bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic dietary erythritol exposure elevates fasting plasma erythritol levels but does not cause weight gain or modify glucose homeostasis in mice
Authors: Ortiz Semira R. , Field Martha S. 
Published: January 2021

AbstractObjectiveErythritol is both a common non-nutritive sweetener (NNS) and an endogenous product of glucose metabolism. Recent reports indicate that elevated plasma erythritol is a predictive biomarker of cardiometabolic disease onset and complications. Although short-term erythritol consumption has been evaluated, the effect of chronically elevated circulating erythritol on adiposity and glucose metabolism has not. This study investigated the effect of longer-term erythritol consumption on weight gain and glucose tolerance, and the interaction between dietary composition and erythritol supplementation on these parameters.Methods8-week-old and 20-week-old C57BL/6J mice were randomized to consume low-fat diet (LFD), high-fat diet (HFD), LFD with 40g/kg erythritol (LFD+ERY), and HFD with 40g/kg erythritol (HFD+ERY) groups. After 8 weeks, plasma erythritol, body weight and composition, food intake, glucose tolerance, and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression were measured.ResultsPlasma erythritol was elevated 40-fold in mice consuming LFD+ERY or HFD+ERY relative to mice consuming LFD or HFD, respectively. Liver and kidney tissue contained higher levels of erythritol than adipose. Unexpectedly, there was no effect of erythritol supplementation on body weight or glucose tolerance in 8- or 20-week-old mice fed LFD+ERY, or in 8-week-old mice fed HFD+ERY. In 20-week-old mice fed HFD+ERY, there was a significant interaction between erythritol and body weight (p<0.0001) compared to controls, but the main effect of diet was not significant. We also found no effect of chronic erythritol consumption on BAT UCP1 expression.ConclusionProlonged erythritol consumption did not significantly impact body weight, composition, or glucose tolerance. This suggests that dietary erythritol does not contribute to the development of cardiometabolic disease.
Protoporphyrin-IX nanostructures modulate their protein aggregation ability via differential oxidation and protein binding
Authors: Maitra Dhiman , Pinsky Benjamin M. , Soherawardy Amenah , Zheng Haiyan , Banerjee Ruma , Omary M. Bishr 
Published: January 2021

ABSTRACTPorphyrias are caused by genetic defects in the heme biosynthetic pathway and are associated with accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures but very little is known about the effect of porphyrin speciation on the cytotoxic effects of porphyrins. Previously we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin IX (PP-IX), to cause organelle selective protein aggregation, which we posit to be a major mechanism by which porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein binding ability. We demonstrate that PP-IX nanostructure formation is reversible in nature, and that nanostructure size modulates consequent protein oxidation and aggregation potential. We also show that albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. Additionally, extracellular albumin protects from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX speciation in the context of the porphyrias, and offers insights into potential novel therapeutic approaches.
Unfolding the Apoptotic Mechanism of Antioxidant Enriched-Leaves ofTabebuia pallidain EAC Cells
Authors: Rahman Md. Mahbubur , Khan Muhammad Ali , Reza A. S. M. Ali , Sujon Khaled Mahmud , Sharmin Rokshana , Rashid Mamunur , Sadik Md. Golam , Reza Md. Abu , Tsukahara Toshifumi , Mosaddik Ashik , Gobe Glenda C , Alam AHM Khurshid 
Published: January 2021

AbstractTargeting apoptosis is a promising approach to inhibit the abnormal cell proliferation of cancer progression. Existing anti-apoptotic drugs, many derived from chemical substances, have often failed to combat cancer development and progression. Therefore, identification of apoptosis-inducing anticancer agents from plant-derived sources has become a key aim in cancer research. The present study was designed to explore the regulation of apoptosis byTabebuia pallida(T. pallida) using an Ehrlich Ascites Carcinoma (EAC) mouse model and compositional analysis by LC-ESI-MS/MS. Dried and powderedT. pallidaleaves (TPL), stem bark (TPSB), root bark (TPRB) and flowers (TPF) were extracted with 80% methanol. Using cultured EAC cells and EAC-bearing mice with and without these extracts, anticancer activities were studied by assessing cytotoxicity and tumor cell growth inhibition, changes in life span of mice, and hematological and biochemical parameters. Apoptosis was analyzed by microscopy and expression of selected apoptosis-related genes (Bcl-2, Bcl-xL, NFκ-B, PARP-1, p53, Bax, caspase-3 and -8) using RT-PCR. LC-ESI-MS analysis was performed to identify the major compounds from the most active extracts. In EAC mice compared with untreated controls, the TPL extract exhibited the highest cytotoxicity with significant tumor cell growth inhibition (p< 0.001), reduced ascites by body weight (p< 0.01), increased the life span (p<0.001), normalized blood parameters (RBC/WBC counts), and increased the levels of superoxide dismutase and catalase. TPL-treated EAC cells showed apoptotic characteristics of membrane blebbing, chromatin condensation and nuclear fragmentation, and caspase-3 activation, compared with untreated EAC cells. Moreover, annexin V-FITC and propidium iodide signals were greatly enhanced in response to TPL treatment, indicating apoptosis induction. Pro- and anti-apoptotic signaling after TPL treatment demonstrated up-regulated p53, Bax and PARP-1, and down-regulated NFκ-B, Bcl-2 and Bcl-xL expression, suggesting that TPL shifts the balance of pro- and anti-apoptotic genes towards cell death. LC-ESI-MS data of TPL showed a mixture of glycosides, lapachol, and quercetin antioxidant and its derivatives that were significantly linked to cancer cell targets. In conclusion, the TPL extract ofT. pallidapossesses significant anticancer activity. The tumor suppressive mechanism is due to apoptosis induced by activation of antioxidant enzymes and caspases and mediated by a change in the balance of pro- and anti-apoptotic genes that promotes cell death.Graphical Abstract
Quantitative dissection of color patterning in the foliar ornamental Coleus reveals underlying features driving aesthetic value
Authors: Li Mao , Coneva Viktoriya , Clark David , Chitwood Dan , Frank Margaret 
Published: January 2021

SummaryColeus is a popular ornamental plant that exhibits a diverse array of foliar color patterns. New cultivars are currently hand selected by both amateur and experienced plant breeders. In this study, we reimagine coleus breeding using a quantitative color analysis framework.Despite impressive advances in high-throughput data collection and processing, complex color patterns remain challenging to extract from image datasets. Using a new phenotyping approach called “ColourQuant,” we extract and analyze pigmentation patterns from one of the largest coleus breeding populations in the world.Working with this massive dataset, we are able to analyze quantitative relationships between maternal plants and their progeny, identify features that underlie breeder-selections, and collect and compare consumer input on trait preferences.This study is one of the most comprehensive explorations into complex color patterning in plant biology and provides new insights and tools for exploring the color pallet of the plant kingdom.
Cortical responses to vagus nerve stimulation are modulated by brain state in non-human primates
Authors: Rembado Irene , Song Weiguo , Su David K. , Levari Ariel , Shupe Larry E. , Perlmutter Steve , Fetz Eberhard , Zanos Stavros 
Published: January 2021

AbstractVagus nerve stimulation (VNS) has been tested as therapy for several brain disorders and as a means to modulate cortical excitability and brain plasticity. Cortical effects of VNS, manifesting as vagal-evoked potentials (VEPs), are thought to arise from activation of ascending cholinergic and noradrenergic systems. However, it is unknown whether those effects are modulated by brain state at the time of stimulation. In 2 freely behaving macaque monkeys, we delivered trains of left cervical VNS at different frequencies (5-300 Hz) while recording local field potentials (LFPs) from sites in contralateral prefrontal, sensorimotor and parietal cortical areas. Brain states were inferred from spectral components of LFPs and the presence of overt movement: active awake, resting awake, REM sleep and NREM sleep. VNS elicited VEPs comprising early (<70 ms), intermediate (70-250 ms) and late (>250 ms) components in all sampled cortical areas. The magnitude of only the intermediate and late components was modulated by brain state and pulsing frequency. These findings have implications for the role of ongoing cortical activity and brain state in shaping cortical responses to peripheral stimuli, for the modulation of vagal interoceptive signaling by cortical states, and for the calibration of VNS therapies.
Single Cell Enhancer Activity Maps Neuronal Lineages in Embryonic Mouse Basal Ganglia
Authors: Su-Feher Linda , Rubin Anna N. , Silberberg Shanni N. , Catta-Preta Rinaldo , Lim Kenneth J. , Zdilar Iva , McGinnis Christopher S. , McKinsey Gabriel L. , Rubino Thomas E. , Hawrylycz Michael , Thompson Carol , Gartner Zev J. , Puelles Luis , Zeng Hongkui , Rubenstein John L. R. , Nord Alex S. 
Published: January 2021

AbstractEnhancers integrate transcription factor signaling pathways that drive cell fate specification in the developing brain. We used single cell RNA-sequencing (scRNA-seq) to capture enhancer activity at single cell resolution and delineate specification of cells labeled by enhancers in mouse medial, lateral, and caudal ganglionic eminences (MGE, LGE, and CGE) at embryonic day (E)11.5. We combine enhancer-based reporter labeling with single-cell transcriptional readout to characterize enhancer activity and define cell populations in vivo. Seven enhancers had diverse activities in specific progenitor and neuronal populations within the GEs. We then applied enhancer-based labeling, scRNA-seq, and analysis of in situ hybridization (ISH) data to distinguish subtypes of MGE-derived GABAergic and cholinergic projection neurons and interneurons. This work demonstrates how the power of scRNA-seq can be extended by enhancer-based labelling and leveraging ISH data and reveals novel lineage specification paths underlying patterning of developing mouse brain.
An SR protein is essential for the recovery of malaria parasites from DNA damage and exposure to artemisinin
Authors: Singh Brajesh Kumar , Goyal Manish , Simantov Karina , Kaufman Yotam , Eshar Shiri , Ron Dzikowski 
Published: January 2021

AbstractPlasmodium falciparum, the parasite responsible for the deadliest form of human malaria, maintains a complex life cycle with a relatively small number of genes.PfSR1 is an alternative splicing factor that regulates expansion of theP. falciparumprotein repertoire. To further investigatePfSR1 functions, we set to unveil its interactome. We found thatPfSR1 interacts with proteins, which are linked to various processes of RNA metabolism in a stage-dependent manner. These include: chromatin re-modeling, transcription, splicing and translation. Intriguingly, some of thePfSR1 interacting proteins are orthologues of proteins implicated in the DNA damage response. We demonstrate thatPfSR1 expression is important for preventing the accumulation of DNA damage in proliferating parasites. In addition, following parasites’ exposure to a source of DNA damage,PfSR1 is recruited to damaged foci where it interacts with the phosphorylated core histonePfH2A, which marks damaged chromatin. Furthermore,PfSR1 expression was found to be essential for the ability of the parasite to activate the DNA repair machinery and recover from DNA damage caused by either irradiation or exposure to artemisinin, the first line anti-malarial drug. These findings unveil a novel role ofPfSR1 in protectingP. falciparumfrom DNA damage and artemisinin exposure.
Deficiency of gluconeogenic enzyme PCK1 promotes non-alcoholic steatohepatitis progression and fibrosis through PI3K/AKT/PDGF axis activation
Authors: Ye Qian , Liu Yi , Zhang Guiji , Deng Haijun , Wang Xiaojun , Tuo Lin , Chen Chang , Pan Xuanming , Wu Kang , Fan Jiangao , Pan Qin , Wang Kai , Huang Ailong , Tang Ni 
Published: January 2021

AbstractNonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in NASH progression. Mice with liverPck1deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a NASH diet. Forced expression of PCK1 by adeno-associated virus in the liver ameliorated NASH in mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated NASH progressionin vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA, highlighting a therapeutic strategy for NASH.
Moderate increases in channel discharge are positively related to ecosystem respiration in forested Ozark streams
Authors: Dodd Allyn K. , Magoulick Daniel D. , Evans-White Michelle A. 
Published: January 2021

ABSTRACTThe natural flow regime is considered the “master variable” in lotic systems, controlling structure and function at organismal, population, community, and ecosystem levels. We sought to estimate forested headwater stream metabolism across two dominant flow regimes (RunoffandGroundwater) in northern Arkansas and evaluate potential differences in, and drivers of, gross primary production, ecosystem respiration, and net ecosystem metabolism. Flow regimes differed in intermittency, substrate heterogeneity, hyporheic connectivity, and dominant water source (subsurface runoff vs. groundwater), which we expected to result in differences in primary production and respiration. Average daily gross primary production (GPP) and ecosystem respiration (ER) estimated from field data collected from May 2015-June 2016 tended to be greater inGroundwaterstreams. Respiration was positively related to discharge (R2= 0.98 p< 0.0001) and net metabolism became more heterotrophic with increasing average annual discharge across sites (R2= 0.94, p= 0.0008). Characterizing ecosystem-level responses to differences in flow can reveal mechanisms governing stream metabolism and, in turn, provide information regarding trophic state and energy inputs as efforts continue to determine global trends in aquatic carbon sources and fates.
Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw
Authors: Hirschberger Christine , Sleight Victoria A. , Criswell Katharine E. , Clark Stephen J. , Gillis J. Andrew 
Published: January 2021

AbstractThe origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral patterning mechanisms within the developing mandibular, hyoid and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralising BMP and endothelin signalling pathways and their effectors, the joint markers bapx1 and gdf5 and pro-chondrogenic transcription factors barx1 and gsc, and the dorsalising transcription factor pou3f3. Additionally, we find that mesenchymal expression ofeya1/six1is an ancestral feature of the mandibular arch of jawed vertebrates, while differences in notch signalling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the dorsoventral axis of the pharyngeal arches, includingscamp5as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.
Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders
Authors: Briscione Maria A. , Dinasarapu Ashok R. , Bagchi Pritha , Donsante Yuping , Downs Anthony M. , Fan Xueliang , Hoehner Jessica , Jinnah H.A. , Hess Ellen J. 
Published: January 2021

AbstractDystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although basal ganglia dysfunction is implicated in many forms of dystonia, the underlying mechanisms are unclear. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented whereas proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated proteins identified in our screen are associated with pathogenic variants that cause inherited dystonic disorders in humans suggesting shared mechanisms across many different forms of dystonia.
The Necroptosis Effector MLKL drives Small Extracellular Vesicle Release and Tumour Growth in Glioblastoma
Authors: André-Grégoire Gwennan , Douanne Tiphaine , Thys An , Maghe Clément , Jacobs Kathryn , Ballu Cyndie , Trillet Kilian , Busnelli Ignacio , Hyenne Vincent , Goetz Jacky G , Bidère Nicolas , Gavard Julie 
Published: January 2021

AbstractExtracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansionin vitro. This function ascribed to MLKL appears independent of its role during necroptosis.In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.
CoSTA: Unsupervised Convolutional Neural Network Learning for Spatial Transcriptomics Analysis
Authors: Xu Yang , McCord Rachel Patton 
Published: January 2021

AbstractThe rise of spatial transcriptomics technologies is leading to new insights about how gene regulation happens in a spatial context. Here, we present CoSTA: a novel approach to learn spatial similarities between gene expression matrices via convolutional neural network (ConvNet) clustering. By analyzing simulated and previously published spatial transcriptomics data, we demonstrate that CoSTA learns spatial relationships between genes in a way that emphasizes whole patterns rather than pixel-level correlation. CoSTA provides a quantitative measure of how similar each pair of genes are by their spatial pattern rather than only classifying genes into categories. We find that CoSTA identifies narrower, but biologically relevant, sets of significantly related genes as compared to other approaches.
Adjunctive treatments for the management of septic shock – a narrative review of the current evidence
Authors: Donovan K. , Shah A. , Day J. , McKechnie S. R. 
Published: January 2021

SummarySeptic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta‐blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta‐blocker therapy may have beneficial cardiac and non‐cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.