Assessing Lifespan and Aging Phenotypes Resulting From FOXO3 Induction Using Mouse Models

Environmental signals, including caloric restriction and oxidative stress, trigger FoxO3 to upregulate genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis that may help mitigate age-related diseases. Activation of FoxO3 has been shown to have a profound life-extending effect on model organisms. Protective SNPs in FOXO3 are strongly associated with exceptional longevity in humans. The objective of this study is test the relation between FoxO3 and longevity using mouse models. We generated a mouse line containing an extra copy of FoxO3 that can be induced at any age. In our model, FoxO3 remains driven by its natural promoter to avoid mis-expression in inappropriate cells and to maintain the gene’s ability to respond to signals such as stress. We are utilizing this new model to assess survival endpoints and test a panel of aging phenotypes reflecting healthspan throughout the mouse lifespan and compare these to similar human phenotypes.

Overview on Regulatory Requirements for Medical Devices in Srilanka - National Medicines Regulatory Authority/NMRA

In the health-care industry, medical devices are becoming increasingly significant. One of the most challenging aspects of developing and manufacturing medical devices is keeping up with regulatory regulations and incorporating them into the process Registration, licensing, manufacture, importation, and all other elements of medical devices shall be regulated and controlled by the National Medicines Regulatory Authority in accordance with the National Medicines Policy. In this article we discuss about regulatory overview and registration of medical devices in Sri Lanka. A “medical device,” as defined by the Act, is any instrument, apparatus, appliance, software, material, or other article, whether used alone or in combination, that is used in or on humans for the purposes of: Diagnosis, prevention, monitoring, treatment, or alleviation of disease; Anatomy or physiological process investigation, replacement, or alteration, Conception control. Any change in product information should be reported to the NMRA as soon as possible during the evaluation process and after product registration, especially if it involves rejection/withdrawal, additional data on product quality, effectiveness, or safety, or the manufacturers' current Good Manufacturing Practice (cGMP) compliance. The sample license will be produced in three copies, each of which will be valid for one year from the date of issue, and will be available for pick-up at the reception point. (An extra copy of the dossier will be included).

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of down syndrome-related phenotypes

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

N-Acetylcysteine prevents amyloid-β secretion in neurons derived from human pluripotent stem cells with trisomy 21

Down syndrome (DS) is caused by the trisomy of chromosome 21. Among the many disabilities found in individuals with DS is an increased risk of early-onset Alzheimer's disease (AD). Although higher oxidative stress and an upregulation of amyloid β (Aβ) peptides from an extra copy of the APP gene are attributed to the AD susceptibility, the relationship between the two factors is unclear. To address this issue, we established an in vitro cellular model using neurons differentiated from DS patient-derived induced pluripotent stem cells (iPSCs) and isogenic euploid iPSCs. Neurons differentiated from DS patient-derived iPSCs secreted more Aβ compared to those differentiated from the euploid iPSCs. Treatment of the neurons with an antioxidant, N-acetylcysteine, significantly suppressed the Aβ secretion. These findings suggest that oxidative stress has an important role in controlling the Aβ level in neurons differentiated from DS patient-derived iPSCs and that N-acetylcysteine can be a potential therapeutic option to ameliorate the Aβ secretion.

Congenital Chylothorax in Newborn with Trisomy 21

Dawn syndrome Trisomy 21 means there’s an extra copy of chromosome 21 in every cell. This is the most common form of Down syndrome, there is three types of Down syndrome. Trisomy 21 which there is an extra copy of chromosome 21 in every cell. Mosaicism occurs when a child is born with an extra chromosome in some but not all of their cells. Translocation in this type of Down syndrome, children have only an extra part of chromosome 21. There are 46 total chromosomes. However, one of them has an extra piece of chromosome 21 attached. Down syndrome is associated with a lots of complication like congenital heart disease. Vision. Hearing behavior and mental problem. Our case is Down syndrome with congenital chylothorax which is rare complication. Neonatal chylothorax results from the accumulation of chyle in the pleural space and may be either congenital or an acquired condition. Congenital chylothorax is most likely due to abnormal development or obstruction of the lymphatic system. It is often associated with hydrops fetalis. It can be idiopathic or may be associated with various chromosomal anomalies including Trisomy 21, Turner syndrome, Noonan syndrome, and other genetic abnormalities [1]. Treatment of chylothorax is multidisplenery need insertion of chest tube to decrease respiratory distress, diet management and pediatric surgery.

Gene Variant of Barrier to Autointegration Factor 2 (Banf2w) Is Concordant with Female Determination in Cichlids

Oreochromis fishes exhibit variability of sex-determination (SD) genes whose characterization contributes to understanding of the sex differentiation network, and to effective tilapia farming, which requires all-male culture. However, O. niloticus (On) amh is the only master-key regulator (MKR) of SD that has been mapped (XY/XX SD-system on LG23). In O. aureus (Oa), LG3 controls a WZ/ZZ SD-system that has recently been delimited to 9.2 Mbp, with an embedded interval rich with female-specific variation, harboring two paics genes and banf2. Developing genetic markers within this interval and using a hybrid Oa stock that demonstrates no recombination repression in LG3, we mapped the critical SD region to 235 Kbp on the orthologous On physical map (p < 1.5 × 10−26). DNA-seq assembly and peak-proportion analysis of variation based on Sanger chromatograms allowed the characterization of copy-number variation (CNV) of banf2. Oa males had three exons capable of encoding 90-amino-acid polypeptides, yet in Oa females, we found an extra copy with an 89-amino-acid polypeptide and three non-conservative amino acid substitutions, designated as banf2w. CNV analysis suggested the existence of two to five copies of banf2 in diploidic Cichlidae. Disrupting the Hardy–Weinberg equilibrium (p < 4.2 × 10−3), banf2w was concordant with female determination in Oa and in three cichlids with LG3 WZ/ZZ SD-systems (O. tanganicae, O. hornorum and Pelmatolapia mariae). Furthermore, exclusive RNA-seq expression in Oa females strengthened the candidacy of banf2w as the long-sought LG3 SD MKR. As banf genes mediate nuclear assembly, chromatin organization, gene expression and gonad development, banf2w may play a fundamental role inducing female nucleus formation that is essential for WZ/ZZ SD.

15q Duplication Syndrome: Report on the First Patient from Ecuador with an Unusual Clinical Presentation

Background. The 15q11.1-13.1 duplication, also known as Dup15q syndrome, is a rare congenital disease affecting 1 in 30,000 to 1 in 60,000 children worldwide. This condition is characterized by the presence of at least one extra copy of genetical material within the Prader-Willi/Angelman Critical Region (PWACR) of the referred 15q11.2-q13.1 chromosome. Case Report. Our study presents the clinical and genetical features of the first patient with a denovo 15q11.2 interstitial duplication on the maternal allele (inv Dup15q) that mimics a milder Prader-Willi syndrome probably due to an atypical disruption of the SNHG14 gene. Methylation-specific MLPA analysis has confirmed the presence of a very unlikely duplication that lies between breakpoint 1 (BP1) and the middle of BP2 and BP3 (BP3). This atypical alteration might be linked to the milder patient’s clinical phenotype. Conclusions. This is the first Dup15q patient reported in Ecuador and of the very few in South America. This aberration has never been described in a patient with Dup15q, and the unusual clinical presentation is probably due to the atypical distal breakpoint occurring within the gene SNHG14 which lies between BP2 and BP3 and does not therefore contain the whole PWACR. If the duplication disrupted the gene, then it is possible that it is the cause of, or contributing to, the patient’s clinical phenotype.

Discovering critical proteins in the learning process in a Down Syndrome model of mouse through machine learning

Caused by an extra copy of the human chromosome21 (Hsa21), Down syndrome produces an intellectual disability that is still unknown and requires further research in order to have a better perception. One research conducted in this area of study has analysed different protein levels of the Ts65Dn mouse model of DS. Many researchers are trying to find the critical proteins that categorize the mice classes accurately by using machine learning. In this study, we expand the problem by trying to find the critical proteins that affect different types of learning. The protein subsets are found using forward feature selection method, ReliefF respectively and four different supervised learning algorithms are used. The experimental results are compared with previous related work, and demonstrated that the proposed method outperforms, or is comparable to, its competitors in term of accuracy. Then, a thorough analysis is done to identify the critical proteins for each learning case, by lowering the number to 9 critical proteins that can help in a better categorization of the mice. We hope that our work withhelp the scientists on their further research on finding a treatment that may help the learning process and ease the intellectual disability caused by Down Syndrome.

The fitness costs and benefits of trisomy of each Candida albicans chromosome

Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.

METTL3-Mediated N6-Methyladenosine Modification Is Involved in the Dysregulation of NRIP1 Expression in Down Syndrome

Down syndrome (DS) is a common genetic condition in which a person is born with an extra copy of chromosome 21. Intellectual disability is the most common characteristic of DS. N6-methyladenosine (m6A) is a common RNA modification that is implicated in many biological processes. It is highly enriched within the brain and plays an essential role in human brain development. However, the mRNA m6A modification in the fetal brain of DS has not been explored. Here, we report m6A mRNA profiles and mRNA expression profiles of fetal brain cortex tissue from DSs and controls. We observed that the m6A modification in DS brain tissues was reduced genome-wide, which may be due to decreased the m6A methyltransferase like 3 (METTL3) protein expression. The nuclear receptor-interacting protein 1 (NRIP1/RIP140) is coded by a highly conserved chromosome 21 (Hsa21) gene. Overexpression of NRIP1 is associated with mitochondrial dysfunction in DS. The NRIP1 mRNA increased in fetal brain tissues of DS, whereas the m6A modification of the NRIP1 mRNA significantly decreased. METTL3 knockdown reduced the m6A modification of NRIP1 mRNA and increased its expression, and an increase in NRIP1 m6A modification and a decrease in its expression were observed in METTL3-overexpressed cells. The Luciferase reporter assay confirmed that METTL3 regulates NRIP1 expression in an m6A-dependent manner. The decay rate of NRIP1 mRNA was significantly reduced in METTL3-knockdown cells but increased in METTL3-overexpressed cells. We proposed that the m6A modification of NRIP1 mRNA in DS fetal brain tissue is reduced, reducing its transcript degradation rate, resulting in abnormally increased expression of NRIP1, at least partially, in the DS brain. It provides a new mechanism for the molecular pathology of DS and leads to a new insight that may become therapeutically relevant.