A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne–Kalscheuer syndrome
Francisco Bustos, Carmen Espejo-Serrano, Anna Segarra-Fas, Rachel Toth, Alison J. Eaton, Kristin D. Kernohan, Meredith J. Wilson, Lisa G. Riley.
Published online 2021 May 5
presented by: Joaquin Aguirre and Daniela Álvarez
Universidad Pontificia Bolivariana - Molecular Biology
RNAi is a highly specific post-transcriptional gene silencing process, a powerful tool for functional genomics. This guide includes protocol reviews, handy tips and troubleshooting help.
Antisense RNA is the complementary RNA to the protein-coding messenger mRNA. The antisense mRNA binds to sense mRNA and the translation was restricted, that is called translation arrest. The nature antisense RNA technology present in hok &sok in E.coli R1 plasmid. The artificial or purpose antisense RNA technology best example is flavr savr tomato.
RNAi is a highly specific post-transcriptional gene silencing process, a powerful tool for functional genomics. This guide includes protocol reviews, handy tips and troubleshooting help.
Antisense RNA is the complementary RNA to the protein-coding messenger mRNA. The antisense mRNA binds to sense mRNA and the translation was restricted, that is called translation arrest. The nature antisense RNA technology present in hok &sok in E.coli R1 plasmid. The artificial or purpose antisense RNA technology best example is flavr savr tomato.
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Clinical molecular diagnostics for drug guidanceNikesh Shah
1. Be familiar with next generation molecular diagnostic techniques that can provide guidance in clinical decision making
2. Identify the utility of these diagnostic approaches with some examples
3. Be aware of the challenges that exist in implementing these tools as part of the routine clinical decision making process, especially in resource limited settings
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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A novel rlimrnf12 variant disrupts protein stability and function to cause severe tonne–kalscheuer syndrome
1. Presented by: Joaquin Aguirre and Daniela Álvarez
Universidad Pontificia Bolivariana
3º semester - Molecular Biology
2. Global developmental delay apparent from early infancy
Speech delay
Behavioural abnormalities
Abnormal gait
It can present variable clinical manifestations
Dysmorphic facial features
Abnormal pulmonary development
Hypogenitalism
Congenital diaphragmatic hernia
Introduction
Tonne–Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome
This syndrome results as a perinatal lethality due to the
diphragmatic hernia in cases of severe tokas.
3. it's a gene that codifies the E3 ubiquitin-protein ligase RLIM enzyme which ubiquitylates
transcription factor substrates to control key developmental processes including imprinted X-
chromosome inactivation, stem cell maintenance, and differentiation.
Specific disruption of RLIM activity by TOKAS variants results in deregulated stem cell
differentiation to neurons.
R L I M / R N F 1 2 .
4. Objective
Understand how the RLIM/RNF12 variant
disrupt proteins stability and function to cause
severe Tonne-Kalscheuer syndrome
5. Genomic DNA sequencing and analysis
DNA sequencing means determining the order of the nitrogenous bases, which make up the
DNA molecule. The sequence tells scientists the kind of genetic information that is carried in
a specific segment of DNA.
This article explains how they use trio exome sequencing of genomic DNA from proband
and parents. The target capture was performed with the Agilent CRE V1.0, and sequencing
was performed on the Illumina NextSeq 500 using 150 base-pair paired-end reads.
6. cDNA expression vectors and transfection
Recombinant DNA technology allows the
manipulation of an individual's genome, which
today is helpful in the medical field, in the
study and diagnosis of diseases that develop
genetic disorders.
in this study, they used this technique on
mESCs (mouse embryonic stem cells) that
were transfected with Lipofectamine LTX
7. Immunoblotting
Lysis Buffer
1.
20 mM Tris (pH 7.4)
150 mM NaCl
1 mM EDTA
1% Nonidet P-40 (NP-40)
0.5% sodium deoxycholate
10 mM β-glycerophosphate
10 mM sodium pyrophosphate
1 mM NaF,
2 mM Na3VO4
Roche Complete Protease Inhibitor
2. SDS-PAGE gels
10–30 μg of cell lysate
3. Polyvinylidene fuoride
(PVDF) membranes
4. Membranes were blocked
Tris bufered saline-tween 20 (TBS-T)
5% non-fat milk bufer
5. Antibodies
Primary:
anti-mouse RLIM amino acids 1–271
anti-ERK1/2
anti-REX1
Secondary antibodies:
Sheep IgG-horseradish peroxidase
Mouse IgG-HRP (Cell Signaling Technology)
Rabbit IgG-HRP (Cell Signaling Technology
6. Chemiluminescence
detection
Immobilon Western
Chemiluminescent HRP substrate
Gel-Doc XR+System
7.Detected protein signals
were quantifed
Image J (NIH) or
Image Studio (LI-COR Biosciences)
8. RNA extraction and quantitative RT‑PCR
It is a technique to identify a gene by means of RNA to know if it is present in the sample.
Omega total RNA extraction kit iScript cDNA synthesis Kit RT PCR
CFX384 real time PCR system
GraphPad Prism v7.0c sofware
Primers
Human RLIM:
Forward (5′–3′): ATCATCAGGCTCATCAGGTGC,
Reverse (3′–5′): AAGGAAGGGCAAAGAGCCAC;
Mouse Xist:
Forward (5′–3′): GGATCCTGCTTGAACTACTGC,
Reverse (3′–5′): CAGGCAATCCTTCTTCTTGAG:
Mouse Gapdh:
Forward (5′–3′): CTCGTCCCGTAGACAAAA,
Reverse (3′–5′): TGAATTTGCCGTGAGTGG.
9.
10.
11.
12.
13. Conclusions
This article could be of use in the medical field thanks to the variants discovery and its new knowledge of
this high-risk perinatal disease.
Its location and the way it expresses makes it easier to identify in time, in addition to discovering it is a
genetic problem and how we could correct it.
the fact that we know it is a gene linked to the X chromosome makes us conclude that it is a gene that
affects mostly the male population and that women may have the variant, but it is not expressed and can
inherit it, makes the DNA analysis easier when looking for these genomic anomalies.
14. Discussion
FRINTS SGM
In the most severe cases,
diaphragmatic hernia causes
death shortly after birth
BUSTOS F
Work from our group has
previously identified a function
for RLIM signaling in controlling
expression of neuronal genes
FRINTS SGM
TONNE E
TOKAS is a developmental disorder
characterized by clinical features including
intellectual disability, facial dysmorphism,
velopharyngeal abnormalities and
diaphragmatic hernia