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The formation of secondary particles in the atmosphere accounts for more than half of global cloud condensation nuclei. Experiments at the CERN CLOUD (Cosmics Leaving OUtdoor Droplets) chamber have underlined the importance of ions for new particle formation, but quantifying their effect in the atmosphere remains challenging. By using a novel instrument setup consisting of two nanoparticle counters, one of them equipped with an ion filter, we were able to further investigate the ion-related mechanisms of new particle formation. In autumn 2015, we carried out experiments at CLOUD on four systems of different chemical compositions involving monoterpenes, sulfuric acid, nitrogen oxides, and ammonia. We measured the influence of ions on the nucleation rates under precisely controlled and atmospherically relevant conditions. Our results indicate that ions enhance the nucleation process when the charge is necessary to stabilize newly formed clusters, i.e., in conditions in which neutral clusters are unstable. For charged clusters that were formed by ion-induced nucleation, we were able to measure, for the first time, their progressive neutralization due to recombination with oppositely charged ions. A large fraction of the clusters carried a charge at 1.5 nm diameter. However, depending on particle growth rates and ion concentrations, charged clusters were largely neutralized by ion–ion recombination before they grew to 2.5 nm. At this size, more than 90 % of particles were neutral. In other words, particles may originate from ion-induced nucleation, although they are neutral upon detection at diameters larger than 2.5 nm. Observations at Hyytiälä, Finland, showed lower ion concentrations and a lower contribution of ion-induced nucleation than measured at CLOUD under similar conditions. Although this can be partly explained by the observation that ion-induced fractions decrease towards lower ion concentrations, further investigations are needed to resolve the origin of the discrepancy., published version, peerReviewed

Tendon function and homeostasis rely on external loading. This study investigates the biological mechanisms behind tendon biomechanical function and how the mechanical performance is affected by reduced daily loading. The Achilles tendons of 16 weeks old female Sprague Dawley rats (n = 40) were unloaded for 5 weeks by inducing muscle paralysis with botulinum toxin injections in the right gastrocnemius and soleus muscles. The contralateral side was used as control. After harvest, the tendons underwent biomechanical testing to assess viscoelasticity (n = 30 rats) and small angle X-ray scattering to determine the structural properties of the collagen fibrils (n = 10 rats). Fourier transform infrared spectroscopy and histological staining (n = 10 rats) were performed to investigate the collagen and proteoglycan content. The results show that the stiffness increased in unloaded tendons, together with an increased collagen content. Creep and axial alignment of the collagen fibers were reduced. Stress-relaxation increased whereas hysteresis was reduced in response to unloading with botox treatment. Our findings indicate that altered matrix deposition relies on mechanical loading to reorganize the newly formed tissue, without which the viscoelastic behavior is impaired. The results demonstrate that reduced daily loading deprives tendons of their viscoelastic properties, which could increase the risk of injury., published version, peerReviewed

Rationale: Focused ultrasound (FUS), in conjunction with circulating microbubbles (MBs), can be used to transiently increase the permeability of the blood-brain barrier (BBB) in a targeted manner, allowing therapeutic agents to enter the brain from systemic circulation. While promising preclinical work has paved the way for the initiation of 3 human trials, there remains concern regarding neuroinflammation following treatment. The aim of this study was to assess the magnitude of this response following sonication and explore the influence of MB dose. Methods: Differential expression of NFκB signaling pathway genes was assessed in rats at 6 h and 4 days following a FUS-mediated increase in BBB permeability. Three sonication schemes were tested: (1) a clinical imaging dose of MBs + peak negative pressure (PNP) controlled by acoustic feedback, (2) 10x clinical imaging dose of MBs + constant PNP of 0.290 MPa, and (3) 10x clinical imaging dose of MBs + PNP controlled by acoustic feedback. Follow-up magnetic resonance imaging (MRI) was performed to assess edema and hemorrhage. Hematoxylin and eosin histology was used to evaluate general tissue health. Results: MB dose has a significant impact on the expression of several key genes involved in acute inflammation and immune activation, including Tnf, Birc3, and Ccl2. At a clinical imaging dose of MBs, there were no significant changes detected in the expression of any NFκB signaling pathway genes. Conversely, a high MB dose resulted in a clear activation of the NFκB signaling pathway, accompanied by edema, neuronal degeneration, neutrophil infiltration, and microhemorrhage. Results also suggest that post-FUS gadolinium enhancement may hold predictive value in assessing the magnitude of inflammatory response. Conclusion: While a significant and damaging inflammatory response was observed at high MB doses, it was demonstrated that FUS can be used to induce increased BBB permeability without an associated upregulation of NFκB signaling pathway gene expression. This emphasizes the importance of employing optimized FUS parameters to mitigate the chances of causing injury to the brain at the targeted locations., published version, peerReviewed

The effect of swelling of articular cartilage, caused by the fixed charge density (FCD) of proteoglycans, has not been demonstrated on knee joint mechanics during simulated walking before. In this study, the influence of the depth-wise variation of FCD was investigated on the internal collagen fibril strains and the mechanical response of the knee joint cartilage during gait using finite element (FE) analysis. The FCD distribution of tibial cartilage was implemented from sodium (23Na) MRI into a 3-D FE-model of the knee joint (“Healthy model”). For comparison, models with decreased FCD values were created according to the decrease in FCD associated with the progression of osteoarthritis (OA) (“Early OA” and “Advanced OA” models). In addition, a model without FCD was created (“No FCD” model). The effect of FCD was studied with five different collagen fibril network moduli of cartilage. Using the reference fibril network moduli, the decrease in FCD from “Healthy model” to “Early OA” and “Advanced OA” models resulted in increased axial strains (by +2 and +6%) and decreased fibril strains (by −3 and −13%) throughout the stance, respectively, calculated as mean values through cartilage depth in the tibiofemoral contact regions. Correspondingly, compared to the “Healthy model”, the removal of the FCD altogether in “NoFCD model” resulted in increased mean axial strains by +16% and decreased mean fibril strains by −24%. This effect was amplified as the fibril network moduli were decreased by 80% from the reference. Then mean axial strains increased by +6, +19 and +49% and mean fibril strains decreased by −9, −20 and −32%, respectively. Our results suggest that the FCD in articular cartilage has influence on cartilage responses in the knee during walking. Furthermore, the FCD is suggested to have larger impact on cartilage function as the collagen network degenerates e.g. in OA., final draft, peerReviewed

In highly organized tissues, such as cartilage, tendons and white matter, several quantitative MRI parameters exhibit dependence on the orientation of the tissue constituents with respect to the main imaging magnetic field (B0). In this study, we investigated the dependence of multiple relaxation parameters on the orientation of articular cartilage specimens in the B0. Bovine patellar cartilage-bone samples (n = 4) were investigated ex vivo at 9.4 Tesla at seven different orientations, and the MRI results were compared with polarized light microscopy findings on specimen structure. Dependences of T2 and continuous wave (CW)-T1ρ relaxation times on cartilage orientation were confirmed. T2 (and T2*) had the highest sensitivity to orientation, followed by TRAFF2 and adiabatic T2ρ. The highest dependence was seen in the highly organized deep cartilage and the smallest in the least organized transitional layer. Increasing spin-lock amplitude decreased the orientation dependence of CW-T1ρ. T1 was found practically orientation-independent and was closely followed by adiabatic T1ρ. The results suggest that T1 and adiabatic T1ρ should be preferred for orientation-independent quantitative assessment of organized tissues such as articular cartilage. On the other hand, based on the literature, parameters with higher orientation anisotropy appear to be more sensitive to degenerative changes in cartilage., published version, peerReviewed

People suffering from depression perceive themselves and their surroundings as more negative than healthy ones. An explanation might be that depressed individuals experience negative information as more stressful than non-depressed subjects and, consequently, respond in an amplified manner on a subjective and physiological level. To test this proposition, we presented 41 patients with recurrent depressive episodes and 42 controls with stimuli from the International Affective Picture System split into three valence categories while different parameters of physiological arousal (e.g., heart rate variability) and subjective perceptions of valence and arousal were assessed. Furthermore, we examined social skills and emotional competence. Results regarding physiological arousal revealed an elevated skin temperature and a more accentuated respiratory frequency in depressed subjects. Furthermore, depressed subjects rated the stimuli as more negative and arousing, which was associated with reduced social and emotional competence. Variation in antidepressant medication, menstrual cycle and other factors that have an impact on HRV are a potential bias. Our findings suggest an intensified perception of negative emotion in depressed individuals as compared to controls that manifests itself in an increased physiological arousal as well as on a subjective level. This intensified emotion perception is further associated with deficits in social and emotional competence., final draft, peerReviewed

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion., published version, peerReviewed

Purpose The cortical characteristics of the iliac crest in male have rarely been investigated with quantitative histomorphometry. Also it is still unknown how cortical microarchitecture may vary between the iliac crest and fractures related sites at the proximal femur. We studied the microarchitecture of both external and internal cortices within the iliac crest, and compared the results with femoral neck and subtrochanteric femoral shaft sites. Methods Undecalcified histological sections of the iliac crest were obtained bicortically from cadavers (n = 20, aged 18–82 years, males). They were cut (7 μm) and stained using modified Masson-Goldner stain. Histomorphometric parameters of cortical bone were analysed with low (× 50) and high (× 100) magnification, after identifying cortical bone boundaries using our previously validated method. Within cortical bone area, only complete osteons with typical concentric lamellae and cement line were selected and measured. Results At the iliac crest, the mean cortical width of external cortex was higher than at the internal cortex (p < 0.001). Also, osteon structural parameters, e.g. mean osteonal perimeter, were higher in the external cortex (p < 0.05). In both external and internal cortices, pore number per cortical bone area was higher in young subjects (≤ 50 years) (p < 0.05) while mean pore perimeter was higher in the old subjects (> 50 years) (p < 0.05). Several cortical parameters (e.g. osteon area per cortical bone area, pore number per cortical area) were the lowest in the femoral neck (p < 0.05). The maximal osteonal diameter and mean wall width were the highest in the external cortex of the iliac crest (p < 0.05), and the mean cortical width, osteon number per cortical area were the highest in the subtrochanteric femoral shaft (p < 0.05). Some osteonal structural parameters (e.g. min osteonal diameter) were significantly positively correlated (0.29 ≤ R2 ≤ 0.45, p < 0.05) between the external iliac crest and the femoral neck. Conclusions This study reveals heterogeneity in cortical microarchitecture between the external and internal iliac crest cortices, as well as between the iliac crest, the femoral neck and the subtrochanteric femoral shaft. Standard iliac crest biopsy does not reflect accurately cortical microarchitecture of other skeletal sites., published version, peerReviewed

Objective We investigate the potential of a prototype multimodality arthroscope, combining ultrasound, optical coherence tomography (OCT) and arthroscopic indentation device, for assessing cartilage lesions, and compare the reliability of this approach with conventional arthroscopic scoring ex vivo. Design Areas of interest (AIs, N = 43) were selected from equine fetlock joints (N = 5). Blind-coded AIs were independently scored by two equine surgeons employing International Cartilage Repair Society (ICRS) scoring system via conventional arthroscope and multimodality arthroscope, in which high-frequency ultrasound and OCT catheters were attached to an arthroscopic indentation device. In addition, cartilage stiffness was measured with the indentation device, and lesions in OCT images scored using custom-made automated software. Measurements and scorings were performed twice in two separate rounds. Finally, the scores were compared to histological ICRS scores. Results OCT and arthroscopic examinations showed the highest average agreements (55.2%) between the scoring by surgeons and histology scores, whereas ultrasound had the lowest (50.6%). Average intraobserver agreements of surgeons and interobserver agreements between rounds were, respectively, for conventional arthroscope (68.6%, 69.8%), ultrasound (68.6%, 68.6%), OCT (65.1%, 61.7%) and automated software (65.1%, 59.3%). Conclusions OCT imaging supplemented with the automated software provided the most reliable lesion scoring. However, limited penetration depth of light limits the clinical potential of OCT in assessing human cartilage thickness; thus, the combination of OCT and ultrasound could be optimal for reliable diagnostics. Present findings suggest imaging and quantitatively analyzing the entire articular surface to eliminate surgeon-related variation in the selection of the most severe lesion to be scored., final draft, peerReviewed

AERONET (AErosol RObotic NETwork), which is a network of ground-based sun photometers, produces a data product called the aerosol spectral deconvolution algorithm (SDA) that utilizes spectral total aerosol optical depth (AOD) data to infer the component fine- and coarse-mode optical depths at 500 nm. Based on its assumptions, SDA identifies cloud optical depth as the coarse-mode AOD component and therefore effectively computes the fine-mode AOD also in mixed cloud–aerosol observations. Therefore, it can be argued that the more representative AOD for fine-mode fraction should be based on all direct sun measurements and not only on those cloud screened for clear-sky conditions, i.e., on those from level 1 (L1) instead of level 2 (L2) in AERONET. The objective of our study was to assess, including all the available AERONET sites, how the fine-mode AOD is enhanced in cloudy conditions, contrasting SDA L1 and L2 in our analysis. Assuming that the cloud screening correctly separates the cloudy and clear-sky conditions, then the increases in fine-mode AOD can be due to various cloud-related processes, mainly by the strong hygroscopic growth of particles in the vicinity of clouds and in-cloud processing leading to growth of accumulation mode particles. We estimated these cloud-related enhancements in fine-mode AOD seasonally and found, for instance, that in June–August season the average over all the AERONET sites was 0.011, when total fine-mode AOD from L2 data was 0.154; therefore, the relative enhancement was 7 %. The enhancements were largest, both absolutely and relatively, in East Asia; for example, in June–August season the absolute and relative differences in fine-mode AOD, between L1 and L2 measurements, were 0.022 and 10 %, respectively. Corresponding values in North America and Europe were about 0.01 and 6–7 %. In some highly polluted areas, the enhancement is greater than these regional averages, e.g., in Beijing region and in June–July–August (JJA) season the corresponding absolute values were about 0.1. It is difficult to separate the fine-mode AOD enhancements due to in-cloud processing and hygroscopic growth, but we attempted to get some understanding by conducting a similar analysis for SDA-based fine-mode Ångström exponent (AE) patterns. Moreover, we exploited a cloud parcel model, in order to understand in detail the relative role of different processes. We found that in marine conditions, were aerosol concentration are low and cloud scavenging is efficient, the AE changes in opposite direction than in the more polluted conditions, were hygroscopic growth of particles leads to a negative AE change., published version, peerReviewed

The terrestrial vegetation emits large amounts of volatile organic compounds (VOC) into the atmosphere, which on oxidation produce secondary organic aerosol (SOA). By acting as cloud condensation nuclei (CCN), SOA influences cloud formation and climate. In a warming climate, changes in environmental factors can cause stresses to plants, inducing changes of the emitted VOC. These can modify particle size and composition. Here we report how induced emissions eventually affect CCN activity of SOA, a key parameter in cloud formation. For boreal forest tree species, insect infestation by aphids causes additional VOC emissions which modifies SOA composition thus hygroscopicity and CCN activity. Moderate heat increases the total amount of constitutive VOC, which has a minor effect on hygroscopicity, but affects CCN activity by increasing the particles’ size. The coupling of plant stresses, VOC composition and CCN activity points to an important impact of induced plant emissions on cloud formation and climate., published version, peerReviewed

Photoacoustic tomography (PAT) is a hybrid imaging modality that combines optical contrast with ultrasound resolution. Most of the PAT configurations are based on high-energy solid-state lasers such as Nd:YAG laser. In this work, a PAT system that uses light-emitting diode (LED) as a light source is introduced. The system is designed so that the imaged target can be stationary. The target is illuminated by a LED light source from one side and the pressure wave is measured using an acoustic transducer that is rotated around the target. Image reconstruction is based on Bayesian approach to ill-posed inverse problems. The system was tested with light absorbing targets also in limited-view and sparse angle measurement situations. The results show that LED-based instrumentation and advanced reconstruction methods can form a potential PAT system that can also be applied in limited-view and sparse angle photoacoustic tomography., final draft, nonPeerReviewed

Background Finite element modelling can be used to evaluate altered loading conditions and failure locations in knee joint tissues. One limitation of this modelling approach has been experimental comparison. The aims of this proof-of-concept study were: 1) identify areas susceptible to osteoarthritis progression in anterior cruciate ligament reconstructed patients using finite element modelling; 2) compare the identified areas against changes in T2 and T1ρ values between 1-year and 3-year follow-up timepoints. Methods Two patient-specific finite element models of knee joints with anterior cruciate ligament reconstruction were created. The knee geometry was based on clinical magnetic resonance imaging and joint loading was obtained via motion capture. We evaluated biomechanical parameters linked with cartilage degeneration and compared the identified risk areas against T2 and T1ρ maps. Findings The risk areas identified by the finite element models matched the follow-up magnetic resonance imaging findings. For Patient 1, excessive values of maximum principal stresses and shear strains were observed in the posterior side of the lateral tibial and femoral cartilage. For Patient 2, high values of maximum principal stresses and shear strains of cartilage were observed in the posterior side of the medial joint compartment. For both patients, increased T2 and T1ρ values between the follow-up times were observed in the same areas. Interpretation Finite element models with patient-specific geometries and motions and relatively simple material models of tissues were able to identify areas susceptible to post-traumatic knee osteoarthritis. We suggest that the methodology presented here may be applied in large cohort studies., final draft, peerReviewed

The relationship between aerosol hygroscopicity and cloud droplet activation was studied at the Puijo measurement station in Kuopio, Finland, during the autumn 2014. The hygroscopic growth of 80, 120 and 150 nm particles was measured at 90 % relative humidity with a hygroscopic tandem differential mobility analyzer. Typically, the growth factor (GF) distributions appeared bimodal with clearly distinguishable peaks around 1.0–1.1 and 1.4–1.6. However, the relative contribution of the two modes appeared highly variable reflecting the probable presence of fresh anthropogenic particle emissions. The hygroscopicity-dependent activation properties were estimated in a case study comprising four separate cloud events with varying characteristics. At 120 and 150 nm, the activation efficiencies within the low- and high-GF modes varied between 0–34 and 57–83 %, respectively, indicating that the less hygroscopic particles remained mostly non-activated, whereas the more hygroscopic mode was predominantly scavenged into cloud droplets. By modifying the measured GF distributions, it was estimated how the cloud droplet concentrations would change if all the particles belonged to the more hygroscopic group. According to κ-Köhler simulations, the cloud droplet concentrations increased up to 70 % when the possible feedback effects on effective peak supersaturation (between 0.16 and 0.29 %) were assumed negligible. This is an indirect but clear illustration of the sensitivity of cloud formation to aerosol chemical composition., published version, peerReviewed

Article, Background and purpose Arthroscopic estimation of articular cartilage thickness is important for scoring of lesion severity, and measurement of cartilage speed of sound (SOS)—a sensitive index of changes in cartilage composition. We investigated the accuracy of optical coherence tomography (OCT) in measurements of cartilage thickness and determined SOS by combining OCT thickness and ultrasound (US) time-of-flight (TOF) measurements. Material and methods Cartilage thickness measurements from OCT and microscopy images of 94 equine osteochondral samples were compared. Then, SOS in cartilage was determined using simultaneous OCT thickness and US TOF measurements. SOS was then compared with the compositional, structural, and mechanical properties of cartilage. Results Measurements of non-calcified cartilage thickness using OCT and microscopy were significantly correlated (ρ = 0.92; p < 0.001). With calcified cartilage included, the correlation was ρ = 0.85 (p < 0.001). The mean cartilage SOS (1,636 m/s) was in agreement with the literature. However, SOS and the other properties of cartilage lacked any statistically significant correlation. Interpretation OCT can give an accurate measurement of articular cartilage thickness. Although SOS measurements lacked accuracy in thin equine cartilage, the concept of SOS measurement using OCT appears promising., published version, peerReviewed

Article, The concentrations of neutral and charged sub-3nm clusters and their connection to new particle formation (NPF) were investigated during the PEGASOS campaign (7 June–9 July 2012) at the San Pietro Capofiume measurement station in the Po Valley, Italy. Continuous high concentrations of sub-3nm clusters were detected during the measurement period, although the condensation sink was relatively high (median value 1.1 × 10−2 s−1). The median cluster concentrations were 2140 and 7980 cm−3 in the size bins of 1.5–1.8 and 1.8–3 nm, and the majority of them were electrically neutral. NPF events were observed during the measurement period frequently, on 86 % of the days. The median growth rates of clusters during the events were 4.3, 6.0 and 7.2 nm h−1 in the size ranges of 1.5–3, 3–7 and 7–20 nm. The median formation rate of 1.6 nm clusters was high, 45 cm−3 s−1, and it exceeded the median formation rate of 2 nm clusters by 1 order of magnitude. The ion-induced nucleation fraction was low; the median values were 0.7 % at 1.6 nm and 3.0 % at 2 nm. On NPF event days the neutral cluster concentration had a maximum around 09:00 (local winter time), which was absent on a non-event day. The increase in the cluster concentrations in the morning coincided with the increase in the boundary layer height. At the same time radiation, temperature and SO2 concentration increased, and RH and condensation sink decreased. The concentrations of neutral and charged clusters were observed to have a positive correlation with sulfuric acid proxy, indicating the significance of sulfuric acid for the cluster formation in San Pietro Capofiume. The condensation sink had a negative correlation with the concentration of charged clusters but no clear relation to the neutral cluster concentration. This finding, together with back-trajectory analysis, suggests that the precursor vapors of the clusters and background aerosol particles, acting as their sink, have possibly originated from the same sources, including e.g., power plants and industrial areas in the Po Valley., published version, peerReviewed

Article, Heterogeneous nucleation of water vapour on insoluble nuclei is a phenomenon that can induce atmospheric water and ice cloud formation. However, modelling of the phenomenon is hampered by the fact that the predictive capability of the classical heterogeneous nucleation theory is rather poor. A reliable theoretical description of the influence of different types of water-insoluble nuclei in triggering the water condensation or ice deposition would help to decrease uncertainty in large-scale model simulations. In this paper we extend a recently formulated adsorption theory of heterogeneous nucleation to be applicable to highly curved surfaces, and test the theory against laboratory data for water vapour nucleation on silica, titanium dioxide and silver oxide nanoparticles. We show that unlike the classical heterogeneous nucleation theory, the new theory is able to quantitatively predict the experimental results., published version, peerReviewed

Ligaments provide stability to the human knee joint and play an essential role in restraining motion during daily activities. Compression-tension nonlinearity is a well-known characteristic of ligaments. Moreover, simpler material representations without this feature might give reasonable results because ligaments are primarily in tension during loading. However, the biomechanical role of different constitutive representations and their fibril-reinforced poroelastic properties is unknown. A numerical knee model which considers geometric and material nonlinearities of meniscus and cartilages was applied. Five different constitutive models for the ligaments (spring, elastic, hyperelastic, porohyperelastic, and fibril-reinforced porohyperelastic (FRPHE)) were implemented. Knee joint forces for the models with elastic, hyperelastic and porohyperelastic properties showed similar behavior throughout the stance, while the model with FRPHE properties exhibited lower joint forces during the last 50% of the stance phase. The model with ligaments as springs produced the lowest joint forces at this same stance phase. The results also showed that the fibril network contributed substantially to the knee joint forces, while the nonfibrillar matrix and fluid had small effects. Our results indicate that simpler material models of ligaments with similar properties in compression and tension can be used when the loading is directed primarily along the ligament axis in tension., published version, peerReviewed

Despite extensive efforts to develop delivery systems for oral administration, subcutaneous (s.c.) injection remains the most common way to administer peptide drugs. To limit the number of frequent injections, sustained release systems that are easy to produce, suitable for various drugs, safe and biodegradable are urgently needed. Porous silicon (PSi) has been recognized to be one of the most promising materials for s.c. peptide delivery, but its biodegradation in s.c. tissue has not been studied in vivo, despite extensive in vitro research. In the present study, differently modified PSi microparticles were injected s.c. in mice, after which the morphology of the particles was thoroughly studied with transmission electron microscopy, micro-computed tomography and X-ray diffraction. Furthermore, histopathology of the s.c. tissue was analyzed to evaluate biocompatibility. To the best of our knowledge, this is the first systematic study which reveals the degradation behavior of various PSi materials in vivo. The PSi surface chemistry significantly affected the biodegradation rate of the s.c. injected microparticles. The most hydrophobic PSi microparticles with hydrocarbonized surface showed the lowest biodegradation rate while the hydrophilic microparticles, with oxide surface, degraded the fastest. The results from different empirical methods complemented each other to deduce the biodegradation mechanism of the inorganic delivery system, providing useful information for future development of s.c. carriers., final draft, peerReviewed

Knee osteoarthritis (KOA) is most common in the medial tibial compartment. We present a novel method to study the effect of gait modifications and lateral wedge insoles (LWIs) on the stresses in the medial tibial cartilage by combining musculoskeletal (MS) modelling with finite element (FE) analysis. Subject’s gait was recorded in a gait laboratory, walking normally, with 5° and 10° LWIs, toes inward (‘Toe in’), and toes outward (‘Toe out wide’). A full lower extremity MRI and a detailed knee MRI were taken. Bones and most soft tissues were segmented from images, and the generic bone architecture of the MS model was morphed into the segmented bones. The output forces from the MS model were then used as an input in the FE model of the subject’s knee. During stance, LWIs failed to reduce medial peak pressures apart from Insole 10° during the second peak. Toe in reduced peak pressures by −11% during the first peak but increased them by 12% during the second. Toe out wide reduced peak pressures by −15% during the first and increased them by 7% during the second. The results show that the work flow can assess the effect of interventions on an individual level. In the future, this method can be applied to patients with KOA., published version, peerReviewed

The formation rates of 3 nm particles were estimated at SMEAR IV, Puijo (Finland), where the continuous measurements extend only down to 7 nm in diameter. We extrapolated the formation rates at 7 nm (J7) down to 3 nm (J3) based on an approximate solution to the aerosol general dynamic equation, assuming a constant condensational growth rate, a power-law size-dependent scavenging rate, and negligible self-coagulation rate for the nucleation mode particles. To evaluate our method, we first applied it to new particle formation (NPF) events in Hyytiälä (Finland), which extend down to 3 nm, and, therefore, J3 and J7 can be determined directly from the measured size distribution evolution. The Hyytiälä results show that the estimated daily mean J3 values slightly overestimate the observed mean J3, but a promising 91 % of the estimated J3 values are within a factor of 2 from the measured ones. However, when considering detailed daily time evolution, the agreement is not as good due to fluctuations in data as well as uncertainties in estimated growth rates, which are required in order to calculate the time lag between formation of 3 and 7 nm particles. At Puijo, the mean J7 for clear NPF days during April 2007–December 2015 was 0.44 cm−3 s−1, while the extrapolated mean J3 was 0.61 cm−3 s−1., published version, peerReviewed

We demonstrate in this study the potential of near infrared (NIR) spectroscopy as a tool for monitoring progression of cartilage degeneration in an animal model. Osteoarthritic degeneration was artificially induced in one joint in laboratory rats, and the animals were sacrificed at four time points: 1, 2, 4, and 6 weeks (3 animals/week). NIR spectra were acquired from both (injured and intact) knees. Subsequently, the joint samples were subjected to histological evaluation and glycosaminoglycan (GAG) content analysis, to assess disease severity based on the Mankin scoring system and to determine proteoglycan loss, respectively. Multivariate spectral techniques were then employed for classification (principal component analysis and support vector machines) and prediction (partial least squares regression) of the samples’ Mankin scores and GAG content from their NIR spectra. Our results demonstrate that NIR spectroscopy is sensitive to degenerative changes in articular cartilage, and is capable of distinguishing between mild (weeks 1&2; Mankin 3) cartilage degeneration. In addition, the spectral data contains information that enables estimation of the tissue’s Mankin score (error = 12.6%, R2 = 86.2%) and GAG content (error = 7.6%, R2 = 95%). We conclude that NIR spectroscopy is a viable tool for assessing cartilage degeneration post-injury, such as, post-traumatic osteoarthritis., published version, peerReviewed

Silicon is being increasingly studied as the next-generation anode material for Li-ion batteries because of its ten times higher gravimetric capacity compared with the widely-used graphite. While nanoparticles and other nanostructured silicon materials often exhibit good cyclability, their volumetric capacity tends to be worse or similar than that of graphite. Furthermore, these materials are commonly complicated and expensive to produce. An effortless way to produce nanostructured silicon is electrochemical anodization. However, there is no systematic study how various material properties affect its performance in LIBs. In the present study, the effects of particle size, surface passivation and boron doping degree were evaluated for the mesoporous silicon with relatively low porosity of 50%. This porosity value was estimated to be the lowest value for the silicon material that still can accommodate the substantial volume change during the charge/discharge cycling. The optimal particle size was between 10–20 µm, the carbide layer enhanced the rate capability by improving the lithiation kinetics, and higher levels of boron doping were beneficial for obtaining higher specific capacity at lower rates. Comparison of pristine and cycled electrodes revealed the loss of electrical contact and electrolyte decay to be the major contributors to the capacity decay., published version, peerReviewed

Economic costs of osteoarthritis (OA) are considerable. However, there are no clinical tools to predict the progression of OA or guide patients to a correct treatment for preventing OA. We tested the ability of our cartilage degeneration algorithm to predict the subject-specific development of OA and separate groups with different OA levels. The algorithm was able to predict OA progression similarly with the experimental follow-up data and separate subjects with radiographical OA (Kellgren-Lawrence (KL) grade 2 and 3) from healthy subjects (KL0). Maximum degeneration and degenerated volumes within cartilage were significantly higher (p, published version, peerReviewed

Measuring the lens gradient refractive index (GRIN) accurately and reliably has proven an extremely challenging technical problem. A fully automated laser ray tracing (LRT) system was built to address this issue. The LRT system captures images of multiple laser projections before and after traversing through an ex vivo lens. These LRT images, combined with accurate measurements of the lens geometry, are used to calculate the lens GRIN profile. Mathematically, this is an ill-conditioned problem; hence, it is essential to apply biologically relevant constraints to produce a feasible solution. The lens GRIN measurements were compared with previously published data. Our GRIN retrieval algorithm produces fast and accurate measurements of the lens GRIN profile. Experiments to study the optics of physiologically perturbed lenses are the future direction of this research., published version, peerReviewed

Cartilage defects are a known risk factor for osteoarthritis. Estimation of structural changes in these defects could help us to identify high risk defects and thus to identify patients that are susceptible for the onset and progression of osteoarthritis. Here, we present an algorithm combined with computational modeling to simulate the disorganization of collagen fibril network in injured cartilage. Several potential triggers for collagen disorganization were tested in the algorithm following the assumption that disorganization is dependent on the mechanical stimulus of the tissue. We found that tensile tissue stimulus alone was unable to preserve collagen architecture in intact cartilage as collagen network reoriented throughout the cartilage thickness. However, when collagen reorientation was based on both tensile tissue stimulus and tensile collagen fibril strains or stresses, the collagen network architecture was preserved in intact cartilage. Using the same approach, substantial collagen reorientation was predicted locally near the cartilage defect and particularly at the cartilage–bone interface. The developed algorithm was able to predict similar structural findings reported in the literature that are associated with experimentally observed remodeling in articular cartilage. The proposed algorithm, if further validated, could help to predict structural changes in articular cartilage following post-traumatic injury potentially advancing to impaired cartilage function., final draft, peerReviewed

Research is ongoing to develop drug therapies to manage osteoarthritis (OA) and articular cartilage (AC) injuries. However, means to deliver drug to localized AC lesions are highly limited and not clinically available. This study investigates the capability of laser ultrasound (laser-induced plasma sound source) to deliver agents (methylene blue, MB, in PBS) into bovine AC. Treatment samples (n = 10) were immersed in MB solution simultaneously with LU exposure, while adjacent control 1 tissue (n = 10) was pre-treated with LU followed by immersion in MB and adjacent control 2 tissue (n = 10) was only immersed in MB. AC exposed (n = 22) or not exposed (n = 27) to LU were characterized for anomalies in structure, composition, viability or RNA expression. Optically detected MB content was significantly (p, published version, peerReviewed

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits. Methods: Aged dogs naturally accumulate plaques and show associated cognitive declines. Low-frequency ultrasound was used to open the BBB unilaterally in aged beagles (9-11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow-up MRI exam 1 week following the final treatment. Results: The permeability of the BBB was successfully increased in all animals (mean enhancement: 19±11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0±1.4 vs 0.4±0.5/5.2±1.8 vs. 4.0±2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Aβ loads in the treated hemisphere. Conclusion: Whole-hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology., published version, peerReviewed

Using reports of forest losses caused directly by large scale windstorms (or primary damage, PD) from the European forest institute database (comprising 276 PD reports from 1951–2010), total growing stock (TGS) statistics of European forests and the daily North Atlantic Oscillation (NAO) index, we identify a statistically significant change in storm intensity in Western, Central and Northern Europe (17 countries). Using the validated set of storms, we found that the year 1990 represents a change-point at which the average intensity of the most destructive storms indicated by PD/TGS > 0.08% increased by more than a factor of three. A likelihood ratio test provides strong evidence that the change-point represents a real shift in the statistical behaviour of the time series. All but one of the seven catastrophic storms (PD/TGS > 0.2%) occurred since 1990. Additionally, we detected a related decrease in September–November PD/TGS and an increase in December–February PD/TGS. Our analyses point to the possibility that the impact of climate change on the North Atlantic storms hitting Europe has started during the last two and half decades., published version, peerReviewed

Trabecular bone is viscoelastic under dynamic loading. However, it is unclear how tissue viscoelasticity controls viscoelasticity at the apparent-level. In this study, viscoelasticity of cylindrical human trabecular bone samples (n = 11, male, age 18–78 years) from 11 proximal femurs were characterized using dynamic and stress-relaxation testing at the apparent-level and with creep nanoindentation at the tissue-level. In addition, bone tissue elasticity was determined using scanning acoustic microscope (SAM). Tissue composition and collagen crosslinks were assessed using Raman micro-spectroscopy and high performance liquid chromatography (HPLC), respectively. Values of material parameters were obtained from finite element (FE) models by optimizing tissue-level creep and apparent-level stress-relaxation to experimental nanoindentation and unconfined compression testing values, respectively, utilizing the second order Prony series to depict viscoelasticity. FE simulations showed that tissue-level equilibrium elastic modulus (Eeq) increased with increasing crystallinity (r = 0.730, p = .011) while at the apparent-level it increased with increasing hydroxylysyl pyridinoline content (r = 0.718, p = .019). In addition, the normalized shear modulus g1 (r = −0.780, p = .005) decreased with increasing collagen ratio (amide III/CH2) at the tissue-level, but increased (r = 0.696, p = .025) with increasing collagen ratio at the apparent-level. No significant relations were found between the measured or simulated viscoelastic parameters at the tissue- and apparent-levels nor were the parameters related to tissue elasticity determined with SAM. However, only Eeq, g2 and relaxation time τ1 from simulated viscoelastic values were statistically different between tissue- and apparent-levels (p < .01). These findings indicate that bone tissue viscoelasticity is affected by tissue composition but may not fully predict the macroscale viscoelasticity in human trabecular bone., final draft, peerReviewed

Electroencephalography (EEG) is a rich source of information regarding brain function. However, the preprocessing of EEG data can be quite complicated, due to several factors. For example, the distinction between true neural sources and noise is indeterminate; EEG data can also be very large. The various factors create a large number of subjective decisions with consequent risk of compound error. Existing tools present the experimenter with a large choice of analysis methods. Yet it remains a challenge for the researcher to integrate methods for batch-processing of the average large datasets, and compare methods to choose an optimal approach across the many possible parameter configurations. Additionally, many tools still require a high degree of manual decision making for, e.g. the classification of artefacts in channels, epochs or segments. This introduces extra subjectivity, is slow and is not reproducible. Batching and well-designed automation can help to regularise EEG preprocessing, and thus reduce human effort, subjectivity and consequent error. We present the computational testing for automated preprocessing (CTAP) toolbox, to facilitate: (i) batch-processing that is easy for experts and novices alike; (ii) testing and manual comparison of preprocessing methods. CTAP extends the existing data structure and functions from the well-known EEGLAB toolbox, based on Matlab and produces extensive quality control outputs. CTAP is available under MIT licence from https://github.com/bwrc/ctap., published version, peerReviewed

Various types of DNA viruses are known to elicit the formation of a large nuclear viral replication compartment and marginalization of the cell chromatin. We used three-dimensional soft x-ray tomography, confocal and electron microscopy, combined with numerical modelling of capsid diffusion to analyse the molecular organization of chromatin in herpes simplex virus 1 infection and its effect on the transport of progeny viral capsids to the nuclear envelope. Our data showed that the formation of the viral replication compartment at late infection resulted in the enrichment of heterochromatin in the nuclear periphery accompanied by the compaction of chromatin. Random walk modelling of herpes simplex virus 1–sized particles in a three-dimensional soft x-ray tomography reconstruction of an infected cell nucleus demonstrated that the peripheral, compacted chromatin restricts viral capsid diffusion, but due to interchromatin channels capsids are able to reach the nuclear envelope, the site of their nuclear egress., published version, peerReviewed

Synthetic schlieren imaging, also known as background oriented schlieren imaging, is used to determine the acoustical field of a focused ultrasound transducer operating at 1.01 MHz frequency with peak pressure amplitude of 0.97 MPa. The measurement setup is composed of a commercial off-the-shelf digital single-lens reflex (DSLR) camera with an ordinary objective, a high power light-emitting diode driven in pulsating mode, water tank, ultrasound transducer, rotation stage, and driving electronics. Measurements are performed in tomographic fashion by rotating the ultrasound transducer within the water tank and photographing an imaged target behind the ultrasound field. The photographs are processed with a Horn-Schunck-type algorithm, commonly used in optical flow analysis, in order to determine the deflection of light rays as caused by ultrasound field induced acousto-optic effect. Inverse Radon transform is then used, with the deflection data, to obtain three-dimensional spatial distribution of the pressure field gradient, from which an approximation of the ultrasonic pressure field is computed. The pressure field obtained with synthetic schlieren tomography is then compared to hydrophone measurements mainly qualitatively., published version, peerReviewed

Collagen is the most prominent protein in biological tissues. Tissue fixation is often required for preservation or sectioning of the tissue. This may affect collagen nanostructure and potentially provide incorrect information when analyzed after fixation. We aimed to unravel the effect of 1) ethanol and formalin fixation and 2) 24 h air-dehydration on the organization and structure of collagen fibers at the nano-scale using small and wide angle X-ray scattering. Samples were divided into 4 groups: ethanol fixed, formalin fixed, and two untreated sample groups. Samples were allowed to air-dehydrate in handmade Kapton pockets during the measurements (24 h) except for one untreated group. Ethanol fixation affected the collagen organization and nanostructure substantially and during 24 h of dehydration dramatic changes were evident. Formalin fixation had minor effects on the collagen organization but after 12 h of air-dehydration the spatial variation increased substantially, not evident in the untreated samples. Generally, collagen shrinkage and loss of alignment was evident in all samples during 24 h of dehydration but the changes were subtle in all groups except the ethanol fixed samples. This study shows that tissue fixation needs to be chosen carefully in order to preserve the features of interest in the tissue., final draft, peerReviewed

This paper reports the investigation of the ability of electrical capacitance tomography (ECT) for imaging two-dimensional (2D) moisture flows in cement-based materials. Additionally, this paper studies the effect of two linear difference imaging methods (globally and sequentially linearized difference approach) on the ECT reconstructions. In the experiments, mortar specimens were monitored with ECT during a 2D moisture ingress. The results demonstrate that ECT is able to detect the evolution of the moisture flow, and, moreover to approximate the shape and position of the water front. In all the test cases the sequentially linearized method performs better than the globally linearized method – not only better in accuracy of localizing the water front but also detecting smaller moisture content at the early stages of the water ingress., published version, peerReviewed

Osteoarthritis is a harmful joint disease but prediction of disease progression is problematic. Currently, there is only one modeling framework which can be applied to predict the progression of knee osteoarthritis but it only considers degenerative changes in the collagen fibril network. Here, we have developed the framework further by considering all of the major tissue changes (proteoglycan content, fluid flow, and collagen fibril network) occurring in osteoarthritis. While excessive levels of tissue stresses controlled degeneration of the collagen fibril network, excessive levels of tissue strains controlled the decrease in proteoglycan content and the increase in permeability. We created four knee joint models with increasing degrees of complexity based on the depth-wise composition. Models were tested for normal and abnormal, physiologically relevant, loading conditions in the knee. Finally, the predicted depth-wise compositional changes from each model were compared against experimentally observed compositional changes in vitro. The model incorporating the typical depth-wise composition of cartilage produced the best match with experimental observations. Consistent with earlier in vitro experiments, this model simulated the greatest proteoglycan depletion in the superficial and middle zones, while the collagen fibril degeneration was located mostly in the superficial zone. The presented algorithm can be used for predicting simultaneous collagen degeneration and proteoglycan loss during the development of knee osteoarthritis., final draft, peerReviewed

Contrast-enhanced micro-computed tomography (CEμCT) with cationic and anionic contrast agents reveals glycosaminoglycan (GAG) content and distribution in articular cartilage (AC). The advantage of using cationic stains (e.g., CA4+) compared to anionic stains (e.g., Hexabrix®), is that it distributes proportionally with GAGs, while anionic stain distribution in AC is inversely proportional to the GAG content. To date, studies using cationic stains have been conducted with sufficient resolution to study its distributions on the macro-scale, but with insufficient resolution to study its distributions on the micro-scale. Therefore, it is not known whether the cationic contrast agents accumulate in extra/pericellular matrix and if they interact with chondrocytes. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low-resolution μCT setups. In this study, we use high-resolution μCT to investigate whether CA4+ accumulates in chondrocytes, and further, to determine whether it affects the low-resolution ex vivo μCT studies of CA4+ stained human AC with varying degree of osteoarthritis. Human osteochondral samples were immersed in three different concentrations of CA4+ (3 mgI/ml, 6 mgI/ml, and 24 mgI/ml) and imaged with high-resolution μCT at several timepoints. Different uptake diffusion profiles of CA4+ were observed between the segmented chondrons and the rest of the tissue. While the X-ray -detected CA4+ concentration in chondrons was greater than in the rest of the AC, its contribution to the uptake into the whole tissue was negligible and in line with macro-scale GAG content detected from histology. The efficient uptake of CA4+ into chondrons and surrounding territorial matrix can be explained by the micro-scale distribution of GAG content. CA4+ uptake in chondrons occurred regardless of the progression stage of osteoarthritis in the samples and the relative difference between the interterritorial matrix and segmented chondron area was less than 4%. To conclude, our results suggest that GAG quantification with CEμCT is not affected by the chondron uptake of CA4+. This further confirms the use of CA4+ for macro-scale assessment of GAG throughout the AC, and highlight the capability of studying chondron properties in 3D at the micro scale., published version, peerReviewed

Therapeutic treatment options for central nervous system diseases are greatly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), in conjunction with circulating microbubbles, can be used to induce a targeted and transient increase in BBB permeability, providing a unique approach for the delivery of drugs from the systemic circulation into the brain. While preclinical research has demonstrated the utility of FUS, there remains a large gap in our knowledge regarding the impact of sonication on BBB gene expression. This work is focused on investigating the transcriptional changes in dorsal hippocampal rat microvessels in the acute stages following sonication. Microarray analysis of microvessels was performed at 6 and 24 hrs post-FUS. Expression changes in individual genes and bioinformatic analysis suggests that FUS may induce a transient inflammatory response in microvessels. Increased transcription of proinflammatory cytokine genes appears to be short-lived, largely returning to baseline by 24 hrs. This observation may help to explain some previously observed bioeffects of FUS and may also be a driving force for the angiogenic processes and reduced drug efflux suggested by this work. While further studies are necessary, these results open up intriguing possibilities for novel FUS applications and suggest possible routes for pharmacologically modifying the technique., published version, peerReviewed

Background Age is a risk factor of obstructive sleep apnea (OSA). It has been shown that OSA progresses over time, although conflicting results have been reported. However, the effect of age on the severity of OSA and individual obstruction events has not been investigated within different OSA severity categories by taking the most prominent confounding factors (i.e., body mass index, gender, smoking, daytime sleepiness, snoring, hypertension, heart failure, and proportion of supine sleep) into account. Methods Polygraphic data of 1090 patients with apnea–hypopnea index (AHI) ≥5 were retrospectively reanalyzed. The effect of age on the severity of OSA and obstruction events was investigated in general, within different OSA severity categories, and in different age groups (age, final draft, peerReviewed

Repetition suppression (RS) is evident as a weakened response to repeated stimuli after the initial response. RS has been demonstrated in motor-evoked potentials (MEPs) induced with transcranial magnetic stimulation (TMS). Here, we investigated the effect of inter-train interval (ITI) on the induction of RS of MEPs with the attempt to optimize the investigative protocols. Trains of TMS pulses, targeted to the primary motor cortex by neuronavigation, were applied at a stimulation intensity of 120% of the resting motor threshold. The stimulus trains included either four or twenty pulses with an inter-stimulus interval (ISI) of 1 s. The ITI was here defined as the interval between the last pulse in a train and the first pulse in the next train; the ITIs used here were 1, 3, 4, 6, 7, 12, and 17 s. RS was observed with all ITIs except with the ITI of 1 s, in which the ITI was equal to ISI. RS was more pronounced with longer ITIs. Shorter ITIs may not allow sufficient time for a return to baseline. RS may reflect a startle-like response to the first pulse of a train followed by habituation. Longer ITIs may allow more recovery time and in turn demonstrate greater RS. Our results indicate that RS can be studied with confidence at relatively short ITIs of 6 s and above., published version, peerReviewed

Objective Rheumatoid arthritis (RA) is characterised by chronic inflammation leading to articular bone and cartilage damage. Despite recent progress in RA management, adverse effects, lack of efficacy and economic barriers to treatment access still limit therapeutic success. Therefore, safer and less expensive treatments that control inflammation and bone resorption are needed. We have previously shown that celastrol is a candidate for RA treatment. We have observed that it inhibits both interleukin (IL)-1β and tumor necrosis factor (TNF) in vitro, and that it has anti-inflammatory properties and ability to decrease synovial CD68+ macrophages in vivo. Herein our goal was to evaluate the effect of celastrol in local and systemic bone loss. Methods Celastrol was administrated intraperitoneally at a dose of 1 µg/g/day to female Wistar adjuvant-induced arthritic rats. Rats were sacrificed after 22 days of disease progression, and blood, femurs, tibiae and paw samples were collected for bone remodelling markers quantification, 3-point bending test, micro-CT analysis, nanoindentation and Fourier transform infrared spectroscopy measurements, and immunohistochemical evaluation. Results We have observed that celastrol preserved articular structures and decreased the number of osteoclasts and osteoblasts present in arthritic joints. Moreover, celastrol reduced tartrate-resistant acid phosphatase 5b, procollagen type 1 amino-terminal propeptide and C terminal crosslinked telopeptide of type II collagen serum levels. Importantly, celastrol prevented bone loss and bone microarchitecture degradation. Celastrol also preserved bone nanoproperties and mineral content. Additionally, animals treated with celastrol had less fragile bones, as depicted by an increase in maximum load and yield displacement. Conclusions These results suggest that celastrol reduces both bone resorption and cartilage degradation, and preserves bone structural properties., published version, peerReviewed

Introduction Changes in movement variability and complexity may reflect an adaptation strategy to fatigue. One unresolved question is whether this adaptation is hampered by the presence of low back pain (LBP). This study investigated if changes in movement variability and complexity after fatigue are influenced by the presence of LBP. It is hypothesised that pain free people and people suffering from LBP differ in their response to fatigue. Methods The effect of an isometric endurance test on lumbar movement was tested in 27 pain free participants and 59 participants suffering from LBP. Movement variability and complexity were quantified with %determinism and sample entropy of lumbar angular displacement and velocity. Generalized linear models were fitted for each outcome. Bayesian estimation of the group-fatigue effect with 95% highest posterior density intervals (95%HPDI) was performed. Results After fatiguing %determinism decreased and sample entropy increased in the pain free group, compared to the LBP group. The corresponding group-fatigue effects were 3.7 (95%HPDI: 2.3–7.1) and −1.4 (95%HPDI: −2.7 to −0.1). These effects manifested in angular velocity, but not in angular displacement. Discussion The effects indicate that pain free participants showed more complex and less predictable lumbar movement with a lower degree of structure in its variability following fatigue while participants suffering from LBP did not. This may be physiological responses to avoid overload of fatigued tissue, increase endurance, or a consequence of reduced movement control caused by fatigue., final draft, peerReviewed

We propose a state estimation approach for functional magnetic resonance imaging (fMRI). In state estimation, time-dependent image reconstruction problem is modeled by separate state evolution and observation models, and the objective is to estimate the time series of system states, given the models and the time-dependent measurement data. Our method computes the state estimates by using the Kalman filter (KF) and Kalman smoother (KS) algorithms. We propose to complement the state estimation formulation with a structural prior which can be derived from the anatomical MRI, acquired as a part of the fMRI protocol. Two different constructions of the structural prior are considered. The first one is a structured smoothness prior where the state observation matrix is augmented with a spatially weighted regularization matrix which promotes structural similarity of the gradient of the unknown image with the gradient of the anatomical image. The second approach is based on applying structured total variation denoising to the KF estimate at each time step of the Kalman recursions. The proposed approaches are evaluated using simulated and experimental, radially sampled, small animal fMRI data from a rat brain. In our method, the state estimates are updated after each new spoke of radial data becomes available, leading to faster frame rate compared to the conventional image reconstruction approaches. The results are compared to a sliding window method and a conventional reconstruction which produces new image only after a full circle of k-space spokes becomes available. The results suggest that the state estimation approach with the structural prior can improve both spatial and temporal resolution of fMRI., published version, peerReviewed

Conventional arthroscopic evaluation of articular cartilage is subjective and poorly reproducible. Therefore, implementation of quantitative diagnostic techniques, such as near infrared spectroscopy (NIRS) and optical coherence tomography (OCT), is essential. Locations (n = 44) with various cartilage conditions were selected from mature equine fetlock joints (n = 5). These locations and their surroundings were measured with NIRS and OCT (n = 530). As a reference, cartilage proteoglycan (PG) and collagen contents, and collagen network organization were determined using quantitative microscopy. Additionally, lesion severity visualized in OCT images was graded with an automatic algorithm according to International Cartilage Research Society (ICRS) scoring system. Artificial neural network with variable selection was then employed to predict cartilage composition in the superficial and deep zones from NIRS data, and the performance of two models, generalized (including all samples) and condition-specific models (based on ICRS-grades), was compared. Spectral data correlated significantly (p, published version, peerReviewed

A sensing skin is a two-dimensional large-area sensor which consists of a thin layer of electrically conductive material applied to the surface of structures in the form of paint or a pre-manufactured thin film. The sensing skin is engineered to locally change electrical conductivity in response to some stimulus such as temperature change, strain, or the presence of specific chemical elements. The local change in electrical conductivity of the sensing skin is then detected, localized, and quantified with electrical resistance tomography (ERT). Sensing skin has many applications in structural health monitoring. In the present paper, we outline our recent works in developing sensing skin for detecting cracking, the presence of chlorides, and temperature change. We also discuss the development of a multi-functional multi-layer sensing skin that simultaneously detects multiple stimuli. We discuss the application-specific computational techniques developed for sensing skin and present experimental results that show the successful applications of sensing skin in structural health monitoring., published version, peerReviewed

A new method has been developed to estimate the global and direct solar irradiance in the UV-A and UV-B at ground level in cloud-free conditions. It is based on a resampling technique applied to the results of the k-distribution method and the correlated-k approximation of Kato et al. (1999) over the UV band. Its inputs are the aerosol properties and total column ozone that are produced by the Copernicus Atmosphere Monitoring Service (CAMS). The estimates from this new method have been compared to instantaneous measurements of global UV irradiances made in cloud-free conditions at five stations at high latitudes in various climates. For the UV-A irradiance, the bias ranges between −0.8 W m−2 (−3 % of the mean of all data) and −0.2 W m−2 (−1 %). The root mean square error (RMSE) ranges from 1.1 W m−2 (6 %) to 1.9 W m−2 (9 %). The coefficient of determination R2 is greater than 0.98. The bias for UV-B is between −0.04 W m−2 (−4 %) and 0.08 W m−2 (+13 %) and the RMSE is 0.1 W m−2 (between 12 and 18 %). R2 ranges between 0.97 and 0.99. This work demonstrates the quality of the proposed method combined with the CAMS products. Improvements, especially in the modeling of the reflectivity of the Earth's surface in the UV region, are necessary prior to its inclusion into an operational tool., published version, peerReviewed

Collagen forms an organized network in articular cartilage to give tensile stiffness to the tissue. Due to its long half-life, collagen is susceptible to cross-links caused by advanced glycation end-products. The current standard method for determination of cross-link concentrations in tissues is the destructive high-performance liquid chromatography (HPLC). The aim of this study was to analyze the cross-link concentrations nondestructively from standard unstained histological articular cartilage sections by using Fourier transform infrared (FTIR) microspectroscopy. Half of the bovine articular cartilage samples ( n = 27 ) were treated with threose to increase the collagen cross-linking while the other half ( n = 27 ) served as a control group. Partial least squares (PLS) regression with variable selection algorithms was used to predict the cross-link concentrations from the measured average FTIR spectra of the samples, and HPLC was used as the reference method for cross-link concentrations. The correlation coefficients between the PLS regression models and the biochemical reference values were r = 0.84 ( p < 0.001 ), r = 0.87 ( p < 0.001 ) and r = 0.92 ( p < 0.001 ) for hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP), and pentosidine (Pent) cross-links, respectively. The study demonstrated that FTIR microspectroscopy is a feasible method for investigating cross-link concentrations in articular cartilage, published version, peerReviewed

Hyperspectral remote sensing data carry information on the leaf area index (LAI) of forests, and thus in principle, LAI can be estimated based on the data by inverting a forest reflectance model. However, LAI is usually not the only unknown in a reflectance model; especially, the leaf spectral albedo and understory reflectance are also not known. If the uncertainties of these parameters are not accounted for, the inversion of a forest reflectance model can lead to biased estimates for LAI. In this paper, we study the effects of reflectance model uncertainties on LAI estimates, and further, investigate whether the LAI estimates could recover from these uncertainties with the aid of Bayesian inference. In the proposed approach, the unknown leaf albedo and understory reflectance are estimated simultaneously with LAI from hyperspectral remote sensing data. The feasibility of the approach is tested with numerical simulation studies. The results show that in the presence of unknown parameters, the Bayesian LAI estimates which account for the model uncertainties outperform the conventional estimates that are based on biased model parameters. Moreover, the results demonstrate that the Bayesian inference can also provide feasible measures for the uncertainty of the estimated LAI., final draft, peerReviewed

Establishing the relationship between marine boundary layer (MBL) aerosols and surface water biogeochemistry is required to understand aerosol and cloud production processes over the remote ocean and represent them more accurately in earth system models and global climate projections. This was addressed by the SOAP (Surface Ocean Aerosol Production) campaign, which examined air–sea interaction over biologically productive frontal waters east of New Zealand. This overview details the objectives, regional context, sampling strategy and provisional findings of a pilot study, PreSOAP, in austral summer 2011 and the following SOAP voyage in late austral summer 2012. Both voyages characterized surface water and MBL composition in three phytoplankton blooms of differing species composition and biogeochemistry, with significant regional correlation observed between chlorophyll a and DMSsw. Surface seawater dimethylsulfide (DMSsw) and associated air–sea DMS flux showed spatial variation during the SOAP voyage, with maxima of 25 nmol L−1 and 100 µmol m−2 d−1, respectively, recorded in a dinoflagellate bloom. Inclusion of SOAP data in a regional DMSsw compilation indicates that the current climatological mean is an underestimate for this region of the southwest Pacific. Estimation of the DMS gas transfer velocity (kDMS) by independent techniques of eddy covariance and gradient flux showed good agreement, although both exhibited periodic deviations from model estimates. Flux anomalies were related to surface warming and sea surface microlayer enrichment and also reflected the heterogeneous distribution of DMSsw and the associated flux footprint. Other aerosol precursors measured included the halides and various volatile organic carbon compounds, with first measurements of the short-lived gases glyoxal and methylglyoxal in pristine Southern Ocean marine air indicating an unidentified local source. The application of a real-time clean sector, contaminant markers and a common aerosol inlet facilitated multi-sensor measurement of uncontaminated air. Aerosol characterization identified variable Aitken mode and consistent submicron-sized accumulation and coarse modes. Submicron aerosol mass was dominated by secondary particles containing ammonium sulfate/bisulfate under light winds, with an increase in sea salt under higher wind speeds. MBL measurements and chamber experiments identified a significant organic component in primary and secondary aerosols. Comparison of SOAP aerosol number and size distributions reveals an underprediction in GLOMAP (GLObal Model of Aerosol Processes)-mode aerosol number in clean marine air masses, suggesting a missing marine aerosol source in the model. The SOAP data will be further examined for evidence of nucleation events and also to identify relationships between MBL composition and surface ocean biogeochemistry that may provide potential proxies for aerosol precursors and production., published version, peerReviewed

Background Transcranial magnetic resonance guided focused ultrasound is an emerging technology under evaluation for treatment of essential tremor, a prevalent movement disorder. A qualitative evaluation is performed by a clinician periodically during the procedure to maximize treatment effects and minimize adverse effects. The present work demonstrates a magnetic resonance-compatible method to enable more precise, quantitative measurement of tremor severity. Methods Tremor severity was measured in 12 patients pre-, post-, and intra-operatively, using a magnetic resonance-compatible tablet and a computerized adaptation of drawing tasks from the widely-used Fahn-Tolosa-Marin Tremor Rating Scale. Tremor metrics based on spectral analysis were calculated for each drawing and compared using Wilcoxon signed rank tests. Results Tremor metrics in the dominant (treated) hand were significantly and consistently lower post-operatively compared to pre-operatively, but there was no significant difference in the non-dominant (untreated) hand, as expected. Intra-operative metrics were intermediate between pre- and post-operative metrics. Conclusions Use of the tablet for quantitative tremor measurement was demonstrated pre-, post-, and intra-operatively during treatment of essential tremor, complementing standard qualitative assessment. With additional work, the system has potential to add objectivity to clinical trials and to aid treatment decision-making by providing a metric for optimization during the procedure, which may eventually lead to more optimal treatment. Enhancements and further studies are suggested, and extensions to fMRI studies of essential tremor and Parkinson’s disease are also likely., published version, peerReviewed