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Neurons are dependent on efficient quality control mechanisms to maintain cellular homeostasis and function due to their polarization and long-life span. Autophagy is a lysosomal degradative pathway that provides nutrients during starvation and recycles damaged and/or aged proteins and organelles. In neurons, autophagosomes constitutively form in distal axons and at synapses and are trafficked retrogradely to the cell soma to fuse with lysosomes for cargo degradation. How the neuronal autophagy pathway is organized and controlled remains poorly understood. Several presynaptic endocytic proteins have been shown to regulate both synaptic vesicle recycling and autophagy. Here, by combining electron, fluorescence, and live imaging microscopy with biochemical analysis, we show that the neuron-specific protein APache, a presynaptic AP-2 interactor, functions in neurons as an important player in the autophagy process, regulating the retrograde transport of autophagosomes. We found that APache colocalizes and co-traffics with autophagosomes in primary cortical neurons and that induction of autophagy by mTOR inhibition increases LC3 and APache protein levels at synaptic boutons. APache silencing causes a blockade of autophagic flux preventing the clearance of p62/SQSTM1, leading to a severe accumulation of autophagosomes and amphisomes at synaptic terminals and along neurites due to defective retrograde transport of TrkB-containing signaling amphisomes along the axons. Together, our data identify APache as a regulator of the autophagic cycle, potentially in cooperation with AP-2, and hypothesize that its dysfunctions contribute to the early synaptic impairments in neurodegenerative conditions associated with impaired autophagy. [ABSTRACT FROM AUTHOR]

Despite the substantial disease burden of anxiety disorders, only limited or conflicting data on prognostic factors is available. Most studies include patients in the secondary healthcare sector thus, the generalizability of findings is limited. The present study examines predictors of symptom reduction and remission in patients with anxiety disorders in a primary care setting. 214 patients with anxiety disorders, recruited as part of the Collabri Flex trial, were included in secondary analyses. Data on potential predictors of anxiety symptoms at 6-month follow-up was collected at baseline, including patient characteristics related to demography, illness, comorbidity, functional level, life quality, and self-efficacy. The outcomes were symptom reduction and remission. Univariate and multivariate linear and logistic regression analyses were conducted to assess the associations between predictor variables and the outcome, and machine-learning methods were also applied. In multiple linear regression analysis, anxiety severity at baseline (β = -6.05, 95% CI = -7.54,-4.56, p < 0.001) and general psychological problems and symptoms of psychopathology (SCL-90-R score) (β = 2.19, 95% CI = 0.24,4.14, p = 0.028) were significantly associated with symptom change at 6 months. Moreover, self-efficacy was associated with the outcome, however no longer significant in the multiple regression model. In multiple logistic regression analysis, anxiety severity at baseline (OR = 0.54, 95% CI = -1.13,-0.12, p = 0.018) was significantly associated with remission at 6 months. There was no predictive performance of the machine-learning models. Our study contributes with information that could be valuable knowledge for managing anxiety disorders in primary care. [ABSTRACT FROM AUTHOR]

This article explores the balance, and the shift in balance, between technologies and practices that coordinate work. The empirical data stems from a primarily qualitative study of a Norwegian shipyard in a phase of transition, where new models of collaboration emerge due to changes in the company environment. The article highlights the interplay between formal and informal articulation work, as well as the role of coordinative IT artifacts in this regard. With this background, the findings show that the balance (between coordinative technologies and practices) shifts depending on circumstances. Thus, the more formal coordination gains importance as transitions increases the need for detailed instructions. The findings also show that the existing IT infrastructure (the legacy) lacks the granularity as a coordinative artifact to facilitate necessary change in the organizational work arrangement, and how the workers cope with such issues. Based on this, the paper provides insights into how articulation work and its sociomaterial aspects develops over time in the interplay of organizational and technological change (or lack thereof). [ABSTRACT FROM AUTHOR]

The creep and nonlinear damage behavior of rocks are two main factors that can cause large deformations and instability in tunnels. In this paper, uniaxial compression creep and triaxial compression tests were conducted to analyze the time-dependent and damage-induced strain-softening response of sandstone obtained from a water-conveyance tunnel in China. Using the test results, a new constitutive model was developed by coupling damage mechanics, Maxwell and Kelvin viscoelastic models, and the Mohr–Coulomb failure criterion. The model is formulated to describe both the full creep process (including the three stages of transient, steady, and accelerated creep) and the damaged-induced strain-softening behavior of the sandstone. The proposed model was validated against experimental data and was adopted to investigate the long-term safety of the segmental liner of the water-conveyance tunnel. The results showed that the differences between the rock peak and residual strength or between the initial and residual stiffness of sandstone increased as the confining pressure increased. In addition, the ratio between the crack damage stress and the peak strength increased initially with the increase in confining pressure and then decreased with a further increase in confining pressure. The ratio between creep deformation and total deformation increased with the increase in applied stress, and the specimen exhibited significant creep behavior at the final loading stage. Furthermore, the steady creep rate increased, and the viscosity coefficient decreased with the increase in loading stress. Good agreement was found between the values of failure strengths and shapes of stress–stain curves between the numerical simulation and experimental results under the uniaxial unconfined compressive creep test or triaxial compressive test. The axial load and bending moment of the tunnel segmental liner increased with the increase in the yield strength of concrete. The plot of axial force along the entire segmental liner ring varied greatly with time, while the plot of bending moment was less affected by time. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate responsiveness and minimal important change (MIC) of Oswestry Disability Index (ODI), pain during activity on a numeric rating scale (NRSa) and health related quality of life (EQ-5D) based on data from the Norwegian neck and back registry (NNRR). Methods: A total of 1617 patients who responded to NNRR follow-up after both 6 and 12 months were included in this study. Responsiveness was calculated using standardized response mean and area under the receiver operating characteristic (ROC) curve. We calculated MIC with both an anchor-based and distribution-based method. Results: The condition specific ODI had best responsiveness, the more generic NRSa and EQ-5D had lower responsiveness. We found that the MIC for ODI varied from 3.0 to 9.5, from 0.4 to 2.5 for NRSa while the EQ5D varied from 0.05 to 0.12 depending on the method for calculation. Conclusion: In a register based back pain population, the condition specific ODI was more responsive to change than the more generic tools NRSa and EQ5D. The variations in responsiveness and MIC estimates also indicate that they should be regarded as indicative, rather than fixed estimates. [ABSTRACT FROM AUTHOR]

Individual differences in global self-esteem are associated with general psychological functioning and well-being, and lower self-esteem could be a target for prevention and treatment interventions. Traditionally, self-esteem is assumed to be influenced by the content of self-beliefs, but the metacognitive model of psychological disorders presents an alternative. It emphasizes mental regulation over the content in self-beliefs and suggests a role for metacognitive beliefs and corresponding metacognitive strategies. Thus, the metacognitive model has the potential to advance our understanding of self-esteem and provide new treatment interventions. Therefore, the aim of this study was to test a basic metacognitive model of self-esteem. In a cross-sectional design, 522 participants from a convenience sample completed a battery of self-report questionnaires. A metacognitive model where metacognitive strategies mediated the relationship between metacognitive beliefs and self-esteem was tested using structural equation modelling. Stronger endorsements of dysfunctional metacognitions were associated with more use of unhelpful metacognitive strategies, which further was significantly related to lower self-esteem. These relationships held even when controlling gender, age, anxiety, and personality traits as covariates. The results suggests that there is a role for dysfunctional metacognitive beliefs and strategies in self-esteem of which metacognitive strategies are the most proximal influence. This observation indicates that individual differences in mental regulation are relevant to understanding and possibly improving self-esteem. Interventions which effectively lead to metacognitive change are likely to have a positive effect on self-esteem. [ABSTRACT FROM AUTHOR]

Background: Surgical management of large ventral hernias (VH) has remained a challenge. Various techniques like anterior component separation and posterior component separation (PCS) with transversus abdominis release (TAR) have been employed. Despite the initial success, the long-term efficacy of TAR is not yet comprehensively studied. Authors aimed to investigate the early-, medium-, and long-term outcomes and health-related quality of life (QoL) in patients treated with PCS and TAR. Methods: This multicenter retrospective study analyzed data of 308 patients who underwent open PCS with TAR for primary or recurrent complex abdominal hernias between 2015 and 2020. The primary endpoint was the rate of hernia recurrence (HR) and mesh bulging (MB) at 3, 6, 12, 24, and 36 months. Secondary outcomes included surgical site events and QoL, assessed using EuraHS-QoL score. Results: The average follow-up was 38.3 ± 12.7 months. The overall HR rate was 3.5% and the MB rate was 4.7%. Most of the recurrences were detected by clinical and ultrasound examination. QoL metrics showed improvement post-surgery. Conclusions: This study supports the long-term efficacy of PCS with TAR in the treatment of large and complex VH, with a low recurrence rate and an improvement in QoL. Further research is needed for a more in-depth understanding of these outcomes and the factors affecting them. [ABSTRACT FROM AUTHOR]

Soil microstructure, often defined as the combination of particle arrangement and bonding, can strongly influence the stiffness and strength of sedimentary deposits. As undisturbed soil sampling is a challenging task in fine-grained soils, seismic in situ testing is becoming increasingly more important to investigate its mechanical behaviour. The aim of this article is to evaluate the influences of sediment depositional age and structure-forming processes on the degree of soil structure development in Alpine deposits. Seismic in situ and laboratory testing comprising X-ray diffraction (XRD), scanning electron microscopy (SEM), pore water chemical analysis and hydrochemical modelling were executed at three Austrian test sites, namely Lokalbahn Salzburg, Rhesi and water reservoir Raggal. Based on the comparison of in situ shear wave velocities (VS,SDMT) with bender element results (VS,BE), executed on reconstituted soil specimens, it is shown that the Pleisto–Holocene-aged deposits are characterized by a VS,BE/VS,SDMT ratio of < 1, indicating the presence of microstructure. However, the youngest sediments (< 50 years) exhibit the weakest microstructure (VS,BE/VS,SDMT ≈ 1). The increase of soil structure with sediment age is represented by the updated normalized small-strain rigidity index, K*G, which is situated at the proposed transition between structured and unstructured soils (K*G = 330), ranging between 250 and 350, at all test sites. The development of microstructure can be attributed to the precipitation of calcite (CaCO3) cements in open pores, which strengthens the interparticle bonding between detrital quartz, feldspar, clay minerals and carbonate grains, subsequently reducing the soil's porosity with increasing sediment age. [ABSTRACT FROM AUTHOR]

Organoid and spheroid technology provide valuable insights into developmental biology and oncology. Optical coherence tomography (OCT) is a label-free technique that has emerged as an excellent tool for monitoring the structure and function of these samples. However, mature organoids are often too opaque for OCT. Access to multi-angle views is highly desirable to overcome this limitation, preferably with non-contact sample handling. To fulfil these requirements, we present an ultrasound-induced reorientation method for multi-angle-OCT, which employs a 3D-printed acoustic trap inserted into an OCT imaging system, to levitate and reorient zebrafish larvae and tumor spheroids in a controlled and reproducible manner. A model-based algorithm was developed for the physically consistent fusion of multi-angle data from a priori unknown angles. We demonstrate enhanced penetration depth in the joint 3D-recovery of reflectivity, attenuation, refractive index, and position registration for zebrafish larvae, creating an enabling tool for future applications in volumetric imaging. Accessing multi-angle views of organoids is important for biology and oncology. The authors propose ultrasound-induced reorientation for multi-angle optical coherence tomography, using a 3D-printed acoustic trap to levitate and rotate samples with a model-based algorithm for reconstruction. [ABSTRACT FROM AUTHOR]

Abstract Reversing or slowing the aging process brings great promise to treat or prevent age‐related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the “classical” histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age‐related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition.

Obsessive–compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clozapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive–compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabolism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant correlation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment duration in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development. [ABSTRACT FROM AUTHOR]

Patients with HBeAg-negative chronic hepatitis B may experience an immune response after stopping nucleos(t)ide analogue (NA)therapy, which may potentially trigger HBsAg loss or off-therapy sustained viral control. The immunological mechanisms determining clinical response remain poorly understood. To identify inflammatory signatures associated with defined outcomes, we analysed plasma cytokines and chemokines from 57 HBeAg-negative patients enrolled in the Nuc-Stop Study at baseline and 12 weeks after NA cessation. Clinical response at 12 weeks was classified into four groups: immune control, viral relapse, evolving clinical relapse, and resolving clinical relapse. Twelve weeks after treatment cessation 17 patients (30%) experienced immune control, 19 (33%) viral relapse, 6 (11%) evolving clinical relapse, and 15 (26%) resolving clinical relapse. There was a significant increase in interferon-γ-induced protein 10 (IP-10; p = 0.012) and tumor necrosis factor (TNF; p = 0.032) in patients with evolving clinical relapse. Sparse partial least-squares multivariate analyses (sPLS-DA) showed higher first component values for the clinical relapse group compared to the other groups, separation was driven mainly by IP-10, TNF, IL-9, IFN-γ, MIP-1β, and IL-12. Our results demonstrate that evolving clinical relapse after NA cessation is associated with a systemic increase in the proinflammatory cytokines IP-10 and TNF. Clinical trial registration: ClinicalTrials.gov, Identifier: NCT03681132. [ABSTRACT FROM AUTHOR]

The ongoing opioid epidemic has been a global concern for years, increasingly due to its heavy toll on young people's lives and prospects. Few studies have investigated trends in use of the wider range of drugs prescribed to alleviate pain, psychological distress and insomnia in children, adolescents and young adults. Our aim was to study dispensation as a proxy for use of prescription analgesics, anxiolytics and hypnotics across age groups (0–29 years) and sex over the last 15 years in a large, representative general population. The study used data from a nationwide prescription database, which included information on all drugs dispensed from any pharmacy in Norway from 2004 through 2019. Age-specific trends revealed that the prevalence of use among children and adolescents up to age 14 was consistently low, with the exception of a substantial increase in use of melatonin from age 5. From age 15–29, adolescents and young adults used more prescription drugs with increasing age at all time points, especially analgesics and drugs with higher potential for misuse. Time trends also revealed that children from age 5 were increasingly dispensed melatonin over time, while adolescents from age 15 were increasingly dispensed analgesics, including opioids, gabapentinoids and paracetamol. In contrast, use of benzodiazepines and z-hypnotics slightly declined in young adults over time. Although trends were similar for both sexes, females used more prescription drugs than their male peers overall. The upsurge in use of prescription analgesics, anxiolytics and hypnotics among young people is alarming. Trial registration The study is part of the overarching Killing Pain project. The rationale behind the Killing Pain research was pre-registered through ClinicalTrials.gov on April 7, 2020. Registration number NCT04336605; https://clinicaltrials.gov/ct2/show/record/NCT04336605. [ABSTRACT FROM AUTHOR]

Thymic T cell development comprises T cell receptor (TCR) recombination and assessment of TCR avidity towards self-peptide-MHC complexes presented by antigen-presenting cells. Self-reactivity may lead to negative selection, or to agonist selection and differentiation into unconventional lineages such as regulatory T cells and CD8 α α T cells. To explore the effect of the adaptive immune receptor repertoire on thymocyte developmental decisions, we performed single cell adaptive immune receptor repertoire sequencing (scAIRR-seq) of thymocytes from human young paediatric thymi and blood. Thymic PDCD1+ cells, a putative CD8 α α T cell precursor population, exhibited several TCR features previously associated with thymic and peripheral ZNF683+ CD8 α α T cells, including enrichment of large and positively charged complementarity-determining region 3 (CDR3) amino acids. Thus, the TCR repertoire may partially explain the decision between conventional vs. agonist selected thymocyte differentiation, an aspect of importance for the development of therapies for patients with immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Purpose: This unselected, population-based cohort study aimed to determine the level of health-related quality of life (HRQoL) in patients with Crohn's disease (CD) and ulcerative colitis (UC) at the time of diagnosis compared with a reference population and identify the demographic factors, psychosocial measures, and disease activity markers associated with HRQoL. Methods: Adult patients newly diagnosed with CD or UC were prospectively enrolled. HRQoL was measured using the Short Form 36 (SF-36) and Norwegian Inflammatory Bowel Disease Questionnaires. Clinical significance was assessed using Cohen's d effect size and further compared with a Norwegian reference population. Associations between HRQoL and symptom scores, demographic factors, psychosocial measures, and disease activity markers were analyzed. Results: Compared with the Norwegian reference population, patients with CD and UC reported significantly lower scores in all SF-36 dimensions, except for physical functioning. Cohen's d effect sizes for men and women in all SF-36 dimensions were at least moderate, except for bodily pain and emotional role for men with UC and physical functioning for both sexes and diagnoses. In the multivariate regression analysis, depression subscale scores ≥ 8 on the Hospital Anxiety and Depression Scale, substantial fatigue, and high symptom scores were associated with reduced HRQoL. Conclusion: Patients newly diagnosed with CD and UC reported statistically and clinically significantly lower scores in seven of the eight SF-36 dimensions than the reference population. Symptoms of depression, fatigue, and elevated symptom scores were associated with poorer HRQoL. [ABSTRACT FROM AUTHOR]

Supercooled water droplets are widely used to study supercooled water1,2, ice nucleation3–5 and droplet freezing6–11. Their freezing in the atmosphere affects the dynamics and climate feedback of clouds12,13 and can accelerate cloud freezing through secondary ice production14–17. Droplet freezing occurs at several timescales and length scales14,18 and is sufficiently stochastic to make it unlikely that two frozen drops are identical. Here we use optical microscopy and X-ray laser diffraction to investigate the freezing of tens of thousands of water microdrops in vacuum after homogeneous ice nucleation around 234–235 K. On the basis of drop images, we developed a seven-stage model of freezing and used it to time the diffraction data. Diffraction from ice crystals showed that long-range crystalline order formed in less than 1 ms after freezing, whereas diffraction from the remaining liquid became similar to that from quasi-liquid layers on premelted ice19,20. The ice had a strained hexagonal crystal structure just after freezing, which is an early metastable state that probably precedes the formation of ice with stacking defects8,9,18. The techniques reported here could help determine the dynamics of freezing in other conditions, such as drop freezing in clouds, or help understand rapid solidification in other materials.Optical microscopy and X-ray diffraction are used to study the freezing of water droplets in vacuum, leading to the development of a seven-stage model of freezing and the mapping of ice structures and crystal order. [ABSTRACT FROM AUTHOR]

Official air quality assessment stations are traditionally in fixed locations and have a low spatial resolution. By the use of Internet of Things, low-cost mobile devices collect environmental data, in global initiatives for high-resolution mapping. However, standardized reference guides are rare, being an obstacle for the repeatability and quality of experiments. This paper presents methods, models, and strategies for high-resolution mapping of air quality in an urban environment, with the purpose that the experiments reduce the uncertainties generated by the non-observation of control variables in their execution. Aiming at efficient air quality mapping, practical approach for the use of low-cost sensors portray important issues incorporated into the integrity of the devices, in the methods of data processing and cartographic map composition. The results demonstrated new perspectives and reliability to spatiotemporal analysis, which may support environmental monitoring entities to complement the fixed networks for evaluating and formulating public policies. [ABSTRACT FROM AUTHOR]

At least 65 million people suffer from long COVID. Treatment guidelines are unclear, especially pertaining to recommendations of increased activity. This longitudinal study evaluated safety, changes in functional level and sick leave following a concentrated rehabilitation program for patients with long COVID. Seventy-eight patients (19–67 years) participated in a 3-day micro-choice based rehabilitation program with 7-day and 3-month follow-up. Fatigue, functional levels, sick leave, dyspnea and exercise capacity were assessed. No adverse events were reported and 97.4% completed the rehabilitation. Fatigue measured with Chalder Fatigue Questionnaire decreased at 7-days [mean difference (MD = − 4.5, 95% CI − 5.5 to − 3.4) and 3-month (MD = − 5.5, 95% CI − 6.7 to − 4.3). Sick leave rates and dyspnea were reduced (p < 0.001) and exercise capacity and functional level increased (p < 0.001) at 3-month follow-up regardless of severity of fatigue at baseline. Micro-choice based concentrated rehabilitation for patients with long COVID was safe, highly acceptable and showed rapid improvements in fatigue and functional levels, sustaining over time. Even though this is a quasi-experimental study, the findings are of importance addressing the tremendous challenges of disability due to long COVID. Our results are also highly relevant for patients, as they provide the base for an optimistic outlook and evidence supported reason for hope. [ABSTRACT FROM AUTHOR]

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A series of recent studies have shown that the once-assumed cognitive advantage of bilingualism finds little support in the evidence available to date. Surprisingly, however, the view that bilingualism incurs linguistic costs (the so-called lexical deficit) has not yet been subjected to the same degree of scrutiny, despite its centrality for our understanding of the human capacity for language. The current study implemented a comprehensive meta-analysis to address this gap. By analyzing 478 effect sizes from 130 studies on expressive vocabulary, we found that observed lexical deficits could not be attributed to bilingualism: Simultaneous bilinguals (who acquired both languages from birth) did not exhibit any lexical deficit, nor did sequential bilinguals (who acquired one language from birth and a second language after that) when tested in their mother tongue. Instead, systematic evidence for a lexical deficit was found among sequential bilinguals when tested in their second language, and more so for late than for early second language learners. This result suggests that a lexical deficit may be a phenomenon of second language acquisition rather than bilingualism per se. [ABSTRACT FROM AUTHOR]

INFN-CHNet is the cultural heritage network of the Italian National Institute of Nuclear Physics (INFN) and is constituted by units from Italy and from outside Europe, one of them at Universidad Nacional de San Martín (UNSAM) in Buenos Aires, Argentina. As a result of the initiative carried out during 2015 by the Accademia dei Lincei for the year of the Italian culture in Latin America, an INFN-CHNet laboratory was set at CEPyA-UNSAM with the collaboration of INFN and the Restoration Workshop Centro Tarea. Noteworthy, this laboratory is conceived as a multidisciplinary research facility with complementary skills, both scientific and humanistic. In this context, the first instrument jointly set up, optimised, and applied to Cultural Heritage was an X-ray fluorescence scanner. In this manuscript, we describe the instrument and its main features together with a set of representative yet novel applications in the field of cultural heritage, namely, the experimental study of hidden rock art through laboratory replicas that imitates the problems found in the archaeological sites (hematite drawings hidden below carbon deposition); the study and chemical characterisation of archaeological decorated pottery; and finally, the application of the XRF scanner to ancient photography, for quick and accurate identification of materials and techniques employed. Beyond these specific results, the primary output of this initiative has been the conception of a future network of scientific laboratories in South America, coordinated by CEPyA at UNSAM. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. Recent Findings: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Summary: Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative. [ABSTRACT FROM AUTHOR]

Designer cellulosomes (DCs) are engineered multi-enzyme complexes, comprising carbohydrate-active enzymes attached to a common backbone, the scaffoldin, via high-affinity cohesin-dockerin interactions. The use of DCs in the degradation of renewable biomass polymers is a promising approach for biorefineries. Indeed, DCs have shown significant hydrolytic activities due to the enhanced enzyme–substrate proximity and inter-enzyme synergies, but technical hurdles in DC engineering have hindered further progress towards industrial application. The challenge in DC engineering lies in the large diversity of possible building blocks and architectures, resulting in a multivariate and immense design space. Simultaneously, the precise DC composition affects many relevant parameters such as activity, stability, and manufacturability. Since protein engineers face a lack of high-throughput approaches to explore this vast design space, DC engineering may result in an unsatisfying outcome. This review provides a roadmap to guide researchers through the process of DC engineering. Each step, starting from concept to evaluation, is described and provided with its challenges, along with possible solutions, both for DCs that are assembled in vitro or are displayed on the yeast cell surface. Key points: • Construction of designer cellulosomes is a multi-step process. • Designer cellulosome research deals with multivariate construction challenges. • Boosting designer cellulosome efficiency requires exploring a vast design space. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that blood platelets contain tumour-specific mRNA profiles tumour-educated platelets (TEPs). Here, we aim to train a TEP-based breast cancer detection classifier. Methods: Platelet mRNA was sequenced from 266 women with stage I–IV breast cancer and 212 female controls from 6 hospitals. A particle swarm optimised support vector machine (PSO-SVM) and an elastic net-based classifier (EN) were trained on 71% of the study population. Classifier performance was evaluated in the remainder (29%) of the population, followed by validation in an independent set (37 cases and 36 controls). Potential confounding was assessed in post hoc analyses. Results: Both classifiers reached an area under the curve (AUC) of 0.85 upon internal validation. Reproducibility in the independent validation set was poor with an AUC of 0.55 and 0.54 for the PSO-SVM and EN classifier, respectively. Post hoc analyses indicated that 19% of the variance in gene expression was associated with hospital. Genes related to platelet activity were differentially expressed between hospitals. Conclusions: We could not validate two TEP-based breast cancer classifiers in an independent validation cohort. The TEP protocol is sensitive to within-protocol variation and revision might be necessary before TEPs can be reconsidered for breast cancer detection. [ABSTRACT FROM AUTHOR]

Using a Norwegian sample of adoptees from South Korea, matched to a sample of Norwegian-born children, we study the intergenerational transmission of labour market outcomes, including earnings, disability insurance participation and sickness absence, as well as education. We find the nurture effect to be substantial for education, labour earnings, and sickness absence, but fairly small and insignificant for disability insurance participation. By carefully comparing adoptees to children living with their biological parents, we also estimate the shares of intergenerational transmission stemming from heritability and environmental factors. Across outcomes we find heritability to account for about 50–100% of intergenerational transmission. [ABSTRACT FROM AUTHOR]

Whether patient-reported outcomes (PROs) can predict overall survival (OS) and non-relapse mortality (NRM) among recipients of allogeneic stem cell transplantation (allo-HSCT), is unclear. We performed an exploratory analysis of the prognostic value of patient-reported outcomes (PROs) among 117 recipients of allogeneic stem cell transplantation (allo-HSCT) who participated in a randomized nutrition intervention trial. Cox proportional hazards models were used to investigate possible associations between PROs collected pre-allo-HSCT (baseline) using scores from the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and 1-year overall survival (OS), whereas logistic regression was used to study associations between these PROs and 1-year non-relapse mortality (NRM). Multivariable analyses indicated that only the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Bone Marrow Transplantation (EBMT) risk score were associated with 1-year OS. In the multivariable model including clinical-sociodemographic factors for 1-year NRM, our analysis showed that living alone (p=0.009), HCT-CI (p=0.016), EBMT risk score (p=0.002), and stem cell source (p=0.046) could be associated with 1-year NRM. Moreover, in the multivariable model, our analysis showed that only appetite loss from the QLQ-C30 was associated with 1-year NRM (p=0.026). In conclusion, in this specific setting, our analysis suggests that the commonly used HCT-CI and EBMT risk scores could be predictive for both 1-year OS and 1-year NRM, whereas baseline PROs in general were not. [ABSTRACT FROM AUTHOR]

Patients with complex incisional hernia (IH) is a growing and challenging category that surgeons are facing in daily practice and represent indeed a technical challenge for most of them. The posterior component separation with TAR (PCS-TAR) has become the procedure of choice to repair most complex abdominal wall defects, including those with loss of domain, subxiphoid, subcostal, parastomal or after trauma and sepsis treated initially with "open abdomen" and in those scenarios in which the fascia closure was not performed to avoid an abdominal compartment syndrome. Most recent studies showed that the PCS-TAR represents a valid procedure in recurrent IH. The purpose of our study is to evaluate the reproducibility of the PCS-TAR, describing our experience, our surgical technique and the rate of postoperative complications and recurrences in a cohort of consecutive patients. 52 consecutive patients with complex IH, who underwent PCS-TAR at "Betania Hospital and Ospedale del Mare Hospital" in Naples between May 2014 and November 2019 were identified from a prospectively maintained database and reviewed retrospectively. There were 36 males (69%) and 16 females (31%) with a mean age of 57.88 (range 39–76) and Body mass index (BMI kg/m2) of 31.2 (24–45). More than half of patients (58%) were active smokers. Mean defect width was 13.6 cm (range 6–30) and mean defect area was about 267.9 cm2. Mean operative time was 228 min. Posterior fascial closure was reached in all cases, while anterior fascial closure only in 29 cases (56%). Mean hospital stay was 5.7 days. 27% of patients developed minor complications (Clavien–Dindo grade I–II) and one case (1.9%) major complication (Clavien–Dindo III). Seroma was registered in 23% of cases. SSI was reported to be 3.8% with no deep wound infection. Recurrence rate was 1.9% in a mean follow-up of 28 months. In Univariate analysis Bio-A surface > 600 cm2 and drain removal at discharge were significantly associated with major complications, while in a multivariate analysis only Bio-A surface > 600 cm2 was related. Considering univariate analysis for recurrences, number of drains, SSO, Clavien–Dindo score > 2 and defect area were significantly associated with recurrence, while in a multivariate analysis no variables were related. PCS-TAR is an indispensable tool in managing complex ventral hernias associated with a low rate of SSO and recurrence. Tobacco use, obesity and comorbidities cannot be considered absolute contraindications to PCS-TAR. Peri and postoperative management of complications and drainages have an impact on short term outcomes. Based on these outcomes, posterior component separation with transversus abdominis release has become our method of choice for the management of patients with complex ventral hernia requiring open hernia repair in selected patients. [ABSTRACT FROM AUTHOR]

Purpose: Gut microbiota has recently been recognized to be influenced by a broad range of pathologies. Alterations of gut microbiota are known as dysbiosis and have found to be related to chronic constipation, a condition which affects also pediatric patients with spina bifida (SB). Methods: In this study, gut microbiota richness and composition were investigated by 16S rRNA sequencing and bioinformatic analysis in 48 SB patients (mean age, 11.9 ± 4.8 years) with secondary neurogenic constipation and 32 healthy controls (mean age, 18.0 ± 9.6 years). The study also aimed at exploring eventual effects of laxatives and transanal irrigation (TAI) adopted by SB subjects to get relief from the symptoms of neurogenic constipation. Results: Collected data demonstrated that the microbiota richness of SB patients was significantly increased compared to healthy controls, with a higher number of dominant bacteria rather than rare species. The absence of SB condition was associated with taxa Coprococcus 2, with the species C. eutactus and Roseburia, Dialister, and the [Eubacterium] coprostanoligenes group. On the other hand, the SB patients displayed a different group of positively associated taxa, namely, Blautia, Collinsella, Intestinibacter, and Romboutsia genera, the [Clostridium] innocuum group, and Clostridium sensu stricto 1. Bifidobacterium and the [Eubacterium] hallii group were also found to be positively associated with SB gut microbiome. Conclusions: Among SB patients, the administration of laxatives and TAI did not negatively affect gut microbiota diversity and composition, even considering long-term use (up to 5 years) of TAI device. [ABSTRACT FROM AUTHOR]

Proline-rich transmembrane protein 2 (PRRT2) is a neuron-specific protein implicated in the control of neurotransmitter release and neural network stability. Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na+ channels NaV1.2/NaV1.6 predominantly expressed in brain glutamatergic neurons. NaV channels form complexes with β-subunits that facilitate the membrane targeting and the activation of the α-subunits. The opposite effects of PRRT2 and β-subunits on NaV channels raises the question of whether PRRT2 and β-subunits interact or compete for common binding sites on the α-subunit, generating Na+ channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that β-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of NaV1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the β4-induced increase in expression and functional activation of the transient and persistent NaV1.2 currents, without affecting resurgent current. The data indicate that β4-subunit and PRRT2 form a push–pull system that finely tunes the membrane expression and function of NaV channels and the intrinsic neuronal excitability. [ABSTRACT FROM AUTHOR]

Background: Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. Methods: We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. Results: Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0–4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. Conclusions: Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype–phenotype correlations that may help to improve the diagnostic approach and patient management. [ABSTRACT FROM AUTHOR]

Capturing and measuring instructional patterns by using standardized observation manuals has become increasingly popular in classroom research. While researchers argue that a common vocabulary of teaching is necessary for the field of classroom research to move forward, instructional features vary across classrooms and contexts, which poses serious measuring challenges. In this article, we argue that potential biases embedded in observation systems have to be identified and addressed in order for interpretations of results across different classrooms and contexts to be valid and relevant. We identify three aspects of possible systematic biases (related to the grain size of conceptualization, operationalization, and sequencing of lessons) and how these may influence ratings of instructional quality when an established observation system (the Protocol for Language Arts Teaching Observations [PLATO]) is applied in the contexts of Nordic mathematics classrooms. We discuss implications of such possible biases and make suggestions for how they may be addressed. [ABSTRACT FROM AUTHOR]

Childhood cancer is the second leading cause of death in children aged 1 to 14. Although survival rates have vastly improved over the past 40 years, cancer resistance and relapse remain a significant challenge. Advances in single-cell technologies enable dissection of tumors to unprecedented resolution. This facilitates unraveling the heterogeneity of childhood cancers to identify cell subtypes that are prone to treatment resistance. The rapid accumulation of single-cell data from different modalities necessitates the development of novel computational approaches for processing, visualizing, and analyzing single-cell data. Here, we review single-cell approaches utilized or under development in the context of childhood cancers. We review computational methods for analyzing single-cell data and discuss best practices for their application. Finally, we review the impact of several studies of childhood tumors analyzed with these approaches and future directions to implement single-cell studies into translational cancer research in pediatric oncology. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative prediction of mortality in femoral neck fracture patients aged 65 years or above may be valuable in the treatment decision-making. A preoperative clinical prediction model can aid surgeons and patients in the shared decision-making process, and optimize care for elderly femoral neck fracture patients. This study aimed to develop and internally validate a clinical prediction model using machine learning (ML) algorithms for 90 day and 2 year mortality in femoral neck fracture patients aged 65 years or above. Methods: A retrospective cohort study at two trauma level I centers and three (non-level I) community hospitals was conducted to identify patients undergoing surgical fixation for a femoral neck fracture. Five different ML algorithms were developed and internally validated and assessed by discrimination, calibration, Brier score and decision curve analysis. Results: In total, 2478 patients were included with 90 day and 2 year mortality rates of 9.1% (n = 225) and 23.5% (n = 582) respectively. The models included patient characteristics, comorbidities and laboratory values. The stochastic gradient boosting algorithm had the best performance for 90 day mortality prediction, with good discrimination (c-statistic = 0.74), calibration (intercept = − 0.05, slope = 1.11) and Brier score (0.078). The elastic-net penalized logistic regression algorithm had the best performance for 2 year mortality prediction, with good discrimination (c-statistic = 0.70), calibration (intercept = − 0.03, slope = 0.89) and Brier score (0.16). The models were incorporated into a freely available web-based application, including individual patient explanations for interpretation of the model to understand the reasoning how the model made a certain prediction: https://sorg-apps.shinyapps.io/hipfracturemortality/ Conclusions: The clinical prediction models show promise in estimating mortality prediction in elderly femoral neck fracture patients. External and prospective validation of the models may improve surgeon ability when faced with the treatment decision-making. Level of evidence: Prognostic Level II. [ABSTRACT FROM AUTHOR]

Morten Levin’s work on Action Research (AR) clearly stated that the three pillars participation, action and research was equally important. During his long practice as an AR pioneer, he campaigned for the legitimacy of AR within academia. In this paper we investigate how AR is perceived as sound research within a large and distributed organization. We present a retrospective case study based on a research collaboration between UiT The Artic University of Norway (UiT) and the Norwegian Labour and Welfare Organization (NAV), that fostered an AR project together, ‘Work inclusion, learning and innovation’ (ALIN), but later led to the termination of the collaboration agreement. The ALIN project fulfils all the criteria for being a successful AR project in terms Levin’s action, research and participation criteria. However, external audit and central NAV actors had different expectations of successful institutional research collaboration. Through our case we illustrate several conflict dimensions within the three AR pillars that must be challenged to strengthen the legitimacy of AR. The debate on rigour and relevance should not be limited to academic fields and include various actors and decision makers within large and distributed organizations. [ABSTRACT FROM AUTHOR]

Background: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse. Objective: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse). Methods: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Results: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85–2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08–2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89–3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02–5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22–4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups. Conclusions: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS. [ABSTRACT FROM AUTHOR]

This research proposes a model for early prediction of collapse incidents in rocks during tunnel boring machine (TBM) operation utilizing TBM and geological survey data. Uncertainties associated with tunnel geology can significantly hamper tunneling progress. So far, various research works have tried to reduce such uncertainties by predicting the geological condition during tunnel excavation. However, specific tunneling responses caused by adverse geology are still poorly studied. In rocks, adverse geology such as karstic caves and fault zones can cause tunnel boundary collapse, a detrimental tunneling response causing unexpected interruptions and casualties. To identify and predict the potential collapse of TBM tunnels in rocks, three machine learning (ML) classifiers are used, namely: (1) multilayer perceptron, (2) support vector machine, and (3) random forest. The ML algorithms are trained and validated using data on collapse incidents in a water conveyance tunneling project in China. The prediction accuracy of the proposed model reached 98% for training data and 97% for validation data. Furthermore, the model can identify an "Influence Zone" for a collapse incident. A unique contribution of this research is that the "Influence Zone" enables the model to predict an impending tunnel collapse and the extent of that collapsed segment ahead of the excavation. Finally, to gain better insight into the ML-based predictions, the relationships between TBM-related features and tunnel geology are carefully analyzed. Highlights: Machine learning classifiers can detect a zone of influence for approaching ground collapse during tunnel excavations through disturbed rock. The zone of influence is found to be proportional to the continuation length of the collapsing ground. Cutterhead rotating speed of tunnel boring machine and rock mass ranks are the two most important indicators for collapsing ground conditions. [ABSTRACT FROM AUTHOR]

Purpose: The lack of epidemiological data on the proportion of olfactory dysfunction (OD) using comprehensive olfactory assessment in healthy adults in Scandinavia motivated to the present study which aimed to explore the proportion of OD in voluntary healthy Norwegian adults, assessed by Sniffin' Sticks, and its correlation to self-reported olfactory function. Furthermore, sociodemographic and clinical factors associated with olfactory function were analysed. Methods: The sample included 405 Norwegian participants, aged 18–78 years, 273 women and 132 men, who underwent olfactory testing with extensive Sniffin' Sticks test, allergy testing, clinical examination with nasal endoscopy and completed a self-administered questionnaire, including self-evaluation of olfactory function on a 100 mm Visual Analogue Scale. Results: We found that 37% had OD, of which 1.2% had anosmia assessed with extensive Sniffin' Sticks test. The proportion of hyposmia and anosmia increased with age. Men and participants with low education had poorer olfactory function scores. Allergy, smoking status, general health and endoscopic findings were not associated with measured olfactory function. We found no correlation between self-reported and measured olfactory function. Conclusions: This study has identified that a large proportion of our sample of voluntary healthy Norwegian adults have OD, considerably more common in older adults and somewhat more common in men and individuals with low education. The lack of correlation between self-reported and measured olfactory function highlights the importance of using validated tests for a reliable olfactory evaluation. [ABSTRACT FROM AUTHOR]

Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1–5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2–5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment. [ABSTRACT FROM AUTHOR]

The aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of "NASH-associated macrophages" can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH. [ABSTRACT FROM AUTHOR]

The Arctic sea-ice extent has strongly declined over recent decades. A large inter-annual variability is superimposed on this negative trend. Previous studies have emphasised a significant warming effect associated with latent energy transport into the Arctic region, in particular due to an enhanced greenhouse effect associated with the convergence of the humidity transport over the Arctic. The atmospheric energy transport into the Arctic is mostly accomplished by waves such as Rossby waves and cyclones. Here we present a systematic study of the effect on Arctic sea ice of these atmospheric wave types. Through a regression analysis we investigate the coupling between transport anomalies of both latent and dry-static energy and sea-ice anomalies. From the state-of-the-art ERA5 reanalysis product the latent and dry-static transport over the Arctic boundary (70 ∘ N) is calculated. The transport is then split into transport by planetary and synoptic-scale waves using a Fourier decomposition. The results show that latent energy transport as compared to that of dry-static shows a much stronger potential to decrease sea ice concentration. However, taking into account that the variability of dry-static transport is of an order of magnitude larger than latent, the actual impact on the sea ice appears similar for the two components. In addition, the energy transport by planetary waves causes a strong decline of the sea ice concentration whereas the transport by synoptic-scale waves shows only little effect on the sea ice. The study emphasises the importance of the large-scale waves on the sea ice variability. [ABSTRACT FROM AUTHOR]

The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80% of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson's disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In LRRK2 G2019S knock-in mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane via Rabs inactivation, causing its intracellular re-localization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD. [ABSTRACT FROM AUTHOR]