Human Chromosome Research Articles

DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models.

Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders.

Regulation of USP25 by SP1 Associates with Amyloidogenesis.

Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down's syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer's disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. The transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student's t-test or one-way ANOVA were applied or statistical analysis. The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis.

A Detail Insight of Wilson’s Disease and its Treatment

Wilson disease is a rare inherited autosomal recessive genetic disorder caused by abnormal copper accumulation in the body, particularly involving the brain, liver, eyes, and other vital organs. This is also known as hepatolenticular degeneration. It primarily affects the liver and basal ganglia of the brain, but it can affect other vital organs too. It results from a mutation in the gene encoding the Wilson disease protein (ATP7B). It results from a mutation in the gene encoding the Wilson disease protein (ATP7B). A healthy body excretes extra copper through urine after the liver filters it out. Wilson's disease prevents the liver from effectively removing the excess copper. The extra copper then builds up in organs such as the brain, liver, and eyes; which is the reason why symptoms are usually related to the brain and liver. One of the 23 chromosomes in humans, chromosome 13, has a gene that causes Wilson's disease. For six months, a 12-year-old kid with Wilson's disease complained of speech problems, swallowing issues, and general stiffness. About 97 percent of those with Wilson's illness have K-F rings. Vomiting, weakness, ascites, yellowing of the skin, and brain or neurological symptoms like tremors, muscle stiffness, difficulty speaking, personality changes, or visual hallucinations are only a few of the symptoms associated with the liver. Sunflower cataracts are visible in 1 in 5 patients with Wilson's illness. One in 90 people in the general population are carriers of Wilson's illness. A liver biopsy, clinical evaluation, blood testing, urine tests, and a challenging diagnosis are all required. The family members of persons with the condition may be screened via genetic testing. For Wilson's disease to be stopped in its tracks, early detection is essential. Treatment can be done by both ayurvedic remedies using herbs and allopathy using drugs with specific target sites important for managing Wilson disease. WD can be treated with Copper chelating agents and Herbs act as a supporting treatment. Some drugs are still in the clinical trial phase.
 Keywords: Kayser-Fleischer rings, Wilson disease (WD), ALXN1840, d-Penicillinase, Vatavyadhi.

Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.

Abstract LB037: Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene

Abstract Chronic myeloid leukemia (CML) is a hematological malignancy mainly caused by the Bcr-Abl oncogene that results from the reciprocal translocation between human chromosome 9 and 22, and occurs in more than 90% of CML cases. Bcr-Abl oncogene is also involved in tumorigenesis of other leukemia such as acute lymphoid leukemia (ALL). Although progress has been made in the understanding of signal transduction in Abl-mediated transformation, the molecular mechanisms underlying Abl-induced tumorigenesis are still not fully understood. It is well known that imatinib treatment can greatly suppress Bcr-Abl-mediated development of leukemia, but intracellular molecules induced by imatinib and their roles in the tumorigenesis remain largely to be determined. On the other hand, the majority of human transcripts lack protein-coding capacity, which are defined as noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) play important roles in various vital biological processes. Notably, increasing number of lncRNAs have been linked to human diseases, including cancers. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Here, we identified several imatinib-induced lncRNAs as critical regulator of Bcr-Abl-induced tumorigenesis. Most of these lncRNAs expressed in a very low levels in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, they could be significantly induced in Abl-positive leukemic cells treated by imatinib. Silencing these lncRNAs promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of particular lncRNAs sensitized the cells to apoptosis and suppressed tumor growth. In concert, knockout of some murine lncRNAs in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, some lncRNA deficient mice were generated, and we observed that knockout of particular murine lncRNAs facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA deficiency promoted Abl-transformed cell survival and development of leukemia in mice. In summary, these findings unveil an inhibitory role of several critical lncRNAs in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis. Citation Format: Jilong Chen, Yun Ma. Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB037.

Actively transcribed rDNA and distal junction (DJ) sequence are involved in association of NORs with nucleoli

Although they are organelles without a limiting membrane, nucleoli have an exclusive structure, built upon the rDNA-rich acrocentric short arms of five human chromosomes (nucleolar organizer regions or NORs). This has raised the question: what are the structural features of a chromosome required for its inclusion in a nucleolus? Previous work has suggested that sequences adjacent to the tandemly repeated rDNA repeat units (DJ, distal junction sequence) may be involved, and we have extended such studies by addressing several issues related to the requirements for the association of NORs with nucleoli. We exploited both a set of somatic cell hybrids containing individual human acrocentric chromosomes and a set of Human Artificial Chromosomes (HACs) carrying different parts of a NOR, including an rDNA unit or DJ or PJ (proximal junction) sequence. Association of NORs with nucleoli was increased when constituent rDNA was transcribed and may be also affected by the status of heterochromatin blocks formed next to the rDNA arrays. Furthermore, our data suggest that a relatively small size DJ region, highly conserved in evolution, is also involved, along with the rDNA repeats, in the localization of p-arms of acrocentric chromosomes in nucleoli. Thus, we infer a cooperative action of rDNA sequence—stimulated by its activity—and sequences distal to rDNA contributing to incorporation into nucleoli. Analysis of NOR sequences also identified LncRNA_038958 in the DJ, a candidate transcript with the region of the suggested promoter that is located close to the DJ/rDNA boundary and contains CTCF binding sites. This LncRNA may affect RNA Polymerase I and/or nucleolar activity. Our findings provide the basis for future studies to determine which RNAs and proteins interact critically with NOR sequences to organize the higher-order structure of nucleoli and their function in normal cells and pathological states.

Matrix Metalloproteinases Contribute to the Calcification Phenotype in Pseudoxanthoma Elasticum.

Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and Abcc6-/- mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl2 resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions.

Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with several cancers of lymphocytic and epithelial origin1-3. EBV encodes EBNA1, which binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome4-6. EBNA1 also associates with host chromosomes at non-sequence-specific sites7, thereby enabling viral persistence. Here we show that the sequence-specific DNA-binding domain of EBNA1 binds to acluster of tandemly repeatedcopies of an EBV-like, 18-base-pair imperfect palindromic sequence encompassing a region of about 21 kilobases at human chromosome 11q23. In situ visualization of the repetitive EBNA1-binding site reveals aberrant structures on mitotic chromosomes characteristic of inherently fragile DNA. We demonstrate that increasing levels of EBNA1 binding trigger dose-dependent breakage at 11q23, producing a fusogenic centromere-containing fragment and an acentric distal fragment, with both mis-segregated into micronuclei in the next cell cycles. In cells latently infected with EBV, elevating EBNA1 abundance by as little as twofold was sufficient to trigger breakage at 11q23. Examination of whole-genome sequencing of EBV-associated nasopharyngeal carcinomas revealed that structural variants are highly enriched on chromosome 11. Presence of EBV is also shown to be associated with an enrichment of chromosome 11 rearrangements across 2,439 tumours from 38 cancer types. Our results identify a previously unappreciated link between EBV and genomic instability, wherein EBNA1-induced breakage at 11q23 triggers acquisition of structural variations in chromosome 11.

Paraoxonases at the Heart of Neurological Disorders.

Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON enzymes family consists of three members (PON-1, PON-2, and PON-3) that share a similar structure and location as a cluster on human chromosome 7. These enzymes exhibit anti-inflammatory and antioxidant properties with well-described roles in preventing cardiovascular disease. Perturbations in PON enzyme levels and their activity have also been linked with the development and progression of many neurological disorders and neurodegenerative diseases. The current review summarizes the available evidence on the role of PONs in these diseases and their ability to modify risk factors for neurological disorders. We present the current findings on the role of PONs in Alzheimer's disease, Parkinson's disease, and other neurodegenerative and neurological diseases.

Abstract 3318: Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis

Abstract Lung adenocarcinoma (LUAD) is a common non-small cell lung cancer disease most commonly found among non-smokers. This cancer is usually diagnosed at an advanced stage and can recur frequently and quickly with low chances of survival. Moreover, LUAD patients live with the fear of developing second primary tumors in their lifetime. A high-resolution SNP array (Affymetrix 250 NspI) analysis of primary LUAD tumors and their follow-up mucosal biopsies identified frequent copy neutral loss of heterozygosity (LOH, loss of 59 SNPs) of CACNA1C, a calcium voltage-gated channel subunit, located to human chromosome 12p13.33. Transcriptomic profiling utilizing The Cancer Genome Atlas (TCGA) revealed frequent loss of mRNA expression of CACNA1C in LUAD tumors (n=515) compared to the normal counterparts (n=59). Loss of CACNA1C mRNA expression was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and worst survival of the LUAD patients. Epigenetic alteration such as DNA methylation could be a potential mechanism of the inactivation of a tumor suppressor gene (TSG) other than LOH, frequently observed in human cancers. We also recorded significantly higher promoter methylation of CACNA1C in the above LUAD tumors compared to the normal counterparts. Higher promoter methylation of CACNA1C was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and poor survival of the LUAD patients. Thus, both allelic loss and methylation appear to be potential mechanisms behind the loss of function of CACNA1C in LUAD patients. Further validation of CACNA1C expression at the protein level confirmed its high membranous expression in normal lung tissues. Analysis of an independent cohort of LUAD subjects revealed significant loss of CACNA1C in primary tumors (n=30) and lymph node metastases (n=10) of LUAD patients compared to their normal counterparts. Loss of CACNA1C protein expression was associated with lymph node metastasis and stage-wise progression of the LUAD patients. Further validation of CACNA1C expression in larger cohorts and functional characterization would be beneficial for potential biomarkers and therapeutic development in the longer run. On the other hand, epigenetically silenced TSGs can be reactivated by CRISPR-CAS9-based technology or demethylating agents, implicating the therapeutic promise of targeting TSGs. Citation Format: Saanvi Dasgupta, Srijan Acharya, Mohammad A. Khan, Paramahansa Pramanik, Stephen M. Marbut, Furhan Yunus, Jose N. Galeas, Seema Singh, Ajay P. Singh, Santanu Dasgupta. Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3318.

Dissection of a Down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome.

As an aneuploidy, trisomy is associated with mammalian embryonic and postnatal abnormalities. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 [Down syndrome (DS)]. Although increased gene dosage effects because of a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e. a 'free trisomy' independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects in mammals. To fill this gap, here we describe a strategy that employed two new mouse models of DS, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparison of these models revealed the gene dosage-independent impacts of an extra chromosome at the phenotypic and molecular levels for the first time. They are reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome plays a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.

Mesenchymal stem cells: a trojan horse to treat glioblastoma

Glioblastoma multiforme (GBM) is the most common and lethal primary tumor of the central nervous system. What makes it so dreadful is the very low survival rate, despite the existence of a standard treatment plan. An innovative and more effective way to treat glioblastoma based on Mesenchymal Stem Cells (MSCs) has been explored recently. MSCs are a group of endogenous multipotent stem cells that could mainly be harvested from adipose tissue, bone marrow, and umbilical cord. Having the ability to migrate toward the tumor using multiple types of binding receptors, they could be used either as a direct treatment (whether they are enhanced or not) or as a delivery vehicle carrying various anti-tumoral agents. Some of these agents are: chemotherapy drugs, prodrug activating therapy, oncolytic viruses, nanoparticles, human artificial chromosome… Promising results have started to surface; however, more evidence is needed to perfect their use as a glioblastoma multiforme treatment option. Alternative treatment, using unloaded or loaded MSCs, leading to a better outcome.

Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome.

Trisomy 21 and mutations in the Sonic hedgehog (SHH) signaling pathway cause overlapping and pleiotropic phenotypes including cerebellar hypoplasia, craniofacial abnormalities, congenital heart defects and Hirschsprung disease. Trisomic cells derived from individuals with Down syndrome possess deficits in SHH signaling, suggesting that overexpression of human chromosome 21 genes may contribute to SHH-associated phenotypes by disrupting normal SHH signaling during development. However, chromosome 21 does not encode any known components of the canonical SHH pathway. Here, we sought to identify chromosome 21 genes that modulate SHH signaling by overexpressing 163 chromosome 21 cDNAs in a series of SHH-responsive mouse cell lines. We confirmed overexpression of trisomic candidate genes using RNA sequencing in the cerebella of Ts65Dn and TcMAC21 mice, model systems for Down syndrome. Our findings indicate that some human chromosome 21 genes, including DYRK1A, upregulate SHH signaling, whereas others, such as HMGN1, inhibit SHH signaling. Individual overexpression of four genes (B3GALT5, ETS2, HMGN1 and MIS18A) inhibits the SHH-dependent proliferation of primary granule cell precursors. Our study prioritizes dosage-sensitive chromosome 21 genes for future mechanistic studies. Identification of the genes that modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.

The Dual Functions of Non-Coding RNA CRNDE in Different Tumors.

Long non-coding RNA has attracted the interest of researchers as a relevant factor that can influence human cancers. As an oncogene and suppressor gene, it has numerous pathways and is closely related to the pathophysiology of human diseases. Meanwhile, it may become a novel treatment option and target for tumor treatment. CRNDE is the gene symbol for Colorectal Neoplasia Differentially Expressed (non-protein-coding) since it was found to be considerably higher in colorectal cancer when it was first discovered. It's transcribed from human chromosome 16. Many studies have shown that it is intimately linked to the etiology of many tumors and malignancies. According to the paper, the biological function and pathophysiological mechanism of CRNDE in tumors have been studied extensively in recent years. PubMed served as an essential platform for conducting literature searches and related analyses. CRNDE, a long non-coding RNA closely related to tumors, was highly expressed in many tumor cells. There were various underlying mechanisms affecting the progression of CRNDE-regulated tumorigenesis, including hepatocellular carcinoma, gastric cancer, prostate carcinoma, oral squamous cell carcinoma, breast cancer, thyroid cancer, myeloma, leukemia, melanoma, colorectal cancer, glioblastoma, osteosarcoma, cervical cancer, intrahepatic cholangiocarcinoma, nonsmall cell lung cancer, hepatoblastoma cell tumor, abdominal aortic aneurysm, nasopharyngeal carcinoma, bladder cancer, Wilms tumor, medulloblastoma, pancreatic cancer, gallbladder cancer, ovarian cancer, and renal cell carcinoma. CRNDE is involved in the processes of proliferation, migration, invasion, and inhibition of apoptosis of various cancer cells.

Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice.

Down syndrome (DS) phenotypes result from triplicated genes, but the effects of three copy genes are not well known. A mouse mapping panel genetically dissecting human chromosome 21 (Hsa21) syntenic regions was used to investigate the contributions and interactions of triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16) on skeletal phenotypes. Skeletal structure and mechanical properties were assessed in femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr and Dp1Tyb;Dyrk1a+/+/- mice. Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 triplicated, display bone deficits similar to those of humans with DS and served as a baseline for other strains in the panel. Bone phenotypes varied based on triplicated gene content, sex and bone compartment. Three copies of Dyrk1a played a sex-specific, essential role in trabecular deficits and may interact with other genes to influence cortical deficits related to DS. Triplicated genes in Dp9Tyb and Dp2Tyb mice improved some skeletal parameters. As triplicated genes can both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.

A review on Angelman syndrome

"Angelman syndrome" AS seems to be a neurodevelopmental illness for whom significant aspects were learning impairment, total absence like presentation, convulsions, and a character trait behavior resume. Its behavior includes the delighted public persona, easily angered amusement, hard time concentrating, and hyper motoric actions, swearing like things, disruptive behavior, and an attachment such as liquid. Developmental problems and delicate dysphoric includes, along with incoordination and other mobility disruptions, have been extra functionality in essential people with the condition. And so is resulting from short invocation of something like the tubulin nutrient ubiquitin E3A (ube3a) mutation, which shows parental bonding. There are four single-molecule classrooms upon as, and somegenotype–phenotype collinearity has popped up. More than stays to be acknowledged about why issues like E6-AP and its nutrient merchandise like UBE3A end up in its noticed neurobehavioral deficit spending. Research like animal studies has allegedly involved UBE3A along with experience-dependent synapses redeveloping. Its pharmacogenetic facets include Angelman disorder, its basic biomolecular tenets, and access to basic service methods. And so is one neurobehavioral disorder that is characterized while also a severely impaired handicap, engine failure to thrive, communication difficulties, impulsiveness, but also ordinary epileptic fits. And so is attributable to interruption of prenatally conveyed but also generationally ingrained UBE3A, which also lossless encoding the ubiquitin secondments. Four methods in the production of its gene encoding UBE3A non - functional were also acknowledged, the most typical of which would be the deactivation of such motherly love human chromosome 15q11-q13. Amazingly, redundancy with the same human chromosome is amongst the few best-described continual chromosomal mutations linked to asperger's syndrome disease, cropping up along >1–2 Percentage among all situations like autism diagnosis. While outcome morphological characteristics of something like the central nervous system and communication like neurons projected numbers are mainly standard in animal studies, primary operating deficiencies were also discovered just at a standard like discussion training. Also, they impeded developmental processes like learning, memory, and neurogenesis circuit design. Offers similar promote confidence a significant involvement such as proteolysis protein ligase E3A along synapses advancement, its operations to dysfunction like tubulin transcription factor E3A results samples pathogenic mechanisms along living beings poor job performance did understand. but even so, current attempts have also shown keep promising through trying to restore continues to function interrupted into it as mouse model, reactivating keep hoping how the effectiveness of treatment's management strategic plan could be discovered.

Inverse Comorbidity between Down Syndrome and Solid Tumors: Insights from In Silico Analyses of Down Syndrome Critical Region Genes.

An inverse comorbidity has been observed between Down syndrome (DS) and solid tumors such as breast and lung cancers, and it is posited that the overexpression of genes within the Down Syndrome Critical Region (DSCR) of human chromosome 21 may account for this phenomenon. By analyzing publicly available DS mouse model transcriptomics data, we aimed to identify DSCR genes that may protect against human breast and lung cancers. Gene expression analyses with GEPIA2 and UALCAN showed that DSCR genes ETS2 and RCAN1 are significantly downregulated in breast and lung cancers, and their expression levels are higher in triple-negative compared to luminal and HER2-positive breast cancers. KM Plotter showed that low levels of ETS2 and RCAN1 are associated with poor survival outcomes in breast and lung cancers. Correlation analyses using OncoDB revealed that both genes are positively correlated in breast and lung cancers, suggesting that they are co-expressed and perhaps have complementary functions. Functional enrichment analyses using LinkedOmics also demonstrated that ETS2 and RCAN1 expression correlates with T-cell receptor signaling, regulation of immunological synapses, TGF-β signaling, EGFR signaling, IFN-γ signaling, TNF signaling, angiogenesis, and the p53 pathway. Altogether, ETS2 and RCAN1 may be essential for the development of breast and lung cancers. Experimental validation of their biological functions may further unravel their roles in DS and breast and lung cancers.

Full-length human dystrophin on human artificial chromosome compensates for mouse dystrophin deficiency in a Duchenne muscular dystrophy mouse model

Dystrophin maintains membrane integrity as a sarcolemmal protein. Dystrophin mutations lead to Duchenne muscular dystrophy, an X-linked recessive disorder. Since dystrophin is one of the largest genes consisting of 79 exons in the human genome, delivering a full-length dystrophin using virus vectors is challenging for gene therapy. Human artificial chromosome is a vector that can load megabase-sized genome without any interference from the host chromosome. Chimeric mice carrying a 2.4-Mb human dystrophin gene-loaded human artificial chromosome (DYS-HAC) was previously generated, and dystrophin expression from DYS-HAC was confirmed in skeletal muscles. Here we investigated whether human dystrophin expression from DYS-HAC rescues the muscle phenotypes seen in dystrophin-deficient mice. Human dystrophin was normally expressed in the sarcolemma of skeletal muscle and heart at expected molecular weights, and it ameliorated histological and functional alterations in dystrophin-deficient mice. These results indicate that the 2.4-Mb gene is enough for dystrophin to be correctly transcribed and translated, improving muscular dystrophy. Therefore, this technique using HAC gives insight into developing new treatments and novel humanized Duchenne muscular dystrophy mouse models with human dystrophin gene mutations.

I kappa B kinase interacting protein as a promising biomarker in pan-cancer: A multi-omics analysis.

Background: Human chromosome 12 contains I kappa B kinase interacting protein (IKBIP) is also commonly known as IKIP. The involvement of IKBIP in the growth of tumors has only been discussed in a small number of publications. Purpose: To explore the role that IKBIP plays in the development of a wide variety of neoplasms, as well as the tumor immunological microenvironment. Methods: UALCAN, HPA, Genotype Tissue Expression, Cancer Genome Maps, and other datasets were used to analyze IKBIP expression. We thoroughly investigated the predictive importance of IKBIP in pan-cancer, clinical traits, and genetic anomalies. We studied whether there is a link between IKBIP and immune-related genes, microsatellite instability (MSI), and the incidence of tumor mutational burden (TMB). The link between immune cell infiltration and IKBIP expression was examined using data on immune cell infiltration from ImmuCellAI, TIMER2, and earlier studies. Finally, gene set enrichment analysis (GSEA) was performed to determine the signaling pathways associated with IKBIP. Results: IKBIP is highly expressed in most cancers and is negatively associated with the prognosis of several major cancer types. Furthermore, IKBIP expression was linked to TMB in 13 cancers and MSI in seven cancers. Additionally, IKBIP is associated with numerous immunological and cancer-promoting pathways. Simultaneously, various cancer types have unique tumor-infiltrating immune cell profiles. Conclusion: IKBIP has the potential to act as a pan-cancer oncogene and is crucial for both carcinogenesis and cancer immunity. Elevated IKBIP expression implies an immunosuppressive environment and may be used as a prognostic biomarker and therapeutic target.

Extraordinary selection on the human X chromosome associated with archaic admixture.

The X chromosome in non-African humans shows less diversity and less Neanderthal introgression than expected from neutral evolution. Analyzing 162 human male X chromosomes worldwide, we identified fourteen chromosomal regions where nearly identical haplotypes spanning several hundred kilobases are found at high frequencies in non-Africans. Genetic drift alone cannot explain the existence of these haplotypes, which must have been associated with strong positive selection in partial selective sweeps. Moreover, the swept haplotypes are entirely devoid of archaic ancestry as opposed to the non-swept haplotypes in the same genomic regions. The ancient Ust'-Ishim male dated at 45,000 before the present (BP)also carries the swept haplotypes, implying that selection on the haplotypes must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selectivesweeps in great ape evolution, suggesting a mechanism of selection unique to X chromosomes.