Статті в журналах: "Nprl3"

1

Wei, Youheng, Brad Reveal, Weili Cai, and Mary A. Lilly. "The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster." G3 Genes|Genomes|Genetics 6, no. 12 (December 1, 2016): 3859–67. http://dx.doi.org/10.1534/g3.116.035337.

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Abstract TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionarily conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here, we characterize null mutants of the GATOR1 components nprl2, nprl3, and iml1 in Drosophila melanogaster. We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability. Consistent with increased TORC1 activity, GATOR1 mutants exhibit a cell autonomous increase in cell growth. Notably, escaper nprl2 and nprl3 mutant adults have a profound locomotion defect. In line with a nonautonomous role in the regulation of systemic metabolism, expressing the Nprl3 protein in the fat body, a nutrient storage organ, and hemocytes but not muscles and neurons rescues the motility of nprl3 mutants. Finally, we show that nprl2 and nprl3 mutants fail to activate autophagy in response to amino acid limitation and are extremely sensitive to both amino acid and complete starvation. Thus, in Drosophila, in addition to maintaining baseline levels of TORC1 activity, the GATOR1 complex has retained a critical role in the response to nutrient stress. In summary, the TORC1 inhibitor GATOR1 contributes to multiple aspects of the development and physiology of Drosophila.

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2

Van ’t Hof, Femke, and Eva Brilstra. "Focale epilepsie en de GATOR1 complex genen." Epilepsie, periodiek voor professionals 19, no. 2 (June 1, 2021): 11–13. http://dx.doi.org/10.54160/epilepsie.11027.

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Een monogene oorzaak bij focale epilepsie is minder zeldzaam dan vroeger werd gedacht. De meest voorkomende groep erfelijke, focale epilepsieën worden veroorzaakt door varianten in de GATOR1 complex genen (DEPDC5, NPRL2 en NPRL3), ook wel de ‘GATORopathieën’ genoemd. Er is steeds meer bekend over de verschillende ziekte-uitingen van deze aandoeningen, en zelfs over de consequenties voor behandeling. Dit maakt genetische diagnostiek belangrijk.

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Cheng, Yang, Jiadong Cai, Yuanyuan Fu, Congjing Feng, Yue Hao, and Youheng Wei. "Royal jelly attenuates metabolic defects in a Drosophila mutant with elevated TORC1 activity." Biology Open 9, no. 11 (October 9, 2020): bio054999. http://dx.doi.org/10.1242/bio.054999.

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ABSTRACTTarget of rapamycin complex 1 (TORC1) is a master regulator of cell metabolism, and its dysregulation has been linked to an array of pathologies, including cancer and age-related diseases. Nprl3, a component of GTPase-activating protein towards Rags complex 1 (GATOR1), inhibits TORC1 activity under nutrient scarcity status. The nprl3 mutant exhibits some metabolic defects due to hyper TORC1 activity in Drosophila. Royal jelly (RJ) is a honeybee-secreted product and plays an essential role in caste differentiation that requires TORC1 activity. RJ is also used as a health-benefit food for its potential roles on antioxidant and anti-aging. In this study, nprl3-mutant flies were used to measure the effect of RJ on metabolic modulation. Interestingly, RJ feeding significantly increased survival and decreased TORC1 activity in the nprl3 mutant. RJ feeding also ameliorated the abnormal reactive oxygen species (ROS) levels and energy status in the nprl3 mutant. The proteins in RJ were characterized to be the essential components in increasing nprl3 mutant viability. These findings suggest that RJ modulates some metabolic defects associated with elevated TORC1 activity and that the nprl3-mutant fly might be a useful tool for investigating the bioactive components of RJ in vivo.

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Miyata, Masato, Nynke Gillemans, Dorit Hockman, Jeroen A. A. Demmers, Jan-Fang Cheng, Jun Hou, Matti Salminen, et al. "An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells." Blood 136, no. 3 (July 16, 2020): 269–78. http://dx.doi.org/10.1182/blood.2020004826.

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Abstract The oxygen transport function of hemoglobin (HB) is thought to have arisen ∼500 million years ago, roughly coinciding with the divergence between jawless (Agnatha) and jawed (Gnathostomata) vertebrates. Intriguingly, extant HBs of jawless and jawed vertebrates were shown to have evolved twice, and independently, from different ancestral globin proteins. This raises the question of whether erythroid-specific expression of HB also evolved twice independently. In all jawed vertebrates studied to date, one of the HB gene clusters is linked to the widely expressed NPRL3 gene. Here we show that the nprl3-linked hb locus of a jawless vertebrate, the river lamprey (Lampetra fluviatilis), shares a range of structural and functional properties with the equivalent jawed vertebrate HB locus. Functional analysis demonstrates that an erythroid-specific enhancer is located in intron 7 of lamprey nprl3, which corresponds to the NPRL3 intron 7 MCS-R1 enhancer of jawed vertebrates. Collectively, our findings signify the presence of an nprl3-linked multiglobin gene locus, which contains a remote enhancer that drives globin expression in erythroid cells, before the divergence of jawless and jawed vertebrates. Different globin genes from this ancestral cluster evolved in the current NPRL3-linked HB genes in jawless and jawed vertebrates. This provides an explanation of the enigma of how, in different species, globin genes linked to the same adjacent gene could undergo convergent evolution.

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5

Ryu, Chang Soo, Jinkun Bae, In Jai Kim, Jinkwon Kim, Seung Hun Oh, Ok Joon Kim, and Nam Keun Kim. "MPG and NPRL3 Polymorphisms Are Associated with Ischemic Stroke Susceptibility and Post-Stroke Mortality." Diagnostics 10, no. 11 (November 13, 2020): 947. http://dx.doi.org/10.3390/diagnostics10110947.

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Ischemic stroke is a complicated disease which is affected by environmental factors and genetic factors. In this field, various studies using whole-exome sequencing (WES) have focused on novel and linkage variants in diverse diseases. Thus, we have investigated the various novel variants, which focused on their linkages to each other, in ischemic stroke. Specifically, we analyzed the N-methylpurine DNA glycosylase (MPG) gene, which plays an initiating role in DNA repair, and the nitrogen permease regulator-like 3 (NPRL3) gene, which is involved in regulating the mammalian target of rapamycin pathway. We took blood samples of 519 ischemic stroke patients and 417 controls. Genetic polymorphisms were detected by polymerase chain reaction (PCR), real-time PCR, and restriction fragment length polymorphism (RFLP) analysis. We found that two NPRL3 polymorphisms (rs2541618 C>T and rs75187722 G>A), as well as the MPG rs2562162 C>T polymorphism, were significantly associated with ischemic stroke. In Cox proportional hazard regression models, the MPG rs2562162 was associated with the survival of small-vessel disease patients in ischemic stroke. Our study showed that NPRL3 and MPG polymorphisms are associated with ischemic stroke prevalence and ischemic stroke survival. Taken together, these findings suggest that NPRL3 and MPG genotypes may be useful clinical biomarkers for ischemic stroke development and prognosis.

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6

Wei, Y., and M. A. Lilly. "The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila." Cell Death & Differentiation 21, no. 9 (May 2, 2014): 1460–68. http://dx.doi.org/10.1038/cdd.2014.63.

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7

Mastrangelo, Mario, Chiara Commone, Carlo Greco, and Vincenzo Leuzzi. "TSC1 as a Novel Gene for Sleep-Related Hypermotor Epilepsy: A Child with a Mild Phenotype of Tuberous Sclerosis." Neuropediatrics 52, no. 02 (February 12, 2021): 146–49. http://dx.doi.org/10.1055/s-0041-1722881.

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AbstractSleep-related hypermotor epilepsy (SHE) is a rare syndrome that presents with hyperkinetic asymmetric tonic/dystonic seizures with vegetative signs, vocalization, and emotional facial expression, mainly during light non-rapid eye movement sleep stages. The role of various genes (CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, NPRL2, NPRL3, and PRIMA1) has previously been reported, though genetic etiology is assessed in less than 10% of cases. We report the case of a 5-year-old female carrying the TSC1 variant c.843del p.(Ser282Glnfs*36) who presented with a mild phenotype of tuberous sclerosis, including carbamazepine-responsive SHE, normal neurocognitive functioning, hypomelanotic macules, no abnormalities outside the central nervous system, and tubers at neuroimaging. The presented case extends the list of SHE-related genes to include TSC1, thus suggesting a central pathogenic role of mammalian target of rapamycin (mTOR) cascade dysfunction in SHE and introducing a possible use of mTOR inhibitors in this epileptic syndrome.

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Bennett, Mark F., Michael S. Hildebrand, Sayaka Kayumi, Mark A. Corbett, Sachin Gupta, Zimeng Ye, Michael Krivanek, et al. "Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy." Neurology Genetics 8, no. 1 (January 25, 2022): e0652. http://dx.doi.org/10.1212/nxg.0000000000000652.

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Background and ObjectivesThe 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways.MethodsWe searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed.ResultsExome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C>T; p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother.DiscussionWe identify a pathogenic germline mTOR pathway variant (NPRL3) and a somatic variant (WNT2) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.

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9

Kowalczyk, Monika S., Jim R. Hughes, Christian Babbs, Luis Sanchez-Pulido, Dorota Szumska, Jacqueline A. Sharpe, Jacqueline A. Sloane-Stanley, et al. "Nprl3 is required for normal development of the cardiovascular system." Mammalian Genome 23, no. 7-8 (April 27, 2012): 404–15. http://dx.doi.org/10.1007/s00335-012-9398-y.

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10

Yuskaitis, Christopher J., Leigh-Ana Rossitto, Sarika Gurnani, Elizabeth Bainbridge, Annapurna Poduri, and Mustafa Sahin. "Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice." Human Molecular Genetics 28, no. 17 (May 17, 2019): 2952–64. http://dx.doi.org/10.1093/hmg/ddz123.

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Abstract DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations. Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy. Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout mice exhibit seizures and neuronal mTORC1 hyperactivation. It is not known if Depdc5cc+ mice have a hyperactivity/anxiety phenotype, die early from terminal seizures or whether mTOR inhibitors rescue DEPDC5-related seizures and associated comorbidities. Herein, we report that Depdc5cc+ mice were hyperactive in open-field testing but did not display anxiety-like behaviors on the elevated-plus maze. Unlike many other mTOR-related models, Depdc5cc+ mice had minimal epileptiform activity and rare seizures prior to seizure-induced death, as confirmed by video-EEG monitoring. Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity. Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size. Loss of Depdc5 led to a decrease in the other GATOR1 protein levels (NPRL2 and NPRL3). Rapamycin failed to rescue GATOR1 protein levels but rather rescued downstream mTORC1 hyperactivity as measured by phosphorylation of S6. Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans.

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Krenn, Martin, Matias Wagner, Christoph Hotzy, Elisabeth Graf, Sandrina Weber, Theresa Brunet, Bettina Lorenz-Depiereux, et al. "Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes." Journal of Medical Genetics 57, no. 9 (February 21, 2020): 624–33. http://dx.doi.org/10.1136/jmedgenet-2019-106658.

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BackgroundThe genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.Methods112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE.ResultsES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants.ConclusionThis study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.

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Vawter-Lee, Marissa, David N. Franz, Christine E. Fuller, and Hansel M. Greiner. "Clinical Letter: A case report of targeted therapy with sirolimus for NPRL3 epilepsy." Seizure 73 (December 2019): 43–45. http://dx.doi.org/10.1016/j.seizure.2019.10.007.

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Abumurad, Sumayyah, Naoum P. Issa, Shasha Wu, Sandra Rose, Yasar Taylan Esengul, Douglas Nordli, Peter C. Warnke, and James X. Tao. "Laser interstitial thermal therapy for NPRL3-related epilepsy with multiple seizure foci: A case report." Epilepsy & Behavior Reports 16 (2021): 100459. http://dx.doi.org/10.1016/j.ebr.2021.100459.

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Chandrasekar, Indira, Anne Tourney, Kamela Loo, Jason Carmichael, Kiely James, Katarzyna A. Ellsworth, David Dimmock, and Maries Joseph. "Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report." American Journal of Medical Genetics Part A 185, no. 7 (March 22, 2021): 2126–30. http://dx.doi.org/10.1002/ajmg.a.62185.

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15

Iffland, Philip H., Marianna Baybis, Allan E. Barnes, Richard J. Leventer, Paul J. Lockhart, and Peter B. Crino. "DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons." Neurobiology of Disease 114 (June 2018): 184–93. http://dx.doi.org/10.1016/j.nbd.2018.02.013.

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Bertuzzi, Maria, Dave Tang, Raffaella Calligaris, Christina Vlachouli, Sara Finaurini, Remo Sanges, Stefano Goldwurm, et al. "A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number‐dependent manner." Human Mutation 41, no. 4 (January 31, 2020): 807–24. http://dx.doi.org/10.1002/humu.23974.

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Lee, Wei Shern, Sarah E. M. Stephenson, Kate Pope, Greta Gillies, Wirginia Maixner, Emma Macdonald-Laurs, Duncan MacGregor, et al. "Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy." Neurology 95, no. 18 (August 26, 2020): e2542-e2551. http://dx.doi.org/10.1212/wnl.0000000000010670.

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ObjectiveTo determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.MethodsTargeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.ResultsBrain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri.ConclusionsBOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.

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Milton, Jacqueline N., Helen Rooks, Emma Drasar, Elizabeth L. McCabe, Clinton T. Baldwin, Efthymia Melista, Victor R. Gordeuk, et al. "Genetic Determinants of Hemolysis in Sickle Cell Anemia." Blood 120, no. 21 (November 16, 2012): 2104. http://dx.doi.org/10.1182/blood.v120.21.2104.2104.

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Abstract Abstract 2104 The phenotype of sickle cell disease is caused by sickle vasoocclusion and hemolytic anemia. Hemolysis in sickle cell anemia has been associated with complications that were presumed to result in part from vascular nitric oxide depletion due to scavenging by free plasma hemoglobin. Though plasma hemoglobin is a specific marker of intravascular hemolysis and red cell survival studies are the most definitive method of establishing the extent of hemolysis, these tests are rarely done and not available in large cohorts. However, the intensity of hemolysis can be estimated by the reticulocyte count, lactate dehydrogenase (LDH), aspartate aminotransaminase (AST) and bilirubin levels, all of which are commonly measured in cohort studies, although none of which is specific for hemolysis. We previously reported the results of a genome-wide association study (GWAS) of hemolysis where we used as a phenotype a new measure of the rate of intravascular hemolysis appropriate for cohort studies and GWAS. Using a principal component analysis of the commonly measured markers of hemolysis we derived a hemolytic score and found that the top SNPs associated with this score included a variant located in the first intron of NPRL3 (rs7203560; chr16p13.3, p=6.04×10−07) This result was replicated in two additional cohorts of 549 and 296 patients. We also established that while rs7203560 was associated with the ∝3.7 thalassemia gene deletion, when adjusted for HbF and ∝ thalassemia the association of NPRL3 with the hemolytic score remained significant (p=0.00375) and this association was also significant when examining only cases without ∝ thalassemia (p=0.02463). To further validate these results we studied 213 additional adult sickle cell anemia patients from King's College Hospital, London, UK. The mean age of these patients was 33 years. None had been treated with hydroxyurea and lab parameters obtained 3 months after, if transfused. Patients had similar clinical characteristics. The hemolytic score was calculated by using principal component analysis of the same markers of hemolysis. The SNPs associated with the hemolytic score in the primary study were genotyped in this cohort using TaqMan SNP genotyping assays according to standard Applied Biosystems protocol and their association with the derived hemolytic score studies using the same additive genetic model. The SNP rs7203560 replicated the association with hemolytic score (p= 0.03674) in this cohort. To examine the linkage disequilibrium (LD) structure of the region, we looked for conserved sequences in the α- globin cluster in multiple divergent species using the Basic Local Alignment Sequencing Tool (BLAST) to identify the approximate locations of the hypersensitive sites that are the major α-globin gene regulatory elements. On examination of the LD structure of SNPs in these regions with rs7203560, we found that rs7203560 was in LD with several SNPs located in and near the hypersensitive sites including rs2238368 (D'=1), rs2541612 (D'=0.89) and rs3331107 (D'=0.61). We hypothesize that rs7203560 is a marker for one or more variants in the major α-globin gene regulatory elements that down-regulate α-globin gene expression and cause a mild α thalassemia-like effect. In sickle cell anemia, perhaps by independently down-regulating expression of the α-globin genes, variants of the major ∝-globin gene regulatory loci reduce HbS concentration, lessen the polymerization potential of deoxy sickle hemoglobin and therefore retard hemolysis. Disclosures: No relevant conflicts of interest to declare.

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Milton, Jacqueline N., Paola Sebastiani, Yingze Zhang, Mehdi Nouraie, Janet Lee, Clinton T. Baldwin, Xuejun Zhao, et al. "Clinical and Genetic Variability of Red Blood Cell Hemolysis in Sickle Cell Anemia." Blood 118, no. 21 (November 18, 2011): 1077. http://dx.doi.org/10.1182/blood.v118.21.1077.1077.

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Abstract Abstract 1077 Intravascular hemolysis is an important pathological mechanism underlying some complications of sickle cell disease and other hemolytic anemias. Hemolysis contributes to endothelial dysfunction, pulmonary and systemic vasculopathy, and platelet and hemostatic activation via nitric oxide catabolism by plasma hemoglobin and arginine catabolism by red blood cell arginase. Little is known about the molecular mechanisms of hemolysis and how the propensity of erythrocytes to hemolyze is modulated. Hemoglobin F concentration and the presence of ∝ thalassemia affect the level of hemolysis but it is likely that other genes and their products are also important. We hypothesize that genetic variation, much of which is outside the β-globin gene-like cluster, underlies the susceptibility of erythrocytes to hemolyze in response to diverse disease stressors. We first characterized hemolysis by creating a principal component analysis (PCA) of age-adjusted values for LDH, AST, reticulocyte count and total bilirubin, but not hemoglobin concentration, to develop a hemolytic component that reflects shared variability among markers. The development of such a component helps to resolve the problem of dealing with correlated predictors in multivariate analyses and confounding variables such as site, and it permits for adjustment for the degree of anemia. To validate the PCA, we measured the plasma hemoglobin levels and red cell microparticle levels in the first and fourth quartile of PCA intensity of hemolysis in 118 HbS-only patients without detectable HbA, from the Walk-PHASST cohort We observed a highly significant increase in plasma hemoglobin (p<0.0001) and red cell microparticles (p=0.0004) based on PCA quartile. Despite the small sample size of this validating cohort we reproduced significant associations between high hemolytic rate and the subphentypes of low arterial oxygen saturation, high pulse pressure, leg ulcers, TRV, high NT-proBNP levels, and low 6-minute walk test distance. More patients with ∝ thalassemia and more females were present in the lower hemolytic index quartile (p=0.006). The hemolytic index and its individual components were then used as phenotypes in genome-wide association studies (GWAS) in the CSSCD (Cooperative Study of Sickle Cell Disease) and walk-PHaSST cohorts to discover novel genes that might be associated with hemolysis. As further validation of our approach using PCA stratification, patients in the quartile with the lowest hemolytic index from the CSSCD also had a much higher prevalence of ∝ thalassemia than patients within the highest quartile of hemolytic index (p=2.2E-16). We first examined 1117 cases from the CSSCD and found 303 SNPs, 265 with a MAF >0.05, that reached a threshold of significance of p<5E-4. For replication, we examined these SNPs in the Walk-PHASST cohort. Eight SNPs replicated with the same effects in a GWAS in 449 subjects from Walk-PHAAST and p-value<0.01. Of the 8 SNPs that replicated, 4 SNPs were in olfactory receptor (OR) genes on chromosome (chr) 11p; OR51L2 (rs7948471, rs7938426. rs1391617), and OR51L1 (rs2445284). Several of these SNPs were also associated with HbF in previous GWAS analyses. Polymorphisms in the OR gene cluster upstream of HBG might modulate HbF levels by altering chromatin structure within the HBB globin gene-like cluster. One SNP in an intron of NPRL3 (rs7203566) on chr16p is ∼34 kb upstream from a SNP causing ∝ thalassemia. In CSSCD cases there was an association of SNPs in NPRL3 with reticulocytes (p=5.1E-0006) and LDH (p=0.0003). In silico analysis did not predict any function for this SNP. Genetic studies to discover new biologic modifiers of hemolysis will help to identify critical molecular determinants of hemolysis for functional studies, to develop new disease severity biomarkers, and to suggest candidate therapies for some common human diseases with intravascular hemolysis. We anticipate that our studies will identify genetic variants enriched in the African-American population primarily determined by the evolved human response to endemic malaria infection. These studies are expected to broadly impact many human diseases and blood banking by providing genomic markers of susceptibility to hemolytic anemia, red cell storage stability and transfusion risk, and insights into novel strategies to reduce anemia and to enhance red blood cell storage and post-transfusion erythrocyte recovery. Disclosures: Gladwin: Patents filed related to treating hemolysis.: Patents & Royalties.

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Rahman, Raphia K., Samuel B. Tomlinson, Joshua Katz, Kathleen Galligan, Peter J. Madsen, Alexander M. Tucker, Sudha Kilaru Kessler, and Benjamin C. Kennedy. "Stereoelectroencephalography before 2 years of age." Neurosurgical Focus 53, no. 4 (October 2022): E3. http://dx.doi.org/10.3171/2022.7.focus22336.

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OBJECTIVE Stereoelectroencephalography (SEEG) is a widely used technique for localizing seizure onset zones prior to resection. However, its use has traditionally been avoided in children under 2 years of age because of concerns regarding pin fixation in the immature skull, intraoperative and postoperative electrode bolt security, and stereotactic registration accuracy. In this retrospective study, the authors describe their experience using SEEG in patients younger than 2 years of age, with a focus on the procedure’s safety, feasibility, and accuracy as well as surgical outcomes. METHODS A retrospective review of children under 2 years of age who had undergone SEEG while at Children’s Hospital of Philadelphia between November 2017 and July 2021 was performed. Data on clinical characteristics, surgical procedure, imaging results, electrode accuracy measurements, and postoperative outcomes were examined. RESULTS Five patients younger than 2 years of age underwent SEEG during the study period (median age 20 months, range 17–23 months). The mean age at seizure onset was 9 months. Developmental delay was present in all patients, and epilepsy-associated genetic diagnoses included tuberous sclerosis (n = 1), KAT6B (n = 1), and NPRL3 (n = 1). Cortical lesions included tubers from tuberous sclerosis (n = 1), mesial temporal sclerosis (n = 1), and cortical dysplasia (n = 3). The mean number of placed electrodes was 11 (range 6–20 electrodes). Bilateral electrodes were placed in 1 patient. Seizure onset zones were identified in all cases. There were no SEEG-related complications, including skull fracture, electrode misplacement, hemorrhage, infection, cerebrospinal fluid leakage, electrode pullout, neurological deficit, or death. The mean target point error for all electrodes was 1.0 mm. All patients proceeded to resective surgery, with a mean follow-up of 21 months (range 8–53 months). All patients attained a favorable epilepsy outcome, including Engel class IA (n = 2), IC (n = 1), ID (n = 1), and IIA (n = 1). CONCLUSIONS SEEG can be safely, accurately, and effectively utilized in children under age 2 with good postoperative outcomes using standard SEEG equipment. With minimal modification, this procedure is feasible in those with immature skulls and guides the epilepsy team’s decision-making for early and optimal treatment of refractory epilepsy through effective localization of seizure onset zones.

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Lund, Mette K., Tracy L. Kress, and Christine Guthrie. "Autoregulation of Npl3, a Yeast SR Protein, Requires a Novel Downstream Region and Serine Phosphorylation." Molecular and Cellular Biology 28, no. 11 (April 7, 2008): 3873–81. http://dx.doi.org/10.1128/mcb.02153-07.

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ABSTRACT Npl3 is an SR-like protein with documented roles in mRNA export and transcription termination. Maintaining appropriate levels of Npl3 protein is critical for cell survival. Here we show that Npl3 negatively regulates its own expression via modulation of its mRNA levels. By creating gene chimeras, we demonstrate that the region downstream of the coding sequence of Npl3 is necessary and sufficient to confer regulation. The use of different polyadenylation sites in this region results in at least two stable RNAs; read-through of these sites causes the formation of 3′-extended RNAs that are highly unstable and therefore largely unproductive. Increasing the amount of Npl3 protein promotes read-through. Notably, the loss of Npl3 phosphorylation promotes the use of the productive polyadenylation sites, resulting in elevated levels of Npl3 protein. We propose that proper levels of Npl3 protein are achieved by a negative feedback loop in which phosphorylated Npl3 suppresses efficient recognition of the productive processing signals in its own transcript.

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Kurrle, Nina, Frank Schnütgen, Juliana Heidler, Ina Poser, Frank Wempe, Diego Yepes, Ilka Wittig, et al. "Exploring the Function of Sestrin/Gator As Novel Regulators of Hematopoiesis." Blood 128, no. 22 (December 2, 2016): 1484. http://dx.doi.org/10.1182/blood.v128.22.1484.1484.

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Abstract The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that responds to multiple environmental cues such as reactive oxygen species (ROS) and thereby regulates many fundamental biological processes including cell growth and autophagy. mTOR is found in two distinct multiprotein complexes, mTORC1 and mTORC2, of which mTORC1 has been established to play an important role in the regulation of hematopoiesis. For example, mTORC1 inhibition, combined with activation of canonical Wnt-signaling, was shown to increase long term repopulating (LT)-HSC self-renewal, whereas its activation depletes LT-HSCs. The activity of mTORC1 is tightly controlled by multiple layers of upstream regulators, including the recently discovered GTPase activating protein (GAP) activity towards Rags (GATOR) complex, which is an AMP-Kinase/Tuberous sclerosis complex (TSC)-independent mTORC1 inhibitor induced by amino acid deprivation. GATOR consists of two subcomplexes, GATOR1 and GATOR2, whereby GATOR2 inhibits GATOR1. Inactivation of GATOR2 prevents mTORC1 activation by amino acids, whereas inactivation of GATOR1 constitutively activates mTORC1. Sestrins (Sesn1, Sesn2 and Sesn3) are a family stress-inducible, redox-sensitive proteins that are involved in cellular- or organism-level adaptation to diverse metabolic challenges. They have been identified as direct interactors of GATOR2 and shown to inhibit mTORC1 by preventing GATOR2 from inhibiting GATOR1 in presence of amino acids. In quantitative affinity purification-mass spectrometry (AP-MS) and coimmunoprecipitation experiments with HeLa- and mouse embryonic stem cells harboring in situ GFP-tagged Sesn2, WDR59 and NPRL3 alleles, we could confirm the Sesn2/GATOR interaction under nearly physiological conditions. To analyze the function of Sestrin/GATOR during hematopoiesis in more detail, we isolated Lin- Sca+ hematopoietic cells from the bone marrow of Sesn2-/- mice and performed serial replating experiments and competitive hematopoietic repopulation experiments in lethally irradiated mice and observed that Sesn2-/- progenitor cells proliferate significantly faster than their wild type counterparts albeit only during the initial engraftment phase. At later stages, the wild type cells took over, exceeding the Sesn2-/- cells by 3-4 fold in peripheral blood, bone marrow and spleen three months after transplantation. This suggests that the increased proliferative potential of Sesn2-/- progenitor cells leads to a depletion of the LT-HSC pool, strikingly resembling the phenotype of activated mTORC1. Disclosures No relevant conflicts of interest to declare.

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Sandhu, Rima, Aniketa Sinha, and Ben Montpetit. "The SR-protein Npl3 is an essential component of the meiotic splicing regulatory network in Saccharomyces cerevisiae." Nucleic Acids Research 49, no. 5 (February 12, 2021): 2552–68. http://dx.doi.org/10.1093/nar/gkab071.

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Abstract The meiotic gene expression program in Saccharomyces cerevisiae involves regulated splicing of meiosis-specific genes via multiple splicing activators (e.g. Mer1, Nam8, Tgs1). Here, we show that the SR protein Npl3 is required for meiotic splicing regulation and is essential for proper execution of the meiotic cell cycle. The loss of Npl3, though not required for viability in mitosis, caused intron retention in meiosis-specific transcripts, inefficient meiotic double strand break processing and an arrest of the meiotic cell cycle. The targets of Npl3 overlapped in some cases with other splicing regulators, while also having unique target transcripts that were not shared. In the absence of Npl3, splicing defects for three transcripts (MER2, HOP2 and SAE3) were rescued by conversion of non-consensus splice sites to the consensus sequence. Methylation of Npl3 was further found to be required for splicing Mer1-dependent transcripts, indicating transcript-specific mechanisms by which Npl3 supports splicing. Together these data identify an essential function for the budding yeast SR protein Npl3 in meiosis as part of the meiotic splicing regulatory network.

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Kita, Shunbun, Hitoshi Nishizawa, Yosuke Okuno, Masaki Tanaka, Atsutaka Yasui, Morihiro Matsuda, Yukio Yamada, and Iichiro Shimomura. "Competitive binding of musclin to natriuretic peptide receptor 3 with atrial natriuretic peptide." Journal of Endocrinology 201, no. 2 (February 20, 2009): 287–95. http://dx.doi.org/10.1677/joe-08-0551.

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Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. Musclin contains a region homologous to natriuretic peptides (NPs). This study investigated the interaction between musclin and NP receptors (NPRs). Musclin specifically bound to NPR3, but not to NPR1 or NPR2. Musclin and atrial natriuretic peptide (ANP) competed for binding to NPR3. We conducted binding assays using various synthetic musclin peptides and mutant musclin proteins. The first NP-homologous region in musclin (88LDRL91) and the second homologous region (117MDRI120) were responsible cooperatively for high-affinity binding to NPR3. The first NP-homologous region was more importantly associated with binding to NPR3, than the second homologous region. The competitive nature of musclin with ANP for the natriuretic clearance receptor NPR3 was also confirmed in vivo. We conclude that musclin binds to NPR3 competitively with ANP and may affect ANP concentrations in a local or systemic manner.

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25

Zeng, Yang, Xiao-Bo Shi, Zheng-Yong Yuan, Mao Ye, Li Jiang, Zhi-Xiong Chen, Jing Xiong, and Wei Tang. "Biological characteristics of renal cancer cells after CTP-mediated cancer suppressor gene NPRL2 protein treatment." Biological Chemistry 397, no. 11 (November 1, 2016): 1163–71. http://dx.doi.org/10.1515/hsz-2016-0143.

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Abstract Nitrogen permease regulator like-2 (NPRL2) has been proved to be a useful suppressor gene in treating many cancers containing renal cancer based on experiments. Transgenic technology which transfect exogenous NPRL2 gene into cancer cell was used in these experiments. However, this technology has defects, such as gene mutation and loss. Cytoplasmic transduction peptide (CTP) can be used to avoid these defects because it can directly mediate proteins to penetrate cell membrane and specifically locate in cytoplasm. In this article, CTP was used to directly mediate NPRL2 protein into the renal cancer cell line 786-O, then cell proliferation was detected by the CCK-8 method, cell cycle and apoptosis were detected by flow cytometry, cell invasion and migration ability were detected by the Transwell assay. Bcl-xl, Cyt-c and caspase-3 were detected by real-time fluorescent quantitative PCR and Western blot for the analysis of the related mechanism. The result showed that CTP successfully mediated NPRL2 protein into renal cancer cells and the growth of cells was significantly inhibited. The mechanism may be NPRL2 down-regulating the expression of Bcl-xl which can up-regulate Cyt-c and further activate caspase-3, and then a cascade reaction is caused for cell apoptosis on the classic mitochondrial apoptosis pathway.

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Henry, Michael, Christina Z. Borland, Mark Bossie, and Pamela A. Silver. "Potential RNA Binding Proteins in Saccharomyces cerevisiae Identified as Suppressors of Temperature-Sensitive Mutations in NPL3." Genetics 142, no. 1 (January 1, 1996): 103–15. http://dx.doi.org/10.1093/genetics/142.1.103.

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The NPL3 gene of the yeast Saccharomyces cerevisiae encodes a protein with similarity to heterogeneous nuclear ribonucleoproteins (hnRNPs). Npl3p has been implicated in many nuclear-related events including RNA export, protein import, and rRNA processing. Several temperature-sensitive alleles of NPL3 have been isolated. We now report the sequence of these alleles. For one allele, npl3-1, four complementation groups of suppressors have been isolated. The cognate genes for the two recessive mutants were cloned. One of these is the previously known RNA15, which, like NPL3, also encodes a protein with similarity to the vertebrate hnRNP A/B protein family. The other suppressor corresponds to a newly defined gene we term HRP1, which also encodes a protein with similarity to the hnRNP A/B proteins of vertebrates. Mutations in HRP1 suppress all npl3 temperature-sensitive alleles but do not bypass an npl3 null allele. We show that HRP1 is essential for cell growth and that the corresponding protein is located in the nucleus. The discovery of two hnRNP homologues that can partially suppress the function of Npl3p, also an RNA binding protein, will be discussed in terms of the possible roles for Npl3p in RNA metabolism.

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Bossie, M. A., C. DeHoratius, G. Barcelo, and P. Silver. "A mutant nuclear protein with similarity to RNA binding proteins interferes with nuclear import in yeast." Molecular Biology of the Cell 3, no. 8 (August 1992): 875–93. http://dx.doi.org/10.1091/mbc.3.8.875.

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We have isolated mutants of the yeast Saccharomyces cerevisiae that are defective in localization of nuclear proteins. Chimeric proteins containing the nuclear localization sequence from SV40 large T-antigen fused to the N-terminus of the mitochondrial F1 beta-ATPase are localized to the nucleus. Npl (nuclear protein localization) mutants were isolated by their ability to grow on glycerol as a consequence of no longer exclusively targeting SV40-F1 beta-ATPase to the nucleus. All mutants with defects in localization of nucleolar proteins and histones are temperature sensitive for growth at 36 degrees C. Seven alleles of NPL3 and single alleles of several additional genes were isolated. NPL3 mutants were studied in detail. NPL3 encodes a nuclear protein with an RNA recognition motif and similarities to a family of proteins involved in RNA metabolism. Our genetic analysis indicates that NPL3 is essential for normal cell growth; cells lacking NPL3 are temperature sensitive for growth but do not exhibit a defect in localization of nuclear proteins. Taken together, these results indicate that the mutant forms of Npl3 protein isolated by this procedure are interfering with nuclear protein uptake in a general manner.

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Flach, J., M. Bossie, J. Vogel, A. Corbett, T. Jinks, D. A. Willins, and P. A. Silver. "A yeast RNA-binding protein shuttles between the nucleus and the cytoplasm." Molecular and Cellular Biology 14, no. 12 (December 1994): 8399–407. http://dx.doi.org/10.1128/mcb.14.12.8399-8407.1994.

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RNA-binding proteins have been suggested to move in association with RNA as it leaves the nucleus. The NPL3 gene of the yeast Saccharomyces cerevisiae encodes in nuclear protein with consensus RNA-binding motifs and similarity to heterogeneous nuclear ribonucleoproteins and members of the S/R protein family. We show that although Npl3 is located in the nucleus, it can shuttle between nuclei in yeast heterokaryons. In contrast, other nucleus-targeted proteins do not leave the nucleus under similar conditions. Mutants missing the RNA-binding motifs or the N terminus are still capable of shuttling in and out of the nucleus. Npl3 mutants missing the C terminus fail to localize to the nucleus. Overproduction of Npl3 in wild-type cells shows cell growth. This toxicity depends on the presence of series of unique repeats in the N terminus and localization to the nucleus. We suggest that the properties of Npl3 are consistent with it being involved in export of RNAs from the nucleus.

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Flach, J., M. Bossie, J. Vogel, A. Corbett, T. Jinks, D. A. Willins, and P. A. Silver. "A yeast RNA-binding protein shuttles between the nucleus and the cytoplasm." Molecular and Cellular Biology 14, no. 12 (December 1994): 8399–407. http://dx.doi.org/10.1128/mcb.14.12.8399.

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RNA-binding proteins have been suggested to move in association with RNA as it leaves the nucleus. The NPL3 gene of the yeast Saccharomyces cerevisiae encodes in nuclear protein with consensus RNA-binding motifs and similarity to heterogeneous nuclear ribonucleoproteins and members of the S/R protein family. We show that although Npl3 is located in the nucleus, it can shuttle between nuclei in yeast heterokaryons. In contrast, other nucleus-targeted proteins do not leave the nucleus under similar conditions. Mutants missing the RNA-binding motifs or the N terminus are still capable of shuttling in and out of the nucleus. Npl3 mutants missing the C terminus fail to localize to the nucleus. Overproduction of Npl3 in wild-type cells shows cell growth. This toxicity depends on the presence of series of unique repeats in the N terminus and localization to the nucleus. We suggest that the properties of Npl3 are consistent with it being involved in export of RNAs from the nucleus.

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30

Singleton, D. R., S. Chen, M. Hitomi, C. Kumagai, and A. M. Tartakoff. "A yeast protein that bidirectionally affects nucleocytoplasmic transport." Journal of Cell Science 108, no. 1 (January 1, 1995): 265–72. http://dx.doi.org/10.1242/jcs.108.1.265.

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We have identified a temperature-sensitive mutant of Saccharomyces cerevisiae (npl3) that accumulates polyadenylated RNA in the nucleus at 37 degrees C, as judged by in situ hybridization. The strong nuclear signal is not simply due to increased cytoplasmic turnover of mRNA, as reincubation at 37 degrees C with an RNA polymerase inhibitor shows no diminution in the in situ signal. Over several hours at 37 degrees C, the average poly(A) tail length increases and a characteristic ultrastructural alteration of the nucleoplasm occurs. Cloning and sequencing indicate that the corresponding gene is NPL3/NOP3, which codes for a nucleolar/nuclear protein implicated in protein import into the nucleus (Bossie et al. (1992). Mol. Biol. Cell 3, 875–893) and in rRNA maturation (Russell and Tollervey (1992). J. Cell Biol. 119, 737–747). NPL3 includes bipartite RNA recognition motifs (RRM) and a Gly-Arg repeat domain, as in several nucleolar proteins. A point mutation adjacent to one of the RRM has been identified in the ts copy of the gene. Although this protein is not concentrated in nuclear pores, NPL3 is implicated in both import and export from the nucleus. Judging from the site of the npl3 mutation and since the block in RNA export can be detected prior to an obvious nuclear import defect in npl3, the defect in RNA export may be primary. Since other mutants that interrupt RNA export do not block protein import, the NPL3 protein itself appears to be implicated in protein import.

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31

Lamper, Cynthia, Mariëlle Kroese, Albère Köke, Dirk Ruwaard, Jeanine Verbunt, and Ivan Huijnen. "Developing the Network Pain Rehabilitation Limburg: a feasibility study protocol." BMJ Open 9, no. 6 (June 2019): e025962. http://dx.doi.org/10.1136/bmjopen-2018-025962.

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IntroductionPatients having chronic musculoskeletal pain (CMP) face challenges as mismatches often exist between the complexity of patient’s pain problem and the rehabilitation treatment offered. This can result in less efficient care for the patient and increased medical shopping. The Network Pain Rehabilitation Limburg (NPRL), a transmural integrated healthcare network, will be designed to improve daily care for patients with CMP. NPRL focusses on improving patient’s level of functioning despite pain by stimulating a biopsychosocial approach given by all involved healthcare professionals. A feasibility study will be performed which will give insight into the barriers and facilitators, perceived value, acceptability and implementation strategies for NPRL.Methods and analysisThis study has a three-phase iterative and incremental design, based on key principles of a user-centred design. Mixed methods will be used in which healthcare professionals and patients involved in NPRL will participate. In phase 1, NPRL will be developed and healthcare professionals educated. Phase 2 focusses on the implementation and phase 3 on the transferability of NPRL. In addition, preliminary data on patient’s work status, general health and participation level will be collected. The qualitative results of each phase will be analysed following the Consolidated Framework for Implementation Research (CFIR) and will be used to refine NPRL in daily practise.Ethics and disseminationInformed consent will be obtained from all participants. The results of this feasibility study will form the basis for refinement of NPRL and planning of a large-scale process and effect evaluation of the Quadruple Aim outcomes. Dissemination will include publications and presentations at national and international conferences. Ethical approval for this study was granted by the Medical Ethics Committee Z, the Netherlands, METC 17 N-133.

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Belaj, F. "Structures of the Phosphazenes [ClC(NPCl3)2]+PCl6 − and [CH3C(NPCl3)2]+SbCl6 − at 90 K." Acta Crystallographica Section B Structural Science 53, no. 6 (December 1, 1997): 953–60. http://dx.doi.org/10.1107/s0108768197008343.

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The asymmetric units of both ionic compounds [N-(chloroformimidoyl)phosphorimidic trichloridato]trichlorophosphorus hexachlorophosphate, [ClC(NPCl3)2]+PCl^{-}_{6} (1), and [N-(acetimidoyl)phosphorimidic trichloridato]trichlorophosphorus hexachloroantimonate, [CH3C(NPCl3)2]+SbCl^{-}_{6} (2), contain two formula units with the atoms located on general positions. All the cations show cis–trans conformations with respect to their X—C—N—P torsion angles [X = Cl for (1), C for (2)], but quite different conformations with respect to their C—N—P—Cl torsion angles. Therefore, the two NPCl3 groups of a cation are inequivalent, even though they are equivalent in solution. The very flexible C—N—P angles ranging from 120.6 (3) to 140.9 (3)° can be attributed to the intramolecular Cl...Cl and Cl...N contacts. A widening of the C—N—P angles correlates with a shortening of the P—N distances. The rigid-body motion analysis shows that the non-rigid intramolecular motions in the cations cannot be explained by allowance for intramolecular torsion of the three rigid subunits about specific bonds.

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33

Iriarte, A. G., E. H. Cutin, S. E. Ulic, J. Jios, and C. O. Della Védova. "Spectroscopic and theoretical studies of N-trichlorophosphazotrifluoroacetyl, CF3C(O)NPCl3 and N-trichlorophosphazotrichloroacetyl, CCl3C(O)NPCl3." Vibrational Spectroscopy 43, no. 2 (March 2007): 290–96. http://dx.doi.org/10.1016/j.vibspec.2006.03.003.

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34

Oh, Rira, Ji-Won Heo, Hyeyoon Kim, Mi-Kyung Sung, and Sung-Eun Kim. "Effects of Sex-Specific Gene on the Adipogenic Differentiation in 3T3-L1 Preadipocytes." Current Developments in Nutrition 5, Supplement_2 (June 2021): 1237. http://dx.doi.org/10.1093/cdn/nzab055_047.

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Abstract Objectives Global statistics indicated that women are more likely to be obese than men, while sex and gender differences have been largely ignored in scientific reports which have caused serious biases in research conclusions. Previously, we have identified female-specific genes including NPR3 (natriuretic peptide receptor 3) in adipose tissue of obese mice by bioinformatics analysis. Here, we further investigated sex-specific effects of the NPR3 gene on the adipogenic differentiation in 3T3-L1 preadipocytes to understand the underlying mechanisms for sex differences. Methods 3T3-L1 preadipocytes were treated with/without 1 µM fulvestrant (FUL, estrogen receptor antagonist) and/or 100 nM AP811 (NPR3 antagonist) during the early stage of differentiation. After cell differentiation, triacylglyceride (TG) accumulation was measured by Oil red O staining and mRNA level of markers related with lipid metabolism was determined by qRT-PCR. Results Karyotyping revealed two X chromosomes were present in 3T3-L1 cells. After differentiation with FUL and AP811, the NPR3 expression significantly decreased compared with 3T3-L1 cells treated with AP811 alone, indicating that NPR3 might be obesity-induced female-specific gene. Treatment with FUL and AP811 increased TG accumulation, which was accounted for the increased expression of adipogenic markers (PPARγ, CEBPα) and reduced expression of markers involved in mitochondrial biogenesis (NRF1, DRP1). Conclusions Our data show that the NPR3 gene influences the adipogenic differentiation in a sex-specific manner, suggesting sex- and gender-based strategies for the prevention and treatment of obesity need to be established. Funding Sources This work was supported by the Support Program for Women in Science, Engineering and Technology through the Center for Women In Science, Engineering and Technology (WISET) funded by the Ministry of Science and ICT (MSIT) and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT).

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Sellmann, Dieter, Johannes Keller, Matthias Moll, Horst Philipp Beck, and Wolfgang Milius. "Übergangsmetallkomplexe mit Schwefelliganden, XXIV* Reduktive Nitrosylierung von [MoCl2(dttd)] zu [Mo(NO)2(dttd)];Eigenschaften, Struktur und Reaktion zu NPR3-Komplexen[Mo(NO)(NPR3)dttd] (PR3=PMe3, PEt3, PMePh2, PEtPh2, PPh3;dttd2-=2,3,8,9-Dibenzo-1,4,7,10-tetrahiadecan(2-)) / Transition Metal Complexes with Sulfur Ligands, XXIV*Reductive Nitrosylation of [MoCl2(dttd)] to [Mo(NO)2(dttd); Properties, Structure an Reaction to NPR3 Complexes [Mo(NO)(NPR3)dttd] (PR3=PMe3, PEt3, PMePh2, PEtPh2, PPh3; dttd2-=2,3,8,9-dibenzo-1,4,7,10-tetrahiadecane (2-))." Zeitschrift für Naturforschung B 41, no. 12 (December 1, 1986): 1551–60. http://dx.doi.org/10.1515/znb-1986-1213.

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AbstractIn order to study the properties of sulfur coordinated transition metal centers. [MoCl2dttd] (dttd2 = 2,3,8,9-dibenzo-1,4.7,10-tetrathiadecane(2-)) was reacted with NO in the presence of Zn. [Mo(NO)2dttd] was obtained whose X-ray structure analysis shows that Mo is coordinated pseudo-octahedrally by two trans thiolato S, two cis thioether S as well as two cis N atoms of nearly linear MoNO groups. With respect to its low v(NO) frequencies (1760/1665 cm -1) and quite normal bond lengths as well as angles [Mo(NO)2dttd] shows unexpectedly facile and rapid reactions with nucleophiles; with two equivalents of PR3 (PMe3, PEt3, PMePh2, PEtPh2, PPh3) it yields the corresponding phosphiniminato complexes [Mo(NO)(NPR3)dttd] and free phosphinoxides OPR3, respectively. Reaction mechanisms as well as the bonding situation in the [Mo(NPR3)] entity are discussed; on the basis of 95Mo and 14N NMR it is concluded that the conversion of NO into NPR3 ligands includes a reduction of N(+2) to N(-3) as well as an oxidation of (formal) Mo(+2) to Mo(+3). With H2O the [Mo(NO)(NPR3)dttd] complexes hydrolyze with loss of the NPR3 ligands and formation of binuclear [Mo(NO)dttd]2. The ease of hydrolysis depends on the substituents R: In THF [Mo(NO)(NPMe3)dttd] hydrolyzes at 20 °C within a few minutes, [Mo(NO)(NPPh3)dttd], however, needs the addition of cone. HCl.

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Yasuda, J., T. Wakasa, M. Dozono, T. Fukunaga, S. Gotanda, K. Hatanaka, Y. Kanaya, et al. "Development of Neutron Polarization Measurement System for Studying NN interaction in Nuclear Medium." International Journal of Modern Physics: Conference Series 40 (January 2016): 1660073. http://dx.doi.org/10.1142/s2010194516600739.

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We have developed the neutron polarization measurement system to perform the first polarization-transfer measurement for the exclusive [Formula: see text] reaction. For the neutron polarization measurement, we have reconstructed the neutron polarimeter NPOL3. The NPOL3 system has been calibrated by using the polarized neutron from the [Formula: see text] reaction, and the resulting effective analyzing power is [Formula: see text]. For the exclusive measurement, the Large Acceptance Spectrometer (LAS) has been used for the recoil proton detection. The energy resolution of 6 MeV is achieved for separation energy, which is sufficient to separate the [Formula: see text] and [Formula: see text] orbits for light nuclei.

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Murphy, William B. "The National Progressive Republican League and the Elusive Quest for Progressive Unity." Journal of the Gilded Age and Progressive Era 8, no. 4 (October 2009): 515–43. http://dx.doi.org/10.1017/s153778140000147x.

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In January 1911, Senator Robert M. La Follette of Wisconsin announced the creation of the National Progressive Republican League (NPRL). Historians have dismissed this organization as a vehicle for La Follette's challenge to William Howard Taft for the Republican presidential nomination in 1912. This article asserts that a primary purpose of the NPRL was to offer progressives around the country a set of principles that would provide the progressive movement with greater cohesion while allowing for continued diversity in local reform agendas. The NPRL's president, Oregon senator Jonathan Bourne, was renowned as a spokesman for the series of direct democratic reforms known as the Oregon System, which La Follette and Bourne placed at the center of the NPRL platform. Bourne argued that these reforms, focused on altering the way in which candidates were nominated or elected to office, campaigns were funded, and legislation was produced, would provide progressives with a national “foundation” upon which various state and local reform agendas could be constructed. During the campaign of 1912, the league became a casualty of the political and personal conflict between Theodore Roosevelt and La Follette, but Roosevelt's Progressive Party later endorsed most of its agenda, and all elements of the NPRL platform found some political expression before or after 1912.

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Pereira, Naveen L., Dong Lin, Linda Pelleymounter, Irene Moon, Gail Stilling, Bruce W. Eckloff, Eric D. Wieben, et al. "Natriuretic Peptide Receptor-3 Gene ( NPR3 )." Circulation: Cardiovascular Genetics 6, no. 2 (April 2013): 201–10. http://dx.doi.org/10.1161/circgenetics.112.964742.

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Zang, Jia, Juanjuan Sun, WenChao Xiu, Xiaoshuang Liu, Yunsheng Chai, and Yanyan Zhou. "Low Expression of AGPAT5 Is Associated With Clinical Stage and Poor Prognosis in Colorectal Cancer and Contributes to Tumour Progression." Clinical Medicine Insights: Oncology 16 (January 2022): 117955492211373. http://dx.doi.org/10.1177/11795549221137399.

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Background: Colorectal cancer (CRC) has a high prevalence and poor prognosis. This study aimed to identify biomarkers related to the clinical stage (I-IV) of CRC. Methods: The LinkedOmics database was used as the discovery cohort, and two Gene Expression Omnibus (GEO) databases (GSE41258 and GSE422848) served as validation cohorts. The trend test of genes related to clinical stage (I-IV) of CRC patients was identified by the Jonckheere-Terpstra test. The cBioPortal database, Gene Expression Profiling Interactive Analysis (GEPIA) and PrognoScan databases were used to explore the expression change and prognostic value of clinical stage-related genes in CRC patients. CRC cells overexpressed AGPAT5 were constructed and used for cell counting kit-8 (CCK-8), flow cytometric, and wound healing assays in vitro. Results: We identified four clinical stage-related genes, GSR, AGPAT5, CRLF1, and NPR3, in CRC. The CNA frequencies of GSR, CRLF1, AGPAT5, and NPR3 occurred in 11%, 2.4%, 13%, and 3% of patients, respectively. The expression of GSR and AGPAT5 tended to decrease with CRC stage (I-IV) progression, and the expression of CRLF1 and NPR3 tended to increase with CRC stage (I-IV) progression. Compared with the normal group, AGPAT5 expression was markedly decreased in stage IV CRC. Higher GSR and AGPAT5 expression levels were associated with better overall survival (OS) and disease-free survival (DFS) in CRC patients. Lower CRLF1 and NPR3 expression levels were associated with better OS and DFS in CRC. GSR, CRLF1, AGPAT5, and NPR3 expression were related to CRC progression, microsatellite instability, and tumour purity in CRC. Furthermore, AGPAT5 was downregulated in CRC cell lines, and overexpression of AGPAT5 inhibited cell proliferation and migration and promoted cell apoptosis in CRC cells. Conclusion: Low AGPAT5 expression may serve as a poor prognostic factor and clinical stage biomarker in CRC. In addition, AGPAT5 acts as a tumour suppressor in CRC progression.

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Shinojima, Naoki, Hideo Nakamura, Masayoshi Tasaki, Kouki Kameno, Shigeo Anai, Ken-ichi Iyama, Yukio Ando, Hiroshi Seto, and Jun-ichi Kuratsu. "A patient with medulloblastoma in its early developmental stage." Journal of Neurosurgery: Pediatrics 14, no. 6 (December 2014): 615–20. http://dx.doi.org/10.3171/2014.8.peds13590.

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Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children and is considered an embryonal tumor. It has been suggested that medulloblastomas be categorized into 4 distinct molecular subgroups— WNT (DKK1), SHH (SFRP1), Group 3 (NPR3), or Group 4 (KCNA1)—since each subgroup is distinct and there is no overlap. The authors report on a 13-year-old boy with medulloblastoma. He presented with sudden-onset nausea and vomiting due to intratumoral hemorrhage. The medulloblastoma was thought to be in an early developmental stage because the tumor volume was extremely small. Immunohistochemical analysis showed that the tumor was mainly composed of DKK1- and NPR3-positive areas. The individual areas of the tumor stained only for DKK1 or NPR3, with no overlap—that is, DKK1 and NPR3 expression were mutually exclusive. Samples obtained by laser microdissection of individual areas and subjected to mass spectrometry confirmed that the expression patterns of proteins were different. Fluorescence in situ hybridization for chromosome 6 showed there were 2 distinct types of cells that exhibited monosomy or disomy of chromosome 6. These results demonstrated that distinct subtypes of medulloblastoma may be present within a single tumor, an observation that has not been previously reported. Our findings in this case indicate that early-stage medulloblastoma may include more than 1 distinct subtype and hint at factors involved in the origin and development of medulloblastomas.

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Gao, Yuzhong, Jian Wang, and Guangyu Fan. "NPRL2 is an independent prognostic factor of osteosarcoma." Cancer Biomarkers 12, no. 1 (January 11, 2013): 31–36. http://dx.doi.org/10.3233/cbm-120290.

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42

Erdem, Can Caglar, Benedict Daly, Ara Ketchedjian, Michael Stone, Richard Shemin, Nirav P. Shah, and Hiran Fernando. "Use of the Navigator Probe after Radiotracer Injection to Identify Nonpalpable Rib Lesions Requiring Surgical Resection." Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery 1, no. 5 (September 2006): 272–75. http://dx.doi.org/10.1097/01.imi.0000239447.92644.de.

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Background Patients with nonpalpable rib lesions (NPRL) requiring biopsy present a challenging problem for the thoracic surgeon. Ideally, a small incision directly over the NPRL should be performed to minimize morbidity, particularly if the lesion is benign. The Navigator probe is routinely used after lymphoscintigraphy by surgical oncologists to isolate sentinel lymph nodes requiring removal, but can also be used to guide resection of nonpalpable focal rib lesions demonstrating increased technetium-99m hydroxymethylene diphosphonate (Tc-99m HDP) uptake. This report describes our initial experience with this technique. Methods Over a 5-month period, 3 patients with focal NPRL underwent rib resection. All patients had solitary lesions demonstrated on recently performed Tc-99m HDP bone scanning. Prior cancers were reported in 2 patients, and pain in 2 patients. Before surgery, all patients underwent intravenous injection of 20 to 25 mCi Tc-99m HDP at least 2 hours before the Navigator probe-guided procedure. Results The Navigator probe identified all 3 lesions, allowing a single 4 cm or smaller incision in all cases. Histology included metastatic breast cancer (1), pathologic fracture secondary to metastatic palatal cancer (1), and eosinophilic granuloma (1). No patient required further resection. Conclusions Intraoperative localization of NPRL that are positive on Tc-99m HDP bone scanning using the Navigator probe is feasible and was 100% successful in our initial experience. This technique allows a minimally invasive approach, which is beneficial for those patients who do not require further resection.

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Henry, M. F., and P. A. Silver. "A novel methyltransferase (Hmt1p) modifies poly(A)+-RNA-binding proteins." Molecular and Cellular Biology 16, no. 7 (July 1996): 3668–78. http://dx.doi.org/10.1128/mcb.16.7.3668.

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RNA-binding proteins play many essential roles in the metabolism of nuclear pre-mRNA. As such, they demonstrate a myriad of dynamic behaviors and modifications. In particular, heterogeneous nuclear ribonucleoproteins (hnRNPs) contain the bulk of methylated arginine residues in eukaryotic cells. We have identified the first eukaryotic hnRNP-specific methyltransferase via a genetic screen for proteins that interact with an abundant poly(A)+-RNA-binding protein termed Npl3p. We have previously shown that npl3-1 mutants are temperature sensitive for growth and defective for export of mRNA from the nucleus. New mutants in interacting genes were isolated by their failure to survive in the presence of the npl3-1 allele. Four alleles of the same gene were identified in this manner. Cloning of the cognate gene revealed an encoded protein with similarity to methyltransferases that was termed HMT1 for hnRNP methyltransferase. HMT1 is not required for normal cell viability except when NPL3 is also defective. The Hmt1 protein is located in the nucleus. We demonstrate that Npl3p is methylated by Hmt1p both in vivo and in vitro. These findings now allow further exploration of the function of this previously uncharacterized class of enzymes.

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Belaj, F. "Structures and electron density distributions of [Cl-P(NPCl3)3]+.Cl− and [Cl-P(NPCl3)3]+.PCl6 −.1/2C2H2Cl4 at 100 K." Acta Crystallographica Section B Structural Science 48, no. 5 (October 1, 1992): 598–604. http://dx.doi.org/10.1107/s010876819200363x.

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45

Loo, S., P. Laurenson, M. Foss, A. Dillin, and J. Rine. "Roles of ABF1, NPL3, and YCL54 in silencing in Saccharomyces cerevisiae." Genetics 141, no. 3 (November 1, 1995): 889–902. http://dx.doi.org/10.1093/genetics/141.3.889.

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Abstract A sensitized genetic screen was carried out to identify essential genes involved in silencing in Saccharomyces cerevisiae. This screen identified temperature-sensitive alleles of ORC2 and ORC5, as described elsewhere, and ABF1, NPL3, and YCL54, as described here. Alleles of ABF1 that caused silencing defects provided the genetic proof of Abflp's role in silencing. The roles of Npl3p and Ycl54p are less clear. These proteins did not act exclusively through any one of the three protein binding sites of the HMR-E silencer. Unlike the orc2, orc5, and abf1 mutations that were isolated in the same (or a similar) screen for silencing mutants, neither temperature-sensitive mutation in NPL3 or YCL54 caused overt replication defects.

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Wakasa, T., Y. Hagihara, M. Sasano, S. Asaji, K. Fujita, K. Hatanaka, T. Ishida, et al. "Performance of the neutron polarimeter NPOL3 for high resolution measurements." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 547, no. 2-3 (August 2005): 569–82. http://dx.doi.org/10.1016/j.nima.2005.03.151.

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47

Dutchak, Paul A., Sunil Laxman, Sandi Jo Estill, Chensu Wang, Yun Wang, Yiguang Wang, Gamze B. Bulut, Jinming Gao, Lily J. Huang, and Benjamin P. Tu. "Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2." Cell Reports 12, no. 3 (July 2015): 371–79. http://dx.doi.org/10.1016/j.celrep.2015.06.042.

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Wang, Pan, and Meiqin Xiang. "Research progress of NPR genes in signal pathway of salicylic acid mediated plant disease resistance." E3S Web of Conferences 145 (2020): 01038. http://dx.doi.org/10.1051/e3sconf/202014501038.

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Salicylic acid (SA) is considered to be an endogenous signal molecule in plants, and it is related to many resistances in plants. In Arabidopsis, Non-expressor of pathogenesis-related gene1 (NPR1) mediates the expression of pathogenesis-related genes (PRs) and systemic acquired resistance (SAR) induced by SA. NPR1 is a key factor in SA signaling pathway, and the research shows that NPR1, NPR3 and NPR4 play a key role in SA mediated plant disease resistance. In this review, the interaction between NPR and transcription factors is discussed, and we also describe the progress of NPR in SA mediated SAR signal transduction pathway, likewise, we introduce the relationship between NPR1 and its paralogues NPR3/NPR4. This paper analyzes the research prospect of NPR as the intersection of multiple signal paths.

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Hunt, Lisa M., Emily W. Hogeland, Maria K. Henry, and Steven J. Swoap. "Hypotension and bradycardia during caloric restriction in mice are independent of salt balance and do not require ANP receptor." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 4 (October 2004): H1446—H1451. http://dx.doi.org/10.1152/ajpheart.00353.2004.

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We hypothesized that caloric restriction (CR)-induced hypotension would correlate with increased sodium excretion through an atrial natriuretic peptide (ANP)-dependent mechanism. To test this hypothesis, the cardiovascular parameters of c57/Bl mice were measured with radiotelemetry while urine was collected. The 23-h mean blood pressure (BP) dropped from 108.6 ± 1.8 to 92.7 ± 2.4 mmHg, and 23-h heart rate dropped from 624 ± 5 to 426 ± 13 beats/min over 7 days of CR at 29°C. Contrary to our hypothesis, urine sodium excretion decreased by 55% by day 7 of CR. Consistent with decreased sodium excretion was the drop in plasma ANP (from 82.4 ± 4.3 to 68.0 ± 5.8 pg/ml). To explore the possibility that CR lowers BP through an ANP receptor-dependent mechanism that is independent of its effect on sodium retention, we measured the cardiovascular parameters of mice deficient in the ANP receptor (NPR1−/−) or the ANP clearance receptor (NPR3−/−). Mean BP fell from 117.1 ± 3.9 to 108.0 ± 4.7 mmHg in the NPR1−/− mice and from 87.0 ± 2.4 to 78.4 ± 1.7 mmHg in the NPR3−/− mice during CR. These data indicate that the hypotension induced by CR does not depend on increased sodium excretion. Rather, it appears that the mouse responds to the low BP induced by CR with an increase in sodium reabsorption. Furthermore, circulating ANP levels and data from NPR1−/− and NPR3−/− mice suggest that the ANP pathway may not be involved in the cardiovascular response to CR.

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Xiao, Jianwei, Xu Cai, Rongsheng Wang, Weijian Zhou, and Zhizhong Ye. "Identification of Synovial Fibroblast-Associated Neuropeptide Genes and m6A Factors in Rheumatoid Arthritis Using Single-Cell Analysis and Machine Learning." Disease Markers 2022 (February 9, 2022): 1–12. http://dx.doi.org/10.1155/2022/5114697.

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Objectives. Synovial fibroblasts (SFs) play an important role in the development and progression of rheumatoid arthritis (RA). However, the pathogenic mechanism of SFs remains unclear. The objective of this study was to investigate how neuropeptides and N6-methyladenosine (m6A) played an important role in the underlying pathogenic processes of SFs that contribute to the development of RA. Methods. Single-cell RNA sequencing data were examined using single-cell analysis and machine learning. SF subgroups were identified based on the clustering and annotation results of the single-cell analysis. Moreover, cell–cell communication was used to analyse neuropeptide-related receptor and ligand pairs on the surface of SF cell membranes. Machine learning was used to explore the m6A factors acting on these neuropeptide genes. Results. NPR3, GHR, BDKRB2, and CALCRL, four neuropeptide genes, were shown to be differently expressed among SF subgroups. Further investigation of receptor–ligand interactions found that NPR3 (in conjunction with NPPC, OSTN, NPPB, and NPPA) and GHR (in conjunction with GH1 and GH2) may have a role in SF interactions. As predicted by machine learning, IGFBP2 and METTL3 were identified as key factors regulating m6A of NPR3 and GHR. The expression levels and enrichment pathways of METTL3 and IGFBP2 were different among SF subgroups. Conclusions. Single-cell analysis and machine learning efficiently identified neuropeptide genes and m6A factors that perform important regulatory functions in RA. Our strategy may provide a basis for future studies to identify pathogenic cell subpopulations and molecular mechanisms in RA and other diseases.

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