bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML
Authors: Charlet Anne , Kappenstein Max , Keye Philip , Kläsener Kathrin , Endres Cornelia , Poggio Teresa , Gorantla Sivahari P. , Kreutmair Stefanie , Sänger Jana , Illert Anna L. , Miething Cornelius , Reth Michael , Duyster Justus , Rummelt Christoph , von Bubnoff Nikolas 
Published: November 2021

AbstractFLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta chain of IL-3, IL-5, and GM-CSF, and therefore examined its significance for FLT3-ITD-dependent oncogenic signaling and transformation. We discovered that FLT3-ITD directly binds to CSF2RB in AML cell lines and blasts isolated from AML patients. A knockdown of CSF2RB in FLT3-ITD positive AML cell lines as well as in a xenograft model decreased STAT5 phosphorylation, attenuated cell proliferation, and sensitized to FLT3 inhibition. Bone marrow from CSF2RB-deficient mice transfected with FLT3-ITD displayed decreased colony formation capacity and delayed disease onset together with increased survival upon transplantation into lethally irradiated mice. FLT3-ITD-dependent CSF2RB phosphorylation required phosphorylation of the FLT3 juxtamembrane domain at tyrosines 589 or 591, whereas the ITD insertion site and sequence were of no relevance. Our results demonstrate that CSF2RB participates in FLT3-ITD-dependent oncogenic signaling and transformation in vitro and in vivo. Thus, CSF2RB constitutes a rational treatment target in FLT3-ITD-positive AML.
Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
Authors: Gomez Juan L. , Bonaventura Jordi , Keighron Jacqueline , Wright Kelsey M. , Marable Dondre L. , Rodriguez Lionel A. , Lam Sherry , Carlton Meghan L. , Ellis Randall J. , Jordan Chloe J. , Bi Guo-hua , Solis Oscar , Pignatelli Marco , Bannon Michael J. , Xi Zheng-Xiong , Tanda Gianluigi , Michaelides Michael 
Published: November 2021

AbstractCocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+were dependent on the Zn2+transporter 3 (ZnT3), a neuronal Zn2+transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+deficiency in mice resulted in decreased striatal Zn2+content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+release and turnover/metabolism in the striatum, and that synaptically released Zn2+potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.
Association between maternal depression during pregnancy and newborn DNA methylation
Authors: Drzymalla Emily , Gladish Nicole , Koen Nastassja , Epstein Michael P. , Kobor Michael S. , Zar Heather J. , Stein Dan J. , Hüls Anke 
Published: November 2021

AbstractAround 15–65% of women globally experience depression during pregnancy, prevalence being particularly high in low- and middle-income countries. Prenatal depression has been associated with adverse birth and child development outcomes. DNA methylation (DNAm) may aid in understanding this association. In this project, we analyzed associations between prenatal depression and DNAm from cord blood from participants of the South African Drakenstein Child Health Study. We examined DNAm in an epigenome-wide association study (EWAS) of 248 mother-child pairs. DNAm was measured using the Infinium MethylationEPIC (N = 145) and the Infinium HumanMethylation450 (N = 103) arrays. Prenatal depression scores, obtained with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory-II (BDI-II), were analyzed as continuous and dichotomized variables. We used linear robust models to estimate associations between depression and newborn DNAm, adjusted for measured (smoking status, household income, sex, preterm birth, cell type proportions, and genetic principal components) and unmeasured confounding using Cate and Bacon algorithms. Bonferroni correction was used to adjust for multiple testing. DMRcate and dmrff were used to test for differentially methylated regions (DMRs). Differential DNAm was significantly associated with BDI-II variables, in cg16473797 (Δ beta = −1.10E-02, p = 6.87E-08), cg23262030 (Δ beta per BDI-II total IQR = 1.47E-03, p = 1.18E-07), and cg04859497 (Δ beta = −6.42E-02, p = 1.06E-09). Five DMRs were associated with at least two depression variables. Further studies are needed to replicate these findings and investigate their biological impact.
Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder
Authors: Doss Manoj K. , Považan Michal , Rosenberg Monica D. , Sepeda Nathan D. , Davis Alan K. , Finan Patrick H. , Smith Gwenn S. , Pekar James J. , Barker Peter B. , Griffiths Roland R. , Barrett Frederick S. 
Published: November 2021

AbstractPsilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.
RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages
Authors: Yang Qiudong , Zhao Wenhua , Chen Yuyi , Chen Yue , Shi Jiali , Qin Ran , Wang Hua , Wang Ruixia , Yuan Hua , Sun Wen 
Published: November 2021

AbstractNLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.
Biased activation of β2-AR/Gi/GRK2 signal pathway attenuated β1-AR sustained activation induced by β1-adrenergic receptor autoantibody
Authors: Chen Hao , Cao Ning , Wang Li , Wu Ye , Wei Haojie , Li Yuming , Zhang Youyi , Zhang Suli , Liu Huirong 
Published: November 2021

AbstractHeart failure is the terminal stage of many cardiac diseases, in which β1-adrenoceptor (β1-AR) autoantibody (β1-AA) has a causative role. By continuously activating β1-AR, β1-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β1-AR by β1-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β2-adrenoceptor (β2-AR) is involved in the regulation of β1-AR signaling. This research aimed to clarify the mechanism of the β1-AA-induced sustained activation of β1-AR and explore the role of the β2-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca2+ levels were examined to detect the activation of β1-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β1-AR. ICI118551 was used to assess β2-AR/Gi function in β1-AR sustained activation induced by β1-AA in vitro and in vivo. Monoclonal β1-AA derived from a mouse hybridoma could continuously activate β1-AR. β1-AA-restricted β1-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β1-AR signaling. β2-AR could promote β1-AR endocytosis, as demonstrated by overexpressing/interfering with β2-AR in HL-1 cells, whereas β1-AA inhibited the binding of β2-AR to β1-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β2-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β1-AR by β1-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β1-AA-positive mice. This study showed that β1-AA continuously activated β1-AR by inhibiting receptor endocytosis. Biased activation of the β2-AR/Gi/GRK2 signaling pathway could promote β1-AR endocytosis restricted by β1-AA, terminate signal transduction, and alleviate heart damage.
HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma
Authors: Tian Tian , Hong Fu , Wang Zhiwen , Hu Jiaru , Chen Ni , Lv Lei , Yi Qiyi 
Published: November 2021

AbstractLung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.
Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc
Authors: Matsuda Shinya , Schaefer Jonas V. , Mii Yusuke , Hori Yutaro , Bieli Dimitri , Taira Masanori , Plückthun Andreas , Affolter Markus 
Published: November 2021

AbstractHow morphogen gradients control patterning and growth in developing tissues remains largely unknown due to lack of tools manipulating morphogen gradients. Here, we generate two membrane-tethered protein binders that manipulate different aspects of Decapentaplegic (Dpp), a morphogen required for overall patterning and growth of the Drosophila wing. One is “HA trap” based on a single-chain variable fragment (scFv) against the HA tag that traps HA-Dpp to mainly block its dispersal, the other is “Dpp trap” based on a Designed Ankyrin Repeat Protein (DARPin) against Dpp that traps Dpp to block both its dispersal and signaling. Using these tools, we found that, while posterior patterning and growth require Dpp dispersal, anterior patterning and growth largely proceed without Dpp dispersal. We show that dpp transcriptional refinement from an initially uniform to a localized expression and persistent signaling in transient dpp source cells render the anterior compartment robust against the absence of Dpp dispersal. Furthermore, despite a critical requirement of dpp for the overall wing growth, neither Dpp dispersal nor direct signaling is critical for lateral wing growth after wing pouch specification. These results challenge the long-standing dogma that Dpp dispersal is strictly required to control and coordinate overall wing patterning and growth.
An siRNA-guided ARGONAUTE protein directs RNA polymerase V to initiate DNA methylation
Authors: Sigman Meredith J. , Panda Kaushik , Kirchner Rachel , McLain Lauren L. , Payne Hayden , Peasari John Reddy , Husbands Aman Y. , Slotkin R. Keith , McCue Andrea D. 
Published: November 2021

AbstractIn mammals and plants, cytosine DNA methylation is essential for the epigenetic repression of transposable elements and foreign DNA. In plants, DNA methylation is guided by small interfering RNAs (siRNAs) in a self-reinforcing cycle termed RNA-directed DNA methylation (RdDM). RdDM requires the specialized RNA polymerase V (Pol V), and the key unanswered question is how Pol V is first recruited to new target sites without pre-existing DNA methylation. We find that Pol V follows and is dependent on the recruitment of an AGO4-clade ARGONAUTE protein, and any siRNA can guide the ARGONAUTE protein to the new target locus independent of pre-existing DNA methylation. These findings reject long-standing models of RdDM initiation and instead demonstrate that siRNA-guided ARGONAUTE targeting is necessary, sufficient and first to target Pol V recruitment and trigger the cycle of RdDM at a transcribed target locus, thereby establishing epigenetic silencing.
MiR-571 affects the development and progression of liver fibrosis by regulating the Notch3 pathway
Authors: Cong Shuo , Liu Yongmei , Li Yi , Chen Yu , Chen Rui , Zhang Baofang , Yu Lei , Hu Yaxin , Zhao Xueke , Mu Mao , Cheng Mingliang , Huang Zhi 
Published: November 2021

AbstractExploring the expression of miR-571 in patients with liver fibrosis and its role in the progression of liver fibrosis. A total of 74 patients with liver fibrosis in our institution from September to December 2018 were collected for study, and the expression of miR-571, Notch3 and Jagged1 in patients with different progressions of liver fibrosis was determined by RT-PCR and Western blot analysis. Set up Notch3 up group and Notch3 down regulated group, RT-PCR and Western blot were used to determine the effect of Notch signaling on the expression of fibrogenic factors. CCK-8, cell scratch assays, Transwell assays, flow cytometry were used to determine the effect of miR-571 on LX-2 proliferation, migration, apoptosis in human stem stellate cells, and RT-PCR, Western blot assays were performed to determine the effect of miR-571 on the Notch3 signaling pathway and the expression of profibrogenic factors. miR-571, Notch3 and Jagged1 are up-regulated in patients with liver fibrosis and is associated with the progression of liver fibrosis. Notch3 signaling pathway can promote the expression of fibroblast in human hepatic stellate cells; miR-571 can inhibit the apoptosis of human hepatic stellate cells, promote cell proliferation and migration; up regulation of miR-571 can promote the expression of Notch3 and Jagged1, and up-regulation of miR-571 also promoted the expression of related fibroblasts. MiR-571 can promote the activation of human stem cell stellate cells and the expression of fibroblast related factors through Notch3 signaling pathway.
Spatial spillover effects from agriculture drive deforestation in Mato Grosso, Brazil
Authors: Kuschnig Nikolas , Cuaresma Jesús Crespo , Krisztin Tamás , Giljum Stefan 
Published: November 2021

AbstractDeforestation of the Amazon rainforest is a threat to global climate, biodiversity, and many other ecosystem services. In order to address this threat, an understanding of the drivers of deforestation processes is required. Spillover effects and factors that differ across locations and over time play important roles in these processes. They are largely disregarded in applied research and thus in the design of evidence-based policies. In this study, we model connectivity between regions and consider heterogeneous effects to gain more accurate quantitative insights into the inherent complexity of deforestation. We investigate the impacts of agriculture in Mato Grosso, Brazil, for the period 2006–2017 considering spatial spillovers and varying impacts over time and space. Spillovers between municipalities that emanate from croplands in the Amazon appear as the major driver of deforestation, with no direct effects from agriculture in recent years. This suggests a moderate success of the Soy Moratorium and Cattle Agreements, but highlights their inability to address indirect effects. We find that the neglect of the spatial dimension and the assumption of homogeneous impacts lead to distorted inference. Researchers need to be aware of the complex and dynamic processes behind deforestation, in order to facilitate effective policy design.
Genomic characterization between strains selected for death-feigning duration for avoiding attack of a beetle
Authors: Tanaka Keisuke , Sasaki Ken , Matsumura Kentarou , Yajima Shunsuke , Miyatake Takahisa 
Published: November 2021

AbstractPredator avoidance is an important behavior that affects the degree of adaptation of organisms. We compared the DNA variation of one of the predator-avoidance behaviors, the recently extensively studied "death-feigning behavior”, between the long strain bred for feigning death for a long time and the short strain bred for feigning death for a short time. To clarify how the difference in DNA sequences between the long and short strains corresponds to the physiological characteristics of the death-feigning duration at the transcriptome level, we performed comprehensive and comparative analyses of gene variants in Tribolium castaneum strains using DNA-resequencing. The duration of death feigning involves many gene pathways, including caffeine metabolism, tyrosine metabolism, tryptophan metabolism, metabolism of xenobiotics by cytochrome P450, longevity regulating pathways, and circadian rhythm. Artificial selection based on the duration of death feigning results in the preservation of variants of genes in these pathways in the long strain. This study suggests that many metabolic pathways and related genes may be involved in the decision-making process of anti-predator animal behavior by forming a network in addition to the tyrosine metabolic system, including dopamine, revealed in previous studies.
Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition
Authors: Handa Takaya , Mori Keita P. , Ishii Akira , Ohno Shoko , Kanai Yugo , Watanabe-Takano Haruko , Yasoda Akihiro , Kuwabara Takashige , Takahashi Nobuyuki , Mochizuki Naoki , Mukoyama Masashi , Yanagita Motoko , Yokoi Hideki 
Published: November 2021

AbstractNatriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.