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Abstract Background Emerging adulthood is often associated with mental health problems. About one in three university students report symptoms of depression and anxiety that can negatively affect their developmental trajectory concerning work, intimate relationships, and health. This can interfere with academic performance, as mood and anxiety disorders are key predictors of dropout from higher education. A treatment gap exists, where a considerable proportion of students do not seek help for mood and anxiety symptoms. Offering internet interventions to students with mental health problems could reduce the treatment gap, increase mental health, and improve academic performance. A meta-analysis on internet interventions for university students showed small effects for depression and none for anxiety. Larger trials are recommended to further explore effects of guidance, transdiagnostic approaches, and individual treatment components. Methods This study will offer 1200 university students in Sweden participation in a three-armed randomized controlled trial (RCT) evaluating a guided or unguided transdiagnostic internet intervention for mild to moderate depression and anxiety, where the waitlist control group accesses the intervention at 6-month follow-up. Students reporting suicidal ideation/behaviors will be excluded and referred to treatment within the existing healthcare system. An embedded study within the trial (SWAT) will assess at week 3 of 8 whether participants in the guided and unguided groups are at higher risk of failing to benefit from treatment. Those at risk will be randomized to an adaptive treatment strategy, or to continue the treatment as originally randomized. Primary outcomes are symptoms of depression and anxiety. Follow-ups will occur at post-treatment and at 6-, 12-, and 24-month post-randomization. Between-group outcome analyses will be reported, and qualitative interviews about treatment experiences are planned. Discussion This study investigates the effects of a transdiagnostic internet intervention among university students in Sweden, with an adaptive treatment strategy employed during the course of treatment to minimize the risk of treatment failure. The study will contribute knowledge about longitudinal trajectories of mental health and well-being following treatment, taking into account possible gender differences in responsiveness to treatment. With time, effective internet interventions could make treatment for mental health issues more widely accessible to the student group.

AbstractIn higher education, students’ trust in the university management may affect both mental health and academic self-efficacy. This longitudinal study, conducted during the most challenging course of the COVID-19 pandemic, uses multinomial regression and causal inference to estimate the effects of students’ trust in their universities’ strategies for managing the pandemic, on students’ self-reported changes in mental health and academic self-efficacy. The analyzed sample (N = 2796) was recruited through online advertising and responded to a baseline online survey in the late spring of 2020, with two follow-up surveys five and ten months later. Results show that positive trust in university management of the pandemic protected against experiencing one’s mental health and academic self-efficacy as worse rather than unchanged, both five and ten months after the baseline assessment. The findings emphasize the importance of developing and maintaining trust-building measures between academia and students to support students’ mental health and academic self-efficacy in times of uncertainty.

Hur vanligt är det att studenter bedriver projekt som inbegriper etiskt känsligt innehåll? I denna artikel redogörs för en undersökning rörande ett högskolepedagogiskt utvecklingsarbete som avser formaliserad etikprövning av studentuppsatser. Undersökningen inbegriper uppsatser som examinerats och godkänts vid fakulteten för hälsa och samhälle vid Malmö universitet under åren 2014–2017. Med etiskt känsligt innehåll avses här känsliga personuppgifter samt intervenerande metoder, som vid forskning kräver etikprövning enligt lag (2003:460) om etikprövning av forskning som avser människor. Av totalt 1215 granskade uppsatser hade 277 (22,8 %) etiskt känsligt innehåll; vanligast var känsliga personuppgifter avseende hälsa. 165 (13.6 %) uppsatser innehöll sådana uppgifter. Etiskt känsligt innehåll var mer vanligt förekommande i uppsatser på avancerad nivå (32,9 %) än på grundnivå (20,4 %). Var femte student på grundnivå genomförde alltså studier som skulle ha krävt Etikprövningsmyndighetens godkännande om de hade varit forskare. Enligt fakultetens riktlinjer ska samtliga studentarbeten med ett innehåll som skulle ha krävt förhandsprövning vid forskning förhandsprövas av fakultetens etikråd för studentarbeten. Men endast 191 av de 277 uppsatser (68,9%) som borde ha genomgått sådan handläggning passerade etikrådet. Implementeringen av formaliserad etikprövning av uppsatsprojekt tycks fungera bäst då studentens handledare är forskarutbildad och kan antas ha egen erfarenhet av etikprövning. Vår undersökning visade också att etikprövningen implementerats i olika grad vid olika institutioner. I artikeln diskuteras möjliga förklaringar till denna skillnad. English abstract Ethical Review of Student Projects: The Responsibility of Higher Education Institutions How common is it for students to undertake projects involving ethically sensitive content? This article presents a study on higher education pedagogical development project concerning the formalized ethical review of student essays. The survey included essays that were examined and approved at the Faculty of Health and Society, Malmö university during 2014–2017. Ethically sensitive content refers here to sensitive personal data and intervention methods that, in research, require ethical review according to the Act (2003:460) on ethical review of research involving humans. Out of a total of 1215 examined thesis, 277 (22.8%) contained ethically sensitive content; the most common being personal health-related data. 165 (13.6%) essays contained such information. Advanced level theses had a higher prevalence of ethically sensitive content (32.9%) compared to undergraduate theses (20.4%). This indicates that a significant proportion of undergraduate students undertook projects involving content that would require ethical review if they were researchers. The faculty’s guidelines stipulate that all student works containing content requiring prior ethical review in research, should be reviewed by the faculty’s ethics council. However, only 68.9% of the essays that necessitated such review passed the ethics council, indicating a gap in compliance with ethical review processes. The study suggests that the effectiveness of formalized ethical review of thesis projects is enhanced when the student’s supervisor holds a doctoral degree, likely due to their familiarity and experience with ethical review procedures. Furthermore, the research highlights variations in the implementation of ethical review across different departments within the faculty. The article delves into possible reasons for these discrepancies.

Abstract Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we discover a dedicated ribosome-associated chaperone, Chp1, that rewires the cotranslational folding machinery to assist in the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). Our results indicate that during eEF1A synthesis, Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production in the absence of Chp1 triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult-to-fold protein that necessitates a biogenesis pathway starting with dedicated folding factor Chp1 at the ribosome to protect the eukaryotic cell from proteostasis collapse.

Abstract The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.

Objective This study used causal inference to estimate the longitudinal effects of contagion in cohabitants and family members on university students’ mental health and academic self-efficacy during the COVID-19 pandemic.Design A prospective longitudinal study including a baseline online measurement in May 2020, and online follow-ups after 5 months and 10 months. Participants were recruited through open-access online advertising.Setting Public universities and university colleges in Sweden.Participants The analytical sample included 2796 students.Outcome measures Contagion in cohabitants and in family members was assessed at baseline and at the 5-month follow-up. Mental health and academic self-efficacy were assessed at the 5-month and 10-month follow-ups.Results Mild symptoms reported in cohabitants at baseline resulted in negative mental health effects at follow-up 5 months later, and mild baseline symptoms in family members resulted in negative effects on academic self-efficacy at follow-ups both 5 and 10 months later.Conclusions Notwithstanding the lack of precision in estimated effects, the findings emphasise the importance of social relationships and the challenges of providing students with sufficient support in times of crisis.

Abstract It is widely believed that human culture originated in the appearance of Oldowan stone-tool production (circa 2.9 Mya) and a primitive but effective ability to copy detailed know-how. Cumulative cultural evolution is then believed to have led to modern humans and human culture via self-reinforcing gene-culture co-evolution. This outline evolutionary trajectory has come to be seen as all but self-evident, but dilemmas have appeared as it has been explored in increasing detail. Can we attribute even a minimally effective know-how copying capability to Oldowan hominins? Do Oldowan tools really demand know-how copying? Is there any other evidence that know-how copying was present? We here argue that this account, which we refer to as “Trajectory A”, may be a red herring, and formulate an alternative “Trajectory B” that resolves these dilemmas. Trajectory B invokes an overlooked group-level channel of cultural inheritance (the Social Protocell) whereby networks of cultural traits can be faithfully inherited and potentially undergo cumulative evolution, also when the underpinning cultural traits are apelike in not being transmitted via know-how copying (Latent Solutions). Since most preconditions of Trajectory B are present in modern-day Pan, Trajectory B may even have its roots considerably before Oldowan toolmaking. The cumulative build-up of networks of non-cumulative cultural traits is then argued to have produced conditions that both called for and afforded a gradual appearance of the ability to copy know-how, but considerably later than the Oldowan.

While proteins populating their native conformations constitute the functional entities of cells, protein aggregates are traditionally associated with cellular dysfunction, stress and disease. During recent years, it has become clear that large aggregate-like protein condensates formed via liquid-liquid phase separation age into more solid aggregate-like particles that harbor misfolded proteins and are decorated by protein quality control factors. The constituent proteins of the condensates/aggregates are disentangled by protein disaggregation systems mainly based on Hsp70 and AAA ATPase Hsp100 chaperones prior to their handover to refolding and degradation systems. Here, we discuss the functional roles that condensate formation/aggregation and disaggregation play in protein quality control to maintain proteostasis and why it matters for understanding health and disease.

Abstract Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.

Abstract Objective The present study investigates if symptoms of COVID-19 contagion in different social contexts (cohabitants, family, acquaintances, and others) are associated with university students' own self-reported symptoms of COVID-19 contagion, mental health, and study capacity. This was investigated by a cross-sectional survey administrated in Sweden during the first wave of the COVID-19 pandemic, at the time when universities were locked down to limit viral spread and contagion. Results Mild to moderate symptoms of COVID-19 in cohabitants and family members were associated with student’s self-reported symptoms of contagion, while no associations could be seen in relation to mental health and study capacity. Symptoms of COVID-19 contagion in acquaintances and others were not associated with students’ self-reported symptoms, nor with their mental health and study capacity. To conclude, during the initial lockdown of universities students’ self-reported symptoms of contagion were mainly associated with cohabitants and family members, while symptoms of contagion in different social contexts were not associated with mental health and study capacity. Findings suggest that lockdown of universities may have contributed to limiting infection pathways, while still allowing students to focus on their studies despite significant contagion among others known to the student.

Abstract Objective During the COVID pandemic, government authorities worldwide have tried to limit the spread of the virus. Sweden’s distinctive feature was the use of voluntary public health recommendations. Few studies have evaluated the effectiveness of this strategy. Based on data collected in the spring of 2020, this study explored associations between compliance with recommendations and observed symptoms of contagion in others, using self-report data from university students. Results Compliance with recommendations ranged between 69.7 and 95.7 percent. Observations of moderate symptoms of contagion in “Someone else I have had contact with” and “Another person” were markedly associated with reported self-quarantine, which is the most restrictive recommendation, complied with by 81.2% of participants. Uncertainty regarding the incidence and severity of contagion in cohabitants was markedly associated with the recommendation to avoid public transportation, a recommendation being followed by 69.7%. It is concluded that students largely followed the voluntary recommendations implemented in Sweden, suggesting that coercive measures were not necessary. Compliance with recommendations were associated with the symptoms students saw in others, and with the perceived risk of contagion in the student’s immediate vicinity. It is recommended that voluntary recommendations should stress personal relevance, and that close relatives are at risk.

We report on three episodes from a case study where upper secondary students numerically explore the definite integral in a Python environment. Our research questions concern how code can mediate and support students' mathematical thinking and what kind of sociomathematical norms emerge as students work together to reach a mutual understanding of a correct solution. The main findings of our investigation are as follows. 1) Students can actively use code as a mediator of their mathematical thinking, and code can even serve as a bridge that helps students to develop their mathematical thinking collaboratively. Further, code can help students to perceive mathematical notions as objects with various properties and to communicate about these properties, even in other semiotic systems than the mathematical language. 2) For the participating students, a common norm was that an acceptable solution is a sufficient condition for the correctness of the solution method although students were aware of a problem in their code, yet also other norms emerged. This demonstrates that learning mathematics with programming can have an effect on what kind of sociomathematical norms emerge in classroom.

In school settings, students' mindset about intelligence (i.e., fixed versus growth mindset) and their sense of belonging to school (SBS) have both been shown to predict academic attainment. However, these constructs have rarely been examined together although both were found to be impacted by students' socioeconomic status (SES). Across the literature, findings are inconsistent concerning this moderating effect of SES. In the present preregistered study, we used data from the French sample of the Programme for International Student Assessment 2018 (PISA; N = 6308) to examine whether growth mindset positively predicted SBS and whether this association was moderated by students' SES. Results showed that growth mindset was positively associated with SBS. On the confirmatory linear regression analyses, we found no moderation effect of any of the SES indicators on the association between growth mindset and SBS. However, pre-registered supplementary multigroup analyses showed descriptively that this association was stronger for high than for low SES students and notably when SES indicators concerned family financial resources. Limitations of this research and perspectives for future studies are discussed, with a focus on why the literature should care about the different meanings and consequences of SES indicators.

Politics and science are inextricably connected, particularly in relation to the climate emergency and other environmental crises, yet science education is an often overlooked site for engaging with the political dimensions of environmental issues. This study examines how science teachers in England experience politics--specifically political participation--in relation to the environment in school science, against a background of increased obstruction in civic space. The study draws on an analysis of theoretically informed in-depth interviews with eleven science teachers about their experiences of political participation in relation to environmental issues. We find that politics enters the science classroom primarily through informal conversations initiated by students rather than planned by teachers. When planned for, the emphasis is on individual, latent-political (civic) engagement rather than manifest political participation. We argue that this is a symptom of the post-political condition and call for a more enabling environment for discussing the strengths and limitations of different forms of political participation in school science.

Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.

Observations of play in animals have been suggested as a promising indicator of positive emotions and thus of positive animal welfare. However, if play can follow the proposed reward cycle concept where animals estimate and value reward differently in different phases of the cycle (anticipation, consummation and post-consummation) is unclear. To investigate if a reward cycle for play exists in growing pigs, we carried out an exploratory study where pigs were tested when they were naïve to a reward cycle test (first occasion) against when they were accustomed to going through the test after having the access to an open play arena with objects. Forty undocked pigs were housed in a weaner stable with two castrated males and two females per pen. Within each litter, we randomly selected and tested one male and one female test pig, each being tested as naïve or accustomed to the testing environment. The first week the pigs (n = 20) were tested four times and regarded as naïve during the first day. After that they were regarded as accustomed, and were tested twice a week for 3 weeks. We observed the behavior of the tested pairs in three subsequent stages: (1) in a holding pen 3 min, (2) in a play arena 15 min, and (3) in their home pen 10 min. When accustomed, pigs showed more locomotor play, social interactions and standing, and a tendency of more orientation toward the play arena and exploring bars facing the play arena (i.e., reward-seeking behavior) in the holding pen than when they were naïve, suggesting an anticipation to enter the play arena. Performing high numbers of object play in all sessions, and for accustomed pigs more exploration and social interaction, but less locomotor play and walking in the play arena may suggest consumption of play and exploration. Finding more lying and sitting in accustomed pigs, but less standing and walking in the home pen is in line with the previous hypothesis of the post-consummatory behaviors. Our study showed mixed results for the existence of a reward cycle for play in pigs and generated questions for future research.

We conducted three preregistered studies using the Organization for Economic Co-operation and Development Programme for International Student Assessment (PISA) data to provide a worldwide estimation of the standardized test gap between students from lower and higher social classes. We investigated: (a) the degree to which academic anxiety contributes to this gap and (b) the role of country-level income inequality in widening this gap. In Study 1, we used PISA 2003 data (250,000+ students from 41 countries) and demonstrated that anxiety accounts for approximately one-fifth of the performance gap between students with less educated parents and those with more educated parents. Unexpectedly, the social class test gap was weaker in more unequal countries than in more equal countries. In Studies 2a and 2b, we used the PISA 2012 and 2015 data (totaling over a million students from 65 countries and 72 countries, respectively) and differentiated the cultural dimension (parental education, cultural capital) and the economic dimension (economic capital) of social class. Regardless of the dimension, anxiety again accounted for between one-tenth and one-fifth of the performance gap between students from lower and higher social classes. Moreover, (a) the culturally based social class achievement gap was weaker in more unequal than in more equal countries, and (b) the economically based social class achievement gap was larger in more unequal than in more equal countries. Unexpectedly, we also find a robust association between national income inequality and academic anxiety across all three studies. Results are discussed in relation to the multidimensionality of social class and literature on the psychology of income inequality.

Abstract Objective We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect. Results MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC50 of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.

The gut microbiota (GM) can regulate bone mass, but its association with incident fractures is unknown. We used Cox regression models to determine whether the GM composition is associated with incident fractures in the large FINRISK 2002 cohort (n = 7043, 1092 incident fracture cases, median follow-up time 18 years) with information on GM composition and functionality from shotgun metagenome sequencing. Higher alpha diversity was associated with decreased fracture risk (hazard ratio [HR] 0.92 per standard deviation increase in Shannon index, 95% confidence interval 0.87-0.96). For beta diversity, the first principal component was associated with fracture risk (Aitchison distance, HR 0.90, 0.85-0.96). In predefined phyla analyses, we observed that the relative abundance of Proteobacteria was associated with increased fracture risk (HR 1.14, 1.07-1.20), while the relative abundance of Tenericutes was associated with decreased fracture risk (HR 0.90, 0.85-0.96). Explorative sub-analyses within the Proteobacteria phylum showed that higher relative abundance of Gammaproteobacteria was associated with increased fracture risk. Functionality analyses showed that pathways related to amino acid metabolism and lipopolysaccharide biosynthesis associated with fracture risk. The relative abundance of Proteobacteria correlated with pathways for amino acid metabolism, while the relative abundance of Tenericutes correlated with pathways for butyrate synthesis. In conclusion, the overall GM composition was associated with incident fractures. The relative abundance of Proteobacteria, especially Gammaproteobacteria, was associated with increased fracture risk, while the relative abundance of Tenericutes was associated with decreased fracture risk. Functionality analyses demonstrated that pathways known to regulate bone health may underlie these associations.

BackgroundLow grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited.AimWe examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors.MethodsParticipants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index).ResultsMean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed.ConclusionsGrip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets.

Rising political polarization in recent decades has hampered and gridlocked policymaking, as well as weakened trust in democratic institutions. These developments have been linked to the idea that new media technology fosters extreme views and political conflict by facilitating self-segregation into "echo chambers" where opinions are isolated and reinforced. This opinion-centered picture has recently been challenged by an emerging political science literature on "affective polarization", which suggests that current polarization is better understood as driven by partisanship emerging as a strong social identity. Through this lens, politics has become a question of competing social groups rather than differences in policy position. Contrary to the opinion-centered view, this identity-centered perspective has not been subject to dynamical formal modeling, which generally permits hypotheses about micro-level explanations for macro-level phenomena to be systematically tested and explored. We here propose a formal model that links new information technology to affective polarization via social psychological mechanisms of social identity. Our results suggest that new information technology catalyzes affective polarization by lowering search and interaction costs, which shifts the balance between centrifugal and centripetal forces of social identity. We find that the macro-dynamics of social identity is characterized by two stable regimes on the societal level: one fluid regime, in which identities are weak and social connections heterogeneous, and one solid regime in which identities are strong and groups homogeneous. We also find evidence of hysteresis, meaning that a transition into a fragmented state is not readily reversed by again increasing those costs. This suggests that, due to systemic feedback effects, if polarization passes certain tipping points, we may experience run-away political polarization that is highly difficult to reverse.