bluuebunny/crossref_metadata_2025_split huggingface dataset:
Os procedimentos de determinação dos preços de transferência
Authors: Amorim José Campos 
Published: January 2019

ResumoOs preços de transferência baseiam-se no princípio da plena concorrência que assenta no pressuposto de que as transações que ocorrem entre empresas relacionadas devem ser idênticas às transações ocorridas entre empresas independentes. Para calcular os preços de transferência podem ser utilizados métodos tradicionais ou métodos não tradicionais. O não cumprimento do princípio da plena concorrência pode levar a correções fiscais efetuadas pela Autoridade Tributária agravando assim o montante de imposto a entregar ao Estado.Palavras-chave: Preços de transferência, Princípio de plena concorrência, Métodos tradicionais, Métodos não tradicionais, Sociedades. ResumenLos precios de transferencia se basan en el principio de plena competencia que parte del supuesto de que las transacciones que se produzcan entre empresas relacionadas deben ser idénticas a las transacciones entre empresas independientes. Para calcular los precios de transferencia pueden utilizarse métodos tradicionales o métodos no tradicionales. El incumplimiento del principio de plena competencia puede llevar a correcciones fiscales efectuadas por la Autoridad Tributaria agravando así el importe de impuesto que debe entregarse al Estado.Palabras clave: Métodos tradicionales, Métodos no tradicionales, Precios de transferencia, Principio de la plena competencia. AbstractThe transfer pricing is based in the arm`s length principle, which is based on the assumption that transactions taking place between related companies must be identical to transactions occurred between the independent companies. Traditional or non-traditional methods can be used to calculate the transfer pricing. Failure to comply with arm`s length principle, may lead to tax corrections made by the tax administration that will increase the amount of tax due to the state.Keywords: Transfer pricing, Arm’s length principle, Traditional methods, Non-traditional methods, Companies.
Reciprocal F1 Hybrids of Two Inbred Mouse Strains Reveal Parent-of-Origin and Perinatal Diet Effects on Behavior and Expression
Authors: Oreper Daniel , Schoenrock Sarah A , McMullan Rachel , Ervin Robin , Farrington Joseph , Miller Darla R , de Villena Fernando Pardo-Manuel , Valdar William , Tarantino Lisa M 
Published: January 2019

AbstractParent-of-origin effects (POE) in mammals typically arise from maternal effects or imprinting. In some instances, such POE have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. However, POE on complex traits such as behavior remain largely uncharacterized. Moreover, although both behavior and epigenetic effects are known to be modified by perinatal environmental exposures such as nutrient deficiency, the architecture of such environment-by-POE is mostly unexplored. To study POE and environment-by-POE, we employ a relatively neglected but especially powerful experimental system for POE-detection: reciprocal F1 hybrids (RF1s). We exposed female NOD/ShiLtJ×C57Bl/6J and C57Bl/6J×NOD/ShiLtJ mice, perinatally, to one of four different diets, then after weaning recorded a set of behaviors that model psychiatric disease. Whole-brain microarray expression data revealed an imprinting-enriched set of 15 genes subject to POE. The most-significant expression POE, on the non-imprinted gene Carmil1 (a.k.a. Lrrc16a), was validated using qPCR in the same and in a new set of mice. Several behaviors, especially locomotor behaviors, also showed POE. Bayesian mediation analysis suggested Carmil1 expression suppresses behavioral POE, and that the imprinted gene Airn suppresses POE on Carmil1 expression. A suggestive diet-by-POE was observed on percent center time in the open field test, and a significant diet-by-POE was observed on one imprinted gene, Mir341, and on 16 non-imprinted genes. The relatively small, tractable set of POE and diet-by-POE detected on behavior and expression here motivates further studies examining such effects across RF1s on multiple genetic backgrounds.
Natural Genetic Variation in Yeast Reveals That NEDD4 Is a Conserved Modifier of Mutant Polyglutamine Aggregation
Authors: Peters Theodore W , Nelson Christopher S , Gerencser Akos A , Dumas Kathleen J , Tavshanjian Brandon , Chang Kyu Chul , Lithgow Gordon J , Hughes Robert E 
Published: January 2019

Abstract
A feature common to late onset proteinopathic disorders is an accumulation of toxic protein conformers and aggregates in affected tissues. In the search for potential drug targets, many studies used high-throughput screens to find genes that modify the cytotoxicity of misfolded proteins. A complement to this approach is to focus on strategies that use protein aggregation as a phenotypic readout to identify pathways that control aggregate formation and maintenance. Here we use natural variation between strains of budding yeast to genetically map loci that influence the aggregation of a polyglutamine-containing protein derived from a mutant form of huntingtin, the causative agent in Huntington disease. Linkage analysis of progeny derived from a cross between wild and laboratory yeast strains revealed two polymorphic loci that modify polyglutamine aggregation. One locus contains the gene RFU1 which modifies ubiquitination states of misfolded proteins targeted by the E3-ubiquitin ligase complex Rsp5. Activity of the Rsp5 complex, and the mammalian homolog NEDD4, are critical in maintaining protein homeostasis in response to proteomic stress. Our analysis also showed linkage of the aggregation phenotype to a distinct locus containing a gene encoding the Rsp5-interacting Bul2 protein. Allele-swap experiments validated the impact of both RFU1 and BUL2 on huntingtin aggregation. Furthermore, we found that the nematode Caenorhabditis elegans’ ortholog of Rsp5, wwp-1, also negatively regulates polyglutamine aggregation. Knockdown of the NEDD4 in human cells likewise altered polyglutamine aggregation. Taken together, these results implicate conserved processes involving the ubiquitin regulation network that modify protein aggregation and provide novel therapeutic targets for polyglutamine and other protein folding diseases.
Bulked-Segregant Analysis Coupled to Whole Genome Sequencing (BSA-Seq) for Rapid Gene Cloning in Maize
Authors: Klein Harry , Xiao Yuguo , Conklin Phillip A , Govindarajulu Rajanikanth , Kelly Jacob A , Scanlon Michael J , Whipple Clinton J , Bartlett Madelaine 
Published: January 2019

AbstractForward genetics remains a powerful method for revealing the genes underpinning organismal form and function, and for revealing how these genes are tied together in gene networks. In maize, forward genetics has been tremendously successful, but the size and complexity of the maize genome made identifying mutant genes an often arduous process with traditional methods. The next generation sequencing revolution has allowed for the gene cloning process to be significantly accelerated in many organisms, even when genomes are large and complex. Here, we describe a bulked-segregant analysis sequencing (BSA-Seq) protocol for cloning mutant genes in maize. Our simple strategy can be used to quickly identify a mapping interval and candidate single nucleotide polymorphisms (SNPs) from whole genome sequencing of pooled F2 individuals. We employed this strategy to identify narrow odd dwarf as an enhancer of teosinte branched1, and to identify a new allele of defective kernel1. Our method provides a quick, simple way to clone genes in maize.
Signatures of Insecticide Selection in the Genome of Drosophila melanogaster
Authors: Duneau David , Sun Haina , Revah Jonathan , San Miguel Keri , Kunerth Henry D , Caldas Ian V , Messer Philipp W , Scott Jeffrey G , Buchon Nicolas 
Published: January 2019

Abstract
Resistance to insecticides has evolved in multiple insect species, leading to increased application rates and even control failures. Understanding the genetic basis of insecticide resistance is fundamental for mitigating its impact on crop production and disease control. We performed a GWAS approach with the Drosophila Genetic Reference Panel (DGRP) to identify the mutations involved in resistance to two widely used classes of insecticides: organophosphates (OPs, parathion) and pyrethroids (deltamethrin). Most variation in parathion resistance was associated with mutations in the target gene Ace, while most variation in deltamethrin resistance was associated with mutations in Cyp6a23, a gene encoding a detoxification enzyme never previously associated with resistance. A “nested GWAS” further revealed the contribution of other loci: Dscam1 and trpl were implicated in resistance to parathion, but only in lines lacking Wolbachia. Cyp6a17, the paralogous gene of Cyp6a23, and CG7627, an ATP-binding cassette transporter, were implicated in deltamethrin resistance. We observed signatures of recent selective sweeps at all of these resistance loci and confirmed that the soft sweep at Ace is indeed driven by the identified resistance mutations. Analysis of allele frequencies in additional population samples revealed that most resistance mutations are segregating across the globe, but that frequencies can vary substantially among populations. Altogether, our data reveal that the widely used OP and pyrethroid insecticides imposed a strong selection pressure on natural insect populations. However, it remains unclear why, in Drosophila, resistance evolved due to changes in the target site for OPs, but due to a detoxification enzyme for pyrethroids.
Mushroom Body Specific Transcriptome Analysis Reveals Dynamic Regulation of Learning and Memory Genes After Acquisition of Long-Term Courtship Memory in Drosophila
Authors: Jones Spencer G , Nixon Kevin C J , Chubak Melissa C , Kramer Jamie M 
Published: January 2019

Abstract
The formation and recall of long-term memory (LTM) requires neuron activity-induced gene expression. Transcriptome analysis has been used to identify genes that have altered expression after memory acquisition, however, we still have an incomplete picture of the transcriptional changes that are required for LTM formation. The complex spatial and temporal dynamics of memory formation creates significant challenges in defining memory-relevant gene expression changes. The Drosophila mushroom body (MB) is a signaling hub in the insect brain that integrates sensory information to form memories across several different experimental memory paradigms. Here, we performed transcriptome analysis in the MB at two time points after the acquisition of LTM: 1 hr and 24 hr. The MB transcriptome was compared to biologically paired whole head (WH) transcriptomes. In both, we identified more transcript level changes at 1 hr after memory acquisition (WH = 322, MB = 302) than at 24 hr (WH = 23, MB = 20). WH samples showed downregulation of developmental genes and upregulation of sensory response genes. In contrast, MB samples showed vastly different changes in transcripts involved in biological processes that are specifically related to LTM. MB-downregulated genes were highly enriched for metabolic function. MB-upregulated genes were highly enriched for known learning and memory processes, including calcium-mediated neurotransmitter release and cAMP signaling. The neuron activity inducible genes Hr38 and sr were also specifically induced in the MB. These results highlight the importance of sampling time and cell type in capturing biologically relevant transcript level changes involved in learning and memory. Our data suggests that MB cells transiently upregulate known memory-related pathways after memory acquisition and provides a critical frame of reference for further investigation into the role of MB-specific gene regulation in memory.
An Efficient Genome Editing Strategy To Generate Putative Null Mutants in Caenorhabditis elegans Using CRISPR/Cas9
Authors: Wang Han , Park Heenam , Liu Jonathan , Sternberg Paul W 
Published: January 2019

Abstract
Null mutants are essential for analyzing gene function. Here, we describe a simple and efficient method to generate Caenorhabditis elegans null mutants using CRISPR/Cas9 and short single stranded DNA oligo repair templates to insert a universal 43-nucleotide-long knock-in cassette (STOP-IN) into the early exons of target genes. This STOP-IN cassette has stop codons in all three reading frames and leads to frameshifts, which will generate putative null mutations regardless of the reading frame of the insertion position in exons. The STOP-IN cassette also contains an exogenous Cas9 target site that allows further genome editing and provides a unique sequence that simplifies the identification of successful insertion events via PCR. As a proof of concept, we inserted the STOP-IN cassette at a Cas9 target site in aex-2 to generate new putative null alleles by injecting preassembled Cas9 ribonucleoprotein and a short synthetic single stranded DNA repair template containing the STOP-IN cassette and two ∼35-nucleotide-long homology arms identical to the sequences flanking the Cas9 cut site. We showed that these new aex-2 alleles phenocopied an existing loss-of-function allele of aex-2. We further showed that the new aex-2 null alleles could be reverted back to the wild-type sequence by targeting the exogenous Cas9 cut site included in the STOP-IN cassette and providing a single stranded wild-type DNA repair oligo. We applied our STOP-IN method to generate new putative null mutants for 20 additional genes, including three pharyngeal muscle-specific genes (clik-1, clik-2, and clik-3), and reported a high insertion rate (46%) based on the animals we screened. We showed that null mutations of clik-2 cause recessive lethality with a severe pumping defect and clik-3 null mutants have a mild pumping defect, while clik-1 is dispensable for pumping. We expect that the knock-in method using the STOP-IN cassette will facilitate the generation of new null mutants to understand gene function in C. elegans and other genetic model organisms.
Spore Germination Requires Ferrichrome Biosynthesis and the Siderophore Transporter Str1 in Schizosaccharomyces pombe
Authors: Plante Samuel , Labbé Simon 
Published: January 2019

Abstract
Spore germination is a process whereby spores exit dormancy to become competent for mitotic cell division. In Schizosaccharomyces pombe, one critical step of germination is the formation of a germ tube that hatches out the spore wall in a stage called outgrowth. Here, we show that iron deficiency blocks the outgrowth of germinating spores. The siderophore synthetase Sib1 and the ornithine N5-oxygenase Sib2 participate in ferrichrome biosynthesis, whereas Str1 functions as a ferrichrome transporter. Expression profiles of sib1+, sib2+, and str1+ transcripts reveal that they are induced shortly after induction of germination and their expression remains upregulated throughout the germination program under low-iron conditions. sib1Δ sib2Δ mutant spores are unable to form a germ tube under iron-poor conditions. Supplementation with exogenous ferrichrome suppresses this phenotype when str1+ is present. Str1 localizes at the contour of swollen spores 4 hr after induction of germination. At the onset of outgrowth, localization of Str1 changes and it moves away from the mother spore to primarily localize at the periphery of the new daughter cell. Two conserved Tyr residues (Tyr553 and Tyr567) are predicted to be located in the last extracellular loop region of Str1. Results show that these amino acid residues are critical to ensure timely completion of the outgrowth phase of spores in response to exogenous ferrichrome. Taken together, the results reveal the essential requirement of ferrichrome biosynthesis to promote outgrowth, as well as the necessity to take up ferrichrome from an external source via Str1 when ferrichrome biosynthesis is blocked.
Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome
Authors: Anthony Lowell B. , Kulke Matthew H. , Caplin Martyn E. , Bergsland Emily , Öberg Kjell , Pavel Marianne , Hörsch Dieter , Warner Richard R.P. , O'Dorisio Thomas M. , Dillon Joseph S. , Lapuerta Pablo , Kassler-Taub Kenneth , Jiang Wenjun 
Published: January 2019

Abstract

Background
Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.

Subjects, Materials, and Methods
Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.

Results
Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.

Conclusion
Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome.
Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer
Authors: Kaklamani Virginia G. , Richardson Andrea L. , Arteaga Carlos L. 
Published: January 2019

AbstractResistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post-ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α-isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan-PI3K-targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor-resistant, HR+, human epidermal growth receptor 2 negative (HER2−) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA-mutated disease versus PIK3CA-wild-type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform-selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform-selective inhibitors alpelisib and taselisib in patients with PIK3CA-mutated HR+, HER2− ABC. Ongoing biomarker-guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost-effective manner.Implications for PracticeThe development of phosphoinositide 3-kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early-phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα-isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.
S-1 plus Raltitrexed for Refractory Metastatic Colorectal Cancer: A Phase II Trial
Authors: Chen Ye , Wu Jing , Cheng Ke , Li Zhi-Ping , Luo De-Yun , Qiu Meng , Gou Hong-Feng , Yi Cheng , Li Qiu , Wang Xin , Yang Yu , Cao Dan , Shen Ya-Li , Bi Feng , Liu Ji-Yan 
Published: January 2019

Abstract

Lessons Learned
The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU. S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC.

Background
5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted.

Methods
Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80–120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.

Results
In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3–117.7) and 373 days (95% CI, 226.2–519.8), respectively. Most of the adverse effects were mild to moderate.

Conclusion
S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.