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Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA) biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies) that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies.

Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals., Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C., Design, Setting, and Participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions., Exposures: COVID-19 vaccination after MIS-C diagnosis., Main Outcomes and Measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables., Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C., Conclusions and Relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.

The study of the membrane protein, CD24, and its emerging role in major disease processes, has made a huge leap forward in the past two decades. It appears to have various key roles in oncogenesis, tumor progression and metastasis, stem cell maintenance and immune modulation. First described in the 1980s as the homologous human protein to the mouse HSA (Heat Stable Antigen), it was reported as a surface marker in developing hematopoietic cell lines. The later discovery of its overexpression in a large number of human neoplasms, lead cancer researchers to discover its various active roles in critical checkpoints during cancer development and progression. Targeting CD24 in directed drug development showed promising results in cancer treatment. More recently, the chimeric CD24-Fc protein has shown exciting results in clinical trials as a specific modulator of auto-inflammatory syndromes. This report is aimed to summarize the relevant literature on CD24 and tie it together with recent advancements in cardiovascular research. We hypothesize that CD24 is a promising focus of research in the understanding of cardiovascular disease processes and the development of novel biological therapies.

Background: Co-existence of eating disorders and NSSI, suicide attempts and ideations is well established yet much is not known about the personality traits and behavioral tendencies that maintain this relationship. To this date no empirical work has been produced that offers a multifactorial view on the contributing variables to the occurrence of self-harm behaviors in EDs., Method: Binge eating, depression, impulsivity, ruminations and loss aversion were assessed in a sample of 93 patients diagnosed with Anorexia-Nervosa and Bulimia-Nervosa and other EDs with a history of NSSI and suicide attempts., Results: Binge eating was found to be a predictor of depression, which in turn was found to be related to NSSI frequency, suicide attempts and suicide ideations. Ruminations were found to mediate a relationship between depression and suicide ideations. Trait impulsivity predicted suicide attempts, while the attentional construct of impulsivity was associated to suicide ideations as well as attempts. Higher loss aversion was positively associated with NSSI frequency and suicide ideations., Conclusion: Our findings suggest that trait and state aspects of impulsivity are related to different self-harm behaviors in EDs. Exploring these differences is potentially of great value in understanding the process of transition from suicidal ideation to suicide attempt and the process of NSSI and may assist clinicians formulate better interventions for patients with EDs at risk. Ways in which individual findings in our model correspond with previous research and future implications are discussed., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study examined the moderating role of loss aversion (LA) on the relationship between impulsivity, nonsuicidal self-injury (NSSI), suicidal attempts, and ideations among Eating Disorder (ED) patients. Methods: Data was collected on 81 ED patients and 37 healthy controls. ED patients were divided into 2 groups: 25 AN-Rs, 56 AN-BPs and BNs. Measurements of trait impulsivity, LA, NSSI, suicide attempts, and suicide ideations were collected. Results: The rate of attempting suicide was highest in the AN-BP/BN (34.8%), lower in the AN-Rs (8%), and the lowest in the controls (2.7%). Suicide ideation was also higher in AN-BP/BN compared to both AN-R and controls. NSSI was higher in the AN-BP/BN group compared to both AN-R and control groups. LA scores were lower among participants with EDs compared to controls. BMI and depression were positively associated with suicide ideation and NSSI. Impulsivity was associated to suicide attempt and suicide ideation. Contrary to our hypothesis, LA scores were positively correlated with NSSI and SI. A stepwise regression revealed that contradictory to our hypothesis, higher LA predicted NSSI prevalence severity of NSSI and suicide ideation. Limitations: (1) Cross-sectional design; (2) Relatively small sample size of clinical subjects and only female participants; (3) Heterogeneity of treatment status. Conclusions: EDs are associated with lower levels of LA compared to general population. Although high LA is considered a protective factor against "high damage" decisions, it may serve as a facilitator of lower risk decisions which help the individual soothe and communicate his or her own suffering such as NSSI., (Copyright © 2019 Sagiv, Hadlaczky, Sheetrit, Gur, Horesh and Gvion.)

Chronic transfusion therapy (CTT) for sickle cell disease (SCD) reduces disease morbidity by suppressing the amount of circulating hemoglobin S (HbS)-containing red blood cells (RBC). The effectiveness of CTT depends on the rate of RBC clearance. Glucose-6-phosphate dehydrogenase (G6PD) deficient donor RBC may exhibit increased hemolysis, but it is unknown if transfusion of these units results in less effective transfusion outcomes in SCD. Children with SCD on CTT were followed prospectively for multiple transfusions. G6PD activity of transfused units was measured prior to expiration date. HbA clearance (ΔHbA) was calculated as the difference of estimated posttransfusion HbA to the pretransfusion HbA of the subsequent transfusion episode. Sixty-two patients received 388 transfusions. Of 755 RBC units, 687 (91%) had normal G6PD (>60% activity), 38 (5%) had moderately low G6PD (10-60% activity), and 30 (4%) had severely low G6PD (<10% activity). Of 358 evaluable transfusions, 54 (15%) included ≥1 G6PD deficient units, and 22 (6%) had ≥1 severely deficient units. The proportion of the transfusion episode consisting of G6PD deficient units was associated with increased ΔHbA for all G6PD deficient units (P = .05) and for severely G6PD deficient units (P = .0070). In multivariate mixed effects modeling, ΔHbA was positively associated with severely G6PD deficient units (P = .0074) and RBC alloimmunization (P = .03) and negatively associated with recipient splenectomy (P = .015). Higher ΔHbA was associated with higher HbS and reticulocyte counts at the subsequent transfusion episode. In conclusion, G6PD deficient RBC transfusions may have shorter in vivo survival and adversely affect the suppression of sickle erythropoiesis., (© 2018 Wiley Periodicals, Inc.)

CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogen-activated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer.

Purpose: Cyclooxygenase-2 inhibitor (celecoxib, Pfizer) is a promising chemopreventive agent, yet its long-term use may be limited due to increased cardiovascular toxicity. This study was aimed to identify genes and pathways involved in colorectal tumorigenesis and affected by celecoxib., Experimental Design: Normal rat enterocytes (IEC18 cells) and their Ras-transformed derivatives (R1) were exposed for 72 h or over 6 months to celecoxib and analyzed for gene expression pattern using Genechip (RG-U34). Cluster and pathway analyses were done using GeneSpring software and Gene Ontology database. Cyclin D1 was overexpressed in IEC18 cells using stable transfection; cell cycle and prostaglandin synthesis were assessed., Results: Five hundred thirty-eight genes were differentially expressed after transformation, and 70 and 126 genes, respectively, were affected by short and long treatments with celecoxib. Clusters of expression showed different expression in the transformed cells that revert to normal after treatment; they included Ras/Erk/Ral-B, Jagged2/Notch, calcineurin, lysyl-oxidase, etc. Cyclin D1 is up-regulated under the Ras pathway and is down-regulated by celecoxib. Thus, we showed that cyclin D1-transformed cells are resistant to inhibition by celecoxib. Celecoxib was also shown to work via cyclooxygenase-2 inhibition in transformed cells., Conclusions: Celecoxib selectively affects transformed and not normal enterocytes by targeting genes and pathways that are involved in the transformation. Thus, an alternative mechanism is proposed for the cancer-preventive role of celecoxib other than the classic mechanism of inhibiting prostaglandin synthesis, stressing mainly the role of cyclin D1. These data may help in the development of safer and more effective preventive drugs.

The adenomatous polyposis coli or beta-catenin genes are frequently mutated in colorectal cancer cells, resulting in oncogenic activation of beta-catenin signaling. We tried to establish in vitro and in vivo models for selectively killing human cancer cells with an activated beta-catenin/T-cell factor (Tcf) pathway. We used a recombinant adenovirus that carries a lethal gene [p53-up-regulated modulator of apoptosis (PUMA)] under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) to selectively target human colorectal cancer cells (SW480, HCT116, DLD-1, and LS174T), hepatocellular carcinoma (HepG2), and gastric cancer cells (AGS) in which the beta-catenin/Tcf pathway is activated, and compared its efficiency in killing cancer cells in which this pathway is inactive or only weakly active. AdFOP-PUMA, carrying a mutant Tcf-binding site, was used as control virus. The combined effect of AdTOP-PUMA with several chemotherapeutic agents (5-florouracil, doxorubicin, and paclitaxel) was also evaluated. The effect of AdTOP-PUMA on colorectal cancer cells was also examined in nude mice: SW480 cells were infected with the AdTOP-PUMA and AdFOP-PUMA, and then inoculated s.c. into nude mice. The TOP-PUMA adenovirus inhibited cell growth in a dose-dependent fashion, depending on the signaling activity of beta-catenin. The growth of cells displaying high levels of active beta-catenin/Tcf signaling was inhibited after infection with AdTOP-PUMA, whereas that of cells with low levels of beta-catenin signaling was not. Growth inhibition was associated with induction of apoptosis. Chemotherapy synergistically enhanced the effect of AdTOP-PUMA. A combination of the adenovirus system with standard therapy may improve the efficacy and reduce the toxicity of therapy in humans.

Background & Aims: The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines., Methods: Gene expression array analysis ([RG-U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase-2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas). Human cancer cell lines were tested for their response to anti-CD24 monoclonal antibodies., Results: A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6%). Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose- and time-dependent manners. These results were repetitive for 3 different antibodies., Conclusions: CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy.