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PubMed2006

Antagonists to human and mouse vascular endothelial growth factor receptor 2 generated by directed protein evolution in vitro.

Using directed in vitro protein evolution, we generated proteins that bound and antagonized the function of vascular endothelial growth factor receptor 2 (VEGFR2). Binders to human VEGFR2 (KDR) with 10-200 nM affinities were selected by using mRNA display from a library (10(13) variants) based on the tenth human fibronectin type III domain (10Fn3) scaffold. Subsequently, a single KDR binding clone (K(d) = 11 nM) was subjected to affinity maturation. This yielded improved KDR binding molecules with affinities ranging from 0.06 to 2 nM. Molecules with dual binding specificities (human/mouse) were also isolated by using both KDR and Flk-1 (mouse VEGFR2) as targets in selection. Proteins encoded by the selected clones bound VEGFR2-expressing cells and inhibited their VEGF-dependent proliferation. Our results demonstrate the potential of these inhibitors in the development of anti-angiogenesis therapeutics.

Amino Acid Sequence↗

PubMed1990

Models of a dual inheritance system.

In higher plants, animals and fungi, there are two inheritance systems: the familiar system, depending on DNA sequence, used in transmitting information between sexual generations, and an epigenetic inheritance system, depending on gene activation, responsible for the transmission of states of differentiation during development. Occasionally, epigenetic changes are transmitted in sexual reproduction. A formal model of such a dual inheritance system is presented, and it is shown how the separation between the two systems can sometimes break down. The evolutionary significance of such breakdowns is discussed.

Animals↗

PubMed2000

Derivation of the relationship between neutral mutation and fixation solely from the definition of selective neutrality.

A mutation whose fixation is independent of natural selection is termed a neutral mutation. Therefore selective neutrality of a mutation can be defined by independence of its fixation from natural selection. By the population genetic approach, Kimura [Kimura, M. (1962) Genetics 47, 713-719] predicted that the probability of fixation of a neutral mutation (u) is equal to the frequency of the new allele at the start (p). The approach traced the temporal sequence of the fixation process, and the prediction was obtained by assuming the selective equality of neutral mutant and wild-type alleles during the fixation process. The prediction, however, has not been verified by observation. In the present study, I search for the mathematical equation that represents the definition of selective neutrality. Because the definition concerns only mutation and fixation, an ideal approach should deal only with these and not with the intervening process of fixation. The approach begins by analysis of the state of fixation of a neutral mutation, and its relation with the initial state is deduced logically from the definition. The approach shows that the equality of the alleles during the fixation process is equivalent to the equality of probability of their ultimate fixation in a steady state. Both are manifestations of the definition of selective neutrality. Then, solely from this dual nature of the definition, the equality between u and p is derived directly. Therefore, the definition of selective neutrality can be represented by the equation u = p.

Alleles↗

PubMed2005

Characterization of gana-1, a Caenorhabditis elegans gene encoding a single ortholog of vertebrate alpha-galactosidase and alpha-N-acetylgalactosaminidase.

BACKGROUND: Human alpha-galactosidase A (alpha-GAL) and alpha-N-acetylgalactosaminidase (alpha-NAGA) are presumed to share a common ancestor. Deficiencies of these enzymes cause two well-characterized human lysosomal storage disorders (LSD)--Fabry (alpha-GAL deficiency) and Schindler (alpha-NAGA deficiency) diseases. Caenorhabditis elegans was previously shown to be a relevant model organism for several late endosomal/lysosomal membrane proteins associated with LSDs. The aim of this study was to identify and characterize C. elegans orthologs to both human lysosomal luminal proteins alpha-GAL and alpha-NAGA. RESULTS: BlastP searches for orthologs of human alpha-GAL and alpha-NAGA revealed a single C. elegans gene (R07B7.11) with homology to both human genes (alpha-galactosidase and alpha-N-acetylgalactosaminidase)--gana-1. We cloned and sequenced the complete gana-1 cDNA and elucidated the gene organization.Phylogenetic analyses and homology modeling of GANA-1 based on the 3D structure of chicken alpha-NAGA, rice alpha-GAL and human alpha-GAL suggest a close evolutionary relationship of GANA-1 to both human alpha-GAL and alpha-NAGA. Both alpha-GAL and alpha-NAGA enzymatic activities were detected in C. elegans mixed culture homogenates. However, alpha-GAL activity on an artificial substrate was completely inhibited by the alpha-NAGA inhibitor, N-acetyl-D-galactosamine.A GANA-1::GFP fusion protein expressed from a transgene, containing the complete gana-1 coding region and 3 kb of its hypothetical promoter, was not detectable under the standard laboratory conditions. The GFP signal was observed solely in a vesicular compartment of coelomocytes of the animals treated with Concanamycin A (CON A) or NH4Cl, agents that increase the pH of the cellular acidic compartment. Immunofluorescence detection of the fusion protein using polyclonal anti-GFP antibody showed a broader and coarsely granular cytoplasmic expression pattern in body wall muscle cells, intestinal cells, and a vesicular compartment of coelomocytes.Inhibition of gana-1 by RNA interference resulted in a decrease of both alpha-GAL and alpha-NAGA activities measured in mixed stage culture homogenates but did not cause any obvious phenotype. CONCLUSIONS: GANA-1 is a single C. elegans ortholog of both human alpha-GAL and alpha-NAGA proteins. Phylogenetic, homology modeling, biochemical and GFP expression analyses support the hypothesis that GANA-1 has dual enzymatic activity and is localized in an acidic cellular compartment.

Animals↗

PubMed1990

A porcine rotavirus strain with dual VP7 serotype specificity.

Porcine rotavirus MDR-13, which on original isolation showed a two-way antigenic relationship with human rotavirus RV-3, shows VP7 relationships with serotype G5 as well as G3 viruses upon gene reassortment. Analysis of porcine MDR-13 and the MD-UK reassortant revealed marked nucleotide and amino acid similarity of VP7 genes of these viruses with those of both serotype G3 and G5 viruses. Evolution of such a strain, possibly by sequential mutations in the VP7 gene, is discussed.

Amino Acid Sequence↗

PubMed2005

HIV diversity, molecular epidemiology, and the role of recombination.

The magnitude of the HIV pandemic and its extensive genetic variation may earn it a unique place among infectious agents. A high mutation rate and a rampant recombination are driving HIV's evolution. Nine subtypes and a variety of recombinant forms of HIV now exist. The source of recombinant forms is the multiple infection of target cells, which becomes highly significant when individuals become infected with two or more divergent strains. In the current paper, we re-examine the role of dual infection and recombination in the generation of HIV-1 diversity, both in individuals and on a global scale. The current molecular epidemiology of HIV-1 is reviewed, emphasizing the latest reports from regional epidemics.

Journal Article↗

PubMed1997

Results of surgical treatment in temporal lobe epilepsy with chronic psychosis.

The combination of psychosis and refractory temporal lobe epilepsy is not rare. However, patients with chronic interictal psychosis and refractory epilepsy are rejected from many epilepsy surgery programmes purely on psychiatric grounds. It is often assumed that disturbed behaviour will prevent adequate preoperative evaluation or that the patients are unable to provide informed consent for preoperative investigations and for surgery. The observation that the psychosis usually does not improve after operation and fears of an exacerbation of psychosis with post-surgical seizure remission, analogous to 'forced normalization', are further deterrents to surgery in these patients. We describe five patients with the dual diagnoses of medically intractable temporal lobe epilepsy and chronic psychosis who underwent temporal lobe resection. The patients were able to provide informed consent and were easily managed during preoperative investigation. Seizure outcome has been excellent in all. Neither temporal lobe resection nor remission of seizures influenced the nature or evolution of the psychosis. Subjectively the patients functioned better in activities of daily living and freedom from seizures improved integration into psychiatric treatment facilities. With appropriate psychiatric intervention, patients with chronic psychosis and refractory epilepsy can participate in presurgical investigation successfully, and can undergo surgery uneventfully.

Adult↗

PubMed1998

Cellular and molecular aspects of thymic T-cell education in neuroendocrine self principles. Implications for autoimmunity.

Thymic epithelial and nurse cells from different species express a repertoire of neuroendocrine polypeptide precursors. This repertoire exerts a dual role in T-lymphocyte selection according to their status either as cryptocrine signals or as neuroendocrine self-antigens of the peptide sequences that are processed from those precursors then presented to pre-T cells. Thymic neuroendocrine self-antigens correspond to peptide sequences highly conserved throughout evolution of their family. Though thymic MHC class I molecules are involved in the processing of thymic neuroendocrine self-antigens, preliminary data show that their presentation to pre-T cells is not allelically restricted. Thymic T-cell education in neuroendocrine families also implies that the structure of a given family may be presented to pre-T cells. Our studies have evidenced the homology between thymic neuroendocrine-related self-antigens and dominant T-cell epitopes of peripheral neuroendocrine signals (neuroendocrine autoantigens). The biochemical difference between neuroendocrine autoantigens and homologous thymic self-antigens might explain the opposite immune responses evoked by those two types of antigens (activation and memory induction vs. tolerogenic effect). Altogether, these studies support the therapeutic use of thymic neuroendocrine self-antigens in reprogramming the immunological self-tolerance that is broken in autoimmune endocrine diseases like insulin-dependent diabetes type I. As recently stated by P. M. Allen in an important review, the fate of developing T lymphocytes in the thymus is influenced by the numerous types of peptidic interactions within the thymic cellular environment. To define the precise nature of thymic cells and naturally occurring biochemical peptide signals involved in positive and negative selection of immature T cells has become a prominent objective for the future research efforts in thymic physiology. This paper will try to show how thymic neuroendocrine-related peptides synthesized and processed within the thymic microenvironment indeed can play a role both in the development of the peripheral T-cell repertoire and in the death of randomly rearranged, self-reactive T cells.

Animals↗

PubMed1999

Calcitonin gene-related peptide can attenuate or augment pancreatic damage in caerulein-induced pancreatitis in rats.

UNLABELLED: We have recently shown that treatment with calcitonin gene-related peptide (CGRP) before and during induction of acute pancreatitis exhibits a protective effect against pancreatic damage evoked by overdose of caerulein. Studies in the stomach have shown that administration of CGRP exhibits dual action on gastric mucosa, CGRP administration before induction of gastric lesions, protects gastric mucosa against damage, whereas treatment with this peptide after development of gastric ulcer exacerbates mucosal injury. These observations prompt us to determine the influence of CGRP administrated before and after induction of pancreatitis on development and evolution of pancreatic tissue damage. METHODS: Acute pancreatitis was induced by s.c. infusion of caerulein (10 microg/kg/h) for 5 h. CGRP was administrated (10 microg/kg s.c. per dose) 30 min prior to caerulein infusion and 3 h later during caerulein infusion or at the time 1 h, 4 h and 7 h after the end of caerulein infusion. Rats were sacrificed at the time 0 h, 3 h or 9 h after cessation of caerulein administration. The pancreatic blood flow (PBF), plasma activity of amylase, plasma interleukin-1beta concentration, cell proliferation, biochemical and morphological signs of pancreatitis were examined. RESULTS: Caerulein-induced pancreatitis (CIP) led to 42% decrease in DNA synthesis, 30% inhibition of PBF, as well as, a significant increase in pancreatic weight, plasma amylase activity, plasma interleukin-1beta concentration, and development of the histological signs of pancreatic damage (edema, leukocyte infiltration and vacuolization). Treatment with CGRP prior and during induction of CIP attenuated the pancreatic damage what was manifested by partial reversion of the drop in DNA synthesis (40.9+1.7 v. 34.2+2.0 dpm/microg DNA) and PBF (83+3% v. 70+3%). Increases in pancreatic weight and plasma interleukin-1beta were reduced. Morphology showed improvement of pancreatic integrity. Administration of CGRP after induction of CIP aggravated pancreatic damage what was manifested by additional decrease in PBF and DNA synthesis. Also pancreatic weight as well as histological signs of pancreatic damage were increased. CONCLUSIONS: (1) Administration of CGRP before and during induction of pancreatitis protects pancreas against pancreatic damage. (2) Treatment with CGRP after development of CIP aggravates pancreatic damage.

Animals↗

PubMed1981

The surgical pathologist as a diagnostician and consultant.

The primary role of the surgical pathologist is to diagnose, and then to transmit this information effectively so that it can be used to guide patient management; therefore, the dual roles of the surgical pathologist as a diagnostician and consultant are inextricable. The diagnostic pathologist determines the nature, extent, and rate of disease processes as well as response to therapy or the effects of medication, on the basis of morphologic observations. This presentation reviews some historic aspects of the evolution of surgical pathology, and its projected status in the medical community. The paradoxical (mis)concept of the pathologist with his microscope and slide, in vacuo, devoid of pertinent clinical data, as a pristine expression of objectivity is discusses and compared with the real world in which veracity is a proper surrogate for blind objectivity. The molding of the scientific method with the art of clinical practice by the pathologist is also considered.

Breast Neoplasms↗

PubMed2006

Magnetization transfer magnetic resonance imaging and clinical changes in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Magnetization transfer (MT) magnetic resonance imaging (MRI) can provide in vivo quantitative estimates of microscopic tissue damage in normal-appearing white matter (NAWM) and gray matter (GM) from patients with multiple sclerosis (MS). OBJECTIVE: To determine whether a one-time MT MRI can provide markers of short-term disease evolution in patients with relapsing-remitting MS. DESIGN: Eighteen-month observational study. SETTING: Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele. PATIENTS: Twenty-two patients with untreated relapsing-remitting MS. MAIN OUTCOME MEASURES: Relapse rate; disability according to the Expanded Disability Status Scale (EDSS); dual-echo, 2-dimensional gradient echo with and without a saturation MT pulse and T1-weighted MRIs of the brain; and MT ratio (MTR) histograms for NAWM and GM. RESULTS: During the study period, 13 patients (59%) experienced 25 relapses. The median EDSS score was 1.25 (range, 0-3.5) at study entry and 1.75 (range, 0-3) at study exit. Significant, although moderate, correlations were found between average GM MTR values at baseline and EDSS changes during the study period (r = -0.44; P = .04). A trend was observed for the correlation between NAWM MTR values at baseline and the EDSS changes throughout 18 months (r = -0.42; P = .05). For the relation between EDSS changes and baseline GM MTR, the slope of the regression line was -0.5 (95% confidence interval, -1.0 to 0.0), indicating that a decrease in the baseline GM MTR of 1% predicted an increase in the EDSS score of 0.5 point throughout the 18 months. CONCLUSION: This study indicates that a "snapshot" MT MRI assessment detects subtle brain tissue changes that are associated with short-term disability accumulation in patients with relapsing-remitting MS.

Adult↗

PubMed2006

Land plants equilibrate O2 and CO2 concentrations in the atmosphere.

The role of land plants in establishing our present day atmosphere is analysed. Before the evolution of land plants, photosynthesis by marine and fresh water organisms was not intensive enough to deplete CO(2) from the atmosphere, the concentration of which was more than the order of magnitude higher than present. With the appearance of land plants, the exudation of organic acids by roots, following respiratory and photorespiratory metabolism, led to phosphate weathering from rocks thus increasing aquatic productivity. Weathering also replaced silicates by carbonates, thus decreasing the atmospheric CO(2) concentration. As a result of both intensive photosynthesis and weathering, CO(2 )was depleted from the atmosphere down to low values approaching the compensation point of land plants. During the same time period, the atmospheric O(2) concentration increased to maximum levels about 300 million years ago (Permo-Carboniferous boundary), establishing an O(2)/CO(2) ratio above 1000. At this point, land plant productivity and weathering strongly decreased, exerting negative feedback on aquatic productivity. Increased CO(2) concentrations were triggered by asteroid impacts and volcanic activity and in the Mesozoic era could be related to the gymnosperm flora with lower metabolic and weathering rates. A high O(2)/CO(2) ratio is metabolically linked to the formation of citrate and oxalate, the main factors causing weathering, and to the production of reactive oxygen species, which triggered mutations and stimulated the evolution of land plants. The development of angiosperms resulted in a decrease in CO(2) concentration during the Cenozoic era, which finally led to the glacial-interglacial oscillations in the Pleistocene epoch. Photorespiration, the rate of which is directly related to the O(2)/CO(2) ratio, due to the dual function of Rubisco, may be an important mechanism in maintaining the limits of O(2) and CO(2) concentrations by restricting land plant productivity and weathering.

Atmosphere↗

PubMed2001

Evolutionary psychology: toward a unifying theory and a hybrid science.

Although evolutionary psychology is typically associated with "selfish gene theory," numerous other approaches to the study of mind and behavior provide a wealth of concepts for theorizing about psychology, culture, and development. These include general evolutionary approaches and theories focused on sociality, dual inheritance, multilevel selection, and developmental systems. Most evolutionary accounts use the same methods as Darwin-the "fit among facts"-to use natural selection as an explanation for behavior. Scientific standards for constraining and evaluating such accounts, research into the mutual influence of science and society on the understanding of evolution, and computational technologies for modeling species-typical processes are important considerations. Coevolutionary theories and developmental systems theories may eventually give rise to unification in a broad and general sense. Such a unification would be interdisciplinary and problem centered rather than discipline centered.

Biological Evolution↗

PubMed2004

Cobalamin-independent methionine synthase (MetE): a face-to-face double barrel that evolved by gene duplication.

Cobalamin-independent methionine synthase (MetE) catalyzes the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine (Hcy) without using an intermediate methyl carrier. Although MetE displays no detectable sequence homology with cobalamin-dependent methionine synthase (MetH), both enzymes require zinc for activation and binding of Hcy. Crystallographic analyses of MetE from T. maritima reveal an unusual dual-barrel structure in which the active site lies between the tops of the two (betaalpha)(8) barrels. The fold of the N-terminal barrel confirms that it has evolved from the C-terminal polypeptide by gene duplication; comparisons of the barrels provide an intriguing example of homologous domain evolution in which binding sites are obliterated. The C-terminal barrel incorporates the zinc ion that binds and activates Hcy. The zinc-binding site in MetE is distinguished from the (Cys)(3)Zn site in the related enzymes, MetH and betaine-homocysteine methyltransferase, by its position in the barrel and by the metal ligands, which are histidine, cysteine, glutamate, and cysteine in the resting form of MetE. Hcy associates at the face of the metal opposite glutamate, which moves away from the zinc in the binary E.Hcy complex. The folate substrate is not intimately associated with the N-terminal barrel; instead, elements from both barrels contribute binding determinants in a binary complex in which the folate substrate is incorrectly oriented for methyl transfer. Atypical locations of the Hcy and folate sites in the C-terminal barrel presumably permit direct interaction of the substrates in a ternary complex. Structures of the binary substrate complexes imply that rearrangement of folate, perhaps accompanied by domain rearrangement, must occur before formation of a ternary complex that is competent for methyl transfer.

Amino Acid Sequence↗

PubMed2005

Toward a "new" paradigm of therapeutic action: neuro-psychoanalysis and downward causation.

Freud's metapsychological assumption, which split the mind from the brain, is increasingly recognized as limiting the growth of psychoanalysis and its integration with other fields, including psychiatry. The dual-aspect monist position, sometimes used to rationalize the mind/body split, is seen to contain a mereological (category) error, which can be avoided by the introduction of the paradigm of psychodynamic science, and by the use of a nondualistic, symbiotic mind/brain formulation, well justified by the study of cultural and organic evolution. Therapeutic action may now be seen as a special case of development that occurs within the interactional context of cultural evolution, personal history, and the genome. Human evolution is increasingly dominated by culture operating on the mind/brain through downward causation. This concept refers to the influence of higher organizational entities (e.g., mind) upon lower ones (e.g., brain). Although little recognized, downward causation is tacitly assumed in psychotherapeutic interventions, and is illustrated in recent fMRI studies. The clinical integration of the downward causation concept links therapeutic action to the power of cultural evolution, and facilitates reunion with traditional science.

Biological Evolution↗

PubMed2005

Axonal injury in early multiple sclerosis is irreversible and independent of the short-term disease evolution.

OBJECTIVE: To define the nature and the temporal evolution of neuronal/axonal injury in patients at the earliest clinical stage of multiple sclerosis (MS), using whole brain N-acetylaspartate (WBNAA) proton MR spectroscopy (1H-MRS). METHODS: Thirty-five patients at presentation with clinically isolated syndromes (CIS) and MRI evidence of disease dissemination in space were studied. The following scans of the brain were acquired within 3 months from the onset of the disease and after 12 months: 1) dual-echo; 2) WBNAA 1H-MRS; 3) pre- and postcontrast T1-weighted. The same scans were obtained in 12 age-matched healthy subjects, without contrast administration. In patients, conventional MRI scans were also repeated 3 months after the first scanning session, to assess the presence of early disease dissemination in time (DIT). RESULTS: Over the study period, 24 patients showed MRI evidence of disease DIT, thus fulfilling the criteria for a diagnosis of MS. The average WBNAA amount was lower in CIS patients than in controls both at baseline (13.7 vs 16.9 mM, p < 0.001) and at 1-year follow-up (12.6 vs 16.2 mM, p < 0.001), but the average yearly percentage change of WBNAA did not differ between the two groups. No MRI or 1H-MRS quantities were significantly associated with the disease DIT over the study period. CONCLUSION: Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes, but it does not seem to be related with the disease evolution in the subsequent short-term period.

Adult↗

PubMedDate not supplied

Clues from Xanthomonas campestris about the evolution of aromatic biosynthesis and its regulation.

The recent placement of major Gram-negative prokaryotes (Superfamily B) on a phylogenetic tree (including, e.g., lineages leading to Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter calcoaceticus) has allowed initial insights into the evolution of the biochemical pathway for aromatic amino acid biosynthesis and its regulation to be obtained. Within this prokaryote grouping, Xanthomonas campestris ATCC 12612 (a representative of the Group V pseudomonads) has played a key role in facilitating deductions about the major evolutionary events that shaped the character of aromatic biosynthesis within this grouping. X. campestris is like P. aeruginosa (and unlike E. coli) in its possession of dual flow routes to both L-phenylalanine and L-tyrosine from prephenate. Like all other members of Superfamily B, X. campestris possesses a bifunctional P-protein bearing the activities of both chorismate mutase and prephenate dehydratase. We have found an unregulated arogenate dehydratase similar to that of P. aeruginosa in X. campestris. We separated the two tyrosine-branch dehydrogenase activities (prephenate dehydrogenase and arogenate dehydrogenase); this marks the first time this has been accomplished in an organism in which these two activities coexist. Superfamily B organisms possess 3-deoxy-D-arabino-heptulosonate 7-P (DAHP) synthase as three isozymes (e.g., in E. coli), as two isozymes (e.g., in P. aeruginosa), or as one enzyme (in X. campestris). The two-isozyme system has been deduced to correspond to the ancestral state of Superfamily B. Thus, E. coli has gained an isozyme, whereas X. campestris has lost one. We conclude that the single, chorismate-sensitive DAHP synthase enzyme of X. campestris is evolutionarily related to the tryptophan-sensitive DAHP synthase present throughout the rest of Superfamily B. In X. campestris, arogenate dehydrogenase, prephenate dehydrogenase, the P-protein, chorismate mutase-F, anthranilate synthase, and DAHP synthase are all allosteric proteins; we compared their regulatory properties with those of enzymes of other Superfamily B members with respect to the evolution of regulatory properties. The network of sequentially operating circuits of allosteric control that exists for feedback regulation of overall carbon flow through the aromatic pathway in X. campestris is thus far unique in nature.

3-Deoxy-7-Phosphoheptulonate Synthase↗

PubMed1997

The murine IgM secretory poly(A) site contains dual upstream and downstream elements which affect polyadenylation.

Regulation of polyadenylation efficiency at the secretory poly(A) site plays an essential role in gene expression at the immunoglobulin (IgM) locus. At this poly(A) site the consensus AAUAAA hexanucleotide sequence is embedded in an extended AU-rich region and there are two downstream GU-rich regions which are suboptimally placed. As these sequences are involved in formation of the polyadenylation pre-initiation complex, we examined their function in vivo and in vitro . We show that the upstream AU-rich region can function in the absence of the consensus hexanucleotide sequence both in vivo and in vitro and that both GU-rich regions are necessary for full polyadenylation activity in vivo and for formation of polyadenylation-specific complexes in vitro . Sequence comparisons reveal that: (i) the dual structure is distinct for the IgM secretory poly(A) site compared with other immunoglobulin isotype secretory poly(A) sites; (ii) the presence of an AU-rich region close to the consensus hexanucleotide is evolutionarily conserved for IgM secretory poly(A) sites. We propose that the dual structure of the IgM secretory poly(A) site provides a flexibility to accommodate changes in polyadenylation complex components during regulation of polyadenylation efficiency.

Alternative Splicing↗