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Related Concept Videos

What is Natural Selection?01:32

What is Natural Selection?

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Natural selection is an evolutionary process in which individuals with survival-promoting traits reproduce at higher rates. These favorable traits become more common within a population or species. Naturally selected traits initially arise via random genetic mutations. In order for selection to occur, there must be variation within a population, the trait controlling the variation must be heritable, and there must be an evolutionary advantage for variation in the trait.
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Types of Selection01:46

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Natural selection influences the frequencies of particular alleles and phenotypes within populations in several different ways. Primarily, natural selection can be directional, stabilizing, or disruptive. Directional selection favors one extreme trait and shifts the population towards that phenotype while selecting against individuals displaying alternate traits. Stabilizing selection favors an intermediate trait with a narrow range of variation. Deviation from the optimal phenotype towards an...
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Frequency-dependent Selection

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When the fitness of a trait is influenced by how common it is (i.e., its frequency) relative to different traits within a population, this is referred to as frequency-dependent selection. Frequency-dependent selection may occur between species or within a single species. This type of selection can either be positive—with more common phenotypes having higher fitness—or negative, with rarer phenotypes conferring increased fitness.
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Organisms that are well-adapted to their environment are more likely to survive and reproduce. However, natural selection does not lead to perfectly adapted organisms. Several factors constrain natural selection.
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Natural selection, a fundamental concept in evolutionary biology, is the mechanism by which evolution is driven, favoring organisms that are best adapted to their environments. This process enhances their chances of survival and reproduction. Adaptation, a key outcome of this process, involves genetic modifications that optimize an organism's functionality under specific environmental challenges, such as extreme cold or thinner air at high altitudes.
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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
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Highly fluorescent and HDAC6 selective scriptaid analogues.

Cassandra L Fleming1, Anthony Natoli2, Jeannette Schreuders2

  • 1School of Life & Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia.

European Journal of Medicinal Chemistry
|November 19, 2018
PubMed
Summary
This summary is machine-generated.

New fluorescent scriptaid analogues offer high HDAC6 selectivity and potency, enabling cellular and whole organism imaging. These compounds visualize cytoplasmic localization and impact in vivo development in zebrafish.

Keywords:
4MSFluorescenceHDACImagingNaphthalimideScriptaidZebrafish

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Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Chemical Biology

Background:

  • Histone deacetylase 6 (HDAC6) is a validated target for various diseases.
  • Existing HDAC6 inhibitors lack sufficient selectivity or fluorescent properties for advanced imaging.
  • Development of targeted imaging probes is crucial for understanding drug distribution and mechanism of action.

Purpose of the Study:

  • To synthesize and evaluate novel fluorescent scriptaid analogues with high selectivity and potency for HDAC6.
  • To assess the suitability of these compounds for cellular and whole organism imaging.
  • To investigate the in vivo effects of HDAC6 inhibition using these fluorescent probes.

Main Methods:

  • Synthesis of fluorescent scriptaid analogues.
  • In vitro enzymatic assays to determine HDAC6 selectivity and potency (IC50).
  • Cellular imaging studies to visualize cytoplasmic localization.
  • Whole organism imaging in zebrafish to assess vascular localization and developmental effects.

Main Results:

  • Novel fluorescent scriptaid analogues were successfully synthesized.
  • Compounds exhibited excellent HDAC6 selectivity (HDAC1/6 > 500) and high potency (HDAC6 IC50 < 5 nM).
  • High fluorescence quantum yields (up to ΦF = 0.83 in DMSO) facilitated cellular imaging and confirmed cytoplasmic localization.
  • Zebrafish imaging demonstrated vascular localization and revealed the impact of HDAC6 inhibition on in vivo development.

Conclusions:

  • Fluorescent scriptaid analogues represent a promising class of highly selective and potent HDAC6 inhibitors.
  • These compounds are well-suited for visualizing HDAC6 activity and localization in biological systems.
  • The developed probes provide valuable tools for studying HDAC6 function and therapeutic potential in vivo.