The histidine-containing phosphocarrier protein (HPr) transfers a phosphate group between components of the prokaryotic phosphoenolpyruvate-dependent phosphotransferase system (PTS), which is finally used to phosphorylate the carbohydrate transported by the PTS through the cell membrane. Recently it has also been found to act as an intermediate in the signaling cascade that regulates transcription of genes related to the carbohydrate-response system. Both functions involve phosphorylation/dephosphorylation reactions, but at different sites. Using multidimensional (1)H-NMR spectroscopy and angular space simulated annealing calculations, we determined the structure of HPr from Enterococcus faecalis in aqueous solution using 1469 distance and 44 angle constraints derived from homonuclear NMR data. It has a similar overall fold to that found in HPrs from other organisms. Four beta strands, A, B, C, D, encompassing residues 2-7, 32-37, 40-42 and 60-66, form an antiparallel beta sheet lying opposite the two antiparallel alpha helices, a and c (residues 16-26 and 70-83). A short alpha helix, b, from residues 47-53 is also observed. The pairwise root mean square displacement for the backbone heavy atoms of the mean of the 16 NMR structures to the crystal structure is 0.164 nm. In contrast with the crystalline state, in which a torsion angle strain in the active-center loop has been described [Jia, Z., Vandonselaar, M., Quail, J.W. & Delbaere, L.T.J. (1993) Nature (London) 361, 94-97], in the solution structure, the active-site His15 rests on top of helix a, and the phosphorylation site N(delta 1) of the histidine ring is oriented towards the surface, making it easily accessible to the solvent. Back calculation of the 2D NOESY NMR spectra from both the NMR and X-ray structures shows that the active-center structure derived by X-ray crystallography is not compatible with experimental data recorded in solution. The observed torsional strain must either be a crystallization artefact or represents a conformational state that exists only to a small extent in solution.
In a previous paper [Lindley et al. (1993), Acta Cryst. D49, 292-304], the X-ray structure analysis of the 18 kDa fragment of duck ovotransferrin, corresponding to the NII domain of the intact protein, was reported at a resolution of 2.3 A. In this structure, the Fe(III) cation binds to two tyrosine residues and the synergistic carbonate anion in an identical manner to that found in the intact protein. However, the aspartate and histidine residues, normally involved in iron binding in transferrins, are absent in the fragment and it was not possible to unequivocally define what had replaced them. The electron density was tentatively assigned to be a mixture of peptides, presumably resulting from the proteolytic preparation of the fragment, binding to the iron through their amino and carboxylate termini. A more recent X-ray analysis of the fragment, from a different preparation, has resulted in a structure at 1.95 A, in which glycine appears to be the predominant residue bound to the cation. In an alternative attempt to clarify the binding of iron to the 18 kDa fragment, the metal was removed by dialysis and replaced in the form of ferric nitrilotriacetate. Crystallization of this complex has resulted in an X-ray structure at 1.90 A in which the Fe(III) is bound to the synergistic carbonate anion and only one tyrosine residue in a manner almost identical to the intact protein. The carboxylate groups and the tertiary amino group of the nitrilotriacetate occupy the remaining coordination sites. The second tyrosine residue, Tyr95, is not bound directly to the iron. The implication of these structures with respect to the mechanism of iron binding by the transferrins is addressed.
To identify outcomes reported after selective dorsal rhizotomy (SDR) in ambulant children and young people with cerebral palsy in different domains of the International Classification of Functioning, Disability and Health (ICF). A scoping review using the JBI Scoping Review methodology was conducted. Six databases were searched for literature published between 1993 and 2024. A total of 214 published papers met the inclusion criteria. Outcomes under the body function and structure domain were most frequently investigated (n = 199, 93%), followed by activity (n = 123, 58%) and participation (n = 33, 15%) across all studies. Quality of life was reported in 16 (8%) studies, and four (2%) studies mentioned individualized goals for SDR surgery. A combination of validated measures and subjective outcomes was used, with 119 (56%) studies reporting outcomes in two or more domains. Impairment-based outcomes remain the primary focus in SDR research. A small shift in emphasis towards participant-reported outcome measures has been seen in recent years. Few studies reported on the impact of personal and environmental factors. Future SDR studies need to incorporate all domains of the ICF to enhance understanding and capture holistic, meaningful changes in the lives of children and young people with cerebral palsy and their families.
Chronic pain is prevalent among military veterans and commonly presents with perceived stress and alcohol use. Allostatic load models suggest moderate-severe chronic pain may reflect a state of physiological dysregulation with heightened associations between pain and behavioural health symptoms. Yet little is known about daily associations between pain intensity, perceived stress, and alcohol use in veterans with and without moderate-severe chronic pain. This study examined day-to-day associations between pain intensity, perceived stress, and alcohol use among veterans, and whether associations differ between those with moderate-severe chronic pain and those with less severe pain. A sample of United States military veterans (n = 74) completed smartphone-based daily diary surveys for up to 3 months, providing 4307 days of data. Multi-group dynamic structural equation modelling examined within-person, day-to-day associations between symptoms, among veterans with moderate-severe chronic pain and those with less severe pain. Among veterans with moderate-severe chronic pain, bidirectional positive day-to-day associations emerged between pain intensity and perceived stress (b = 0.06-0.13), and between perceived stress and alcohol use (b = 0.05-0.07). Pain intensity also predicted increased next-day alcohol use (b = 0.04). Perceived stress appeared to act as a mechanism linking alcohol use to subsequent pain intensity (b = 0.01). For veterans with less severe pain, symptom associations differed markedly; higher perceived stress predicted lower next-day pain intensity (b = -0.05). Among veterans with moderate-severe chronic pain, day-to-day associations between pain intensity, perceived stress, and alcohol use appear more entangled. These veterans may experience heightened stress reactivity and poorer coping, requiring tailored interventions to monitor and address day-to-day symptom fluctuations.
Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) are a well-established cause of amyotrophic lateral sclerosis (ALS). The mutations promote SOD1 misfolding, resulting in protein aggregation and motor neuron degeneration. SOD1 is normally a structurally stable enzyme, and the mechanisms underlying SOD1 misfolding remain poorly understood. Approximately one third of SOD1 in cerebrospinal fluid (CSF) exhibits an N-terminal truncation, the biological significance of which remains unclear. This is remarkable given the dramatic effects ALS-linked C-terminal truncations have on the enzyme. In this study, we identified the truncation site and investigated its impact on SOD1 stability and enzymatic activity. Edman degradation revealed the cleavage site between Asn-26 and Gly-27, generating a 26-residue peptide that was confirmed by mass spectrometry. We analyzed postmortem tissues from different parts of the central nervous system (CNS), including the choroid plexus, and found only trace amounts of N-terminally truncated SOD1. Biochemical characterization of the SOD1 in CSF was done by size exclusion chromatography, ion exchange chromatography, and mass spectrometry. Our findings demonstrate that SOD1 in CSF retains full enzymatic activity, that the N-terminally truncated variant is mainly present in heterodimers with native SOD1 subunits, and that the dimer remains folded and active, with both fragments of the truncated SOD1 fixed after proteolysis. Truncated SOD1 was absent in human plasma. In mice, only transgenically expressed human SOD1 underwent truncation in CSF, whereas endogenous murine SOD1 remained intact. Lastly, the N-terminal truncation does not induce misfolding, unlike the destabilizing effects observed with C-terminal truncations. The location where the truncation takes place and the underlying mechanism could not be identified. Whether the N-truncated SOD1 variant contributes to ALS pathogenesis remains to be determined.
A programme of incentives was set up in the London Initiative Zones to improve primary care in inner London based on the findings of the Tomlinson Enquiry in 1992. This descriptive study is a 4-y time series analysis of changes in general practice structure in East London as the result of London Initiative Zone investment, and an exploration of the possible effect of investment on practice performance. We used routinely available administrative data for the whole analysis. General practice characteristics and two selected performance indicators: the asthma prophylaxis to bronchodilator ratio and cervical cytology screening rate, for all practices in the East London and the City Health Authority for 4 y, 1993-1996, were used. Both reflect practice efficiency, but relate to different aspects of practice performance. The prescribing indicator is more indicative of the quality of clinical practise, whereas cervical screening coverage relates more to the characteristics of the practice population and to practice organisation. Repeated measures analyses were used to identify trends and to explore the relationship between changes in practice characteristics and performance. Graphical methods were used to compare East London trends with the rest of England. There were significant improvements in practice structure as the consequence of London Initiative Zone investment. There was a positive association with improvements in practice performance, but East London still lagged some way behind national patterns. The findings suggest that while improvements in asthma prescribing follow the national trend, practices have difficulty in achieving and sustaining the 80% target for cervical cytology screening, and that an overall population coverage of 80% may be in doubt.Increased investment in practice staffing may be influential in improving some aspects of performance. However, in common with other inner cities, a greater effort and more innovative strategies may be needed to achieve a standard of performance equal to the best.
Atypical face processing is commonly reported in autism. Its neural correlates have been explored extensively across single neuroimaging modalities within key regions of the face processing network, such as the fusiform gyrus (FFG). Nonetheless, it is poorly understood how variation in brain anatomy and function jointly impacts face processing and social functioning. Here we leveraged a large multimodal sample to study the cross-modal signature of face processing within the FFG across four imaging modalities (structural magnetic resonance imaging (MRI), resting-state functional magnetic resonance imaging, task-functional magnetic resonance imaging and electroencephalography) in 204 autistic and nonautistic individuals aged 7-30 years (case-control design). We combined two methodological innovations-normative modeling and linked independent component analysis-to integrate individual-level deviations across modalities and assessed how multimodal components differentiated groups and informed social functioning in autism. Groups differed significantly in a multimodal component driven by bilateral resting-state functional MRI, bilateral structure, right task-functional MRI and left electroencephalography loadings in face-selective and retinotopic FFG. Multimodal components outperformed unimodal ones in differentiating groups. In autistic individuals, multimodal components were associated with cognitive and clinical features linked to social, but not nonsocial, functioning. These findings underscore the importance of elucidating multimodal neural associations of social functioning in autism, offering potential for the identification of mechanistic and prognostic biomarkers.
Adaptive behaviour refers to the everyday skills that individuals are expected to have to function independently, based on their age and societal norms. Currently, we know little about the role of genetic and environmental factors in parent-rated adaptive behaviours in early infancy. The aim of this study was to investigate the aetiological factors that influence individual variability in different adaptive behaviour domains at 5 months, and the degree of genetic and environmental influences that are unique and shared across these domains. We analysed data from the Vineland Adaptive Behaviour Scale (VABS-II) motor domain and combined domain of socialization and communication (social-communication) using a multivariate twin modelling approach. Participants were a community sample of monozygotic and dizygotic twins assessed at 5 months of age (n = 594). The results show high shared environmental influence on both motor (0.67) and social-communication (0.78) domains with 45% shared variance. Both had low, but significant heritability estimates (0.21 and 0.12, respectively) but did not share genetic variance. No statistically significant associations were found between polygenic scores for autism, ADHD, schizophrenia, depression, and bipolar disorder, and either of the adaptive behaviours measured here. Our results highlight the importance of shared environmental factors in the development of social-communication and motor skills in infancy, whether it is through social interaction with caregivers, or the stimuli and opportunities presented at home. SUMMARY: During development structural arm length representation is underestimated, while the functional arm length representation is overestimated. Underestimation of structural arm length is driven by an underestimation of hand length, as forearm length is accurate. Structural hand length is underestimated, supporting that underestimation of hand length is a characteristic of human body representation. The opposite pattern of results between structural and functional arm representation suggests the existence of multiple independent representations of the body.
Intimate partner violence (IPV) affects an estimated 27% of women globally, with consequences spanning mental, physical and societal well-being. Previous research identifies individual and relational risk factors for IPV, but less is known about wider structural factors. This study examines the association between food insecurity and IPV using nationally-representative data from 156 countries, exploring gendered asset policies as a potential mediator. We used nationally representative survey data on women's experience of IPV (1993-2019) and the Food and Agriculture Organization data on moderate to severe food insecurity. Multilevel mixed-effects generalised linear models estimated the association between standardised variables for food insecurity and IPV, accounting for country-level clustering and adjusting for gross domestic product (GDP). Mediation analysis estimated the role of gendered asset policies (Women, Business and the Law Index Score). Sensitivity analyses lagged food insecurity by at least 4 years among a subset of 59 countries. We examined data from 219 country-years representing 156 countries globally across the period of 1993-2019. After controlling for national GDP, models estimated an independent cross-sectional association between food insecurity and IPV (b=0.49; 95% CI 0.37 to 0.62). Gendered asset policies mediated 18.9% of the food insecurity-IPV relationship (indirect effect 0.099 (0.044-0.155); total effect 0.526 (0.422-0.631)). In lagged analysis, food insecurity was associated with higher IPV 2 years later (b=0.78; 95% CI 0.48 to 1.06), with a similar mediation effect (21.0%). This study is among the first to harness global data to demonstrate country-level effects of food insecurity on IPV, which countries enacting more equitable asset policies were able to mitigate a substantial proportion of. Future research should prospectively pinpoint how supportive gender policies and asset ownership can amplify the benefits of food security for women's safety and longevity.
For the conduct of future interventional age-related macular degeneration (AMD) trials, the availability of clinical study endpoints is key. However, no endpoints have been accepted by regulators for evaluation of treatment for intermediate (i) AMD, i.e. the AMD stage at highest risk of developing irreversible geographic atrophy or macular neovascularization. The European MACUSTAR consortium has recruited more than 700 individuals to develop and validate structural, functional and patient-reported endpoints, enabling future iAMD trials based on a prospective observational, multi-centre cohort study. Reliably assessing candidate endpoints in a setting that involves multiple clinical sites across countries comes with a plurality of challenges in the study set-up, quality of data, recruitment of participants and study conduct. Therefore, the MACUSTAR consortium has established a framework that successfully addresses these topics, provides relevant insights into the natural history of iAMD and its sub-phenotypes, and will open new regulatory pathways. The MACUSTAR study is registered on ClinicalTrials.gov under NCT03349801.
A one-year study of gastro-intestinal parasitism in a free-ranging population of maras at Whipsnade Wild Animal Park, UK, revealed a strong relationship between membership of social units and both intensity and prevalence of infection. The mara, a hystricomorph rodent from southern Argentina, has a social organization including both monogamy and communal denning of the young, an apparently unique combination among mammals. From October 1992 to September 1993, strongyloid parasite loads were estimated from faecal egg counts. A minimum adequate model was fitted to the data using the Genstat statistical package. This showed that family membership had a highly significant effect on the intensity of egg shedding in faeces, and a significant effect on the prevalence of infection. After controlling for both extrinsic environmental and intrinsic demographic factors, homogeneity of infection was greater within than between families and adult pairs.
The DSM Level 1 Cross-Cutting Symptom Measure (DSM-XC) allows for assessing multiple psychopathological domains. However, its capability to screen for mental disorders in a population-based sample and the impact of adverbial framings (intensity and frequency) on its performance are unknown. The study was based on cross-sectional data from the 1993 Pelotas birth cohort in Brazil. Participants with completed DSM-XC and structured diagnostic interviews (n = 3578, aged 22, 53.6% females) were included. Sensitivity, specificity, positive (LR+), and negative (LR-) likelihood ratios for each of the 13 DSM-XC domains were estimated for detecting five internalizing disorders (bipolar, generalized anxiety, major depressive, post-traumatic stress, and social anxiety disorders) and three externalizing disorders (antisocial personality, attention-deficit/hyperactivity, and alcohol use disorders). Sensitivities and specificities >0.75, LR+ > 2 and LR- < 0.5 were considered meaningful. Values were calculated for the DSM-XC's original scoring and for adverbial framings. Several DSM-XC domains demonstrated meaningful screening properties. The anxiety domain exhibited acceptable sensitivity and LR- values for all internalizing disorders. The suicidal ideation, psychosis, memory, repetitive thoughts and behaviors, and dissociation domains displayed acceptable specificity for all disorders. Domains also yielded small but meaningful LR+ values for internalizing disorders. However, LR+ and LR- values were not generally meaningful for externalizing disorders. Frequency-framed questions improved screening properties. The DSM-XC domains showed transdiagnostic screening properties, providing small but meaningful changes in the likelihood of internalizing disorders in the community, which can be improved by asking frequency of symptoms compared to intensity. The DSM-XC is currently lacking meaningful domains for externalizing disorders.
There are very few mechanistic studies of the long-term impact of psychosocial interventions in childhood. The parent-mediated Paediatric Autism Communication Therapy (PACT) RCT showed sustained effects on autistic child outcomes from pre-school to mid-childhood. We investigated the mechanism by which the PACT intervention achieved these effects. Of 152 children randomised to receive PACT or treatment as usual between 2 and 5 years of age, 121 (79.6%) were followed 5-6 years after the endpoint at a mean age of 10.5 years. Assessors, blind to the intervention group, measured Autism Diagnostic Observation Scale Calibrated Severity Score (ADOS CSS) for child autistic behaviours and Teacher Vineland (TVABS) for adaptive behaviour in school. Hypothesised mediators were child communication initiations with caregivers in a standard play observation (Dyadic Communication Measure for Autism, DCMA). Hypothesised moderators of mediation were baseline child non-verbal age equivalent scores (AE), communication and symbolic development (CSBS) and 'insistence on sameness' (IS). Structural equation modelling was used in a repeated measures mediation design. Good model fits were obtained. The treatment effect on child dyadic initiation with the caregiver was sustained through the follow-up period. Increased child initiation at treatment midpoint mediated the majority (73%) of the treatment effect on follow-up ADOS CSS. A combination of partial mediation from midpoint child initiations and the direct effect of treatment also contributed to a near-significant total effect on follow-up TVABS. No moderation of this mediation was found for AE, CSBS or IS. Early sustained increase in an autistic child's communication initiation with their caregiver is largely responsible for the long-term effects from PACT therapy on autistic and adaptive behaviour outcomes. This supports the theoretical logic model of PACT therapy but also illuminates fundamental causal processes of social and adaptive development in autism over time: early social engagement in autism can be improved and this can have long-term generalised outcome effects.
Penetrating neck injury is associated with significant morbidity due to the several structures (neurological, vascular and aerodigestive) within close proximity to one another. This case highlights an uncommon presentation of an embedded foreign body following penetrating neck trauma and the decision-making required during management.
We studied the population dynamics of feral oilseed rape (Brassica napus) for 10 years (1993-2002) in 3658 adjacent permanent 100 m quadrats in the verges of the M25 motorway around London, UK. The aim was to determine the relative importance of different factors affecting the observed temporal patterns of population dynamics and their spatial correlations. A wide range of population dynamics was observed (downward or upward trends, cycles, local extinctions and recolonizations), but overall the populations were not self-replacing (lambda < 1). Many quadrats remained unoccupied throughout the study period, but a few were occupied at high densities for all 10 years. Most quadrats showed transient oilseed rape populations, lasting 1-4 years. There were strong spatial patterns in mean population density, associated with soil conditions and the successional age of the plant community dominating the verge, and these large-scale spatial patterns were highly consistent from year to year. The importance of seed spilled from trucks in transit to the processing plant at Erith in Kent was confirmed: rape populations were significantly higher on the 'to Erith' verge than the 'from Erith' verge (overall mean 2.83-fold greater stem density). Quadrats in which lambda > 1 were much more frequent in the 'to Erith' verge, indicating that seed immigration can give the spurious impression of self-replacing population dynamics in time-series analysis. There was little evidence of a pervasive Moran effect, and climatic forcing did not produce widespread large-scale synchrony in population dynamics for the motorway as a whole; just 23% of quadrats had significant rank correlations with the mean time-series. There was, however, significant local spatial synchrony of population dynamics, apparently associated with soil disturbance and seed input. This study draws attention to the possibility that different processes may impose population synchrony at different scales. We hypothesize that synchrony in this system is driven by at least three processes: small-scale, local forcing caused by soil disturbance, intermediate-scale forcing as a result of seed input, and large-scale climatic forcing (e.g. winter rainfall) that affects the motorway as a whole.
Acyl glucuronide metabolites have been implicated in the toxicity of several carboxylic acid-containing drugs, and the rate of their degradation via intramolecular transacylation and hydrolysis has been associated with the degree of protein adduct formation. Although not yet proven, the formation of protein adducts in vivo - and subsequent downstream effects - has been proposed as a mechanism of toxicity for carboxylic acid-containing xenobiotics capable of forming acyl glucuronides. A structurally-related series of metabolites, the acyl glucosides, have also been shown to undergo similar degradation reactions and consequently the potential to display a similar mode of toxicity. Here we report detailed kinetic models of each transacylation and hydrolysis reaction for a series of phenylacetic acid acyl glucuronides and their analogous acyl glucosides. Differences in reactivity were observed for the individual transacylation steps between the compound series; our findings suggest that the charged carboxylate ion and neutral hydroxyl group in the glucuronide and glucoside conjugates, respectively, are responsible for these differences. The transacylation reaction was modelled using density functional theory and the calculated activation energy for this reaction showed a close correlation with the degradation rate of the 1-β anomer. Comparison of optimised geometries between the two series of conjugates revealed differences in hydrogen bonding which may further explain the differences in reactivity observed. Together, these models may find application in drug discovery for prediction of acyl glucuronide and glucoside metabolite behaviour.
Social camouflaging (hereafter camouflaging) in autism includes factors such as masking and compensating for one's neurodevelopmental differences, and to assimilate or 'fit in' with non-autistic peers. Efforts to hide one's authentic self and autism traits (masking) resemble impression management (IM) in safety behaviours identified in Clark and Wells' (1995) cognitive model of social anxiety (SA). This study explores the relationship between camouflaging in autism and safety behaviours in SA among autistic and non-autistic adolescents. One hundred fifteen adolescents (14-19 years) with (n = 61; 36 female) and without (n = 54; 37 female) a clinical diagnosis of autism matched on age and SA symptom severity were recruited from clinics, schools and online. Adolescents completed online measures including autism traits, SA symptoms, camouflaging behaviours, SA-related safety behaviours and SA-related negative cognitions. Partial and bivariate Pearson's correlations and structural equation modelling were used to understand the relationship between camouflaging, safety behaviours, autism traits and SA in both groups. Exploratory factor analysis assessed item-level factor cross-loadings between camouflaging and safety behaviours. Across both groups, masking and IM were significantly associated with SA symptom severity, not autism traits, via SA-related social cognitions. Exploratory factor analysis indicated construct overlap across masking, assimilation, IM and avoidance behaviours and identified factors analogous to self-focused attention, social avoidance and mental rehearsal identified in the Clark and Wells' (1995) model of SA. This is the first study using group-matched design to identify that masking (factor in social camouflaging) and IM both relate to SA in autistic and non-autistic adolescents. Assessment and formulation of construct overlap between masking and IM may inform psychoeducation and adaptation of SA treatment for autistic adolescents.
The wide uptake of anterior right thoracotomy (ART) as an approach for aortic valve replacement (AVR) has been limited despite initial reports of its use in 1993. Compared with median sternotomy, and even ministernotomy, ART is considered to be less traumatic to the chest wall and to help facilitate quicker patient recovery. In this statement, a consensus agreement is outlined that describes the potential benefits of the ART AVR. The technical considerations that require specific attention are described and the initiation of an ART programme at a UK centre is recommended through simulation and/or use of specialist instruments in conventional cases. The use of soft tissue retractors, peripheral cannulation, modified aortic clamping and the use of intraoperative adjuncts, such as sutureless valves and/or automated knot fasteners, are important to consider in order to circumvent the challenges of minimal the altered exposure via an ART.A coordinated team-based approach that encourages ownership of the programme by team members is critical. A designated proctor/mentor is also recommended. The organisation of structured training and simulation, as well as planning the initial cases are important steps to consider.
Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.
Inflammation-related proteins constitute a promising avenue in studying biological correlates of major depressive disorder (MDD). However, MDD is a heterogeneous condition - a crucial aspect to be considered in association studies. We examined whether inflammatory proteins are associated with categorical diagnosis, a dimensional total sum-score, and specific depressive symptoms among youths. We analyzed data from the 1993 Pelotas Birth Cohort, a population-based study in Brazil that followed individuals up to age 22 years. Categorical psychiatric diagnoses were derived using adapted modules of the Mini International Neuropsychiatric Interview (MINI). Dimensional symptomatology was assessed using the Brazilian Portuguese version of the Center for Epidemiological Studies-Depression Scale-Revised (CESD-R). We estimated network structures that included individual depressive symptoms as measured by CESD-R items, peripheral inflammatory markers (C-Reactive Protein [CRP] and Interleukin-6 [IL-6]), as well as relevant covariates. We evaluated 2586 participants (mean age = 22.5[SD = 0.33]) There were no associations between concentrations of inflammatory proteins and categorical diagnosis of MDD or with CESD-R total sum-scores. In symptom-specific analysis, CRP and IL-6 were positively connected to somatic and cognitive items. We found cross-sectional connections of two commonly studied inflammatory proteins and specific depressive symptoms. Conducting symptom-specific analyses in relation to biological markers might advance our understanding of the heterogeneity of MDD.