPrimary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.
Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis
Authors: Morales Torres Cristina , Wu Mary Y. , Hobor Sebastijan , Wainwright Elanor N. , Martin Matthew J. , Patel Harshil , Grey William , Grönroos Eva , Howell Steven , Carvalho Joana , Snijders Ambrosius P. , Bustin Michael , Bonnet Dominique , Smith Paul D. , Swanton Charles , Howell Michael , Scaffidi Paola 
Published: April 2020

AbstractContinuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.
Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling
Authors: Tran Diem Hong , May Herman I. , Li Qinfeng , Luo Xiang , Huang Jian , Zhang Guangyu , Niewold Erica , Wang Xiaoding , Gillette Thomas G. , Deng Yingfeng , Wang Zhao V. 
Published: April 2020

AbstractThe hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.
An in vivo platform to select and evolve aggregation-resistant proteins
Authors: Ebo Jessica S. , Saunders Janet C. , Devine Paul W. A. , Gordon Alice M. , Warwick Amy S. , Schiffrin Bob , Chin Stacey E. , England Elizabeth , Button James D. , Lloyd Christopher , Bond Nicholas J. , Ashcroft Alison E. , Radford Sheena E. , Lowe David C. , Brockwell David J. 
Published: April 2020

AbstractProtein biopharmaceuticals are highly successful, but their utility is compromised by their propensity to aggregate during manufacture and storage. As aggregation can be triggered by non-native states, whose population is not necessarily related to thermodynamic stability, prediction of poorly-behaving biologics is difficult, and searching for sequences with desired properties is labour-intensive and time-consuming. Here we show that an assay in the periplasm of E. coli linking aggregation directly to antibiotic resistance acts as a sensor for the innate (un-accelerated) aggregation of antibody fragments. Using this assay as a directed evolution screen, we demonstrate the generation of aggregation resistant scFv sequences when reformatted as IgGs. This powerful tool can thus screen and evolve ‘manufacturable’ biopharmaceuticals early in industrial development. By comparing the mutational profiles of three different immunoglobulin scaffolds, we show the applicability of this method to investigate protein aggregation mechanisms important to both industrial manufacture and amyloid disease.
Computational analysis of pathological images enables a better diagnosis of TFE3 Xp11.2 translocation renal cell carcinoma
Authors: Cheng Jun , Han Zhi , Mehra Rohit , Shao Wei , Cheng Michael , Feng Qianjin , Ni Dong , Huang Kun , Cheng Liang , Zhang Jie 
Published: April 2020

AbstractTFE3 Xp11.2 translocation renal cell carcinoma (TFE3-RCC) generally progresses more aggressively compared with other RCC subtypes, but it is challenging to diagnose TFE3-RCC by traditional visual inspection of pathological images. In this study, we collect hematoxylin and eosin- stained histopathology whole-slide images of 74 TFE3-RCC cases (the largest cohort to date) and 74 clear cell RCC cases (ccRCC, the most common RCC subtype) with matched gender and tumor grade. An automatic computational pipeline is implemented to extract image features. Comparative study identifies 52 image features with significant differences between TFE3-RCC and ccRCC. Machine learning models are built to distinguish TFE3-RCC from ccRCC. Tests of the classification models on an external validation set reveal high accuracy with areas under ROC curve ranging from 0.842 to 0.894. Our results suggest that automatically derived image features can capture subtle morphological differences between TFE3-RCC and ccRCC and contribute to a potential guideline for TFE3-RCC diagnosis.