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Abstract During the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition, the Balloon-bornE moduLar Utility for profilinG the lower Atmosphere (BELUGA) was deployed from an ice floe drifting in the Fram Strait from 29 June to 27 July 2020. The BELUGA observations aimed to characterize the cloudy Arctic atmospheric boundary layer above the sea ice using a modular setup of five instrument packages. The in situ measurements included atmospheric thermodynamic and dynamic state parameters (air temperature, humidity, pressure, and three-dimensional wind), broadband solar and terrestrial irradiance, aerosol particle microphysical properties, and cloud particle images. In total, 66 profile observations were collected during 33 balloon flights from the surface to maximum altitudes of 0.3 to 1.5 km. The profiles feature a high vertical resolution of 0.01 m to 1 m, including measurements below, inside, and above frequently occurring low-level clouds. This publication describes the balloon operations, instruments, and the obtained data set. We invite the scientific community for joint analysis and model application of the freely available data on PANGAEA.

Lewis Fry Richardson proposed his famous picture of turbulent flows in 1922, where the kinetic energy is transferred from large-scale to small-scale structures until the viscosity converts it into heat. This cascade idea, also known as the forward energy cascade, is now widely accepted and is treated as the cornerstone of not only turbulent modeling, but also global circulation models of the ocean and atmosphere. In this work, the Filter-Space-Technique is applied to the oceanic flow field provided by the CMEMS reanalysis model to quantify the scale-to-scale energy flux. A rich dynamical pattern associated with different scales is observed. More precisely, either positive or negative fluxes are observed, indicating the direction of the energy cascade, where the energy is transferred from large-scale structures to small-scale ones or vice versa. High-intensity energy exchange is found mainly in the Western Boundary Current Systems and Equatorial Counter Currents. For the latter case, a wavelike pattern is observed on the westward travel. Moreover, strong seasonal variation is evident for some scales and regions. These results confirm the existence of forward and inverse cascades and rich regional dynamics.

In a fully developed sea, the significant wave height (Hs) and wind speed (U10) are conventionally related to a pure quadratic equation. This relation is often violated, since in the field the measured local Hs is often contaminated by the swell, which is propagated from distant places. Therefore, a swell partition is required before the establishment of the wind-wave relation. The Spectra Energy Partition (SEP) is regarded as the best way to isolate the swell and the wind wave relation: it is based on the identification of a separation frequency in the ocean wave spectrum. However, for most field observations, the wave spectra information is unavailable, and thus the SEP is inapplicable. This work proposes a probability-based algorithm to identify the averaged swell without knowing the wave spectrum a priori. The local wind-wave relation is established by either a linear or an energy-conserved decomposition. We also find that the local wind-wave relation is a power-law when the wind speed U10 is above 4 m/s. The proposed method is first validated by applying the SEP method to buoy collected wave spectra data. The global pattern of the swell and the local wind waves is retrieved by applying the proposed method to a 17-year wind and wave database from the JASON satellite. Strong seasonal and spatial variations are obtained. Finally, a prediction model based on the empirical wind-wave relation is shown to successfully retrieve the wave field when the wind field is available.

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

In fully developed turbulence, there is a flux of energy from large to small scales in the inertial range until the dissipation at small scales. It is associated with irreversibility, i.e., a breaking of the time reversal symmetry. Such turbulent flows are characterized by scaling properties, and we consider here how irreversibility depends on the scale. Indicators of time-reversal symmetry for time series are tested involving triple correlations in a non-symmetric way. These indicators are built so that they are zero for a time-reversal symmetric time series, and a departure from zero is an indicator of irreversibility. We study these indicators applied to two fully developed turbulence time series, from flume tank and wind tunnel databases. It is found that irreversibility occurs in the inertial range and has scaling properties with slopes close to one. A maximum value is found around the injection scale. This confirms that the irreversibility is associated with the turbulent cascade in the inertial range and shows that the irreversibility is maximal at the injection scale, the largest scale of the turbulent cascade.

Because climate change will likely have major impacts in low-lying coastal areas, our ability for evaluating predictable consequences of coastal hazards in the future already represents a key issue in coastal risk reduction. This paper presents examples of the application of a method aimed at assessing the future position of the shoreline and at mapping areas that will be at risk of flooding by 2065 with future sea-level rise at two coastal localities of northern France where properties are already threatened by erosion or flooding. Our results show that erosion is the main coastal hazard at one of the two study sites where a large part of a housing estate may disappear by 2065 if no action is taken for limiting coastal erosion. Although marine flooding represents the primary risk at the second study site, coastal erosion will increase the risk of flooding of properties in the future due to the decrease in width of the protective coastal dunes. Comparison of our results with the coastal hazard maps published by the French government shows significant differences that can be explained by the fact that the risk of erosion was not considered in the Coastal Risk Protection Plans (PPRL) of the two municipalities considered in this study, which raises the question of the reliability of areas at risk defined without taking into account future shoreline evolution trends.

Andean glaciers have melted rapidly since the 1960s. While some melting is likely due to anthropogenic climate change driven by increasing greenhouse gases, deposition of light-absorbing particles such as black carbon (BC) may also play a role. We hypothesize that BC from fires in the Amazon Basin and elsewhere may be deposited on Andean glaciers, reducing the surface albedo and inducing further melting. Here we investigate the role of BC deposition on albedo changes in the Andes for 2014–2019 by combining atmospheric chemistry modeling with observations of BC in snow or ice at four mountain sites in Peru (Quelccaya, Huascarán, Yanapaccha, and Shallap) and at one site in Bolivia (Illimani). We find that annual mean ice BC concentrations simulated by the chemical transport model GEOS-Chem for 2014–2019 are roughly consistent with those observed at the site with the longest record, Huascarán, with overestimates of 15%–40%. Smoke from fires account for 20%–70% of total wet and dry deposition fluxes, depending on the site. The rest of BC deposited comes from fossil fuel combustion. Using a snow albedo model, we find that the annual mean radiative forcing from the deposition of smoke BC alone on snow ranges from +0.1 to +3.2 W m ^−2 under clear-sky conditions, with corresponding average albedo reductions of 0.04%–1.1%. These ranges are dependent on site and snow grain size. This result implies a potentially significant climate impact of biomass burning in the Amazon on radiative forcing in the Andes.

A new instrument for the quantification of light absorption by particles collected on filters has been developed to address long standing environmental questions about light-absorbing particles in air, water, and on snow and ice. The Light Absorption Heating Method (LAHM) uses temperature changes when filters are exposed to light to quantify absorption. Through the use of calibration standards, the observed temperature response of unknown materials can be related to the absorption cross section of the substance collected on the filter. Here, we present a detailed description of the instrument and calibration. The results of the calibration tests using a common surrogate for black carbon, Fullerene soot, show that the instrument provides stable results even when exposed to adverse laboratory conditions, and that there is little drift in the instrument over longer periods of time. Calibration studies using Fullerene soot suspended in water, airborne propane soot, as well as atmospheric particulates show consistent results for absorption cross section when using accepted values for the mass absorption cross section of the soot and when compared to results from a 3-wavelength photoacoustic instrument. While filter sampling cannot provide the time resolution of other instrumentation, the LAHM instrument fills a niche where time averaging is reasonable and high-cost instrumentation is not available. The optimal range of absorption cross sections for LAHM is from 0.1 to 5.0 cm2 (~1.0–50.0 µg soot) for 25 mm filters and 0.4 to 20 cm2 (4.0–200.0 µg soot) for 47 mm filters, with reduced sensitivity to higher values.

Introduction: Mucopolysaccharidosis type II (MPS II) is caused by deficiency of the enzyme iduronate-2-sulfatase; one possible therapy for MPS II is hematopoietic stem cell transplantation (HSCT). It is established that there is excessive production of reactive species in MPS II patients, which can trigger several processes, such as the inflammatory cascade., Objectives: Our aim was to outline an inflammatory profile and lipoperoxidation of MPS II patients for a better understanding of disease and possible benefits that HSCT can bring in these processes., Materials and Methods: We investigate oxidative damage to lipids by 15-F2t-isoprostane urinary concentrations and plasma pro-and anti-inflammatory cytokine concentrations in MPS II patients at diagnosis, MPS II post-HSCT patients, and controls., Results: Interleukin (IL)-1β and IL-17a concentrations were significantly increased and a tendency toward increased IL-6 production in the diagnosis group was verified. We found significant decrease in IL-4 and increase in 15-F2t-isoprostane concentrations in the diagnosis group, while IL-1β, IL-6, IL-17a and 15-F2t-isoprostane concentrations were similar between control and post-HSCT groups., Conclusions: Our study demonstrated that MPS II patients at diagnosis are in a pro-inflammatory state, bringing a novel result showing increased production of IL-17a, an osteoclastogenic cytokine, as well as demonstrating that these patients have oxidative damage to lipids. Furthermore, evidence suggests that HSCT can reduce inflammation and lipoperoxidation in MPS II patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Giugliani received educational grants and speaker honoraria, and has been an investigator in clinical trials sponsored by BioMarin and other companies. The other authors declare that they have no conflict of interest., (Copyright © 2024 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Parenting behaviors play an important role in the transmission of depressive symptoms from mothers to children. Although reduced positive affect is a central feature of depression, models of intergenerational transmission have neglected maternal socialization of positive affect as a mediating mechanism. This study investigated whether maternal responses to infant positive affect mediate the link between mothers' and toddlers' depressive symptoms. A community sample of 128 mothers (58% White) and their infants ( M age = 6.65 months, SD = 0.53 at first visit) participated in 3 assessments over a 1-year period. Assessments included self-reports of postpartum depressive symptoms, observational measures of maternal responses to infant positive affect and maternal sensitivity, and mother report of toddlers' depressive problems. Mediation analyses revealed that mothers with elevated postpartum depressive symptoms displayed fewer supportive responses to their infants' positive affect. In turn, infants who received fewer supportive responses had more depressive problems in toddlerhood. The indirect effect of postpartum depressive symptoms on toddlers' depressive problems via maternal supportive responses remained significant after controlling for maternal sensitivity. Findings suggest that maternal responses to infant positive affect play a unique role in the intergenerational transmission of depressive symptoms. The theoretical and practical implications of these findings are discussed.

Lowering the levels of the cellular prion protein (PrPC) is widely considered a promising strategy for the treatment of prion diseases. Building on work that established immediate spatial proximity of PrPC and Na+, K+-ATPases (NKAs) in the brain, we recently showed that PrPC levels can be reduced by targeting NKAs with their natural cardiac glycoside (CG) inhibitors. We then introduced C4'-dehydro-oleandrin as a CG with improved pharmacological properties for this indication, showing that it reduced PrPC levels by 84% in immortalized human cells that had been differentiated to acquire neural or astrocytic characteristics. Here we report that our lead compound caused cell surface PrPC levels to drop also in other human cell models, even when the analyses of whole cell lysates suggested otherwise. Because mice are refractory to CGs, we explored guinea pigs as an alternative rodent model for the preclinical evaluation of C4'-dehydro-oleandrin. We found that guinea pig cell lines, primary cells, and brain slices were responsive to our lead compound, albeit it at 30-fold higher concentrations than human cells. Of potential significance for other PrPC lowering approaches, we observed that cells attempted to compensate for the loss of cell surface PrPC levels by increasing the expression of the prion gene, requiring daily administration of C4'-dehydro-oleandrin for a sustained PrPC lowering effect. Regrettably, when administered systemically in vivo, the levels of C4'-dehydro-oleandrin that reached the guinea pig brain remained insufficient for the PrPC lowering effect to manifest. A more suitable preclinical model is still needed to determine if C4'-dehydro-oleandrin can offer a cost-effective complementary strategy for pushing PrPC levels below a threshold required for long-term prion disease survival., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: GS and DW declare that they are co-inventors on patent applications named ‘Compounds for altering levels of one or more NKA alpha subunits and their use in treating prion diseases or brain diseases associated with cellular prion protein’ filed in the US and Canada as well as a European patent application named ‘Compounds and methods to treat prion and related diseases’ based on a PCT international filing (PCT/CA2022/050358). These patent applications describe the use of CGs for the purpose of reducing steady-state levels of PrPC. This potential conflict-of-interest does not affect the adherence of all authors to journal policies on the sharing of data and materials. This does not alter our adherence to PLoS One policies on sharing data and materials., (Copyright: © 2024 Eid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon is mediated by the bank vole prion protein (BVPrP). The molecular determinants of BVPrP's ability to function as a universal prion acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we systematically identified key residues in BVPrP that permit cross-species prion replication. We found that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict prion accumulation following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kinetics in vitro. These findings suggest that BVPrP's unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arshad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With the increasing pervasiveness of Artificial Intelligence (AI), many visual analytics tools have been proposed to examine fairness, but they mostly focus on data scientist users. Instead, tackling fairness must be inclusive and involve domain experts with specialized tools and workflows. Thus, domain-specific visualizations are needed for algorithmic fairness. Furthermore, while much work on AI fairness has focused on predictive decisions, less has been done for fair allocation and planning, which require human expertise and iterative design to integrate myriad constraints. We propose the Intelligible Fair Allocation (IF-Alloc) Framework that leverages explanations of causal attribution (Why), contrastive (Why Not) and counterfactual reasoning (What If, How To) to aid domain experts to assess and alleviate unfairness in allocation problems. We apply the framework to fair urban planning for designing cities that provide equal access to amenities and benefits for diverse resident types. Specifically, we propose an interactive visual tool, Intelligible Fair City Planner (IF-City), to help urban planners to perceive inequality across groups, identify and attribute sources of inequality, and mitigate inequality with automatic allocation simulations and constraint-satisfying recommendations (IF-Plan). We demonstrate and evaluate the usage and usefulness of IF-City on a real neighborhood in New York City, US, with practicing urban planners from multiple countries, and discuss generalizing our findings, application, and framework to other use cases and applications of fair allocation.

Objective: To investigate whether tibiofemoral alignment influences early knee osteoarthritis (OA). We hypothesized that varus overload exacerbates early degenerative osteochondral changes, and that valgus underload diminishes early OA., Method: Normal, over- and underload were induced by altering alignment via high tibial osteotomy in adult sheep (n = 8 each). Simultaneously, OA was induced by partial medial anterior meniscectomy. At 6 weeks postoperatively, OA was examined in five individual subregions of the medial tibial plateau using Kellgren-Lawrence grading, quantification of macroscopic OA, semiquantitative histopathological OA and immunohistochemical type-II collagen, ADAMTS-5, and MMP-13 scoring, biochemical determination of DNA and proteoglycan contents, and micro-computed tomographic evaluation of the subchondral bone., Results: Multivariate analyses revealed that OA cartilaginous changes had a temporal priority over subchondral bone changes. Underload inhibited early cartilage degeneration in a characteristic topographic pattern (P ≥ 0.0983 vs. normal), in particular below the meniscal damage, avoided alterations of the subarticular spongiosa (P ≥ 0.162 vs. normal), and prevented the disturbance of otherwise normal osteochondral correlations. Overload induced early alterations of the subchondral bone plate microstructure towards osteopenia, including significantly decreased percent bone volume and increased bone surface-to-volume ratio (all P ≤ 0.0359 vs. normal)., Conclusion: The data provide high-resolution evidence that tibiofemoral alignment modulates early OA induced by a medial meniscus injury in adult sheep. Since underload inhibits early OA, these data also support the clinical value of strategies to reduce the load in an affected knee compartment to possibly decelerate structural OA progression., Competing Interests: Competing interests H.M. received grants from DFG (German Research Foundation), Deutsche Arthrose-Hilfe, Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie, Sorbonne University Paris, and Fidia farmaceutici S.p.A., speaker fees, and travel fees from Novartis and Fidia farmaceutici S.p.A., is a member of the Scientific Advisory Board of Thuasne and Bone therapeutics and received travel fees and was a member of the Scientific Advisory Board of Kolon TissueGene. All other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Restoration of osteochondral defects is critical, because osteoarthritis (OA) can arise., Hypothesis: Overexpression of insulin-like growth factor 1 (IGF-1) via recombinant adeno-associated viral (rAAV) vectors (rAAV-IGF-1) would improve osteochondral repair and reduce parameters of early perifocal OA in sheep after 6 months in vivo., Study Design: Controlled laboratory study., Methods: Osteochondral defects were created in the femoral trochlea of adult sheep and treated with rAAV-IGF-1 or rAAV- lacZ (control) (24 defects in 6 knees per group). After 6 months in vivo, osteochondral repair and perifocal OA were assessed by well-established macroscopic, histological, and immunohistochemical scoring systems as well as biochemical and micro-computed tomography evaluations., Results: Application of rAAV-IGF-1 led to prolonged (6 months) IGF-1 overexpression without adverse effects, maintaining a significantly superior overall cartilage repair, together with significantly improved defect filling, extracellular matrix staining, cellular morphology, and surface architecture compared with rAAV- lacZ . Expression of type II collagen significantly increased and that of type I collagen significantly decreased. Subchondral bone repair and tidemark formation were significantly improved, and subchondral bone plate thickness and subarticular spongiosa mineral density returned to normal. The OA parameters of perifocal structure, cell cloning, and matrix staining were significantly better preserved upon rAAV-IGF-1 compared with rAAV- lacZ . Novel mechanistic associations between parameters of osteochondral repair and OA were identified., Conclusion: Local rAAV-mediated IGF-1 overexpression enhanced osteochondral repair and ameliorated parameters of perifocal early OA., Clinical Relevance: IGF-1 gene therapy may be beneficial in repair of focal osteochondral defects and prevention of perifocal OA., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was funded by Deutsche Arthrose-Hilfe e.V. P229-A15-Madry-EP1-madr7-allgemein-pr-I-226k-2010-14 (M.C., H.M.). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Significant links exist between one's perception of available social support and mental health outcomes, including during the transition to motherhood. Yet, attachment theory posits that individuals do not benefit equally from social support. As such, we examined the influence of attachment representations (i.e., secure base script knowledge) as they potentially moderate links between social support and psychological distress in a 1-year longitudinal study of an ethnically diverse (56% White) sample of infant-mother dyads. We hypothesized that higher social support would predict lower maternal psychological distress and this relation would be strongest in those with higher secure base script knowledge. Results indicated that maternal perceptions of social support were significantly negatively correlated with psychological distress. Analyses revealed that secure base script scores significantly moderated these associations. Interestingly, for those high in script knowledge, low social support predicted greater psychological distress. For those low in script knowledge, social support was unrelated to psychological distress. This pattern suggested that those who expect care (i.e., high secure base script knowledge) but receive minimal support (i.e., low perceived social support) find motherhood uniquely dysregulating. Practitioners may do well to examine individuals' attachment expectations in relation to their current social support.

Purpose: We report a case of a polydrug user who consumed various synthetic cannabinoids and fentanyl from a transdermal patch via a bucket bong. Toxicological results from postmortem matrices with special focus on synthetic cannabinoids are discussed in terms of their relevance to the death., Methods: The samples were analyzed by toxicological screening procedures involving immunoassays and gas chromatography-mass spectrometry (GC-MS) as well as quantitative analyses by means of GC-MS and high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: At the autopsy, coronary artery disease and signs of liver congestion were noted, in the absence of acute myocardial ischemic changes. Femoral blood concentrations of fentanyl and pregabalin were 14 ng/mL and 3,200 ng/mL, respectively. In addition, 2.7 ng/mL 5F-ADB and 13 ng/mL 5F-MDMB-P7AICA were detected together with relatively low amounts of 5 other synthetic cannabinoids in cardiac blood. A total number of up to 17 synthetic cannabinoids were detected in kidney, liver, urine and hair. Fentanyl and 5F-ADB were also detected in the water of the bucket bong., Conclusions: The cause of death could be attributed to an acute mixed intoxication by fentanyl and 5F-ADB (both Toxicological Significance Score (TSS) = 3) with a contribution of pregabalin and 5F-MDMB-P7AICA (TSS = 2), in a subject suffering from pre-existing heart damage. The most plausible mechanism of death consists in a respiratory depression. This case report demonstrates that use of opioids in combination with synthetic cannabinoids might be particularly dangerous., (© 2023. The Author(s).)

Recombinant adeno-associated virus (rAAV) vectors are gene therapy delivery tools that offer a promising platform for the treatment of neurodegenerative diseases. Keeping up with developments in this fast-moving area of research is a challenge. This review was thus written with the intention to introduce this field of study to those who are new to it and direct others who are struggling to stay abreast of the literature towards notable recent studies. In ten sections, we briefly highlight early milestones within this field and its first clinical success stories. We showcase current clinical trials, which focus on gene replacement, gene augmentation, or gene suppression strategies. Next, we discuss ongoing efforts to improve the tropism of rAAV vectors for brain applications and introduce pre-clinical research directed toward harnessing rAAV vectors for gene editing applications. Subsequently, we present common genetic elements coded by the single-stranded DNA of rAAV vectors, their so-called payloads. Our focus is on recent advances that are bound to increase treatment efficacies. As needed, we included studies outside the neurodegenerative disease field that showcased improved pre-clinical designs of all-in-one rAAV vectors for gene editing applications. Finally, we discuss risks associated with off-target effects and inadvertent immunogenicity that these technologies harbor as well as the mitigation strategies available to date to make their application safer.

Articular cartilage defects represent an unsolved clinical challenge. Photopolymerizable hydrogels are attractive candidates supporting repair. This study investigates the short-term safety and efficacy of two novel hyaluronic acid (HA)-triethylene glycol (TEG)-coumarin hydrogels photocrosslinked in situ in a clinically relevant large animal model. It is hypothesized that HA-hydrogel-augmented microfracture (MFX) is superior to MFX in enhancing early cartilage repair, and that the molar degree of substitution and concentration of HA affects repair. Chondral full-thickness defects in the knees of adult minipigs are treated with either 1) debridement (No MFX), 2) debridement and MFX, 3) debridement, MFX, and HA hydrogel (30% molar derivatization, 30 mg mL -1 HA; F3) (MFX+F3), and 4) debridement, MFX, and HA hydrogel (40% molar derivatization, 20 mg mL -1 HA; F4) (MFX+F4). After 8 weeks postoperatively, MFX+F3 significantly improves total macroscopic and histological scores compared with all other groups without negative effects, besides significantly enhancing the individual repair parameters "defect architecture," "repair tissue surface" (compared with No MFX, MFX), and "subchondral bone" (compared with MFX). These data indicate that photopolymerizable HA hydrogels enable a favorable metastable microenvironment promoting early chondrogenesis in vivo. This work also uncovers a mechanism for effective HA-augmented cartilage repair by combining lower molar derivatization with higher concentrations., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Objectives: To compare the cytotoxicity of octenidine dihydrochloride and chlorhexidine gluconate at different concentrations on primary human articular chondrocytes and cartilage., Materials and Methods: Primary cultures of human normal adult articular chondrocytes were exposed to octenidine dihydrochloride (0.001562%, 0.003125%, 0.00625%, 0.0125%, 0.025%, 0.05%, and 0.1%), chlorhexidine gluconate (0.003125%, 0.00625%, 0.0125%, 0.025%, 0.05%, 0.1%, and 0.2%), and control (Dulbecco's modified Eagle medium or phosphate-buffered saline) for 30 s. Normal human articular cartilage explants were exposed to octenidine dihydrochloride (0.1% versus control) and chlorhexidine gluconate (0.1% versus control) for 30 s. The viability of human articular chondrocytes was measured by Trypan blue staining, Cell Proliferation Reagent WST-1, and Live/Dead staining. The proliferation of human chondrocytes was measured using the Cell Proliferation Reagent WST-1. The viability of human articular cartilage explants was measured by using Live/Dead staining., Results: Octenidine dihydrochloride and chlorhexidine gluconate exposure decreased cell viability and proliferation in a dose-dependent manner in primary human articular chondrocytes. Octenidine dihydrochloride and chlorhexidine gluconate exposure decreased cell viability in human articular cartilage explant cultures., Conclusion: The degree of toxicity varied between octenidine dihydrochloride and chlorhexidine gluconate, with chlorhexidine gluconate being less toxic than octenidine dihydrochloride at the same concentration. Additionally, both octenidine dihydrochloride and chlorhexidine gluconate evaluation had cytotoxic effects on human articular cartilage. Therefore, dosing for the antimicrobial mouthwash ingredients administration would ideally be determined to remain below IC50., Clinical Relevance: These data support the in vitro safety of antimicrobial mouthwashes on primary adult human articular chondrocytes., (© 2023. The Author(s).)

Transcriptional regulators encoded by the Myocyte Enhancer Factor 2 (MEF2) gene family play a fundamental role in cardiac development, homeostasis and pathology. Previous studies indicate that MEF2A protein-protein interactions serve as a network hub in several cardiomyocyte cellular processes. Based on the idea that interactions with regulatory protein partners underly the diverse roles of MEF2A in cardiomyocyte gene expression, we undertook a systematic unbiased screen of the MEF2A protein interactome in primary cardiomyocytes using an affinity purification-based quantitative mass spectrometry approach. Bioinformatic processing of the MEF2A interactome revealed protein networks involved in the regulation of programmed cell death, inflammatory responses, actin dynamics and stress signaling in primary cardiomyocytes. Further biochemical and functional confirmation of specific protein-protein interactions documented a dynamic interaction between MEF2A and STAT3 proteins. Integration of transcriptome level data from MEF2A and STAT3-depleted cardiomyocytes reveals that the balance between MEF2A and STAT3 activity exerts a level of executive control over the inflammatory response and cardiomyocyte cell survival and experimentally ameliorates Phenylephrine induced cardiomyocyte hypertrophy. Lastly, we identified several MEF2A/STAT3 co-regulated genes, including the MMP9 gene. Herein, we document the cardiomyocyte MEF2A interactome, which furthers our understanding of protein networks involved in the hierarchical control of normal and pathophysiological cardiomyocyte gene expression in the mammalian heart., (© 2023. The Author(s).)

The bank vole (BV) prion protein (PrP) can function as a universal acceptor of prions. However, the molecular details of BVPrP's promiscuity for replicating a diverse range of prion strains remain obscure. To develop a cultured cell paradigm capable of interrogating the unique properties of BVPrP, we generated monoclonal lines of CAD5 cells lacking endogenous PrP but stably expressing either hamster (Ha), mouse (Mo), or BVPrP (M109 or I109 polymorphic variants) and then challenged them with various strains of mouse or hamster prions. Cells expressing BVPrP were susceptible to both mouse and hamster prions, whereas cells expressing MoPrP or HaPrP could only be infected with species-matched prions. Propagation of mouse and hamster prions in cells expressing BVPrP resulted in strain adaptation in several instances, as evidenced by alterations in conformational stability, glycosylation, susceptibility to anti-prion small molecules, and the inability of BVPrP-adapted mouse prion strains to infect cells expressing MoPrP. Interestingly, cells expressing BVPrP containing the G127V prion gene variant, identified in individuals resistant to kuru, were unable to become infected with prions. Moreover, the G127V polymorphic variant impeded the spontaneous aggregation of recombinant BVPrP. These results demonstrate that BVPrP can facilitate cross-species prion replication in cultured cells and that a single amino acid change can override the prion-permissive nature of BVPrP. This cellular paradigm will be useful for dissecting the molecular features of BVPrP that allow it to function as a universal prion acceptor., (© 2022 International Society for Neurochemistry.)

Objective: Osteoarthritis (OA) is a serious consequence of focal osteochondral defects. Gene transfer of human transforming growth factor beta (hTGF-β) with recombinant adeno-associated virus (rAAV) vectors offers a strategy to improve osteochondral repair. However, the long-term in vivo effects of such rAAV-mediated TGF-β overexpression including its potential benefits on OA development remain unknown., Method: Focal osteochondral defects in minipig knees received rAAV-lacZ (control) or rAAV-hTGF-β in vivo. After one year, osteochondral repair and perifocal OA were visualized using validated macroscopic scoring, ultra-high-field MRI at 9.4 T, and micro-CT. A quantitative estimation of the cellular densities and a validated semi-quantitative scoring of histological and immunohistological parameters completed the analysis of microarchitectural parameters., Results: Direct rAAV-hTGF-β application induced and maintained significantly improved defect filling and safranin O staining intensity and overall cartilage repair at one year in vivo. In addition, rAAV-hTGF-β led to significantly higher chondrocyte densities within the cartilaginous repair tissue without affecting chondrocyte hypertrophy and minimized subarticular trabecular separation. Of note, rAAV-hTGF-β significantly improved the adjacent cartilage structure and chondrocyte density and reduced overall perifocal OA development after one year in vivo., Conclusions: rAAV-hTGF-β treatment improves long-term osteochondral repair and delays the progression of perifocal OA in a translational model. These findings have considerable potential for targeted molecular approaches to treat focal osteochondral defects., (Copyright © 2022. Published by Elsevier Ltd.)