980 resultados para microRNA 169


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The silver-headed antechinus (Antechinus argentus) is one of Australia’s most recently described mammals, and the single known population at Kroombit Tops in south-east Queensland is threatened. Nothing is known of the species’ ecology, so during 2014 we collected faecal pellets each month (March–September) from a population at the type locality to gather baseline data on diet composition. A total of 38 faecal pellets were collected from 12 individuals (eight females, four males) and microscopic analysis of pellets identified seven invertebrate orders, with 70% combined mean composition of beetles (Coleoptera: 38%) and cockroaches (Blattodea: 32%). Other orders that featured as prey were ants, crickets/grasshoppers, butterflies/moths, spiders, and true bugs. Given that faecal pellets could only be collected from a single habitat type (Eucalyptus montivaga high-altitude open forest) and location, this is best described as a generalist insectivorous diet that is characteristic of other previously studied congeners.

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A mathematical model is developed to simulate oxygen consumption, heat generation and cell growth in solid state fermentation (SSF). The fungal growth on the solid substrate particles results in the increase of the cell film thickness around the particles. The model incorporates this increase in the biofilm size which leads to decrease in the porosity of the substrate bed and diffusivity of oxygen in the bed. The model also takes into account the effect of steric hindrance limitations in SSF. The growth of cells around single particle and resulting expansion of biofilm around the particle is analyzed for simplified zero and first order oxygen consumption kinetics. Under conditions of zero order kinetics, the model predicts upper limit on cell density. The model simulations for packed bed of solid particles in tray bioreactor show distinct limitations on growth due to simultaneous heat and mass transport phenomena accompanying solid state fermentation process. The extent of limitation due to heat and/or mass transport phenomena is analyzed during different stages of fermentation. It is expected that the model will lead to better understanding of the transport processes in SSF, and therefore, will assist in optimal design of bioreactors for SSF.

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Esophageal atresia (EA), a common congenital anomaly comprising interrupted esophagus with or without a tracheoesophageal fistula (TEF), affects one in 2840 newborns. Over half have associated anomalies. After EA repair in infancy, gastroesophageal reflux (GER) and esophageal dysmotility and respiratory problems are common. As there exist no previous population-based long-term follow-up-studies on EA, its long-term sequelae are unclear. The aims of this study were to assess the cancer incidence (I), esophageal morbidity and function (II), respiratory morbidity (III), and the spinal defects (IV) in adults with repaired EA. All patients treated for EA at the Hospital for Children and Adolescents, University of Helsinki, from 1947 to 1985 were identified, and those alive with their native esophagus were contacted, and the first hundred who replied made up the study group. The patients were interviewed, they filled in symptom questionnaires, and they underwent esophageal endoscopy and manometry, pulmonary function tests, and a full orthopedic evaluation was performed with radiographs of the spine. The questionnaire was also sent by mail to adults with repaired EA not attending the clinical study, and to 287 general population-derived controls matched for age, gender, and municipality of residence. Incidence of cancer among the study population was evaluated from the population-based countrywide cancer registry. 169 (72%) adults with repaired EA replied; 101 (42%) (58 male) participated in the clinical studies at a median age of 36 years (range, 22-56). Symptomatic GER occurred in 34% and dysphagia in 85% of the patients and in 8% and 2% of the controls (P<0.001 for both). The main endoscopic findings included hiatal hernia (28%), Barrett´s esophagus (11%), esophagitis (8%), and stenotic anastomosis (8%). Histology revealed esophagitis in 25 individuals, and epithelial metaplasia in another 21. At immunohistochemistry, CDX2-positive columnar epithelial metaplasia was present in all 21 individuals, and 6 of these also demonstrated goblet cells and MUC2 positivity. In all histological groups, GER and dysphagia were equally common (P=ns). Esophageal manometry demonstrated non-propagating peristalsis in most of the patients, and low ineffective pressure of the distal esophageal body in all. The changes were significantly worse in those with epithelial metaplasia (P≤0.022). Anastomotic complications (OR 8.6-24, 95%CI 1.7-260, P=0.011-0.008), age (OR 20, 95%CI 1.3-310, P=0.034), low distal esophageal body pressure (OR 2.6, 95%CI 0.7-10, P=0.002), and defective esophageal peristalsis (OR 2.2, 95%CI 0.4-11, P=0.014) all predicted development of epithelial metaplasia. Despite the high incidence of esophageal metaplasia, none of the EA patients had suffered esophageal cancer, according to the Finnish Cancer Registry. Although three had had cancer (SIR, 1.0; 95% CI, 0.20-2.8). The overall cancer incidence among adults with repaired EA did not differ from that of the general Finnish population. Current respiratory symptoms occurred in 11% of the patients and 2% of the controls (P<0.001). Of the patients, 16%, and 6% of the controls had doctor-diagnosed asthma (P<0.001). A total of 56% and 70% of the patients and 20% and 50% of the controls had a history of pneumonia and of bronchitis (P<0.001 for both). Respiratory-related impaired quality of life was observable in 11% of the patients in contrast to 6% of the controls (P<0.001). PFT revealed obstruction in 21 of the patients, restriction in 21, and both in 36. A total of 41 had bronchial hyper-responsiveness (BHR) in HCT, and 15 others had an asthma-like response. Thoracotomy-induced rib fusion (OR 3.4, 95%CI 1.3-8.7, P=0.01) and GER-associated epithelial metaplasia in adulthood (OR 3.0, 95%CI 1.0-8.9, P=0.05) were the most significant risk factors for restrictive ventilatory defect. Vertebral anomalies were evident in 45 patients, predominating in the cervical spine in 38. The most significant risk factor for the occurrence of vertebral anomalies was any additional anomaly (OR 27, 95%C I8-100). Scoliosis (over 10 degrees) was observable in 56 patients, over 20 degrees in 11, and over 45 degrees in one. In the EA patients, risk for scoliosis over 10 degrees was 13-fold (OR 13, 95%CI 8.3-21) and over 20 degrees, 38-fold (OR 38, 95%CI 14-106) when compared to that of the general population. Thoracotomy-induced rib fusion (OR 3.6, 95%CI 0.7-19) and other associated anomalies (OR 2.1, 95%CI 0.9-2.9) were the strongest predictive factors for scoliosis. Significant esophageal morbidity associated with EA extends into adulthood. No association existed between the esophageal symptoms and histological findings. Surgical complications, increasing age, and impaired esophageal motility predicted development of epithelial metaplasia after repair of EA. According to our data, the risk for esophageal cancer is less than 500-fold that of the general population. However, the overall cancer incidence among adults with repaired EA did not differ from that of the general population. Adults with repaired EA have had significantly more respiratory symptoms and infections, as well as more asthma, and allergies than does the general population. Thoracotomy-induced rib fusion and GER-associated columnar epithelial metaplasia were the most significant risk factors for the restrictive ventilatory defect that occurred in over half the patients. Over half the patients with repaired EA are likely to develop scoliosis. Risk for scoliosis is 13-fold after repair of EA in relation to that of the general population. Nearly half the patients had vertebral anomalies. Most of these deformities were diagnosed neither in infancy nor during growth. The natural history of spinal deformities seems, however, rather benign, with spinal surgery rarely indicated.

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Without estrogen action, the fusion of the growth plates is postponed and statural growth continues for an exceptionally long time. Aromatase inhibitors, blockers of estrogen biosynthesis, have therefore emerged as a new potential option for the treatment of children with short stature. We investigated the efficacy of the aromatase inhibitor letrozole in the treatment of boys with idiopathic short stature (ISS) using a randomised, placebo-controlled, double-blind research setting. A total of 30 boys completed the two-year treatment. By decreasing estrogen-mediated central negative feedback, letrozole increased gonadotrophin and testosterone secretion in pubertal boys, whereas the pubertal increase in IGF-I was inhibited. Treatment with letrozole effectively delayed bone maturation and increased predicted adult height by 5.9 cm (P0.001), while placebo had no effect on either parameter. The effect of letrozole treatment on near-final height was studied in another population, in boys with constitutional delay of puberty, who received letrozole (n=9) or placebo (n=8) for one year, in combination with low-dose testosterone for six months during adolescence. The mean near-final height of boys randomised to receive testosterone and letrozole was significantly greater than that of boys who received testosterone and placebo (175.8 vs. 169.1 cm, P=0.04). As regards safety, treatment effects on bone health, lipid metabolism, insulin sensitivity, and body composition were monitored in boys with ISS. During treatment, no differences in bone mass accrual were evident between the treatment groups, as evaluated by dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck. Bone turnover and cortical bone growth, however, were affected by letrozole treatment. As indicated by differences in markers of bone resorption (U-INTP) and formation (S-PINP and S-ALP), the long-term rate of bone turnover was lower in letrozole-treated boys, despite their more rapid advancement in puberty. Letrozole stimulated cortical bone growth in those who progressed in puberty: the metacarpal index (MCI), a measure of cortical bone thickness, increased more in letrozole-treated pubertal boys than in placebo-treated pubertal boys (25% vs. 9%, P=0.007). The change in MCI correlated positively with the mean testosterone-to-estradiol ratio. In post-treatment radiographic evaluation of the spine, a high rate of vertebral deformities - mild anterior wedging and mild compression deformities - were found in both placebo and letrozole groups. In pubertal boys with ISS treated with letrozole, stimulated testosterone secretion was associated with a decrease in the percentage of fat mass and in HDL-cholesterol, while LDL-cholesterol and triglycerides remained unchanged. Insulin sensitivity, as evaluated by HOMA-IR, was not significantly affected by the treatment. In summary, treatment with the aromatase inhibitor letrozole effectively delayed bone maturation and increased predicted adult height in boys with ISS. Long-term follow-up data of boys with constitutional delay of puberty, treated with letrozole for one year during adolescence, suggest that the achieved gain in predicted adult height also results in increased adult height. However, until the safety of aromatase inhibitor treatment in children and adolescents is confirmed, such treatment should be considered experimental.

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One of the major challenges in the treatment of lung cancer is the development of drug resistance. This represents a major obstacle in the treatment of patients, limiting the efficacy of both conventional chemotherapy and biological therapies. Deciphering the mechanisms of resistance is critical to further understanding the multifactorial pathways involved, and in developing more specific targeted treatments. To date, numerous studies have reported the potential role of microRNAs (miRNAs) in resistance to various cancer treatments. MicroRNAs are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing translational repression or mRNA degradation. More than 1200 validated human miRNAs have been identified to date. While as little as one miRNA can regulate hundreds of targets, a single target can also be affected by multiple miRNAs. Evidence suggests that dysregulation of specific miRNAs may be involved in the acquisition of resistance to a number of cancer treatments, thereby modulating the sensitivity of cancer cells to such therapies. Therefore, targeting miRNAs may be an attractive strategy for developing novel and more effective individualized therapies, improving drug efficiency, and for predicting patient response to different treatments. In this review, we provide an overview on the role of miRNAs in resistance to current lung cancer therapies and novel biological agents.

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Epigenetics is the study of heritable changes in gene expression that are not the result of genetic alterations. These changes include DNA methylation, histone modifications, or indeed microRNA expression. Chromatin is a tightly compacted DNA–protein complex that allows approximately two meters of DNA to be packaged inside a cell, only a few micrometers across. Although the resulting DNA structure is very stable, it is not very amiable to DNA-dependent processes, so mechanisms have to exist to allow processes such as transcription, replication, and DNA repair to occur. This chapter will look at how a cell responds to and deals with genomic instability at the epigenetic level and highlight how critical chromatin remodeling is for correct DNA repair and cell survival following DNA damage. This chapter will initially look at the DNA repair pathways that function in human cells and then at how the repair of DNA damage is controlled by epigenetics.

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Expression of the F-Box protein Leaf Curling Responsiveness (LCR) is regulated by microRNA, miR394, and alterations to this interplay in Arabidopsis thaliana produce defects in leaf polarity and shoot apical meristem (SAM) organisation. Although the miR394-LCR node has been documented in Arabidopsis, the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Major Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28 expression was reduced through an artificial miRNA technology, displayed severe developmental defects, including changes in leaf patterning and morphology, shoot apex defects, and eventual premature death. These phenotypic characteristics resemble those of Arabidopsis plants modified to over-express LCR. Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated with the LCR regulation that is critical for normal Arabidopsis development.

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Thermodynamic analysis of carbohydrate binding by Artocarpus integrifolia (jackfruit) agglutinin (jacalin) shows that, among monosaccharides, Me alpha GalNAc (methyl-alpha-N-acetylgalactosamine) is the strongest binding ligand. Despite its strong affinity for Me alpha GalNAc and Me alpha Gal, the lectin binds very poorly when Gal and GalNAc are in alpha-linkage with other sugars such as in A- and B-blood-group trisaccharides, Gal alpha 1-3Gal and Gal alpha 1-4Gal. These binding properties are explained by considering the thermodynamic parameters in conjunction with the minimum energy conformations of these sugars. It binds to Gal beta 1-3GalNAc alpha Me with 2800-fold stronger affinity over Gal beta 1-3GalNAc beta Me. It does not bind to asialo-GM1 (monosialoganglioside) oligosaccharide. Moreover, it binds to Gal beta 1-3GalNAc alpha Ser, the authentic T (Thomsen-Friedenreich)-antigen, with about 2.5-fold greater affinity as compared with Gal beta 1-3GalNAc. Asialoglycophorin A was found to be about 169,333 times stronger an inhibitor than Gal beta 1-3GalNAc. The present study thus reveals the exquisite specificity of A. integrifolia lectin for the T-antigen. Appreciable binding of disaccharides Glc beta 1-3GalNAc and GlcNAc beta 1-3Gal and the very poor binding of beta-linked disaccharides, which instead of Gal and GalNAc contain other sugars at the reducing end, underscore the important contribution made by Gal and GalNAc at the reducing end for recognition by the lectin. The ligand-structure-dependent alterations of the c.d. spectrum in the tertiary structural region of the protein allows the placement of various sugar units in the combining region of the lectin. These studies suggest that the primary subsite (subsite A) can accommodate only Gal or GalNAc or alpha-linked Gal or GalNAc, whereas the secondary subsite (subsite B) can associate either with GalNAc beta Me or Gal beta Me. Considering these factors a likely arrangement for various disaccharides in the binding site of the lectin is proposed. Its exquisite specificity for the authentic T-antigen, Gal beta 1-3GalNAc alpha Ser, together with its virtual non-binding to A- and B-blood-group antigens, Gal beta 1-3GalNAc beta Me and asialo-GM1 should make A. integrifolia lectin a valuable probe for monitoring the expression of T-antigen on cell surfaces.

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We present measurements of the top quark mass using the \mT2, a variable related to the transverse mass in events with two missing particles. We use the template method applied to t\tbar dilepton events produced in p\pbar collisions at Fermilab's Tevatron and collected by the CDF detector. From a data sample corresponding to an integrated luminosity of 3.4 \invfb, we select 236 t\tbar candidate events. Using the \mT2 distribution, we measure the top quark mass to be M_{Top} = 168.0^{+4.8}_{-4.0} $\pm$ {2.9} GeV/c^{2}. By combining the \mT2 with the reconstructed top mass distributions based on a neutrino weighting method, we measure M_{top}=169.3 $\pm$ 2.7 $\pm$ 3.2 GeV/c^{2}. This is the first application of the \mT2 variable in a mass measurement at a hadron collider.

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Evidence has been presented to show that the autotrophic nitrifying organisms get stimulated in the mulberry rhizosphere. Three species of Pseudomonas, one each of Achromobacter and Bacillus capable of degrading methionine were shown to be stimulated in the rhizosphere. These bacteria were capable of reversing the inhibitory effect of methionine on soil nitrification. Two of them were able to form nitrite from methionine. The possibility that the increased nitrifying activity in the mulberry rhizosphere in the presence of methionine found in mulberry root exudations was the result of the activity of these organisms was suggested.

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We present measurements of the top quark mass using the \mT2, a variable related to the transverse mass in events with two missing particles. We use the template method applied to t\tbar dilepton events produced in p\pbar collisions at Fermilab's Tevatron and collected by the CDF detector. From a data sample corresponding to an integrated luminosity of 3.4 \invfb, we select 236 t\tbar candidate events. Using the \mT2 distribution, we measure the top quark mass to be M_{Top} = 168.0^{+4.8}_{-4.0} $\pm$ {2.9} GeV/c^{2}. By combining the \mT2 with the reconstructed top mass distributions based on a neutrino weighting method, we measure M_{top}=169.3 $\pm$ 2.7 $\pm$ 3.2 GeV/c^{2}. This is the first application of the \mT2 variable in a mass measurement at a hadron collider.

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Raman spectrum of a single crystal of potassium sulphamate has been recorded for the first time using λ 2536 radiation of mercury as the exciter. Thirty-three Raman lines have been observed of which nine belong to the lattice oscillations. The infra-red absorption spectrum of the substance was taken in the powder form in potassium bromide disc using Carl Zeiss UR 10 IR spectrometer. Thirty-six absorption maxima could be identified of which twenty-five have been recorded for the first time. The analysis clearly shows that the N-H bond in the crystalline potassium sulphamate is not hydrogen-bonded to any appreciable extent.

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Sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) are important detoxification enzymes and they contribute to bioavailability and elimination of many drugs. SULT1A3 is an extrahepatic enzyme responsible for the sulfonation of dopamine, which is often used as its probe substrate. A new method for analyzing dopamine-3-O-sulfate and dopamine-4-O-sulfate by high-performance liquid chromatography was developed and the enzyme kinetic parameters for their formation were determined using purified recombinant human SULT1A3. The results show that SULT1A3 strongly favors the 3-hydroxy group of dopamine, which indicates that it may be the major enzyme responsible for the difference between the circulating levels of dopamine sulfates in human blood. All 19 known human UGTs were expressed as recombinant enzymes in baculovirus infected insect cells and their activities toward dopamine and estradiol were studied. UGT1A10 was identified as the only UGT capable of dopamine glucuronidation at a substantial level. The results were supported by studies with human intestinal and liver microsomes. The affinity was low indicating that UGT1A10 is not an important enzyme in dopamine metabolism in vivo. Despite the low affinity, dopamine is a potential new probe substrate for UGT1A10 due to its selectivity. Dopamine was used to study the importance of phenylalanines 90 and 93 in UGT1A10. The results revealed distinct effects that are dependent on differences in the size of the side chain and on the differences in their position within the protein. Examination of twelve mutants revealed lower activity in all of them. However, the enzyme kinetic studies of four mutants showed that their affinities were similar to that of UGT1A10 suggesting that F90 and F93 are not directly involved in dopamine binding in the active site. The glucuronidation of β-estradiol and epiestradiol (α-estradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. The results show that there are clear differences in the regio- and stereoselectivities of UGTs. The most active isoforms were UGT1A10 and UGT2B7 demonstrating opposite regioselectivity. The stereoselectivities of UGT2Bs were more complex than those of UGT1As. The amino acid sequences of the human UGTs 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. Several mutants were constructed to identify the residues responsible for the activity differences. The results revealed that the residues between Leu86 and Tyr176 of UGT1A9 determine the differences between UGT1A9 and UGT1A10. Phe117 of UGT1A9 participated in 1-naphthol binding and the residues at positions 152 and 169 contributed to the higher glucuronidation rates of UGT1A10. In summary, the results emphasize that the substrate selectivities, including regio- and stereoselectivities, of UGTs are complex and they are controlled by many amino acids rather than one critical residue.

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Lappiin suunnitteilla olevat Pajala–Kolarin rauta- ja Soklin fosforikaivos ovat megaluokan hankkeita. Kaivosten rakentaminen ei voi kuitenkaan toteutua jos niiden tarvitsemia rautatie-, satama- ja tieinvestointeja ei voida toteuttaa. Tutkimuksen tavoitteena oli arvioida näiden väyläinvestointien aluetaloudellisia vaikutuksia. Tutkimus on jatkoa Ruraliassa juuri valmistuneelle yhdeksää Pohjois- ja Itä-Suomen kaivoshanketta koskevalle tutkimukselle, jossa keskitytään itse kaivosinvestointien vaikutuksiin. Tutkimuksen on rahoittanut Liikenne- ja viestintäministeriö yhdessä Työ- ja elinkeinoministeriön kanssa. Työvälineenä oli Ruraliassa kehitetty RegFinDyn-aluemalli. Simuloinnit suoritettiin vuosille 2008–2030 ja raportoitiin Lapin seutukuntien tasolla. Tulosten mukaan kaikki, mutta erityisesti mittavat rautatieinvestoinnit olisivat merkittäviä seutukuntien taloudelliselle kasvulle. Äkäsjoki–Ajos radan rakentaminen auttaisi Tunturi-Lapin, Torniolaakson ja Kemi–Tornion seutukuntia taantuman yli. Taloudellinen kasvu voisi lisääntyä läntisen Lapin seutukunnissa yhteensä 0,6–2,2% vuoteen 2011 ja yhteensä 1,3–4,3% vuoteen 2016 mennessä. Tämä olisi keskimäärin 0,1–0,5% vuodessa. Soklin kaivoksen tapauksessa Kemijärvi–Kelloselkä–Sokli rautatien vaikutukset Itä- ja Pohjois-Lapin seutukuntiin olisivat merkittäviä. Investointien edetessä Itä-Lapin seutukunnan taloudellinen kasvu voisi vahvistua kumulatiivisesti tarkasteltuna 8,3% vuoteen 2013 mennessä. Vuosikeskiarvona tämä olisi 2,8%. Radan vaikutus Pohjois-Lapin taloudelliseen kasvuun olisi pienempi, vuoteen 2014 mennessä yhteensä 3% eli keskimäärin 0,8% vuodessa. Väyläinvestointien työllisyysvaikutukset olisivat myönteisiä. Pajala–Kolarin kaivoksen rautatieinvestoinnit toisivat läntiseen Lappiin uusia työpaikkoja vuoteen 2015 mennessä yhteensä 418. Tästä Tunturi-Lapin osuus olisi 147, Torniolaakson 114 ja Kemi–Tornion seutukunnan 157. Vastaavat vuosikeskiarvot olisivat 52, 18, 14 ja 20. Soklin kaivoksen rautatieinvestoinnit toisivat jonkun verran enemmän uusia työpaikkoja Pajala–Kolariin verrattuna koska investoinnit olisivat suuremmat. Radan rakentaminen voisi tuoda Itä-Lappiin yhteensä 506 uutta työpaikkaa vuoden 2013 loppuun mennessä. Pohjois-Lapin työllisyys voisi lisääntyä 153 uudella työpaikalla. Yhteensä voisi siten syntyä 660 uutta työpaikkaa. Vastaavat vuosikeskiarvot olisivat 169, 51, 220 uutta työpaikkaa. Kun kaivoksia tarkastellaan yhdessä, työllisyysvaikutukset olisivat suurimmat vuonna 2015, jonka loppuun mennessä väyläinvestoinnit voisivat luoda yhteensä 1288 uutta työpaikkaa. Vastaava vuosikeskiarvo olisi 161. Taloudellisen kasvun ohella työllisyystulokset korostavat analysoitujen väyläinvestointien myönteistä aluetaloudellista merkitystä. Ruralia-instituutin arvioinnin perusteella molempien kaivosten rautatie-, satama- ja tieinvestoinnit olisivat toteuttamiskelpoisia aluetaloudellisin perustein. Ne lisäisivät tuotantoa, työllisyyttä, tuloja, kulutusta ja verotuloja useissa Lapin seutukunnissa.