bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second Climate Survey of Biomedical PhD Students in the Time of Covid
Authors: Ramadoss Deepti , Horn John P. 
Published: January 2022

AbstractIn July 2021, sixteen months into the Covid-19 pandemic, the institutional climate for PhD training in the School of Medicine was assessed for a second time. This survey of graduate students occurred 1 year after initial surveys of graduate students and training faculty in July 2020. The 2021 survey was completed by 99 PhD students in 11 PhD-granting programs. To allow comparisons between years, most of the 2021 questions were repeated with only minor edits. A few items were added to assess impacts of school-wide town hall meetings, a new PhD career club program, and enlarged mental health services. Several themes emerged. Students remain extremely concerned about the pandemic’s impact upon their training and long-term career prospects. They worry specifically about pandemic related reductions in research productivity and networking opportunities. Many students successfully adapted to laboratory research under pandemic restrictions but suffer from the continuing lack of social interaction even after in-person work hours increased. Symptoms of anxiety and/or depression persist amongst 46% of the students, as compared to 51% in 2020. Nearly 80% of students continue to report strong satisfaction with mentoring relationships with their dissertation advisors, but to lesser extents with programs (66%), departments or centers (71%), the School of Medicine (32%) and the University (49%). Students (26%) express interest in the Ombuds office that was announced in late 2021. Some students wrote that the medical school could do a better job in embracing diversity and inclusion and in mentor training, and many stated that town hall meetings do not serve them well. Coping mechanisms shared by some students demonstrate impressive resilience. These results present a mixed picture. While aspects of biomedical PhD training have begun to recover as the pandemic continues, long-term consequences of the disruption raise challenges that must be addressed by efforts to restore and improve the learning environment required for 21st century research education.
Differential remodelling in small and large murine airways revealed by novel whole lung airway analysis
Authors: Tatler Amanda L , Philp Christopher J , Hill Michael R , Cox Sam , Bullock Andrew , Habgood Anthony , John Alison , Middlewick Robert , Stephenson Katherine E , Goodwin Amanda T , Billington Charlotte K , O’Dea Reuben D , Brook Bindi S , Johnson Simon R 
Published: January 2022

AbstractAirway remodelling occurs in chronic asthma leading to increased airway smooth muscle (ASM) mass and extra-cellular matrix (ECM) deposition. Whilst extensively studied in murine airways; studies report only selected larger airways at one time point meaning the spatial distribution and resolution of remodelling are poorly understood. Here we use a new method allowing comprehensive assessment of the spatial and temporal changes in ASM, ECM and epithelium in large numbers of murine airways after allergen challenge. Using image processing to analyse 20-50 airways from a whole lung section revealed increases in ASM and ECM after allergen challenge were greater in small and large rather than intermediate airways. ASM predominantly accumulated adjacent to the basement membrane whereas ECM was distributed across the airway wall. Epithelial hyperplasia was most marked in small and intermediate airways. Post challenge, ASM changes resolved over seven days whereas ECM and epithelial changes persisted. The new method suggests large and small airways remodel differently and the long-term consequences of airway inflammation may depend more on ECM and epithelial changes than ASM. The method reduces the number of animals needed, reveals important spatial differences in remodelling and could set new analysis standards for murine asthma models.
scSampler: fast diversity-preserving subsampling of large-scale single-cell transcriptomic data
Authors: Song Dongyuan , Xi Nan Miles , Li Jingyi Jessica , Wang Lin 
Published: January 2022

AbstractSummaryThe number of cells measured in single-cell transcriptomic data has grown fast in recent years. For such large-scale data, subsampling is a powerful and often necessary tool for exploratory data analysis. However, the easiest random subsampling is not ideal from the perspective of preserving rare cell types. Therefore, diversity-preserving subsampling is required for fast exploration of cell types in a large-scale dataset. Here we propose scSampler, an algorithm for fast diversity-preserving subsampling of single-cell transcriptomic data. Using simulated and real data, we show that scSampler consistently outperforms existing subsam-pling methods in terms of both the computational time and the Hausdorff distance between the full and subsampled datasets.AvailabilityscSampler is implemented in Python and is published under the MIT source license. It can be installed by pip install scsampler and used with the Scanpy pipline. The code is available on GitHub: https://github.com/SONGDONGYUAN1994/scsampler.Contactlinwang@gwu.edu; jli@stat.ucla.edu
Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models
Authors: Sauer Carolin M , Heider Katrin , Belic Jelena , Boyle Samantha E , Hall James A , Couturier Dominique-Laurent , An Angela , Vijayaraghavan Aadhitthya , Reinius Marika AV , Hosking Karen , Vias Maria , Rosenfeld Nitzan , Brenton James D 
Published: January 2022

AbstractWhole genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital pre-clinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a pre-clinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays will transform future trial designs in both mice and patients.
Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity
Authors: Kawalec Philip , Martens Matthew D. , Field Jared T. , Mughal Wajihah , Caymo Andrei Miguel , Chapman Donald , Xiang Bo , Ghavami Saeid , Dolinsky Vernon W. , Gordon Joseph W. 
Published: January 2022

AbstractDoxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had little impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.
The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background
Authors: Banse Stephen A. , Jackson E. Grace , Sedore Christine A. , Onken Brian , Hall David , Coleman-Hulbert Anna , Huynh Phu , Garrett Theo , Johnson Erik , Harinath Girish , Inman Delaney , Guo Suzhen , Morshead Mackenzie , Xue Jian , Falkowski Ron , Chen Esteban , Herrera Christopher , Kirsch Allie J , Perez Viviana I. , Guo Max , Lithgow Gordon J. , Driscoll Monica , Phillips Patrick C. 
Published: January 2022

AbstractAging is characterized by declining health that results in decreased neuromuscular function and cellular resilience. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of anti-aging interventions. Here we combined survival under thermal and oxidative stress with swimming performance, to evaluate health effects across a nematode genetic diversity panel for three compounds previously studied in the Caenorhabditis Intervention Testing Program – NP1, propyl gallate, and resveratrol. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. Additionally, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible aging interventions.
De novoanalysis of bulk RNA-seq data at spatially resolved single-cell resolution
Authors: Liao Jie , Qian Jingyang , Fang Yin , Chen Zhuo , Zhuang Xiang , Zhang Ningyu , Shao Xin , Hu Yining , Yang Penghui , Cheng Junyun , Hu Yang , Yu Lingqi , Yang Haihong , Zhang Jinlu , Lu Xiaoyan , Shao Li , Wu Dan , Gao Yue , Chen Huajun , Fan Xiaohui 
Published: January 2022

AbstractUncovering the tissue molecular architecture at single-cell resolution could help better understand organisms’ biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space (https://github.com/ZJUFanLab/bulk2space), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.
Yeast biopanning for detecting antibody binding to site-specific phosphorylations in tau
Authors: Arbaciauskaite Monika , Pirhanov Azady , Lei Yu , Cho Yong Ku 
Published: January 2022

AbstractThe detection of phosphorylated tau (p-tau) levels in clinical samples is of extreme importance for the detection of Alzheimer’s Disease (AD) as well as other neurodegenerative diseases. Recent reports show that detecting low levels of p-tau in plasma can be used as a reliable biomarker for detecting AD prior to the onset of memory loss. The ability to detect such low levels of p-tau is dependent on antibodies specific to the post translationally modified protein. However, the need for reliable phospho-site specific antibodies persists due to a lack of approaches for identifying monoclonal antibodies and characterizing non-specific binding. Here, we report a novel approach using the principles of yeast biopanning to create a robust platform that uses synthetic peptides as target antigens. Using peptides as antigens enables screening antibodies against defined post-translational modification sites, particularly for targeting intrinsically disordered proteins such as the human tau protein. To readily assess yeast binding and distinguish non-specific binding, we developed bi-directional expression vectors that allow antibody fragment surface display and intracellular fluorescent protein expression. We show that our platform can specifically and robustly detect a specific site within the p-tau target peptide when compared against non-phosphorylated controls. By improving biopanning parameters, we enabled phospho-specific capture of yeast cells displaying single-chain variable region fragments (scFvs) against p-tau with a wide range of affinities (KD = 0.2 to 60 nM). These results demonstrate that yeast biopanning can robustly capture yeast cells based on phospho-site specific antibody binding, opening doors for facile identification of high-quality monoclonal antibodies.
Wireless closed-loop smart bandage for chronic wound management and accelerated tissue regeneration
Authors: Jiang Yuanwen , Trotsyuk Artem A. , Niu Simiao , Henn Dominic , Chen Kellen , Shih Chien-Chung , Larson Madelyn R. , Mermin-Bunnell Alana M. , Mittal Smiti , Lai Jian-Cheng , Saberi Aref , Beard Ethan , Jing Serena , Zhong Donglai , Steele Sydney R. , Sun Kefan , Jain Tanish , Zhao Eric , Neimeth Christopher R. , Viana Willian G. , Tang Jing , Sivaraj Dharshan , Padmanabhan Jagannath , Rodrigues Melanie , Perrault David P. , Chattopadhyay Arhana , Maan Zeshaan N. , Leeolou Melissa C. , Bonham Clark A. , Kwon Sun Hyung , Kussie Hudson C. , Fischer Katharina S. , Gurusankar Gurupranav , Liang Kui , Zhang Kailiang , Nag Ronjon , Snyder Michael P. , Januszyk Michael , Gurtner Geoffrey C. , Bao Zhenan 
Published: January 2022

AbstractChronic non-healing wounds represent a major source of morbidity for patients and a significant economic burden. Current wound care treatments are generally passive and are unable to adapt to changes in the wound environment in real time. By integrating multimodal sensors and adding stimulators in a bandage, real-time physiological monitoring is possible and provides an opportunity for active intervention into the complex wound environment. Here, we develop a battery-free flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with tissue-interfacing tough conducting hydrogel electrodes for robust signal transduction, on-demand adhesion, and detachment. Using multiple pre-clinical models, we demonstrate the capability of our wound care system to continuously monitor skin impedance and temperature, to trigger directional electrical stimulation. The accelerated wound closure was confirmed to be due to the activation of pro-regenerative genes linked to accelerated wound closure, increased neovascularization, and enhanced dermal recovery.
ISSAAC-seq enables sensitive and flexible multimodal profiling of chromatin accessibility and gene expression in single cells
Authors: Xu Wei , Yang Weilong , Zhang Yunlong , Chen Yawen , Hong Ni , Zhang Qian , Wang Xuefei , Hu Yukun , Song Kun , Jin Wenfei , Chen Xi 
Published: January 2022

SummaryJoint profiling of chromatin accessibility and gene expression from the same single cell/nucleus provides critical information about cell types in a tissue and cell states during a dynamic process. These emerging multi-omics techniques help the investigation of cell-type resolved gene regulatory mechanisms1–7. However, many methods are currently limited by low sensitivity, low throughput or complex workflow. Here, we developed in situ SHERRY after ATAC-seq (ISSAAC-seq), a highly sensitive and flexible single cell multi-omics method to interrogate chromatin accessibility and gene expression from the same single nucleus. We demonstrated that ISSAAC-seq is sensitive and provides high quality data with orders of magnitude more features than existing methods. Using the joint profiles from over 10,000 nuclei from the mouse cerebral cortex, we uncovered major and rare cell types and cell-type specific regulatory elements and identified heterogeneity at the chromatin level within established cell types defined by gene expression. Finally, we revealed distinct dynamics and relationships of gene expression and chromatin accessibility during an oligodendrocyte maturation trajectory.
Stomatal anatomy, leaf structure and nutrients of tropical rainforest tree species respond to altitude in a coordinated manner in accordance with the leaf economics spectrum
Authors: Weththasinghe Bhagya , Caldera Iroja , Sanjeewani Nimalka , Samarasinghe Dilum , Jayasinghe Himesh , Wijethunga Asanga , De Costa Janendra 
Published: January 2022

AbstractUnderstanding taxon level responses of key plant traits to environmental variation across tropical rainforests (TRFs) is important to determine their response to climate change. We used an altitudinal gradient (from 150 to 2100 m above sea level, asl) across TRFs in Sri Lanka to answer the following questions: (a) Does the response to altitude by stomatal traits differ among plant taxa in TRFs?; (b) Are the altitudinal responses of key leaf structural traits (e.g. leaf mass per area, LMA) and major leaf nutrient (nitrogen, N, and phosphorus, P) concentrations linked to the corresponding variation in stomatal traits in a coordinated response across taxa?; (c) How strong is the influence of climatic variation on responses of leaf traits to altitude?. Leaf samples were collected in permanent sampling plots within rainforest reserves at Kanneliya (150 m asl), Sinharaja-Enasalwatta (1050 m), Hakgala (1800 m) and Piduruthalagala (2100 m) from 19 species in three plant genera (Calophyllum, Semecarpus and Syzygium). Stomatal density, guard cell length and epidermal density showed variation among taxa, but did not respond to altitude. Potential conductance index (PCI), a proxy for photosynthetic capacity, decreased with increasing altitude, in a common response across taxa. We found evidence that altitudinal responses of LMA, leaf N and P were linked to stomatal responses in a coordinated manner, where key features were the negative correlations between PCI and LMA and between proxy photosynthetic N- and P-use efficiencies (‘PNUE’ and ‘PPUE’) and LMA. We found strong responses to climatic variation across taxa and altitudes, where PCI, ‘PNUE’ and ‘PPUE’ increased and LMA decreased with increasing temperature, precipitation and solar irradiance. We conclude that stomatal traits of tree species in TRFs form part of a coordinated leaf trait response to environmental change which is in accordance with the leaf economics spectrum.
MutSigCVsyn: Identification of Thirty Synonymous Cancer Drivers
Authors: Rao Yiyun , Ahmed Nabeel , Pritchard Justin , O’Brien Edward 
Published: January 2022

AbstractSynonymous mutations, which change only the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations can act as cancer drivers has been explored in several recent studies. However, none of these studies control for all three levels (patient, histology, and gene) of mutational heterogeneity that are known to affect the accurate identification of non-synonymous cancer drivers. Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify synonymous cancer drivers based on a novel non-coding background model that takes into account the mutational heterogeneity across these levels. Examining 2,572 PCAWG cancer whole-genome sequences, MutSigCVsyn identifies 30 novel synonymous drivers that include mutations in promising candidates like BCL-2. By bringing the best practices in non-synonymous driver identification to the analysis of synonymous drivers, these are promising candidates for future experimental study.
Blocking Kir6.2 channels with SpTx1 potentiates glucose-stimulated insulin secretion from murine pancreatic β cells and lowers blood glucose in diabetic mice
Authors: Ramu Yajamana , Yamakaze Jayden , Zhou Yufeng , Hoshi Toshinori , Lu Zhe 
Published: January 2022

AbstractATP-sensitive K+ (KATP) channels in pancreatic β cells comprise pore-forming subunits (Kir6.2) and modulatory sulfonylurea receptor subunits (SUR1). The ATP sensitivity of these channels enables them to couple metabolic state to insulin secretion in β cells. Antidiabetic sulfonylureas such as glibenclamide target SUR1 and indirectly suppress Kir6.2 activity. Glibenclamide acts as both primary and secondary secretagogues to trigger insulin secretion and potentiate glucose-stimulated insulin secretion, respectively. We tested whether blocking Kir6.2 itself causes the same effects as glibenclamide, and found that the Kir6.2 pore-blocker SpTx1 acts as a strong secondary, but not a primary, secretagogue. SpTx1 triggered a transient rise of plasma insulin and lowered the elevated blood glucose of diabetic mice over-expressing Kir6.2 but did not affect those of non-diabetic mice. This proof-of-concept study suggests that blocking Kir6.2 may serve as an effective treatment for diabetes and other diseases stemming from Kir6.2 hyperactivity that cannot be suppressed with sulfonylureas.
Mod(mdg4) variants repress telomeric retrotransposon HeT-A by blocking subtelomeric enhancers
Authors: Takeuchi Chikara , Yokoshi Moe , Kondo Shu , Shibuya Aoi , Saito Kuniaki , Fukaya Takashi , Siomi Haruhiko , Iwasaki Yuka W. 
Published: January 2022

SummaryTelomeres in Drosophila are composed of sequential non-LTR retrotransposons: HeT-A, TART, and TAHRE. Although they are repressed by the piRNA pathway in the germline, how these retrotransposons are regulated in somatic cells is poorly understood. Here, we show that specific splice variants of Mod(mdg4) repress HeT-A by blocking subtelomeric enhancers in ovarian somatic cells. We found that the Mod(mdg4)-N variant represses HeT-A expression most efficiently among the variants. Mod(mdg4)-N mutant flies show elevated HeT-A expression and female sterility. Mod(mdg4)-N-binding subtelomeric sequences exhibit enhancer-blocking activity, and recruitment of RNA polymerase II (Pol II) on subtelomeres by Mod(mdg4)-N is essential for this enhancer-blocking. Moreover, Mod(mdg4)-N functions to form chromatin boundaries of higher-order chromatin conformation but this mechanism is independent of its Pol II recruitment activity at telomeres/subtelomeres. This study provides a link between enhancer-blocking and telomere regulation, and two different molecular mechanisms exhibited by an insulator protein to orchestrate precise gene expression.