Selective Defect Research Articles

Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.

Defects, Entropy, and the Stabilization of Alternative Phase Boundary Orientations in Battery Electrode Particles

Using a novel statistical approach that efficiently explores the space of possible defect configurations, the present study investigates the chemomechanical coupling between interfacial structural defects and phase boundary alignments within phase‐separating electrode particles. Applied to the battery cathode material LiXFePO4 as an example, the theoretical analysis reveals that small, defect‐induced deviations from an ideal interface can lead to dramatic shifts in the orientations of phase boundaries between Li‐rich and Li‐lean phases, stabilizing otherwise unfavorable orientations. Significantly, this stabilization arises predominantly from configurational entropic factors associated with the presence of the interfacial defects rather than from absolute energetic considerations. The specific entropic factors pertain to the diversity of defect configurations and their contributions to rotational/orientational rigidity of phase boundaries. Comparison of the predictions with experimental observations indicates that the additional entropy contributions indeed play a dominant role under actual cycling conditions, leading to the conclusion that interfacial defects must be considered when analyzing the stability and evolution kinetics of the internal phase microstructure of strongly phase‐separating systems. Possible implications for tuning the kinetics of (de)lithiation based on selective defect incorporation are discussed. This understanding can be generalized to the chemomechanics of other defective solid phase boundaries.

Perichondrial Cutaneous Grafts in Facial Reconstruction

ABSTRACT Aim: The purpose of this study is to review the indications, techniques, advantages, and outcomes of perichondrial cutaneous grafts (PCCG). Background The PCCG is a composite graft utilized in the reconstruction of select head and neck defects. This graft, much studied and popularized by Dr Frederick Stucker, has several intrinsic benefits due to its size, thickness, contour, and unique perichondrial layer. Results The PCCG is primarily utilized in the reconstruction of nasal and lower eyelid defects. This graft has been demonstrated to yield superior results to a full-thickness skin graft (FTSG) in these cosmetically sensitive locations and has the convenience of a single-stage procedure that may be performed under local anesthesia in contrast to a paramedian forehead flap (PMFF). Animal studies have shown less contraction in comparison to FTSGs. Large case series have reported low rates of graft loss and good esthetic outcomes. Conclusion The PCCG is an option to consider in the reconstruction of select head and neck defects, as it tends to offer excellent cosmetic results and minimal morbidity. Clinical significance The PCCG has several advantages over a FTSG for moderate to large defects of the face, and is an excellent reconstructive option for nasal defects in which a PMFF may not be a viable option. How to cite this article Bizzell JG, Boyette JR. Perichondrial Cutaneous Grafts in Facial Reconstruction. Int J Head Neck Surg 2016;7(3):182-187.

Seed Dormancy in Arabidopsis Is Controlled by Alternative Polyadenylation of DOG1.

DOG1 (Delay of Germination 1) is a key regulator of seed dormancy in Arabidopsis (Arabidopsis thaliana) and other plants. Interestingly, the C terminus of DOG1 is either absent or not conserved in many plant species. Here, we show that in Arabidopsis, DOG1 transcript is subject to alternative polyadenylation. In line with this, mutants in RNA 3' processing complex display weakened seed dormancy in parallel with defects in DOG1 proximal polyadenylation site selection, suggesting that the short DOG1 transcript is functional. This is corroborated by the finding that the proximally polyadenylated short DOG1 mRNA is translated in vivo and complements the dog1 mutant. In summary, our findings indicate that the short DOG1 protein isoform produced from the proximally polyadenylated DOG1 mRNA is a key player in the establishment of seed dormancy in Arabidopsis and characterizes a set of mutants in RNA 3' processing complex required for production of proximally polyadenylated functional DOG1 transcript.

Abstract 18132: Prenatal Evaluation of the Fetal Cardiovascular Profile Score in a Multicenter Study of Ebstein Anomaly/Tricuspid Valve Dysplasia

Introduction: The cardiovascular profile (CVP) score is an echo based multivariable approach for assessment of fetal hemodynamics. The CVP score has been shown to be useful in predicting the outcome of fetuses with heart failure, growth restriction, and select congenital heart defects. The score ranges from 0 to 10, with points deducted for abnormal hemodynamics. In a previous pilot study of 21 fetuses with EA/TVD, a CVP score <7 was associated with poor outcomes. The aim of this study was to investigate the prognostic significance of the CVP score in a larger cohort of fetuses with EA/TVD. Methods: This 23-center study was a retrospective review of fetal echo data and outcomes in a cohort of 243 fetuses diagnosed with EA/TVD from 2005-2011. Both the first and last fetal echo in gestation were evaluated. Hydrops, heart size, cardiac function, and umbilical arterial and venous Dopplers were scored. The primary outcome was perinatal death, defined as fetal demise or death prior to neonatal discharge. Categorical variables were compared using Chi-squared tests; p-values <0.05 were considered statistically significant. Results: Complete data on the first and last fetal echocardiograms to calculate a CVP score were available in 144 fetuses at the time of the first fetal echo (median GA 26.07 wks, range 14-40) and 73 fetuses at the time of the last fetal echo (median GA: 25 wks, range 18 -34). The median CVP scores for the first and last fetal echo were 8 (range 4-9) and 7 (range 7-9) among survivors vs. 7 (range 0-10) and 6 (range 1-8) among non-survivors. Fetuses with EA/TVD that died were more likely to have a CVP score <7 compared to those that survived: 33.3% vs. 11.6 %, (p=0.004) on the first fetal echo and 60.0% vs. 28.6 % (p=0.015) on the last fetal echo. However, no statistically significant difference in survival was observed for fetuses whose CVP score decreased from the first to the last echo. (p=0.95). Conclusions: In this study, fetuses with EA/TVD with CVP scores <7 on the first or last fetal echo were less likely to survive. The CVP score may be a valuable tool to identify fetuses with EA/TVD at risk of poor outcome for whom novel therapeutic approaches might be warranted.

Abstract 19967: Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis

Objective: Reactive oxygen species (ROS) generated from activated platelets is known to regulate platelet activation. However, it remains unclear whether and how different isoforms of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases (NOXs) play roles in different platelet activation pathways. Here we investigated the role of NOX1 and NOX2 in different platelet activation pathways using NOX1 and NOX2 knockout mice. Approach and Results: NOX1-/- platelets showed selective defects in G protein coupled receptor (GPCR)-mediated platelet activation induced by thrombin, protease-activated receptor 4 agonist peptide (PAR4AP) and thromboxane A2 analog U46619, but was not affected in platelet activation induced by collagen-related peptide (CRP), a glycoprotein VI (GPVI) agonist. In contrast, NOX2-/- platelets showed potent inhibition of CRP-induced platelet activation, and also showed partial inhibition of thrombin-induced platelet aggregation and secretion. Consistently, production of reactive oxygen species (ROS) was inhibited in NOX1-/- platelets stimulated with thrombin, but not CRP, whereas NOX2-/- platelets showed reduced ROS generation induced by CRP or thrombin. Interestingly, laser-induced arterial thrombosis was impaired in NOX2-/- mice, and in thrombocytopenic mice transfused with NOX2-/- platelets, suggesting an important role for NOX2-dependent platelet ROS production in the laser-induced injury model of thrombosis. Conclusions: NOX1 and NOX2 play differential roles in different platelet activation pathways: NOX1 mediates GPCR-mediated ROS production and platelet activation, whereas NOX2 plays a general role in GPVI- and GPCR-induced ROS production and platelet activation in vitro , and in laser-induced thrombosis in vivo .

What makes children outgrow food allergy?

What makes children outgrow food allergy?

Caenorhabditis elegans ALG-1 antimorphic mutations uncover functions for Argonaute in microRNA guide strand selection and passenger strand disposal.

MicroRNAs are regulators of gene expression whose functions are critical for normal development and physiology. We have previously characterized mutations in a Caenorhabditis elegans microRNA-specific Argonaute ALG-1 (Argonaute-like gene) that are antimorphic [alg-1(anti)]. alg-1(anti) mutants have dramatically stronger microRNA-related phenotypes than animals with a complete loss of ALG-1. ALG-1(anti) miRISC (microRNA induced silencing complex) fails to undergo a functional transition from microRNA processing to target repression. To better understand this transition, we characterized the small RNA and protein populations associated with ALG-1(anti) complexes in vivo. We extensively characterized proteins associated with wild-type and mutant ALG-1 and found that the mutant ALG-1(anti) protein fails to interact with numerous miRISC cofactors, including proteins known to be necessary for target repression. In addition, alg-1(anti) mutants dramatically overaccumulated microRNA* (passenger) strands, and immunoprecipitated ALG-1(anti) complexes contained nonstoichiometric yields of mature microRNA and microRNA* strands, with some microRNA* strands present in the ALG-1(anti) Argonaute far in excess of the corresponding mature microRNAs. We show complex and microRNA-specific defects in microRNA strand selection and microRNA* strand disposal. For certain microRNAs (for example mir-58), microRNA guide strand selection by ALG-1(anti) appeared normal, but microRNA* strand release was inefficient. For other microRNAs (such as mir-2), both the microRNA and microRNA* strands were selected as guide by ALG-1(anti), indicating a defect in normal specificity of the strand choice. Our results suggest that wild-type ALG-1 complexes recognize structural features of particular microRNAs in the context of conducting the strand selection and microRNA* ejection steps of miRISC maturation.

The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders.

The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific.

CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the D(3.49)R(3.50)Y(3.51) sequence, and all but two contain A(3.53) at the cytoplasmic terminus of the third transmembrane helix (H3C), a region within class A G protein-coupled receptors that contacts G proteins. In CXCR6, H3C contains D(3.49)R(3.50)F(3.51)I(3.52)V(3.53) at positions 126-130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individual Gi/o proteins; and the effects of mutations in H3C on receptor function and selectivity in Gi/o protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available Gi/o proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments.

Defects in Germinal Center Selection in SLE.

Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to differentiate into effector cells. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nucleic acid antigens. While defects in tolerance occur in the naïve repertoire of SLE patients, pathogenic autoantibodies also arise in the GC by somatic mutation from non-autoreactive precursors. Several B cell defects contribute to the loss of GC tolerance in SLE, including polymorphisms of genes encoded by the Sle1 locus, excess TLR7 signaling, defects in FcRIIB expression, or defects of B cell apoptosis. Extrinsic soluble factors, such as Type-1 IFN and B cell-activating factor, or an increased number of T follicular helper cells in the GC also alter B cell-negative selection. Finally, defects in clearance of apoptotic debris within the GC result in BCR-mediated internalization of nucleic acid containing material and stimulation of autoantibody production by endosomal TLR-driven mechanisms.

Recent advances in head and neck free tissue transfer.

Free tissue transfer is a versatile and valuable method for reconstructing select head and neck defects following trauma or oncologic resection. Microvascular reconstructive cases are among the longest, most technically challenging, and most labor-intensive operations performed by departments of otolaryngology/head and neck surgery. However, technical advances, increased experience, and robust training programs have permitted realization of microvascular success rates in excess of 97% at most high-volume centers. Given this unprecedented degree of success, research emphasis has shifted to advancing techniques, expanding indications, and increasing efficiencies. Although numerous topics are important for discussion, this update focuses on recent notable advances in reconstruction. These include expanding utility of the anterolateral thigh free flap in soft tissue reconstruction, prefabricated plating for fibula free flap mandibular reconstruction, use of venous couplers, and postoperative free tissue monitoring techniques. Improvements in technique, technology, and monitoring continue to improve success rates, reduce operative time and associated morbidity, improve overall functional outcomes, and improve patient-specific quality of life. These highlighted recent advances, amongst others, promote further advancement and simplification of reconstructive capabilities.

3D-imaging of selective laser melting defects in a Co–Cr–Mo alloy by synchrotron radiation micro-CT

Microstructure defects set the mechanical property limits for solid Co–Cr–Mo alloy prepared by selective laser melting (SLM). Previous studies were mainly based on 2D SEM images and thus not able to provide information of the 3D morphologies of the complex defects. In this paper, the remaining porosities in Co–Cr–Mo alloy parts prepared by selective laser melting were presented in relation to the laser processing parameters. In order to understand the defect forming mechanism, accurate 3D images of defects inside SLM fabricated Co–Cr–Mo samples were provided by synchrotron radiation micro-CT imaging of 300μm thick slices cut from a 10mm cube. With 3D reconstructed images distinctive morphologies of SLM defects spanning across the consolidated powder layers were generated. The faults can be classified as single layer or multi-layers defects. The accidental single layer defects form as gaps between adjacent laser melt tracks or melt track discontinuousness caused by inherent fluid instability under various disturbances. The first formed single layer defect generates often a multi-layer defect spanning for 2–3 subsequent powder layers. By stabilizing the melt pool flow and by reducing the surface roughness through adjusting processing parameters it appears possible to reduce the defect concentrations.

Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports

Objective To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects...

Leptin receptor signaling in T cells is required for Th17 differentiation.

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function.

Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.

The intracellular parasite Toxoplasma gondii depends on the synthesis of long-chain and very long-chain unsaturated fatty acids not supplied by the host cell.

Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed intracellular parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the parasite and availability of specific fatty acids in the host cell that the parasite has to close using a dedicated synthesis and modification pathway.

Elucidation of the EP defect in Diamond-Blackfan anemia by characterization and prospective isolation of human EPs

AbstractDiamond-Blackfan anemia (DBA) is a disorder characterized by a selective defect in erythropoiesis. Delineation of the precise defect is hampered by a lack of markers that define cells giving rise to erythroid burst- and erythroid colony-forming unit (BFU-E and CFU-E) colonies, the clonogenic assays that quantify early and late erythroid progenitor (EEP and LEP) potential, respectively. By combining flow cytometry, cell-sorting, and single-cell clonogenic assays, we identified Lin−CD34+CD38+CD45RA−CD123−CD71+CD41a−CD105−CD36− bone marrow cells as EEP giving rise to BFU-E, and Lin−CD34+/−CD38+CD45RA−CD123−CD71+CD41a−CD105+CD36+ cells as LEP giving rise to CFU-E, in a hierarchical fashion. We then applied these definitions to DBA and identified that, compared with controls, frequency, and clonogenicity of DBA, EEP and LEP are significantly decreased in transfusion-dependent but restored in corticosteroid-responsive patients. Thus, both quantitative and qualitative defects in erythroid progenitor (EP) contribute to defective erythropoiesis in DBA. Prospective isolation of defined EPs will facilitate more incisive study of normal and aberrant erythropoiesis.

Defective natural killer cell anti-viral capacity in paediatric HBV infection.

Natural killer (NK) cells exhibit dysregulated effector function in adult chronic hepatitis B virus (HBV) infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK cell frequency, phenotype and function in HBV-infected children relative to uninfected children. We observed a selective defect in NK cell interferon (IFN)-γ production, with conserved cytolytic function, mirroring the functional dichotomy observed in adult infection. Reduced expression of NKp30 on NK cells suggests a role of impaired NK-dendritic cell (DC) cellular interactions as a potential mechanism leading to reduced IFN-γ production. The finding that NK cells are already defective in paediatric CHB, albeit less extensively than in adult CHB, has potential implications for the timing of anti-viral therapy aiming to restore immune control.

Sertraline use during pregnancy and the risk of major malformations

Given the current debate and growing public concerns on selective serotonin reuptake inhibitors (SSRIs) and birth defects generated by Food and Drug Administration warnings, we aim to quantify the association between first-trimester exposure to sertraline, a first-line treatment, and the risk of congenital malformations in a cohort of depressed women. This was a population-based cohort study in Quebec, Canada, 1998 through 2010. From a cohort of 18,493 depressed/anxious pregnancies, sertraline-exposed, nonsertraline SSRI-exposed, non-SSRI exposed, and unexposed (reference category) women were studied. Major malformations overall and organ-specific malformations in the first year of life were identified. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Analyses were adjusted for potential confounders. Among the 18,493 eligible pregnancies, 366 were exposed to sertraline, 1963 to other SSRIs, and 1296 to non-SSRI antidepressants during the first trimester of pregnancy. Sertraline use was not statistically significantly associated with the risk of overall major malformations when compared to nonuse of antidepressants. However, sertraline exposure was associated with an increased risk of atrial/ventricular defects specifically (risk ratio [RR], 1.34; 95% CI, 1.02-1.76; 9 exposed cases), and craniosynostosis (RR, 2.03; 95% CI, 1.09-3.75; 3 exposed cases). Exposure to SSRIs other than sertraline during the first trimester of pregnancy was associated with craniosynostosis (RR, 2.43; 95% CI, 1.44-4.11; 19 exposed cases), and musculoskeletal defects (RR, 1.28; 95% CI, 1.03-1.58; 104 exposed cases). Sertraline use during the first trimester of pregnancy was associated with an increased risk of atrial/ventricular defects and craniosynostosis above and beyond the effect of maternal depression. Nonsertraline SSRIs were associated with an increased risk of craniosynostosis and musculoskeletal defects.