Preclinical evaluation of novel radiopharmaceuticals for positron emission tomography imaging of animal models of multiple sclerosis

Multiple sclerosis (MS) is the most common autoimmune disease of central nervous system (CNS) that causes chronic neurological impairment and clinical disability. Neuroinflammation is a major element in MS pathology and is present throughout the disease course contributing to clinical symptoms and irreversible neuronal damage. Magnetic resonance imaging (MRI) is the preferred imaging modality to diagnose MS. However, traditional clinical diagnosis tools are not accurate for comprehensive pathological assessment or short-term treatment evaluation. Therefore, new medical imaging methods are needed for better understanding of the disease process. The goal of this work was to evaluate novel vascular adhesion protein-1 (VAP-1) and folate receptor (FR) targeted radiotracers and compare them with translocator protein 18-kDa (TSPO) targeted radiotracer for positron emission tomography (PET) using rat models of MS. PET studies were performed using 68Ga-DOTA-Siglec-9, 18F-FOL, 68Ga-FOL and 11C-PBR28 radioligands to assess their ability to monitor neuroinflammation, disease progression and efficacy of therapies. MRI, histology, immunofluorescence and immunohistochemistry were performed to validate novel findings and to support PET data. VAP-1-targeting 68Ga-DOTA-Siglec-9 was able to visualize acute neuroinflammatory lesions ex vivo, but lacked the sensitivity to detect treatment effect and early MS-like lesions. FR-targeting 18F-FOL could also visualize the lesions and, most importantly, was able to outperform 11C-PBR28 by differentiating between acute and chronic lesions. 68Ga-FOL was not sensitive enough to detect treatment effect or lesion progression although it could visualize the MS-like lesions. In conclusion, FR targeting radioligands provide more specificity to PET imaging of MS-like lesions. FR is a potential target for in vivo imaging and development of therapies for MS patients.Uusien positroniemissiotomografia kuvantamisen radiolääkeaineiden prekliininen arviointi MS-taudin eläinmalleilla Multippeliskleroosi eli MS-tauti on yleisin keskushermoston autoimmunisairaus, joka aiheuttaa kroonisia neurologisia toimintahäiriöitä ja kliinistä toimintakyvyn alenemaa. Tulehdus on merkittävä osatekijä MS-taudissa ja esiintyy koko taudin ajan vaikuttaen kliiniseen oirekuvaan ja pysyvään hermosolujen rappeutumiseen. Magneettikuvaus on ensisijainen kuvantamismenetelmä MS-taudin diagnostiikassa. Perinteiset kliiniset diagnosointimenetelmät eivät kuitenkaan ole tarpeeksi tarkkoja kokonaisvaltaisen diagnoosin tai lyhyen ajan hoitovasteen arvioinnissa. Siksi uusia lääketieteellisiä kuvantamismenetelmiä tarvitaan ymmärtääksemme paremmin MStaudin kulkua. Tämän tutkimuksen tarkoituksena oli arvioida uusien verisuonen pinnan tartuntamolekyyli-1:een (VAP-1), ja folaattireseptoriin (FR) kohdentuvien radioaktiivisten PET merkkiaineiden käyttökelpoisuutta verrattuna 18-kDa:n translokaatio proteiiniin (TSPO) kohdentuvaan merkkiaineeseen MS-taudin rottamalleissa. PET tutkimukset tehtiin 68Ga-DOTA-Siglec-9, 18F-FOL, 68Ga-FOL ja 11C-PBR28 merkkiaineilla, jotta voitaisiin arvioida näiden merkkiaineiden kykyä seurata tulehdusreaktiota, taudin etenemistä ja lääkehoitojen vastetta. Magneettikuvausta, histologiaa, immunofluoresenssia ja immunohistokemiaa käytettiin uusien löydösten validointiin ja PET löydösten tukemiseen. VAP-1:een kohdentuva 68Ga-DOTA-Siglec-9 pystyi havaitsemaan akuutin vaiheen tulehdukselliset leesiot, mutta ei lääkkeen hoitovastetta tai uusia MS-taudin kaltaisia leesioita. FR:iin kohdentuva 18F-FOL kykeni myös havaitsemaan leesioita ja ennen kaikkea onnistui erottamaan akuutin ja kroonisen vaiheen leesiot toisistaan paremmin kuin 11C-PBR28. Myös 68Ga-FOL havaitsi leesioita, mutta ei osoittanut lääkehoidon vastetta tai leesioiden etenemistä. Yhteenvetona voidaan todeta, että FR:iin kohdentuvat merkkiaineet tarjoavat lisää spesifisyyttä MS-taudin kaltaisten leesioiden PET-kuvantamiseen. FR on lupaava kohde sekä MS-taudin in vivo kuvantamiselle että lääkehoitojen kehittämiselle

Stability condition for the drive bunch in a collinear wakefield accelerator

The beam breakup instability of the drive bunch in the structure-based collinear wakefield accel- erator is considered and a stabilizing method is proposed. The method includes using the specially designed beam focusing channel, applying the energy chirp along the electron bunch, and keeping energy chirp constant during the drive bunch deceleration. A stability condition is derived that defines the limit on the accelerating field for the witness bunch.Comment: 10 pages, 6 figure

Finnish Parliament on the Semantic Web: Using ParliamentSampo Data Service and Semantic Portal for Studying Political Culture and Language

Peer reviewe

Finnish Parliament on the Semantic Web: Using ParliamentSampo Data Service and Semantic Portal for Studying Political Culture and Language

Peer reviewe

Data-Independent Acquisition Mass Spectrometry in Metaproteomics of Gut Microbiota—Implementation and Computational Analysis

Metagenomic approaches focus on taxonomy or gene annotation but lack power in defining functionality of gut microbiota. Therefore, metaproteomics approaches have been introduced to overcome this limitation. However, the common metaproteomics approach uses data-dependent acquisition mass spectrometry, which is known to have limited reproducibility when analyzing samples with complex microbial composition. In this work, we provide a proof-of-concept for data-independent acquisition (DIA) metaproteomics. To this end, we analyze metaproteomes using DIA mass spectrometry and introduce an open-source data analysis software package diatools, which enables accurate and consistent quantification of DIA metaproteomics data. We demonstrate the feasibility of our approach in gut microbiota metaproteomics using laboratory assembled microbial mixtures as well as human fecal samples. </p

Cytokinin and Auxin Display Distinct but Interconnected Distribution and Signaling Profiles to Stimulate Cambial Activity.

Despite the crucial roles of phytohormones in plant development, comparison of the exact distribution profiles of different hormones within plant meristems has thus far remained scarce. Vascular cambium, a wide lateral meristem with an extensive developmental zonation, provides an optimal system for hormonal and genetic profiling. By taking advantage of this spatial resolution, we show here that two major phytohormones, cytokinin and auxin, display different yet partially overlapping distribution profiles across the cambium. In contrast to auxin, which has its highest concentration in the actively dividing cambial cells, cytokinins peak in the developing phloem tissue of a Populus trichocarpa stem. Gene expression patterns of cytokinin biosynthetic and signaling genes coincided with this hormonal gradient. To explore the functional significance of cytokinin signaling for cambial development, we engineered transgenic Populus tremula × tremuloides trees with an elevated cytokinin biosynthesis level. Confirming that cytokinins function as major regulators of cambial activity, these trees displayed stimulated cambial cell division activity resulting in dramatically increased (up to 80% in dry weight) production of the lignocellulosic trunk biomass. To connect the increased growth to hormonal status, we analyzed the hormone distribution and genome-wide gene expression profiles in unprecedentedly high resolution across the cambial zone. Interestingly, in addition to showing an elevated cambial cytokinin content and signaling level, the cambial auxin concentration and auxin-responsive gene expression were also increased in the transgenic trees. Our results indicate that cytokinin signaling specifies meristematic activity through a graded distribution that influences the amplitude of the cambial auxin gradient.J.I., K.N., J.A.S. and Y.H. were funded by ERC, Fibic EffFibre, Academy of Finland (by Centre of Excellence and other programs) and Tekes. O.P.S., L.P. and P.A. were funded by Academy of Finland. The hormone analysis was supported by Japan Advanced Plant Science Network. R.P.B. was funded by grants from Berzili, TC4F and FUTURE trees.This is the author accepted manuscript. The final version is available from Cell Press via http://dx.doi.org/10.1016/j.cub.2016.05.05

Parlamenttisampo: eduskunnan aineistojen linkitetyn avoimen datan palvelu ja sen käyttömahdollisuudet

Semanttinen parlamentti -hankkeessa 2020–2022 luodaan eduskunnan tietokannoista ja niihin liittyvistä muista aineistoista uudenlainen linkitetyn avoimen datan (Linked Open Data, LOD) palvelu, tietoinfrastruktuuri ja semanttinen portaali Parlamenttisampo – eduskunta semant­tisessa webissä, joiden avulla tutkitaan poliittista kulttuuria ja kieltä. Dataa linkittämällä voi-daan rikastaa eduskuntadataa muilla tietolähteillä kuten biografisella tiedolla, terminologioilla ja lainsäädännön dokumenteilla. Parlamenttisampo on kieli- ja semanttisen webin teknologioihin perustuva palvelukokonaisuus tutkijoita, kansalaisia, mediaa ja valtionhallintoa varten. Artik­kelissa esitellään hankkeen visio, ensimmäisiä tuloksia ja niiden hyödyntämismahdollisuuksia: eduskunnan kaikkien täysistuntojen 1907–2021 yli 900 000 puheesta on valmistunut linkitetyn datan tietämysgraafi (knowledge graph); data on myös saatavilla XML-muodossa, jossa hyö­dynnetään uutta kansainvälistä Parla-CLARIN-formaattia. Ensimmäistä kertaa eduskunnan puheiden koko aikasarja on muunnettu dataksi ja datapalveluksi yhtenäisessä muodossa. Lisäksi puheet on yhdistetty eduskunnan kansanedustajien tietokannasta luotuun ja muista tietolähteistä rikastettuun toiseen tietämysgraafiin laajemmaksi ontologiaperustaiseksi datapalveluksi Fin- Parla. Datapalvelua voidaan käyttää eduskuntatutkimukseen parlamentaarisesta ja edustuksel-lisesta kulttuurista sekä poliittisen kielen käytöstä analysoimalla kansanedustajien täysistunnois­sa pitämiä puheita ja poliitikkojen verkostoja data-analyysin keinoin. Palvelun rajapinnan avulla voidaan myös kehittää eri käyttäjäryhmille sovelluksia, kuten hankkeessa valmistuva Parlament­tisampo-portaali.</p

Comparison of: (2S,4R)-4-[F-18]Fluoroglutamine, [C-11]Methionine, and 2-Deoxy-2-[F-18]Fluoro-D-Glucose and Two Small-Animal PET/CT Systems Imaging Rat Gliomas

Purpose: The three positron emission tomography (PET) imaging compounds: (2S,4R)-4-[F-18]Fluoroglutamine ([F-18]FGln), L-[methyl-C-11]Methionine ([C-11]Met), and 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) were investigated to contrast their ability to image orthotopic BT4C gliomas in BDIX rats. Two separate small animal imaging systems were compared for their tumor detection potential. Dynamic acquisition of [F-18]FGln was evaluated with multiple pharmacokinetic models for future quantitative comparison.Procedures: Up to four imaging studies were performed on each orthotopically grafted BT4C glioma-bearing BDIX rat subject (n = 16) on four consecutive days. First, a DOTAREM(R) contrast enhanced MRI followed by attenuation correction CT and dynamic PET imaging with each radiopharmaceutical (20 min [C-11]Met, 60 min [F-18]FDG, and 60 min [F-18]FGln with either the Molecubes PET/CT (n = 5) or Inveon PET/CT cameras (n = 11). Ex vivo brain autoradiography was completed for each radiopharmaceutical and [F-18]FGln pharmacokinetics were studied by injecting 40 MBq into healthy BDIX rats (n = 10) and collecting blood samples between 5 and 60 min. Erythrocyte uptake, plasma protein binding and plasma parent-fraction were combined to estimate the total blood bioavailability of [F-18]FGln over time. The corrected PET-image blood data was then applied to multiple pharmacokinetic models.Results: Average BT4C tumor-to-healthy brain tissue uptake ratios (TBR) for PET images reached maxima of: [F-18]FGln TBR: 1.99 +/- 0.19 (n = 13), [F-18]FDG TBR: 1.41 +/- 0.11 (n = 6), and [C-11]Met TBR: 1.08 +/- 0.08, (n = 12) for the dynamic PET images. Pharmacokinetic modeling in dynamic [F-18]FGln studies suggested both reversible and irreversible uptake play a similar role. Imaging with Inveon and Molecubes yielded similar end-result ratios with insignificant differences (p > 0.25).Conclusions: In orthotopic BT4C gliomas, [F-18]FGln may offer improved imaging versus [C-11]Met and [F-18]FDG. No significant difference in normalized end-result data was found between the Inveon and Molecubes camera systems. Kinetic modelling of [F-18]FGln uptake suggests that both reversible and irreversible uptake play an important role in BDIX rat pharmacokinetics.</p

A molecular-based identification resource for the arthropods of Finland

Publisher Copyright: © 2021 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.To associate specimens identified by molecular characters to other biological knowledge, we need reference sequences annotated by Linnaean taxonomy. In this study, we (1) report the creation of a comprehensive reference library of DNA barcodes for the arthropods of an entire country (Finland), (2) publish this library, and (3) deliver a new identification tool for insects and spiders, as based on this resource. The reference library contains mtDNA COI barcodes for 11,275 (43%) of 26,437 arthropod species known from Finland, including 10,811 (45%) of 23,956 insect species. To quantify the improvement in identification accuracy enabled by the current reference library, we ran 1000 Finnish insect and spider species through the Barcode of Life Data system (BOLD) identification engine. Of these, 91% were correctly assigned to a unique species when compared to the new reference library alone, 85% were correctly identified when compared to BOLD with the new material included, and 75% with the new material excluded. To capitalize on this resource, we used the new reference material to train a probabilistic taxonomic assignment tool, FinPROTAX, scoring high success. For the full-length barcode region, the accuracy of taxonomic assignments at the level of classes, orders, families, subfamilies, tribes, genera, and species reached 99.9%, 99.9%, 99.8%, 99.7%, 99.4%, 96.8%, and 88.5%, respectively. The FinBOL arthropod reference library and FinPROTAX are available through the Finnish Biodiversity Information Facility (www.laji.fi) at https://laji.fi/en/theme/protax. Overall, the FinBOL investment represents a massive capacity-transfer from the taxonomic community of Finland to all sectors of society.Peer reviewe

Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis

BackgroundActivated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-beta (FR-beta), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of Ga-68-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (Ga-68-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-beta is expressed in the brain of patients with MS.MethodsFocal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). Ga-68-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-beta expression in postmortem brain samples from 5 patients with MS and 5 healthy controls.ResultsImmunofluorescence and histological analyses revealed significant reductions in FR-beta expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected Ga-68-FOL in the brain was low and did not differ between the groups, but the in vitro binding of Ga-68-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-beta positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples.ConclusionsEC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-beta -positive cells in chronically active plaques, which suggests that these results may have translational relevance