bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-resolution positron emission microscopy of patient-derived tumor organoids
Authors: Khan Syamantak , Shin June Ho , Ferri Valentina , Cheng Ning , Noel Julia E. , Kuo Calvin , Sunwoo John B. , Pratx Guillem 
Published: July 2020

AbstractOrganoid tumor models have found application in a growing array of cancer studies due to their ability to closely recapitulate the structural and functional characteristics of solid tumors. However, organoids are too small to be compatible with common radiological tools used in oncology clinics. Here, we present a microscopy method to image18F-fluorodeoxyglucose in patient-derived tumor organoids with spatial resolution up to 100-fold better than that of clinical positron emission tomography (PET). When combined with brightfield imaging, this metabolic imaging approach functionally mirrors clinical PET/CT scans and provides a quantitative readout of cell glycolysis. In particular, the specific avidity of a tumor for FDG, or lack thereof, was maintained when the tumor cells were grownex vivoas tumor organoids. In addition, cisplatin treatment caused a dose-dependent decrease in the metabolic activity of these organoids, with the exception of one patient whose tumor was also resistant to cisplatin treatment. Thus, FDG-imaging of organoids could be used to predict the response of individual patients to different treatments and provide a more personalized approach to cancer care.
Natural food intake patterns do not synchronize peripheral clocks
Authors: Xie Xiaobin , Kukino Ayaka , Calcagno Haley E. , Berman Alec , Garner Joseph P. , Butler Matthew P. 
Published: July 2020

AbstractFood is thought to synchronize circadian clocks in the body, but this is based on time-restricted feeding (TRF) protocols. To test whether naturalistic feeding patterns are sufficient to phase-shift and entrain peripheral tissues, we measured circadian rhythms of the liver, kidney, and submandibular gland inmPer2Lucmice under different feeding schedules. In ad lib feeding as well as in a schedule designed to mimic the ad lib pattern, PER2::LUC bioluminescence peaked during the night as expected. Surprisingly, shifting the scheduled feeding by 12h caused only small advances (<3h). To isolate the effects of feeding from the light-dark cycle, clock phase was then measured in mice acclimated to scheduled feeding and housed in constant darkness. In these conditions, peripheral clock phases were better predicted by the rest-activity cycle than the food schedule. Under natural feeding patterns, the master pacemaker in the brain sets the phase of peripheral organs independent of feeding behavior.
Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions
Authors: Wanjalla Celestine N. , Guo Liang , Fuller Daniela T. , Mashayekhi Mona , Bailin Samuel , Gabriel Curtis L. , Temu Tecla , Gong Jingjing , Liang Yan , Virmani Renu , Finn Aloke V. , Kalams Spyros A. , Mallal Simon A. , Miner Jonathan J. , Beckman Joshua A. , Koethe John R. 
Published: July 2020

AbstractBackgroundChronic innate and adaptive immune activation may contribute to high prevalence of cardiovascular disease in persons living with HIV (PLWH).MethodsWe assessed coronary plaques from deceased PLWH (n=6) and HIV-negative (n=6) persons matched by age and gender. Formalin-fixed, paraffin-embedded 5μm thick sections were processed using Movat, hematoxylin and eosin, immunohistochemical and immunofluorescence stains. Immune cell populations were measured using surface antibodies, and immune-related protein expression from macrophage rich, T-cell rich and perivascular adipose tissue regions using GeoMx®digital spatial profiling.ResultsCoronary plaques from PLWH and HIV-negative persons had similar plaque area and percent stenosis. Percent CD163+cells as measured by immunohistochemical staining was significantly higher in PLWH, median 0.29% (IQR 0.11-0.90) vs. 0.01% (IQR 0.0013-0.11) in HIV-negative plaque, p = 0.02 (Figure 1A). Other surface markers of innate cells (CD68+, p=0.18), adaptive immune cells (CD3+, p=0.39; CD4+, p=0.09; CD8+, p=0.18) and immune trafficking markers (CX3CR1+, p=0.09) within the coronary plaque trended higher in HIV-positive plaques but did not reach statistical significance. GeoMx®digital spatial profiling showed higher differential protein expression of CD163 (scavenger receptor for hemoglobin-haptoglobin complex), stimulator of interferon gamma (STING, a cytosolic DNA sensor), CD25 and granzyme-B in the HIV-positive compared to HIV-negative, p<0.05(Figure 1B).ConclusionsIncreased inflammation within the coronary plaques of PLWH is characterized by more innate and adaptive immune cells. Higher STING expression in PLWH suggests that immune response to viral antigens within the plaque might be a driver above other stimulants. STING inhibitors are available and could be investigated as a future therapeutic target in PWH if these results are replicated with a larger number of plaques.Graphical AbstractHighlightsImmunohistochemical and fluorescent stains combined with GeoMx®digital spatial profiling allowed for deep characterization of immune cells within intact coronary plaques and perivascular adipose tissueCoronary plaques from HIV-positive persons had higher proportion of CD163+immune cells compared to HIV-negative personsDifferential protein expression of immune-rich regions of interest within intact 5μm sections of coronary plaques revealed higher levels of stimulator of interferon gamma (STING) in HIV-positive persons
Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress
Authors: Ruiz-Lopez Noemi , Pérez-Sancho Jessica , del Valle Alicia Esteban , Haslam Richard P. , Vanneste Steffen , Catalá Rafael , Perea-Resa Carlos , Van Damme Daniël , García-Hernández Selene , Albert Armando , Vallarino José , Lin Jinxing , Friml Jir□í , Macho Alberto P. , Salinas Julio , Rosado Abel , Napier Johnathan A. , Amorim-Silva Vitor , Botella Miguel A. 
Published: July 2020

SUMMARYEndoplasmic Reticulum-Plasma Membrane contact sites (ER-PM CS) play fundamental roles in all eukaryotic cells. Arabidopsis mutants lacking the ER-PM protein tether synaptotagmin1 (SYT1) exhibit decreased plasma membrane (PM) integrity under multiple abiotic stresses such as freezing, high salt, osmotic stress and mechanical damage. Here, we show that, together withSYT1, the stress-inducedSYT3is an ER-PM tether that also functions in maintaining PM integrity. The ER-PM CS localization of SYT1 and SYT3 is dependent on PM phosphatidylinositol-4-phosphate and is regulated by abiotic stress. Lipidomic analysis revealed that cold stress increased the accumulation of diacylglycerol at the PM in asyt1/3double mutant relative to WT while the levels of most glycerolipid species remain unchanged. Additionally, SYT1-GFP preferentially binds diacylglycerolin vivowith little affinity for polar glycerolipids. Our work uncovers a crucial SYT-dependent mechanism of stress adaptation counteracting the detrimental accumulation of diacylglycerol at the PM produced during episodes of abiotic stress.
Disrupting the biodiversity – ecosystem function relationship: response of shredders and leaf breakdown to urbanization in Andean streams
Authors: Zúñiga-Sarango Wilson , Gaona Fernando P. , Reyes-Castillo Valeria , Iñiguez-Armijos Carlos 
Published: July 2020

AbstractUrbanization is a major driver of stream ecosystems impairment and often associated with multiple stressors and species loss. A challenge is to understand how those stressors alter the relationship between biodiversity and ecosystem functioning (B-EF). In Andean streams of southern Ecuador, we assessed the response of shredder diversity and organic matter breakdown (OMB) to urbanization and identified the urban-associated stressors disrupting the B-EF relationship. A leaf-litter bag experiment during stable flow conditions in 2016 was carried out to quantify total OMB and shredder-mediated OMB, which was estimated to represent the B-EF relationship. We calculated the taxonomic and functional diversity of shredder invertebrates associated with leaf packs. Also, a suite of physicochemical and habitat stressors was weekly measured during the field experiment. Along the urbanization gradient, both taxonomic and functional diversity of shredders declined while OMB rates decayed. Shredders were absent and their contribution to OMB was null at the most urbanized sites. The B-EF relationship was interrupted through nutrient enrichment and physical habitat homogenization as a consequence of urbanization. These results demonstrate how species loss propagates to ecosystem functions in urbanized streams and how environmental stressors alter the B-EF relationship. Better land-use practices are crucial in Andean catchments to guarantee ecosystem services which are the result of a successful B-EF relationships.
Multinomial Convolutions for Joint Modeling of Sequence Motifs and Enhancer Activities
Authors: Park Minjun , Singh Salvi , Canozo Francisco Jose Grisanti , Samee Md. Abul Hassan 
Published: July 2020

AbstractMassively parallel reporter assays (MPRAs) have enabled the study of transcriptional regulatory mechanisms at an unprecedented scale and with high quantitative resolution. However, this realm lacks models that can discover sequence-specific signals de novo from the data and integrate them in a mechanistic way. We present MuSeAM (Multinomial CNNs for Sequence Activity Modeling), a convolutional neural network that overcomes this gap. MuSeAM utilizes multinomial convolutions that directly model sequence-specific motifs of protein-DNA binding. We demonstrate that MuSeAM fits MPRA data with high accuracy and generalizes over other tasks such as predicting chromatin accessibility and prioritizing potentially functional variants.
TOR coordinates with transcriptional and chromatin machinery to regulate thermotolerance and thermomemory
Authors: Sharma Mohan , Jamsheer K Muhammed , Shukla Brihaspati Narayan , Sharma Manvi , Awasthi Prakhar , Mahtha Sanjeet Kumar , Yadav Gitanjali , Laxmi Ashverya 
Published: July 2020

ABSTRACTGlobal warming exhibits profound effects on plant fitness and productivity. To withstand stress, plants sacrifice their growth and activate protective stress responses for ensuring survival. However, the switch between growth and stress is largely elusive. In the past decade, emerging role of Target of Rapamycin (TOR) has been studied linking energy and stress signaling. Here, we have identified an important role of Glc-TOR signaling in plant adaptation to heat stress (HS). Glc-TOR via the E2Fa signaling module regulates the transcription of heat shock factor genes through direct recruitment of E2Fa onto their promoter regions. Glc also epigenetically governs the transcription of core HS signaling genes in a TOR-dependent manner. TOR acts in concert with p300/CREB HISTONE ACETYLTRANSFERASE1 (HAC1) and dictates the epigenetic landscape of HS loci to regulate thermotolerance. Arabidopsis plants defective inTORandHAC1exhibited reduced thermotolerance with a decrease in expression of core HS signaling genes. In addition, TOR also promotes accumulation of histone H3K4me3 marks at the promoters of thermomemory-related genes and therefore, governs thermomemory. Collectively, our findings thus reveal a mechanistic framework in which Glc-TOR signaling through different modules determines the integration of stress and energy signaling to regulate thermotolerance and thermomemory.
Early Postnatal Tobacco Smoke Exposure Aggravates Experimental Autoimmune Encephalomyelitis in Adult Rats
Authors: Wang Zhaowei , Wang Liping , Zhong Fangfang , Wu Chenglong , Hou Sheng-Tao 
Published: July 2020

AbstractAlthough substantial evidence supports smoking as a risk factor for the development of multiple sclerosis (MS) in adulthood, it remains controversial as to whether early-life exposure to environmental tobacco smoke (ETS) increases the risk of MS later in life. Here, using experimental autoimmune encephalomyelitis (EAE) as an animal model for MS, we show that exposing neonatal rats during the 1stweek (ETS1-EAE), but not the 2ndweek (ETS2-EAE) and the 3rdweek (ETS3-EAE) after birth, increased the severity of EAE in adulthood in comparison to pups exposed to filtered compressed air (AIR-EAE). The EST1-EAE rats showed a worse neurological deficit score and a significant increase in CD4+cell infiltration, demyelination, and axonal injury in the spinal cord compared to AIR-EAE, ETS2-EAE, and ETS3-EAE groups. Flow cytometry analysis showed that the ETS1 group had decreased numbers of regulatory T (Treg) cells and increased effector T (Teff) cells in the brain and spinal cord. The expressions of Treg upstream regulator Foxp3 and downstream cytokines such as IL-10 were also altered accordingly. Together, these findings demonstrate that neonatal ETS exposure suppresses Treg functions and aggravates the severity of EAE, confirming early-life exposure to EST as a potential risk factor for multiple sclerosis in adulthood.
Regulation of specific cell clusters in TCR-T cells responding to differential expression of tumor PD-L1
Authors: Ding Renpeng , Liu Shang , Chen Huanyi , Kang Bin , Drmanac Radoje , Gu Ying , Dong Xuan , Gao Qianqian 
Published: July 2020

AbstractPD-L1 signaling is important in regulating T cell function and keeping balance of tumor microenvironment, but its role in modifying TCR-T cell cytotoxicity remains unknown. MART-1-specific TCR-T cells (TCR-TMART-1) were stimulated by MEL-526 tumor cells expressing different proportions of PD-L1 and used to perform cytotoxicity assays and single-cell RNA sequencing. Percentage changes of different specific cell clusters were analyzed. The percentage of cluster HLA-DR+CD38+CD8+was upregulated after antigen stimulation and tumor PD-L1 modified TCR-T cell function through downregulating the percentages of clusters HLA-DR+CD28+CD8+and HLA-DR+CD38+CD8+which were higher in TCR-TMART-1than in Tnull.
MSK-mediated phosphorylation of Histone 3 Ser28 couples MAPK signaling with early gene induction and cardiac hypertrophy
Authors: Robinson Emma L. , Drawnel Faye M , Mehdi Saher , Archer Caroline R. , Liu Wei , Okkenhaug Hanneke , Alkass Kanar , Aronsen Jan Magnus , Nagaraju Chandan K , Sjaastad Ivar , Sipido Karin R , Bergmann Olaf , Arthur J. Simon C. , Wang Xin , Roderick H. Llewelyn 
Published: July 2020

AbstractHeart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not yet resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the Mitogen and Stress activated protein Kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights and highlight the role of signalling to the epigenome in gene expression regulation during cardiac hypertrophy.Brief summary one sentenceMSK1/2 phosphorylation of Histone 3 Serine 28 couples MAPK signalling with chromatin remodelling and immediate early gene expression to induce pro-hypertrophic cardiac transcriptional responses.
Further evidence that CP-AMPARs are critically involved in synaptic tag and capture at hippocampal CA1 synapses
Authors: Park Pojeong , Kang Heather , Georgiou John , Zhuo Min , Kaang Bong-Kiun , Collingridge Graham L. 
Published: July 2020

ABSTRACTThe synaptic tag and capture (STC) hypothesis provides an important theoretical basis for understanding the synaptic basis of associative learning. We recently provided pharmacological evidence that calcium-permeable AMPA receptors (CP-AMPARs) are a crucial component of this process. Here we have investigated two predictions that arise on the basis of CP-AMPARs serving as a trigger of the STC effect. Firstly, we compared the effects of the order in which we delivered a strong theta burst stimulation (TBS) protocol (75 pulses) and a weak TBS protocol (15 pulses) to two independent inputs. We only observed a significant STC effect when the strong preceded the weak TBS. Second, we found that pausing stimulation following either the sTBS or the wTBS for ∼20 min largely eliminates the STC effect. These observations are exactly as predicted for a process that is triggered by the synaptic insertion of CP-AMPARs and provide a framework for establishing the underlying molecular mechanism.
Sustained anti-obesity effects of life-style change and anti-inflammatory interventions after conditional inactivation of the activin receptor ALK7
Authors: Srivastava Raj Kamal , Lee Ee-Soo , Sim Eunice , Sheng New Chih , Ibáñez Carlos F. 
Published: July 2020

AbstractLife-style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, specially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity. Here, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre-existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low-fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet-switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of β3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of β3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer-lasting benefits in obesity.
Light environment influences mating behaviours during the early stages of divergence in tropical butterflies
Authors: Hausmann Alexander E. , Kuo Chi-Yun , Freire Marília , Rueda-M Nicol , Linares Mauricio , Pardo-Diaz Carolina , Salazar Camilo , Merrill Richard M. 
Published: July 2020

ABSTRACTSpecies divergence is facilitated when traits under divergent selection also act as mating cues. Fluctuations in sensory conditions can alter signal perception independently of adaptation to contrasting sensory environments, but how this fine scale variation affects behavioural isolation has received less attention, especially in terrestrial organisms. The warning patterns ofHeliconiusbutterflies are under selection for aposematism and act as mating cues. Using computer vision, we extracted behavioural data from 1481 hours of video footage for 387 individuals. We show that the putative hybrid speciesH. heurippaand its close relativeH. timareta linaresidiffer in their response to divergent warning patterns, and that these differences are strengthened with increased local illuminance. Trials with live individuals reveal low-level assortative mating that are sufficiently explained by differences in visual attraction. Finally, results from hybrid butterflies are consistent with linkage between a major warning pattern gene and the corresponding behaviour, though the differences in behaviour we observe are unlikely to cause rapid reproductive isolation as predicted under a model of hybrid trait speciation. Overall, our results highlight that the role of ecological mating cues for behavioural isolation may depend on the immediate sensory conditions during which they are displayed to conspecifics.
The PopN gate-keeper complex acts on the ATPase PscN to regulate the T3SS secretion switch from early to middle substrates inPseudomonas aeruginosa
Authors: Ngo Tuan-Dung , Perdu Caroline , Jneid Bakhos , Ragno Michel , Ducassou Julia Novion , Kraut Alexandra , Couté Yohann , Stopford Charles , Attree Ina , Rietsch Arne , Faudry Eric 
Published: July 2020

AbstractPseudomonas aeruginosais an opportunistic bacterium of which the main virulence factor is the Type III Secretion System. The ATPase of this machinery, PscN (SctN), is thought to be localized at the base of the secretion apparatus and to participate in the recognition, chaperone dissociation and unfolding of exported T3SS proteins. In this work, a protein-protein interaction ELISA revealed the interaction of PscN with a wide range of exported T3SS proteins including the needle, translocator, gate-keeper and effector. These interactions were further confirmed by Microscale Thermophoresis that also indicated a preferential interaction of PscN with secreted proteins or protein-chaperone complex rather than with chaperones alone, in line with the release of the chaperones in the bacterial cytoplasm after the dissociation from their exported proteins. Moreover, we suggest a new role of the gate-keeper complex and the ATPase in the regulation of early substrates recognition by the T3SS. This finding sheds a new light on the mechanism of secretion switching from early to middle substrates inP. aeruginosa.HighlightsT3SS substrates are secreted sequentially but information on the switches are missingInteraction of the T3SS ATPase with secreted proteins were investigated by different approachesMicroscale Thermophoresis revealed a lower affinity for chaperones alone compared to complexesThe Gate-keeper complex binds to the ATPase and increases its affinity for the needle complexA new role of the Gate-keeper complex is proposed, directly acting on the T3SS ATPase
Discerning cellular response using statistical discrimination of fluorescence images of membrane receptors
Authors: Munaweera Rangika , O’Neill William D. , Hu Ying S. 
Published: July 2020

AbstractWe demonstrate a statistical modeling technique to recognize T cell responses to different external environmental conditions using membrane distributions of T cell receptors. We transformed fluorescence images of T cell receptors from each T cell into estimated model parameters of a partial differential equation. The model parameters enabled the construction of an accurate classification model using linear discrimination techniques. We further demonstrated that the technique successfully differentiated immobilized T cells on non-activating and activating surfaces. Compared to machine learning techniques, our statistical technique relies upon robust image-derived statistics and achieves effective classification with a limited sample size and a minimal computational footprint. The technique provides an effective strategy to quantitatively characterize the global distribution of membrane receptors under various physiological and pathological conditions.