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A typical pregnancy lasts, on average, 280 days, or 40 weeks—starting with the first day of the last normal menstrual period as day 1. An estimated due date can be calculated by following steps 1 through 3:

For example: Your last menstrual period began on September 9, 2010. Counting back 3 calendar months would be June 9, 2010. Adding 1 year and 7 days would bring you to June 16, 2011, as your estimated due date.

This 3-step method is referred to as Naegele's Rule and is based on a normal 28-day menstrual cycle. Therefore, dates may have to be adjusted for longer or shorter menstrual cycles.

You may also estimate your delivery date by using the steps 1 and 2 and the chart:

Sounds as we hear them are exactly air vibrations Musical instruments use various means to vibrate the air and produce sound A drum is a diaphragm that moves

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There are enhancers and silencers

The cis-acting sequence and trans-operating factor regulate alternative splicing. Exonic splicing enhancers and silencers are included in the latter.

Trans-acting factors include members of the hnRNP family of genes, as well as tissue specific factors. Some of these factors are activated, while others are not, and the direction of the effect depends on the position of the binding site in the pre-mRNA 5.

Alternative splicing and transcription are combined.

The abundance and post-translational modifications of splicing factors are regulated by functional and physical interactions between the transcriptional and splicing machineries. The idea of alternative splicing with transcription was introduced by our laboratory more than 20 years ago, when we found that different RNAPII promoters placed in front of the same transcriptional unit cause different ratios of two splicing isoforms from the same gene.

It was shown that factors that affect the structure of the human body influence alternative splicing decisions. Two mechanisms that are not exclusive have been proposed to explain the relationship between transcription and splicing. The first suggests that the transcription machinery recruits splicing factors that operate on pre-mRNA. In the second, the use of weak and strong splicing sites by the components of the spliceosome can affect the proportions of the spliceosomes. The use of a "slow" variant of the RNAPII was the most direct proof of the principle of kinetics.

The reduced transcription rate can be seen in both in vitro and invivo, as a result of the substitution of an amino acid in the catalytic domain. The inclusion of alternative exons in studies of individual genes 11 and global ones is increased by the use of this Mutant. The recruitment of positive splicing factors to weak splicing sites causes greater alternative exon inclusion in the most common form ofkineticcoupling.

Slowness creates a window of opportunity for negative splicing factors to bind to their "target" sequence in the pre-mRNA, and this is the opposite effect of the less frequent form. The mechanism by which the inclusion of an alternative exon of the CFTR is lower when the elongation rate is slower was described by our group. Positive or negative effects at exon inclusion will depend on the identity and architecture of the particular regulatory sequence surrounding each alternative splicing event.

Alternative splicing and chlorination.

In the nucleus, the histones are associated with the genes that make up the nucleus.

The repetitive units of the chromatin structure allow the genome to be compressed within the nucleus and at the same time allow adequate access to it. A "pearl necklace" of nucosomes is connected by segments of histone-free DNA. In its most compact form, the nucleosomes approximate each other and impede the binding of genes. The nucleosomes move away from each other.

In this scenario, the DNA relaxes and the RNAPII proceeds more efficiently. Our group has shown that the degree of chromatin compaction around the region occupied by an exon undergoing alternative splicing has a direct impact on its inclusion levels. The levels of inclusion of specific alternative exon progress are affected by treatments or conditions that promote chromatin compaction.

H3K9me2 is one of the histone amino acid residues that is promoted by histone methylation. The opposite effect is promoted by treatments or conditions that relax the chromatin structure.

The effects are dependent on the specific exon involved. The lab also demonstrated that the introduction into cells of small interfering RNAs (siRNAs) (20-25 nucleotides long) that interact with sequences of introns close to alternative exons, modifies the pattern of exon inclusion in mature mRNA through to induce changes in chromatin condensation and in the rate of transcription 16, 17, representing a new way of controlling alternative splicing.

The control of alternative splicing is the cure of spinal muscular atrophy.

One in 10,000 births are affected by SMA, which is a severe hereditary, autosomal recessive disease.

SMA is the most important genetic cause of infant mortality. It is caused by a loss of function in the survival motor neuron 1 gene. Babies who have two copies of the SMN1 gene are not able to produce enough of the SMNProtein. This is a part of the machinery.

Although its absence should cause multiple effects, motor neurons in the spinal cord seem to be more sensitive than other cells in the body to the decrease in the amount of SMN, and its degeneration causes patients to gradually lose the ability to contract their muscles. , both those of its extremities and those of its rib cage. Babies affected by the most severe form of SMA would suffocate to death within a few months of being born if there was no external mechanical Ventilation.

Patients with SMA type I are bedridden for the rest of their lives. The treatment with SMA curative power was approved in December of 2016 The cure was found by a researcher who has worked in the US for more than 30 years and runs a laboratory in Cold Spring Harbor.

Krainer's strategy did not consist in "curing" the mutated SMN1 gene but in taking advantage of the fact that in humans there is a paralogue gene, called SMN2, which could function as a backup, or "backup" of SMN1, because its product is also the SMN protein. . The problem is that SMN2 has 11 base changes. The optimal sequence of a exon 7 is altered.

This causes exon 7 to be poorly included in the mature SMN2 mRNA and, consequently, the non-functional alternative splicing variant that lacks it predominates. of said exon and that is why the SMN2 gene does not produce a sufficient amount of SMN protein to prevent neurodegeneration (Fig. 1B). Krainer's study of the cis sequence and the trans factors that regulate alternative splicing led to his identification of intron 7 an ISS that bind the hnRNP A1 and A2 splicing factors that act negatively on the exon 7. Krainer was able to design a synthetic oligonucleotide with a base sequence that was similar to the intron 7. By introducing this short segment of nucleic acid into cells, it pairs with its "target" sequence in the pre-mRNA of SMN2 and, by competition, blocks the binding of hnRNP A1 and A2, thereby causing the SMN2 gene to produce sufficient amounts of the SMN protein, something that the SMN1 gene cannot do because it is mutated 18 (Fig. 1C).

This type of strategy is not included in gene therapy, but is a therapy using allele specific antisense oligonucleotides. ASO, whose trade name is Spinraza, was approved by the FDA in 2016 and by the ANMAT in 2019. Spinraza antisense oligonucleotide is modified with a 2'-O-(2-methoxetyl) (MOE) phosphorothioate18 group that prevents its degradation in body fluids and is administered by injection into the cerebrospinal fluid.

Krainer was the first scientist to cure a disease. The parents and relatives of the sick children received recognition from the academic world.

The control of alternative splicing has been studied by our laboratory in Buenos Aires for more than 25 years. We had never faced the cure of a disease until 4 years ago, promoted by the relatives of Argentine patients with SMA, nucleated in FAME (Argentine Spinal Muscular Atrophy Families), we began a research project that intends to use the knowledge discovered in our group to generate a combined therapy that adds our tools to the already consecrated treatment with Spinraza. We established a scientific collaboration with Dr. Krainer, we obtained funding not only from FAME but also from CureSMA, the foundation for relatives of SMA patients in the US, two disciples won doctoral scholarships from CONICET to carry out the experiments, and Today we can say that the results obtained, for now in cultured cells and in mice, are very promising. Broadly speaking, we verified that if we treat the cells with drugs that generate post-translational modifications of histones that relax chromatin, by causing RNAPII to transcribe faster than normal, the effect of Spinraza in ensuring that adequate amounts are manufactured of the SMN protein is much higher, with which a combined therapy between Spinraza and drugs that modify chromatin could be applied, perhaps lowering the cost of Spinraza, which in the private sector is around more than 100,000 dollars per application, having to perform 3 or 4 applications per year.

Basic science and medicine are important.