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Kidney organoids are a promising model to study kidney disease, but their use is constrained by limited knowledge of their functional protein expression profile. Here, we define the organoid proteome and transcriptome trajectories over culture duration and upon exposure to TNFα, a cytokine stressor. Older organoids increase deposition of extracellular matrix but decrease expression of glomerular proteins. Single cell transcriptome integration reveals that most proteome changes localize to podocytes, tubular and stromal cells. TNFα treatment of organoids results in 322 differentially expressed proteins, including cytokines and complement components. Transcript expression of these 322 proteins is significantly higher in individuals with poorer clinical outcomes in proteinuric kidney disease. Key TNFα-associated protein (C3 and VCAM1) expression is increased in both human tubular and organoid kidney cell populations, highlighting the potential for organoids to advance biomarker development. By integrating kidney organoid omic layers, incorporating a disease-relevant cytokine stressor and comparing with human data, we provide crucial evidence for the functional relevance of the kidney organoid model to human kidney disease.
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Enfermedades Renales , Factor de Necrosis Tumoral alfa , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Proteoma/metabolismo , Riñón , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Organoides/metabolismoRESUMEN
The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.
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Glomeruloesclerosis Focal y Segmentaria , Nefrología , Nefrosis Lipoidea , Síndrome Nefrótico , Humanos , Glomeruloesclerosis Focal y Segmentaria/patología , Nefrosis Lipoidea/diagnóstico , Inhibidor Tisular de Metaloproteinasa-1 , Síndrome Nefrótico/diagnóstico , Factores de Necrosis Tumoral/uso terapéuticoRESUMEN
Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.
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Glomeruloesclerosis Focal y Segmentaria , Fallo Renal Crónico , Síndrome Nefrótico , Adolescente , Adulto , Apolipoproteína L1 , Niño , Estudios de Cohortes , Femenino , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Humanos , Riñón/patología , Fallo Renal Crónico/complicaciones , Masculino , Síndrome Nefrótico/tratamiento farmacológico , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. METHODS: Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. RESULTS: Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3ß, resulting in dysregulated calcineurin activity and apoptosis. CONCLUSIONS: These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3ß, in the treatment of FSGS.
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BACKGROUND: Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism. METHODS: Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study. RESULTS: Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation. CONCLUSIONS: Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants' parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally.
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Trastorno Depresivo Mayor , Adulto , Amígdala del Cerebelo , Depresión , Emociones , Humanos , Estudios Longitudinales , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Longitudinal studies of children with disruptive disorders (DDs) have shown high rates of antisocial personality disorder (ASPD) and substance use in adulthood, but few have examined the contribution of parental disorders. We examine child-/adulthood outcomes of DDs in offspring, whose biological parents did not have a history of ASPD, bipolar disorder, or substance use disorders. METHOD: Offspring (Nâ¯=â¯267) of parents with or without major depression (MDD), but no ASPD or bipolar disorders were followed longitudinally over 33 years, and associations between DDs and psychiatric and functional outcomes were tested. RESULTS: Eighty-nine (33%) offspring had a DD. Those with, compared to without DDs, had higher rates of MDD (adjusted odds ratio, AORâ¯=â¯3.42, pâ¯<â¯0.0001), bipolar disorder (AORâ¯=â¯3.10, pâ¯=â¯0.03), and substance use disorders (AORâ¯=â¯5.69, pâ¯<â¯0.0001) by age 18, as well as poorer school performance and global functioning. DDs continued to predict MDD and substance use outcomes in adulthood, even after accounting for presence of the corresponding disorder in childhood (MDD: hazards ratio, HRâ¯=â¯3.25, pâ¯<â¯0.0001; SUD, HRâ¯=â¯2.52, pâ¯<â¯0.0001). Associations were similar among the offspring of parents with and without major depression. DDs did not predict adulthood ASPD in either group. LIMITATIONS: Associations are largely accounted for by conduct disorder (CD), as there were few offspring with ADHD, and oppositional defiant disorder (ODD) was not diagnosed at the time this study began. CONCLUSION: If there is no familial risk for ASPD, bipolar disorder or substance use, childhood DDs do not lead to ASPD in adulthood; however, the children still have poorer prognosis into midlife. Early treatment of children with DD, particularly CD, while carefully considering familial risk for these disorders, may help mitigate later adversity.
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Hijo de Padres Discapacitados/psicología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/epidemiología , Adolescente , Adulto , Trastorno de Personalidad Antisocial/epidemiología , Trastorno Bipolar/epidemiología , Estudios de Casos y Controles , Niño , Trastorno de la Conducta/epidemiología , Trastorno Depresivo Mayor/epidemiología , Femenino , Humanos , Masculino , Oportunidad Relativa , Trastornos Relacionados con Sustancias/epidemiología , Adulto JovenRESUMEN
The personal importance of religion or spirituality (R/S) has been associated with a lower risk for major depression (MDD), suicidal behavior, reduced cortical thinning and increased posterior EEG alpha, which has also been linked to antidepressant treatment response in MDD. Building on prior event-related potential (ERP) findings using an emotional hemifield paradigm, this study examined whether abnormal early (preconscious) responsivity to negative arousing stimuli, which is indicative of right parietotemporal dysfunction in both MDD patients and individuals at clinical high risk for MDD, is likewise moderated by R/S. We reanalyzed 72-channel ERP data from 127 individuals at high or low family risk for MDD (Kayser et al., 2017, NeuroImage Clin. 14, 692-707) after R/S stratification (low R/S importance, low/high risk, n = 38/61; high R/S importance, n = 15/13). ERPs were transformed to reference-free current source density (CSD) and quantified by temporal principal components analysis (tPCA). This report focused on N2 sink (peak latency 212 ms), the earliest prominent CSD-tPCA component previously found to be sensitive to emotional content. While overall N2 sink reflected activation of occipitotemporal cortex (prestriate/cuneus), as estimated via a distributed inverse solution, affective significance was marked by a relative (i.e., superimposed) positivity. Statistical analyses employed both non-parametric permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including sex, age, and clinical covariates. Participants with low R/S importance, independent of risk status, showed greater ERP responsivity to negative than neutral stimuli, particularly over the right hemisphere. In contrast, early emotional ERP responsivity and asymmetry was substantially reduced for high risk individuals with high R/S importance, however, enhanced for low risk individuals with high R/S importance. Hemifield modulations of these effects (i.e., emotional ERP enhancements with left visual field/right hemisphere stimulus presentations) further corroborated these observations. Results suggest down-regulation of a right-lateralized network for salience detection at an early processing stage in high risk and high R/S importance individuals, presumably to prevent overactivation of ventral brain regions further downstream. These findings may point to a neurophysiological mechanism underlying resilience of families at risk for depression with high R/S prioritization.
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INTRODUCTION: In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children. METHODS: Seeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients. RESULTS: Homozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS. CONCLUSION: NPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.
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A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.
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Alelos , Hipopituitarismo/genética , Proteínas de la Membrana/genética , Fenotipo , Retinitis Pigmentosa/genética , Adulto , Codón sin Sentido , Heterocigoto , Humanos , Hipopituitarismo/patología , Masculino , Mutación Missense , Empalme del ARN , Retinitis Pigmentosa/patologíaRESUMEN
OBJECTIVE: We previously identified posterior EEG alpha as a potential biomarker for antidepressant treatment response. To meet the definition of a trait biomarker or endophenotype, it should be independent of the course of depression. Accordingly, this report evaluated the temporal stability of posterior EEG alpha at rest. METHODS: Resting EEG was recorded from 70 participants (29 male; 46 adults), during testing sessions separated by 12⯱â¯1.1â¯years. EEG alpha was identified, separated and quantified using reference-free methods that combine current source density (CSD) with principal components analysis (PCA). Measures of overall (eyes closed-plus-open) and net (eyes closed-minus-open) posterior alpha amplitude and asymmetry were compared across testing sessions. RESULTS: Overall alpha was stable for the full sample (Spearman-Brown [rSB]â¯=â¯.834, Pearson's râ¯=â¯.718), and showed excellent reliability for adults (rSBâ¯=â¯.918; râ¯=â¯0.848). Net alpha showed acceptable reliability for adults (rSBâ¯=â¯.750; râ¯=â¯.600). Hemispheric asymmetries (right-minus-left hemisphere) of posterior overall alpha showed significant correlations, but revealed acceptable reliability only for adults (rSBâ¯=â¯.728; râ¯=â¯.573). Findings were highly comparable between 29 male and 41 female participants. CONCLUSIONS: Overall posterior EEG alpha amplitude is reliable over long time intervals in adults. SIGNIFICANCE: The temporal stability of posterior EEG alpha oscillations at rest over long time intervals is indicative of an individual trait.
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Ritmo alfa/fisiología , Corteza Cerebral/fisiología , Análisis de Componente Principal , Adolescente , Adulto , Niño , Preescolar , Electroencefalografía/métodos , Electroencefalografía/tendencias , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: A biological marker of vulnerability should precede onset of illness and be independent of disease course. We previously reported that cortical thinning may serve as a potential biomarker for risk for familial depression. We now test stability of the cortical thinning across 8 years, and whether thinning mediates associations between familial risk and depressive traits. METHOD: Participants were from a 3-generation family study of depression, where 2nd and 3rd generation offspring were characterized as being at high- or low-risk for depression based on the presence/absence of major depression in the 1st generation. The analysis includes 82 offspring with anatomical MRI scans across two assessment waves, 7.8 (S.D.1.3, range: 5.2-10.9) years apart. RESULTS: High-risk offspring had thinner bilateral superior and middle frontal gyri, and left inferior parietal lobule, at both time-points. High intra-subject correlation (0.60
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Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10-5 for novel LOF, increased to p = 4.1 × 10-6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10-7). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.
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Anomalías Congénitas/genética , Exoma/genética , Enfermedades Renales/congénito , Riñón/anomalías , Mutación/genética , Proteínas de Neoplasias/genética , Alelos , Animales , Estudios de Casos y Controles , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Femenino , Heterogeneidad Genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Herencia/genética , Homocigoto , Humanos , Enfermedades Renales/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Fenotipo , ARN Largo no Codificante/genética , Sistema Urinario/anomalías , Anomalías Urogenitales/genética , Pez CebraRESUMEN
OBJECTIVE: To examine potential neural substrates that underlie the interplay between religiosity/spirituality and risk-for-depression. A new wave of data from a longitudinal, three generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. MEASURES PARTICIPANTS AND METHODS: Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. Religiosity/spirituality measures were collected at the same time as the MRI scans and comprised self-report ratings of personal religious/spiritual (R/S) importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of religiosity/spirituality and risk-for-depression were examined on measures of cortical thickness and cortical surface area. RESULTS: A high degree of belief in the importance of religion/spirituality was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. CONCLUSIONS AND RELEVANCE: The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to religious/spiritual individuals at high risk for depression.
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Behavioral and electrophysiologic evidence suggests that major depression (MDD) involves right parietotemporal dysfunction, a region activated by arousing affective stimuli. Building on prior event-related potential (ERP) findings (Kayser et al. 2016 NeuroImage 142:337-350), this study examined whether these abnormalities also characterize individuals at clinical high risk for MDD. We systematically explored the impact of family risk status and personal history of depression and anxiety on three distinct stages of emotional processing comprising the late positive potential (LPP). ERPs (72 channels) were recorded from 74 high and 53 low risk individuals (age 13-59 years, 58 male) during a visual half-field paradigm using highly-controlled pictures of cosmetic surgery patients showing disordered (negative) or healed (neutral) facial areas before or after treatment. Reference-free current source density (CSD) transformations of ERP waveforms were quantified by temporal principal components analysis (tPCA). Component scores of prominent CSD-tPCA factors sensitive to emotional content were analyzed via permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including gender, age and clinical covariates. Factor-based distributed inverse solutions provided descriptive estimates of emotional brain activations at group level corresponding to hierarchical activations along ventral visual processing stream. Risk status affected emotional responsivity (increased positivity to negative-than-neutral stimuli) overlapping early N2 sink (peak latency 212 ms), P3 source (385 ms), and a late centroparietal source (630 ms). High risk individuals had reduced right-greater-than-left emotional lateralization involving occipitotemporal cortex (N2 sink) and bilaterally reduced emotional effects involving posterior cingulate (P3 source) and inferior temporal cortex (630 ms) when compared to those at low risk. While the early emotional effects were enhanced for left hemifield (right hemisphere) presentations, hemifield modulations did not differ between risk groups, suggesting top-down rather than bottom-up effects of risk. Groups did not differ in their stimulus valence or arousal ratings. Similar effects were seen for individuals with a lifetime history of depression or anxiety disorder in comparison to those without. However, there was no evidence that risk status and history of MDD or anxiety disorder interacted in their impact on emotional responsivity, suggesting largely independent attenuation of attentional resource allocation to enhance perceptual processing of motivationally salient stimuli. These findings further suggest that a deficit in motivated attention preceding conscious awareness may be a marker of risk for depression.
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Depresión/complicaciones , Emociones/fisiología , Potenciales Evocados/fisiología , Lateralidad Funcional/fisiología , Motivación/fisiología , Adolescente , Adulto , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estimulación Luminosa , Análisis de Componente Principal , Campos Visuales/fisiología , Adulto JovenRESUMEN
A prior report (Tenke et al., 2013 Biol. Psychol. 94:426-432) found that participants who rated religion or spirituality (R/S) highly important had greater posterior alpha after 10 years compared to those who did not. Participants who subsequently lowered their rating also had prominent alpha, while those who increased their rating did not. Here we report EEG findings 20 years after initial assessment. Clinical evaluations and R/S ratings were obtained from 73 (52 new) participants in a longitudinal study of family risk for depression. Frequency PCA of current source density transformed EEG concisely quantified posterior alpha. Those who initially rated R/S as highly important had greater alpha compared to those who did not, even if their R/S rating later increased. Furthermore, changes in religious denomination were associated with decreased alpha. Results suggest the possibility of a critical stage in the ontogenesis of R/S that is linked to posterior resting alpha.
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Ritmo alfa/fisiología , Electroencefalografía/métodos , Religión , Espiritualidad , Adulto , Depresión/psicología , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Factores de Riesgo , Identificación SocialRESUMEN
BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).