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ELife Apr 2024Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB)...
Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during, e.g., food processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL from that provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.
Topics: Humans; Animals; Listeria monocytogenes; Cell Death; Estrus; Food; HSP70 Heat-Shock Proteins; Neural Tube Defects
PubMed: 38598269
DOI: 10.7554/eLife.92746 -
BioRxiv : the Preprint Server For... Mar 2024Nonketotic hyperglycinemia due to deficient glycine cleavage enzyme activity causes a severe neonatal epileptic encephalopathy. Current therapies based on mitigating...
UNLABELLED
Nonketotic hyperglycinemia due to deficient glycine cleavage enzyme activity causes a severe neonatal epileptic encephalopathy. Current therapies based on mitigating glycine excess have only limited impact. An animal model with postnatal phenotyping is needed to explore new therapeutic approaches. We developed a p.Ala394Val mutant model and bred it to congenic status in 2 colonies on C57Bl/6J (B6) and J129X1/SvJ (J129) backgrounds. Mutant mice had reduced P-protein and enzyme activity indicating a hypomorphic mutant. Glycine levels were increased in blood and brain regions, exacerbated by dietary glycine, with higher levels in female than male J129 mice. Birth defects were more prevalent in mutant B6 than J129 mice, and hydrocephalus was more frequent in B6 (40%) compared to J129 (none). The hydrocephalus rate was increased by postnatal glycine challenge in B6 mice, more so when delivered from the first neonatal week than from the fourth. Mutant mice had reduced weight gain following weaning until the eighth postnatal week, which was exacerbated by glycine loading. The electrographic spike rate was increased in mutant mice following glycine loading, but no seizures were observed. The alpha/delta band intensity ratio was decreased in the left cortex in female J129 mice, which were less active in an open field test and explored less in a Y-maze, suggesting an encephalopathic effect. Mutant mice showed no evidence of memory dysfunction. This partial recapitulation of human symptoms and biochemistry will facilitate the evaluation of new therapeutic approaches with an early postnatal time window likely most effective.
TAKE HOME MESSAGE
A mouse model of nonketotic hyperglycinemia is described that shows postnatal abnormalities in glycine levels, neural tube defects, body weight, electroencephalographic recordings, and in activity in young mice making it amenable for the evaluation of novel treatment interventions.
AUTHOR CONTRIBUTIONS
Study concept and design: JVH, MHM, NB, KNMAnimal study data: MAS, HJ, NB, MHM, JC, CBBiochemical and genetic studies: MAS, RAVH, MWFStatistical analysis: NB, JVHFirst draft writing: JVH, NB, MHMCritical rewriting: MAS, NB, MHM, TAB, JC, MWF, KNM, JVHFinal responsibility, guarantor, and communicating author: JVH.
COMPETING INTEREST STATEMENT
The University of Colorado (JVH, MS, KNM, HJ) has the intention to file Intellectual property protection for certain biochemical treatments of NKH. Otherwise, the authors have stated that they had no interests that might be perceived as posing a conflict or bias to this subject matter.
FUNDING SUPPORT
Financial support is acknowledged form the NKH Crusaders, Brodyn's Friends, Nora Jane Almany Foundation, the Dickens Family Foundation, the Lucas John Foundation, Les Petits Bourdons, Joseph's Fund, the Barnett Family, Maud & Vic Foundation, Lucy's BEElievers fund, Hope for NKH, Madi's Mission NKH fund, and from Dr. and Ms. Shaw, and the University of Colorado Foundation NKH research fund. The study was supported by a grant (CNS-X-19-103) from the University of Colorado School of Medicine and the Colorado Clinical Translational Science Institute, which is supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors' sole responsibility and do not necessarily represent official NIH views. All funding sources had no role in the design or execution of the study, the interpretation of data, or the writing of the study.
ETHICS APPROVAL ON LABORATORY ANIMAL STUDIES
Mouse studies were carried out with approval from the Institutional Animal Care and Use Committee of the University of Colorado Anschutz Medical Campus (IACUC# 00413).
DATA SHARING STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
PubMed: 38586005
DOI: 10.1101/2024.03.26.586818 -
Clinical Case Reports Apr 2024An encephalocele is a congenital malformation characterized by protrusion of the intracranial contents through a cranial defect. We report that a fetus of a pregnant...
An encephalocele is a congenital malformation characterized by protrusion of the intracranial contents through a cranial defect. We report that a fetus of a pregnant mother who had two consecutive pregnancies with ultrasound-detected encephalocele carried compound heterozygous variants in NM_152490.5:c.[1423C > T (p.Gln475Ter)]; [261-2A > G] of maternal and paternal origins, respectively, as confirmed by exome sequencing followed by Sanger sequencing validation. The present case implies that mutations in , a well-known dystroglycanopathy causative gene, may result in a phenotype of neural tube defect, providing new insights into the clinical spectrum of -related disorders. Our study may contribute to prenatal screening/diagnosis and genetic counseling of congenital brain malformations.
PubMed: 38585583
DOI: 10.1002/ccr3.8691 -
The Journal of Maternal-fetal &... Dec 2024Neural tube defects (NTDs) represent a spectrum of heterogeneous birth anomalies characterized by the incomplete closure of the neural tube. In Jordan, NTDs are...
INTRODUCTION
Neural tube defects (NTDs) represent a spectrum of heterogeneous birth anomalies characterized by the incomplete closure of the neural tube. In Jordan, NTDs are estimated to occur in approximately one out of every 1000 live births. Timely identification of NTDs during the 18-22 weeks of gestation period offers parents various management options, including intrauterine NTD repair and termination of pregnancy (TOP). This study aims to assess and compare parental knowledge and perceptions of these management modalities between parents of affected children and those with healthy offspring.
MATERIALS AND METHODS
This retrospective case-control study was conducted at Jordan University Hospital (JUH) using telephone-administered questionnaires. Categorical variables were summarized using counts and percentages, while continuous variables were analyzed using mean and standard deviation. The association between exposure variables and outcomes was explored using binary logistic regression. Data analysis was performed using SPSS for Windows version 26 (SPSS Inc., Chicago, IL).
RESULTS
The study sample comprised 143 participants, with 49.7% being parents of children with NTDs. The majority of NTD cases were associated with unplanned pregnancies, lack of folic acid supplementation, and postnatal diagnosis. Concerning parental knowledge of TOP in Jordan, 86% believed it to be legally permissible in certain situations. However, there was no statistically significant difference between cases and controls regarding attitudes toward TOP. While the majority of parents with NTD-affected children (88.7%) expressed a willingness to consider intrauterine surgery, this percentage decreased significantly (to 77.6%) after receiving detailed information about the procedure's risks and benefits ( = .013).
CONCLUSIONS
This study represents the first case-control investigational study in Jordan focusing on parental perspectives regarding TOP versus intrauterine repair of myelomeningocele following a diagnosis of an NTD-affected fetus. Based on our findings, we urge the implementation of a national and international surveillance program for NTDs, assessing the disease burden, facilitating resource allocation toward prevention strategies, and promoting early diagnosis initiatives either by using newly suggested diagnostic biomarkers or early Antenatal ultrasonography.
Topics: Child; Pregnancy; Female; Humans; Folic Acid; Jordan; Case-Control Studies; Retrospective Studies; Neural Tube Defects; Parents
PubMed: 38584146
DOI: 10.1080/14767058.2024.2334846 -
BMC Pregnancy and Childbirth Apr 2024Folic acid, a water-soluble B-complex vitamin, plays a crucial role in DNA synthesis and maintenance, making it particularly significant during reproduction. Its...
BACKGROUND
Folic acid, a water-soluble B-complex vitamin, plays a crucial role in DNA synthesis and maintenance, making it particularly significant during reproduction. Its well-known ability to reduce the risk of congenital anomalies during the periconceptional period underscores its importance. The increased requirement for folate during pregnancy and lactation is essential to support the physiological changes of the mother and ensure optimal growth and development of the foetus and offspring. This study assessed the knowledge, awareness, and use of folic acid among pregnant and lactating women of reproductive age residing in Dodowa in the Shai Osu-Doku District, Accra, Ghana.
METHODS
The study was a cross-sectional design that involved 388 randomly selected participants (97 pregnant and 291 lactating women). Structured questionnaires were administered to gather information on the socioeconomic demographic characteristics, knowledge, awareness, and use of folic acid of the participants. Dietary intake was assessed using a food frequency questionnaire. The data were analysed using descriptive statistics and Pearson's chi-square analysis tests and are presented as frequencies and percentages, means, standard deviations, bar graphs, and pie charts. The significance of the results was determined at a 95% confidence interval.
RESULTS
The mean age of the participants was 31 ± 5.0 years. Among the study participants, 46.1% demonstrated knowledge of folic acid deficiency, while approximately 68.3% had a high awareness of folic acid supplementation. Approximately 75% of the participants indicated that they had not used folic acid supplements within the week, and 15.5% reported consuming folic acid-fortified food per week.
CONCLUSIONS
The women exhibited high awareness but poor knowledge regarding the usage of folic acid supplementation during pregnancy and lactation. Consequently, this lack of knowledge influenced the low use of folic acid supplements and low intake of folate-rich foods among pregnant and lactating mothers.
Topics: Pregnancy; Female; Humans; Adult; Folic Acid; Cross-Sectional Studies; Ghana; Lactation; Neural Tube Defects; Health Knowledge, Attitudes, Practice; Dietary Supplements; Vitamin B Complex; Surveys and Questionnaires
PubMed: 38580949
DOI: 10.1186/s12884-024-06408-z -
BMC Ophthalmology Apr 2024Knobloch syndrome (KNO, OMIM # 267,750) is a rare ciliopathy group sydrome characterized by a collagen synthesis disorder. It represents an uncommon cause of pediatric... (Review)
Review
BACKGROUND
Knobloch syndrome (KNO, OMIM # 267,750) is a rare ciliopathy group sydrome characterized by a collagen synthesis disorder. It represents an uncommon cause of pediatric retinal detachment. This report presents two cases with different COL18A1 gene mutations, complicated by retinal detachment.
CASE PRESENTATION
Both cases exhibited high myopia and various degrees of occipital skull defect. The first case, a female, had bilateral congenital retinal detachment, posterior embryotoxon, and strabismus. The second case, a male, had unilateral congenital retinal detachment and neuromotor developmental delay. The first case, diagnosed in the early months of life, underwent successful retinal reattachment surgery. However, surgery was not performed on the second case, who presented with late-stage unilateral retinal detachment and pre-phthisis.
CONCLUSIONS
The report describes two patients with Knobloch syndrome, one of whom responded favorably to surgery for retinal detachment in both eyes. Successful anatomical results were achieved with early surgical interventions. It is essential to recognize the phenotypic and genetic heterogeneity within KNO.
Topics: Child; Female; Humans; Male; Encephalocele; Mutation; Retina; Retinal Degeneration; Retinal Detachment
PubMed: 38575892
DOI: 10.1186/s12886-024-03418-5 -
Ecotoxicology and Environmental Safety Apr 2024As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of...
BACKGROUND
As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development.
METHODS
In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE.
RESULTS
Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water.
CONCLUSIONS
Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.
Topics: Infant; Humans; Female; Pregnancy; Case-Control Studies; Anti-Bacterial Agents; Placenta; Neural Tube Defects; Risk Factors; Environmental Pollutants; Macrolides; Water
PubMed: 38564868
DOI: 10.1016/j.ecoenv.2024.116271 -
Cureus Feb 2024This case report presents the clinical and radiological findings of a seven-year-old female with type 2 diastematomyelia and spina bifida, emphasizing the complexity of...
This case report presents the clinical and radiological findings of a seven-year-old female with type 2 diastematomyelia and spina bifida, emphasizing the complexity of congenital spinal anomalies in pediatric patients. The patient presented with a two-month history of lower back pain, prompting diagnostic investigations. Radiographic examination revealed spina bifida at the L3-L5 levels, subsequently confirmed by magnetic resonance imaging (MRI), which disclosed bifid spinous processes, an absent posterior arch, and a split spinal cord terminating at the L3-L4 disc levels. The Vancouver classification system facilitated a standardized characterization of congenital spinal anomalies. The multidisciplinary approach involving orthopedic and neurosurgical specialists led to a conclusive diagnosis of type 2 diastematomyelia with simple spinal dysraphism. Surgical intervention, encompassing laminectomy and correction of the split spinal cord, was successfully performed, resulting in the stabilization of the patient. This case underscores the importance of early diagnosis, advanced imaging modalities, and collaborative management in addressing rare congenital spinal anomalies. The discussion delves into the clinical implications, diagnostic challenges, and the pivotal role of surgical intervention. Insights from this case contribute to the existing literature, guiding healthcare professionals in understanding and managing similar cases with potential implications for future research and treatment strategies.
PubMed: 38558588
DOI: 10.7759/cureus.55197 -
African Journal of Paediatric Surgery :... Apr 2024Spina bifida is a congenital malformation involving an open vertebral column resulting from failure in neural tube closure. It is among the most frequently occurring...
BACKGROUND
Spina bifida is a congenital malformation involving an open vertebral column resulting from failure in neural tube closure. It is among the most frequently occurring birth defects, observed in 1-3 cases per 1,000 live births worldwide. Conventionally requiring surgical repair, it can cause severe neurologic and musculoskeletal complications. However, consumption of prophylactic folic acid in mothers, at least 3 months before to 12 weeks after conception (periconceptional) has been shown to reduce the incidence of spina bifida by approximately 75%. This makes ascertaining parental understanding of such benefits critical. Therefore, this study provides baseline information on the awareness of periconceptional folic acid among parents whose children previously underwent surgical repair of spina bifida defects.
MATERIALS AND METHODS
The study subjects constituted 80 parents whose biological children had undergone surgical repair of spina bifida defects from 2014 to 2021 at a large paediatric tertiary care centre in South India. Upon providing informed consent, the subjects answered a cross-sectional telephonic survey containing 21 questions aimed at exposing their understanding of folic acid and its association with spina bifida.
RESULTS
None of the mothers had consumed folic acid before conception. However, 75% of them had consumed it as prescribed by their obstetrician during the first trimester of pregnancy. Finally, only 35% of them were aware of its role in preventing spina bifida.
CONCLUSION
The awareness of periconceptional folic acid and its preventive role in spina bifida was low amongst parents whose children were once treated for same congenital abnormality.
Topics: Pregnancy; Female; Humans; Child; Folic Acid; Pilot Projects; Cross-Sectional Studies; Spinal Dysraphism; Parents
PubMed: 38546248
DOI: 10.4103/ajps.ajps_102_22 -
Frontiers in Cell and Developmental... 2024In the early stage of embryonic development, the neural tube (NT) cannot be closed properly due to some complex factors, including environmental factors, genetic...
In the early stage of embryonic development, the neural tube (NT) cannot be closed properly due to some complex factors, including environmental factors, genetic factors, and the relationship between various factors, leading to the occurrence of neural tube defects (NTDs). In this study, we induced a mouse model of NTDs by feeding mice with a low-folate diet and intraperitoneally injecting them with 1.5 mg/kg methotrexate on E7.5. Fetal mice were achieved at E13.5, and we extracted proteins from brain tissues with trypsin digestion. After enzymatic digestion, peptides were labeled with TMT/iTRAQ and separated in high-performance liquid chromatography (HPLC) for subsequent liquid chromatography tandem mass spectroscopy (LC-MS/MS) analysis. We used gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation to analyze proteomic changes and analyze the functional enrichment of differentially expressed proteins (DEPs) in the NTD mice tissues. A low-folate-induced mouse model was successfully constructed. Folate was used as a sensitizing agent, and the teratogenicity rate of the NTD fetal mice increased to 36.5% when the concentration of methotrexate was at 1.5 mg/kg. Mass spectrometry was used to identify 6,614 proteins, and among them, 5,656 proteins were quantified. In the following proteomic analysis, GO classification and KEGG pathway enrichment analysis were conducted, and heatmaps were drawn for differentially expressed proteins (DEPs). The main pathways associated with NTDs, such as the Hedgehog, Wnt, p53, and Hippo signaling pathways and the one-carbon pool mediated by folate, can be identified through a protein-protein interaction (PPI) network. It was also found that the regulation of ribosomal proteins, such as RPL13 and RPL14, which are upregulated in NTDs, has a certain impact on neural tube development. Our results revealed proteomic changes in the tissues of low-folate-induced NTD mice. Validation showed that ribosomal proteins play a regulatory role during the development of NTDs and provides new ideas for the pathogenesis and preventive measures of NTDs.
PubMed: 38544816
DOI: 10.3389/fcell.2024.1294726