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Viruses May 2024Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved...
Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A and Alhydrogel as adjuvants to further stimulate the immune response. MPL-A induces a Th1-mediated immune response and Alhydrogel (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of -19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4 helper and CD8 cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally.
Topics: Animals; Administration, Intranasal; Zika Virus Infection; Zika Virus; Mice; Antibodies, Viral; Viral Vaccines; Female; Immunization; Adjuvants, Immunologic; Disease Models, Animal; Adjuvants, Vaccine; Vaccination; Cytokines; Antibodies, Neutralizing
PubMed: 38932158
DOI: 10.3390/v16060865 -
Journal of Clinical Medicine Jun 2024Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder connected with a distinctive facial appearance, various skeletal malformations, delayed bone age,...
Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder connected with a distinctive facial appearance, various skeletal malformations, delayed bone age, and expressive language delays. It is caused by heterozygous mutations in the Snf2-related CREBBP activator protein (SRCAP) gene. The aim of this paper is to describe the case of a 14-year-old male with FHS, referring to a review of the literature, and to collect all reported symptoms. In addition, the orthodontic treatment of the patient is described. For this, the electronic databases PubMed and Scopus were searched using the keyword "Floating-Harbor syndrome". Similar to previous cases in the literature, the patient presented with short stature; a triangular face with a large bulbous nose; deep-set eyes and narrow eyelid gaps; a wide mouth with a thin vermilion border of the upper lip; and dorsally rotated, small ears. They also presented some less-described symptoms, such as macrodontia and micrognathia. Moreover, mild mental retardation, microcephaly, and delayed psychomotor development were found. On the basis of an extraoral, intraoral examination, X-rays, and CBCT, he was diagnosed with overbite, canine class I and angle class III, on both sides. To the best of our knowledge, orthodontic treatment of this disease has not been assessed in detail so far, so this is the first case.
PubMed: 38929963
DOI: 10.3390/jcm13123435 -
Cureus May 2024TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient...
TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient presented similarly to previous cases with features including microcephaly, epilepsy, and speech and motor delay. Unique characteristics were also present such as trigonocephaly, tethered frenulum, scoliosis, nystagmus, and a concurrent FBXW7 mutation. This case expands our breadth of knowledge on TUBG1 genotypic and phenotypic variation. However, further work is needed to fully understand this rare mutation and the associations between TUBG1 and FBXW7 mutations.
PubMed: 38919239
DOI: 10.7759/cureus.61132 -
Cureus May 2024Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in...
Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in genes implicated in megakaryocyte differentiation and function. Diaphanous-related formin 1 (DIAPH1) is a protein-coding gene. Dominant gain-of-function DIAPH1 variants cause macrothrombocytopenia and sensorineural deafness (autosomal dominant non-syndromic hearing loss 1 (DFNA1)), while homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). This rare genetic disease is characterized by progressive and severe hearing loss with onset in the first decade of life, is associated with mild thrombocytopenia, and has no significant bleeding tendency. This case report presents the clinical findings of a 14-year-old Saudi pediatric girl. We investigated the potential association of DIAPH1 as a novel candidate gene linked to dominant MTP and autosomal dominant non-syndromic hearing loss (ADNSHL), which was evaluated through audiometry. Notably, a novel variant, c.3633_3636del, was identified in the DIAPH1 gene. To date, only a small number of mutations in this gene have been reported as the cause of MTP and ADNSHL.
PubMed: 38915998
DOI: 10.7759/cureus.61044 -
Cureus May 2024Congenital toxoplasmosis is caused by transplacental infection of during pregnancy. We present a case of a congenital toxoplasma with intracranial calcifications,...
Congenital toxoplasmosis is caused by transplacental infection of during pregnancy. We present a case of a congenital toxoplasma with intracranial calcifications, microcephaly, growth restriction, a unilateral cataract that developed in the third trimester, and a coincidental post-axial-polydactyly. Antenatal imaging findings are important to guide further testing and confirmation of diagnosis, it is important to know all possible associations and prognoses for timely counseling, testing, and intervention. To our knowledge, no case has been published with findings of unilateral cataract in congenital toxoplasmosis and associated coincidental polydactyly. Therefore, we wish to add this case to the current scientific literature.
PubMed: 38915958
DOI: 10.7759/cureus.61058 -
Cureus Jun 2024Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in...
Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.
PubMed: 38912084
DOI: 10.7759/cureus.62749 -
BioRxiv : the Preprint Server For... Mar 2024The transitioning of neural stem cells (NSCs) between quiescent and proliferative states is fundamental for brain development and homeostasis. Defects in NSC...
The transitioning of neural stem cells (NSCs) between quiescent and proliferative states is fundamental for brain development and homeostasis. Defects in NSC reactivation are associated with neurodevelopmental disorders. quiescent NSCs extend an actin-rich primary protrusion toward the neuropil. However, the function of the actin cytoskeleton during NSC reactivation is unknown. Here, we reveal the fine F-actin structures in the protrusions of quiescent NSCs by expansion and super-resolution microscopy. We show that F-actin polymerization promotes the nuclear translocation of Mrtf, a microcephaly-associated transcription factor, for NSC reactivation and brain development. F-actin polymerization is regulated by a signaling cascade composed of G-protein-coupled receptor (GPCR) Smog, G-protein αq subunit, Rho1 GTPase, and Diaphanous (Dia)/Formin during NSC reactivation. Further, astrocytes secrete a Smog ligand Fog to regulate Gαq-Rho1-Dia-mediated NSC reactivation. Together, we establish that the Smog-Gαq-Rho1 signaling axis derived from astrocytes, a NSC niche, regulates Dia-mediated F-actin dynamics in NSC reactivation.
PubMed: 38903085
DOI: 10.1101/2024.03.11.584337 -
Nature Communications Jun 2024Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly...
Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly understood. We utilize an established female pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We find prenatal ZikV exposure leads to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses reveal marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals shows multi-focal decompaction, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.
Topics: Animals; Zika Virus Infection; Oligodendroglia; Female; Myelin Sheath; Pregnancy; Zika Virus; Disease Models, Animal; Pregnancy Complications, Infectious; Macaca nemestrina; Brain; Humans; Myelin Basic Protein
PubMed: 38890352
DOI: 10.1038/s41467-024-49524-2 -
Medicine Jun 2024Gastric cancer typically originates from the abnormal proliferation of normal cells within the gastric mucosa, eventually forming tumors. The roles of sperm-associated... (Observational Study)
Observational Study
Gastric cancer typically originates from the abnormal proliferation of normal cells within the gastric mucosa, eventually forming tumors. The roles of sperm-associated antigen 5 (SPAG5) and abnormal spindle-like microcephaly (ASPM) associated genes in gastric cancer are not yet clear. Gastric cancer datasets GSE51575 and GSE36076 profiles were downloaded from the GPL13607 and GPL570-generated gene expression omnibus database. The analysis included filtering for differentially expressed genes, weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, immune infiltration analysis, construction and analysis of the protein-protein interaction network, survival analysis, and Comparative Toxicogenomics Database analysis. Heatmaps of gene expression were also created. A total of 1457 differentially expressed genes were identified. According to gene ontology analysis, they are primarily enriched in the metabolic processes of organic acids, condensed chromosome centromere regions, and oxidoreductase activity. Kyoto Encyclopedia of Gene and Genome analysis showed they are mainly involved in metabolic pathways, P53 signaling pathway, and PPAR signaling pathway. The soft threshold power for weighted gene co-expression network analysis was set to 8. Three core genes (CENPE, SPAG5, and ASPM) were identified. Heatmaps of core gene expression revealed that SPAG5 and ASPM are highly expressed in gastric cancer samples and low in normal samples. Comparative Toxicogenomics Database analysis indicated that the core genes (CENPE, SPAG5, and ASPM) are associated with gastric tumors, gastric diseases, gastritis, gastric ulcers, tumors, inflammation, and necrosis. The SPAG5 and ASPM genes are overexpressed in gastric cancer tissues, and higher expression levels are associated with worse prognosis, may serve as potential prognostic markers.
Topics: Stomach Neoplasms; Humans; Cell Cycle Proteins; Gene Expression Regulation, Neoplastic; Protein Interaction Maps; Adaptor Proteins, Signal Transducing; Biomarkers, Tumor; Gene Expression Profiling; Nerve Tissue Proteins
PubMed: 38875410
DOI: 10.1097/MD.0000000000038499 -
Cureus May 2024Trisomy 13, also known as Patau syndrome, is a widely congenital anomaly syndrome characterized by microphthalmia, cleft lip, and palate, microcephaly with a sloping...
Trisomy 13, also known as Patau syndrome, is a widely congenital anomaly syndrome characterized by microphthalmia, cleft lip, and palate, microcephaly with a sloping forehead, congenital heart disease, and polydactyly of the limbs. Patau syndrome is identified either prenatally or postnatally. Its survival rate is low, and most of the patients die even before their first year of life. The risk of trisomy 13 is higher in women of advanced maternal age. Brain and cardiovascular abnormalities are typically the primary factors contributing to the syndrome's poor prognosis. We report a case of a male newborn born at full term from a first-degree consanguineous marriage. Upon initial inspection, the patient had classic dysmorphic features, including low-set ears, a cleft lip and palate, a short neck, bilateral anophthalmia, and polydactyly of the limbs. After chromosomal analysis, the diagnosis was made, and a trisomy 13 was discovered.
PubMed: 38872687
DOI: 10.7759/cureus.60264