bluuebunny/crossref_metadata_2025_split huggingface dataset:
Not all Icequakes are Created Equal: Basal Icequakes Suggest Diverse Bed Deformation Mechanisms at Rutford Ice Stream, West Antarctica
Authors: Kufner Sofia‐Katerina , Brisbourne Alex M. , Smith Andrew M. , Hudson Thomas S. , Murray Tavi , Schlegel Rebecca , Kendall John M. , Anandakrishnan Sridhar , Lee Ian 
Published: March 2021

AbstractMicroseismicity, induced by the sliding of a glacier over its bed, can be used to characterize frictional properties of the ice‐bed interface, which are a key parameter controlling ice stream flow. We use naturally occurring seismicity to monitor spatiotemporally varying bed properties at Rutford Ice Stream, West Antarctica. We locate 230,000 micro‐earthquakes with local magnitudes from −2.0 to −0.3 using 90 days of recordings from a 35‐station seismic network located ∼40 km upstream of the grounding line. Events exclusively occur near the ice‐bed interface and indicate predominantly flow‐parallel stick‐slip. They mostly lie within a region of interpreted stiff till and along the likely stiffer part of mega‐scale glacial lineations. Within these regions, micro‐earthquakes occur in spatially (<100 m radius) and temporally (mostly 1–5 days activity) restricted event‐clusters (up to 4,000 events), which exhibit an increase, followed by a decrease, in event magnitude with time. This may indicate event triggering once activity is initiated. Although ocean tides modulate the surface ice flow velocity, we observe little periodic variation in overall event frequency over time and conclude that water content, bed topography and stiffness are the major factors controlling microseismicity. Based on variable rupture mechanisms and spatiotemporal characteristics, we suggest the event‐clusters relate to three end‐member types of bed deformation: (1) continuous creation and seismogenic destruction of small‐scale bed‐roughness, (2) ploughed clasts, and (3) flow‐oblique deformation during landform formation or along bedrock outcrops. This indicates that multiple processes, simultaneously active during glacial sliding, can accommodate stick‐slip behavior and that the bed continuously reorganizes.
Inherent Dissipation of Upwind‐Biased Potential Temperature Advection and its Feedback on Model Dynamics
Authors: Gassmann A. 
Published: March 2021

AbstractHigher order upwind‐biased advection schemes are often used for potential temperature advection in dynamical cores of atmospheric models. The inherent diffusive and antidiffusive fluxes are interpreted here as the effect of irreversible sub‐gridscale dynamics. For those, total energy conservation and positive internal entropy production must be guaranteed. As a consequence of energy conservation, the pressure gradient term should be formulated in Exner pressure form. The presence of local antidiffusive fluxes in potential temperature advection schemes foils the validity of the second law of thermodynamics. Due to this failure, a spurious wind acceleration into the wrong direction is locally induced via the pressure gradient term. When correcting the advection scheme to be more entropically consistent, the spurious acceleration is avoided, but two side effects come to the fore: (i) the overall accuracy of the advection scheme decreases and (ii) the now purely diffusive fluxes become more discontinuous compared to the original ones, which leads to more sudden body forces in the momentum equation. Therefore, the amplitudes of excited gravity waves from jets and fronts increase compared to the original formulation with inherent local antidiffusive fluxes. The means used for supporting the argumentation line are theoretical arguments concerning total energy conservation and internal entropy production, pure advection tests, one‐dimensional advection‐dynamics interaction tests and evaluation of runs with a global atmospheric dry dynamical core.
Bentho‐Pelagic Decoupling: The Marine Biological Carbon Pump During Eocene Hyperthermals
Authors: Griffith Elizabeth M. , Thomas Ellen , Lewis Angela R. , Penman Donald E. , Westerhold Thomas , Winguth Arne M. E. 
Published: March 2021

AbstractFuture environmental change may profoundly affect oceanic ecosystems in a complex way, due to the synergy between rising temperatures, reduction in mixing and upwelling due to enhanced stratification, ocean acidification, and associated biogeochemical dynamics. Changes in primary productivity, in export of organic carbon from the surface ocean, and in remineralization deeper in the water column in the so‐called “twilight zone” may substantially alter the marine biological carbon pump, thus carbon storage in the oceans. We present different proxy records commonly used for reconstructing paleoproductivity, and re‐evaluate their use for understanding dynamic change within and between different constituents of the marine biological pump during transient global warming episodes in the past. Marine pelagic barite records are a proxy for carbon export from the photic and/or mesopelagic zone, and are not positively correlated with benthic foraminiferal proxies for arrival of organic matter to the seafloor over three early Eocene periods of global warming (Ocean Drilling Program Site 1263, SE Atlantic). These two proxies reflect processes in different parts of the water column, thus different components of the biological pump. An increase in temperature‐dependent organic carbon remineralization in the water column would have caused decreased arrival of food at the seafloor, starving the benthic biota and explaining the differences between the proxies, and may have led to ocean deoxygenation. Carbon cycle modeling demonstrates the feasibility of enhanced water‐column remineralization to explain both Site 1263 records, suggesting that this mechanism amplifies pCO2 increase, representing a positive feedback during hyperthermal warming.
PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling
Authors: Cui Bomiao , Chen Jiao , Luo Min , Liu Yiying , Chen Hongli , Lü Die , Wang Liwei , Kang Yingzhu , Feng Yun , Huang Libin , Zhang Ping 
Published: March 2021

AbstractOral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumour immunotherapy targeting PD-L1 or PD-1 has been revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is essential to gain insights into the molecular mechanisms underlying the growth and metastasis of OSCC. In this study, we analysed the expression levels of protein kinase D3 (PKD3) and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis and invasion of OSCC cells, while its overexpression promoted these processes. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Furthermore, silencing PKD3 significantly inhibited the expression of PD-L1, and lymph node metastasis of OSCC was investigated with a mouse footpad xenograft model. Thus, our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis.
Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation
Authors: Wang Yue , Lu Ji , Zhang Shuai , Li Jie , Mao Likai , Yuan Zhiguo , Bond Philip L , Guo Jianhua 
Published: March 2021

AbstractAntibiotic resistance is a global threat to public health. The use of antibiotics at sub-inhibitory concentrations has been recognized as an important factor in disseminating antibiotic resistance via horizontal gene transfer. Although non-antibiotic, human-targeted pharmaceuticals are widely used by society (95% of the pharmaceuticals market), the potential contribution to the spread of antibiotic resistance is not clear. Here, we report that commonly consumed, non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propranolol), at clinically and environmentally relevant concentrations, significantly accelerated the dissemination of antibiotic resistance via plasmid-borne bacterial conjugation. Various indicators were used to study the bacterial response to these drugs, including monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. Enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. Additionally, these non-antibiotic pharmaceuticals induced responses similar to those detected when bacteria are exposed to antibiotics, such as inducing the SOS response and enhancing efflux pumps. The findings advance understanding of the transfer of antibiotic resistance genes, emphasizing the concern that non-antibiotic, human-targeted pharmaceuticals enhance the spread of antibiotic resistance among bacterial populations.
CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway
Authors: Wang Gang , Chen Jiao-Jiao , Deng Wen-Yi , Ren Kun , Yin Shan-Hui , Yu Xiao-Hua 
Published: March 2021

AbstractC1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.
Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells
Authors: Hu Yuan , Fang Keke , Wang Yanan , Lu Nan , Sun Haoyu , Zhang Cai 
Published: March 2021

Abstractγδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin−Sca-1+Mac-1+ (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma+ (IFN-γ+) but not interleukin-17a+ (IL-17a+) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
Epidemiology of moderately severe and severe non-proliferative diabetic retinopathy in South West England
Authors: Nevill Clareece R. , Stratton Irene M. , Maruti Sonia S. , Massó-González Elvira L. , Sivaprasad Sobha , Bailey Clare , Ehrlich Michael , Chong Victor , Scanlon Peter H. 
Published: March 2021

Abstract
Aims
To estimate the incidence of early treatment diabetic retinopathy study (ETDRS) level 47 and 53 and progression to treatment with panretinal photocoagulation (PRP) for proliferative DR (PDR).

Methods
Log-linear regression was used to estimate the incidence of level 47–53 or worse for 33,009 people with diabetes (PWD) in Gloucestershire during 2013–2016 by calendar year and diabetes type, based on the first recording. Progression was analysed in Gloucestershire and Bristol with a parametric survival analysis examining the association of baseline and time-varying demographic and clinical factors on time to PRP after the first recording of level 47–53.

Results
Incidence decreased from 0.57 (95% confidence intervals (CI) 0.48–0.67) per 100 PWD in 2013 to 0.35 (95% CI 0.29–0.43) in 2016 (p < 0.001). For progression, 338 eligible PWD from Gloucestershire and 418 from Bristol were followed for a median of 1.4 years; 78 and 83% had Type 2 diabetes and a median (interquartile range) of 15 (10–22) and 17 (11–25) years duration of diagnosed diabetes respectively. Three years from the incident ETDRS 47–53, 18.9% and 17.2% had received PRP respectively. For Gloucestershire, severe IRMA and updated mean HbA1c were associated with an increase in the risk of initiating PRP (hazard ratio 3.14 (95% CI: 1.60–6.15) and 1.21 (95% CI: 1.06–1.38 per 10 mmol/mol) respectively).

Conclusion
This study provides additional understanding of this population and shows that a high proportion of patients with ETDRS levels 47–53 need to be monitored as they are at high risk of progressing to PDR.
Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells
Authors: Dreismann Anna K. , McClements Michelle E. , Barnard Alun R. , Orhan Elise , Hughes Jane P. , Lachmann Peter J. , MacLaren Robert E. 
Published: March 2021

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).
Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies
Authors: Kai Hisashi , Kai Mamiko , Niiyama Hiroshi , Okina Norihito , Sasaki Motoki , Maeda Takanobu , Katoh Atsushi 
Published: March 2021

AbstractAngiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.
Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
Authors: Prieto Marta , Folci Alessandra , Poupon Gwénola , Schiavi Sara , Buzzelli Valeria , Pronot Marie , François Urielle , Pousinha Paula , Lattuada Norma , Abelanet Sophie , Castagnola Sara , Chafai Magda , Khayachi Anouar , Gwizdek Carole , Brau Frédéric , Deval Emmanuel , Francolini Maura , Bardoni Barbara , Humeau Yann , Trezza Viviana , Martin Stéphane 
Published: March 2021

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.
Development of a mugineic acid family phytosiderophore analog as an iron fertilizer
Authors: Suzuki Motofumi , Urabe Atsumi , Sasaki Sayaka , Tsugawa Ryo , Nishio Satoshi , Mukaiyama Haruka , Murata Yoshiko , Masuda Hiroshi , Aung May Sann , Mera Akane , Takeuchi Masaki , Fukushima Keijo , Kanaki Michika , Kobayashi Kaori , Chiba Yuichi , Shrestha Binod Babu , Nakanishi Hiromi , Watanabe Takehiro , Nakayama Atsushi , Fujino Hiromichi , Kobayashi Takanori , Tanino Keiji , Nishizawa Naoko K. , Namba Kosuke 
Published: March 2021

AbstractIron (Fe) is an essential nutrient, but is poorly bioavailable because of its low solubility in alkaline soils; this leads to reduced agricultural productivity. To overcome this problem, we first showed that the soil application of synthetic 2′-deoxymugineic acid, a natural phytosiderophore from the Poaceae, can recover Fe deficiency in rice grown in calcareous soil. However, the high cost and poor stability of synthetic 2′-deoxymugineic acid preclude its agricultural use. In this work, we develop a more stable and less expensive analog, proline-2′-deoxymugineic acid, and demonstrate its practical synthesis and transport of its Fe-chelated form across the plasma membrane by Fe(III)•2’-deoxymugineic acid transporters. Possibility of its use as an iron fertilizer on alkaline soils is supported by promotion of rice growth in a calcareous soil by soil application of metal free proline-2’-deoxymugineic acid.
Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage
Authors: Hurskainen Maria , Mižíková Ivana , Cook David P. , Andersson Noora , Cyr-Depauw Chanèle , Lesage Flore , Helle Emmi , Renesme Laurent , Jankov Robert P. , Heikinheimo Markku , Vanderhyden Barbara C. , Thébaud Bernard 
Published: March 2021

AbstractDuring late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.