Aberrant Development Research Articles

Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex.

Structural Maintenance of Chromosome (SMC) complexes are molecular machines ensuring chromatin organization at higher levels. They play direct roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of long-armed SMC, kleisin, and kleisin-associated subunits. Additional factors, like NSE6 within SMC5/6, bind to SMC core complexes and regulate their activities. In the human HsNSE6/SLF2, we recently identified a new CANIN domain. Here we tracked down its sequence homology to lower plants, selected bryophyte Physcomitrium patens (Pp), and analyzed PpNSE6 protein-protein interactions to explore its conservation in detail. We identified a previously unrecognized core sequence motif conserved from yeasts to humans within the NSE6 CANIN domain. This motif mediates the interaction between NSE6 and its NSE5 partner in yeasts and plants. In addition, the CANIN domain and its preceding PpNSE6 sequences bind both PpSMC5 and PpSMC6 arms. Interestingly, we mapped the PpNSE6-binding site at the PpSMC5 arm right next to the PpNSE2-binding surface. The position of NSE6 at SMC arms suggests its role in SMC5/6 dynamics regulation. Consistent with the regulatory role of NSE6 subunits, Ppnse6 mutant lines were viable, sensitive to the DNA-damaging drug bleomycin and lost a large portion of rDNA copies. These moss mutants also exhibited reduced growth and developmental aberrations. Altogether, our data showed the conserved function of the NSE6 subunit and architecture of the SMC5/6 complex across species.

ASH2L, a COMPASS core subunit, is involved in the cell invasion and migration of triple-negative breast cancer cells through the epigenetic control of histone H3 lysine 4 methylation

ASH2L (Absent-Small-Homeotic-2-Like protein) is a core subunit of the COMPASS (COMplex of Proteins ASsociated with Set1) complex, the most notable writer of the methylation of histone H3 lysine 4 (H3K4). The COMPASS complex regulates active promoters or enhancers for gene expression, and its dysfunction is associated with aberrant development and disease. Here, we demonstrated that ASH2L mediated the cell invasion and migration activity of triple-negative breast cancer cells through the interaction with the COMPASS components and the target genomic regions. Transcriptome analysis indicated a potential correlation between ASH2L and the genes involved in inflammatory/immune responses. Among them, we found that the intrinsic expression of IL1B (interleukin 1 beta), an essential proinflammatory gene, was directly regulated by ASH2L. These results revealed a novel role of ASH2L on the maintenance of breast cancer malignancy possibly through H3K4 methylation of the target inflammatory/immune responsive genes.

Current Trends in the Diagnosis and Evidence-Based Management of Patients with Myeloproliferative Disorders

Myeloproliferative disorders (MPD) are clonal hematopoietic disorders characterized by abnormal clone expansion of haematological progenitor cells, which can lead to thrombosis, bleeding, and/or transformation to leukaemia. Chronic myelogenous leukaemia (CML) is characterised by increasing granulocytic cell proliferation with no loss of differentiation, leading to an increased number of granulocytes and their immature progenitors, with occasional blast cells on peripheral blood film. Polycythaemia Vera (PV) is a disorder of stem cells that presents a total hyperplasia, malignant, and cancerous marrow. Its most prominent feature is an increased absolute red blood cell mass due to uncontrolled red blood cell production, followed by increased myeloid and megakaryocytic production due to an abnormal clone of the haematopoietic stem cells with increased sensitivity to growth factors. Essential thrombocythemia (ET) is defined by a persistent increase in platelet count with a proclivity for thrombosis and haemorrhage. Expansion of megakaryocytes in the cell lineage leads to high platelet count, and the condition is thought to be clonal. Primary myelofibrosis (PMF) results in aberrant megakaryocyte development. Extramedullary haematopoiesis and reactive connective tissues are found in fully mature bone marrow (BM). PMF is linked to uncontrolled megakaryopoiesis as well as atypical, fibrosis, and hypercellularity. Haematological and morphological abnormalities in combinations with mutations (BCR-ABL, CARL, JAK2 or MPL) represent major diagnostic criteria for MPD. The WHO criteria for tumours of the hemopoietic and lymphoid tissues was revised in 2016. Prognostic models rely on clinical and haematological data, but new models with genetic information are being created for clinical trial environments. Management of most patients with MPDs involves treatment or monitoring symptoms associated with presenting disease and/or preventing other events such as thrombosis. Treatment modalities include symptomatic treatments, surgery, therapeutic radiation, therapeutic phlebotomy, therapeutic apheresis, cytoreductive therapy and haematopoietic stem cells transplantations.

A heterozygous mutation in UBE2H in a patient with developmental delay leads to an aberrant brain development in zebrafish

BackgroundUbiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin–proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants.MethodsIn our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis.ResultsThrough trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos.ConclusionA de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly.

Complex lymphatic anomalies are debilitating conditions characterized by aberrant development of the lymphatic vasculature (lymphangiogenesis). Diagnosis is typically made by history, examination, radiology, and histologic findings. However, there is significant overlap between conditions, making accurate diagnosis difficult. Recently, genetic analysis has been offered as an additional diagnostic modality. Here, we describe four cases of complex lymphatic anomalies, all with PIK3CA variants but with varying clinical phenotypes. Identification of PIK3CA resulted in transition to a targeted inhibitor, alpelisib. These cases highlight the genetic overlap between phenotypically diverse lymphatic anomalies.

Prediction of Disease from Blood Microscopic Analysis Classification using Deep Learning Algorithm

Traditional blood disease detection based on visual inspection of blood smears using a microscope is time consuming, error-prone, and limited by the physical acuity of the hematologist. To facilitate clinical decision-making, an automated optical image processing system is required. Leukemia is a kind of cancer that is distinguished by the aberrant development of immature, abnormally shaped white blood cells (WBC) known as "blasts." Leukemia is a cancer of the white blood cells (WBCs) that affects the bone marrow and/or blood. A timely, safe, and accurate diagnosis of leukemia at an early stage is critical to treating and preserving patients' lives. The white blood cells in a blood smear are often examined under a microscope to determine the diagnosis.Many machine learning have been created to diagnose various illnesses, such as leukemia, and to deliver a high mis-classification error rate. As a result, we may use a deep learning system to identify microscope pictures for White Blood Cell Count study. The WBC differential counting system was divided into two modules: detection and classification. The detection module first processed the raw bone smear pictures, detecting all WBCs including red blood cells, platelet counts, staining impurities, and so on. The discovered cells were then sent into the categorization module.The categorization module was divided into two phases. In the first step, we separated a large number of cells, such as crushed cells, degenerated cells, and so on, that are not employed in the diagnosis for leukemia. The countable WBCs were then presented for multi-class separation using the Convolutional neural network technique in the second step

Delayed onset ADA-SCID presenting as secondary HLH in a patient with normal newborn screening

Severe combined immunodeficiency (SCID) is a rare genetic syndrome caused by aberrant immune cell development or function and is fatal without early identification and treatment. The Centers for Disease Control estimates the annual incidence of SCID to be one case per 40,000 to 100,000 live births. Newborn screening using T-cell receptor excision circles (TREC) allows for early detection and timely treatment of SCID. Adenosine deaminase (ADA) is a vital enzyme in the purine salvage pathway, and its deficiency results in disruption of T, B and NK cell development, accounting for 10–20% of SCID cases. The timing of ADA-SCID presentation ranges from birth to delayed onset disease. Importantly, without early recognition and treatment, delayed onset ADA-SCID results in accumulation of toxic metabolites causing immune dysfunction, recurrent infections, and subsequent organ damage. Recently, some groups have questioned whether traditional TREC newborn screening adequately identifies ADA-SCID, especially those cases with delayed onset. We present the case of a 2-year-old male with normal newborn screening but a history of recurrent otitis media and respiratory infections who developed multisystem organ failure and septicemia with Escherichia coli, candida, adenovirus and enterovirus despite broad-spectrum antimicrobials. The patient also had features of a hyperinflammatory syndrome with fever, pancytopenia, hypertriglyceridemia, and hyperferritinemia and was treated for hemophagocytic lymphohistiocytosis (HLH) with dexamethasone and plasma exchange followed by anakinra, etoposide, and emapalumab. The patient was maximally supported with mechanical ventilation, extracorporeal membrane oxygenation, and renal replacement therapy but had progressive clinical deterioration and ultimately expired. Autopsy was notable for thymic aplasia and erythrophagocytosis in the bone marrow and lymph nodes. Genetic testing revealed a heterozygous missense pathogenic variant in exon 7 in the ADA gene as well as novel heterozygous intronic variant of unknown significance in the ADA gene. Postmortem data suggests this patient had ADA-SCID with multi-pathogen infections and secondary HLH. This case potentially identifies a novel pathogenic variant in ADA missed by traditional TREC newborn screening and highlights the need to retain a high clinical suspicion of SCID in patients with a history of recurrent infections despite normal TREC screening.

Delayed B-cell maturation with extra-follicular B-cell response and broad autoantibody repertoire are characteristic B-cell dysregulation signatures in patients with multi-lineage cytopenia

IntroductionMulti-lineage cytopenia (m-IC) are increasingly recognized as presenting manifestation of inborn errors immunity (IEI). Although around 40% of these patients are associated with known IEI, the underlying immune anomalies at onset of m-IC are poorly understood. Recently, we published a unique immune signature characterized by abnormal expansion of circulating T-follicular helper cells (cTfh), increased T-cell activation and decreased naïve CD4+ T (Kumar et.al Blood 2022). Despite our improved understanding of T-cell immune abnormalities, the underlying B-cell dysfunction is largely undefined at onset of m-IC. MethodsIn this study, we enrolled 20 patients with pES, 30 patients with chronic ITP (cITP) and 18 healthy controls (HCs). High dimensional B cell immunophenotyping was performed to assess B-cell maturation, extrafollicular B cell development, and autoreactivity. Autoantibody profiling was performed using human protein microarrays. Multiplex immunofluorescence staining of lymph nodes was performed to evaluate germinal center reaction. ResultsWe observed that patients with m-IC had increased frequency of CD10+ immature B cells in comparison to cITP and HCs. Despite an expansion of cTfh and elevated levels of plasma CXCL13, we observed decreased frequency of CSMB which suggests underlying defects in B-cell maturation. While canonical B-cell maturation was defective, we noticed aberrant extrafollicular B-cell development characterized by significantly higher proportion of DN2 (CD11c+CD21low) and decreased proportion of DN1 (CD21+ CD11c-) populations (Figure 1A). However, the frequency of parent population i.e., double negative (DN) (IgD- CD27-) B-cells was similar across the cohorts. In addition, we also noted decreased proportion of CXCR5+ B cells in 30% of patients and overall skewed CXCR5 expression on B versus T cells. Furthermore, we noted increase in autoreactivity in B cells as evident by increase in proportion of 9G4+ B cells. To further assess auto-antibody driven pathophysiology, we evaluated the auto-antibody repertoire and found broad auto-antibody repertoire targeting several biological processes (Figure 1B). [Display omitted] ConclusionsTaken together, our findings identified broad B-cell immune abnormalities along with unique auto-antibody repertoire in patients with m-IC. In addition to enhancing our current knowledge of disease pathology, the utility of these findings could further help in disease monitoring and evaluating response to the therapeutics.

Proprioception and Tactile Perception in Schizophrenia

The aim of this review is to investigate the relationship between proprioceptive and tactile perceptual aberrations and the psychotic symptoms of schizophrenia, a correlation which has already been established by several studies (Lenzenweger, 2006; Postmes et al., 2014; Chang and Lenzenweger, 2005; Michael and Park, 2016; Germine et al., 2013; Kent et al., 2010). However, the direction of causality within the correlation is still unknown. Because several studies indicate an abnormal and uneven weighting of the senses in schizophrenic multisensory integration, it is possible that the psychotic symptoms of schizophrenia may be due to multisensory integration abnormalities involving proprioceptive and tactile perception. Several theories have also been proposed that schizophrenia itself is the cause of these proprioceptive and tactile perception anomalies. There could also be neuroanatomical factors that underlie both the schizophrenia psychotic symptoms and proprioceptive and tactile perception aberrations. Because of limitations in the current research, a definite causal direction is still unable to be determined. Several practices to improve the methods of analysis in this field of study include incorporating measures of schizotypy with less subjectivity and using longitudinal neurodevelopmental studies to pinpoint developmental aberrations in proprioception, tactile perception, and the correlated psychotic symptoms of schizophrenia. These methods may lead to better pre-emptive target interventions and could establish the directionality of causation between proprioception and tactile perception anomalies and positive schizophrenia symptoms.

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development.

Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex development (DSD). To date, pathogenic variants of three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) have been reported to cause DSD via atypical testicular development. In this review article, we describe the clinical significance of the NR5A1 variants as the cause of DSD and introduce novel findings from recent studies. NR5A1 variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. Notably, both 46,XX DSD and 46,XY DSD caused by the NR5A1 variants show remarkable phenotypic variability, to which digenic/oligogenic inheritances potentially contribute. Additionally, we discuss the roles of NR0B1 and NR2F2 in the etiology of DSD. NR0B1 acts as an anti-testicular gene. Duplications containing NR0B1 result in 46,XY DSD, whereas deletions encompassing NR0B1 can underlie 46,XX testicular/ovotesticular DSD. NR2F2 has recently been reported as a causative gene for 46,XX testicular/ovotesticular DSD and possibly for 46,XY DSD, although the role of NR2F2 in gonadal development is unclear. The knowledge about these three nuclear receptors provides novel insights into the molecular networks involved in the gonadal development in human fetuses.

A simplified protocol for the generation of cortical brain organoids.

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.

No difference in extra-axial cerebrospinal fluid volumes across neurodevelopmental and psychiatric conditions in later childhood and adolescence

BackgroundWhile autism spectrum disorder has been associated with various organizational and developmental aberrations in the brain, an increase in extra-axial cerebrospinal fluid volume has recently garnered attention. A series of studies indicate that an increased volume between the ages of 6 months and 4 years was both predictive of the autism diagnosis and symptom severity regardless of genetic risk for the condition. However, there remains a minimal understanding regarding the specificity of an increased volume of extra-axial cerebrospinal fluid to autism.MethodsIn the present study, we explored extra-axial cerebrospinal fluid volumes in children and adolescents ages 5–21 years with various neurodevelopmental and psychiatric conditions. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism compared with typical development and the other diagnostic group. We tested this hypothesis by employing a cross-sectional dataset of 446 individuals (85 autistic, 60 typically developing, and 301 other diagnosis). An analysis of covariance was used to examine differences in extra-axial cerebrospinal fluid volumes between these groups as well as a group by age interaction in extra-axial cerebrospinal fluid volumes.ResultsInconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort. However, in replication of previous work, a doubling of extra-axial cerebrospinal fluid volume across adolescence was found. Further investigation into the relationship between extra-axial cerebrospinal fluid volume and cortical thickness suggested that this increase in extra-axial cerebrospinal fluid volume may be driven by a decrease in cortical thickness. Furthermore, an exploratory analysis found no relationship between extra-axial cerebrospinal fluid volume and sleep disturbances.ConclusionsThese results indicate that an increased volume of extra-axial cerebrospinal fluid may be limited to autistic individuals younger than 5 years. Additionally, extra-axial cerebrospinal fluid volume does not differ between autistic, neurotypical, and other psychiatric conditions after age 4.

PD06-11 LOSS OF WNT4 IN THE GUBERNACULUM CAUSES UNILATERAL CRYPTORCHIDISM AND FERTILITY DEFECTS DUE TO IMBALANCE OF MALE AND FEMALE GENES

You have accessJournal of UrologyCME1 Apr 2023PD06-11 LOSS OF WNT4 IN THE GUBERNACULUM CAUSES UNILATERAL CRYPTORCHIDISM AND FERTILITY DEFECTS DUE TO IMBALANCE OF MALE AND FEMALE GENES Abhishek Seth, Hunter Flores, Ahmed Chahdi, and Carolina Jorgez Abhishek SethAbhishek Seth More articles by this author , Hunter FloresHunter Flores More articles by this author , Ahmed ChahdiAhmed Chahdi More articles by this author , and Carolina JorgezCarolina Jorgez More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003230.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Undescended testis (UDT) is the most common urological birth defect affecting 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. We hypothesized that WNT4 plays a significant role in gonadal development since mutations in WNT4 are associated with ambiguous genitalia, and overexpression of WNT4 in mice deficient in E2F1 leads to infertility. METHODS: A Wnt4 gubernaculum-specific knock-out mouse was created and phenotyped by crossing RARß2-cre mice to Wnt4-flox mice. Fertility was determined by 6-month paired mating of a wild type (WT) female to a Wnt4f/f;cre+ (Wnt4-cKO) male. RESULTS: All Wnt4-cKO mice presented with a smaller left unilateral UDT, and an equal number of mice had inguinal vs. abdominal UDT. The abdominal UDT had a Sertoli cell-only phenotype. The inguinal UDT had a combination of normal and abnormal seminiferous tubules (ST), including maturation arrest. Half of the mice with inguinal UDT had no sperm in the left epididymis, and the ones with sperm had 33% fewer sperm with a 96% decrease in motility compared to those of WT mice. The left gubernaculum of Wnt4-cKO was longer and thinner with increased collagen and reduced muscle content compared to the right CDT. The fertility of the Wnt4-cKO male was significantly reduced as they produced 23 litters and 88 pups within the same time that 8 WT mice produced 48 litter and 395 pups. Wnt4-cKO mice with abdominal UDT had an increase in serum FSH and LH. Wnt4-cKO UDT and CDT had an increase in ER-a in Leydig cells. Wnt4-cKO CDT and inguinal UDT had an increase in the number of SOX9-positive cells in which SOX9 expression was high in both the cytoplasm and nucleus. Wnt4-cKO testes revealed an up-regulation of genes essential for female gonadal development and function, such as Rspo1, Wnt4,and Foxl2 in both CDT and UDT. Several WNT4 variants were identified in boys with UDT that could potentially cause or contribute to their condition. CONCLUSIONS: Conditional loss of Wnt4 in the gubernaculum leads to aberrant testicular decent and development unilaterally. Although these mice have one normal descended testis, the existence of fertility defects and molecular alterations in the CDT supports our hypothesis that unilateral UDT is a bilateral defect. Our results indicate that the androgen-estrogen imbalance affects both testes and suggest that estrogen impacts the ability of SOX9 to translocate into the nucleus to activate the male developmental pathway. Source of Funding: NIH grant 1R01HD100985 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e160 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhishek Seth More articles by this author Hunter Flores More articles by this author Ahmed Chahdi More articles by this author Carolina Jorgez More articles by this author Expand All Advertisement PDF downloadLoading ...

Is paternal immune activation just as important as maternal immune activation? Time to rethink the bi-parental immune priming of neurodevelopmental model of schizophrenia

The neurodevelopmental origin of schizophrenia is a paradigmatic etiological construct. Parental exposure to environmental adversities and altered parental immune and stress-regulatory pathways affect the neurodevelopment of the fetus and may enhance the risk of schizophrenia in offspring. With respect to the parental contribution to these neurodevelopmental aberrations, most research has been on the maternal contribution. Maternal Immune activation, induced by maternal infections has been identified as a key pathway in the neurodevelopmental model of schizophrenia. Recent understanding points towards the fact that both the maternal and paternal priming offers survival advantages of the offspring to pathogen exposure. However, notwithstanding common epigenetic mechanisms applicable to both sexes, there is a lack of empirical data on the effect of paternal immune activation on neurodevelopmental aberrations and the consequent risk of schizophrenia in offspring.Large birth-cohort studies suggest a comparable impact of maternal and paternal infections on the risk of schizophrenia in offspring. The link between maternal infection and the risk of schizophrenia is mediated by the elements of the immune system through induction of maternal immune activation and subsequent neural and immune developmental aberrations. The contribution of paternal immune activation to schizophrenia risk has not yet been adequately explored. It is rational to assume that paternal infections might also enhance the risk of schizophrenia in offspring through paternal immune activation leading to neuroimmunodevelopmental aberrations. However, the underlying mechanisms whereby paternal infections as well as paternal immune activation might confer the risk of schizophrenia in the offspring seem to be distinct from maternal infection as the modes of transfer of the maternal and paternal factors are different. Maternal immune priming during gestation seems primarily through the direct effect of soluble immune factors, while the paternal immune priming might be mediated predominantly by epigenetic processes or through the effect of modifying factors in sperm. An account of plausible underlying mechanisms linking paternal immune activation and risk of schizophrenia are highlighted in this article. Furthermore, we propose the possibility of bi-parental immune priming in driving the neuroimmunodevelopmental abnormality as a risk mechanism of schizophrenia. It is envisaged that the neuroimmunodevelopmental aberration-associated risk of schizophrenia could be the result of cumulative effects of maternal as well as paternal immune stimulation. Delineation of the underlying maternal and paternal immune priming mechanism(s) will have important implications in resolving dilemmas of schizophrenia etiology as well as prevention.

A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family.

Isolated growth hormone deficiency (IGHD) is caused by a severe shortage or absence of growth hormone (GH), which results in aberrant growth and development. Patients with IGHD type IV (IGHD4) have a short stature, reduced serum GH levels, and delayed bone age. To identify the causative mutation of IGHD in a consanguineous family comprising four affected patients with IGHD4 (MIM#618157) and explore its functional impact in silico. Clinical and radiological studies were performed to determine the phenotypic spectrum and hormonal profile of the disease, while whole-exome sequencing (WES) and Sanger sequencing were performed to identify the disease-causing mutation. In-silico studies involved protein structural modeling and docking, and molecular dynamic simulation analyses using computational tools. Finally, data from the Qatar Genome Program (QGP) were screened for the presence of the founder variant in the Qatari population. All affected individuals presented with a short stature without gross skeletal anomalies and significantly reduced serum GH levels. Genetic mapping revealed a homozygous nonsense mutation [NM_000823:c.G214T:p.(Glu72*)] in the third exon of the growth-hormone-releasing hormone receptor gene GHRHR (MIM#139191) that was segregated in all patients. The substituted amber codon (UAG) seems to truncate the protein by deleting the C-terminus GPCR domain, thus markedly disturbing the GHRHR receptor and its interaction with the growth hormone-releasing hormone. These data support that a p.Glu72* founder mutation in GHRHR perturbs growth hormone signaling and causes IGHD type IV. In-silico and biochemical analyses support the pathogenic effect of this nonsense mutation, while our comprehensive phenotype and hormonal profiling has established the genotype-phenotype correlation. Based on the current study, early detection of GHRHR may help in better therapeutic intervention.

Chitosan oligosaccharide improves ovarian granulosa cells inflammation and oxidative stress in patients with polycystic ovary syndrome.

Polycystic Ovary Syndrome (PCOS) is the most common reproductive endocrine disorder among women of reproductive age, which is one of the main causes of anovulatory infertility. Even though the rapidly developed assisted reproductive technology (ART) could effectively solve fertility problems, some PCOS patients still have not obtained satisfactory clinical outcomes. The poor quality of oocytes caused by the abnormal follicular development of PCOS may directly contribute to the failure of ART treatment. Ovarian granulosa cells (GCs) are the most closely related cells to oocytes, and changes in their functional status have a direct impact on oocyte formation. Previous studies have shown that changes in the ovarian microenvironment, like oxidative stress and inflammation, may cause PCOS-related aberrant follicular development by impairing the physiological state of the GCs. Therefore, optimizing the ovarian microenvironment is a feasible method for enhancing the development potential of PCOS oocytes. In this study, we first detected the expression of inflammatory-related factors (TGF-β1, IL-10, TNFα, IL-6) and oxidative stress-related factors (HIF-1α and VEGFA), as well as the proliferation ability and apoptosis level of GCs, which were collected from control patients (non-PCOS) and PCOS patients, respectively. Subsequently, human ovarian granulosa cell line (KGN) cells were used to verify the anti-inflammatory and anti-oxidative stress effects of chitosan oligosaccharide (COS) on GCs, as well as to investigate the optimal culture time and concentration of COS. The optimal culture conditions were then used to culture GCs from PCOS patients and control patients. The results showed that GCs from PCOS patients exhibited obvious inflammation and oxidative stress and significantly reduced proliferation and increased apoptosis. Furthermore, COS can increase the expression of anti-inflammatory factors (TGF-β1 and IL-10) and decrease the expression of pro-inflammatory factors (TNFα and IL-6), as well as promote the proliferation of GCs. Moreover, we found that COS can reduce the level of reactive oxygen species in GCs under oxidative stress by inhibiting the expression of HIF-1α and VEGFA and by suppressing the apoptosis of GCs induced by oxidative stress. We find that inflammation and oxidative stress exist in the GCs of PCOS patients, and COS can reduce these factors, thereby improving the function of GCs.

Assessment of First-Trimester Utero-Placental Vascular Morphology by 3D Power Doppler Ultrasound Image Analysis Using a Skeletonization Algorithm: The Rotterdam Periconception Cohort

ABSTRACT Abnormal uteroplacental vascular development is one of the primary causes of the major disorders of pregnancy. Identification of this aberrant development in the preconception stage and in the first trimester, when measures to prevent complications are most effective, remains a challenge. Recent advances in offline imaging processing and Doppler techniques have allowed ultrasonographic analysis of placental volume (PV) and uteroplacental vascular volume (uPVV) in the first trimester. The ability of ultrasound to assess specific vascular morphology is not fully understood. The aim of this study was to investigate morphologic development of the first-trimester human uteroplacental vasculature in vivo using 3-dimensional power Doppler ultrasound and advanced image processing to generate the uteroplacental vascular skeleton (uPVS). Data were obtained from the VIRTUAL Placenta study, an ongoing observational study including adult women carrying a singleton pregnancy at less than 10-week gestational age (GA). At least 2 study visits were scheduled in the first trimester, at 7, 9, and 11 weeks' GA. The image quality of ultrasound scans was scored on a 4-point scale ranging between 0 (optimal) and 3 (unusable), and PV was measured using VOCAL software. The uPVV was measured using a virtual reality desktop system with the V-scope volume-rendering application. A skeletonization algorithm was then applied to the uPVV segmentation to generate the uPVS, and 7 morphological uPVS characteristics were used to determine the density of vascular branching within the placenta. A total of 214 women from the VIRTUAL cohort were eligible for inclusion, and 81% of all ultrasound data were of sufficient quality for generation of the uPVS. The distribution of endpoints, vessel points, bifurcation points, and crossing points in the uPVS and the distribution of uPVS characteristics per cm3 uPVV show consistent morphologic patterns throughout the first trimester. Moderate to strong positive correlations between uPVS characteristics and PV and strong positive correlations between uPVS characteristics and uPVV were identified. All uPVS characteristics increased significantly through the first trimester, except for uPVS average length, which remained constant between 7, 9, and 11 weeks' GA. When stratifying for placenta-related complications among the cohort, no significant differences in the uPVS characteristics were seen at 7 weeks' GA (n = 94). However, at 9 weeks (n = 170), there were significantly fewer number of vessel points (P = 0.040), bifurcation points (P = 0.050), crossing points (P = 0.020), and a shorter total network length (P = 0.023) among pregnancies with placenta-related complications. At 11 weeks' GA (n = 129), uPVS average vascular thickness was significantly lower in pregnancies with placenta-related complications (P = 0.007), but no other uPVS differences were observed. At 11 weeks' GA, pregnancies with placenta-related complications were found to have an increased density of vascular branching in the uPVV. The results of this study demonstrate a quantitative morphologic analysis of the human uteroplacental vasculature in the first trimester of pregnancy and key differences in the vascular morphology between pregnancies with and without placenta-related complications.

Aberrant Right Subclavian Artery: Cadaver Case Report

While examining the anatomy of a cadaver in a medical school gross anatomy course, an aortic arch anomaly was discovered. This variant is consistent with an aberrant right subclavian artery (ARSA). In this variant the right subclavian artery branches from the most distal part of the aortic arch and runs both retrotracheal and retroesophageal as it courses to the right shoulder. This variant is a result of aberrant development of the aortic arch and may include presenting symptoms such as dysphagia and shortness of breath, if any at all. Additional to the ARSA exists a common bicarotid trunk and a direct branching of the left vertebral artery from the aortic arch, both of which are rare anomalies. The cadaver’s medical history includes dysphagia and stretched esophagus, although the severity is unknown. This case report draws attention to these rare anatomical anomalies and includes a discussion of the most common clinical presentation, and surgical implications of an aberrant right subclavian artery anomaly.

Understanding the increased susceptibility to asthma development in preterm infants.

Preterm birth is associated with aberrant pulmonary development and increased susceptibility to a range of chronic lung diseases. Even in healthy preterms, the prevalence of physician-diagnosed asthma is far higher than in infants born at term. While physiological, environmental, and genetic factors have been studied extensively, few studies have investigated the immunological factors underpinning this increased susceptibility. Lower rates of atopy and allergic sensitization in preterm compared to term infants suggests non-allergic mechanisms may be driving asthma development in preterms. Preterm infants are more likely to develop severe RSV and HRV disease and have altered microbiomes compared to term infants. Therefore, investigating the differences in immunological interactions (e.g., response to viral infections, microbiome) between children born preterm and term will aid in understanding the immunological basis for their increased susceptibility to asthma development. This is critical to inform the development of interventions to reduce the burden of asthma in this highly vulnerable demographic.