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Translational Biology Challenges
Welcome to my new YouTube channel dedicated to translational biology. We have created this channel to serve the whole scientific community working or showing interest in biological sciences. We will publish short videos focusing every time on a specific topic or concept in different disciplines such as “Molecular Genetics“, “Functional Genomics“, “Evolutionary Biology“, “Biotechnology” and others. We will attempt to emphasize the translational values of the scientific knowledge, from fundamental to applied science, from genomic data to therapeutic molecules, and from bench basic research to bedside therapeutic solutions. “Translational“, “Precision“, or “Personalized Medicine” are sometimes used to refer to translational biology; however, the latter is a wider arena seeking to infer or find solutions beyond the medical sector. Target groups are biology learners, graduate and postgraduate, including PhDs and Postdocs, who need to refresh their knowledge or strengthen their background, physicians and medical professionals, and all other scholars in other disciplines looking to bridge their research interests with or move into biological sciences. You are all invited to watch and comment the videos. The questions you may have on the presentations and posted as comments will be answered and webinars will be organized to debate strenuous concepts.
Kindly use the following link to find and subscribe to my YouTube Channel:
https://youtube.com/channel/UCov8rapX1hhxXkioJzq59-A
VI. Sixth YouTube video on ” Complex DNA structures: Translational Insights”!
Negatively supercoiled DNAs are energetically favorable for DNA replication, transcription and recombination. A negatively supercoiled DNA can unwind locally and that favors the formation of other complex DNA structures. We will speak briefly of complex DNA structures and their functional roles as well as their translational values since some of them are likely to be involved in human diseases. First, palindromes that have the potential to form a tertiary structure known as cruciform. These can occur in many regulatory sequences and DNA replication origins and seem to be important e.g. they potentially produce distinctive recognition sites for specific DNA-binding proteins. Second, DNA Triplexes or H-DNAs That are formed by homopurine-homopyrimidine mirror repeats. Formation of H-DNA is topologically equivalent to an unwinding of the entire mirror repeat; then one strand, the homopyrimidine or homopurine will fold back and pairs with the homopurine strand of the normal, classic B-form mirror repeat, in a reversed fashion, through unusual base pairing called Hoogsteen bonds. Repeat sequences within a genome are also known as suicide motifs for DNA polymerase. As a direct application of this knowledge synthetic DNA strands designed to pair with these sequences to form triplex DNA could disrupt gene expression. This approach to controlling cellular metabolism is of growing commercial interest for its potential application in medicine and agriculture. As an example of a human disease associated with H-DNA triplex is Friedreich’s ataxia (FRDA). FRDA, an autosomal recessive degenerative disorder of nervous and muscles tissue, is caused by the massive expansion of (GAA) repeats that occur in the first intron of Frataxin gene on chromosome 9. Third, G-quadruplexes or G4, which are formed in nucleic acids by sequences that are rich in guanine. G4 DNAs may stall replication or transcription, or prevent a sequence-specific transcription factor from recognizing or binding its site in duplex DNA. As cells have evolved mechanisms for resolving G4 that form, quadruplex formation may be potentially damaging for a cell. Many helicases that bind G4 DNAs have been involved in human diseases. The helicases WRN and Bloom syndrome protein having a high affinity for resolving G4 DNA are two examples. As G4 structure formation can drive genome instability by creating mutations, deletions and stimulating recombination events, this suggests that G4 structures might support the identification of new personalized treatment approaches in the future. G4 structures are currently tested as a therapeutic target to down regulate transcription or to block telomere elongation in cancer cells.
#HDNA #cruciform #quadruplex #DNAtriplex #G4motif #G4DNA #genome #cancer #helicase #Friedreichataxia #bloomsyndrome #wernersyndrome #palimdrome #frataxin #hoogsteen
V. Fifth YouTube video on “Pharmacogenomics In a Nutshell!”
I have previously introduced a new and challenging field, that of Precision Medicine. It is a disruptive and innovative approach in medical practice, a new way to look at patients and diseases, where we strive to find the most effective treatment for each patient as per the patient’s genetic makeup and other predominant factors. This emerging field will create many opportunities for young scientists to come up with new drugs and therapies tailored to serve patients now and in the future. Many training programs on precision medicine have been blossoming everywhere in the last decade. Despite the general interest in this field it seems that many master programs dubbed precision, personalized or translational are no more than a mere attempt to link basic science to clinics and some are no more than a developed version of the so called pharmacogenomics (PG). This presentation is about PG, which is the study of how genes affect a person’s response to drugs. This field that combines pharmacology and genomics aims to develop effective, safe medications that can be prescribed based on a person’s genetic makeup. Finding out how variations at the genetic level correlate with different responses to the same treatment is the objective of the PG discipline, which is a part of precision medicine. This technologically complex field is highly dynamic and will help find the adequate therapeutic strategies taking into account the genomic differences, environmental influences and the life style of the patient. A case study of PG is mercaptopurine (or 6-MP). This purine analogue is effective both as an anticancer and an immunosuppressive agent, and is used to treat leukemia and autoimmune diseases. 6-MP inhibits DNA synthesis by inhibiting the production of the purine containing nucleotides. 6-MP is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-MP. TPMT catalyzes the methylation of 6-MP into the inactive metabolite 6-methylMP preventing mercaptopurine from further conversion into active, cytotoxic TGN metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these alleles may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression when receiving mercaptopurine. A simple blood test is used to identify low metabolizers or TMPT deficient. Hence, individuals will be given the doses that are tailored with their genotype.
#pharmacogenomics #mercaptopurine #precisionmedicine #leukemia #autoimmunedisease #immunosuppression #genomics #pharmacogenetics #pkpdprofiling #pharmacology #genotype #myelosuppression #thioguanine #environmental #medicine #medical #science
IV. Fourth YouTube video on “Precision Medicine: An Expected Journey”
“Precision Medicine” (PM) is as a challenging field that will change terminally the medical practice towards the delivery of tailored therapies, which depends mainly on the individual genetic signature. This new discipline, dubbed translational, will offer many career opportunities in the near future for young scientists. Its multidisciplinary character is expected to bring together scientists working in quite different disciplines to foster the development of a new concept in the use of genomic data for medical purposes. PM is generally referred to as an approach to treat and prevent diseases based on the patient’s genetic makeup, as well as the environment and lifestyle of the person. This means that two people with the same disease would get different treatments. As an emerging and interesting new discipline, many masters programs around the world have been designed to train professionals in this field. However, most of the so called “Precision/Translational Medicine” programs are nothing more than a developed version of pharmacogenomics, which is a field of research that studies how a person’s genes affect how they respond to medications. PM is not a simple link of basic research to clinical trials; rather it is a global patient-centric and population-centric approach. Precision Medicine is a perfect interdisciplinary field that involves professionals from various areas of expertise e.g. genetics, genomics, medicine, pharmacology, structural biology, bioinformatics, mathematics, computer science, law, business, and others. PM comprises specifically customized diagnostic and therapeutic strategies targeting a patient subpopulation with susceptibility to a distinct disease condition based on the individualized discrepancies of select criteria, including genomic profiles, environmental influences, lifestyle habits and family history. From genomic data to therapeutic molecules, and from bench basic research to bedside therapeutic solutions, a huge progress has been achieved in the decoding of the human genome so that the road is paved to better understanding of the different diseases. Once the causal factors of a disease are known, the ability to treat the root causes is now within reach! A number of disease-associated molecular biomarkers enable scientists to analyze the flow of information through the cell networks. Several layers of complexity are associated with the expression of genomic DNA. To decipher the different molecular parameters and read the change in the flow of metabolites, new technologies, termed disruptive, change the principles and practices embodied in many existing molecular diagnostic assays. The multidimensional systems biology combined with biomedical informatics allowed the analysis of large data sets resulting in unprecedented diagnostic precision and the ability to predict the efficacies of individual drugs or combined therapies. Plenty of discoveries are in store for the young generation of PM professionals.
I have already mind mapped all the components of PM and designed a dynamic and far-reaching Master program to train new graduates in this demanding field to face all sorts of future challenges and turn them into realistic opportunities to develop new concepts and put unprecedented therapies into reach. I am prepared to collaborate with academic institutions/research centers for the implementation of this PM Master program.
#precisionmedicine #translationalmedicine #genomics #genetics #stratifiedmedicine #discovery #systemsbiology #interdisciplinary #biomarker #clinic #pharmacogenomics #modeling #disease #diseasome #therapy #medicine #law #ethics #environment
III. Third YouTube video on “Lambda: an insignificant miracle”
The phage lambda infects Escherichia coli cells. As a temperate phage, Lambda has two survival strategies referred to as lytic and lyzogenic pathways. The lytic pathway culminates by the death or lysis of the host bacterium and the release of progeny virions. In the lyzogenic pathway the phage establishes a stable, non-lytic relationship with the host bacterium, which can then be transmitted in a latent form, termed prophage, to subsequent generations. This pathway entails the integration of the prophage in the bacterium chromosome. When lysogenic pathway is established, the lysogenic bacterium displays a so-called immunity against infection by further phage particles of the same kind. The gene regulatory network controlling both pathways is nothing less than a wonderful model of co-evolution and adaptation. Lambda has been a source of inspiration for many scientists, biologists and non-biologists. It has motivated many scholars to move from their areas of expertise into biology. The study of the bacteriophage lambda led to many key discoveries in the mechanisms of gene regulation, recombination, and transcription. Lambda was originally discovered in 1951 when it was released from the laboratory E. coli strain K-12 after ultraviolet irradiation. Since then it never stopped to amaze us. The lysis/lysogeny bistable switch directs two mutually exclusive cell fates. We will see how the intricate gene regulatory network is controlled by a few key factors but dominated to some extent by stochasticity. New models have showed critical roles of gpcII and qpQ thresholds in the bistable genetic switch that controls the lystic and lyzogenic pathways.
#phagelambda #genetics #translationalbiology #lyzogen #lytic #bistableswitch #coevolution #ecoli #genenetwork #stochasticity
II. Second YouTube video on “Genes and Alleles”
Despite its simplicity the concept of “Genes and Alleles” is widely misunderstood and some of the assumptions are confusing or wrong. In the effortless definition, a gene is a sequence of nucleotides that codes for a product that could be either a functional RNA or a polypeptide. The part of the sequence specifying the gene product is flanked by a promoter region where transcription initiates and a termination region where the process of transcription comes to an end and releases the RNA molecule. A gene may have different forms called alleles, some are functional and others are not. The latter could be amorphic or codes for a non functional product. If a given population harbors several alleles of a gene, any individual of that population can carry a maximum of two different alleles. Individuals are diploid and could be either homozygous or heterozygous. In the heterozygous condition, one allele may be expressed and determines the phenotype, we would call it dominant, and the other that is masked is called recessive. The dominant-recessive relationship is in general considered as constant regardless of the conditions. This is where one of the assumptions is wrong! Two alleles can be in turn dominant/recessive, recessive/dominant, incompletely dominant or co-dominant depending on the prevailing conditions and the nature of the phenotype under investigation. To illustrate this fact we will resort to a well known disease: the sickle-cell anemia. This autosomal recessive disorder is caused by a mutated version of the gene coding for the beta subunit of hemoglobin. Such abnormal polypeptide causes the red blood cells to distort and take on the sickle shape. This disease may prove fatal. However, medical management relieves the associated pain and prevents further complications that might threaten the patient life. Furthermore, the allele for sickle-cell disease HbS is most common in people of African ancestry. The reason for this probably has to do with the relationship between the sickle-cell trait and malaria. Malaria, a disease common in parts of Africa, affects red blood cells. The scientists observed an increased frequency of the HbS allele in regions with a high incidence of malaria. This is because people with the sickle cell allele are resistant to malaria. Malaria is an acute febrile illness caused by Plasmodium parasites, which are spread to people through the bites of infected female Anopheles mosquitoes. There are several parasite species that cause malaria in humans, and 2 of these species, P. falciparum and P. vivax . pose the greatest threat. This video will shed light on the variable relationship between the two alleles HbA (normal) and HbS as per the prevailing condition and the investigated phenotype.
#genomics #genetics #genepool #sicklecell #malaria #translationalbiology #geneconcept
I. First YouTube video on “DNA topology”
DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms. The conformation that DNA adopts depends on several factors such as the hydration level, DNA sequence, supercoiling, chemical modifications of the bases, etc. These conformations share a common secondary structural theme, the double helix. Although DNA is assumed to be in a regular and linear form, DNA can adopt regular structures of higher complexity in several ways. For instance, most of bacterial chromosomes are double-stranded covalently closed circular DNA (dscccDNA) i.e. they have no free 3′ and 5′ ends. DNA molecules with fewer or additional helical turns generate densely packed and compact structures called superhelices. From studies of the most known bacterium E. coli it was recognized that its circular genome is supercoiled i.e. the genomic DNA carries superhelical turns generating the so-called torsional stress. Note that supercoiling is only possible for DNA molecules without free ends! The topology of DNA is defined by how the two complementary single strands are intertwined. Several parameters are used to describe the topological properties of DNA. One of the parameters is the “linking number”, a topological invariant value of the dscccDNAs. The linking number (designated by L, LK or a) is defined by the number of times one strand winds around the other in any dscccDNA. By convention the linking number is designated positive in a right-handed DNA. L can further be equated to the twist (T or Tw), being related to the pitch (p) of the helix and corresponding to the number of helical turns (T=N/p where N is the number of base pairs per molecule), and writhe (W) or writhing number (Wr), which is the number of crossings the double helix makes around itself or simply the number of superhelical turns; L=T+W. The linking number of a specific topoisomeric form can only change by the action of topoisomerases. DNA molecules with negative supercoils are energetically favorable for all processes involving DNA: replication, transcription and recombination. As topoisomerases are essential functions for cycling cells, they are potential targets for inhibitory molecules. The latter serve well as anticancer drugs and antibiotics.
yeastwonderfulworld 