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Mineral phase discrimination of the chelyabinsk meteorite by LIBS mapping/cluster analysis
No full textThe Chelyabinsk meteorite, resulting from one of the most extensively studied meteor events of the 21st century, was analyzed to investigate compositional heterogeneity across its inner matrix, fusion crust, and metallic inclusions using non-invasive techniques such as Laser-Induced Breakdown Spectroscopy (LIBS) and Raman spectroscopy, which allowed the preservation of the integrity of the sample. A high-resolution scanning micro-LIBS analysis was conducted to visualize the spatial heterogeneity of the meteorite at the micrometer scale. Unsupervised K-means clustering enabled segmentation of chemically distinct domains and correlation with major mineral phases identified by Raman spectroscopy, including olivine, pyroxene, chromite, and plagioclase. Calibration-Free LIBS (CF-LIBS) was applied to achieve semi-quantitative elemental analysis without the need for external calibration standards, yielding compositions consistent with LL-type ordinary chondrites and confirming the classification of the Chelyabinsk meteorite as an LL chondrite. The methodology demonstrated here highlights the utility of combining LIBS and Raman spectroscopy for non-destructive, high-resolution chemical and mineralogical characterization of meteorites, offering a valuable toolset for planetary science and meteoritic research.Peer reviewe
Inflammatory mechanisms contribute to long-term cognitive deficits induced by perinatal asphyxia via interleukin-1
No full textPerinatal asphyxia remains a leading cause of neonatal mortality and a major contributor to permanent neurological deficits. Even mild cases can result in long-term neurodevelopmental, cognitive, behavioural and psychiatric disorders. However, the mechanisms underlying asphyxia-induced hypoxic-ischaemic brain injury remain poorly understood, limiting the development of targeted interventions during the critical early plastic period. To explore the behavioural and molecular outcomes of perinatal asphyxia that may model important aspects of neuropsychiatric disorders observed in humans, we utilised a translationally relevant, non-invasive oxygen deprivation model of asphyxia in postnatal day 7 rats. We conducted a comprehensive assessment of asphyxia-induced changes, integrating neurobehavioural profiling (evaluating cognitive, emotional, social and neuromotor functions), microglial morphology analysis, neuroimaging, stress hormone measurement and whole-transcriptome sequencing techniques to elucidate the acute and long-term functional consequences. Consistent with clinical observations, the extensive functional assessment revealed distinct sex-dependent effects, including increased anxiety and impulsivity, attention deficits and impaired inhibitory control, which were observed exclusively in males, with no apparent sensorimotor deficits. This phenotype resembling attention deficit hyperactivity disorder (ADHD) in adult rats was associated with a lasting increase in inhibitory bouton densities in the medial prefrontal cortex. The development of an acute inflammatory response after perinatal asphyxia marked by phenotypic transformation of microglia, paralleled brain perfusion and stress hormone changes. Notably, microglial changes were mitigated by the blockade of proinflammatory interleukin-1 signalling via systemic IL-1 receptor antagonist (IL-1RA) administration in a therapeutically relevant time window. Importantly, early blockade of proinflammatory responses was able to prevent cognitive deficits in adulthood and normalise inhibitory bouton densities. RNA sequencing analysis revealed asphyxia-induced dysregulation of molecular pathways targeting GABAergic signalling, potentially contributing to subsequent morphological and neuropsychiatric alterations. IL-1RA treatment appeared to engage distinct epigenetic regulatory mechanisms, rather than merely reversing these disruptions in the acute post-asphyxia period. Collectively, these findings demonstrate that perinatal asphyxia induces marked behavioural deficits in attention and inhibitory control, paralleled by lasting inhibitory and epigenetic dysregulation, preceded by acute induction of microglia-driven inflammatory processes in the medial prefrontal cortex. Systemic IL-1RA administration may represent a promising therapeutic opportunity to prevent long-term cognitive impairments caused by perinatal asphyxia.Peer reviewe
Ambient temperature, solar radiation and sickness absence due to mental disorders in Finland : A distributed lag non-linear regional analysis
No full textBackground Changes in ambient temperature and solar radiation have been associated with mental health but their relationship with sickness absence due to mental disorders is unclear. Methods We linked nationwide weekly sickness absence registers with meteorological data (2006 to 2017), collected from all 22 mainland counties and 5 larger areas in Finland, and used distributed lag non-linear models (DLNM) to explore potential non-linear and delayed relationships. Results Our results indicate higher levels of sickness absence when solar radiation is low. We did not find statistically significant associations at cold temperature extremes even though the findings pointed towards higher sickness absence levels at colder extreme temperatures. The modelling showed lower levels of sickness absence when the temperature was more than + 10 °C. For solar radiation, sickness absence rates were higher when solar radiation was less than approximately 8000 to 9000 KJ/m2 and lower when it exceeded 10,000 to 12,000 KJ/m2. To some extent, the relationships of sickness absence with both temperature and solar radiation reflected the climatic differences between the northern and southern parts of the country. Conclusions In Finland, higher exposure to temperature and solar radiation are associated with lower levels of sickness absence due to mental disorders whereas colder temperatures and lower amount of solar radiation are associated with higher levels. The associations for low solar radiation were more robust than those for low temperatures, with a typical delay of up to a couple of weeks.Peer reviewe
Saliva samples in SARS-Cov-2 virus detection compared to the nasopharyngeal RT-PCR findings in individuals with suspected COVID-19 infection
No full textAccurate and cost-effective testing for SARS-CoV-2 is an ongoing need in public health. Nasopharyngeal swab (NPS) samples have been the benchmark as testing material but there are challenges connected to sample collection. We examined the usability of saliva as sample material for high-throughput laboratory molecular testing for SARS-CoV-2. Saliva samples from 108 individuals with suspected acute SARS-CoV-2 infection were collected and tested with cobas® SARS-CoV-2 and cobas® SARS-CoV-2 Duo tests (both Roche Molecular Diagnostics) to detect SARS-CoV-2 nucleic acids and compared to findings from NPS samples. Both cobas® tests performed well for saliva samples with 96 % positive percent agreement for both tests, 98 % negative percent agreement for cobas® SARS-CoV-2 test, and 100 % negative percent agreement for cobas® SARS-CoV-2 Duo test when compared to NPS samples. Saliva is a potential sample material for detecting SARS-CoV-2 infection in adult outpatients and can be considered as sample material to conserve health care resources.Peer reviewe
Modelling lung permeability of pharmaceuticals: The effectiveness of biomimetic open tubular capillary electrochromatography and immobilised artificial membrane chromatography coupled with mass spectrometry
No full textIn this study, the potential of mass spectrometry (MS) −compatible biomimetic chromatography (BMC) was explored to assess drug permeability across biological membranes, pioneering a comparison of its application to model pulmonary absorption. Two BMC techniques were evaluated i.e., immobilised artificial membrane liquid chromatography (IAM-LC) and open-tubular capillary electrochromatography (OT-CEC) on fused silica capillaries coated with phospholipid vesicles. This application was validated on a dataset of 53 structurally diverse compounds whose pulmonary permeability is already evidenced in scientific literature. The IAM-LC model exhibited a stronger correlation with conventional n-octanol/water partitioning metrics (log Po/w and log D7.4) than OT-CEC. Analytical retention appeared to be influenced by a complex interplay of hydrophobic, electrostatic, and structural factors, leading to weaker correlations particularly with log Po/w. Coupling these techniques with MS enabled high-throughput analysis of mixtures and allowed detection of compounds lacking UV chromophores. The MS-based IAM-LC approach demonstrated excellent robustness with data obtained using a CE setup with UV detection (R2 = 0.95). On the other hand, stable phospholipid coatings were achieved in OT-CEC-MS providing effectiveness across varying liposomal compositions. IAM-LC, mimicking a phosphatidylcholine (PC) −based lipid bilayer, displayed a strong correlation between log kwIAM and log Papp, with an R2 value of 0.72 observed for compounds with molecular masses > 300 g mol−1 where paracellular diffusion is negligible. Meanwhile, OT-CEC-MS allowed for the incorporation of phospholipids other than PC in the stationary phase, offering complementary insights into drug–membrane interactions beyond partitioning. The strongest correlations between IAM-LC and OT-CEC parameters were observed for cationic species with log KD > 1.5. These techniques demonstrated significant potential to support drug development programmes in both industrial and academic settings by facilitating high-throughput permeability screening and pharmacokinetics −focused lead optimisation.Peer reviewe
Kirkas-soluisen munuaissyövän kasvaimen mikroympäristön kartoitus
No full textAbstract:
Understanding the tumour microenvironment is crucial for advancing our knowledge of cancer progression and pathogenesis, as well as for enhancing the efficacy of the new wave of immune-based therapies. Further research is needed to develop robust biomarkers for Immuno-oncological (IO) treatments, enhancing the precision of novel cancer therapies. Here, spatial transcriptomics technologies can offer valuable insights into the immune architecture of the tumour microenvironment (TME).
This MSc thesis investigates the heterogeneity of clear cell renal cell carcinoma (ccRCC) using ccRCC patients’ (n=3) tissue samples. Advanced methodologies such as spatial transcriptomics, multiplex immunohistochemistry (mIHC), and single-cell RNA sequencing (scRNA-seq), were used to characterize TME. By integrating machine learning algorithms and highly developed image analysis pipelines, immune architectures were mapped to identify potential biomarkers associated with sensitivity to immuno-oncological (IO) therapies.
The findings of this MSc thesis reveal significant inter-patient variability in immune architecture, with distinct patterns of immune cell infiltration. Notably, patient samples exhibited varying degrees of immune activation, with patient one (pt1.) demonstrating a robust immune response characterized by a high proportion of cytotoxic T-cells and the presence of tertiary lymphoid structures. In contrast, other two patients displayed immune-suppressive environments dominated by regulatory T-cells and M2 macrophages, which may contribute to poorer therapeutic outcomes.
Comparative analyses of spatial transcriptomics and mIHC highlight the strengths and limitations of each approach, with mIHC providing more detailed insights into the spatial relationships between immune cell types and tumour structures. Furthermore, scRNA-seq allowed for the identification of distinct clonal populations within ccRCC tumours, revealing genomic heterogeneity not detectable through bulk analyses.
Integrating machine learning techniques to deconvolute spatial transcriptomics data enhances our understanding of the TME and its cellular composition. This work underscores the necessity for personalized medicine approaches that accurately model patient TME, paving the way for future studies aimed at improving therapeutic strategies for ccRCC. Expanding the patient cohort, and incorporating longitudinal analyses, will be essential for validating our findings and exploring novel therapeutic pipelines targeting the TME.Kasvaimen mikroympäristön ymmärtäminen on ratkaisevan tärkeää syövän etenemisen ja patogeneesin ymmärtämisessä sekä uusien immuunijärjestelmää aktivoivien hoitojen kohdentamisessa. Lisätutkimusta tarvitaan luotettavien biomarkkereiden kehittämiseksi immuunijärjestelmää aktivoiville hoidoille. Uudenlaiset mikroympäristöön pohjautuvat biomarkkerit voivat parantaa syöpähoitojen kohdennusta ja tehokkuutta.
Tämä pro gradu -tutkielma tutkii kirkassoluisen munuaissyövän (ccRCC) heterogeenisyyttä käyttäen ccRCC-potilaiden (n=3) kudosnäytteitä. Hyödyntämällä menetelmiä, kuten spatiaalista transkriptomiikkaa, moninkertaistettua immunohistokemiaa (mIHC) ja yksisolu-RNA-sekvensointia (scRNA-seq) mittasimme immuuni solujen määrää ja aktivaatiota kasvaimen ympäristössä. Integroimalla koneoppimisalgoritmeja ja kehittyneitä kuvantamismenetelmiä spatiaalisen transkriptomiikan kanssa onnituin kartoittamaan immuunivasteita kasvaimen mikroympäristössä.
Tuloksemme paljastavat merkittävää potilaiden välistä vaihtelua immuunisolujen järjestäytymisessä, eritoten immuunisolujen tunkeutumisessa kasvaimeen. Erityisen huomionarvoista oli, että yhdellä potilaista (pt1) oli voimakkaampi immuunivaste, johon liittyi korkea sytotoksisten T-solujen osuus ja kolmannen asteen lymfaattisten rakenteiden muodostuminen kasvaimeen. Kahdella muulla potilaalla kasvaimen mikroympäristö oli immunosuppressiivisempi: siinä hallitsivat säätelijä-T-solut ja M2-makrofagit, joiden tiedetään vaikuttavan negatiivisesti immunoterapioiden hoitovasteisiin.
Spatiaalisen transkriptomiikan ja mIHC:n vertailu toi esiin kummankin menetelmän vahvuudet ja rajoitteet. mIHC mahdollistaa immuunisolujen ja kasvaimen avaruudellisten suhteiden tarkemman hahmottamisen, kun taas spatiaalinen transkriptomiikka tarjoaa mahdollisuuden tarkemman phenotyyppien tarkastelun koneoppimisanalyysi metodeilla.
Koneoppimisen integrointi spatiaaliseen transkriptomiikkaan syvensi ymmärrystämme kasvaimen mikroympäristöstä ja sen solukoostumuksesta. Tutkimukseni korostaa tuumorin soluarkkitehtuurin tarkemman mallintamisen hyötyä henkilökohtaisessa lääketieteessä, erityisesti immuno-onkologisten hoitojen mahdollisen tehokkuuden arvioinnissa ccRCC-potilailla. Jatkossa laajempi potilasaineisto ja pitkäaikaiset tutkimukset ovat välttämättömiä tulosten vahvistamiseksi ja uusien syöpähoitostrategioiden kehittämiseksi
Balancing grazing and biodiversity : Arthropod responses to modern cattle farming practices
No full textRuminant production exerts severe pressure on ecosystems through land use change for pasture and fodder production, contributing to biodiversity loss, disruption of natural biogeochemical fluxes, and climate change. Whereas ruminant production can support biodiversity that has co-evolved with grasslands and grazing animals, the values of temporary grasslands are poorly understood. In this study, we assessed the effects of grazing regimes practised on modern cattle farms, including no grazing, on the abundance, biomass, and taxonomic richness of aerial and ground-dwelling arthropods. We assessed the potential value of organic management compared to grazing on conventional farms, and the role of vegetation structure on the pastures. We sampled arthropods in temporary pastures and silage grasslands, spring cereal fields, and in farmyards on 43 dairy and suckler cow farms in Finland. We show that grazing benefits the richness of ground-dwelling arthropods in fields, and the benefits were most evident at extensive levels of grazing at the farm scale. Grazing had no significant benefits for the biomass of ground-dwelling arthropods or relative abundance of aerial arthropods over field vegetation. Grazed rotational grasslands had similar levels of arthropods as mown grasslands or cereal crops, except for a higher richness of ground-dwelling arthropods. Taxonomic richness of ground-dwelling arthropods was higher on organic farms than conventional, but only at low grazing intensities. Although our study suggests several ways in which livestock farmers can maintain and increase arthropod populations on their farms, these may be associated with some reduction in production output on modern farms oriented towards high yields.Peer reviewe
Selective cytotoxicity of anhydroicaritin in ER-positive breast cancer via ESR1-mediated MAPK and apoptotic signaling
No full textAnhydroicaritin (AHI), a chemically characterized prenylated flavonoid, exhibits strong and selective cytotoxicity against estrogen receptor-positive (ER+) breast cancer cells. In this study, we aimed to elucidate its molecular and cellular toxicological mechanisms using an integrated strategy consisting of chemoinformatics, machine learning-based target prioritization, Mendelian randomization (MR) causal inference, and in vitro mechanistic assays. Network pharmacology analysis revealed that ESR1 (estrogen receptor 1) was ranked as the top hit hub gene and was further supported as a functional mediator of AHI action by machine learning models and MR analysis. Molecular docking and 100-ns molecular dynamics simulations demonstrated that AHI could form a stable and energetically preferred interaction with estrogen receptor 1 (ESR1). Subsequent mechanistic experiments in MCF-7 and ZR-75-1 cells revealed that AHI could attenuate the activity of MAPK signaling pathway and induce apoptosis by downregulating ESR1 mRNA expression through reducing ER alpha phosphorylation. Notably, AHI exhibited weak cytotoxicity against normal mammary epithelial cells, suggesting that it might exhibit selective toxicity toward malignant phenotypes. Our findings offered mechanistic evidence for the duallevel (post-translational and transcriptional) regulation of ESR1 signaling by AHI in ER+ breast cancer and suggested that AHI might be a subtype-specific chemotherapeutic lead compound.Peer reviewe
Kasvaimen mikroympäristön kliininen merkitys klassisessa Hodgkinin lymfoomassa
No full textClassic Hodgkin lymphoma (cHL) is an aggressive malignancy originating from B lymphocytes, which treatment aims at a permanent cure and has an excellent prognosis. It is one of the most common malignancies in young adults. Treatment is designed based on clinical risk factors, which, however, are not sufficient to identify patients with poor prognosis. For that reason, there is an unmet need for more accurate biological prognostic factors as part of disease risk classification and for more effective therapies that consider individual biological features of the tumor. In addition, taking into account the young age of patients with excellent overall prognosis, there is also a need for new targeted therapies with lower toxicity.
The composition of the tumor is exceptional in cHL, as it consists mainly of benign immune-related and stromal cells, which form the tumor microenvironment (TME). Malignant Hodgkin Reed-Sternberg (HRS) cells comprise only about 1-3% of the total tumor cellularity, but they actively shape the microenvironment to favor their growth and to evade immune defenses. TME is known to have a significant role in the pathogenesis of cHL.
The purpose of this study was 1) to investigate the composition of TME in primary cHL both in gene and protein expression levels focusing on T-cells, macrophages, checkpoint molecules, and cancer-associated fibroblasts (CAFs), 2) to correlate findings with clinical risk factors and prognosis, and 3) to search for new biomarkers that could be utilized in targeted treatments in the future.
We found that the composition of TME is very heterogeneous between patients. TME is enriched in either macrophages or T-cells, which, however, did not associate with the outcome. Instead, high expression of different checkpoint molecules in the TME associated with shortened overall survival. Particularly high number of tumor-associated macrophages expressing checkpoint molecules PD-L1 or IDO-1 predicted poor treatment outcome. We also identified a rare macrophage phenotype, which expressed FAP-enzyme and associated with an inferior progression-free survival (PFS). In contrast, high proportion of CAFs translated with better PFS independent of the clinical covariables. In interaction analysis, we found that despite the positive impact of CAFs on survival, patients with HRS cells surrounded by PDGFRβ-expressing CAFs had an inferior outcome.
In conclusion, our study highlighted the prognostic significance of checkpoint molecules in cHL and significant differences in tumor cell composition between patients. In addition, the spatial architecture of the cells within the tumor plays a crucial role in determining the outcome. The results underscore the need for more accurate individual prognostic factors and targeted therapies in cHL.Klassinen Hodgkinin lymfooma on aggressiivinen B-imusoluista lähtöisin oleva syöpä, jonka hoito tähtää pysyvään parantumiseen ja sen ennuste on erinomainen. Se on yksi nuorten yleisimmistä syövistä. Hoito suunnitellaan kliinisten riskitekijöiden perusteella, vaikkakaan ne eivät ole riittävän tarkkoja tunnistamaan huonon ennusteen potilaita. Tämän vuoksi olisi tarvetta tarkemmille biologisille ennustetekijöille osana potilaiden riskiluokittelua sekä kasvaimen yksilölliset biologiset ominaisuudet huomioiville tehokkaammille hoidoille. Lisäksi huomioiden potilaiden nuori ikä ja erinomainen kokonaisennuste, olisi myös tarvetta vähemmän haittavaikutuksia aiheuttaville kohdennetuille hoidoille.
Klassisessa Hodgkinin lymfoomassa kasvain koostuu pääosin hyvänlaatuisista immuunipuolustuksen ja tukikudoksen soluista, jotka muodostavat kasvaimen mikroympäristön. Pahanlaatuiset Hodgkin Reed-Sternbergin (HRS) solut käsittävät vain noin 1-3% kasvaimen kokonaissolukkuudesta, mutta ne muokkaavat aktiivisesti mikroympäristöä kasvulleen suotuisaksi ja immuunipuolustuksen välttämiseksi. Kasvaimen mikroympäristöllä onkin merkittävä rooli klassisen Hodgkinin lymfooman patogeneesissä.
Tutkimuksen tarkoituksena oli selvittää primaarissa klassisessa Hodgkinin lymfoomassa: 1) kasvaimen mikroympäristön koostumusta geeni- ja proteiini-ilmentymätasolla, keskittyen T-soluihin, makrofageihin, tarkastuspistemolekyyleihin sekä syöpään liittyviin fibroblasteihin, 2) korreloida löydöksiä kliinisiin riskitekijöihin ja ennusteeseen sekä 3) etsiä uusia biomarkkereita, joita voitaisiin tulevaisuudessa hyödyntää kohdennetuissa hoidoissa.
Tutkimuksessa todettiin, että klassisessa Hodgkinin lymfoomassa mikroympäristö on hyvin heterogeeninen. Se on rikastunut joko makrofageilla tai T-soluilla, mutta tällä ei todettu olevan ennusteellista merkitystä. Sen sijaan runsas eri tarkastuspistemolekyylien ilmentyminen mikroympäristössä liittyi lyhentyneeseen kokonaiselossaoloaikaan. Erityisesti runsas määrä PD-L1 tai IDO-1 tarkastuspistemolekyylejä ilmentäviä makrofageja tuumorikudoksessa ennustivat huonompaa hoitotulosta. Tunnistimme myös harvinaisen makrofagityypin, joka ilmensi FAP-entsyymiä ja liittyi huonontuneeseen ennusteeseen. Sen sijaan syöpään liittyvien fibroblastien suuri osuus liittyi pidempään taudin etenemisvapaaseen aikaan itsenäisenä ennustetekijänä, mutta niillä potilailla, joiden tuumorikudoksessa PDGFRβ-proteiinia ilmentävät fibroblastit olivat vuorovaikutuksessa HRS-solujen kanssa, oli huonompi ennuste.
Yhteenvetona tutkimuksessamme korostui tarkastuspistemolekyylien ennusteellinen merkitys ja potilaskohtaiset merkittävät erot kasvaimen solukoostumuksessa. Tulokset korostavat tarvetta yksilöllisille ennustetekijöille ja kohdennetuille hoidoille klassisessa Hodgkinin lymfoomassa