Cause Of Birth Defects Research Articles

Knowledge and Attitude of Young Married Women Regarding Congenital Anomalies in the Fetus: A Cross-Sectional Questionnaire-Based Study from South-Central India

Abstract Background Although congenital anomalies are a significant cause of neonatal mortality and morbidity in both developed and developing countries, middle- and low-income countries, including India, account for approximately 95% of all children born with congenital anomalies. Some birth defects/congenital anomalies are preventable, if their risk factors are modified. Young married women must have a good knowledge regarding these preventable risk factors because this is the population who will be bearing children in the near future. Therefore, this study aims to determine the knowledge and attitude of young married women regarding congenital anomalies/ birth defects, their risk factors, preventive measures, and treatment options available. Materials and Methods An analytical cross-sectional study was conducted in a tertiary care center in South-Central, India, for over 1 year. Five hundred young married women (range: 18–30 years) answered a questionnaire, mainly focusing on what are birth defects, what are their risk factors and preventive strategies against them. It also included questions on how birth defects are diagnosed, and if carrying a baby with birth defects, what they would do for their management and also their knowledge regarding fetal medicine centers and fetal medicine specialists. Results The mean knowledge score of the study participants was 18 ± 4.08 (range: 8–27). About 82.8% of the study participants had average knowledge regarding birth defects, and only 17.2% had good and adequate knowledge scores. The knowledge regarding risk factors is grossly inadequate. The knowledge regarding advanced maternal age, maternal obesity, and consanguinity as risk factors for congenital anomalies was deficient in more than 50% of the study population. The mean attitude score was 4.42 + 0.985 (range: 1–7), indicating overall positive attitudes. Conclusion Knowledge regarding birth defects, their risk factors, and preventive strategies was moderate in the majority of the study participants. Education has some bearing on the knowledge and attitude, but the knowledge base still seems to be influenced by religious beliefs. Awareness campaigns to increase the knowledge about preventable causes of birth defects and their management strategies are urgently needed in this region.

Investigating the causes of birth defects.

Background: Understanding and investigating the causes of birth defects is a critical approach toward the findings and development of helpful treatments and diagnostic strategies to overcome the issue of birth defects. We aim to investigate birth defects' causes by identifying the most common abnormal genes found in an inheritance pattern. Collecting genetic causes of the most common birth defects found in Pakistan and searching the link between birth defects and other harmful diseases.
 Methodology: The birth defects data is systematically gathered and critically analyzed to assess the role of insertions and deletions as the causative agents. Analysis was conducted on genomic data to investigate the genetic causes of congenital abnormalities. 
 Results: The most common birth defects, namely neural tube defect (spina bifida), Facial palate (cleft/lip palate), heart defects (atrial septal defect, ventricular septal defect, tetralogy of Fallot), deletion syndrome, and laryngomalacia caused by the main problematic genes namely MTHFR, MEIS2, TBX1, and NKX2-5. The results show that about eighty-six percent (86%) of gene variants overlap completely with the defective genes transcript, including both insertions/gain and deletions/loss. 
 Conclusion: Identification of the main genes which are involved in most of the common birth defects highlights the major twelve genes, namely LMNA, MTHFR, POMC, TTN, SLC25A13, FGFR3, GCH1, TBX1, MEIS2, NKX2-5, GATA4, and GATA6.

Mitigating the detrimental developmental impact of early fetal alcohol exposure using a maternal methyl donor-enriched diet.

Fetal alcohol exposure at any stage of pregnancy can lead to fetal alcohol spectrum disorder (FASD), a group of life-long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8-cell stage) fetal alcohol exposure (2 × 2.5 g/kg ethanol with a 2h interval) in mice leads to long-term FASD-like morphological phenotypes (e.g. growth restriction, brain malformations, skeletal delays) in late-gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol-induced morphological defects without altering DNA methylation status of imprinting control regions and regulation of associated imprinted genes. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizes the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.

Fetal alcohol spectrum disorders.

Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed by people living with FASD and beguided by cultural context, seek consensus on diagnostic criteria and evidence-based treatments, and describe the pathophysiology and lifelong effects of FASD. Imperatives include reducing stigma, equitable access to services, improved quality of life for people with FASD and FASD prevention in future generations.

Parents' Supernatural Beliefs on Causes of Birth Defects: A Review from Islamic Perspective.

In this article, parents' supernatural beliefs on causes of birth defects were reviewed and discussed from Islamic perspective to draw attention to the importance of supernatural powers in Islamic teachings. Birth defects have been known since ancient ages and many people with different birth defects, who lived in antiquity, have been described. Although reasons for birth defects given in early medieval, 13th, 16th, and 21st centuries medical texts showed differences, numerous people in different cultures of the world have believed the effects of supernatural powers can cause birth defects since early medieval ages. Sixteenth century medical authors associated biomedical explanations with social upheavals and theology in order to understand the individual sins and the signs of the times presented by Allah through malformed human births. However, there is no religious phrase mentioning about causes of birth defects in medical textbooks of the 21st century. Based on the Islamic teachings, we would like to emphasize that supernatural beliefs including "Allah's will and qadar," "a test from Allah," "a punishment from Allah," "nazar (evil eye)," "sihr (magic or sorcery)," and "jinn possession" believed by parents as a cause of birth defects are right, real, and true, and not superstition or misconception. The Quran says "everything is determined by Almighty Allah" and "no kind of calamity can occur, except by the leave of Allah." So, we strongly believe that religious teachings must be integrated into modern medicine. The need for religion is not only for Muslims but also for all people a need of pre-eternity and posteternity. The unfortunate humanity today suffers in great pain from the constant sorrow and disasters of being deprived of the religion blessing.

The effects of polyunsaturated fatty acids on the cardiac IKR channel.

The cardiac action potential is primarily generated by sodium and calcium channels, which depolarize the membrane potential, and by potassium channels that repolarize the membrane potential and terminate the action potential. Mutations in potassium channels Kv11.1 (also called hERG) and Kv7.1/KCNE1 (also called KCNQ1/KCNE1), which generate the IKr and IKs currents, respectively, are the most common cause of congenital defects that lead to Long QT Syndrome (LQTS). LQTS is an arrhythmia disorder that predisposes individuals to ventricular fibrillation and sudden cardiac death and is characterized by a delayed repolarization phase and a prolonged QT interval. Some PUFA (Polyunsaturated Fatty Acid) analogs have been shown to be IKs activators that have the potential to reduce the QT interval and lessen risks associated with LQTS. However, the broad modulating effects of different PUFA analogs on all three cardiac ion channel families (NaV, CaV, and Kv) make it necessary for promising analogs to be channel specific to avoid off- target effects. So far the effects of PUFA analogs on hERG channels remain unknown. To determine how the application of PUFA analogs modifies the hERG channel we use the Two-Electrode Voltage Clamp (TEVC) electrophysiology method to record whole cell channel activity from Xenopus oocytes expressing the hERG channel. Here we evaluate both Gmax and V0.5, as well as the rate of activation, inactivation and recovery from inactivation, as measurements of the PUFA analog effects on channel activity. It is important to rule out hERG modulation by PUFA analogs to fill this gap in our understanding of the PUFA pharmacophore that currently limits our ability to design channel-specific PUFA compounds.

Zika virus as a cause of birth defects: Were the teratogenic effects of Zika virus missed for decades?

Zika virus (ZIKV) was identified as a teratogen in 2016 when an increase in severe microcephaly and other brain defects was observed in fetuses and newborns following outbreaks in French Polynesia (2013-2014) and Brazil (2015-2016) and among travelers to other countries experiencing outbreaks. Some have questioned why ZIKV was not recognized as a teratogen before these outbreaks: whether novel genetic changes in ZIKV had increased its teratogenicity or whether its association with birth defects had previously been undetected. Here we examine the evidence for these two possibilities. We describe evidence for specific mutations that arose before the French Polynesia outbreak that might have increased ZIKV teratogenicity. We also present information on children born with findings consistent with congenital Zika syndrome (CZS) as early as 2009 and epidemiological evidence that suggests increases in CZS-type birth defects before 2013. We also explore reasons why a link between ZIKV and birth defects might have been missed, including issues with surveillance of ZIKV infections and of birth defects, challenges to ZIKV diagnostic testing, and the susceptibility of different populations to ZIKV infection at the time of pregnancy. Although it is not possible to prove definitively that ZIKV had teratogenic properties before 2013, several pieces of evidence support the hypothesis that its teratogenicity had been missed in the past. These findings emphasize the need for further investments in global surveillance for emerging infections and for birth defects so that infectious teratogens can be identified more expeditiously in the future.

Human cytomegalovirus induces neuronal enolase to support virally mediated metabolic remodeling

Viruses depend on cellular metabolic resources to supply the energy and biomolecular building blocks necessary for their replication. Human cytomegalovirus (HCMV), a leading cause of birth defects and morbidity in immunosuppressed individuals, induces numerous metabolic activities that are important for productive infection. However, many of the mechanisms through which these metabolic activities are induced and how they contribute to infection are unclear. We find that HCMV infection of fibroblasts induces a neuronal gene signature as well as the expression of several metabolic enzyme isoforms that are typically expressed in other tissue types. Of these, the most substantially induced glycolytic gene was the neuron-specific isoform of enolase 2 (ENO2). Induction of ENO2 expression is important for HCMV-mediated glycolytic activation as well as for the virally induced remodeling of pyrimidine-sugar metabolism, which provides the glycosyl subunits necessary for protein glycosylation. Inhibition of ENO2 expression or activity reduced uridine diphosphate (UDP)-sugar pools, attenuated the accumulation of viral glycoproteins, and induced the accumulation of noninfectious viral particles. In addition, our data indicate that the induction of ENO2 expression depends on the HCMV UL38 protein. Collectively, our data indicate that HCMV infection induces a tissue atypical neuronal glycolytic enzyme to activate glycolysis and UDP-sugar metabolism, increase the accumulation of glycosyl building blocks, and enable the expression of an essential viral glycoprotein and the production of infectious virions.

Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies.

Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. IMPORTANCE The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection.

Single Nucleotide Polymorphism Array Versus Karyotype for Prenatal Diagnosis in Fetuses With Abnormal Ultrasound: A Systematic Review and Meta-analysis

(Abstracted from Eur J Obstet Gynecol Reprod Biol 2022;271:235–244) Chromosomal aberrations occur at a frequency of approximately 1 in 150 to 200 live births and are one of the most important causes of congenital anomalies and miscarriages. The introduction of chromosomal microarray (CMA) in the 1990s advanced the detection of chromosomal aberrations to include small copy number variants that previously were not detectable when only karyotype was used.

Identification of a novel MAP3K1 variant in a family with 46, XY DSD and partial growth hormone deficiency

The 46, XY disorder of sex development (DSD) is the main cause of birth defects; however, as it is a group of highly heterogeneous diseases, >50% of cases are not accurately diagnosed. Identification of more cases will improve understanding of the relationship between genotype and phenotype for DSD. The present study conducted a systematic analysis of the clinical characteristics of a proband with 46, XY DSD, applied genetic analysis by whole-exome sequencing to this pedigree and performed bioinformatics analysis of the identified variant. The proband presented with a short penis, lack of testicles and partial growth hormone (GH) deficiency at 1 year old. Histopathological examination revealed there were oviduct, epididymis and fibrous vascular tissue on both sides of the abdomen. The last follow-up at 5 years of age revealed that the patient exhibited restricted growth, a 1.5-cm penis and lack of testicles. Notably, a novel pathogenic mitogen-activated protein kinase kinase kinase 1 (MAP3K1) variant (c.3020A>G) was identified in the proband, resulting in a change in the 1,007th amino acid (glutamine) of the encoded protein. This variant caused the uncharged neutral glutamine to be replaced by a positively charged basic arginine. p.Gln1007 in MAP3K1 was confirmed to be conserved across various species. Pathogenicity analysis using bioinformatics tools suggested that this MAP3K1 variant may cause functional defects. In conclusion, the present study identified a novel MAP3K1 variant that was the cause of 46, XY DSD and partial GH deficiency. The present findings extend the mutation spectrum of MAP3K1 and provide novel characteristics of 46, XY DSD.

Scrutinising the factors determining the adverse outcome following duodenal atresia surgery in children

Introduction: The most common causes of congenital abnormalities reported in newborns is duodenal obstruction. There are several conditions which may lead to worsen the patient’s prognosis are prematurity, type of obstruction and the type of surgery performed. The major objective of the present study was to summarise our clinical experience with 34 infants with duodenal atresia who underwent surgical procedures over the past 20 years. Materials and Methodology: Of the total of 96 patients, those who were reported with the diagnosis of duodenal atresia were included in the study. And this group comprised of 34 patients. The group was compared in terms of sex, birth weight, age at the time of the operation and morbidity rates. All patients were assessed by neonatal and other relevant specialists when observed to be presented with additional anomalies. Data were analysed using SPSS software (ver. 15.0; SPSS Inc., Chicago, IL, USA). Results: Of the 34 patients, 22 were males and 12 females, with a mean birth weight of 2.282.92 ± 592.98 (range, 1,180-3,400) g. The average age at the time of the operation was 6.98 ± 5.09 (range, 1-38) days.

Diagnosis of 22q11.2 deletion syndrome in children with congenital heart diseases and facial dysmorphisms

BackgroundCongenital heart diseases (CHDs) are the leading cause of birth defects. Approximately, 30% of CHDs are related to genetic syndromes accompanied by extracardiac anomalies. Aneuploidies and 22q11.2 deletions account for majority of cases. 22q11.2 deletion involves deletion of 30-40 genes, and varying deletions in this region lead to different phenotypes. Fluorescent in situ hybridization probes span a narrow region on chromosome 22 as compared to other recent techniques like multiplex ligation probe amplification assay (MLPA) which may also identify any gene duplications if present. MethodsPresent study was a cross-sectional descriptive study. In total, 350 children with CHD reported to pediatric cardiology clinic during the study period. Of these, 60 children had associated facial dysmorphism. Out of these 60 children, 18 children had clinical phenotype characteristic of Down syndrome and hence these children were excluded from the study. Forty-two children with CHDs (conotruncal and other defects) and craniofacial features (subtle or obvious) suggestive of 22q11.2 deletion spectrum disorder were included in this study. ResultsNineteen percent of children presenting with CHDs and facial dysmorphisms had 22q11.2 deletion syndrome. All the samples were subjected to karyotyping. ConclusionMetaphase FISH has been the method of choice for microdeletions. However, apart from technical challenges and longer turnaround time, FISH probes span a very narrow region in 22q11.2 chromosome (LCR22 D) and provide information about DiGeorge syndrome (DGS) only. Take home message is that patients of CHDs with facial dysmorphism should be investigated in an approach-based manner.

In Utero Activation of Natural Killer Cells in Congenital Cytomegalovirus Infection.

BackgroundCongenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for natural killer (NK) cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero.MethodsHere, we investigate the impact of congenital CMV infection on the neonatal NK-cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants.ResultsWe find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56− NK cells, an NK-cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero.ConclusionsThese findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV.Clinical Trials RegistrationNCT02793622.

Human Cytomegalovirus Manipulates Syntaxin 6 for Successful Trafficking and Subsequent Infection of Monocytes.

Human cytomegalovirus (HCMV) exhibits a complex host-pathogen interaction with peripheral blood monocytes. We have identified a unique, cell-type specific retrograde-like intracellular trafficking pattern that HCMV utilizes to gain access to the monocyte nucleus and for productive infection. We show that infection of primary human monocytes, epithelial cells, and fibroblasts leads to an increase in the amount of the trafficking protein Syntaxin 6 (Stx6). However, only knockdown (KD) of Stx6 in monocytes inhibited viral trafficking to the trans-Golgi network (TGN), a requisite step for nuclear translocation in monocytes. Conversely, KD of Stx6 in epithelial cells and fibroblasts did not change the kinetics of nuclear translocation and productive infection. Stx6 predominantly functions at the level of the TGN where it facilitates retrograde transport, a trafficking pathway used by only a few cellular proteins and seldom by pathogens. We also newly identify that in monocytes, Stx6 exhibits an irregular vesicular localization rather than being concentrated at the TGN as seen in other cell-types. Lastly, we implicate that viral particles that associate with both Stx6 and EEA1 early in infection are the viral population that successfully traffics to the TGN at later time points and undergo nuclear translocation. Additionally, we show for the first time that HCMV enters the TGN, and that lack of Stx6 prevents viral trafficking to this organelle. We argue that we have identified an essential cell-type specific regulator that controls early steps in efficient productive infection of a cell-type required for viral persistence and disease. IMPORTANCE Human cytomegalovirus (HCMV) infection causes severe and often fatal disease in the immunocompromised. It is one of the leading infectious causes of birth defects and causes severe complications in transplant recipients. By uncovering the unique pathways used by the virus to infect key cells, such as monocytes, responsible for dissemination and persistence, we provide new potential targets for therapeutic intervention.

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. Clinical data was collected through an extensive web-based survey. We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.

Role of systemic immune-inflammatory index in early diagnosis of sepsis in newborns with CHD.

Congenital heart diseases (CHD) are the most common causes of birth defects that have increased the risk of infections. Neonatal sepsis is a life-threatening condition and early diagnosis can be life-saving. We aimed to evaluate the potential role of the systemic immune-inflammatory index in the early diagnosis of neonatal sepsis. A retrospective cohort study was conducted on 166 newborns with a diagnosis of neonatal sepsis who were admitted to our hospital with CHD between January 2017 and June 2021. Haematological indices including neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and systemic immune-inflammatory index were calculated for all patients at the time of diagnosis of neonatal sepsis (sepsis). The sepsis values of these indices were compared with the admission values (pre-sepsis) of the patients. The mean gestational age and birth weight of the patients were 38.36 ± 1.42 weeks and 3057.75 ± 484.68 g. It was found that absolute neutrophil count, systemic immune-inflammatory index, neutrophil/lymphocyte ratio, but not platelet/lymphocyte ratio were significantly increased at the time of sepsis. The receiver operating characteristic curve showed that systemic immune-inflammatory index, neutrophil/lymphocyte ratio, and absolute neutrophil count have predictive ability to define neonatal sepsis among newborns with CHD. The systemic immune-inflammatory index produced an area under the curve receiver operating characteristic curve of 0.76 (70% sensitivity, 70.5% specificity). To discriminate neonatal sepsis, the cut-off values of systemic immune-inflammatory index, neutrophil/lymphocyte ratio, and absolute neutrophil count were 517.19, 2.62, and 9210/mm3, respectively. As an easily accessible and reliable indicator, systemic immune-inflammatory index may be used in combination with the other parameters in the early diagnosis of neonatal sepsis.

Inhibition of Wnt/β‐catenin Signaling Pathway on Melanogenesis‐ Insights from Zebrafish (Danio rerio)

IntroductionVertebrate color patterns are composed of specialized pigment‐producing cells, the chromatophores. Melanin is the main pigment type that colors the skin and skin appendages in mammals. Melanin is produced by specialized cells called melanocytes. Melanocytes have embryonic neural crest cells origin and their development and functions are ubiquitous across vertebrates, residing in dermal and epidermal skin layers. Studies of melanogenesis have provided experimentalists with a valuable system for understanding pattern formation in the developing embryo. In addition, studying these mechanisms may have important consequences for the clinical sciences. Alcohol is a widely abused teratogenic substance. Fetal alcohol spectrum disorder (FASD) is described as birth defects associated with prenatal alcohol exposure (PAE). PAE is likely one of the leading causes of birth defects but pathophysiology of FASD associated body pigmentation disorders are needed to be investigated further. Zebrafish (Danio rerio) (ZF) is identified as a good model to study FASD and melanocyte biology. Wnt signaling pathway is a conserved signal transduction pathway which is important in embryonic development and it regulates many aspects of melanogenesis. The current study was designed to investigate the effect of Alcohol‐Wnt signaling pathway activity on ZF melanogenesis.Materials and MethodsWild‐type (WT) ZF embryos were treated with Wnt pathway inhibitor (LiCl) and combined chemical treatment (LiCl and 1% alcohol) at 10 hours post fertilization (hpf). The differential effects of above substances on early development, differentiation, patterning of melanocytes were investigated using cell biology and imaging techniques.ResultsMelanocytes of LiCl exposed samples showed defects in migration, arrangement and survival. Ectopic melanocytes and developmental aberrations of eye pigmentation were noticed in both chemical treatments. Significant variation of the melanocyte cell size, shape and body pigmentation patterning was observed among the LiCl and combined treated samples compared to the control.ConclusionEmbryonic LiCl and alcohol exposures affect the development and patterning of the melanocytes in ZF. The molecular mechanisms underlying the above phenotypes will be investigated further to understand the FASD associated pigmentation defects.

UL25 Deletion in hCMV and Impacts on Viral Replication Cycles

Human Cytomegalovirus (hCMV) is a beta herpes virus that impacts a significant portion of the adult U.S. population (50‐94% seroprevalence, depending on the region). Furthermore, hCMV is the leading infectious cause of congenital defects, predominantly sensory neural hearing loss and various neurological disorders. hCMV is a problem for immunocompromised transplant recipients. A major challenge in dealing with hCMV infections, as well as herpes virus infections in general, is the ability of the virus to go into a latent state of replication, where it produces very little gene products, and avoids host immune responses. Understanding the parameters of latent infectious phases of herpesviruses is necessary if substantial progress is to be made in treating all herpes virus infections. Additionally, understanding the mechanisms of latency in one herpes virus will provide insight on the mechanisms of all herpes virus, since they are evolutionarily related. With this in mind, the purpose of our research is to understand the molecular mechanisms that transition herpesviruses from a latent phase of replication, to a more productive, lytic phase. Specifically, we are asking what the role of the hCMV tegument protein UL25 was in the latent phase of replication. UL25 is a protein known to impact chromatin structure, transcription activation, and p53 inhibition. To understand hCMVs role in latent replication, we are designing UL25 deficient recombinants of clinical hCMV strains. After recovering and characterizing the recombinant virus lacking UL25, we will measure expression of marker genes for latent infection in cells quiescently infected with either wild‐type or UL25 deficient hCMV strains to see if UL25 plays a significant role in the maintenance or establishment of latency using cell culture models of quiescent infections.

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review

BackgroundCongenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD.MethodsDatabases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis’s five-class evidence grade.ResultsA total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as “Moderate”. One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed.ConclusionThe present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.