Normal Siblings Research Articles

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.

Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with a small eye morphological phenotype and demonstrate that even the morphologically normal siblings exhibit dysregulated gene pathways related to vision and stress response. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities and provide insight into maternal nutritional strategies that optimize infant brain health.

Challenges to Implement the Inclusive Education in Pakistan: A Case of Intellectually Disabled Children

This study aimed to explore the current education status of Intellectually Disabled Children and the challenges to inclusion of Intellectually Disabled Children in Pakistan. Using a quantitative research approach, data was gathered from the families of students having intellectual disabilities using mother’s reports about the interaction of normal sibling with intellectually disabled children in a school environment. The findings of the study reveal that the level of warmth is much higher in the inclusive education classes as compared to the Rivalries, Relative Status and Conflicts with intellectually disabled students. A higher level of empathy increases the sense of responsibility, tolerance, and encouragement. The research strongly recommends that the educationist and professionals must initiate the teachers’ awareness programs about disabilities. Government and media can assist in spreading awareness about relationship and interactions among students by establishing awareness programs that focuses on the implementation of the inclusive education systems in Pakistan.

Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.

To investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings. This case-control study, conducted at the Schneider Children's Medical Center's Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation. Fecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (p<0.001). ISS children with higher levels of Methanobrevibacter, the dominant species in the archaeal gut community, were significantly shorter in stature than those with lower levels (p=0.022). Mice receiving fecal transplants from ISS children did not experience stunted growth, probably due to the eradication of Methanobrevibacter caused by exposure to oxygen during fecal collection. Our findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.

Beckwith-Wiedemann syndrome and twinning: case report and brief review of literature

BackgroundBeckwith-Wiedemann syndrome (BWS, OMIM #130,650) is a pediatric overgrowth disorder involving a predisposition to tumor development. Although the clinical management of affected patients is well established, it is less clear how to handle with the cases of siblings of affected patients, since the prevalence of the condition in twins (1:1000) is ten times higher than in singletones (1:10000).Case presentationWe report the case of a premature twin patient who during her follow-up develops a clinical phenotype compatible with BWS, genetically confirmed in blood. However, the methylation alteration characteristic of the condition was also found in the almost phenotypically normal sibling, making it challening her management.ConclusionThrough our case report we highlight how the diagnosis of BWS can be made without any prenatal suspicion and we propose a review of the literature on how to manage siblings of affected patients in twinning situation.

Branched-chain amino acid supplementation does not enhance lean tissue accretion in low birth weight neonatal pigs, despite lower Sestrin2 expression in skeletal muscle.

Postnatal muscle growth is impaired in low birth weight (L) neonatal pigs. Leucine supplementation has been established as a dietary intervention to enhance muscle growth in growing animals. The aim of this study was to investigate the efficacy of supplementing L neonatal pig formulas with branched-chain amino acids (B) to enhance the rate of protein accretion. Twenty-four 3-day old pigs were divided into two groups low (L) and normal birth weight (N) based on weight at birth. Pigs were assigned to a control (C) or 1% branched-chain amino acids (B) formulas, and fed at 250mL·kg body weight -1·d-1 for 28 d. Body weight of pigs in the L group was less than those in the N group (P < 0.01). However, fractional body weight was greater for L pigs compared with their N siblings from day 24 to 28 of feeding regardless of formula (P < 0.01). In addition, feed efficiency (P < 0.0001) and efficiently of protein accretion (P < 0.0001) were greater for L than N pigs regardless of supplementation. Pigs fed the B formula had greater plasma leucine, isoleucine, and valine concentrations compared with those fed the C formula (P < 0.05). Longissimus dorsi Sestrin2 protein expression was less for pigs in the L group compared with those in the N group (P < 0.01), but did not result in a corresponding increase in translation initiation signaling. Longissimus dorsi mRNAexpression of BCAT2 was less for LB pigs compared with those in the LC group, and was intermediate for NC and NB pigs (P < 0.05). Hepatic mRNA expression of BCKDHA was greater for pigs in the L compared with those in the N groups (P < 0.05). However, plasma branched-chain keto-acid concentration was reduced for C compared with those in the B group (P < 0.05). These data suggest that branched-chain amino acid supplementation does not improve lean tissue accretion of low and normal birth weight pigs, despite a reduction in Sestrin2 expression in skeletal muscle of low birth weight pigs. The modest improvement in fractional growth rate of low birth weight pigs compared with their normal birth weight siblings was likely due to a more efficient dietary protein utilization.

Identifying the genetic causes of phenotypically diagnosed Pakistani mucopolysaccharidoses patients by whole genome sequencing.

Background: Lysosomal storage disorders (LSDs) are a group of inherited metabolic diseases, which encompass more than 50 different subtypes of pathologies. These disorders are caused by defects in lysosomal enzymes, transporters, and other non-lysosomal proteins. Mucopolysaccharidosis (MPS) is the most common subgroup of lysosomal storage disorders in which the body is unable to properly breakdown mucopolysaccharides. The aim of the present study was to identify novel genes and pathogenic variants in families from diverse regions of Pakistan with clinically diagnosed mucopolysaccharidosis type I and mucopolysaccharidosis type II. Methods: Clinical diagnosis identified 12 with mucopolysaccharidosis I and 2 with mucopolysaccharidosis II in 14 families and whole genome sequencing (WGS) was performed to identify the causative variations in 15 affected individuals. Twenty-two unaffected individuals including parents or normal siblings of patients were also sequenced. Putative causal variants were identified by co-segregation and functional annotation. Results: Analysis of whole genome sequencing data revealed ten novel and six previously reported variants in lysosomal storage disorders-associated genes (IDUA, GALNS, SGSH, GAA, IDS, ALDOB, TRAPPC4, MASP1, SMARCAL, KIAA1109, HERC1, RRAS2) and a novel candidate gene (ABCA5) for lysosomal storage disorder-like phenotypes, which has previously been associated with symptoms strongly related with lysosomal storage disorder in animal models. Conclusion: Multigenic inheritance was found in several families highlighting the importance of searching for homozygous pathogenic variants in several genes also in families with a high degree of consanguinity.

Comparison of third-party disability between normal hearing siblings of children using hearing aids and those using cochlear implants

Purpose: Historically, research tends to focus on the experiences of deaf children and the difficulties faced, as well as the difficulties their parents endure. Less attention has been focused on siblings of children with hearing impairment (CWHI). This study aimed to compare the Third-Party Disability between normal hearing siblings of children using hearing aids (HAs) with those using cochlear implants (CI). The objective was to develop International Classification of Functioning, Disability and Health (ICF) based-tools across different domains and categories that describe third-party disability in siblings of children with hearing impairment. Method: 45 Normal Hearing Older Siblings (NHOS) from the two groups of children with hearing impairment using HAs and CI participated in the study. A tool was developed and mapped onto ICF components of Activities and Participation and Environmental factors. The developed tool consisting of 43-items across six-domains was administered through interviews, independent of the sibling. Frequency distribution and descriptive statistics were obtained. Shapiro-Wilk test was performed to assess normality of the distribution. Mann Whitney U test was administered to compare the domain-wise distributions for the two groups. Results: NHOS of CWHI using HAs perceive greater third-party disability as compared to the NHOS of CWHI using unilateral CI across all the six domains included in the study. The differences were striking in the domain of communication, interpersonal interaction and relationship, support and relationship. There were differences across the other three domains which were not found to be statistically significant. Conclusion: Hearing loss is a disabling condition that not only effects the individual, but is an experience shared by immediate family members including siblings. The extent of third-party disability in NHOS is influenced by the hearing device. This study has provided insights into the difficulties faced by normal hearing siblings of children with hearing impairment. Implication: Utilization of an ICF-based tool has provided an idea about the specific domains(s) in which they perceive maximum difficulties, which will help clinicians counsel parents, focusing not only on the needs and issues of the CWHI but also the hearing siblings. Keywords: children with hearing aids, children with cochlear implants, normal hearing siblings

PMON311 45,X/46,XY mixed gonadal dysgenesis: a case report from Saudi Arabia

Abstract Introduction Mixed gonadal dysgenesis is a sex developmental disorder where the gonads are abnormal from there being some cells with XY chromosomes and some with just asingle X, known as chromosome Y mosaicism. This results in a wide range of male/female genitalia that are not typically, or clearly, male or female The case: 3 years old Saudi boy was born term to 35 year old G5P5 Normal anti natal and history of consanguinity. Birth weight 2 kilogram and found to have genital ambiguity in the form of short phallus structure and hypospiadius testis were felt at the right inguinal canal. his investigation showed abnormal chromosomes 45×46XY musiac . Mother chromosomes were 46XX normal female karyotype. normal siblings and Wes WES: CNV DESCRIPTION*: seq[GRCh37] Yp11.31q11.23 (mosaic∼50% of the cells) SIZE (KB): ∼26Mb, GENE COUNT**: 116, INTERPRETATION***: Pathogenic. RELATED DISORDER: 45,X/46,XY mixed gonadal dysgenesis The radiological investigations showed small oval shaped mass over the right inguinal canal 0.8/0.6/0.8 cm in size .the left testis couldn't be seen . And Genetogram showed presence of vagina and small uterus. his laboratory investigations showed at age of 2.5 years LH: less than o.3 and his Testosterone basal was less than 0.09 and Testosterone post HCG 8.29 which should excellent response to HCG.. the case was discussed with the paediatric urologist and the decision was as per the anatomical finding and results of the stimulated Testosterone to give Testosterone injections and asses the response. The child respond very well to the testosterone treatment which leads to improvement in the size and length of the phallus. Discussion mixed gonadal dysgenesis is one of the causes of DSD .45, X/ 46, XY mosaic: At birth around 90 per cent of babies with 45,X/46,XY have normal-appearing external male genitals, five per cent have normal-appearing female genitals and in five percent the external reproductive organs are neither fully male nor fully female. They may find one or two gonads that are very inadequate testes, possibly with some ovary-like tubules present. They may find one streak gonad and one immature, dysgenetic or normal testis. They may find an internal vagina, cervix and uterus, although these are usually quite small compared to a normal female. Some people with a 45,X/46,XY karyotype have reduced fertility and some are infertile. No judgment can be made about fertility until well after puberty in the apparently normal males. Children with a 45,X/46,XY karyotype can have any of the medical conditions that are more common among girls with Turner syndrome (who have a 45,X karyotype), which includes heart and disorders, autoimmune disorders and short stature. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Cluster of Differentiation 24 Polymorphism Has No Significant Association with Chronic Hepatitis B Virus Infection in the Chinese Han Population: A Family-Based Association Study.

ObjectiveStudies have shown that cluster of differentiation (CD) 24 gene polymorphism is associated with several diseases. Among these, chronic hepatitis B (CHB) infection has not been investigated. This study aimed to assess the function of CD24 in CHB.MethodsThe study included 478 cases of CHB and 318 cases without CHB from 230 families that underwent genotyping. Polymerase chain reaction-restriction fragment length polymorphism was performed to assess the single nucleotide polymorphism (SNP) P170 of the CD24 gene. The detected genotypes were TT, CT, and CC. Then, family based-association analysis was carried out to investigate the association between CD24 gene polymorphism and susceptibility to CHB.ResultsIn the 478 patients with CHB, the frequencies of CD24 P170 T and C alleles were 35.5% and 64.5%, respectively, and the frequencies of CD24 P170 CC, CT, and TT genotypes were 39.3%, 50.4% and 10.3%, respectively. In a CD24 single-locus analysis by a family-based association test of P170 polymorphisms, T and C were not significantly associated with CHB in the additive (Z = 0.169, P = 0.866; Z = −0.169, P = 0.866, respectively), dominant (Z = 0.522, P = 0.602; Z = 0.428, P = 0.669, respectively), or recessive (Z = −0.428, P = 0.669; Z = −0.522, P = 0.602, respectively) models. Transmission-disequilibrium (TD) and sib-transmission disequilibrium (STD) tests revealed no excess of T or C alleles from heterozygous parents to their children with the disease or higher frequencies of these alleles in patients compared with their normal siblings (χ2 = 0.06, P = 0.897).ConclusionThe study findings suggest that the SNP P170 of CD24 has no significant association with susceptibility to the HB virus and related phenotypes in Chinese patients.

Frequency of Fetal Hemoglobin Level in Siblings of Betathalassemia Major patients

Aim: To see the frequency of fetal haemoglobin level in siblings of beta thalassemia major (BTM) patients. Study population: A total of 400 subjects were included. Grouping: Group A includes normal siblings of BTM cases, B includes beta thalassemia trait (BTT) siblings of BTM cases and group C were healthy controls. Selection criteria: Asymptomatic siblings of diagnosed cases of beta thalassemia major were included. Patients with history or diagnosis of any acute or chronic illnesses were excluded from the study. 5 ml of blood was taken in EDTA vial and used for haemoglobin electrophoresis. Results: In 200 cases, 78% (156) were beta thalassemia trait (BTT) siblings and fetal Hb was also more in BTT siblings i.e. Group B. Conclusion: Fetal haemoglobin (HbF) was increased in BTT siblings (group B) of BTM cases. Keywords: Hb electrophoresis, fetal Hb, beta thalassemia major

Genetic Analysis of Father-Daughter Incest Using Multifaceted STR Markers and Study of Inheritance Pattern of Alleles

Background: Two cases involving father-daughter incest, a rare report in the Indian population, have been analyzed in the current study. STR markers on both autosomal and sex chromosomes were employed to expound the cases. Objective: The objective of this study is to confirm the identity of the fetus as a product of father-- daughter incest and to study the inheritance pattern of alleles in such cases. Methods: Autosomal, X, and Y chromosomal analyses were performed to confirm the identity of the fetus. Statistical analyses were carried out to strengthen the evidentiary value of the obtained results. Results: In both cases, the aborted fetus was found to be the product of an incestuous father-daughter relationship. The probability of paternity as well as maternity was found to be &gt;99.9999% in both cases. Analysis of other paternity and forensic parameters also substantiated the inclusion of the alleged individuals. Father-daughter incest had a tremendous effect on the genome as evidenced from the dramatical decrease in unrelated alleles between father/child [16.66% (Case 1), 20% (Case 2)] and mother/child [26.66% (Case 1), 21.66% (Case 2)]. Genetic evidence also suggested an increased biallelic match i.e., 26.66% (Case 1) and 33.33% (Case 2) between mother and fetus, which are at par/ above the normal siblings’ values i.e., 26.66%. Conclusion: A significant increase in the percentage of homozygous alleles (53.33% in both cases) was observed in the product of father-daughter incest. Both daughters share the same X chromosome from the father, which also suggested the case to be of father-daughter incest. Similarly, the same Y-STR profile between the male fetus and alleged father confirmed the correct pattern of inheritance of the Y chromosome in this case.

Somatotropic Axis, Pace of Life and Aging.

Mice with genetic growth hormone (GH) deficiency or GH resistance live much longer than their normal siblings maintained under identical conditions with unlimited access to food. Extended longevity of these mutants is associated with extension of their healthspan (period of life free of disability and disease) and with delayed and/or slower aging. Importantly, GH and GH-related traits have been linked to the regulation of aging and longevity also in mice that have not been genetically altered and in other mammalian species including humans. Avai+lable evidence indicates that the impact of suppressed GH signaling on aging is mediated by multiple interacting mechanisms and involves trade-offs among growth, reproduction, and longevity. Life history traits of long-lived GH-related mutants include slow postnatal growth, delayed sexual maturation, and reduced fecundity (smaller litter size and increased intervals between the litters). These traits are consistent with a slower pace-of-life, a well-documented characteristic of species of wild animals that are long-lived in their natural environment. Apparently, slower pace-of-life (or at least some of its features) is associated with extended longevity both within and between species. This association is unexpected and may appear counterintuitive, because the relationships between adult body size (a GH-dependent trait) and longevity within and between species are opposite rather than similar. Studies of energy metabolism and nutrient-dependent signaling pathways at different stages of the life course will be needed to elucidate mechanisms of these relationships.

Vitamin D abnormalities of children with recurrence of malignancy and comparison with newly diagnosed patients.

Vitamin D (Vit-D) is a necessary ingredient for human growth and its deficiency may increase the risk of cancer and its recurrence. The main purpose of this research was to assess the levels of Vit-D in children with recurrence of malignancy and compare it with new cases of malignancy and the control group. The status of 25(OH) Vit-D was determined utilizing the HPLC method in 47 patients with recurrence of malignancy (group A), 50 children with new malignancy (group B) and 49 normal healthy siblings of the two groups as a control (group C). Vit-D was low (<30 ng/ml) in the 92% of patients with recurrence of malignancy, which was a significant difference compared to groups B (60%) and C (45%). Vit-D insufficiency (10-30 ng/dl) in group A was also higher than the other two groups. The mean levels of Vit-D in patients with recurrence were significantly lower than the new cases and controls. Low Vit-D (<30 ng/ml) in group A in both male and female, and also in all ages (<6 and ≥ 6 years) was higher than groups B and C. Also, low Vit-D in terms of the type of malignancy in group A was higher than group B only in leukemic patients while this was not different for non-leukemic patients in these two groups. Results of this study showed an increased prevalence of low Vit-D in children with recurrence of malignancies. Therefore, it may increase the risk of recurrence of malignancies in children.

“Postnatal Growth of Intrauterine Growth Restricted Newborns”

Introduction: Intrauterine growth restriction plays a significant role in short and long term adverse outcome. It is reflected in the relatively high incidence of neurodevelopmental impairment and somatic growth failure. Growth in the first year of life gets an opportunity to recover its growth deficit of intrauterine life and to catch up with its normal birth weight siblings Objective of the Study: To assess the postnatal growth of intrauterine growth restricted newborns at 3, 6 and 9 months of age. Methodology: A Prognostic cohort study was conducted at Department of Neonatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh from 1st April 2017 to 20th September 2018. It involved monitoring of 31 intrauterine growth restricted newborns and 39 normal birth weight neonates over a period of 9 months. Follow up were done at 3, 6 and 9 month of age. At every visit weight, length, occipitofrontal circumference and chest circumference were measured. Data was analyzed using SPSS 20 and plotted in tables and graphs. Data imputation was done for the missing data. Multiple regression analysis was done for confounder of growth when data was statistically significant. Results: Mean birth weight were 1748 ±437.09 g and 2893.54±467.07g, birth length 44 ±4.2439 cm and 49.26±1.634cm, birth occipitofrontal circumference 30.76 ±2.380 cm and 34.35±1.083cm, birth chest circumference 24.39 ±1.940 cm and 29.15±2.933cm in IUGR and control group respectively which was statistically significant. There were catch-up weight gain in 3, 6 and 9 months of age in IUGR group but it was less than the normal birth weight group during the followed-up period. During the follow-up period, cacth up growth in length achieved in first 9 months of age. During the first 3 months there were no catch up growth in IUGR babies head circumference but it increases in normal rates. Mean chest circumference values at 3 months were statistically significant and after multiple regression analysis, it is significant for birth length. In general, IUGR babies when compared with the control group remained small in all the four growth parameters but it had catch up growth in first 9 months of age. Conclusion: During the follow-up period, catch-up of growth achieved regarding weight, length, OFC and chest circumference but the growth parameters were lower than the appropriate for gestational age birth weight newborns

Mutational Studies of Gene HBB in β-Thalassemia Patients from Balochistan, Pakistan

Thalassemia is a hereditary blood disorder. It occurs due to two mutations in the HBB gene located on chromosome 11. This gene has 1606 base pairs and contains three exons. Moreover, HBB gene codes for β globin protein have been identified to posses 868 mutations, which comprise point mutation, insertion, deletion, and gene arrangement. In β thalassemia major, both alleles are mutated and no β chain is synthesized. In this study, three human families with thalassemia were selectedfrom different areas of Balochistan. For DNA extraction and estimation, 5 ml blood samples were extracted intravenously from the affected individuals, their normal siblings, and parents in 15ml falcon tubes containing 200μl EDTA. Primer sequences were designed on primer 3 for the mutational analysis of the HBB gene. Since the gene has a total of three exons and two introns, three primers, namely HBBX1, HBBX2 and HBBX3, were designed. These primers were used to amplify the HBB gene responsible for β thalassemia in all family samples. The amplified product was sequenced through an automated 3100 ABI Prism DNA sequence. The sequencing results were analyzed by the SaqMan software. This was done to determine if any genetic variable in the selected families showed mutations. In Family 1, 1 bp substitution mutation (c.9T&gt;C) (p.his3his) and 1bp insertion (c.111T&gt;G) (p.Ser10 val) in exon 1 of HBB gene were identified in thalassemia locus, while in in Family 2, 1bp substitution mutation (c.9T&gt;C) (p.His3His) in exon 1 of HBB gene was identified in thalassemia locus. No mutation was observed in Family 03after sequencing.

Clinical Aspects of Microcephaly Patients Regarding Endocrine Profile

Introduction: Microcephaly is characterized as an occipitofrontal head circumference (OFC) underneath the third centile or more than 2 standard deviations (SD) below the mean for sex, age, and ethnicity. The term ‘severe’ microcephaly is connected to an OFC more than 3SD below the mean. Microcephaly is associated with a reduction in brain volume and frequently intellectual and/or motor inabilities. The pathogenesis of microcephaly is heterogeneous, extending from hereditary causes to environmental components that can have an effect on developmental process that impact brain size. Objective: The main objective of this study was to compare the BMI and endocrine profile of patients having microcephaly with age matched to normal siblings in their families. Materials and Methods: Study design: Quantitative cross sectional Settings: Services Hospital Lahore Duration: 01 year i.e. 1st January 2020 to 30th December 2020 Methodology: This is a quantitative cross sectional study arrangement based on 12 persons. On the basis of microcephaly, the subjects were separated into the two groups: Group I: Subjects with microcephaly (n=10), Group II: Normal kin as controls (n=2). Five families including add up to of 12 individuals was selected. Ten people with microcephaly (cases) and two normal kin (without microcephaly) were taken as controls. Cooperation of the subjects in this study was selected voluntarily and written informed consent was taken to take part in the study from each individual and from their guardians. The individuals and their guardians were educated about the potential benefits and risks of this study. Results: There was little difference within the mean age of microcephaly individuals as compared to healthy siblings. Conclusion: In light of this study it can be recommended that there's a significant affiliation of BMI and microcephaly but the affiliation of Leptin, Cortisol, GH and TSH with microcephaly seem not be found as proposed by non-significant results. This may moreover emphasize on heredity perspective of this condition. Keywords: Microcephaly, Leptin, Growth Hormone, BMI, TSH

A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential.

Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD and possibly affects mitochondrial function. This study aimed to elucidate the link between mitochondrial dysregulation and idiopathic ASD by focusing on mitochondrial respiratory capacity and membrane potential. Our findings showed that mitochondrial function in the energy metabolism pathway was significantly dysregulated in a lymphoblastoid cell line (LCL) derived from an autistic child (ALCL). Respiratory capacities of oxidative phosphorylation (OXPHOS), electron transfer of the Complex I and Complex II linked pathways, membrane potential, and Complex IV activity of the ALCL were analyzed and compared with control cell lines derived from a developmentally normal non-autistic sibling (NALCL). All experiments were performed using high-resolution respirometry. Respiratory capacities of OXPHOS, electron transfer of the Complex I- and Complex II-linked pathways, and Complex IV activity of the ALCL were significantly higher compared to healthy controls. Mitochondrial membrane potential was also significantly higher, measured in the Complex II-linked pathway during LEAK respiration and OXPHOS. These results indicate the abnormalities in mitochondrial respiratory control linking mitochondrial function with autism. Correlating mitochondrial dysfunction and autism is important for a better understanding of ASD pathogenesis in order to produce effective interventions.

Network Inference of Transcriptional Regulation in Germinating Low Phytic Acid Soybean Seeds.

The low phytic acid (lpa) trait in soybeans can be conferred by loss-of-function mutations in genes encoding myo-inositol phosphate synthase and two epistatically interacting genes encoding multidrug-resistance protein ATP-binding cassette (ABC) transporters. However, perturbations in phytic acid biosynthesis are associated with poor seed vigor. Since the benefits of the lpa trait, in terms of end-use quality and sustainability, far outweigh the negatives associated with poor seed performance, a fuller understanding of the molecular basis behind the negatives will assist crop breeders and engineers in producing variates with lpa and better germination rate. The gene regulatory network (GRN) for developing low and normal phytic acid soybean seeds was previously constructed, with genes modulating a variety of processes pertinent to phytic acid metabolism and seed viability being identified. In this study, a comparative time series analysis of low and normal phytic acid soybeans was carried out to investigate the transcriptional regulatory elements governing the transitional dynamics from dry seed to germinated seed. GRNs were reverse engineered from time series transcriptomic data of three distinct genotypic subsets composed of lpa soybean lines and their normal phytic acid sibling lines. Using a robust unsupervised network inference scheme, putative regulatory interactions were inferred for each subset of genotypes. These interactions were further validated by published regulatory interactions found in Arabidopsis thaliana and motif sequence analysis. Results indicate that lpa seeds have increased sensitivity to stress, which could be due to changes in phytic acid levels, disrupted inositol phosphate signaling, disrupted phosphate ion (Pi) homeostasis, and altered myo-inositol metabolism. Putative regulatory interactions were identified for the latter two processes. Changes in abscisic acid (ABA) signaling candidate transcription factors (TFs) putatively regulating genes in this process were identified as well. Analysis of the GRNs reveal altered regulation in processes that may be affecting the germination of lpa soybean seeds. Therefore, this work contributes to the ongoing effort to elucidate molecular mechanisms underlying altered seed viability, germination and field emergence of lpa crops, understanding of which is necessary in order to mitigate these problems.

ANXIETY AND DEPRESSION AMONG SIBLINGS OF CHILDREN WITH CEREBRAL PALSY ATTENDING NEUROLOGY CLINIC AT ALEXANDRIA UNIVERSITY CHILDREN'S HOSPITAL Elham Elsayed Elsakka, Shimaa Anwar Mohamed, Mohamed Abdelhady Ali Abdelhady Department of Pediatrics, Faculty of Medicine, Alexandria University, Egypt

: CP is a group of permanent disorders of motor function, which are due to a non-progressive lesion, or abnormality of the developing/immature brain. Motor function disorders are often accompanied by other dysfunctions, such as: sensation, perceptual, cognitive, communication and behavioral disorders, epilepsy, and secondary musculoskeletal disorders. (1) It is the most common cause of motor disability in childhood. (2)The worldwide prevalence of CP ranges from 1 to 4 per 1,000 live births. In Egypt, the prevalence is about 2.6-4.6 per 1,000 live births.Having a child with CP in the family not only affects parents’ lives including physical and psychological well-being, financial stability and support of services , but also affects normal siblings, who are considered as “population at risk to experience psychological difficulties” .(5, 6) According to the American Psychiatric Association, behavioral disorders , anxiety disorders, and depression are the most common pediatric psychiatric disorders.(7)Anxiety disorders are among the most common childhood emotional problems, with lifetime prevalence ranging from 8.3% to 27%.(8)Depression: is a mental state or chronic mental disorder characterized by feelings of sadness, loneliness, despair, low self-esteem, signs of psychomotor retardation ,or less frequently, agitation, withdrawal from social contact ,change of appetite and insomnia.(10)The overall prevalence of pediatric depressive disorders is 12.3% with 14.1% for females and 8.6% for males.(11)

Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis.

Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.