bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irisin Protects Against LPS-Stressed Cardiac Damage Through Inhibiting Inflammation, Apoptosis, and Pyroptosis
Authors: Li Qian , Zhang Mingming , Zhao Ying , Dong Maolong 
Published: March 2021

ABSTRACT
Septic cardiac dysfunction remains a clinical problem due to its high morbidity and mortality. Uncontrolled cell death and excessive inflammatory response are closely related to sepsis-induced cardiac dysfunction. Irisin has been found to play cardioprotective roles in sepsis. However, there is enough uncertainty in the mechanism of irisin-mediated cardioprotection. We hypothesized that irisin may ameliorate myocardial dysfunction via reducing cardiac apoptosis, pyroptosis, and inflammation during LPS-induced sepsis. Mice were subjected to LPS with or without irisin treatment. After stimuli of LPS, the function of myocardium was distinctly impaired, which was closely related to increased level of apoptosis (decreased expression of Bcl-2 and elevated expression of Caspase-3 and Bax), pyroptosis (increased expression of Caspase1, NLR family pyrin domain containing 3 (NLRP3), and gasdermin D) and inflammatory mediators (increased level of IL-1β, TNF-α, and IL-6). This process is consistent with increased toll-like receptor 4 (TLR4)/nuclear factor-kappa B signal, apoptotic signal, and NLRP3-mediated pyroptotic signal. Activation of apoptosis and pyroptosis enhanced the expression of proinflammatory cytokines and further exacerbated septic myocardial damage. However, irisin can inhibit the expression of TLR4 and its downstream signaling molecules and also lower the level of apoptosis and pyroptosis. Besides, similar results were also found in vitro model of LPS-induced H9c2 cardiomyocyte injury. In general, irisin suppressed inflammation, apoptosis, and pyroptosis by blocking the TLR4 and NLRP3 inflammasome signalings to mitigate myocardial dysfunction in sepsis.
Estrogen Enhances the Microvascular Reactivity Through RhoA-ROCK Pathway in Female Mice During Hemorrhagic Shock
Authors: Yue Yun-Xue , Zhai Jia-Yi , Du Hui-Bo , Jiang Li-Na , Zhang Li-Min , Wang Chen , Zhao Zhen-Ao , Zhang Chun-Hui , Zhao Zi-Gang 
Published: March 2021

ABSTRACT
Vascular hypo-reactivity plays a critical role inducing organ injury during hemorrhagic shock. 17β-estradiol (E2) can induce vasodilation to increase blood flow in various vascular beds. This study observed whether E2 can restore vascular hypo-reactivity induced by hemorrhagic shock, and whether E2 effects are associated with RhoA-Rho kinase (ROCK)-myosin light chain kinase phosphatase (MLCP) pathway. The hemorrhagic shock model (40 ± 2 mm Hg for 1 h, resuscitation for 4 h) was established in ovary intact sham operation (OVI), ovariectomized (OVX), and OVX plus E2 supplement female mice. Intestinal microvascular loop was used to assess blood flow in vivo, mRNA expression and vascular reactivity in vitro. Hemorrhagic shock significantly reduced norepinephrine microvascular reactivity. Decreased microvascular reactivity was exacerbated by OVX and reversed by E2 supplement. U-46619 (RhoA agonist) increased microvascular reactivity, and C3 transferase (an ADP ribosyl transferase that selectively induces RhoA ribosylation) or Y-27632 (ROCK inhibitor) inhibited sham mice microvascular reactivity. Similarly, U-46619 increased microvascular reactivity in OVI and OVX mice following hemorrhagic shock, which was abolished by Y-27632 or concomitant incubation of okadaic acid (OA) (MLCP inhibitor) and Y-27632. In OVX plus E2 supplement mice with hemorrhagic shock, Y-27632 inhibited microvascular reactivity, which was abolished by concomitant U-46619 application. Lastly, hemorrhagic shock remarkably decreased intestinal loop blood flow, RhoA and ROCK mRNA expressions in vascular tissues in OVX females, but not in OVI females, which were reversed by E2 supplement. These results indicate that estrogen improves microvascular reactivity during hemorrhagic shock, and RhoA-ROCK signaling pathway may mediate E2 effects.
Could Soluble Endothelial Protein C Receptor Levels Recognize SARS-CoV2-Positive Patients Requiring Hospitalization?
Authors: Vassiliou Alice G. , Keskinidou Chrysi , Jahaj Edison , Gallos Parisis , Zacharis Alexandros , Athanasiou Nikolaos , Tsipilis Stamatios , Mastora Zafeiria , Dimopoulou Ioanna , Kotanidou Anastasia , Orfanos Stylianos E. 
Published: March 2021

ABSTRACT

Introduction:
The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in COVID-19 has not been explored. In this study, we investigated whether sEPCR levels were related to COVID-19 patients’ requirement for hospitalization.

Methods:
Plasma sEPCR levels were measured on hospital admission in 84 COVID-19 patients, and in 11 non-hospitalized SARS-CoV2-positive patients approximately 6 days after reported manifestation of their symptoms. Multiple logistic regression analysis was performed to identify potential risk factors for hospitalization and receiver operating characteristic (ROC) curves were generated to assess their value.

Results:
In our cohort, hospitalized patients had considerably higher sEPCR levels upon admission compared with outpatients [107.5 (76.7–156.3) vs. 44.6 (12.1–84.4) ng/mL; P < 0.0001)]. The ROC curve using hospitalization as the classification variable and sEPCR levels as the prognostic variable generated an area under the curve at 0.845 (95% CI = 0.710–0.981, P < 0.001). Additionally, we investigated the predictive value of sEPCR combined with BMI, age, or D-dimers.

Conclusions:
In our cohort, sEPCR levels in COVID-19 patients upon hospital admission appear considerably elevated compared with outpatients; this could lead to impaired APC activities and might contribute to the pro-coagulant phenotype reported in such patients. sEPCR measurement might be useful as a point-of-care test in SARS-CoV2-positive patients.
Detection of Mutations Associated with Variants of Concern Via High Throughput Sequencing of SARS-CoV-2 Isolated from NYC Wastewater
Authors: Smyth Davida S. , Trujillo Monica , Cheung Kristen , Gao Anna , Hoxie Irene , Kannoly Sherin , Kubota Nanami , Markman Michelle , San Kaung Myat , Sompanya Geena , Dennehy John J. 
Published: March 2021

ABSTRACTMonitoring SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To date, most data on SARS-CoV-2 genetic diversity has come from the sequencing of clinical samples, but such studies may suffer limitations due to costs and throughput. Wastewater-based epidemiology may provide an alternative and complementary approach for monitoring communities for novel variants. Given that SARS-CoV-2 can infect the cells of the human gut and is found in high concentrations in feces, wastewater may be a valuable source of SARS-CoV-2 RNA, which can be deep sequenced to provide information on the circulating variants in a community. Here we describe a safe, affordable protocol for the sequencing of SARS-CoV-2 RNA using high-throughput Illumina sequencing technology. Our targeted sequencing approach revealed the presence of mutations associated with several Variants of Concern at appreciable frequencies. Our work demonstrates that wastewater-based SARS-CoV-2 sequencing can inform surveillance efforts monitoring the community spread of SARS-CoV-2 Variants of Concern and detect the appearance of novel emerging variants more cheaply, safely, and efficiently than the sequencing of individual clinical samples.IMPORTANCEThe SARS-CoV-2 pandemic has caused millions of deaths around the world as countries struggle to contain infections. The pandemic will not end until herd immunity is reached, that is, when most of the population has either recovered from SARS-CoV-2 infection or is vaccinated against SARS-CoV-2. However, the emergence of new SARS-CoV-2 variants of concern threatens to erase gains. Emerging new variants may re-infect persons who have recovered from COVID-19 or may evade vaccine-induced immunity. However, scaling up SARS-CoV-2 genetic sequencing to monitor Variants of Concern in communities around the world is challenging. Wastewater-based sequencing of SARS-CoV-2 RNA can be used to monitor the presence of emerging variants in large communities to enact control measures to minimize the spread of these variants. We describe here the identification of alleles associated with several variants of concern in wastewater obtained from NYC watersheds.
A baton-relay and proofreading mechanism for selective ER retrieval signal capture by the KDEL receptor
Authors: Gerondopoulos Andreas , Bräuer Philipp , Sobajima Tomoaki , Wu Zhiyi , Parker Joanne L. , Biggin Philip C. , Barr Francis A. , Newstead Simon 
Published: March 2021

ABSTRACTThe KDEL-retrieval pathway captures escaped ER proteins with a KDEL or variant C-terminal signal at acidic pH in the Golgi and releases them at neutral pH in the ER. To address the mechanism of signal binding and the molecular basis for differences in signal affinity, we determined the HDEL and RDEL bound structures of the KDEL-receptor. Affinity differences are explained by interactions between the variable −4 position of the signal and W120, whereas initial capture of retrieval signals by their carboxyl-terminus is mediated by a baton-relay mechanism involving a series of conserved arginine residues in the receptor. This explains how the signal is first captured and then pulled into the binding cavity. During capture, retrieval signals undergo a selective proofreading step involving two gatekeeper residues D50 and E117 in the receptor. These mechanisms operate upstream of the pH-dependent closure of the receptor and explain the selectivity of the KDEL-retrieval pathway.
A novel approach to comparative RNA-Seq does not support a conserved set of genes underlying animal regeneration
Authors: Sierra Noemie , Olsman Noah , Yi Lynn , Pachter Lior , Goentoro Lea , Gold David A. 
Published: March 2021

ABSTRACTMolecular studies of animal regeneration typically focus on conserved genes and signaling pathways that underlie morphogenesis. To date, a holistic analysis of gene expression across animals has not been attempted, as it presents a suite of problems related to differences in experimental design and gene homology. By combining orthology analysis with a novel statistical method for testing gene enrichment across large datasets, we are able to test whether biological processes across organisms share transcriptional regulation. We applied this method to six publicly available RNA-seq datasets from diverse examples of animal regeneration. We recovered 160 conserved orthologous gene clusters, which are enriched in structural genes as opposed to those regulating morphogenesis. A breakdown of gene presence/absence provides only limited support for the conservation of pathways typically implicated in regeneration, such as Wnt signaling and cell pluripotency. Specifically, these pathways are only conserved if we allow gene paralogs to be interchangeable through evolution. Overall, our analysis does not support the hypothesis that a shared set of ancestral genes underlie regeneration mechanisms in animals. The methods described in this paper will be broadly applicable for studying the genetic underpinnings of traits across distantly related organisms.
Over-expression of the Regulator of the Signaling of G Protein-Coupled Receptors RGS9-2 reduces the signaling elicited by the human histamine H3receptor in HEK-293T cells
Authors: Nieto-Alamilla Gustavo , Escamilla-Sánchez Juan , Arias-Montaño José-Antonio 
Published: March 2021

AbstractIn HEK-293T cells transiently transfected with the human histamine H3receptor (hH3R), we studied the effect of over-expressing the human RGS9-2 protein on H3R-mediated stimulation of [35S]-GTPγS binding and inhibition of forskolin-induced cAMP formation. Maximal specific binding (Bmax) of [3H]-N-methyl-histamine to cell membranes was 468 ± 12 and 442 ± 38 fmol/mg protein for HEK-293T-hH3R and HEK-293T-hH3R/hRGS9-2 cells, respectively, with dissociation constants (Kd) 2.57 nM and 3.38 nM. The H3R agonist immepip stimulated [35S]-GTPγS binding with similar potency and efficacy (Emax146.3 ± 4.4 % and 150.0 ± 5.3 % of basal, pEC508.57 ± 0.26 and 9.00 ± 0.33, respectively), but was significantly less efficacious to inhibit forskolin-induced cAMP accumulation in HEK-293T-hH3R/hRGS9 cells (−19.2 ± 5.3 versus −37.7 ± 5.1 % in HEK-293T-hH3R cells) with no significant difference in potency (pEC509.60 ± 0.14 and 9.07 ± 0.29, respectively). These results indicate that in HEK-293T cells hRGS9-2 regulates hH3R445signaling downstream G protein activation.
TWIST1 expression is associated with high-risk Neuroblastoma and promotes Primary and Metastatic Tumor Growth
Authors: Sepporta Maria-Vittoria , Praz Viviane , Bourloud Katia Balmas , Joseph Jean-Marc , Jauquier Nicolas , Riggi Nicolo’ , Nardou-Auderset Katya , Petit Audrey , Scoazec Jean-Yves , Sartelet Hervé , Renella Raffaele , Mühlethaler-Mottet Annick 
Published: March 2021

AbstractThe embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings suggest TWIST1 as novel therapeutic target in NB.
The plant circadian clock gene LHY influences Medicago truncatula nodulation
Authors: Achom M , Roy P , Lagunas B , Bonyadi-Pour R , Pardal AJ , Baxter L , Richmond B , Aschauer N , Fletcher E , Picot E , Rowson M , Blackwell J , Rich-Griffin C , Mysore KS , Wen J , Ott S , Carré IA , Gifford ML 
Published: March 2021

AbstractLegumes house nitrogen-fixing endosymbiotic rhizobia in specialized polyploid cells within root nodules, which are factories of metabolic activity. We discovered that the circadian clock-associated transcriptional factor LATE ELONGATED HYPOCOTYL (LHY) affects nodulation in Medicago truncatula. By carrying out expression analysis of transcripts over time in nodules we found that the clock enables coordinated control of metabolic and regulatory processes linked to nitrogen fixation. Rhythmic transcripts in root nodules include a subset of Nodule-specific Cysteine Rich peptides (NCRs) that have the LHY-bound conserved Evening Element in their promoters. Until now, studies have suggested that NCRs act to regulate bacteroid differentiation and keep the rhizobial population in check. However, these conclusions came from the study of a few members of this very large gene family that has complex diversified spatio-temporal expression. We suggest that rhythmic expression of NCRs may be important for temporal coordination of bacterial activity with the rhythms of the plant host, in order to ensure optimal symbiosis.HighlightsThe circadian clock-associated transcriptional factor LATE ELONGATED HYPOCOTYL (LHY) impacts on successful Medicago truncatula-rhizobial symbiosisThe plant clock coordinates rhythmic patterns of metabolic and regulatory activity in nodules and drives rhythmic expression of a subset of Nodule-specific Cysteine Rich (NCR) genes.Rhythmic expression of NCRs may be important for temporal coordination of bacterial activity with plant host rhythms to ensure optimal symbiosis.
NHE6-Depletion Corrects ApoE4-Mediated Synaptic Impairments and Reduces Amyloid Plaque Load
Authors: Pohlkamp Theresa , Xian Xunde , Wong Connie H , Durakoglugil Murat , Werthmann Gordon C , Saido Takaomi , Evers Bret M , White Charles L , Connor Jade , Hammer Robert E , Herz Joachim 
Published: March 2021

ABSTRACTApolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer’s disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger NHE6 restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of early endosomes caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect and reduces amyloid.
Metabolic-sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum
Authors: Reichenbach Alex , Clarke Rachel E , Stark Romana , Lockie Sarah Haas , Mequinion Mathieu , Reed Felicia , Rawlinson Sasha , Dempsey Harry , Sepehrizadeh Tara , DeVeer Michael , Munder Astrid C , Nunez-Iglesias Juan , Spanswick David C. , Mynatt Randall , Kravitz Alexxai V. , Dayas Christopher V. , Brown Robyn , Andrews Zane B. 
Published: March 2021

ABSTRACTHunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods. While hunger-sensing Agouti-related peptide (AgRP) neurons influence this process, whether metabolic detection of homeostatic state via metabolic sensing in AgRP neurons potentiates motivation through the midbrain dopamine system is unexplored. Here, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, as a model of impaired metabolic-sensing in AgRP neurons. We then tested the hypothesis that appropriate metabolic-sensing in AgRP neurons is required to increase food reward motivation by modulating accumbal or striatal dopamine release. Electrophysiological studies confirm that Crat deletion in AgRP neurons (KO) impairs normalex vivoglucose-sensing, andin vivophotometry experiments show that AgRP neurons in KO mice do not exhibit normal responses to repeated palatable food presentation and consumption, highlighting that this model is appropriate to test the hypothesis. Fiber photometry experiments, using the dopamine sensor GRAB-DA, revealed that impaired metabolic-sensing reduces acute dopamine release (seconds) in the nucleus accumbens, but not the dorsal striatum, to palatable food consumption and during operant responding. Positron electron tomography (PET) methods indicated that impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ∼30 minutes in the dorsal striatum but not the ventral striatum, suggesting a role for AgRP neurons to restrict a long term post-ingestive dopamine response in the dorsal striatum. Finally, impaired metabolic-sensing in AgRP neurons suppresses motivated operant responding for sucrose rewards. Notably, these behavioural effects are potentiated in the hungry state and therefore highlight that metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.
Grp78 alleviates sodium iodate-induced retinal cell injury in vivo and in vitro
Authors: Shuang Jiang , Yongpeng Guo , Ning Yi , Hongdan Li , Hua Liu 
Published: March 2021

AbstractObjectiveGlucose-regulated protein 78 (Grp78) has been regarded as a main member of the endoplasmic reticulum proteins, Grp78 could protect cells from apoptosis under stress conditions. However, whether Grp78 could protect retinal pigment epithelium (RPE) cells from oxidative injury and then protect retinas from morphological changes and functional abnormalities remain undetermined. Here, we try to explore the effect of Grp78 on retinal cell injury induced by sodium iodate in vivo and in vitro.MethodsTo investigate whether Grp78 has a protective effect on RPE injury in vitro, human retinal pigment epithelium (ARPE-19) cells were treated with sodium iodate. The cell proliferation, morphology, apoptosis and ROS production assays were detected. In vivo, We established sodium iodate-induced retinal injury model in mice by intravenous injection of sodium iodate into tail vein. After that, we examined the morphology and function of retina in mice by fundus photography, OCT and ERG. Finally, we removed the retina of mice for histological examination.ResultsGrp78 significantly inhibited sodium iodate-induced reactive oxygen species (ROS), and decreased apoptosis of RPE in vitro. Furthermore, Grp78 significantly decreased the apoptosis of retinal cells in vivo, resulting in the inhibition of morphological changes of retina, and improving the function of retina. The underlying mechanisms included inhibited caspase3 and Nos, and increased expression of Bcl2, thereby protecting RPE from SI-induced ROS and apoptosis.ConclusionGrp78 could reduce the injury of retinal cells induced by sodium iodate in vitro and in vivo. These findings suggested Grp78 may become a new therapeutic target for retinal injury in clinical practice.