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Mutation Research Jun 2024Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion... (Review)
Review
Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.
PubMed: 38944932
DOI: 10.1016/j.mrfmmm.2024.111870 -
Clinical Dysmorphology Jun 2024
PubMed: 38934085
DOI: 10.1097/MCD.0000000000000504 -
Microorganisms May 2024Parvovirus infection affects several animal species, especially young animals. In birds, parvovirus infection has been described in Muscovy ducks, turkeys, and chickens,...
Parvovirus infection affects several animal species, especially young animals. In birds, parvovirus infection has been described in Muscovy ducks, turkeys, and chickens, all of which had enteric diseases characterized by diarrhea. Chicken parvovirus (ChPV) has been detected in poultry around the world in animals affected by enteric problems, showing dwarfism, cloacal pasting, and diarrhea. In Brazil, ChPV was detected in chickens affected by diarrhea fifteen years ago. However, the genetic characteristics of ChPV circulating in chicken flocks were not determined. Therefore, the aim of the present investigation was to determine the genetic characteristics of the VP1 gene from ChPV detected in chickens affected by enteric diseases in Brazil. For this purpose, a molecular approach was used. Specific primers were designed to flank the complete VP1 gene of ChPV and amplify it using PCR. The amplified products from samples of chickens with enteric diseases were sequenced, and 22 complete CDs of the VP1 gene were obtained. These samples, compared to the ABU-P1 sequence, showed 17 sequences with high nucleotide (NT) similarity of 92.7-97.4% and amino acid (AA) similarity of 94.8-99.5% associated with Runting and Stunting syndrome (RSS); there were also five samples associated with hens with diarrhea with unusual jejunal dilatation (JD) that had less similarity than the RSS sequences (NT of 86.5% and AA of 93-93.1%). The phylogenetic analysis determined four groups. Group I had sequences from Korea. The second group included sequences from Korea, China, and Brazil (not included in this work). The third group had studied RSS sequences grouped with the ABU-P1 strain and sequences from China and the United States. Finally, the sequences from JD were clustered in a separate group with a bootstrap of 100%, a group that was denoted as group IV, and included sequences from China. RDP4 and SimPlot analysis showed one point of recombination with the sequences of group III ChPV in the JD sequences. Herein, we show that circulating strains of ChPV exhibit genetic differences in the VP1 gene in Brazilian chicken flocks. Nevertheless, more studies are needed to determine the probability of a new genetic group of ChPV based on the analysis of the complete genome.
PubMed: 38930446
DOI: 10.3390/microorganisms12061065 -
Veterinary World May 2024Short beak and dwarfism syndrome (SBDS), a highly contagious disease, has been reported in duck farms in Vietnam since 2019. In this study, we evaluated the virulence...
BACKGROUND AND AIM
Short beak and dwarfism syndrome (SBDS), a highly contagious disease, has been reported in duck farms in Vietnam since 2019. In this study, we evaluated the virulence and characterized the virus obtained from SBDS cases in North Vietnam.
MATERIALS AND METHODS
Polymerase chain reaction was used to detect waterfowl parvovirus in ducks, and the virus from positive samples was inoculated into 10-day-old duck-embryonated eggs to reproduce the disease in young ducklings to determine the virulence and subjected to phylogenetic analysis of non-structural (NS) and VP1 gene sequences.
RESULTS AND DISCUSSION
Goose parvovirus (GPV) was isolated from ducks associated with SDBS in Vietnam. The virus Han-GPV2001 is highly virulent when inoculated into 10-day-old duck embryos and 3-day-old ducklings. The mortality rate of duck embryos was 94.35% within 6 days of virus inoculation. Inoculating 3-day-old ducks with the virus stock with 10 EID through intramuscular and neck intravenous administration resulted in 80% and 66.67% of clinical signs of SDBS, respectively, were shown. Phylogenetic analysis based on the partial NS and VP1 gene sequences revealed that the viral isolate obtained in this study belonged to novel GPV (NGPV) and was closely related to previous Vietnamese and Chinese strains.
CONCLUSION
A GPV strain, Han-GPV2001, has been successfully isolated and has virulence in duck-embryonated eggs as well as caused clinical signs of SBDS in ducks. Phylogenetic analyses of partial genes encoding NS and capsid proteins indicated that the obtained GPV isolate belongs to the NGPV group.
PubMed: 38911086
DOI: 10.14202/vetworld.2024.981-987 -
Medicine Jun 2024Treatment outcomes for different causes of childhood dwarfism vary widely, and there are no studies on the economic burden of treatment in relation to outcomes. This...
Treatment outcomes for different causes of childhood dwarfism vary widely, and there are no studies on the economic burden of treatment in relation to outcomes. This paper compared the efficacy and healthcare costs per unit height of recombinant human growth hormone (rhGH) for the treatment of growth hormone deficiency (GHD) and idiopathic short stature (ISS) with a view to providing a more cost-effective treatment option for children. We retrospectively analyzed 117 cases (66 cases of GHD and 51 cases of ISS) of short-stature children who first visited Weifang People's Hospital between 2019.1 and 2022.1 and were treated with rhGH for 1 to 3 years to track the treatment effect and statistically analyzed by using paired t tests, non-parametric tests, and chi-square tests, to evaluate the efficacy of rhGH treatment for GHD and ISS children and the medicinal cost. The annual growth velocity (GV) of children with GHD and ISS increased the fastest during 3 to 6 months after treatment and then gradually slowed down. The GV of the GHD group was higher than that of the ISS group from 0 to 36 months after treatment (P < .05 at 3, 6, 9, and 12 months); the height standard deviation scores (HtSDS) of the children in the GHD and ISS groups increased gradually with the increase of the treatment time, and the changes in the height standard deviation scores (ΔHtSDS) of the GHD group were more significant than those of the ISS group (P < .05 at 3, 6, 9, and 12 months). (2) The medical costs in the pubertal group for a 1-cm increase in height were higher than those of children in the pre-pubertal group at the same stage (3 to 24 months P < .05). The longer the treatment time within the same group, the higher the medical cost of increasing 1cm height. RhGH is effective in treating children with dwarfism to promote height growth, and the effect on children with GHD is better than that of children with ISS; the earlier the treatment time, the lower the medical cost and the higher the comprehensive benefit.
Topics: Humans; Human Growth Hormone; Child; Retrospective Studies; Male; Female; Dwarfism; Recombinant Proteins; Body Height; Treatment Outcome; Child, Preschool; Growth Disorders; Economics, Pharmaceutical; Cost-Benefit Analysis; Health Care Costs; Adolescent
PubMed: 38905369
DOI: 10.1097/MD.0000000000038350 -
Frontiers in Pediatrics 2024Small-for-gestational age (SGA) has been a great concern in the perinatal period as it leads to adverse perinatal outcomes and increased neonatal morbidity and... (Review)
Review
Small-for-gestational age (SGA) has been a great concern in the perinatal period as it leads to adverse perinatal outcomes and increased neonatal morbidity and mortality, has an impact on long-term health outcomes, and increases the risk of metabolic disorders, cardiovascular, and endocrine diseases in adulthood. As an endogenous ligand of the growth hormone secretagotor (GHS-R), ghrelin may play an important role in regulating growth and energy metabolic homeostasis from fetal to adult life. We reviewed the role of ghrelin in catch-up growth and energy metabolism of SGA in recent years. In addition to promoting SGA catch-up growth, ghrelin may also participate in SGA energy metabolism and maintain metabolic homeostasis. The causes of small gestational age infants are very complex and may be related to a variety of metabolic pathway disorders. The related signaling pathways regulated by ghrelin may help to identify high-risk groups of SGA metabolic disorders and formulate targeted interventions to prevent the occurrence of adult dwarfism, insulin resistance-related metabolic syndrome and other diseases.
PubMed: 38903769
DOI: 10.3389/fped.2024.1395571 -
Molecular Biology and Evolution Jun 2024The feral cattle of the subantarctic island of Amsterdam provide an outstanding case study of a large mammalian population that was established by a handful of founders...
The feral cattle of the subantarctic island of Amsterdam provide an outstanding case study of a large mammalian population that was established by a handful of founders and thrived within a few generations in a seemingly inhospitable environment. Here, we investigated the genetic history and composition of this population using genotyping and sequencing data. Our inference showed an intense but brief founding bottleneck around the late 19th century and revealed contributions from European taurine and Indian Ocean zebu in the founder ancestry. Comparative analysis of whole genome sequences further revealed a moderate reduction in genetic diversity despite high levels of inbreeding. The brief and intense bottleneck was associated with high levels of drift, a flattening of the site frequency spectrum and a slight relaxation of purifying selection on mildly deleterious variants. Unlike some populations that have experienced prolonged reductions in effective population size, we did not observe any significant purging of highly deleterious variants. Interestingly, the population's success in the harsh environment can be attributed to pre-adaptation from their European taurine ancestry, suggesting no strong bioclimatic challenge, and also contradicting evidence for insular dwarfism. Genome scan for footprints of selection uncovered a majority of candidate genes related to nervous system function, likely reflecting rapid feralization driven by behavioral changes and complex social restructuring. The Amsterdam Island cattle offers valuable insights into rapid population establishment, feralization, and genetic adaptation in challenging environments. It also sheds light on the unique genetic legacies of feral populations, raising ethical questions according to conservation efforts.
PubMed: 38889245
DOI: 10.1093/molbev/msae121 -
Human Molecular Genetics Jun 2024The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also...
The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.
PubMed: 38888340
DOI: 10.1093/hmg/ddae101 -
Microbial Pathogenesis Jun 2024Short-beak and dwarfism syndrome (SBDS) is a new disease caused by a genetic variant of goose parvovirus in ducks that results in enormous economic losses for the...
Short-beak and dwarfism syndrome (SBDS) is a new disease caused by a genetic variant of goose parvovirus in ducks that results in enormous economic losses for the waterfowl industry. Currently, there is no commercial vaccine for this disease, so it is urgent to develop a safer and more effective vaccine to prevent this disease. In this study, we optimized the production conditions to enhance the expression of the recombinant VP2 protein and identified the optimal conditions for subsequent large-scale expression. Furthermore, the protein underwent purification via nickel column affinity chromatography, followed by concentration using ultrafiltration tube. Subsequently, it was observed by transmission electron microscopy (TEM) that the NGPV recombinant VP2 protein assembled into virus-like particles (VLPs) resembling those of the original virus. Finally, the ISA 78-VG adjuvant was mixed with the NGPV-VP2 VLPs to be prepared as a subunit vaccine. Furthermore, both agar gel precipitation test (AGP) and serum neutralization test demonstrated that NGPV VLP subunit vaccine could induce the increase of NGPV antibody in breeding ducks. The ducklings were also challenged with the NGPV, and the results showed that the maternal antibody level could provide sufficient protection to the ducklings. These results indicated that the use of the NGPV VLP subunit vaccine based on the baculovirus expression system could facilitate the large-scale development of a reliable vaccine in the future.
PubMed: 38880314
DOI: 10.1016/j.micpath.2024.106751 -
Proceedings of the National Academy of... Jun 2024Endoplasmic reticulum (ER)-associated degradation (ERAD) plays key roles in controlling protein levels and quality in eukaryotes. The Ring Finger Protein 185...
Endoplasmic reticulum (ER)-associated degradation (ERAD) plays key roles in controlling protein levels and quality in eukaryotes. The Ring Finger Protein 185 (RNF185)/membralin ubiquitin ligase complex was recently identified as a branch in mammals and is essential for neuronal function, but its function in plant development is unknown. Here, we report the map-based cloning and characterization of (), which encodes the ER membrane-localized protein membralin and specifically interacts with maize homologs of RNF185 and related components. The mutant shows defective leaf and root development due to reduced cell number. The defects of were largely restored by expressing membralin genes from and mice, highlighting the conserved roles of membralin proteins in animals and plants. The excessive accumulation of β-hydroxy β-methylglutaryl-CoA reductase in indicates that the enzyme is a membralin-mediated ERAD target. The activation of mRNA splicing-related unfolded protein response signaling and marker gene expression in , as well as DNA fragment and cell viability assays, indicate that membralin deficiency induces ER stress and cell death in maize, thereby affecting organogenesis. Our findings uncover the conserved, indispensable role of the membralin-mediated branch of the ERAD pathway in plants. In addition, contributes to plant architecture in a dose-dependent manner, which can serve as a potential target for genetic engineering to shape ideal plant architecture, thereby enhancing high-density maize yields.
Topics: Zea mays; Endoplasmic Reticulum-Associated Degradation; Plant Proteins; Ubiquitin-Protein Ligases; Endoplasmic Reticulum; Arabidopsis; Animals; Gene Expression Regulation, Plant; Endoplasmic Reticulum Stress; Membrane Proteins; Mice; Arabidopsis Proteins; Plant Leaves; Unfolded Protein Response
PubMed: 38865274
DOI: 10.1073/pnas.2406090121