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Somatodendritic missorting of the axonal microtubule‐associated protein Tau is an early hallmark of Alzheimer's disease (AD) and other tauopathies. Tau missorting causes synaptic loss and neuronal dysfunction, but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. The six human brain Tau isoforms show different axodendritic distribution, but the Tau domains governing intracellular sorting and essential interactors are unknown. Here, we aimed to identify domains or motifs of human Tau and cellular binding partners required for efficient axonal Tau sorting and to unravel isoform‐specific Tau interactors. Using human MAPT‐KO induced pluripotent stem cell (iPSC)‐derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncation‐ or phosphorylation‐mutant Tau constructs and used TurboID‐based proximity labeling and proteomics to identify sorting‐ and isoform‐specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N‐terminal tail, the C‐terminal repeat domains, AD‐associated phosphorylation, and the general microtubule affinity of Tau, but it requires the presence of the proline‐rich region 2 (PRR2). Our interactome data revealed peroxisomal accumulation of the Tau N‐terminal half, while axonal Tau interacted with the PP2A activator HSP110. Further, we found 0N4R‐specific interactions of Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, including members of the CDC42 pathway and the RAB11 proteins, while 0N3R‐Tau bound to various cytoskeletal elements. In sum, our study i) postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity and ii) unravels a potential isoform‐specific role in synaptic function and AD‐related dysfunction. Efficient axonal Tau sorting requires the PRR2 domain but does not depend on AT8 or KXGS phosphorylation, the MT affinity, the C‐terminal repeat domains, or the N‐terminal tail of Tau. Human 0N4R‐Tau shows isoform‐specific interaction with modulators of synaptic plasticity involved in spine function under both normal and AD conditions.

The present paper aims to resolve ambiguous findings on the accuracy or inaccuracy of human judgments based on sparse information by arguing that accurate thin-slice judgments can be understood as driven by the wisdom of the crowd. To test this hypothesis, participants estimated the performance of track and field athletes in different competitions based on thin slices of pre- and post-performance nonverbal behavior. Results suggest that averaged judgments based on thin slices of athletes’ nonverbal behavior (NVB) are correlated with actual performance and that averaged judgments are better than individual judgments, thus validating the wisdom of the crowd hypothesis. Taken together, the present paper suggests that understanding thin-slice judgments from a wisdom of the crowd perspective has the potential to resolve the apparent contradiction regarding the accuracy or inaccuracy of human judgments. Furthermore, the paper highlights the potential of averaged thin-slice judgments of naturally occurring NVB as an addition to resource consuming coding procedures.

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N’s role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N’s requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif–containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin–mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Plasmodium vivax infection, when it occurs during pregnancy, has often been associated with serious adverse pregnancy outcomes. However, immunological alterations in pregnancy and their consequences have been little explored. We characterized the humoral immune response in pregnant women exposed to malaria by P. vivax antigens and its association with the maternal inflammatory profile and poor pregnancy outcomes. An observational cohort study in the Brazilian Amazon was conducted between 2013 and 2015. After applying exclusion criteria, 242 mother-child pairs were included in the analysis. Data on maternal infection, gestational outcomes, and inflammatory factors were evaluated in the maternal peripheral plasma. In samples from the first infection, the presence of total IgG and its subclasses in plasma against PvMSP119 protein were also quantified. Previous exposure to malaria, observed by anti-total IgG antibodies to the PvMSP119 antigen, increased the inflammatory response to infection when the pregnant woman had malaria during pregnancy. IL-6 and IL-10 levels were positively correlated with parasitemia and with total IgG levels; but they were negatively correlated with the gestational age at delivery from Pv-infected woman. In multivariate linear regression analyses, IgG 1, 2 and 4 was negatively and positively associated with cytokines IL-6 and IL-10, respectively, in P. vivax-infection. An association between the humoral immune response and the peripheral inflammatory cytokine profile with the adverse outcomes in malaria in pregnancy by P. vivax was observed. Previous exposure to the parasite can influence the IL-6 and IL-10 response, which is associated with increased parasitemia, reduced maternal weight gain and premature delivery.

Alarm fatigue can negatively impact patient safety and quality of health care, particularly in Intensive Care Units (ICUs). The Charité Alarm Fatigue Questionnaire (CAFQa) is a German questionnaire measuring alarm fatigue in two scales (alarm stress and alarm coping) in nurses and physicians. Its hypothesized dimensionality has not been investigated in non-German-speaking countries. This multi-centre study aimed to translate and validate CAFQa in Dutch-speaking ICUs. Forward and backward translation of CAFQa by two bilingual staff members, evaluation by an expert panel, cognitive interviews and a pilot test were performed to obtain the final Dutch questionnaire. Confirmatory factor analysis was performed, Cronbach's alpha (internal homogeneity) and correlation between self-reported alarm fatigue and item scores (convergent validity) were calculated. CAFQa was translated into Dutch, approved by the expert panel and cognitive interviews showed good face validity. Responses from 418 healthcare professionals from 11 centres (10 Dutch, 1 Belgian) were used. Cronbach's alpha was 0.69 (overall), 0.74 (alarm stress scale) and 0.46 (alarm coping scale). Strong correlations of item scores with self-reported alarm fatigue were found (overall: r = 0.51, alarm stress: r = 0.48, alarm coping: r = 0.30), supporting convergent validity. Confirmatory factor analysis indicated an adequate model fit (CFI = 0.961, TLI = 0.946, RMSEA = 0.052), and all factor loadings (0.20–0.74) proved statistically significant, albeit being higher for alarm stress (0.60–0.74) than alarm coping (0.21–0.70). CAFQa was translated and validated in a Dutch speaking population for the first time. This instrument can benchmark, measure and compare alarm fatigue of nurses and physicians. •The CAFQa questionnaire presents a valuable tool for alarm fatigue in ICU clinical settings.•This is the first Dutch translation and validation of the CAFQa in nurses and physicians on ICU•Linguistic adaptation of alarm fatigue questionnaires is feasible and methodologically sound.•This questionnaire overall demonstrates validity in measuring alarm fatigue for Dutch speaking

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2- conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR- activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Objective The number of couples experiencing infertility treatment has increased, as has the number of women and men experiencing infertility treatment-related stress and anxiety. Therefore, there is a need to provide information and support to both men and women facing fertility concerns. To achieve this goal, we designed a mhealth app, Infotility, that provided men and women with tailored medical, psychosocial, lifestyle, and legal information. Methods This study specifically examined how fertility factors (e.g. time in infertility treatment, parity), socio-demographic characteristics (e.g. gender, education, immigrant status), and mental health characteristics (e.g. stress, depression, anxiety, fertility-related quality of life) were related to male and female fertility patients’ patterns of use of the Infotility app. Results Overall, the lifestyle section of the app was the most highly used section by both men and women. In addition, women without children and highly educated women were more likely to use Infotility. No demographic, mental health or fertility characteristics were significantly associated with app use for men. Conclusion This study shows the feasibility of a mhealth app to address the psychosocial and informational needs of fertility patients.

Defect engineering is foundational to classical electronic device development and for emerging quantum devices. Here, we report on defect engineering of silicon with ion pulses from a laser accelerator in the laser intensity range of 10 19  W cm −2 and ion flux levels of up to 10 22  ions cm −2 s −1 , about five orders of magnitude higher than conventional ion implanters. Low energy ions from plasma expansion of the laser-foil target are implanted near the surface and then diffuse into silicon samples locally pre-heated by high energy ions from the same laser-ion pulse. Silicon crystals exfoliate in the areas of highest energy deposition. Color centers, predominantly W and G-centers, form directly in response to ion pulses without a subsequent annealing step. We find that the linewidth of G-centers increases with high ion flux faster than the linewidth of W-centers, consistent with density functional theory calculations of their electronic structure. Intense ion pulses from a laser-accelerator drive materials far from equilibrium and enable direct local defect engineering and high flux doping of semiconductors. Defect engineering and doping of semiconductors by ion irradiation are essential in large-scale integration of electronic devices. Here, intense ion pulses from a laser-accelerator, with flux levels up to 10 22  ions cm -2 s -1 , are used to induce and optimize silicon color centers and photon emitters in the telecom band.

ObjectiveAtrial fibrillation or atrial flutter (AF) and heart failure (HF) often go hand in hand and, in combination, lead to an increased risk of death compared with patients with just one of both entities. Sex-specific differences in patients with AF and HF are under-reported. Therefore, the aim of this study was to investigate sex-specific catheter ablation (CA) use and acute in-hospital outcomes in patients with AF and concomitant HF in a retrospective cohort study.MethodsUsing International Statistical Classification of Diseases and Related Health Problems and Operations and Procedures codes, administrative data of 75 hospitals from 2010 to 2018 were analysed to identify cases with AF and HF. Sex differences were compared for baseline characteristics, right and left atrial CA use, procedure-related adverse outcomes and in-hospital mortality.ResultsOf 54 645 analysed cases with AF and HF, 46.2% were women. Women were significantly older (75.4±9.5 vs 68.7±11.1 years, p<0.001), had different comorbidities (more frequently: cerebrovascular disease (2.4% vs 1.8%, p<0.001), dementia (5.3% vs 2.2%, p<0.001), rheumatic disease (2.1% vs 0.8%, p<0.001), diabetes with chronic complications (9.7% vs 9.1%, p=0.033), hemiplegia or paraplegia (1.7% vs 1.2%, p<0.001) and chronic kidney disease (43.7% vs 33.5%, p<0.001); less frequently: myocardial infarction (5.4% vs 10.5%, p<0.001), peripheral vascular disease (6.9% vs 11.3%, p<0.001), mild liver disease (2.0% vs 2.3%, p=0.003) or any malignancy (1.0% vs 1.3%, p<0.001), underwent less often CA (12.0% vs 20.7%, p<0.001), had longer hospitalisations (6.6±5.8 vs 5.2±5.2 days, p<0.001) and higher in-hospital mortality (1.6% vs 0.9%, p<0.001). However, in the multivariable generalised linear mixed model for in-hospital mortality, sex did not remain an independent predictor (OR 0.96, 95% CI 0.82 to 1.12, p=0.579) when adjusted for age and comorbidities. Vascular access complications requiring interventions (4.8% vs 4.2%, p=0.001) and cardiac tamponade (0.3% vs 0.1%, p<0.001) occurred more frequently in women, whereas stroke (0.6% vs 0.5%, p=0.179) and death (0.3% vs 0.1%, p=0.101) showed no sex difference in patients undergoing CA.ConclusionsThere are sex differences in patients with AF and HF with respect to demographics, resource utilisation and in-hospital outcomes. This needs to be considered when treating women with AF and HF, especially for a sufficient patient informed decision making in clinical practice.

With increasing transient error rates, distinguishing intermittent and transient faults is especially challenging. In addition to particle strikes relatively high transient error rates are observed in architectures for opportunistic computing and in technologies under high variations. This paper presents a method to classify faults into permanent, intermittent and transient faults based on some intermediate signatures during embedded test or built-in self-test. Permanent faults are easily determined by repeating test sessions. Intermittent and transient faults can be identified by the amount of failing test sessions in many cases. For the remaining faults, a Bayesian classification technique has been developed which is applicable to large digital circuits. The combination of these methods is able to identify intermittent faults with a probability of more than 98 %.