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At least 703 records · Page 39Linked to original sources
PubMed2006

Intravenous contrast-enhanced dynamic MR urography: diagnosis of vesicoureteral reflux during bladder filling with time-signal intensity curves.

PURPOSE: To evaluate the time-signal intensity (SI) curves generated from intravenous (IV) gadodiamide-enhanced dynamic magnetic resonance (MR) urographic scans for identifying vesicoureteral reflux (VUR) during bladder filling. MATERIALS AND METHODS: MR urographic studies of children were retrospectively reviewed, and 52 ureterorenal units of 26 patients (15 females and 11 males, mean age = 5.5 years) who had also undergone voiding cystourethrographic (VCUG) examination were included in this study. The patients were examined on a 1.5T scanner. For functional MR urography and to generate time-SI curves, we used a post IV contrast-enhanced two-dimensional (2D) fast field echo (FFE) sequence (TR = 17 msec, TE = 3.2 msec, flip angle (FA) = 90 degrees ) in the coronal plane. MR urographic time-SI curves that demonstrated a prompt and concave fall of the initial third phase followed by intermittent or constantly increasing SI peaks above the baseline from which the second phase starts were considered to have VUR. We compared the differences in time-SI curves between the control group and patients with VUR during bladder filling. RESULTS: Twelve ureterorenal units of eight patients (four bilateral and four unilateral) had VUR during bladder filling on VCUG. The time-SI curves of these patients showed intermittent (N = 8 ureterorenal units), and constantly increasing (N = 4 ureterorenal units) SI peaks consistent with VUR. One patient also had bilateral abnormal time-SI curves suggesting VUR despite the normal VCUG study. In the control group, 25 units had normal triphase time-SI curves, six renal units had urinary dilatation with good washout after diuretic injection, and four renal units had upper urinary dilatation without contrast washout, while five renal units did not show any function. None of the patients in the control group revealed distortion in the time-SI curve. The differences in time-SI curves patterns between the control group and patients with VUR during bladder filling were statistically significant (P < 0.001). CONCLUSION: After a prompt and concave decrease of the initial third phase of the time-SI curve, intermittent spikes or a constant rise in SI above the baseline suggest the existence of VUR.

Case-Control Studies↗
PubMed2006

Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.

Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.

Adolescent↗
PubMed1996

Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes.

Purified human myeloperoxidase (MPO) converted human C5 to an activated form, i.e. the C5 protein adopted a configuration expressing a binding site for C6; the resulting C56 complex then reacted with C7, C8 and C9 forming a hemolytic C5-9 complex. For the activation by myeloperoxidase chloride and hydrogen peroxide were essential. This indicates that the peroxidase acted through the generation of HOCl which had been shown earlier to oxidize and activate C5. Human polymorphonuclear leukocytes (PMN) were stimulated in vitro by incubation with opsonized zymosan; thereafter the supernatants were tested for C5 activating potency. Stimulated PMN release H2O2 and MPO that produces hypochlorite and secondarily various chloramines. As a trap for the labile hypochlorite generated excess taurine was added to the PMN suspensions during the incubation. Hypochlorite is then stoichiometrically converted to the relatively stable taurine chloramine. In order to rule out interfering activities of proteolytic enzymes released from the PMN and known to attack C5, the supernatants were ultracentrifuged, and the ultrafiltrates, containing only low molecular weight compounds, were used for the further studies. They contained taurine chloramine, estimated photometrically, and they activated C5 upon incubation, assayed functionally by reactive lysis. Azide, an inhibitor of myeloperoxidase, and catalase which destroys H2O2, essential for MPO-catalyzed oxidations, prevented the generation of C5 activating potency and of chloramines. Unstimulated PMN produced neither oxidants nor C5 activating potency. When taurine was omitted from the PMN suspensions during stimulations much less oxidant was found in the supernatants and less C5 activating potency. These findings indicate that the C5 activating agent was produced by stimulated PMN through MPO-generated hypochlorite, trapped as taurine chloramine. In the absence of added taurine the hypochlorite formed by MPO oxidized endogenous amines that also activated C5. Further studies suggested that among these was some monochloramine derived from endogenous ammonia. Activation of the terminal complement reaction sequence by MPO released from stimulated PMN may represent a third pathway to complement activation contributing to and reinforcing complement and PMN functions at the site of inflammation or tissue injury.

Complement Activation↗
PubMed1995

Variations of hepatitis C virus NS5B sequence (nucleotides 8261-8566) do not correlate with response to interferon-alpha therapy.

Hepatitis C virus (HCV) is an RNA virus with the NS5B gene encoding an RNA-dependent RNA polymerase. Interferon-alpha (IFN-alpha) is effective against HCV and its effect is believed to be related to its antiviral activity. To determine whether sequence variations of the HCV NS5B region correlate with response to IFN therapy, pretreatment serum samples from 40 patients with chronic HCV infection who were subsequently treated with IFN (> or = 3 MU thrice weekly for 24 weeks) and had well-characterized biochemical responses were studied. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to generate an approximately 365-bp fragment from which nucleotide sequence and genotypes were determined. By comparing the nucleotide sequences and the encoded amino acid sequences of samples from each group, no response group-specific nucleotide or encoded amino acid substitution was identified. Most of the substitutions identified were synonymous (usually by changes at the third position of the codon). These data suggest that these substitutions were selective rather than spontaneous events. Of the few non-synonymous substitutions identified, none was correlated with subsequent response to IFN, either within or across genotypes.

Adult↗
PubMed1995

Exonic MHC-DRB polymorphisms and intronic simple repeat sequences: Janus' faces of DNA sequence evolution.

The evolution of highly polymorphic gene loci is following routes that cannot be extrapolated from the existing knowledge of single copy genes. In addition, interpreting the evolution of the most polymorphic loci in vertebrates requires a plethora of data from different taxa. We evaluate here the rules for the evolution of Major Histocompatibility Complex (MHC-)DRB genes recently established in humans and other primates on the basis of sequences from several artiodactyl species. MHC genes encode essential molecules for self/altered-self/non-self discrimination in the interaction of the organism with its environment. The necessity to effectively present various different antigens to immunocompetent cells causes positive selection pressure on the variability of these genes in the population. Artiodactyls represent the third mammalian order in which this phenomenon was evidence independently. A further incentive to investigate also the surroundings of MHC-DRB loci was the presence of a particular repetitive sequence stretch in the vicinity of the polymorphic exon--in addition to the evolutionarily old alleles, ancient polymorphisms and the mechanisms for their generation and/or maintenance. Besides their utility for indirect gene diagnosis (MHC-DRB typing), the closely linked stretches of simple repetitive DNA in the neighborhood of the highly polymorphic MHC-DRB genes are also interesting remains of the evolutionary history. Evolutionary development is different in genetically inert intronic DNA compared to the exonic counterparts, despite their close vicinity. The persistence of these simple repeats over nearly 100 million years in one location preserving the same basic motif structure is startling. Indirect evidence is weighed that biological meaning should be considered for these elements. The combined analysis of the polymorphic DRB genes and the (highly variable but persistent) simple repeat stretches deepen our understanding of the complexities within a unique genomic compartment encoding essential molecules for self/non-self differentiation in the interaction of the organism with its environment.

Amino Acid Sequence↗
PubMed1990

Molecular comparison of a nonhemolytic and a hemolytic phospholipase C from Pseudomonas aeruginosa.

Pseudomonas aeruginosa produces two secreted phospholipase C (PLC) enzymes. The expression of both PLCs is regulated by Pi. One of the PLCs is hemolytic, and one is nonhemolytic. Low-stringency hybridization studies suggested that the genes encoding these two PLCs shared DNA homology. This information was used to clone plcN, the gene encoding the 77-kilodalton nonhemolytic PLC, PLC-N. A fragment of plcN was used to mutate the chromosomal copy of plcN by the generation of a gene interruption mutation. This mutant produces 55% less total PLC activity than the wild type, confirming the successful cloning of plcN. plcN was sequenced and encodes a protein which is 40% identical to the hemolytic PLC (PLC-H). The majority of the homology lies within the NH2 two-thirds of the proteins, while the remaining third of the amino acid sequence of the two proteins shows very little homology. Both PLCs hydrolyze phosphatidylcholine; however, each enzyme has a distinct substrate specificity. PLC-H hydrolyzes sphingomyelin in addition to phosphatidylcholine, whereas PLC-N is active on phosphatidylserine as well as phosphatidylcholine. These studies suggest structure-function relationships between PLC activity and hemolysis.

Amino Acid Sequence↗
PubMed2005

Humanized recombinant vaccinia virus complement control protein (hrVCP) with three amino acid changes, H98Y, E102K, and E120K creating an additional putative heparin binding site, is 100-fold more active than rVCP in blocking both classical and alternative complement pathways.

Vaccinia virus complement control protein (VCP) is able to modulate the host complement system by regulating both pathways of complement activation. Efficient downregulation of complement activation depends on the ability of the regulatory protein to effectively bind the activated third (C3b) and fourth (C4b) complement components. Based on native crystallographic structure, molecular modeling, and sequence alignment with other Orthopoxviral complement control proteins (CCPs) and their host homologs, putative sites have been found on VCP as contact points for C3b/C4b. Here, we report that using site-directed mutagenesis, modified proteins have been generated. In addition, we report that the generated modified proteins with postulated contact point substitutions have shown greater ability to regulate both the classical and the alternative pathways of complement activation than the recombinant Western Reserve VCP, with one modified protein showing nearly 100-fold more potency in regulating both complement activation pathways independently. The augmented in vitro inhibitory activity of the modified protein together with the newly created putative heparin binding site suggests its promising potential as a competent therapeutic agent in modulating various complement-mediated ailments, for example, traumatic brain injury, Alzheimer's disease, rheumatoid arthritis, multiple organ dysfunction syndrome, reperfusion injury, and xenorejection.

Amino Acid Sequence↗
PubMed1984

Two introns define functional domains of a neuropeptide precursor in Aplysia.

Biologically active peptides are synthesized as parts of precursor proteins which are proteolytically processed to generate active molecules. The structure of the gene encoding peptides expressed in Aplysia neurons R3-14 suggests that two intervening sequences split the transcript into functional domains. The first exon encodes the 5' untranslated region, the second exon the signal sequence and the bulk of the negative charge of the precursor protein while the third exon encodes the remainder of the precursor and the 3' untranslated region.

Animals↗
PubMed2001

Preliminary experience with pure antiestrogens.

Endocrine therapy plays an important role in the management of all stages of breast cancer, and the development of effective endocrine therapies has focused on modifying the response of hormone-sensitive tumors to estrogen. The most widely used agents are the nonsteroidal antiestrogens or selective estrogen receptor (ER) modulators, the class to which tamoxifen, the standard in terms of antiestrogen therapy, belongs. Tamoxifen is effective in both adjuvant and first-line settings and is now used as prophylactic therapy in high-risk individuals. However, the partial agonist activity of tamoxifen on the uterus, coupled with "tumor flare" and the development of tamoxifen resistance, has limited its therapeutic utility. Attempts to eliminate the partial agonist activity of tamoxifen and increase its potency have led to the development of fulvestrant (Faslodex), the first in a new class of pure antiestrogens, the ER down-regulators. Fulvestrant has a high affinity for the ER compared with tamoxifen but has none of the agonist activities of tamoxifen. This new agent is showing promising clinical activity in the treatment of advanced breast cancer after tamoxifen therapy. Fulvestrant's lack of ER agonist activity may provide a longer duration of response compared with tamoxifen, as it did in a preclinical setting. Fulvestrant has demonstrated that it is at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or recurred on prior endocrine therapy and is currently being evaluated in Phase III trials versus tamoxifen for the first-line therapy of advanced breast cancer. Future clinical studies will evaluate fulvestrant in adjuvant and neoadjuvant settings, together with its optimal sequencing in relation to tamoxifen and other endocrine therapies.

Animals↗
PubMed2005

[Progress in detection methods of single nucleotide polymorphisms].

Single nucleotide polymorphism (SNP) is the third generation genetic marker. SNP detection now is becoming increasingly important means in molecular diagnostics, clinical assay and novel drug development. It plays an essential role in drug resistance and anaphylactic reaction and has the importance in theoretical studies of gene location, hereditary diseases and human origin. With the accomplishment of human genome sequencing, the genotyping and discovering of SNP are becoming hot subjects in genetics and biomedicine researches. The methods for SNP detection were renewed rapidly and developed fast in past few years. In this review, several newly established detection methods including gene chip, molecular probe, fluorescence polarization and resonance, mass spectrometry, and bacterial magnetic particle are discussed. It could be expected that an accurate and sensitive, simple and easy-to-handle SNP technology with low cost and high throughput will be available on the basis of research breakthroughs of biochemistry, engineering and analytic software.

Fluorescence Polarization↗
PubMed2002

Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor.

The repair of DNA damage, caused by both endogenous and exogenous sources, is necessary to remove lesions that either miscode or block DNA or RNA polymerases. We propose that damage also must be repaired to maintain sequence-specific DNA-protein interactions. In this paper, we have systematically studied two lesions that interfere with one important DNA landmark, the thymine methyl group. Oxidation of the thymine methyl group in DNA generates 5-hydroxymethyluracil (HmU) whereas the misincorporation of dUMP into DNA generates uracil (U), replacing the methyl group with a hydrogen. Both substitutions are shown to inhibit binding of the AP-1 (c-Jun) transcription factor. The energy cost of the perturbation, approximately 0.4 kcal/mol, is similar in magnitude for both U and HmU substitutions and is additive when multiple substitutions are present. A third lesion, substitution of the central C:G base pair of the AP-1 DNA binding domain with the pro-mutagenic U:G mispair, unexpectedly increases AP-1 binding, allowing the transcription factor to interfere with uracil DNA glycosylase activity. Our results support the hypothesis that an additional role for DNA repair systems is to maintain the integrity of sequence-specific DNA-protein interactions, a role of particular importance in long-lived organisms.

Adenine↗
PubMed2001

Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia.

Anhidrotic ectodermal dysplasia (EDA) is caused by mutations in the EDA gene encoding ectodysplasin A, a member of the TNF ligand superfamily involved in the communication between the cells. The structure of the EDA gene was investigated in three patients exhibiting clinical symptoms of EDA in an attempt to correlate the molecular findings with the phenotype of the patients. Genomic DNA was analyzed by single stranded conformation polymorphism (SSCP) followed by direct sequencing. In one of the patients, as well as in his heterozygous mother and sister, a single T insertion was evidenced in exon 3 between nucleotides 713 and 714 that changed Lys codon (AAA) into a termination codon TAA (Lys158Ter). In the other patient, A1321T transversion was demonstrated. The same mutation was found in his heterozygous mother and resulted in a change of Ileu360Asn that might generate an additional glycosylation site. In the third patient an A1285G transition was revealed. This mutation that originated de novo was localized in a region that is highly conserved in TNF ligand family and caused substitution of Ala349Thr. Localization of the mutations in the extracellular domain of ectodysplasin A suggested that the primary cause of EDA is a defect in communication between the cells responsible for the development of skin appendages. Despite a different character and localization of the mutations, no apparent correlation between phenotype and genotype of the patients was evidenced. Some differences in the patients' phenotype were observed.

Child↗
PubMed1996

Phylogeny of nearctic members of the Anopheles maculipennis species group derived from the D2 variable region of 28S ribosomal RNA.

Phylogenetic affinities among taxa associated with the Nearctic component of the Anopheles maculipennis species group (subgenus Anopheles) were inferred from sequence divergence in the D2 variable region of 28S ribosomal RNA. The base composition of this region had a marked GC bias which ranged from 59.9% in Anopheles walkeri to 65.1% in Anopheles punctipennis E. Although over two-thirds of the base positions in the D2 region were double-stranded (stem), substitution frequencies at single-stranded (loop) positions (0.068 over all taxa) were 2.7 times greater than at stem positions (0.025). Most mutations were point mutations and were most frequent at loop positions. In the shortest trees generated by both parsimony and distance methods, the four American species traditionally identified with the maculipennis complex (Anopheles aztecus, Anopheles earlei, Anopheles freeborni, and Anopheles occidentalis) were monophyletic with A. punctipennis E and W as sister taxa. The latter two correspond to genetically distinct forms from the eastern United States and California, respectively. The sibling species of the Anopheles quadrimaculatus complex formed a distinct clade, and A. quadrimaculatus D, with six autapomorphies, was the most divergent of these taxa. Sequence divergence between A. walkeri and the other taxa included in the study was of such magnitude as to suggest only a distant affinity to these species.

Animals↗
PubMed1987

Novel rearrangements of IS30 carrying plasmids leading to the reactivation of gene expression.

Unusual DNA rearrangements involving the prokaryote mobile genetic element IS30 have been identified. In order to study the potential mechanisms for the reactivation of a gene after IS element insertion, IS30 was introduced between the lacUV5 promoter and the galK gene of the multicopy plasmid pFR100. In this plasmid terminators of RNA transcription in the sequence of IS30 prevent expression of the galK gene from the lacUV5 promoter. A number of independently isolated mutant plasmids re-expressing the galK gene were studied and shown to be tandemly repeated dimers of the original plasmid. However, the two copies of IS30 were tandemly repeated at one of the original sites of insertion, while at the other site IS30 and three base pairs were missing. The repeated copies of IS30 were separated by two base pairs, the same as those originally flanking the elements. An apparently identical mechanism generated cointegrates between a derivative of plasmid pFD51 carrying IS30 upstream of a promoterless galK gene and a derivative of plasmid pACYC177 carrying IS30 inserted into the beta-lactamase gene. This arrangement brought the galK gene under the control of the beta-lactamase promoter of pACYC177. A mechanism involving aborted conservative transposition of IS30 is discussed as a possible route for the generation of these novel cointegrates. In a third experiment we isolated an insert of IS30 which was also two base pairs away from an already resident IS30 element. This insertion of IS30 created a strong promoter of RNA transcription, which has the potential to increase the expression of the transposase in the downstream copy of the element.

Base Sequence↗
PubMed1999

An infectious molecular clone of a Japanese genotype 1b hepatitis C virus.

We describe an infectious molecular clone of a Japanese genotype 1b strain of hepatitis C virus (HCV-N). The molecularly cloned sequence of HCV-N was compared with alignments of other HCV sequences, leading to the identification of 15 unique, nonconservative amino acid substitutions within the HCV-N open reading frame (ORF). These were repaired to the consensus genotype 1b residue, and the infectivity of RNA transcribed from the repaired clone was assessed by intrahepatic inoculation of a chimpanzee. Viral RNA was first detected in the serum of this chimpanzee 3 weeks following inoculation, and was intermittently present over the next 14 weeks. A strong and persistent anti-HCV serological response developed 13 weeks following inoculation, with seroconversion in the recombinant immunoblot assay (RIBA). A weaker, transient serological response, characterized by seroconversion in a third-generation enzyme-linked immunosorbent assay (ELISA) but not RIBA, occurred between weeks 1 and 5. This may have represented an anamnestic response to HCV antigens translated directly from the intrahepatically inoculated RNA, because the animal previously had undergone 2 unsuccessful attempts at rescue of HCV by intrahepatic RNA inoculation. There was neither biochemical nor histological evidence of liver disease. Although this is within the range of expected outcomes in an HCV-naive chimpanzee, prior immunologic priming may have modified the infection in this animal. The HCV-N clone is the first infectious molecular clone of HCV that is comprised entirely of genotype 1b sequence, and it contains an ORF sequence that is significantly divergent from that of a previously described genotype 1a/1b chimera.

3' Untranslated Regions↗
PubMed1993

Chicken major histocompatibility complex class II B genes: analysis of interallelic and interlocus sequence variance.

Five different chicken B-LB genes were cloned and sequenced. The comparison of these sequences shows that they can be classified as members of two different families, the B-LBII family (containing the B-LBI and B-LBII genes) and the B-LBIII family (containing the B-LBIII, B-LBIV, and B-LBV genes). The extent of polymorphism within each of these families was assessed by in vitro amplification of DNA fragments encompassing exon 2 in several haplotypes. The nucleotide sequences were determined, and pairwise relationships were evaluated. In the course of this work, a sixth gene termed B-LBVI was identified, defining a third family (B-LBVI family). Polymorphism of the B-LBIII or B-LBVI families is far less extensive than that of the B-LBII family. In this latter, the distribution of conserved and polymorphic residues is similar to what has been described in mammals. These families seem to have been generated by gene duplication events giving rise to several isotypes, as observed in mammals. However, phylogenetic analyses indicate that these families are not homologous to their mammalian counterparts. Evaluation of the level of transcription of these different genes showed that genes from the B-LBII family are predominantly transcribed over those of the other families.

Alleles↗
PubMed1998

Fluorescent chemical cleavage of mismatches for efficient screening of the factor VIII gene.

The detection of mutations in large and complex genes represents a practical challenge in research and diagnostic laboratories. Available methods are either time-consuming or lack sensitivity. Mutation detection in the factor VIII gene, responsible for haemophilia A, is hampered by its large size, its many exons, and the high frequency of de novo mutations that result in different mutations in unrelated patients. For an exhaustive analysis of mutations in the factor VIII gene, we established a nonradioactive screening method based on chemical cleavage of mismatches (CCM). PCR-fragments of approximately 1 kb were generated from genomic DNA (exon 14) or after reverse transcription from mRNA isolated from blood cells. Some modifications have been made to improve the CCM strategy. First, using a fluorescent tag, the method gains safety and flexibility. Second, fluorescent detection allows an accurate sizing of digested fragments when measured on an automated DNA sequencer. Third, by labelling both 5' ends of the PCR-fragment, the detection rate is virtually 100%. Finally, in the case of an X-linked disease, samples from two patients can be mixed, which reduces the workload without losing information. In a pilot experiment, mutations were detected in 20 of 20 patients. In this series, three small insertions, two small deletions, one nonsense mutation, 13 missense mutations, and one splice mutation were found. Fifteen of these mutations are new. Thus virtually all kind of mutations are detectable by this method. Moreover, the analysis of the gene can be completed in 2 days.

DNA↗
PubMed1996

The sensory guidance of movement: a comparison of the cerebellum and basal ganglia.

We used positron emission tomography (PET) to compare the contribution of the cerebellum and basal ganglia to the sensory guidance of movement. In one condition the subjects used a computer mouse to draw a series of lines on a computer screen (DRAW). In the second condition the same lines were presented to the subjects, and they had to track the lines with a mouse pointer on the screen (COPY). In a third condition the subjects were again presented with the same lines, and they simply followed movements of the pointer with their eyes (EYES). In the fourth condition, the subjects fixated a central point, ignoring the sequence of presented lines (FIX). The pons and cerebellum were activated more during visually guided tracking than in freely generated drawing (COPY vs DRAW). The basal ganglia were activated equally in both DRAW and COPY. The prefrontal and inferior temporal cortex were activated more when subjects drew lines freely (DRAW) than when they copied them (COPY). We conclude that the cerebellum is specialized for using sensory information to correct movements, but that the basal ganglia are involved both in movements that are self-generated and in movements that are guided by external cues.

Adult↗