scholarly journals A strong preference for the TA/TA dinucleotide step discovered for an acridine-based, potent antitumor dsDNA intercalator, C-1305: NMR-driven structural and sequence-specificity studies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tomasz Laskowski ◽  
Witold Andrałojć ◽  
Jakub Grynda ◽  
Paulina Gwarda ◽  
Jan Mazerski ◽  
...  
Keyword(s):  
Strong Preference ◽  
Sequence Specificity ◽  
Dinucleotide Step

Structural Aspects of Phonological Development

1988 ◽  
Vol 19 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Karen E. Pollock ◽  
Richard G. Schwartz
Keyword(s):  
Clinical Management ◽  
Structural Complexity ◽  
Strong Preference ◽  
Phonological Development ◽  
Structural Position ◽  
Phonological Disorders ◽  
Syllabic Structure ◽  
The Relationship ◽  
Structural Aspects ◽  
Target Words

The relationship between syllabic structure and segmental development was examined longitudinally in a child with a severe phonological disorder. Six speech samples were collected over a 4-year period (3:5 to 7:3). Analyses revealed gradual increases in the complexity and diversity of the syllable structures produced, and positional preferences for sounds within these forms. With a strong preference for [d] and [n] at the beginning of syllables, other consonants appeared first at the end of syllables. Implications for clinical management of phonological disorders include the need to consider both structural position and structural complexity in assessing segmental skills and in choosing target words for intervention.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Heterogeneous Polymer ◽  
Non Local ◽  
Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

scholarly journals Rely on Each Other: DNA Binding Cooperativity Shapes p53 Functions in Tumor Suppression and Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2422
Author(s):  
Oleg Timofeev ◽  
Thorsten Stiewe
Keyword(s):  
Cancer Therapy ◽  
Dna Binding ◽  
Cell Fate ◽  
Tumor Suppression ◽  
Quaternary Structure ◽  
Three Dimensional ◽  
Structural Basis ◽  
Sequence Specificity ◽  
Cell Fate Decisions ◽  
Cancer Mutations

p53 is a tumor suppressor that is mutated in half of all cancers. The high clinical relevance has made p53 a model transcription factor for delineating general mechanisms of transcriptional regulation. p53 forms tetramers that bind DNA in a highly cooperative manner. The DNA binding cooperativity of p53 has been studied by structural and molecular biologists as well as clinical oncologists. These experiments have revealed the structural basis for cooperative DNA binding and its impact on sequence specificity and target gene spectrum. Cooperativity was found to be critical for the control of p53-mediated cell fate decisions and tumor suppression. Importantly, an estimated number of 34,000 cancer patients per year world-wide have mutations of the amino acids mediating cooperativity, and knock-in mouse models have confirmed such mutations to be tumorigenic. While p53 cancer mutations are classically subdivided into “contact” and “structural” mutations, “cooperativity” mutations form a mechanistically distinct third class that affect the quaternary structure but leave DNA contacting residues and the three-dimensional folding of the DNA-binding domain intact. In this review we discuss the concept of DNA binding cooperativity and highlight the unique nature of cooperativity mutations and their clinical implications for cancer therapy.

scholarly journals Cis-Elements Governing Trinucleotide Repeat Instability in Saccharomyces cerevisiae

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1569-1579 ◽  
Author(s):  
Michael L Rolfsmeier ◽  
Michael J Dixon ◽  
Luis Pessoa-Brandão ◽  
Richard Pelletier ◽  
Juan José Miret ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Repair ◽  
Sequence Analysis ◽  
Trinucleotide Repeat ◽  
Model Systems ◽  
Sequence Specificity ◽  
Cis Elements ◽  
Frequent Mutations ◽  
Yeast Genetic ◽  
Molecular Nature

Abstract Trinucleotide repeat (TNR) instability in humans is governed by unique cis-elements. One element is a threshold, or minimal repeat length, conferring frequent mutations. Since thresholds have not been directly demonstrated in model systems, their molecular nature remains uncertain. Another element is sequence specificity. Unstable TNR sequences are almost always CNG, whose hairpin-forming ability is thought to promote instability by inhibiting DNA repair. To understand these cis-elements further, TNR expansions and contractions were monitored by yeast genetic assays. A threshold of ∼15–17 repeats was observed for CTG expansions and contractions, indicating that thresholds function in organisms besides humans. Mutants lacking the flap endonuclease Rad27p showed little change in the expansion threshold, suggesting that this element is not altered by the presence or absence of flap processing. CNG or GNC sequences yielded frequent mutations, whereas A-T rich sequences were substantially more stable. This sequence analysis further supports a hairpin-mediated mechanism of TNR instability. Expansions and contractions occurred at comparable rates for CTG tract lengths between 15 and 25 repeats, indicating that expansions can comprise a significant fraction of mutations in yeast. These results indicate that several unique cis-elements of human TNR instability are functional in yeast.

scholarly journals Discrete choice experiment for eliciting preference for health services for patients with ALS and their informal caregivers

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Katy Tobin ◽  
Sinead Maguire ◽  
Bernie Corr ◽  
Charles Normand ◽  
Orla Hardiman ◽  
...  
Keyword(s):  
Health Services ◽  
Discrete Choice Experiment ◽  
Discrete Choice ◽  
Choice Experiment ◽  
Strong Preference ◽  
Multidisciplinary Teams ◽  
Relative Importance ◽  
Trade Offs ◽  
Als Patients ◽  
The Impact

Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition with a mean life expectancy of 3 years from first symptom. Understanding the factors that are important to both patients and their caregivers has the potential to enhance service delivery and engagement, and improve efficiency. The Discrete Choice Experiment (DCE) is a stated preferences method which asks service users to make trade-offs for various attributes of health services. This method is used to quantify preferences and shows the relative importance of the attributes in the experiment, to the service user. Methods A DCE with nine choice sets was developed to measure the preferences for health services of ALS patients and their caregivers and the relative importance of various aspects of care, such as timing of care, availability of services, and decision making. The DCE was presented to patients with ALS, and their caregivers, recruited from a national multidisciplinary clinic. A random effects probit model was applied to estimate the impact of each attribute on a participant’s choice. Results Patients demonstrated the strongest preferences about timing of receiving information about ALS. A strong preference was also placed on seeing the hospice care team later rather than early on in the illness. Patients also indicated their willingness to consider the use of communication devices. Grouping by stage of disease, patients who were in earlier stages of disease showed a strong preference for receipt of extensive information about ALS at the time of diagnosis. Caregivers showed a strong preference for engagement with healthcare professionals, an attribute that was not prioritised by patients. Conclusions The DCE method can be useful in uncovering priorities of patients and caregivers with ALS. Patients and caregivers have different priorities relating to health services and the provision of care in ALS, and patient preferences differ based on the stage and duration of their illness. Multidisciplinary teams must calibrate the delivery of care in the context of the differing expectations, needs and priorities of the patient/caregiver dyad.

scholarly journals Fine-Structure Mapping of Meiosis-Specific Double-Strand DNA Breaks at a Recombination Hotspot Associated With an Insertion of Telomeric Sequences Upstream of the HIS4 Locus in Yeast

Genetics ◽  
1996 ◽  
Vol 143 (3) ◽  
pp. 1115-1125 ◽  
Author(s):  
Fei Xu ◽  
Thomas D Petes
Keyword(s):  
Meiotic Recombination ◽  
Hydroxyl Groups ◽  
Sequence Specificity ◽  
Structure Mapping ◽  
Dna Breaks ◽  
Exonuclease Iii ◽  
Recombination Hotspot ◽  
Telomeric Sequences ◽  
Double Strand Dna Breaks ◽  
Double Strand Dna

Abstract Meiotic recombination in Saccharomyces cerevisiae is initiated by double-strand DNA breaks (DSBs). Using two approaches, we mapped the position of DSBs associated with a recombination hotspot created by insertion of telomeric sequences into the region upstream of HIS4. We found that the breaks have no obvious sequence specificity and localize to a region of ~50 bp adjacent to the telomeric insertion. By mapping the breaks and by studies of the exonuclease III sensitivity of the broken ends, we conclude that most of the broken DNA molecules have blunt ends with 3′-hydroxyl groups.

scholarly journals The DNA sequence specificity of stimulation of DNA polymerases by factor D.

1987 ◽  
Vol 262 (18) ◽  
pp. 8868-8874 ◽  
Author(s):  
M Fry ◽  
R Sharf ◽  
P Weisman-Shomer ◽  
P C Evers ◽  
L A Loeb
Keyword(s):  
Dna Sequence ◽  
Dna Polymerases ◽  
Sequence Specificity ◽  
Dna Sequence Specificity ◽  
Stimulation Of

scholarly journals Domestic cats (Felis catus) prefer freely available food over food that requires effort

2021 ◽  
Author(s):  
Mikel M. Delgado ◽  
Brandon Sang Gyuc Han ◽  
Melissa J. Bain
Keyword(s):  
Home Environment ◽  
Felis Catus ◽  
Strong Preference ◽  
Domestic Cats ◽  
Size And Shape ◽  
Activity Tracker ◽  
Feed Tray

AbstractContrafreeloading is the willingness of animals to work for food when equivalent food is freely available. This behavior is observed in laboratory, domesticated, and captive animals. However, previous research found that six laboratory cats failed to contrafreeload. We hypothesized that cats would contrafreeload in the home environment when given a choice between a food puzzle and a tray of similar size and shape. We also hypothesized that more active cats would be more likely to contrafreeload. We assessed the behavior of 17 neutered, indoor domestic cats (Felis catus) when presented with both a food puzzle and a tray across ten 30-min trials. Each cat wore an activity tracker, and all sessions were video recorded. Cats ate more food from the free feed tray than the puzzle (t (16) = 6.77, p < 0.001). Cats made more first choices to approach and eat from the tray. There was no relationship between activity and contrafreeloading, and there was no effect of sex, age, or previous food puzzle experience on contrafreeloading. Our results suggest that cats do not show strong tendencies to contrafreeload in the home environment, although some cats (N = 4) ate most food offered in the puzzle or showed weak contrafreeloading tendencies (N = 5). Eight cats did not contrafreeload. Cats who consumed more food from the puzzle, consumed more food in general, suggesting a relationship between hunger and effort. Further research is required to understand why domestic cats, unlike other tested species, do not show a strong preference to work for food.

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