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Association Between Accelerometer-Measured Physical Activity and Mobility Limitations in Twins
No full textBackground: The associations between mobility limitations and device-measured physical activity are sparsely studied. In this study, these associations are studied among community-dwelling older twins. Methods: This cross-sectional study utilized data gathered in 2014-2016 for the MOBILETWIN study. Participants were twins born in Finland between 1940 and 1944 (774 participants, mean age 73 years). Physical activity was measured with a hip-worn accelerometer. Mobility limitations were assessed with a questionnaire. Results: Individual-level analyses revealed that physical activity was associated with mobility limitations. Participants with severe mobility limitations took 2,637 (SD = 1,747) steps per day, those with some mobility limitations 4,437 (SD = 2,637) steps, and those without mobility limitations 7,074 (SD = 2,931) steps (p < .05). The within-twin pair analyses revealed the same pattern for the 144 dizygotic twin pairs, but no associations were seen for the 117 monozygotic twin pairs. Conclusions: Accelerometer-measured physical activity and mobility limitations were associated in community-dwelling older adults. Genetic factors may explain some of the variations in physical activity.Peer reviewe
Characterizing randomness in parameterized quantum circuits through expressibility and average entanglement
No full textWhile scalable error correction schemes and fault tolerant quantum computing seem not to be universally accessible in the near sight, the efforts of many researchers have been directed to the exploration of the contemporary available quantum hardware. Due to these limitations, the depth and dimension of the possible quantum circuits are restricted. This motivates the study of circuits with parameterized operations that can be classically optimized in hybrid methods as variational quantum algorithms, enabling the reduction of circuit depth and size. The characteristics of these Parameterized Quantum Circuits (PQCs) are still not fully understood outside the scope of their principal application, motivating the study of their intrinsic properties. In this work, we analyse the generation of random states in PQCs under restrictions on the qubits connectivities, justified by different quantum computer architectures. We apply the expressibility quantifier and the average entanglement as diagnostics for the characteristics of the generated states and classify the circuits depending on the topology of the quantum computer where they can be implemented. As a function of the number of layers and qubits, circuits following a Ring topology will have the highest entanglement and expressibility values, followed by Linear/All-to-all almost together and the Star topology. In addition to the characterization of the differences between the entanglement and expressibility of these circuits, we also place a connection between how steep is the increase on the uniformity of the distribution of the generated states and the generation of entanglement. Circuits generating average and standard deviation for entanglement closer to values obtained with the truly uniformly random ensemble of unitaries present a steeper evolution when compared to others.Peer reviewe
Background characteristics and neuropathological findings of medico-legal autopsy cases with chronic alcohol use and acute head injury
No full textChronic alcohol use is often associated with traumatic brain injury (TBI). This study aimed to compare background characteristics, injury circumstances, primary head injuries, and secondary brain injuries among TBI cases with and without a documented history of chronic alcohol use. The sample comprised neuropathologically examined medico-legal autopsy cases with acute head injuries from Helsinki, Finland, over the years 2016–2022. Data on chronic excessive alcohol use were collected from medical records and police files; other background and circumstantial data were collected from medical records, police files, and cause-of-death investigation documents; and data on primary head injuries and secondary brain injuries were collected from autopsy and neuropathology reports. The dataset comprised 47 cases, of whom 19 had a history of chronic alcohol use (40.4%). Assault was the most common circumstance of injury among chronic alcohol users (47.4%) while falls prevailed among control cases (32.1%); unknown circumstances were common among both groups. There were no statistically significant differences in the prevalence of primary head injuries or postinjury survival between the groups. As for secondary brain injuries, hypoxic-ischaemic neuronal injury was significantly more common among chronic alcohol users in the frontal cortex (84.2% vs. 28.6%), parietal cortex (84.2% vs. 32.1%), hippocampus (63.2% vs. 25.0%), and lenticular nucleus (73.7% vs. 21.4%). Our findings suggest that chronic alcohol users may not necessarily have more diverse or complex primary injuries, but they may have more extensive secondary injuries. Further research should aim to explore the potential aetiology of hypoxic-ischaemic neuronal injury among chronic alcohol users.Peer reviewe
Comparison of cyclosporine and tacrolimus after liver transplantation for primary biliary cholangitis : A propensity score–matched intention-to-treat registry study
No full textThe optimal calcineurin inhibitor after liver transplantation (LT) for primary biliary cholangitis (PBC) remains debated. We compared tacrolimus with cyclosporine in a propensity score–matched intention-to-treat analysis from the Scientific Registry of Transplant Recipients. We included adults with PBC who underwent primary LT from 1995 to 2022. Patients with initial cyclosporine treatment were 1:3 matched with those with initial tacrolimus treatment, ensuring exact calendar-period match. Primary outcomes were patient and graft survival. After matching, 579 patients with PBC and initial cyclosporine and 1348 with tacrolimus were well balanced for baseline characteristics. During a median follow-up of 11.1 years, 1044 (54%) deaths and 124 (6%) re-LTs occurred. In the overall matched sample, no significant survival difference emerged between cyclosporine and tacrolimus. However, tacrolimus conferred a survival advantage in some secondary analysis, such as LT after year 2000 and women, and in a 6-month landmark analysis excluding early postoperative events and calcineurin inhibitor switches. Cyclosporine did not reduce graft loss from PBC recurrence or affect laboratory markers of recurrence. In conclusion, we found no benefit of starting immunosuppression with cyclosporine after LT for PBC.Peer reviewe
Diverging benthic trait diversity and drivers across fjord to slope habitats of the high Arctic
No full textClimate change is challenging species' abilities to respond and function. In the Arctic, shifts in temperature and ice cover are disrupting established biological interactions and thereby ecosystem structure and function. By examining epibenthic communities in coastal and continental shelf habitats of Northeast Greenland that have been ice-locked for centuries, we provide a contemporary baseline of benthic functional diversity through a trait- based approach. We show clear trends in biodiversity and traits from a priori defined groups of fjord, shelf, shelf break, and slope habitats. With biodiversity and functional indices, we identified how fjord and shelf communities could be vulnerable to current and future changes in climate conditions. Using a hierarchical model of species communities (HMSC) we found taxa occurrences, regardless of taxonomic relatedness, were mainly driven by changes in depth, salinity, and oxygen and less so by temperature. Though rising global temperatures are undoubtedly altering the physiochemical structure of the shelf area, our study underscores the significance of often-overlooked environmental factors in Arctic climate change studies. Moreover, we highlight how species traits have a significant role in forming and maintaining community composition by explaining a high amount of among-taxa variation in taxa occurrences and taxa responses to the environment. While the significance of this is not known in relation to community resilience, as Arctic shelf processes intensify ( e.g., Atlantification), changes in benthic communities and their ecological roles will ultimately affect ecosystem functioning and the broader dynamics of complex seascapes.Peer reviewe
Evaluation of potential irrigation water savings by assessing the soil water balance in a vineyard in central Chile
No full textThe main aim of this study was to evaluate the potential savings of irrigation water by assessing the soil water balance during the growing season in a wine vineyard in the Maule region, Chile. This study provides insights into the influences of different irrigation water applications on soil water status and its potential effects on grape yields, water use efficiency (WUE) and the cost of irrigation to help improve irrigation practices in the region and other similar Mediterranean regions. The field experiment compared three levels of irrigation water applied: current irrigation of the vineyard (T0) and two deficit irrigation treatments with reductions to 75% (T1) and 50% of the irrigated water (T2). The measurements included volumetric soil water content, shallow groundwater table, canopy cover and grape yield at harvest during the entire growing season (October 2017 to April 2018). We found a potential reduction of 25% or 50% in the current irrigation system while maintaining the grape yield, increasing the WUE and reducing the cost of irrigation. Consideration of the water stored in the soil by the accumulation of rainfall in the winter season and the potential for capillary rise of shallow groundwaters is crucial for adjusting irrigation to vine water requirements.Peer reviewe
Pseudophakic cystoid macular oedema and posterior capsular opacification rates after combined phaco-trabeculectomy vs. phaco alone
No full textPurpose: To assess the risk for pseudophakic cystoid macular oedema (PCME) and posterior capsular opacification (PCO) associated with combined cataract surgery and trabeculectomy compared to cataract surgery alone. Methods: Data analysis of subjects who underwent routine cataract surgery without and with concomitant trabeculectomy at the Department of Ophthalmology, Bristol Eye Hospital, the UK, between January 2008 and December 2017. Odds ratios (ORs) for PCME between the types of surgeries were calculated using univariate and multivariate regression analysis. Multivariate Cox regression controlling for age and gender was used to estimate the hazard ratio (HR) for neodymium-doped yttrium aluminium garnet (Nd:YAG) laser capsulotomies. Results: This study included 56 973 cataract surgeries without and 288 with concomitant trabeculectomy (phaco-trab) with a mean follow-up time of 6.9 ± 4.2 years. Baseline variables (age and gender, diabetes, pseudoexfoliation, use of pupil expansion device and postoperative follow-up time) were comparable between the groups. Postoperative rates of PCME remained non-significant between the cataract surgery and phaco-trabe groups both in uni- and multi-variate analysis (OR 0.347, 95%CI 0.049–2.477, p = 0.291). Furthermore, in Cox regression analysis adjusted for the patients' age and gender, Nd:YAG laser capsulotomy rates remained non-significant between the cataract surgery and phaco-trabe groups (HR 1.250, 95%CI 0.883–1.769, p = 0.209). Conclusions: In our large cohort study, combining trabeculectomy with cataract surgery did not predispose to an increased PCME or Nd:YAG laser capsulotomy rates.Peer reviewe
Auditory hair cell synaptopathy and stereociliapathy in endoplasmic reticulum stress
No full textThe auditory hair cells of the cochlea are the biological components that allow us to hear. They harbour two specialized structures to fulfil this function—a bundle of small protrusions called the stereocilia on their surface, and a collection of neuronal connections called the ribbon synapses at the base of the cells. The stereocilia allow the conversion of sound into electric signals that are sent to the brain via the ribbon synapses in a process termed mechanotransduction (MET). MET, initiated by healthy stereocilia, is critical for sensitive hearing and, for instance, speech understanding. Healthy stereocilia are the key component of a functional hair cell and the hair cell must maintain its stereocilia throughout the lifespan. Hearing is a vulnerable sense, however. The stereocilia can be damaged structurally and functionally and the hair cells can undergo cell death. Hearing loss is often the result of damage sustained to the hair cells. Ageing, specific gene mutations, and excessive exposure to loud sounds or continuous noise are the common triggers of hearing loss. While the triggers and the problem are identified, it is not well understood what cell-biological mechanisms drive the vulnerability of the hair cells. Here, the overall aim of the presented research is to contribute to the understanding of the biological mechanisms underlying damage to auditory hair cells.
We began by studying genetically modified mouse models where mesencephalic astrocyte-derived neurotrophic factor (Manf) was inactivated. MANF is an endoplasmic reticulum (ER)-resident protein that promotes cell health by antagonizing ER stress-induced cellular dyshomeostasis. Manf-inactivated mice provided a model for studying the impact of ER stress in hair cell pathology. We utilised functional hearing measurements (auditory brainstem response ABR, and distortion product otoacoustic emissions DPOAE) and high-resolution light- and electron microscopy to study the hearing and the cochlea in detail. From hearing onset, Manf-inactivation caused dysfunction of the outer hair cells (OHC), which exhibited structural disarray of the hair bundles. This manifested most prominently as extensive stereocilia fusion in early adulthood—a progressive “stereociliapathy”. The high-frequency basal region of the cochlea was mainly affected. This was accompanied by severe inner hair cell (IHC) ribbon synapse loss—a cochlear “synaptopathy”. Severe hearing loss was apparent in the affected mice. Correspondingly, we found that MANF mutation in a human patient case correlated with severe sensorineural hearing loss from a young age onward.
The phenotype of the Manf-inactivated mice was distinctly dependent on the genetics of the mouse strain, as the C57BL/6J and CD-1 strains mice exhibited pathology, but the CBA/Ca strain did not. The genetic predisposition of the mouse strain determined the hearing loss outcome in these ER stress models. Conditional Manf-inactivation targeted to the cochlea demonstrated that MANF has a local function in the cochlea. Further, conditional Manf-inactivation targeted specifically to the supporting cells in the cochlea showed no pathology, thereby indicating that MANF has an intracellular function in the hair cells.
Following the above findings, we focused on stereocilia fusion, a prominent component of the hair bundle pathology in mature hair cells. How stereocilia fusion forms, what is its molecular structure, and how it contributes to hearing loss are poorly understood. We developed and utilized a super-resolution expansion microscopy protocol for the cochlea to examine the molecular anatomy of OHC stereocilia fusion in mouse models of Manf-activation, age-related hearing loss, and prolonged acoustic noise exposure. All the mouse models showed a notable amount of OHC stereocilia fusion. We found reduced MET capability, reduced labelling of key stereocilia-tip proteins, as well as abnormal expression of calcium-regulating proteins in the OHCs exhibiting stereocilia fusion. In all, we have provided evidence suggesting that stereocilia fusion and cochlear synaptopathy are linked with the failure to maintain ER homeostasis. In this dissertation, I present and discuss our experiments and the aforementioned findings together with related scientific literature. Based on our evidence, we suggest that genetic predisposition, ageing, and acoustic noise challenge the maintenance of the hair cell ER function and thereby result in hair cell stereociliapathy, synaptopathy, and hearing loss.Kuuloaistimme perustuu sisäkorvamme kuuloaistinsolujen eli karvasolujen toimintaan. Karvasoluilla on kaksi keskeistä rakennetta, jotka mahdollistavat kuulotoiminnan: karvasolujen yläpinnalta löytyvät äänenpaineen muutoksiin reagoivat värekarvat (eng. stereocilia) ja karvasolujen tyvestä löytyvät hermoliitokset eli synapsit, joiden välityksellä karvasolut viestivät kuulohermoa pitkin aivoille äänen havaitsemisesta. Hyvään kuuloon tarvitaan sekä terveet värekarvat että synapsit.
Kuuloaisti on herkkä vaurioitumaan. Yleiset vauriotekijät kuten voimakas äänialtistus ja ikääntyminen vahingoittavat sisäkorvan karvasoluja. Vaikka edellä mainitut vauriotekijät tunnetaan, ei ole kuitenkaan täysin selvää miten karvasolut vahingoittuvat. Soluista puhuttaessa pitää tarkastelu kohdentaa solutason biologiaan. Tämä perustutkimuksellinen väitöskirjani tarkasteleekin kuulovauriota solutasolla. Väitöskirjani perustuu tutkimusryhmämme alkuperäisiin tutkimustuloksiin, jotka tuotimme Helsingin yliopistolla vuosina 2019–2024. Tässä esittämäni tutkimustuloksien, aikaisemman kirjallisuuden ja näiden tulkintani tarkoitus on lisätä ymmärrystämme niistä solubiologisista mekanismeista, jotka ajavat karvasolujen vahingoittumista kuulovaurion yhteydessä.
Karvasolujen solubiologian ymmärryksessä on ollut merkittävä aukko liittyen solulle keskeisen soluelimen, solulimakalvoston (eng. endoplasmic reticulum, ER), toimintaan. Solulimakalvosto toimii normaalisti keskeisenä solun aineenvaihdunnan tukipilarina esimerkiksi proteiinien tuotannossa. Haastavissa olosuhteissa tämä toiminta voi häiriintyä ja häiriintynyttä tilaa voidaan luonnehtia solulimakalvoston ”stressiksi” (eng. ER stress). Tutkimme solulimakalvoston stressiä karvasoluissa kuulovaurion yhteydessä. Tutkimuksemme perustui hiirien (mus musculus) empiiriseen tarkasteluun ja mittauksiin rajoittuen sisäkorvan kuuloelimeen. Aloitimme tarkastelun hiirimalleilla, joissa kohdensimme hiljentävän geenimutaation solulimakalvoston stressiä säätelevään geeniin Manf (eng. mesencephalic astrocyte-derived neurotrophic factor) sisäkorvassa. Mittasimme sähköfysiologian ja mikroskopian tutkimusmenetelmillämme hiirimallin kuulovaurion, karvasolujen värekarvojen vaurioitumisen ja synapsien vähenemisen asteen. Manf-mutaatio johti sekä karvasolujen värekarvojen että synapsien vaurioitumiseen, solukuolemaan, ja vakavaan kuulovaurioon. Kohdensimme Manf-mutaation vaikuttamaan vain karvasolujen viereisiin tukisoluihin. Tällöin emme havainneet vaurioita, mikä kertoo siitä, että Manf-geenin oleellinen rooli sisäkorvassa on karvasolujen sisäisessä säätelyssä. Toistimme kokeen geneettisesti eroavalla hiirikannalla ja havaitsimme merkittävän riippuvuuden kuulovaurion laajuuden ja hiirimallin geneettisen kannan välillä; hiiren genetiikka määritti Manf-mutaation vaikutuksen kuuloon.
Hyödynsimme Manf-mutaation lisäksi sekä ikääntymisen että pitkäkestoisen äänialtistuksen aiheuttamaa kuulovauriota mallintavia hiiriä. Syvennyimme karvasolujen värekarvojen vaurioitumiseen. Mittasimme ja vertasimme hiirimalleissa havaitsemaamme värekarvojen yhteen liimautumista (”fuusiota”) ja värekarvojen proteiinirakenteen muutoksia. Värekarvojen fuusio ja proteiinirakenteen häiriöt keskittyivät toiseen karvasolujen alatyypeistä, ulkokarvasoluihin, ja tämä vaikutus näkyi kaikissa kuulovauriota ilmentävissä hiirimalleissamme. Solulimakalvoston stressiä mallintavan hiiren, ikääntyneen hiiren ja melualtistetun hiiren välillä havaitsemiemme yhtäläisyyksien pohjalta voin esittää tämän väitöskirjan yhteenvetävän, laajemman hypoteesin: solulimakalvoston stressi on olennainen osa karvasolujen vahingoittumisesta johtuvan kuulovaurion solubiologista mekanismia.ei saavutettav
Tavoite-T-soluepitooppien tunnistaminen ja valinta terapeuttisten syöpärokotteiden kehittämiseksi
No full textThe immune system plays a pivotal role in maintaining the overall well-being of an organism. Cells communicate their metabolic status to different components of the immune system through the presentation of small peptides on their surface via Major Histocompatibility Complexes (MHCs). Among the immune system players, CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), are responsible for detecting and eliminating cells displaying abnormal peptide products resulting from viral infections or malignant transformations. Vaccines, based on leveraging the immune system to recognize and eliminate specific targets associated with infection or cancer, have had a transformative impact on public health.
While vaccines have been successful in eradicating diseases that were once major causes of mortality, the development of effective cancer vaccines remains a challenge. This thesis focuses on identifying appropriate targets and inclusion criteria for their selection in the development of vaccines addressing different cancer types.
In the first study, we addressed malignant pleural mesothelioma (MPM), an aggressive tumor with a poor prognosis. Previous research on MPM has primarily focused on molecular signatures to classify and characterize the disease, neglecting therapeutic targets that engage cytotoxic T cells. Our investigation into the presented antigen-presented landscape of MPM using state-of-the-art MHC immuno-affinity purification methodologies revealed promising candidate peptides presented on the surface of malignant cells. We characterized the immunogenicity profile of these peptides in both healthy donors and cancer patients. Furthermore, we formulated an oncolytic virus-based cancer vaccine (PeptiCRAd) utilizing the most promising peptides and tested its efficacy in a mouse model of mesothelioma. Our results demonstrated the feasibility and effectiveness of combining immunopeptidomic analysis with oncolytic immunotherapy for treating untreatable tumors.
Next, we explored the identification of target antigens for ovarian cancer. Epithelial ovarian cancers (EOC) comprise immunogenic tumor subtypes with antigen-specific T cells identified within the tumor milieu. Despite this, antigen-specific immunotherapies have shown limited success. Using state-of-the-art immunopeptidomics and proteogenomic profiling methods, we identified potential immunogenic human leukocyte antigen (HLA) Class I-presented peptides from high-grade serous ovarian cancer (HGSC) in patient-derived tumors. We synthesized and tested the best 13 candidate peptides, observing T cell-specific activation in both healthy donors and cancer patients.
In the third study, we investigated the antigen selection process, specifically focusing on molecular mimicry as a potential inclusion criterion. T-cell receptors (TCRs) exhibit promiscuity, allowing limited amount of T cells to recognize a variety of targets. We developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes and demonstrated that preexisting immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in mice. We also analyzed melanoma patients undergoing anti-PD1 treatment and observed a correlation between high levels of cytomegalovirus (CMV)-specific antibodies and prolonged progression-free survival, along with cross-reactivity between melanoma and CMV peptides. These findings suggest that preexisting immunity and molecular mimicry influence the response to immunotherapies.
In conclusion, this thesis showcases advancements in harnessing the immune system for targeted vaccines. The studies conducted provide insights into target identification, inclusion criteria, and the potential of molecular mimicry in immunotherapies. Furthermore, the application of our peptide-decorated Adenoviral vaccine platforms shows promise in addressing different tumor types. These findings contribute to the ongoing efforts in developing effective vaccines and expanding our understanding of immune responses for improved therapeutic outcomes.The immune system is a powerful defender, protecting the body from infections and diseases by recognizing and eliminating abnormal cells. A key player in this process is the T cell, especially the cytotoxic T lymphocyte (called CD8+). This cell type patrols the body for signs of trouble by detecting tiny protein fragments, called peptides, displayed on the surface of cells. This natural mechanism has been the inspiration behind vaccines, which train the immune system to target and destroy harmful cells. While vaccines have successfully eradicated many infectious diseases, developing effective cancer vaccines remains a formidable challenge.
This research takes a step forward in the fight against cancer by exploring how to better design vaccines for aggressive and hard-to-treat tumors. The studies highlight promising new strategies for identifying targets—specific peptides that can activate T cells—and using them in innovative vaccine platforms.
In one study, the focus was on malignant pleural mesothelioma (MPM), a rare and deadly cancer. By analyzing the peptides displayed by MPM cells, using a technique called immunoeptidomics, we aimed to identify potential targets that could alert T cells to attack. Using these targets, we developed a cancer vaccine that showed encouraging results in a mouse model, offering hope for new therapies against tumors that are otherwise resistant to treatment.
The second study centered on ovarian cancer, particularly high-grade serous ovarian cancer (HGSC). Using immunopeptidomics, we identified 13 peptides capable of activating T cells, providing a foundation for more precise and effective immunotherapies.
The final study delved into an intriguing phenomenon called molecular mimicry, where cancer peptides resemble those from viruses. This resemblance allows the immune system, which may already have defenses against the virus, to recognize and attack the cancer. Our findings revealed that existing immunity to certain viruses, like cytomegalovirus (CMV), could improve the success of cancer immunotherapy in melanoma patients.
Together, these studies investigate the process of target identification and selection for the development of therapeutic cancer vaccines. By combining cutting-edge techniques such as immunopeptidomics and bioinformatics with novel vaccine platforms, this work represents an exciting leap toward turning the immune system into a precise weapon against cancer. These advances pave the way for new therapeutic approaches and a hopefully brighter future in cancer treatment.ei saavutettav
Experiences of breast cancer patients on medication treatment – A focus group interview study investigating challenges and success factors of care
No full textPurpose
Studying patients’ experiences on breast cancer medication treatment is an important way to identify the targets of improvement in the care process, but it is still a limitedly studied area. This study’s emphasis was on the patients’ view on the challenges, targets of improvement and experienced success factors of the medication treatment process and care pathway of breast cancer.
Methods
A qualitative focus group interview study was conducted with a semi-structured interview scaffold, which was based on previous research evidence on the topic. The interviews were audio recorded and transcribed verbatim, and the data analysis was performed via inductive qualitative content analysis applying Atlas.ti software.
Results
The themes deriving from the analysis comprised challenges in care process, sources of treatment information, targets of improvement and success factors in treatment. The major problems from the patients’ viewpoint started when the active care at the hospital ended and the interaction between the patient and care provider decreased. Limited resources of care led to dissatisfactions during and after the care process. According to the interviewees the information supply could also be more personalized and easier to access. Among the successes was the professional performance of the healthcare staff, especially in regard to nurses. Other successes were the experienced overall quality of the care and the patients’ trust in the care process, as well as patients’ medication adherence and will to perform well in self-care.
Conclusion
The need for better patient-staff communication as well as access to information and care contact continue to be central challenges in breast cancer medication treatment. Especially the end of active care should be targeted with supportive actions for patients. The experienced success factors should be strengthened in healthcare systems, whereas further research on interventions to improve the medication treatment process of breast cancer is warranted