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Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox – Cureus

September 4th, 2024 2:46 am

Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox  Cureus

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Somite.ai takes pre-seed to $10M as it eyes to become the OpenAI of stem cell biology – CTech

September 4th, 2024 2:46 am

Somite.ai takes pre-seed to $10M as it eyes to become the OpenAI of stem cell biology  CTech

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Longeveron Announces Positive Type C Meeting with U.S. FDA Regarding Pathway to BLA for Lomecel-B in Hypoplastic Left Heart Syndrome (HLHS) – Yahoo…

September 4th, 2024 2:46 am

Longeveron Announces Positive Type C Meeting with U.S. FDA Regarding Pathway to BLA for Lomecel-B in Hypoplastic Left Heart Syndrome (HLHS)  Yahoo Finance

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Study Explores Potential Of 3D Printed Regenerative Breast Implants – Forbes

September 4th, 2024 2:45 am

Study Explores Potential Of 3D Printed Regenerative Breast Implants  Forbes

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Nikon Announces New Image Analysis Functions to Empower Drug Discovery Research for Cancer, Neurological Disease, and Regenerative Medicine – PR…

September 4th, 2024 2:45 am

Nikon Announces New Image Analysis Functions to Empower Drug Discovery Research for Cancer, Neurological Disease, and Regenerative Medicine  PR Newswire

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Trinity researcher scores 800,000 to boost regenerative medicine – SiliconRepublic.com

September 4th, 2024 2:45 am

Trinity researcher scores 800,000 to boost regenerative medicine  SiliconRepublic.com

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Seeing the future: Zebrafish regenerates fully functional photoreceptor cells and restores its vision – EurekAlert

September 4th, 2024 2:45 am

Seeing the future: Zebrafish regenerates fully functional photoreceptor cells and restores its vision  EurekAlert

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Regenerative Medicine Industry Projected to Surge to USD 73,084.2 Million by 2033, Growing at an 18.5% CAGR – Future Market Insights

September 4th, 2024 2:45 am

Regenerative Medicine Industry Projected to Surge to USD 73,084.2 Million by 2033, Growing at an 18.5% CAGR  Future Market Insights

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8: Techniques of Molecular Genetics – Biology LibreTexts

September 4th, 2024 2:45 am

Genetics is the study of the inheritance and variation of biological traits. We have previously noted that it is possible to conduct genetic research without directly studying DNA. Indeed some of the greatest geneticists had no special knowledge of DNA at all, but relied instead on analysis of phenotypes, inheritance patterns, and their ratios in carefully designed crosses.

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1.5: Molecular Genetics – Biology LibreTexts

September 4th, 2024 2:45 am

Genes and Proteins

Since the rediscovery of Mendels work in 1900, the definition of the gene has progressed from an abstract unit of heredity to a tangible molecular entity capable of replication, transcription, translation, and mutation. Genes are composed of DNA and are linearly arranged on chromosomes. Some genes encode structural and regulatory RNAs. There is increasing evidence from research that profiles the transcriptome of cells (the complete set all RNA transcripts present in a cell) that these may be the largest classes of RNAs produced by eukaryotic cells, far outnumbering the protein-encoding messenger RNAs (mRNAs), but the 20,000 protein-encoding genes typically found in animal cells, and the 30,o00 protein-encoding genes typically found in plant cells, nonetheless have huge impacts on cellular functioning.

Protein-encoding genes specify the sequences of amino acids, which are the building blocks of proteins. In turn, proteins are responsible for orchestrating nearly every function of the cell. Both protein-encoding genes and the proteins that are their gene products are absolutely essential to life as we know it.

Replication, Transcription, and Translation are the three main processes used by all cells to maintain their genetic information and to convert the genetic information encoded in DNA into gene products, which are either RNAs or proteins, depending on the gene. In eukaryotic cells, or those cells that have a nucleus, replication and transcription take place within the nucleus while translation takes place outside of the nucleus in cytoplasm. In prokaryotic cells, or those cells that do not have a nucleus, all three processes occur in the cytoplasm.

Replication is the basis for biological inheritance. It copies a cells DNA. The enzyme DNA polymerase copies a single parental double-stranded DNA molecule into two daughter double-stranded DNA molecules. Transcription makes RNA from DNA. The enzyme RNA polymerase creates an RNA molecule that is complementary to a gene-encoding stretch of DNA. Translation makes protein from mRNA. The ribosome generates a polypeptide chain of amino acids using mRNA as a template. The polypeptide chain folds up to become a protein.

The central dogma of molecular biology describes the flow of genetic information in cells from DNA to messenger RNA (mRNA) to protein. It states that genes specify the sequence of mRNA molecules, which in turn specify the sequence of proteins. Because the information stored in DNA is so central to cellular function, the cell keeps the DNA protected and copies it in the form of RNA. An enzyme adds one nucleotide to the mRNA strand for every nucleotide it reads in the DNA strand. The translation of this information to a protein is more complex because three mRNA nucleotides correspond to one amino acid in the polypeptide sequence.

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that enzymes can convert back and forth from DNA to RNA. During transcription, a DNA sequence is read by RNA polymerase, which produces a complementary, antiparallel RNA strand. Unlike DNA replication, transcription results in an RNA complement that substitutes the RNA uracil (U) in all instances where the DNA thymine (T) would have occurred. Transcription is the first step in gene expression. The stretch of DNA transcribed into an RNA molecule is called a transcript. Some transcripts are used as structural or regulatory RNAs, and others encode one or more proteins. If the transcribed gene encodes a protein, the result of transcription is messenger RNA (mRNA), which will then be used to create that protein in the process of translation.

Translation is the process by which mRNA is decoded and translated to produce a polypeptide sequence, otherwise known as a protein. This method of synthesizing proteins is directed by the mRNA and accomplished with the help of a ribosome, a large complex of ribosomal RNAs (rRNAs) and proteins. In translation, a cell decodes the mRNAs genetic message and assembles the brand-new polypeptide chain. Transfer RNA, or tRNA, translates the sequence of codons on the mRNA strand. The main function of tRNA is to transfer a free amino acid from the cytoplasm to a ribosome, where it is attached to the growing polypeptide chain. tRNAs continue to add amino acids to the growing end of the polypeptide chain until they reach a stop codon on the mRNA. The ribosome then releases the completed protein into the cell.

DNA to protein: This interactive shows the process of DNA code being translated to a protein from start to finish!

The genetic code is degenerate as there are 64 possible nucleotide triplets (43), which is far more than the number of amino acids. These nucleotide triplets are called codons; they instruct the addition of a specific amino acid to a polypeptide chain. Sixty-one of the codons encode twenty different amino acids. Most of these amino acids can be encoded by more than one codon. Three of the 64 codons terminate protein synthesis and release the polypeptide from the translation machinery. These triplets are called stop codons. The stop codon UGA is sometimes used to encode a 21st amino acid called selenocysteine (Sec), but only if the mRNA additionally contains a specific sequence of nucleotides called a selenocysteine insertion sequence (SECIS). The stop codon UAG is sometimes used by a few species of microorganisms to encode a 22nd amino acid called pyrrolysine (Pyl). The codon AUG, also has a special function. In addition to specifying the amino acid methionine, it also serves as the start codon to initiate translation. The reading frame for translation is set by the AUG start codon.

The genetic code is universal. With a few exceptions, virtually all species use the same genetic code for protein synthesis. The universal nature of the genetic code is powerful evidence that all of life on Earth shares a common origin.

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Molecular genetics made simple – PMC – National Center for …

September 4th, 2024 2:45 am

Abstract

Genetics have undoubtedly become an integral part of biomedical science and clinical practice, with important implications in deciphering disease pathogenesis and progression, identifying diagnostic and prognostic markers, as well as designing better targeted treatments. The exponential growth of our understanding of different genetic concepts is paralleled by a growing list of genetic terminology that can easily intimidate the unfamiliar reader. Rendering genetics incomprehensible to the clinician however, defeats the very essence of genetic research: its utilization for combating disease and improving quality of life. Herein we attempt to correct this notion by presenting the basic genetic concepts along with their usefulness in the cardiology clinic. Bringing genetics closer to the clinician will enable its harmonious incorporation into clinical care, thus not only restoring our perception of its simple and elegant nature, but importantly ensuring the maximal benefit for our patients.

All inheritable traits of living organisms are determined by their genetic material, the genome, a long nucleic acid called deoxyribonucleic acid (DNA). The DNA consists of 3109 nucleotides. Each nucleotide is made up of a sugar (deoxyribose), a nitrogenous base (adenine (A), guanine (G), cytosine (C) or thymine (T)) and a phosphate group () [1,2]. The four nitrogenous bases are divided into two groups: purines (including A and G) have two joined heterocyclinc rings and pyrimides (including C and T) have a single heterocyclic ring. Successive sugar and phosphate residues are linked by covalent phosphodiester bonds, forming the backbone of the DNA molecule and a nitrogenous base is attached to each sugar. The stability of DNA is primarily dependent on the strong covalent bonds that connect the constituent atoms of its linear backbone, and also on a number of weak non-covalent bonds that exist. Meanwhile, because of the phosphate group charges present in each nucleotide, DNA is negatively charged and therefore highly soluble in water.

The chemical structure of a nucleotide including the phosphate (yellow), the sugar (deoxyribose in green) and adenine as the nitrogenous base (pink).

The DNA structure is a double helix, in which two DNA molecules are held together by weak hydrogen bonds [37]. Hydrogen bonding occurs between laterally opposed bases, of the two strands according to Watson-Crick rules: A specifically binds to T, and G to C. The two strands are therefore complementary [8]. As the phosphodiester bonds link carbon atoms number 3 and number 5 of successive sugar residues, the end of each DNA strand will have a terminal sugar residue where carbon atom number 5 is not linked to a neighboring sugar residue, and is therefore called 5 end. The other end of the molecule is similarly called 3 end. The two DNA strands are antiparallel because they always associate (anneal) in such a way that the 53 direction of one DNA strand is the opposite to that of its partner. To describe a DNA sequence, the sequence of bases of one strand only, are usually provided, and are provided in the 53 direction. This is the direction of DNA replication as well as transcription.

The human DNA is estimated to be approximately 2 m long. In order for it to fit in the 10 m nucleus of human cells it is imperative that it is tightly folded. The DNA double helix is therefore subjected to at least two levels of coiling: the first involving coiling around a central core of eight histone proteins, resulting in units called nucleosomes, which are connected by spacer DNA; and the second involving coiling of this string of nucleosomes into a chromatin fiber [3]. During the different phases of the cell cycle, the DNA varies in the extent of its condensation. For example, during interphase the chromatin fibers are organized into long loops, whereas in metaphase chromosomes, the DNA is compacted to about 1/10,000 of its stretched out length. In humans there are 24 different chromosomes, namely 122 autosomes, and sex chromosomes X and Y [9]. Since humans are diploid organisms, our DNA is found in two copies, one inherited from each parent, and is folded into 46 chromosomes. Among the major DNA sequence elements of each chromosome are: the centromeres (constriction site where sister chromatics are joined and chromosomes link to the mitotic spindle), the telomeres (structures capping the ends of chromosomes) and the origins of replication (where DNA replication begins). Chromatin is encountered in extended (euchromatin) or highly condensed (heterochromatin) states, which in turn affect the transcriptional status of the corresponding DNA regions (being active or inactive, respectively) [10]. Under the light microscope, these regions appear as light and dark bands of metaphase chromosomes ().

Diagrammatical representation of the human karyotype of haploid chromosome set with X and Y as the sex chromosome complement. The alternating light and dark bands are characteristic of each chromosome in standard G-banding karyotype, and they represent euchromatic and heterochromatic regions, respectively.

Genomic DNA contains coding as well as non-coding regions. The non-coding regions are involved in DNA folding, chromosome formation, chromatin organization within the nucleus, regulation of transcription and more [1114]. The coding regions are responsible for the transcription of RNA molecules and ultimately protein synthesis.

The genes are stretches of DNA that code for polypeptides. Specifically, genes contain regulatory and coding regions, which regulate their transcription or code for the polypeptide product, respectively. A key regulatory region is the promoter, where the transcription machinery binds for transcription to be initiated. Other possible regulatory regions include enhancers, which regulate gene expression in different tissues or cells, and can be found upstream or downstream of the coding region, as far as several thousand bases. The coding regions are represented by exons, whose size and number varies among different genes. Interspersed between gene exons, there are non-coding sequences named introns, which tend to make up the largest percentage of a gene. The human genome is estimated to contain approximately 20,000 different genes [15]. Interestingly, it is estimated that 80% of the human genome is expressed, yet only 2% is coding for proteins [16].

The central dogma of molecular biology was first stated in 1958 and re-stated in 1970 by Francis Crick [17,18]. According to this dogma there are three major classes of biopolymers: DNA, RNA and protein, and three classes of direct transfer of information that can occur between these biopolymers: general transfers, special transfers and unknown transfers. Of these, only the general transfers are believed to occur normally in most cells and they involve DNA replication to DNA, DNA transcription to mRNA and mRNA translation to proteins ().

The central dogma of molecular biology, as it currently applies in most cells (general transfers = black),or under specific conditions (in some viruses and in vitro: special transfers = grey).

The transfer of information from the DNA to the protein level is achieved step-wise and starts with the transcription of a gene to mRNA. Specifically, the transcription machinery (including RNA polymerase and a variety of transcription factors) binds to the gene promoter, the double helix opens in that location and a single strand primary mRNA molecule (hn-RNA), complementary to that gene sequence, is synthesized base by base () [19]. RNA as opposed to DNA, is a single strand nucleic acid containing ribose instead of deoxyribose and uracil instead of thymine. The heterogenous (hn)-RNA molecules go through a series of processing steps including a 5 cap, a poly-A (50250 adenine molecules and a 70kDa protein) tail at the 3 end and splicing, to remove the intronic sequences () [2023]. Alternative splicing can also occur, which removes certain exons and contributes to the diversity of proteins any single gene can produce [24].

During transcription the transcription machinery (including RNA polymerase and a variety of transcription factors) binds to the gene promoter, the double helix opens in that location and a single strand primary mRNA molecule (hn-RNA),complementary to that gene sequence, is synthesized base by base.

The promoter and enhancer elements of each gene are involved in gene transcription to precursor mRNA (hn-RNA) molecules which are then appropriately processed to give mature mRNA.

The mature mRNA molecules can be translated to proteins [25]. This process takes place in the cytoplasm with the aid of ribosomes, which are complexes of RNAs and proteins called ribonucleoproteins. The ribosomes are divided into two subunits: the smaller subunit binds to the mRNA, while the larger subunit binds to the tRNA which carries the amino acids. When a ribosome finishes reading a mRNA, these two subunits split apart. In particular, ribosomes bind mRNA and read through it as triplet codons, usually starting with an AUG triplet (initiation codon) downstream of the ribosome binding site. For each codon, the ribosome, with the aid of initiation and elongation factors, recruits a complementary tRNA molecule, which in turn carries a specific amino acid. Each codon codes for a specific amino acid as shown in . As the amino acids are linked into the growing peptide chain, they begin folding into the correct conformation. The translation process ends with the stop codons UAA, UGA or UAG. The nascent polypeptide chain is then released from the ribosome as a mature protein [25]. In some cases the new polypeptide chain requires additional processing to make a mature protein. Mature proteins in turn can be subjected to a range of post-translational modifications. Their ultimate roles in cell physiology can be highly variable including cytoarchitecture, enzymatic activity, intracellular signalling, transportation, communication etc.

Genetic variation refers to genetic difference between individuals within or between different populations. This variation is what renders each individual unique in its phenotypic characteristics. Genetic variation occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. These variations can be divided in polymorphisms and mutations.

Polymorphisms are defined as variants found in >1% of the general population [26]. Due to their high frequency they are considered unlikely to be causative of genetic disease. They can however, together with other genetic and environmental factors, affect disease predisposition, disease progression or response to treatments (e.g. [27]). Three common types of polymorphisms are the single nucleotide polymorphisms (SNPs), small insertions/deletions (indels) and the large-scale copy number polymorphisms (CNPs or CNVs). SNPs are single base changes that occur on average about every 1000 bases in the genome. Their distribution is not homogenous and they occur more frequently in non-coding regions where there is less selective pressure () [28,29]. Most SNPs are neutral; yet 35% are thought to have a functional role, i.e. affect the phenotype of the individual carrying them. Depending on their effect at the protein level, SNPs can be characterized as synonymous (coding for the same amino acid as the wild type DNA sequence) or non-synonymous (coding for a different amino acid than the wild type DNA sequence) [29]. Indels are small insertions or deletions ranging from 1 to 10,000 bp in length, although the majority involves only a few nucleotides [30,31]. They are considered the second most common form of variation in the human genome following SNPs, with over 3 million short indels listed in public databases. CNVs are variations in the number of copies of DNA regions. They can involve loss of one or both copies of a region of DNA, or the presence of more than two copies of this region. They can arise from DNA deletions, amplifications, inversions or insertions and their size can range from 1 kb (1,000 bases) to several megabases [32]. SNPs, indels and CNVs can either be inherited or arise de novo.

A Single-Nucleotide DNA Polymorphism (SNP) is defined as a single DNA variation detected when a single nucleotide in the genome (or other common sequence) is different between species or paired chromosomes in an individual. In this case there is a substitution of a C (Cytosine) in a T (Tymine) which causes the change of a G (Guanine) in a A (Adenine) in the complementary DNA strand.

Mutations on the other hand, are rare (by some defined as variations with <1% frequency in the general population, although there are many exceptions to this rule) changes in the DNA sequence that can change the resulting protein, impair or inhibit the expression of the gene, or leave both the gene function and protein levels/structure unaffected. Although a variety of definitions have been considered over the years, for most scientists mutation has become synonymous with disease. They can arise during DNA replication or as a result of DNA damage through environmental agents including sunlight, cigarette smoke and radiation. A variety of different types of mutations exist and the terminology used to describe them is based on their effect either on DNA structure, on protein product function, or on the fitness of the individual carrying them.

In terms of DNA structure modification, mutations can be categorized as:

A) point mutations in which a single nucleotide is changed for a different one (). These are divided into missense mutations (meaning that when translated this DNA sequence leads to the incorporation of a different amino acid into the produced protein, with possible implications in the protein function), nonsense mutations (where the new nucleotide changes the sequence so that a stop codon is formed earlier than in the normal sequence and therefore the produced protein is truncated), silent mutations (where the nucleotide change does not affect the amino acid in the corresponding position of the produced protein, and therefore the final protein product remains unaltered), and splice-site mutations (which affects the splice site invariant donor or acceptor dinucleotides (5GT or 3AG).

Different types of mutation and possible conseuquence on protein function:A) missense mutation; B) nonsense mutation; C) deletion; D) inversion.

B) insertions in which one or more nucleotides are inserted in the normal DNA sequence, therefore disrupting it. This can have a moderate or severe effect on the corresponding mutant protein product. For example it can affect the splicing or the reading frame ( frame-shift mutations), therefore leading an incorrect reading of all the downstream nucleotide triplets and consequently their translation to a significantly different and/or truncated amino acid sequence.

C) deletions in which one or more nucleotides are deleted from the normal DNA sequence (). As in the case of insertions this can lead to minor (e.g. single amino acid changes) or major protein defects (e.g. reading frame modifications with implications for the entire downstream amino acid sequence of the mutant protein). When larger chromosomal regions are deleted, multiple genes can be lost and/or previously distant DNA sequences can now be juxtaposed (such juxtapositions can lead, for example, to the production of abnormal proteins containing sequences from different genes that have now been merged or abnormal expression of otherwise normal proteins by deletions affecting their upstream regulatory regions).

D) amplifications leading to multiple copies of chromosomal regions and consequently to an increased number of copies of the genes located within them and increased levels of the corresponding proteins.

E) inversions involving the reversal of the orientation of a DNA segment, with variable implications for the protein product, similar to the ones described above ().

F) translocations where regions from non-homologous chromosomes are interchanged.

Mutations can affect the expression of a transcript and its corresponding protein, or modify the structure of the resulting protein therefore impairing its function [33]. Depending on their functional effect, mutations can be classified as dominant negative (the mutant gene product acts antagonistically to the wild-type allele), gain-of-function (the mutant gene product gains a new and abnormal function), and loss-of-function (the mutant gene product has less or no function). Loss-of-function mutations can be associated with haploinsufficiency, a common occurrence in the molecular cardiomyopathy setting.

Haploinsufficiency occurs when the gene product of one of the two alleles in an individual is lost due to a DNA deletion or to instability/degradation of the mutant protein. Other terms used to describe the effect of a mutation on the fitness of the carrier are: harmful or deleterious mutations (decreases the fitness of the carrier), beneficial or advantageous mutations (increases the fitness of the carrier), and lethal mutations (leading to the death of the individual carrying them).

In the field of cardiovascular genetics, when a new genetic variant is identified a common occurrence given the large number of genes and different variants thereof being screened it is crucial to first determine whether it represents a benign polymorphism or a pathogenic mutation. Identifying pathogenic mutations enables the characterization of the molecular mechanisms of pathogenesis, and more importantly for the clinical setting, it allows the development of genetic tests for mutation detection in other family members (including pre-symptomatically) as well as unrelated patients with similar phenotypes (see section on Cardiovascular genetics in clinical practice).

The Clinical Molecular Genetics Society1 and the American College of Medical Genetics2 have issued guidelines to facilitate the determination of the potential pathogenic role of a novel/unclassified variant (). The Human Gene Mutation Database,3 along with locus-specific or disease-specific mutation databases, are valuable resources for first deciphering whether a detected genetic variant represents a known mutation. The databases Online Mendelian Inheritance in Man,4 dbSNP5 and Ensembl,6 along with thorough searches of the literature via PubMED, Google Scholar, Scopus or the Web of Science, can also provide valuable information. From thereon carefully matched controls need to be included in the study populations, co-occurrence with known (in trans) deleterious mutations in the same gene needs to be ruled out, co-segregation with the disease in the family represents useful information, and occurrence of the novel variant concurrent with the incidence of a sporadic disease can be a strong indicator. Bioinformatically, it is important to determine if the unclassified variant leads to an animo acid change and how different the biophysical properties of the new amino acid are: the greater the difference, the higher the likelihood to possess a pathogenic role. Similarly, the more conserved a DNA region is across species, the greater an impact any variations therein are likely to have. A range of in silico analysis tools can also be used for the predication of a pathogenic effect (e.g. Align GVGD, Sorting Intolerant From Tolerant [SIFT], Polyphen, and Alamut) or the prediction of splice sites. One of the best means of determining pathogenicity, however, is the use of suitable functional assays and transgenic animal models [34,35].

From mutation to disease. A DNA mutation can cause qualitative or quantitative changes at the protein level, leading to either a dysfunctional/non-functional protein product and/or aberrant protein expression levels. Both mechanisms can in turn lead to CVD.

Once a mutation has been directly associated with a pathological phenotype a number of additional parameters need to be evaluated in order to maximize its value in the clinical setting. These parameters relate to the mode of inheritance of a mutation, which impacts directly the chances of detecting it in other family members of the patient, or his/her offspring. The categorization gonosomal or autosomal depends on whether the mutations are located on either of the sex chromosomes or not. For example a mutation on the Y chromosome will only affect males. The dominant or recessive nature relates to the need of one or both alleles, respectively, to carry the mutation for the pathogenic phenotype to develop. In hypertrophic cardiomyopathy (HCM) a number of cases have been reported with homozygosity for the pathogenic mutation. Nishi et al. first reported homozygosity for a MYH7 mutation in two brothers with HCM [36]. Homozygous mutations were also detected in MyBPC in HCM patients [37]. The patients who harbour homozygous mutations present with a more severe clinical phenotype than their heterozygous family members. These observations support the notion of a mutation dosage effect, in which a larger amount of the defective protein leads to a greater disruption of the sarcomere function and results in a more severe clinical outcome. For example, in our Egyptian HCM cohort, none of the mutation-positive patients were homozygous for the mutation detected (data not published) which might be explained either by the rarity of its occurrence in the specific cohort or due to technical limitations in the mutation screening method ().

Mutation screening by denaturing high performance liquid chromatography (dHPLC) using WAVE, Transgenomics. dHPLC can be used as an initial mutation screening method, being dependent on heteroduplex (wild type-mutant) formation, and variant profiles from the wild pattern are subsequently sequenced. Note however, that dHPLC is not capable of detecting homozygosity.

Importantly, a number of exceptions apply to the aforementioned inheritance mode rules, such as in the case of incomplete penetrance (a percentage of the individuals carrying the mutation fail to present the corresponding trait) where mutation carriers may not present with any symptoms even in the presence of a dominant mutation. Furthermore, the phenomena of variable expressivity (variations in a phenotype among individuals carrying a particular genotype) and epistasis (one gene is modified by one or several other genes, e.g. modifier genes) can lead to a range of pathological characteristics despite the presence of the same mutation. These parameters, potentially in combination with environmental factors, can often lead to significant clinical heterogeneity in most inherited CVDs, between unrelated individuals as well as family members carrying the same mutation () [38].

Role of genetic and environmental factors in determining the spectrum of the disease phenotype.(Strachan T, Read AP. Genes in pedigrees and populations in Human molecular genetics 3. 3rd ed. London; New York: Garland Press; 2004).

Another exception is this of compound heterozygotes (carriers of two different mutations on the two alleles of the same gene) or double heterozygotes (carriers of mutations in two different genes), which carry one copy of each mutation, yet they can develop the disease. Notably, the concomitant presence of multiple genetic defects contributing to the same disease is usually associated with a more severe clinical phenotype. For example, in HCM the presence of multiple pathogenic mutations could be included amongst the risk stratification criteria [39]. Multiple mutations have been observed in about 5% of HCM patients and they are usually associated with higher septal thickness and worse clinical outcomes, such as heart failure and sudden death [4043]. Double heterozygosity is commonly detected in the Myosin heavy chain (MYH7) and Myosin binding protein C (MyBPC) genes, probably because they represent the most commonly involved genes in the pathogenesis of HCM. Compound heterozygosity in MyBPC however, leading to the absence of a normal protein, has been reported to results in neonatal death in two independent cases, where the parents were each heterozygous for one of the mutations [44]. Similarly to HCM, double heterozygosity has been reported in other CVDs such as long QT, with a similar frequency of 5% [45].

Hereditary CVDs include a variety of different aspects and structures of the cardiovascular system such as inherited cardiomyopathies, arrhythmias, metabolic disorders affecting the heart, congenital heart diseases, as well as vascular disorders such as Marfan syndrome [4648]. Over the past two decades significant progress has been made towards the identification of the genetic basis of CVD, with tens of genes now known to be implicated in almost all of the different disorders. The magnitude of the role of genetics however, remains elusive. Although in some cases the pathogenesis appears to involve complex mechanisms and multifactorial (genetic and environmental) aetiology, multigenic inheritance (e.g. familial hypercholesterolemia: LDLR, APOB, ABCG5, ABCG8, ARH, PCSK9; hypertrophic cardiomyopathy: MYH7, TNNT2, TPM1, TNNI3, MYL2, MYBPC3, ACTC, MYL3) or even monogenic, also known as Mendelian, inheritance (e.g. Marfan syndrome: FNB1) has been described. Pinpointing the gene(s) and their specific mutations that lead to each pathological phenotype can give rise to valuable, complementary genetic diagnostic/prognostic tools for significantly improved clinical management of CVD patients and their families.

For example, the recently published consensus statement on the state of genetic testing for cardiomyopathies and channelopathies has elegantly presented the list of different genes which contribute by >5% to these inherited disorders. [49,50]. There are more than 50 distinct channelopathy/cardiomyopathy-associated genes with hundreds of mutations discovered to date. Each of these mutations/genes usually accounts for a small percentage of the reported cases, while in many cases the causative mutation/gene is never identified. For example, in channelopathies a mutation is found in <20% of short QT syndrome cases and up to 75% in long QT syndrome cases. An exceptional scenario is this of mutations in the cardiac ryanodine receptor (RYR2) gene in catecholaminergic polymorphic ventricular tachychardia, which account for up to 65% of affected patients [51]. In cardiomyopathies, positive genetic testing results range in frequency from <20% in restrictive cardiomyopathy to 60% in familial HCM. Despite the fact that two decades ago, HCM was termed a disease of the sarcomere involving at least 8 causative genes, the rate of mutation detection ranged in frequency from 2530% in MyBPC and MYH7 to 5% in TNNT2 and TNNTI3, and 1% in other sarcomeric genes [42,52]. Additionally, there are HCM phenocopies (same phenotype) associated with non-sarcomeric gene mutations and different modes of inheritance, which may on occasion be difficult to exclude from sarcomeric HCM based on clinical evaluation alone. Therefore, multiple genes need to be screened for a multigenic disease such as HCM.

Overall, our understanding of the genetic basis of CVD has been rapidly expanding over the years with important lessons learned both on monogenic as well as complex disease forms [53]. However, the true value of these findings lies in their translation to the clinical setting and their utilisation towards improved CVD diagnosis, prognosis and treatment. Along these lines, genetic testing is currently available for a number of CVDs in the form of clinical service in most Western countries, and increasingly in the developing world.

Genetic testing can serve three main goals in the clinical practice: first to determine the mode of inheritance of the specific disease in the specific family and identify if there is risk for other family members; second to organize the clinical assessment of unaffected family members through predictive genetic testing so as to distinguish those who are at risk for the disease and should have regular cardiac follow-up (mutation carriers) and those who are not (mutation non-carriers); third, following the establishment of distinct genotypephenotype correlations, the application of genetic testing in disease diagnosis, prognosis and personalized treatment (i.e. identification of the drugs to which each patient will respond best) [54].

The clinical value of genetic screening of a cardiovascular disease patient is therefore valuable initially at the diagnostic/prognostic/therapeutic level, provided the genotypephenotype associations have been established first. These associations vary considerably among different cardiovascular diseases, different genes and different mutations thereof. The relevance of genetic testing towards these three levels of clinical management is possibly best shown in the setting of the long QT syndrome [49,50]. It is critical to note however, that genetic testing in the cardiovascular disease setting cannot be the basis for clinical management of patients, but can serve a complementary role to the comprehensive clinical evaluation to better address the patient's and his/her family's needs.

Identifying the causative mutation of a proband further allows the genetic screening of its family members, a process of marked predictive power and therefore high importance in the cardiovascular clinic [55]. The significance of such pre-symptomatic genetic testing for the probands family members ranges from ensuring that unaffected mutation carriers receive regular clinical follow-up and prophylactic treatment (where available) to reassurance that clinically suspicious findings are unlikely to be indicative of the specific form of the disease in the absence of the specific family mutation (e.g. ) [56,57]. Importantly however, a negative genetic test result in the proband's family members cannot by itself exclude the presence of disease in general, since a large number of different genes and a variety of mutations thereof can contribute to the same or a different pathological cardiovascular phenotype and by chance, a family member could be a carrier of a different gene mutation.

Pedigree of an HCM positive family from the BA HCM Study. A pathogenic mutation in MYH7 exon 23 (Glu927Lys) was detected in the proband II-4. Echo screening of all siblings was undertaken, and sister II-10 was found to have an interventricular septal measurement of 14 mm. Genetic screening of all family members excluded HCM diagnosis for the sister (II-10).However, the symptom free and echo clear son of the proband, was positive for the mutation and therefore given a pre-symptomatic diagnosis of HCM at the age of12 years. Symbols in white represent unaffected individuals, in black are individuals with HCM based on clinical or genetic findings, and in blue are individuals who have not been screened by echo or genetic testing (unpublished data).

Genetic testing of children in the family has always posed an ethical concern, particularly for adult-onset diseases. Therefore pre-symptomatic testing of children should be extensively discussed with the family after a mutation has been identified in the proband, and in the context of the specific cardiovascular disease [58]. In cases where pre-symptomatic genetic screening and mutation identification has direct implications on the child's clinical follow-up, lifestyle adaptations and preventive treatments, it would be valuable to proceed with genetic testing, upon the parents approval. For example, for long QT syndrome and catecholaminergic polymorphic ventricular tachychardia, and occasionally in high risk HCM families, in which preventive measures or prophylactic therapy is advisable for asymptomatic mutation positive family members, genetic testing should be undertaken in early childhood, i.e. regardless of age. On the other hand, for late-onset and/or reduced penetrance diseases, it is reasonable to proceed with clinical monitoring as needed during childhood, leaving the genetic testing option open for when the individual reaches adulthood [49,50]. When a child has already presented with a CVD, the use of genetic testing is complementary to all other clinical tests, and especially valuable for identifying other family members at risk, since childhood-onset cases, even when presumed as sporadic, can often have a genetic aetiology. For example, approximately half of the presumed sporadic cases of childhood-onset hypertrophy have genetic causes [59].

Although the translation of molecular genetics to routine clinical practice is slow, a series of certified genetic testing centers (www.genetests.org) have been established, and guidelines have already been issued for a number of cardiovascular diseases such as HCM, dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) [60,61]. The consensus is that a minimum of three to four generation family history needs to be obtained, the relatives at risk need to be identified and directed for clinical screening, the potential genetic nature of the disease needs to be explained, and the possibility of genetic testing should be discussed where appropriate.

In order to follow these guidelines, cardiology clinics around the world need to ensure that cardiologists are provided with appropriate training in key genetic concepts, along with information on the latest developments in cardiovascular genetics and the best means to apply them in the clinic. Importantly, the close interaction between cardiologists, geneticists and genetic counsellors, especially in complex cases, will significantly expedite the benchside-to-bedside translation of the latest genetic discoveries and optimize the clinical care provided to the patient [62,63]. For example, when routine cardiovascular genetic screening fails to detect the causative mutations, screening can be extended to include broad gene panels and/or application of high throughput technologies. Similarly, in cases where new mutations are identified, targeted genetic tests can be designed, if needed, for screening family members at risk. Currently, different modes of cardiologist-geneticist interactions are being adopted in clinical settings around the world, a process that requires time, continuing education and to some extent, reorganization of health systems [64]. An example of such an evolving system of interdisciplinary interactions is that of the Egyptian National Genetic study of HCM ().

Combined clinical and genetic evaluation of CVD patients will allow for improved disease management and patient care.

In conclusion, cardiovascular genetic testing is valuable for improving the standards of care for CVD patients and their families at the diagnostic, prognostic and therapeutic level. Importantly, for healthcare systems worldwide, it further represents a cost-effective approach by enabling the timely identification of individuals at risk, ensuring regular follow-up only for the individuals at risk and early disease detection, as well as enabling, where possible, the use of disease preventative measures in order to minimize the environmental contributing factors [65]. To this end, clinical cardiovascular genetics is increasingly emphasized in undergraduate and postgraduate medical education and incorporated in cardiological clinics worldwide [54].

The tremendous technological advancements over the past decade have empowered the discovery of new biological concepts and the emergence of entirely new scientific fields. Among them, cardiac systems genetics a systems-based analysis of genetic variants considering all different levels spanning from their effect on the cardiac transcriptome, proteome, metabolome to organ physiology/pathophysiology (phenome) (). The global analysis of the downstream functional molecular and cellular implications of different genetic variants, will allow the meaningful integration of molecular and clinical data in a powerful way.

To fully unravel the intricate pathways regulating cardiac physiology and pathophysiology the global studies of the human genome will need to be extended to similar studies at the epigenome (chemical changes to the DNA and histone affecting the chromatin structure and function of the genome),transcriptome (the full set of transcripts produced from the human DNA), miRNome (the full set of microRNAs produced from the human DNA), proteome (the full set of proteins) and metabolome (full set of metabolites) levels.

Systems genetics will in turn, serve as an integral part of network medicine, an advanced form of molecular medicine, where perturbations, rather than individual molecules, are investigated as the underlying causes of complex diseases [66]. In cardiology, examples of important first steps in this direction are the identification of cardiac gene expression signatures related with response to left ventricular assist device implantation [67,68] and peripheral leukocyte expression signatures indicative of post-cardiac transplantation tissue rejection [69]. Parameters such as epigenetics and microRNAs are increasingly integrated in network medicine, adding new dimensions to the intricate mechanisms of cardiovascular disease (e.g. [70,71]). A likely next addition to network medicine, based on emerging new data [72,73], could be this of metagenomics the genomic investigation of micro-organisms inside the human body, and their effect on the global networks orchestrating human cardiac physiology/pathophysiology.

Cardiology is rapidly transformed with powerful new technologies expediting the acquisition of new knowledge and exciting new discoveries enriching our understanding of the intricate genotypephenotype correlations. The close interaction of cardiologists and geneticists is facilitating the transition of novel findings to clinical practice and vice versa. It is also enabling the rapid establishment of appropriate research strategies to address emerging clinical questions. Ultimately the convergence of the two disciplines promises to transform the way we perceive, manage and treat CVD.

None.

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4 Introduction to Molecular Genetics – University of Minnesota Twin Cities

September 4th, 2024 2:45 am

Figure 1: Dolly the sheep was the first cloned mammal.

The three letters DNA have now become associated with crime solving, paternity testing, human identification, and genetic testing. DNA can be retrieved from hair, blood, or saliva. With the exception of identical twins, each persons DNA is unique and it is possible to detect differences between human beings on the basis of their unique DNA sequence.

DNA analysis has many practical applications beyond forensics and paternity testing. DNA testing is used for tracing genealogy and identifying pathogens. In the medical field, DNA is used in diagnostics, new vaccine development, and cancer therapy. It is now possible to determine predisposition to many diseases by analyzing genes.

DNA is the genetic material passed from parent to offspring for all life on Earth. The technology of molecular genetics developed in the last half century has enabled us to see deep into the history of life to deduce the relationships between living things in ways never thought possible. It also allows us to understand the workings of evolution in populations of organisms. Over a thousand species have had their entire genome sequenced, and there have been thousands of individual human genome sequences completed. These sequences will allow us to understand human disease and the relationship of humans to the rest of the tree of life. Finally, molecular genetics techniques have revolutionized plant and animal breeding for human agricultural needs. All of these advances in biotechnology depended on basic research leading to the discovery of the structure of DNA in 1953, and the research since then has uncovered the details of DNA replication and the complex process leading to the expression of DNA in the form of proteins in the cell.

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Molecular genetics – Definition and Examples – Biology Online

September 4th, 2024 2:44 am

DefinitionnounA branch of genetics that deal with the structure and function of genes at a molecular levelSupplementGenetics is a basically a study in heredity, particularly the mechanisms of hereditary transmission, and the variation of inherited characteristics among similar or related organisms. Some of the branches of genetics include behavioural genetics, classical genetics, cytogenetics, molecular genetics, developmental genetics, and population genetics.Molecular genetics, in particular, is a study of heredity and variation at the molecular level. It is focused on the flow and regulation of genetic information between DNA, RNA, and proteins. Its sub-fields are genomics (i.e. the study of all the nucleotide sequences, including structural genes, regulatory sequences, and noncoding DNA segments, in the chromosomes of an organism) and proteomics (i.e. the study of proteins from DNA replication). The different techniques employed in molecular genetics include amplification, polymerase chain reaction, DNA cloning, DNA isolation, mRNA isolation, and so on. Molecular genetics is essential in understanding and treating genetic disorders. It is regarded as the most advanced field of genetics. The Human Genome Project was a large scientific research endeavor in molecular genetics. It began in 1990s and finished in 2003 with the intent of identifying the genes and the sequences of chemical base pairs in human DNA.See also:

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A Detailed Look at the Science of Molecular Genetics – KnowYourDNA

September 4th, 2024 2:44 am

Genetics has become one of the most diverse branches of science as it deals with heredity, inheritance, and how certain traits are expressed.

Molecular genetics focuses more on the molecules at work in geneticsspecifically DNA, RNA, and the proteins responsible for expressing traits.

This branch of genetics is instrumental in diagnosing genetic disorders. With molecular genetics, scientists and doctors can pinpoint abnormalities or changes within gene sequences.

The study of human DNA has propelled modern medicine towards actionable solutions for even the most difficult genetic conditions and mutations. By observing the molecular structure of DNA, geneticists can determine any deviation and mutation that may cause trouble down the road.

Molecular genetics is concerned with what makes DNAthat is, the molecules that are at work.1 Its a biomedical science concerned with human genes and the genetic material DNA consists of, as well as their nucleotide sequences and structures at the molecular level.

It is also considered the marriage of genetics and molecular biology, the study of the building blocks of every object.

This science shows us how genes inside our DNA determine everything from eye color to disease risk.

Geneticists, scientists, and medical professionals can determine how genes work and how any divergence from the norm can contribute to genetic disorders and abnormalities by exploring the special processes and properties of DNA molecules and their molecular mechanisms.

Molecular genetics breaks down into smaller fields, including:

Don't miss out on the opportunity to learn more about yourself. Read our best DNA test page to find the best one for you.

Yes. Molecular genetics falls under genetics.

Genetics is a broader branch of biology that deals with anything related to genes, traits, and inheritance. Its the study of how genes are passed down from parents to offspring through DNA sequences.2

19th-century monk Gregor Mendels famed pea plant experiments laid the foundation for modern genetics. Since then, niche branches of genetics have become specializations, such as:

DNA, or deoxyribonucleic acid, has a double helix structure thats made up of chemical components called nucleotides.3

Nucleotides, which form the DNA ladder, have three important parts:

The entirety of an organisms set of DNA or genetic material is called a genome. Each genome has all the instructions necessary for an organism to develop.

Every cell in that organism will have the same genome so that when they replicate themselves, they all still contain the exact same instructions.

Molecular genetic testing is when a DNA segment or a gene sequence is inspected for any mutations.4 A DNA strand is often looked closely at and analyzed to determine any variations at the molecular level.

Its compared to normal genetic material and any deviations or mutations are taken note of. Any variance in a gene is then explored.

Different mutations can lead to different genetic conditions. For example, a copy of a chromosome can lead to specific genetic disorders, depending on which chromosome has been duplicated.

Other conditions can also arise from the complex interplay of multiple genetic variants. So a thorough study of the DNA sequence is necessary to determine potential congenital risks.

A DNA molecule can also be further looked at to see how its structure contributes to the persons traits.

Genetic tests can be a little pricey, but its well worth the price tag when you consider what they can tell you.

Molecular genetics is being used today all over the world. Its especially used in a lot of genetic research and genetic testing.

When you get a genetic test done to find out more about your ancestry and heritage, you are investing in molecular genetics.

Your DNA sequence may exhibit similarities with the sequences of people who originate from a certain region. If you share certain key similarities, its a good indicator that you or your ancestors may also be from that area.

This helps you unlock more of your past and potentially provide you with closure around your past. Who knows, you may even find out you have royal ancestry.

If your parents had a genetic test done on you when they were pregnant with you to determine if you were at risk for any genetic disease, molecular genetics provided the results.

Geneticists and genetic counselors who tap into family history and rely on testing delve into your molecular structure and practice molecular genetics to give you better insight into your health. Many human diseases can be traced in family medical history via molecular genetics.

You can also determine if any diseases run in your family and what you can do to prevent contracting them.

In biological sciences, molecular genetics helps us understand the molecular basis of living things. It reveals the why behind how our bodies work at the very smallest level.

The biology of genes has helped us understand why certain genes are expressed over others, how we inherit traits, and the way our alleles work together.

Through the biological lens of genetics, weve been able to develop more medicine, apply more agricultural uses, and even explore gene editing.

Molecular genetics has made strides in forensics, given that its allowed us to identify DNA matches via fingerprints or other potential DNA samples.

Its also a huge help in the courtroom, as legal systems often use DNA testing to prove paternity or exonerate crimes.

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Molecular Genetics | NHLBI, NIH

September 4th, 2024 2:44 am

Research Interests

Mendelian principles have been the cornerstone for identifying nuclear genes in biological and diseases processes and ordering these genes into functional cascades. However, the limitation of Mendelian genetics to explain many complex traits has redirected attention beyond the nucleus. In addition to the nuclear genome, each eukaryotic cell contains hundreds to thousands of copies of mitochondrial genome, the small circular DNAs inside mitochondria. Mutations on mitochondrial genome often impair cellular energy homeostasis and have been linked to many diseases including various age-related disorders. Despite the immense impact of mtDNA mutations on health and disease, our understanding of mitochondrial genetics remains rudimentary. Genetic analyses on mitochondrial genome are complicated by the peculiarities of the mitochondrial genetic system that features maternal inheritance, polyploidy, and amitotic segregation.

We are working with fruit flies and other model organisms to understand the basic principles guiding the transmission of mitochondrial genome. We are trying to understand why evolution favors the transmission of mitochondrial genome from the maternal linage exclusively, how mothers limit the transmission of harmful mtDNA variants to their offsring, how organisms prevent the accumulation of mtDNA mutations in somatic tissues and with aging. We are also exploring the coordination and potential genetic conflicts between nuclear and mitochondrial genome, and their impact on health and diseases. Additionally, we are actively developing new tools to advance the genetic study of mtDNA.

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Molecular biology – Wikipedia

September 4th, 2024 2:44 am

Branch of biology that studies biological systems at the molecular level

Molecular biology is a branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions.[1][2][3]

Though cells and other microscopic structures had been observed in living organisms as early as the 18th century, a detailed understanding of the mechanisms and interactions governing their behavior did not emerge until the 20th century, when technologies used in physics and chemistry had advanced sufficiently to permit their application in the biological sciences. The term 'molecular biology' was first used in 1945 by the English physicist William Astbury, who described it as an approach focused on discerning the underpinnings of biological phenomenai.e. uncovering the physical and chemical structures and properties of biological molecules, as well as their interactions with other molecules and how these interactions explain observations of so-called classical biology, which instead studies biological processes at larger scales and higher levels of organization.[4] In 1953, Francis Crick, James Watson, Rosalind Franklin, and their colleagues at the Medical Research Council Unit, Cavendish Laboratory, were the first to describe the double helix model for the chemical structure of deoxyribonucleic acid (DNA), which is often considered a landmark event for the nascent field because it provided a physico-chemical basis by which to understand the previously nebulous idea of nucleic acids as the primary substance of biological inheritance. They proposed this structure based on previous research done by Franklin, which was conveyed to them by Maurice Wilkins and Max Perutz.[5] Their work led to the discovery of DNA in other microorganisms, plants, and animals.[6]

The field of molecular biology includes techniques which enable scientists to learn about molecular processes.[7] These techniques are used to efficiently target new drugs, diagnose disease, and better understand cell physiology.[8] Some clinical research and medical therapies arising from molecular biology are covered under gene therapy, whereas the use of molecular biology or molecular cell biology in medicine is now referred to as molecular medicine.

Molecular biology sits at the intersection of biochemistry and genetics; as these scientific disciplines emerged and evolved in the 20th century, it became clear that they both sought to determine the molecular mechanisms which underlie vital cellular functions.[9][10] Advances in molecular biology have been closely related to the development of new technologies and their optimization.[11] Molecular biology has been elucidated by the work of many scientists, and thus the history of the field depends on an understanding of these scientists and their experiments.[citation needed]

The field of genetics arose from attempts to understand the set of rules underlying reproduction and heredity, and the nature of the hypothetical units of heredity known as genes. Gregor Mendel pioneered this work in 1866, when he first described the laws of inheritance he observed in his studies of mating crosses in pea plants.[12] One such law of genetic inheritance is the law of segregation, which states that diploid individuals with two alleles for a particular gene will pass one of these alleles to their offspring.[13] Because of his critical work, the study of genetic inheritance is commonly referred to as Mendelian genetics.[14]

A major milestone in molecular biology was the discovery of the structure of DNA. This work began in 1869 by Friedrich Miescher, a Swiss biochemist who first proposed a structure called nuclein, which we now know to be (deoxyribonucleic acid), or DNA.[15] He discovered this unique substance by studying the components of pus-filled bandages, and noting the unique properties of the "phosphorus-containing substances".[16] Another notable contributor to the DNA model was Phoebus Levene, who proposed the "polynucleotide model" of DNA in 1919 as a result of his biochemical experiments on yeast.[17] In 1950, Erwin Chargaff expanded on the work of Levene and elucidated a few critical properties of nucleic acids: first, the sequence of nucleic acids varies across species.[18] Second, the total concentration of purines (adenine and guanine) is always equal to the total concentration of pyrimidines (cysteine and thymine).[15] This is now known as Chargaff's rule. In 1953, James Watson and Francis Crick published the double helical structure of DNA,[19] based on the X-ray crystallography work done by Rosalind Franklin which was conveyed to them by Maurice Wilkins and Max Perutz.[5] Watson and Crick described the structure of DNA and conjectured about the implications of this unique structure for possible mechanisms of DNA replication.[19] Watson and Crick were awarded the Nobel Prize in Physiology or Medicine in 1962, along with Wilkins, for proposing a model of the structure of DNA.[6]

In 1961, it was demonstrated that when a gene encodes a protein, three sequential bases of a gene's DNA specify each successive amino acid of the protein.[20] Thus the genetic code is a triplet code, where each triplet (called a codon) specifies a particular amino acid. Furthermore, it was shown that the codons do not overlap with each other in the DNA sequence encoding a protein, and that each sequence is read from a fixed starting point.During 19621964, through the use of conditional lethal mutants of a bacterial virus,[21] fundamental advances were made in our understanding of the functions and interactions of the proteins employed in the machinery of DNA replication, DNA repair, DNA recombination, and in the assembly of molecular structures.[22]

In 1928, Frederick Griffith, encountered a virulence property in pneumococcus bacteria, which was killing lab rats. According to Mendel, prevalent at that time, gene transfer could occur only from parent to daughter cells. Griffith advanced another theory, stating that gene transfer occurring in member of same generation is known as horizontal gene transfer (HGT). This phenomenon is now referred to as genetic transformation.[23]

Griffith's experiment addressed the pneumococcus bacteria, which had two different strains, one virulent and smooth and one avirulent and rough. The smooth strain had glistering appearance owing to the presence of a type of specific polysaccharide a polymer of glucose and glucuronic acid capsule. Due to this polysaccharide layer of bacteria, a host's immune system cannot recognize the bacteria and it kills the host. The other, avirulent, rough strain lacks this polysaccharide capsule and has a dull, rough appearance.[citation needed]

Presence or absence of capsule in the strain, is known to be genetically determined. Smooth and rough strains occur in several different type such as S-I, S-II, S-III, etc. and R-I, R-II, R-III, etc. respectively. All this subtypes of S and R bacteria differ with each other in antigen type they produce.[6]

The AveryMacLeodMcCarty experiment was a landmark study conducted in 1944 that demonstrated that DNA, not protein as previously thought, carries genetic information in bacteria. Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty used an extract from a strain of pneumococcus that could cause pneumonia in mice. They showed that genetic transformation in the bacteria could be accomplished by injecting them with purified DNA from the extract. They discovered that when they digested the DNA in the extract with DNase, transformation of harmless bacteria into virulent ones was lost. This provided strong evidence that DNA was the genetic material, challenging the prevailing belief that proteins were responsible. It laid the basis for the subsequent discovery of its structure by Watson and Crick.

Confirmation that DNA is the genetic material which is cause of infection came from the HersheyChase experiment. They used E.coli and bacteriophage for the experiment. This experiment is also known as blender experiment, as kitchen blender was used as a major piece of apparatus. Alfred Hershey and Martha Chase demonstrated that the DNA injected by a phage particle into a bacterium contains all information required to synthesize progeny phage particles. They used radioactivity to tag the bacteriophage's protein coat with radioactive sulphur and DNA with radioactive phosphorus, into two different test tubes respectively. After mixing bacteriophage and E.coli into the test tube, the incubation period starts in which phage transforms the genetic material in the E.coli cells. Then the mixture is blended or agitated, which separates the phage from E.coli cells. The whole mixture is centrifuged and the pellet which contains E.coli cells was checked and the supernatant was discarded. The E.coli cells showed radioactive phosphorus, which indicated that the transformed material was DNA not the protein coat.

The transformed DNA gets attached to the DNA of E.coli and radioactivity is only seen onto the bacteriophage's DNA. This mutated DNA can be passed to the next generation and the theory of Transduction came into existence. Transduction is a process in which the bacterial DNA carry the fragment of bacteriophages and pass it on the next generation. This is also a type of horizontal gene transfer.[6]

The Meselson-Stahl experiment was a landmark experiment in molecular biology that provided evidence for the semiconservative replication of DNA. Conducted in 1958 by Matthew Meselson and Franklin Stahl, the experiment involved growing E. coli bacteria in a medium containing heavy isotope of nitrogen (15N) for several generations. This caused all the newly synthesized bacterial DNA to be incorporated with the heavy isotope.

After allowing the bacteria to replicate in a medium containing normal nitrogen (14N), samples were taken at various time points. These samples were then subjected to centrifugation in a density gradient, which separated the DNA molecules based on their density.

The results showed that after one generation of replication in the 14N medium, the DNA formed a band of intermediate density between that of pure 15N DNA and pure 14N DNA. This supported the semiconservative DNA replication proposed by Watson and Crick, where each strand of the parental DNA molecule serves as a template for the synthesis of a new complementary strand, resulting in two daughter DNA molecules, each consisting of one parental and one newly synthesized strand.

The Meselson-Stahl experiment provided compelling evidence for the semiconservative replication of DNA, which is fundamental to the understanding of genetics and molecular biology.

In the early 2020s, molecular biology entered a golden age defined by both vertical and horizontal technical development. Vertically, novel technologies are allowing for real-time monitoring of biological processes at the atomic level.[24] Molecular biologists today have access to increasingly affordable sequencing data at increasingly higher depths, facilitating the development of novel genetic manipulation methods in new non-model organisms. Likewise, synthetic molecular biologists will drive the industrial production of small and macro molecules through the introduction of exogenous metabolic pathways in various prokaryotic and eukaryotic cell lines.[25]

Horizontally, sequencing data is becoming more affordable and used in many different scientific fields. This will drive the development of industries in developing nations and increase accessibility to individual researchers. Likewise, CRISPR-Cas9 gene editing experiments can now be conceived and implemented by individuals for under $10,000 in novel organisms, which will drive the development of industrial and medical applications.[26]

The following list describes a viewpoint on the interdisciplinary relationships between molecular biology and other related fields.[27]

While researchers practice techniques specific to molecular biology, it is common to combine these with methods from genetics and biochemistry. Much of molecular biology is quantitative, and recently a significant amount of work has been done using computer science techniques such as bioinformatics and computational biology. Molecular genetics, the study of gene structure and function, has been among the most prominent sub-fields of molecular biology since the early 2000s. Other branches of biology are informed by molecular biology, by either directly studying the interactions of molecules in their own right such as in cell biology and developmental biology, or indirectly, where molecular techniques are used to infer historical attributes of populations or species, as in fields in evolutionary biology such as population genetics and phylogenetics. There is also a long tradition of studying biomolecules "from the ground up", or molecularly, in biophysics.[30]

Molecular cloning is used to isolate and then transfer a DNA sequence of interest into a plasmid vector.[31] This recombinant DNA technology was first developed in the 1960s.[32] In this technique, a DNA sequence coding for a protein of interest is cloned using polymerase chain reaction (PCR), and/or restriction enzymes, into a plasmid (expression vector). The plasmid vector usually has at least 3 distinctive features: an origin of replication, a multiple cloning site (MCS), and a selective marker (usually antibiotic resistance). Additionally, upstream of the MCS are the promoter regions and the transcription start site, which regulate the expression of cloned gene.

This plasmid can be inserted into either bacterial or animal cells. Introducing DNA into bacterial cells can be done by transformation via uptake of naked DNA, conjugation via cell-cell contact or by transduction via viral vector. Introducing DNA into eukaryotic cells, such as animal cells, by physical or chemical means is called transfection. Several different transfection techniques are available, such as calcium phosphate transfection, electroporation, microinjection and liposome transfection. The plasmid may be integrated into the genome, resulting in a stable transfection, or may remain independent of the genome and expressed temporarily, called a transient transfection.[33][34]

DNA coding for a protein of interest is now inside a cell, and the protein can now be expressed. A variety of systems, such as inducible promoters and specific cell-signaling factors, are available to help express the protein of interest at high levels. Large quantities of a protein can then be extracted from the bacterial or eukaryotic cell. The protein can be tested for enzymatic activity under a variety of situations, the protein may be crystallized so its tertiary structure can be studied, or, in the pharmaceutical industry, the activity of new drugs against the protein can be studied.[35]

Polymerase chain reaction (PCR) is an extremely versatile technique for copying DNA. In brief, PCR allows a specific DNA sequence to be copied or modified in predetermined ways. The reaction is extremely powerful and under perfect conditions could amplify one DNA molecule to become 1.07 billion molecules in less than two hours. PCR has many applications, including the study of gene expression, the detection of pathogenic microorganisms, the detection of genetic mutations, and the introduction of mutations to DNA.[36] The PCR technique can be used to introduce restriction enzyme sites to ends of DNA molecules, or to mutate particular bases of DNA, the latter is a method referred to as site-directed mutagenesis. PCR can also be used to determine whether a particular DNA fragment is found in a cDNA library. PCR has many variations, like reverse transcription PCR (RT-PCR) for amplification of RNA, and, more recently, quantitative PCR which allow for quantitative measurement of DNA or RNA molecules.[37][38]

Gel electrophoresis is a technique which separates molecules by their size using an agarose or polyacrylamide gel.[39] This technique is one of the principal tools of molecular biology. The basic principle is that DNA fragments can be separated by applying an electric current across the gel - because the DNA backbone contains negatively charged phosphate groups, the DNA will migrate through the agarose gel towards the positive end of the current.[39] Proteins can also be separated on the basis of size using an SDS-PAGE gel, or on the basis of size and their electric charge by using what is known as a 2D gel electrophoresis.[40]

The Bradford assay is a molecular biology technique which enables the fast, accurate quantitation of protein molecules utilizing the unique properties of a dye called Coomassie Brilliant Blue G-250.[41] Coomassie Blue undergoes a visible color shift from reddish-brown to bright blue upon binding to protein.[41] In its unstable, cationic state, Coomassie Blue has a background wavelength of 465nm and gives off a reddish-brown color.[42] When Coomassie Blue binds to protein in an acidic solution, the background wavelength shifts to 595nm and the dye gives off a bright blue color.[42] Proteins in the assay bind Coomassie blue in about 2 minutes, and the protein-dye complex is stable for about an hour, although it is recommended that absorbance readings are taken within 5 to 20 minutes of reaction initiation.[41] The concentration of protein in the Bradford assay can then be measured using a visible light spectrophotometer, and therefore does not require extensive equipment.[42]

This method was developed in 1975 by Marion M. Bradford, and has enabled significantly faster, more accurate protein quantitation compared to previous methods: the Lowry procedure and the biuret assay.[41] Unlike the previous methods, the Bradford assay is not susceptible to interference by several non-protein molecules, including ethanol, sodium chloride, and magnesium chloride.[41] However, it is susceptible to influence by strong alkaline buffering agents, such as sodium dodecyl sulfate (SDS).[41]

The terms northern, western and eastern blotting are derived from what initially was a molecular biology joke that played on the term Southern blotting, after the technique described by Edwin Southern for the hybridisation of blotted DNA. Patricia Thomas, developer of the RNA blot which then became known as the northern blot, actually did not use the term.[43]

Named after its inventor, biologist Edwin Southern, the Southern blot is a method for probing for the presence of a specific DNA sequence within a DNA sample. DNA samples before or after restriction enzyme (restriction endonuclease) digestion are separated by gel electrophoresis and then transferred to a membrane by blotting via capillary action. The membrane is then exposed to a labeled DNA probe that has a complement base sequence to the sequence on the DNA of interest.[44] Southern blotting is less commonly used in laboratory science due to the capacity of other techniques, such as PCR, to detect specific DNA sequences from DNA samples. These blots are still used for some applications, however, such as measuring transgene copy number in transgenic mice or in the engineering of gene knockout embryonic stem cell lines.[30]

The northern blot is used to study the presence of specific RNA molecules as relative comparison among a set of different samples of RNA. It is essentially a combination of denaturing RNA gel electrophoresis, and a blot. In this process RNA is separated based on size and is then transferred to a membrane that is then probed with a labeled complement of a sequence of interest. The results may be visualized through a variety of ways depending on the label used; however, most result in the revelation of bands representing the sizes of the RNA detected in sample. The intensity of these bands is related to the amount of the target RNA in the samples analyzed. The procedure is commonly used to study when and how much gene expression is occurring by measuring how much of that RNA is present in different samples, assuming that no post-transcriptional regulation occurs and that the levels of mRNA reflect proportional levels of the corresponding protein being produced. It is one of the most basic tools for determining at what time, and under what conditions, certain genes are expressed in living tissues.[45][46]

A western blot is a technique by which specific proteins can be detected from a mixture of proteins.[47] Western blots can be used to determine the size of isolated proteins, as well as to quantify their expression.[48] In western blotting, proteins are first separated by size, in a thin gel sandwiched between two glass plates in a technique known as SDS-PAGE. The proteins in the gel are then transferred to a polyvinylidene fluoride (PVDF), nitrocellulose, nylon, or other support membrane. This membrane can then be probed with solutions of antibodies. Antibodies that specifically bind to the protein of interest can then be visualized by a variety of techniques, including colored products, chemiluminescence, or autoradiography. Often, the antibodies are labeled with enzymes. When a chemiluminescent substrate is exposed to the enzyme it allows detection. Using western blotting techniques allows not only detection but also quantitative analysis. Analogous methods to western blotting can be used to directly stain specific proteins in live cells or tissue sections.[47][49]

The eastern blotting technique is used to detect post-translational modification of proteins. Proteins blotted on to the PVDF or nitrocellulose membrane are probed for modifications using specific substrates.[50]

A DNA microarray is a collection of spots attached to a solid support such as a microscope slide where each spot contains one or more single-stranded DNA oligonucleotide fragments. Arrays make it possible to put down large quantities of very small (100 micrometre diameter) spots on a single slide. Each spot has a DNA fragment molecule that is complementary to a single DNA sequence. A variation of this technique allows the gene expression of an organism at a particular stage in development to be qualified (expression profiling). In this technique the RNA in a tissue is isolated and converted to labeled complementary DNA (cDNA). This cDNA is then hybridized to the fragments on the array and visualization of the hybridization can be done. Since multiple arrays can be made with exactly the same position of fragments, they are particularly useful for comparing the gene expression of two different tissues, such as a healthy and cancerous tissue. Also, one can measure what genes are expressed and how that expression changes with time or with other factors.There are many different ways to fabricate microarrays; the most common are silicon chips, microscope slides with spots of ~100 micrometre diameter, custom arrays, and arrays with larger spots on porous membranes (macroarrays). There can be anywhere from 100 spots to more than 10,000 on a given array. Arrays can also be made with molecules other than DNA.[51][52][53][54]

Allele-specific oligonucleotide (ASO) is a technique that allows detection of single base mutations without the need for PCR or gel electrophoresis. Short (2025 nucleotides in length), labeled probes are exposed to the non-fragmented target DNA, hybridization occurs with high specificity due to the short length of the probes and even a single base change will hinder hybridization. The target DNA is then washed and the unhybridized probes are removed. The target DNA is then analyzed for the presence of the probe via radioactivity or fluorescence. In this experiment, as in most molecular biology techniques, a control must be used to ensure successful experimentation.[55][56]

In molecular biology, procedures and technologies are continually being developed and older technologies abandoned. For example, before the advent of DNA gel electrophoresis (agarose or polyacrylamide), the size of DNA molecules was typically determined by rate sedimentation in sucrose gradients, a slow and labor-intensive technique requiring expensive instrumentation; prior to sucrose gradients, viscometry was used. Aside from their historical interest, it is often worth knowing about older technology, as it is occasionally useful to solve another new problem for which the newer technique is inappropriate.[57]

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Genetics, Molecular & Cellular Biology Admissions

September 4th, 2024 2:44 am

Students seeking admission to the Genetics, Molecular and Cell Biology (GMCB) program apply to the Graduate School of Biomedical Sciences and select the GMCB program. Students interested in the Mammalian Genetics at JAX track must select this track when they apply to GMCB.

Prospective applicants are evaluated based on prior grades, three letters of recommendation, and personal statements. Prior research experience is strongly valued but is not required.

A personal interview is an important part of our evaluation process and may be conducted in person or virtually. An undergraduate major in the biological or life sciences is recommended, but not required.

The GRE is not required but can be submitted with the application.

The application is completed online on the GSBS Application Portal.

Information about application deadlines and the application process can be found in the Admissions section of this website.

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Genetics, Molecular & Cellular Biology Admissions

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Researchers map 50,000 of DNAs mysterious knots in the human genome – EurekAlert

September 4th, 2024 2:44 am

Researchers map 50,000 of DNAs mysterious knots in the human genome  EurekAlert

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Researchers map 50,000 of DNAs mysterious knots in the human genome - EurekAlert

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Artificial selection of mutations in two nearby genes gave rise to shattering resistance in soybean – Nature.com

September 4th, 2024 2:44 am

Artificial selection of mutations in two nearby genes gave rise to shattering resistance in soybean  Nature.com

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Artificial selection of mutations in two nearby genes gave rise to shattering resistance in soybean - Nature.com

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Stem cells: Therapy, controversy, and research – Medical News Today

September 4th, 2024 2:42 am

Researchers have been looking for something that can help the body heal itself. Although studies are ongoing, stem cell research brings this notion of regenerative medicine a step closer. However, many of its ideas and concepts remain controversial. So, what are stem cells, and why are they so important?

Stem cells are cells that can develop into other types of cells. For example, they can become muscle or brain cells. They can also renew themselves by dividing, even after they have been inactive for a long time.

Stem cell research is helping scientists understand how an organism develops from a single cell and how healthy cells could be useful in replacing cells that are not working correctly in people and animals.

Researchers are now studying stem cells to see if they could help treat a variety of conditions that impact different body systems and parts.

This article looks at types of stem cells, their potential uses, and some ethical concerns about their use.

The human body requires many different types of cells to function, but it does not produce every cell type fully formed and ready to use.

Scientists call a stem cell an undifferentiated cell because it can become any cell. In contrast, a blood cell, for example, is a differentiated cell because it has already formed into a specific kind of cell.

The sections below look at some types of stem cells in more detail.

Scientists extract embryonic stem cells from unused embryos left over from in vitro fertilization procedures. They do this by taking the cells from the embryos at the blastocyst stage, which is the phase in development before the embryo implants in the uterus.

These cells are undifferentiated cells that divide and replicate. However, they are also able to differentiate into specific types of cells.

There are two main types of adult stem cells: those in developed bodily tissues and induced pluripotent stem (iPS) cells.

Developed bodily tissues such as organs, muscles, skin, and bone include some stem cells. These cells can typically become differentiated cells based on where they exist. For example, a brain stem cell can only become a brain cell.

On the other hand, scientists manipulate iPS cells to make them behave more like embryonic stem cells for use in regenerative medicine. After collecting the stem cells, scientists usually store them in liquid nitrogen for future use. However, researchers have not yet been able to turn these cells into any kind of bodily cell.

Scientists are researching how to use stem cells to regenerate or treat the human body.

The list of conditions that stem cell therapy could help treat may be endless. Among other things, it could include conditions such as Alzheimers disease, heart disease, diabetes, and rheumatoid arthritis. Doctors may also be able to use stem cells to treat injuries in the spinal cord or other parts of the body.

They may do this in several ways, including the following.

In some tissues, stem cells play an essential role in regeneration, as they can divide easily to replace dead cells. Scientists believe that knowing how stem cells work can help treat damaged tissue.

For instance, if someones heart contains damaged tissue, doctors might be able to stimulate healthy tissue to grow by transplanting laboratory-grown stem cells into the persons heart. This could cause the heart tissue to renew itself.

One study suggested that people with heart failure showed some improvement 2 years after a single-dose administration of stem cell therapy. However, the effect of stem cell therapy on the heart is still not fully clear, and research is still ongoing.

Another investigation suggested that stem cell therapies could be the basis of personalized diabetes treatment. In mice and laboratory-grown cultures, researchers successfully produced insulin-secreting cells from stem cells derived from the skin of people with type 1 diabetes.

Study author Jeffrey R. Millman an assistant professor of medicine and biomedical engineering at the Washington University School of Medicine in St. Louis, MO said, What were envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin.

Millman hopes that these stem cell-derived beta cells could be ready for research in humans within 35 years.

Stem cells could also have vast potential in developing other new therapies.

Another way that scientists could use stem cells is in developing and testing new drugs.

The type of stem cell that scientists commonly use for this purpose is the iPS cell. These are cells that have already undergone differentiation but which scientists have genetically reprogrammed using genetic manipulation, sometimes using viruses.

In theory, this allows iPS cells to divide and become any cell. In this way, they could act like undifferentiated stem cells.

For example, scientists want to grow differentiated cells from iPS cells to resemble cancer cells and use them to test anticancer drugs. This could be possible because conditions such as cancer, as well as some congenital disabilities, happen because cells divide abnormally.

However, more research is taking place to determine whether or not scientists really can turn iPS cells into any kind of differentiated cell and how they can use this process to help treat these conditions.

In recent years, clinics have opened that offer different types of stem cell treatments. One 2016 study counted 570 of these clinics in the United States alone. They appear to offer stem cell-based therapies for conditions ranging from sports injuries to cancer.

However, most stem cell therapies are still theoretical rather than evidence-based. For example, researchers are studying how to use stem cells from amniotic fluid which experts can save after an amniocentesis test to treat various conditions.

The Food and Drug Administration (FDA) does allow clinics to inject people with their own stem cells as long as the cells are intended to perform only their normal function.

Aside from that, however, the FDA has only approved the use of blood-forming stem cells known as hematopoietic progenitor cells. Doctors derive these from umbilical cord blood and use them to treat conditions that affect the production of blood. Currently, for example, a doctor can preserve blood from an umbilical cord after a babys birth to save for this purpose in the future.

The FDA lists specific approved stem cell products, such as cord blood, and the medical facilities that use them on its website. It also warns people to be wary of undergoing any unproven treatments because very few stem cell treatments have actually reached the earliest phase of a clinical trial.

Historically, the use of stem cells in medical research has been controversial. This is because when the therapeutic use of stem cells first came to the publics attention in the late 1990s, scientists were only deriving human stem cells from embryos.

Many people disagree with using human embryonic cells for medical research because extracting them means destroying the embryo. This creates complex issues, as people have different beliefs about what constitutes the start of human life.

For some people, life starts when a baby is born, while for others, it starts when an embryo develops into a fetus. Meanwhile, other people believe that human life begins at conception, so an embryo has the same moral status and rights as a human child.

Former U.S. president George W. Bush had strong antiabortion views. He believed that an embryo should be considered a life and not be used for scientific experiments. Bush banned government funding for human stem cell research in 2001, but former U.S. president Barack Obama then revoked this order. Former U.S. president Donald Trump and current U.S. president Joe Biden have also gone back and forth with legislation on this.

However, by 2006, researchers had already started using iPS cells. Scientists do not derive these stem cells from embryonic stem cells. As a result, this technique does not have the same ethical concerns. With this and other recent advances in stem cell technology, attitudes toward stem cell research are slowly beginning to change.

However, other concerns related to using iPS cells still exist. This includes ensuring that donors of biological material give proper consent to have iPS cells extracted and carefully designing any clinical studies.

Researchers also have some concerns that manipulating these cells as part of stem cell therapy could lead to the growth of cancerous tumors.

Although scientists need to do much more research before stem cell therapies can become part of regular medical practice, the science around stem cells is developing all the time.

Scientists still conduct embryonic stem cell research, but research into iPS cells could help reduce some of the ethical concerns around regenerative medicine. This could lead to much more personalized treatment for many conditions and the ability to regenerate parts of the human body.

Learn more about stem cells, where they come from, and their possible uses here.

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Stem cells: Therapy, controversy, and research - Medical News Today

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