bluuebunny/crossref_metadata_2025_split huggingface dataset:
Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese
Authors: Todorčević Marijana , Manuel Ari R. , Austen Luke , Michailidou Zoi , Hazlehurst Jonathan M. , Neville Matt , Stradling John R. , Karpe Fredrik 
Published: March 2021

AbstractIt has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O2 saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m2) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30–34.9 kg/m2) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.
Recurrent neural network-based volumetric fluorescence microscopy
Authors: Huang Luzhe , Chen Hanlong , Luo Yilin , Rivenson Yair , Ozcan Aydogan 
Published: March 2021

AbstractVolumetric imaging of samples using fluorescence microscopy plays an important role in various fields including physical, medical and life sciences. Here we report a deep learning-based volumetric image inference framework that uses 2D images that are sparsely captured by a standard wide-field fluorescence microscope at arbitrary axial positions within the sample volume. Through a recurrent convolutional neural network, which we term as Recurrent-MZ, 2D fluorescence information from a few axial planes within the sample is explicitly incorporated to digitally reconstruct the sample volume over an extended depth-of-field. Using experiments on C. elegans and nanobead samples, Recurrent-MZ is demonstrated to significantly increase the depth-of-field of a 63×/1.4NA objective lens, also providing a 30-fold reduction in the number of axial scans required to image the same sample volume. We further illustrated the generalization of this recurrent network for 3D imaging by showing its resilience to varying imaging conditions, including e.g., different sequences of input images, covering various axial permutations and unknown axial positioning errors. We also demonstrated wide-field to confocal cross-modality image transformations using Recurrent-MZ framework and performed 3D image reconstruction of a sample using a few wide-field 2D fluorescence images as input, matching confocal microscopy images of the same sample volume. Recurrent-MZ demonstrates the first application of recurrent neural networks in microscopic image reconstruction and provides a flexible and rapid volumetric imaging framework, overcoming the limitations of current 3D scanning microscopy tools.
Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients
Authors: Qi Han-zhou , Ye Yi-ling , Suo Yuan , Qu Hong , Zhang Hai-yan , Yang Kai-bo , Fan Zhi-ping , Huang Fen , Xuan Li , Chen Yan-qiu , Jin Hua , Liu Qi-fa 
Published: March 2021

AbstractChronic graft-versus-host disease (cGVHD) is the main cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) in bone marrow (BM) remain unclear in the pathophysiology of cGVHD. In this study, we analyzed BM-MSCs from 66 patients after allo-HSCT, including 33 with active cGVHD and 33 without cGVHD. BM-MSCs showed similar morphology, frequency, phenotype, and proliferation in patients with or without cGVHD. MSCs from the active cGVHD group showed a decreased apoptosis rate (P < 0.01). Osteogenic capacity was increased while adipogenic capacity was decreased in the active cGVHD MSCs compared with no-cGVHD MSCs. The expressions of osteogenic gene RUNX2 and COL1A1 were higher (P < 0.001) while adipogenic gene PPAR-γ and FABP4 were lower (P < 0.001) in the active cGVHD MSCs than no-cGVHD MSCs. These changes were associated with the severity of cGVHD (P < 0.0001; r = 0.534, r = 0.476, r = −0.796, and r = −0.747, respectively in RUNX2, COL1A1, PPAR-γ, and FABP4). The expression of Wnt/β-catenin pathway ligand Wnt3a was increased in cGVHD-MSCs. The dysfunction of cGVHD-MSCs could be reversed by Dickkopf related protein 1(DKK1) to inhibit the binding of Wnt3a. In summary, the differentiation of BM-MSCs was abnormal in active cGVHD, and its underlying mechanism is the upregulated of Wnt3a through Wnt/β-catenin signaling pathway of MSCs.
Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events
Authors: Kapuy Orsolya , Holczer Marianna , Márton Margita , Korcsmáros Tamás 
Published: March 2021

AbstractAlthough autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we explore the dynamical features of autophagy induction. We propose that the switch-like characteristic of autophagy induction is achieved by a control network, containing essential feedback loops of four components, so-called autophagy inducer, autophagy controller, mTORC1 and autophagy executor, respectively. We show how an autophagy inducer is capable to turn on autophagy in a cellular stress-specific way. The autophagy controller acts as a molecular switch and not only promotes autophagy but also blocks the permanent hyperactivation of the process via downregulating the autophagy inducer. In this theoretical analysis, we explore in detail the properties of all four proposed controlling elements and their connections. Here we also prove that the kinetic features of this control network can be considered accurate in various stress processes (such as starvation, endoplasmic reticulum stress and oxidative stress), even if the exact components may be different. The robust response of the resulting control network is essential during cellular stress.
Strain rate dependency of dislocation plasticity
Authors: Fan Haidong , Wang Qingyuan , El-Awady Jaafar A. , Raabe Dierk , Zaiser Michael 
Published: March 2021

AbstractDislocation glide is a general deformation mode, governing the strength of metals. Via discrete dislocation dynamics and molecular dynamics simulations, we investigate the strain rate and dislocation density dependence of the strength of bulk copper and aluminum single crystals. An analytical relationship between material strength, dislocation density, strain rate and dislocation mobility is proposed, which agrees well with current simulations and published experiments. Results show that material strength displays a decreasing regime (strain rate hardening) and then increasing regime (classical forest hardening) as the dislocation density increases. Accordingly, the strength displays universally, as the strain rate increases, a strain rate-independent regime followed by a strain rate hardening regime. All results are captured by a single scaling function, which relates the scaled strength to a coupling parameter between dislocation density and strain rate. Such coupling parameter also controls the localization of plasticity, fluctuations of dislocation flow and distribution of dislocation velocity.
Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice
Authors: Yoshida Tomoyuki , Yamagata Atsushi , Imai Ayako , Kim Juhyon , Izumi Hironori , Nakashima Shogo , Shiroshima Tomoko , Maeda Asami , Iwasawa-Okamoto Shiho , Azechi Kenji , Osaka Fumina , Saitoh Takashi , Maenaka Katsumi , Shimada Takashi , Fukata Yuko , Fukata Masaki , Matsumoto Jumpei , Nishijo Hisao , Takao Keizo , Tanaka Shinji , Okabe Shigeo , Tabuchi Katsuhiko , Uemura Takeshi , Mishina Masayoshi , Mori Hisashi , Fukai Shuya 
Published: March 2021

AbstractNeuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.
Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level
Authors: Clark Helen R. , McKenney Connor , Livingston Nathan M. , Gershman Ariel , Sajjan Seema , Chan Isaac S. , Ewald Andrew J. , Timp Winston , Wu Bin , Singh Abhyudai , Regot Sergi 
Published: March 2021

AbstractTo prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.
Common Era sea-level budgets along the U.S. Atlantic coast
Authors: Walker Jennifer S. , Kopp Robert E. , Shaw Timothy A. , Cahill Niamh , Khan Nicole S. , Barber Donald C. , Ashe Erica L. , Brain Matthew J. , Clear Jennifer L. , Corbett D. Reide , Horton Benjamin P. 
Published: March 2021

AbstractSea-level budgets account for the contributions of processes driving sea-level change, but are predominantly focused on global-mean sea level and limited to the 20th and 21st centuries. Here we estimate site-specific sea-level budgets along the U.S. Atlantic coast during the Common Era (0–2000 CE) by separating relative sea-level (RSL) records into process-related signals on different spatial scales. Regional-scale, temporally linear processes driven by glacial isostatic adjustment dominate RSL change and exhibit a spatial gradient, with fastest rates of rise in southern New Jersey (1.6 ± 0.02 mm yr−1). Regional and local, temporally non-linear processes, such as ocean/atmosphere dynamics and groundwater withdrawal, contributed between −0.3 and 0.4 mm yr−1 over centennial timescales. The most significant change in the budgets is the increasing influence of the common global signal due to ice melt and thermal expansion since 1800 CE, which became a dominant contributor to RSL with a 20th century rate of 1.3 ± 0.1 mm yr−1.
Vegetation feedback causes delayed ecosystem response to East Asian Summer Monsoon Rainfall during the Holocene
Authors: Cheng Jun , Wu Haibin , Liu Zhengyu , Gu Peng , Wang Jingjing , Zhao Cheng , Li Qin , Chen Haishan , Lu Huayu , Hu Haibo , Gao Yu , Yu Miao , Song Yaoming 
Published: March 2021

AbstractOne long-standing issue in the paleoclimate records is whether East Asian Summer Monsoon peaked in the early Holocene or mid-Holocene. Here, combining a set of transient earth system model simulations with proxy records, we propose that, over northern China, monsoon rainfall peaked in the early Holocene, while soil moisture and tree cover peaked in the mid-Holocene. The delayed ecosystem (soil moisture and tree cover) response to rainfall is caused by the vegetation response to winter warming and the subsequent feedback with soil moisture. Our study provides a mechanism for reconciling different evolution behaviors of monsoon proxy records; it sheds light on the driving mechanism of the monsoon evolution and monsoon-ecosystem feedback over northern China, with implications to climate changes in other high climate sensitivity regions over the globe.
NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients
Authors: March Michael E. , Gutierrez-Uzquiza Alvaro , Snorradottir Asbjorg Osk , Matsuoka Leticia S. , Balvis Noelia Fonseca , Gestsson Thorgeir , Nguyen Kenny , Sleiman Patrick M. A. , Kao Charlly , Isaksson Helgi J. , Bragason Birkir Thor , Olafsson Elias , Palsdottir Astridur , Hakonarson Hakon 
Published: March 2021

AbstractHereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.
Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis
Authors: Liu Xiaonan , Chai Yu , Liu Guanqiao , Su Weiping , Guo Qiaoyue , Lv Xiao , Gao Peisong , Yu Bin , Ferbeyre Gerardo , Cao Xu , Wan Mei 
Published: March 2021

AbstractSynthetic glucocorticoids (GCs), one of the most effective treatments for chronic inflammatory and autoimmune conditions in children, have adverse effects on the growing skeleton. GCs inhibit angiogenesis in growing bone, but the underlying mechanisms remain unclear. Here, we show that GC treatment in young mice induces vascular endothelial cell senescence in metaphysis of long bone, and that inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis with coupled osteogenesis. We identify angiogenin (ANG), a ribonuclease with pro-angiogenic activity, secreted by osteoclasts as a key factor for protecting the neighboring vascular cells against senescence. ANG maintains the proliferative activity of endothelial cells through plexin-B2 (PLXNB2)-mediated transcription of ribosomal RNA (rRNA). GC treatment inhibits ANG production by suppressing osteoclast formation in metaphysis, resulting in impaired endothelial cell rRNA transcription and subsequent cellular senescence. These findings reveal the role of metaphyseal blood vessel senescence in mediating the action of GCs on growing skeleton and establish the ANG/PLXNB2 axis as a molecular basis for the osteoclast-vascular interplay in skeletal angiogenesis.
Multiple analyses of various factors affecting the plantlet regeneration of Picea mongolica (H. Q. Wu) W.D. Xu from somatic embryos
Authors: Yan Jia , Peng Peng , Duan Guozhen , Lin Tao , Bai Yu´e 
Published: March 2021

AbstractPicea mongolica, a native species with excellent industrial wood quality and strong sand-fixing capacity, may be utilized in construction of urban green spaces in arid areas in China. However, now the sustainability of the ecosystems where this species grows is at serious risk due to a lack of natural regeneration. In this study, we developed an efficient regeneration system and comprehensively analyzed various factors affecting somatic embryogenesis (SE) using zygotic embryos as explants. We identified the optimal plant growth regulators (PGRs) performance and the best donor trees (k81) for the generation of somatic embryos (SEMs). Additionally, we confirmed that the positive developmental window of SEMs initiation was at the end of July to early August, which is when zygotic embryos was at the late embryogeny. In this time period, specific transcripts associated with the regulation of epigenetic modifications, plant hormone-related genes, and embryonic development-related transcription factors play important roles for early SEMs initiation. These results may provide a valuable resource for vegetative propagation of Picea mongolica. Our results may help to establish a reliable protocol for plantlet regeneration, which may facilitate urban greening applications and industrialization in arid areas.
PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
Authors: Brown Sarah J. , Boussaad Ibrahim , Jarazo Javier , Fitzgerald Julia C. , Antony Paul , Keatinge Marcus , Blechman Janna , Schwamborn Jens C. , Krüger Rejko , Placzek Marysia , Bandmann Oliver 
Published: March 2021

AbstractRecent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.
Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease
Authors: Baliga Madhurima M. , Klawitter Jost , Christians Uwe , Hopp Katharina , Chonchol Michel , Gitomer Berenice Y. , Cadnapaphornchai Melissa A. , Klawitter Jelena 
Published: March 2021

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. Although children with ADPKD show normal renal function, cyst development is already occurring. In this study, we aimed to identify markers and associated molecular pathways of disease progression in children and young adults with ADPKD. Plasma samples were collected during a 3-year randomized, double-blind, placebo-controlled, phase III clinical trial that was designed to test the efficacy of pravastatin on slowing down ADPKD progression in pediatric patients. Samples from 58 patients were available at baseline and at the 3-year endpoint of the study, respectively. Furthermore, plasma samples from 98 healthy children were used as controls. Metabolomic analysis was performed using liquid chromatography-tandem mass spectrometry and differences in metabolic profiles over time and within study groups were evaluated. While pravastatin therapy led to a decrease in a percent change of total kidney volume (HtTKV) in ADPKD patients, it had minimal effects on metabolite changes. Oxidative stress, endothelial dysfunction, inflammation and immune response were the most affected signaling pathways that distinguished healthy from diseased children. Pathway analysis revealed that metabolites in the arginine metabolism (urea and nitric oxide cycles), asparagine and glutamine metabolism, in the methylation cycle and kynurenine pathway were significantly changed between healthy and children with ADPDK and continued to diverge from the control levels while the disease progressed. Detected metabolite changes were primarily governed by disease progression, and less by pravastatin treatment. Identified metabolic pathways, from arginine and asparagine to kynurenine metabolism could present therapeutic targets and should be further investigated for potential to treat ADPKD progression at an early stage.
MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
Authors: Oka Sugako , Leon Julio , Sakumi Kunihiko , Abolhassani Nona , Sheng Zijing , Tsuchimoto Daisuke , LaFerla Frank M. , Nakabeppu Yusaku 
Published: March 2021

Abstract8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.