The interplay of collagen, macrophages, and microcalcification in atherosclerotic plaque cap rupture mechanics.

The rupture of an atherosclerotic plaque cap overlying a lipid pool and/or necrotic core can lead to thrombotic cardiovascular events. In essence, the rupture of the plaque cap is a mechanical event, which occurs when the local stress exceeds the local tissue strength. However, due to inter- and intra-cap heterogeneity, the resulting ultimate cap strength varies, causing proper assessment of the plaque at risk of rupture to be lacking. Important players involved in tissue strength include the load-bearing collagenous matrix, macrophages, as major promoters of extracellular matrix degradation, and microcalcifications, deposits that can exacerbate local stress, increasing tissue propensity for rupture. This review summarizes the role of these components individually in tissue mechanics, along with the interplay between them. We argue that to be able to improve risk assessment, a better understanding of the effect of these individual components, as well as their reciprocal relationships on cap mechanics, is required. Finally, we discuss potential future steps, including a holistic multidisciplinary approach, multifactorial 3D in vitro model systems, and advancements in imaging techniques. The obtained knowledge will ultimately serve as input to help diagnose, prevent, and treat atherosclerotic cap rupture.

Validation of Photoplethysmography Using a Mobile Phone Application for the Assessment of Heart Rate Variability in the Context of Heart Rate Variability-Biofeedback.

OBJECTIVE: Heart rate variability-biofeedback (HRV-BF) is an effective intervention to reduce stress and anxiety and requires accurate measures of real-time HRV. HRV can be measured through photoplethysmography (PPG) using the camera of a mobile phone. No studies have directly compared HRV-BF supported through PPG against classical electrocardiogram (ECG). The current study aimed to validate PPG HRV measurements during HRV-BF against ECG. METHODS: Fifty-seven healthy participants (70% women) with a mean (standard deviation) age of 26.70 (9.86) years received HRV-BF in the laboratory. Participants filled out questionnaires and performed five times a 5-minute diaphragmatic breathing exercise at different paces (range, ~6.5 to ~4.5 breaths/min). Four HRV indices obtained through PPG, using the Happitech software development kit, and ECG, using the validated NeXus apparatus, were calculated and compared: RMSSD, pNN50, LFpower, and HFpower. Resonance frequency (i.e., optimal breathing pace) was also compared between methods. RESULTS: All intraclass correlation coefficient values of the five different breathing paces were "near perfect" (>0.90) for all HRV indices: lnRMSSD, lnpNN50, lnLFpower, and lnHFpower. All Bland-Altman analyses (with just three incidental exceptions) showed good interchangeability of PPG- and ECG-derived HRV indices. No systematic evidence for proportional bias was found for any of the HRV indices. In addition, correspondence in resonance frequency detection was good with 76.6% agreement between PPG and ECG. CONCLUSIONS: PPG is a potentially reliable and valid method for the assessment of HRV. PPG is a promising replacement of ECG assessment to measure resonance frequency during HRV-BF.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

A Few Close Friends? Adolescent Friendships' Effect on Internalizing Symptoms Is Serially Mediated by Desire for More Friends and Social Goal Orientation.

Interpersonal connection is a fundamental human motivation, and the extent to which it is fulfilled is a strong predictor of symptoms of internalizing disorders such as social anxiety and depression, perhaps especially during the "social reorienting" period of adolescence. However, little is known about the contribution to this effect of the individual's social motivations, which are intensified during adolescence. Furthermore, social goal orientation - an individual's priorities and intentions in social interactions - is an important predictor of vulnerability to internalizing symptoms. Adolescents spend most of their waking lives in classrooms, bounded social networks with a limited pool of candidates for befriending. This study investigated whether friendships within one's class protects against internalizing symptoms in part by reducing the desire for more classmate friendships, which may tend to promote maladaptive social goals. Participants were 423 young adolescents (M age = 13.2, sd = 0.52 years; 49.4% girls). As predicted, adolescents' number of reciprocated classroom friendships had a protective effect on internalizing symptoms which was serially mediated by desire for more such friendships, and social goal orientation. However, only demonstration-avoidance goals significantly predicted internalizing symptoms. Unreciprocated friendship nominations were unexpectedly associated with stronger desire and more social anxiety symptoms. The results suggest that the effect of number of friends is mediated by the individual's thoughts and feelings about their number of friendships, such that a strong desire for more friendships promotes maladaptive goals, oriented toward social status and consequently less oriented toward the cultivation of interpersonal intimacy with the friends they already have.

Neural, behavioural and real-life correlates of social context sensitivity and social reward learning during interpersonal interactions in the schizophrenia spectrum.

OBJECTIVE: Recent findings suggest that diminished processing of positive contextual information about others during interactions may contribute to social impairment in the schizophrenia spectrum. This could be due to general social context processing deficits or specific biases against positive information. We studied the impact of positive and negative social contextual information during social interactions using functional neuroimaging and probed whether these neural mechanisms were associated with real-life social functioning in schizophrenia spectrum disorders. METHODS: Patients with a schizophrenia spectrum disorder (N = 23) and controls disorder (N = 25) played three multi-round trust games during functional magnetic resonance imaging scanning, with no, positive and negative information about the counterpart's trustworthiness, while all counterparts were programmed to behave trustworthy. The main outcome variable was the height of the shared amount in the trust game, i.e. investment, representing an indication of trust. The first investment in the game was considered to be basic trust, since no behavioural feedback was given yet. We performed region-of-interest analyses and examined the association with real-life social functioning using the experience sampling method. RESULTS: Social contextual information had no effect on patients' first investments, whereas controls made the lowest investment after negative and the highest investments after positive contextual information was provided. Over trials, patients decreased investments, suggesting reduced social reward learning, whereas controls increased investments in response to behavioural feedback in the negative context. Patients engaged the dorsolateral prefrontal cortex less than controls during context presentation and showed reduced activity within the caudate during repayments. In patients, lower investments were associated with more time spent alone and social exclusion and lower caudate activation was marginally significantly associated with higher perceived social exclusion. CONCLUSION: The failure to adapt trust to positive and negative social contexts suggests that patients have a general insensitivity to prior social information, indicating top-down processing impairments. In addition, patients show reduced sensitivity to social reward, i.e. bottom-up processing deficits. Moreover, lower trust and lower neural activation were related to lower real-life social functioning. Together, these findings indicate that improving trust and social interactions in schizophrenia spectrum needs a multi-faceted approach that targets both mechanisms.

Exploring the association between social behaviour, trust, and its neural correlates in first episode psychosis patients and in individuals at clinical high risk for psychosis.

OBJECTIVES: Psychosis is characterized by paranoid delusions, social withdrawal, and distrust towards others. Trust is essential for successful social interactions. It remains unknown which aspects of social functioning are associated with reduced trust in psychosis. Therefore, we investigated the association between social behaviour, trust, and its neural correlates in a group of individuals with psychotic symptoms (PS-group), consisting of first episode psychosis patients combined with individuals at clinical high risk. METHODS: We compared 24 PS individuals and 25 healthy controls. Affect and social withdrawal were assessed using the Experience Sampling Method. Trust was measured during functional magnetic resonance imaging (fMRI) scanning, using a trust game with a cooperative and unfair counterpart. RESULTS: The PS-group showed lower baseline trust compared to controls and reported less positive and more negative general affect. Social withdrawal did not differ between the groups. Social withdrawal and social reactivity in affect (i.e., changes in affect when with others compared to when alone) were not associated with trust. On the neural level, in controls but not in the PS-group, social withdrawal was associated with caudate activation during interactions with an unfair partner. An increase in positive social reactivity, was associated with reduced insula activation in the whole sample. CONCLUSIONS: Social withdrawal and social reactivity were not associated with reduced initial trust in the PS-group. Like controls, the PS-group showed a positive response in affect when with others, suggesting a decrease in emotional distress. Supporting patients to keep engaging in social interactions, may alleviate their emotional distress. PRACTITIONER POINTS: Individuals with psychotic symptoms show reduced initial trust towards unknown others. Trust in others is not associated with social withdrawal and reported affect when with others, nor when alone. Like controls, individuals with psychotic symptoms showed reduced negative affect and increased positive affect when with others compared to when alone. We emphasize to support individuals with psychotic symptoms to keep engaging in social interactions, given it may reduce social withdrawal and alleviate their emotional distress.

Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo.

Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.

Stress- and smoke free pregnancy study protocol: a randomized controlled trial of a personalized eHealth intervention including heart rate variability-biofeedback to support pregnant women quit smoking via stress reduction.

BACKGROUND: Maternal smoking and stress during pregnancy are associated with adverse health effects for women themselves and are risk factors for adverse developmental outcomes of the unborn child. Smoking and stress seem to be intertwined in various ways. First, the majority of smoking pregnant women is of lower socio-economic status, which is associated with higher levels of perceived stress. Second, smoking women often report to smoke because they feel stressed. Third, quitting smoking often increases perceived stress levels initially. Therefore, effective interventions are needed to support women with smoking cessation by reducing stress. The aim of this study is to test the effectiveness of an eHealth intervention on stress reduction and smoking cessation. METHODS/DESIGN: The Stress- and Smoke Free Start of Life (SSFSL) study is a randomized controlled trial (RCT) comparing a personalized eHealth intervention with a control condition. Inclusion criteria for the women are: (1) > 18 years of age, (2) < 28 weeks pregnant at recruitment, (3) currently smoking. Consenting participants will be randomly assigned to the intervention or control group. Participants allocated to the intervention group will receive an 8-week intervention delivered on their smartphone. The application includes psycho-education on pregnancy, stress, and smoking (cessation); stress-management training consisting of Heart Rate Variability-biofeedback; and a personalized stop-smoking-plan. Participants in the control condition will be invited to visit a webpage with information on pregnancy, stress, and smoking (cessation). Study outcomes will be collected via online questionnaires, at four timepoints: pre-intervention (baseline; t0), post-intervention (8 weeks + 1 day after t0; t1), follow up at two weeks after birth (t2), and follow up at three months after birth (t3). The primary outcome measure is self-reported smoking cessation. Secondary outcomes include daily self-reported number of cigarettes smoked, perceived stress, pregnancy experience, birth outcomes, and negative affectivity scores of the baby. Moreover, the mediating effect of stress reduction on smoking cessation will be examined, and possible moderators will be tested. DISCUSSION: If the eHealth intervention is effective in smoking cessation among pregnant smoking women, it can be implemented as a tool into the health care in the Netherlands. TRIAL REGISTRATION: Netherlands Trial Register, ID: NL8156 . Registered on 11 November 2019.

Trust and the city: Linking urban upbringing to neural mechanisms of trust in psychosis.

OBJECTIVE: Elevated prevalence of non-affective psychotic disorders is often found in densely populated areas. This functional magnetic resonance imaging study investigates if reduced trust, a component of impaired social functioning in patients with psychotic disorder, is associated with urban upbringing. METHODS: In total, 39 patients (22 first episode and 17 clinical high risk) and 30 healthy controls, aged 16-29, performed two multi-round trust games, with a cooperative and unfair partner during functional magnetic resonance imaging scanning. Baseline trust was operationalized as the first investment made, and changes of trust as changes in investments made over the 20 trials during the games. Urban exposure during upbringing (0-15 years) was defined as higher urban (≥2500 inhabitants/km2) or lower urban (<2500 inhabitants/km2). RESULTS: Patients displayed lower baseline trust (first investment) than controls, regardless of urbanicity exposure. During cooperative interactions, lower-urban patients showed increasing investments. In addition, during cooperative interactions, group-by-developmental urbanicity interactions were found in the right and left amygdalae, although for the latter only at trend level. Higher urbanicity was associated with decreased activation of the left amygdala in patients and controls during investments and with increased activation of the right and left amygdalae in patients only, during repayments. During unfair interactions, no associations of urbanicity with behavior or brain activation were found. CONCLUSION: Urban upbringing was unrelated to baseline trust. Associations with urbanicity were stronger for patients compared to controls, suggesting greater susceptibility to urbanicity effects during the developmental period. Higher-urban patients failed to compensate for the initial distrust specifically during repeated cooperative interactions. This finding highlights potential implications for social functioning. Urban upbringing was linked to differential amygdala activation, suggesting altered mechanisms of feedback learning, but this was not associated with trust game behavior.

Learning to trust: social feedback normalizes trust behavior in first-episode psychosis and clinical high risk.

BACKGROUND: Psychosis is characterized by problems in social functioning that exist well before illness onset, and in individuals at clinical high risk (CHR) for psychosis. Trust is an essential element for social interactions that is impaired in psychosis. In the trust game, chronic patients showed reduced baseline trust, impaired response to positive social feedback, and attenuated brain activation in reward and mentalizing areas. We investigated whether first-episode psychosis patients (FEP) and CHR show similar abnormalities in the neural and behavioral mechanisms underlying trust. METHODS: Twenty-two FEP, 17 CHR, and 43 healthy controls performed two trust games, with a cooperative and an unfair partner in the fMRI scanner. Region of interest analyses were performed on mentalizing and reward processing areas, during the investment and outcome phases of the games. RESULTS: Compared with healthy controls, FEP and CHR showed reduced baseline trust, but like controls, learned to trust in response to cooperative and unfair feedback. Symptom severity was not associated with baseline trust, however in FEP associated with reduced response to feedback. The only group differences in brain activation were that CHR recruited the temporo-parietal junction (TPJ) more than FEP and controls during investment in the unfair condition. This hyper-activation in CHR was associated with greater symptom severity. CONCLUSIONS: Reduced baseline trust may be associated with risk for psychotic illness, or generally with poor mental health. Feedback learning is still intact in CHR and FEP, as opposed to chronic patients. CHR however show distinct neural activation patterns of hyper-activation of the TPJ.

Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.

E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C(C) (dc20). Importantly, atypical E2Fs can activate APC/C(C) (dh1) by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C(C) (dh1), which ensures balanced expression of cell cycle genes and normal cell cycle progression.

Derivatization Strategies for the Detection of Triamcinolone Acetonide in Cartilage by Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging.

Osteoarthritis (OA), characterized by degeneration of the cartilaginous tissue in articular joints, severely impairs mobility in many people worldwide. The degeneration is thought to be mediated by inflammatory processes occurring in the tissue of the joint, including the cartilage. Intra-articular administered triamcinolone acetonide (TAA) is one of the drug treatments employed to ameliorate the inflammation and pain that characterizes OA. However, the penetration and distribution of TAA into the avascular cartilage is not well understood. We employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which has been previously used to directly monitor the distribution of drugs in biological tissues, to evaluate the distribution of TAA in human cartilage after in vitro incubation. Unfortunately, TAA is not easily ionized by regular electrospray ionization (ESI) or MALDI. To overcome this problem, we developed an on-tissue derivatization method with Girard's reagent T (GirT) in human incubated cartilage being able to study its distribution and quantify the drug abundance (up to 3.3 ng/µL). Our results demonstrate the depth of penetration of a corticosteroid drug in human OA cartilage using MALDI-MSI.

I spy with my little eye - the detection of intentional contingency in early psychosis.

INTRODUCTION: Paranoid delusions have been associated with a tendency to over-attribute intentionality and contingency to others' actions and incidental events in individuals with chronic psychosis. However, this hyper-associative perception bias has not been investigated in the early illness stages of psychosis, during which it may play a particularly crucial role in the formation of symptoms. METHOD: We used an experimental paradigm with 20 short film clips of simple animate and inanimate shapes that either moved in a contingent or non-contingent manner to investigate the perception of contingency in 38 adolescents with early psychosis and 93 healthy control adolescents. Participants rated the contingency between the shapes' movements on a scale from 0 to 10. The data were analysed with multilevel regression analyses to account for repeated measures within subjects. RESULTS: There were no significant differences between patients and controls; both perceived the contingency of the shapes' movements similarly across all conditions and patients' contingency perception was unrelated to their levels of paranoid delusions. CONCLUSION: Contingency perception was unimpaired in patients with early psychosis, suggesting that it might still be intact in the early illness stages. Future studies should set out to determine whether the early illness stages could offer a window for interventions that counteract the development of hyper-associative perceptions of contingency.

Smoking cessation in pregnant women: A randomized controlled trial investigating the effectiveness of an eHealth intervention including heart rate variability-biofeedback training.

BACKGROUND: Prenatal smoking and stress are associated with adverse health effects for women themselves and are risk factors for adverse outcomes of the child. Effective interventions are needed to support women with smoking cessation and reducing stress. The aims were (1) to test the effectiveness of an 8-week eHealth intervention targeting stress reduction and smoking cessation; (2) to examine whether stress reduction mediated the intervention effect on smoking behavior; (3) to test motivation to quit as a moderator; and (4) to investigate a dose-response effect of program usage. METHODS: Pregnant women were included if they were >18 years of age, < 28 weeks pregnant at recruitment, and currently smoking. In total, 156 consenting participants were randomly assigned to the intervention or active control condition. Study outcomes on smoking (yes/no, frequency, and quantity) were collected via online questionnaires at pre-intervention (baseline; t0), post-intervention (8 weeks after t0; t1), and follow up at two weeks (t2) and three months (t3) after birth. RESULTS: Smoking and stress reduced over the 8-week period in both conditions. The intervention effect on smoking was not mediated by stress reduction. Motivation to quit was found to moderate the intervention effect (smoking frequency and quantity) and a dose-response effect was found for program usage in the intervention for the reduction on smoking frequency and quantity. CONCLUSION: Program usage and motivation to quit are important for smoking reduction in pregnant women. Further research is needed to examine how the intervention could be improved to increase treatment effectiveness.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

The social cognitive and neural mechanisms that underlie social functioning in individuals with schizophrenia - a review.

In many individuals with a diagnosis of schizophrenia social functioning is impaired across the lifespan. Social cognition has emerged as one of the possible factors that may contribute to these challenges. Neuroimaging research can give further insights into the underlying mechanisms of social (cognitive) difficulties. This review summarises the evidence on the associations between social cognition in the domains of theory of mind and emotion perception and processing, and individuals' social functioning and social skills, as well as associated neural mechanisms. Eighteen behavioural studies were conducted since the last major review and meta-analysis in the field (inclusion between 7/2017 and 1/2022). No major review has investigated the link between the neural mechanisms of social cognition and their association with social functioning in schizophrenia. Fourteen relevant studies were included (from 1/2000 to 1/2022). The findings of the behavioural studies showed that associations with social outcomes were slightly stronger for theory of mind than for emotion perception and processing. Moreover, performance in both social cognitive domains was more strongly associated with performance on social skill measures than questionnaire-based assessment of social functioning in the community. Studies on the underlying neural substrate of these associations presented mixed findings. In general, higher activation in various regions of the social brain was associated with better social functioning. The available evidence suggests some shared regions that might underlie the social cognition-social outcome link between different domains. However, due to the heterogeneity in approaches and findings, the current knowledge base will need to be expanded before firm conclusions can be drawn.

A tissue-engineered model of the atherosclerotic plaque cap: Toward understanding the role of microcalcifications in plaque rupture.

Rupture of the cap of an atherosclerotic plaque can lead to thrombotic cardiovascular events. It has been suggested, through computational models, that the presence of microcalcifications in the atherosclerotic cap can increase the risk of cap rupture. However, the experimental confirmation of this hypothesis is still lacking. In this study, we have developed a novel tissue-engineered model to mimic the atherosclerotic fibrous cap with microcalcifications and assess the impact of microcalcifications on cap mechanics. First, human carotid plaque caps were analyzed to determine the distribution, size, and density of microcalcifications in real cap tissue. Hydroxyapatite particles with features similar to real cap microcalcifications were used as microcalcification mimics. Injected clusters of hydroxyapatite particles were embedded in a fibrin gel seeded with human myofibroblasts which deposited a native-like collagenous matrix around the particles, during the 21-day culture period. Second harmonic multiphoton microscopy imaging revealed higher local collagen fiber dispersion in regions of hydroxyapatite clusters. Tissue-engineered caps with hydroxyapatite particles demonstrated lower stiffness and ultimate tensile stress than the control group samples under uniaxial tensile loading, suggesting increased rupture risk in atherosclerotic plaques with microcalcifications. This model supports previous computational findings regarding a detrimental role for microcalcifications in cap rupture risk and can further be deployed to elucidate tissue mechanics in pathologies with calcifying soft tissues.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

An albumin-angiotensin converting enzyme 2-based SARS-CoV-2 decoy with FcRn-driven half-life extension.

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants and breakthrough infections despite available coronavirus disease 2019 (COVID-19) vaccines calls for antiviral therapeutics. The application of soluble angiotensin converting enzyme 2 (ACE2) as a SARS-CoV-2 decoy that reduces cell bound ACE2-mediated virus entry is limited by a short plasma half-life. This work presents a recombinant human albumin ACE2 genetic fusion (rHA-ACE2) to increase the plasma half-life by an FcRn-driven cellular recycling mechanism, investigated using a wild type (WT) albumin sequence and sequence engineered with null FcRn binding (NB). Binding of rHA-ACE2 fusions to SARS-CoV-2 spike protein subdomain 1 (S1) was demonstrated (WT-ACE2 KD = 32.8 nM and NB-ACE2 KD = 31.7 nM) using Bio-Layer Interferometry and dose-dependent in vitro inhibition of host cell infection of pseudotyped viruses displaying surface SARS-CoV-2 spike (S) protein. FcRn-mediated in vitro recycling was translated to a five times greater plasma half-life of WT-ACE2 (t½ ß = 13.5 h) than soluble ACE2 (t½ ß = 2.8 h) in humanised FcRn/albumin double transgenic mice. The rHA-ACE2-based SARS-CoV-2 decoy system exhibiting FcRn-driven circulatory half-life extension introduced in this work offers the potential to expand and improve the anti-COVID-19 anti-viral drug armoury. STATEMENT OF SIGNIFICANCE: The COVID-19 pandemic has highlighted the need for rapid development of efficient antiviral therapeutics to combat SARS-CoV-2 and new mutants to lower morbidity and mortality in severe cases, and for people that are unable to receive a vaccine. Here we report a therapeutic albumin ACE2 fusion protein (rHA-ACE2), that can bind SARS-CoV-2 S protein decorated virus-like particles to inhibit viral infection, and exhibits extended in vivo half-life compared to ACE2 alone. Employing ACE2 as a binding decoy for the virus is expected to efficiently inhibit all SARS-CoV-2 mutants as they all rely on binding with endogenous ACE2 for viral cell entry and, therefore, rHA-ACE2 constitutes a versatile addition to the therapeutic arsenal for combatting COVID-19.