Brazilian wasp venom kills cancer cells by opening them up

Date:
September 1, 2015
Source:
Cell Press
Summary:
The social wasp Polybia paulista protects itself against predators by
producing venom known to contain a powerful cancer-fighting ingredient. A
new study reveals exactly how the venom's toxin -- called MP1 (Polybia-MP1)
-- selectively kills cancer cells without harming normal cells. MP1 interacts
with lipids that are abnormally distributed on the surface of cancer cells,
creating gaping holes that allow molecules crucial for cell function to leak
out.
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This is the Brazilain social wasp Polybia paulista.

Credit: Prof. Mario Palma/Sao Paulo State University

The social wasp Polybia paulista protects itself against predators by
producing venom known to contain a powerful cancer-fighting ingredient.
ABiophysical Journal study published September 1 reveals exactly how the
venom's toxin--called MP1 (Polybia-MP1)--selectively kills cancer cells
without harming normal cells. MP1 interacts with lipids that are abnormally
distributed on the surface of cancer cells, creating gaping holes that allow
molecules crucial for cell function to leak out.
"Cancer therapies that attack the lipid composition of the cell membrane
would be an entirely new class of anticancer drugs," says co-senior study
author Paul Beales, of the University of Leeds in the UK. "This could be
useful in developing new combination therapies, where multiple drugs are
used simultaneously to treat a cancer by attacking different parts of the
cancer cells at the same time."
MP1 acts against microbial pathogens by disrupting the bacterial cell
membrane. Serendipitously, the antimicrobial peptide shows promise for
protecting humans from cancer; it can inhibit the growth of prostate and
bladder cancer cells, as well as multi-drug resistant leukemic cells. However,
until now, it was not clear how MP1 selectively destroys cancer cells without
harming normal cells.
Beales and co-senior study author Joo Ruggiero Neto of So Paulo State
University in Brazil suspected that the reason might have something to do
with the unique properties of cancer cell membranes. In healthy cell
membranes, phospholipids called phosphatidylserine (PS) and
phosphatidylethanolamine (PE) are located in the inner membrane leaflet
facing the inside of the cell. But in cancer cells, PS and PE are embedded in
the outer membrane leaflet facing the cell surroundings.
The researchers tested their theory by creating model membranes, some of
which contained PE and/or PS, and exposing them to MP1. They used a wide
range of imaging and biophysical techniques to characterize MP1's
destructive effects on the membranes. Strikingly, the presence of PS
increased the binding of MP1 to the membrane by a factor of 7 to 8. On the
other hand, the presence of PE enhanced MP1's ability to quickly disrupt the
membrane, increasing the size of holes by a factor of 20 to 30.
"Formed in only seconds, these large pores are big enough to allow critical
molecules such as RNA and proteins to easily escape cells," Neto says. "The
dramatic enhancement of the permeabilization induced by the peptide in
the presence of PE and the dimensions of the pores in these membranes
was surprising."
In future studies, the researchers plan to alter MP1's amino acid sequence to
examine how the peptide's structure relates to its function and further
improve the peptide's selectivity and potency for clinical purposes.
"Understanding the mechanism of action of this peptide will help in

translational studies to further assess the potential for this peptide to be

used in medicine," Beales says. "As it has been shown to be selective to
cancer cells and non-toxic to normal cells in the lab, this peptide has the
potential to be safe, but further work would be required to prove that."

DNA division can slow to a halt

Date:
September 1, 2015
Source:
KAUST - King Abdullah University of Science and Technology
Summary:
A key mystery of the DNA replication process has been unraveled by
researchers, resolving a long-standing mystery that has clouded our
understanding of DNA replication, and also has important implications for all
domains of life.
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Single-molecule imaging reveals that DNA replication termination in E. coli is

mediated by kinetic competition between speed of strand separation by the
replisomal helicase and rearrangement of Tus?Terinteractions during
separation of the first six base pairs of Ter. Multiple termination sites are
required to insure fork stoppage.
Credit: Image courtesy of KAUST - King Abdullah University of Science and
Technology
A key mystery of the DNA replication process has been unraveled by
researchers from King Abdullah University of Science and Technology
(KAUST).
Before a bacterium can divide, it must make a copy of its genetic material,
the circular DNA molecules that resemble bunched rubber bands, through a
process called DNA replication. In this process, the two strands of DNA
making up the circular DNA molecule unwind and separate to become
templates for generating new strands.
To ensure the process is well regulated, the bacterium has set a number of
"roadblocks," or termination sites on the DNA, to ensure the permanent
stoppage of replication forks, Y-shaped structures formed between the
strands as the DNA molecule splits.
The Nature study, led by KAUST Ph.D. student Mohamed Elshenawy and
Associate Professor Samir Hamdan from KAUST's Division of Biological and
Environmental Science and Engineering, along with colleagues from the
University of Wollongong in Australia, showed why termination sites were
able to permanently stop replication forks in vitro, while in living bacteria,

more than 50 percent of the replication forks that moved towards the
termination site continued synthesis without stopping1.
A termination site comprises a 23-base pair termination sequence (Ter)
bound to the protein terminus utilization substance (Tus). TusTer is unusual
in that it acts like the ratcheting knot on a climbing rope by allowing
progression of replication forks from one direction but not the other. This
polarity sets up a "trap" that allows the first arriving fork to enter but not to
leave the terminus region until the other fork has arrived.
Hamdan and his team suspected that the energy from movement (or
kinetics) might be acting on these termination sites. They used singlemolecule imaging to record molecular movies that zoomed in with high
temporal and spatial resolution on the fate of Escherichia coli replication
forks as they approached a termination site from either direction.
Their results showed that efficiency of fork arrest is weakened by kinetic
competition between the rate of strand separation by the helicase motor at
the fork and the rate of rearrangement of TusTer interactions that maintain
Tus's strong grip on the DNA. This means that faster moving forks beat
TusTer rearrangement and displace Tus, while slower ones are effectively
blocked.
This resolves a long-standing mystery that has clouded our understanding of
DNA replication, and also has important implications for all domains of life.
"These findings are striking for the field of enzymology," Hamdan stated. He
noted that the demonstration that the rates of individual enzymes fluctuate
during catalysis and that rates can differ among presumably identical
enzyme molecules are both novel contributions of single-molecule imaging
to biology.
"This study demonstrated for the first time that these intrinsic properties of
enzyme molecules actually impact biology," explained Hamdan.
The communication between molecular motors and double-stranded DNA
binding proteins is a common feature in DNA replication, repair,
recombination and transcription and also in instances where conflict occurs
between these processes. The evolution of different responses to the
average rate of different molecular motors could regulate the
communication among these processes, Hamdan said.

Story Source:
The above post is reprinted from materials provided by KAUST - King
Abdullah University of Science and Technology. Note: Materials may
be edited for content and length.
Change in environment can lead to rapid evolution

Date:
September 2, 2015
Source:
Florida State University
Summary:
A new study is showing that rapid evolution can occur in response to
environmental changes.
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Kimberly Hughes is a professor of Biological Science at Florida State

University.
Credit: Ray Stanyard/Florida State University
A new Florida State University study is giving researchers a glimpse at how
organisms from fish to flowers to tumors evolve in response to rapid
environmental change.

The findings could have a broad ripple effect on a number of research areas,
including climate change and cancer treatment. And it's all because of
guppies.
FSU Professor of Biological Science Kimberly Hughes and a team of
researchers set out to find how this tiny tropical fish would evolve if they
transplanted wild Trinidadian guppy fish from a stream with predatory fish
into two-predator-free streams. Because guppies reproduce multiple times in
a year, they were able to track three to four generations of the fish living in
a predator-free zone.
The findings, published today in the academic journal Nature, were
staggering.
By sequencing genetic material in the guppies' brains, researchers found
that 135 genes evolved in response to the new environment. Most of the
changes in the gene expression were internal and dealt with a fish's
biological processes such as metabolism, immune function and
development.
But more importantly, the immediate response of genes to change in the
environment did not reflect the eventual evolutionary change.
Genes can change their activity levels in an immediate response to the
environment -- what evolutionary biologists call plasticity -- or in an
evolutionary response that occurs over many generations.
What Hughes and her colleagues found was that the evolutionary change in
gene activity was usually opposite in direction to the immediate plasticity of
gene activity. A gene that had changed in response to drastic change in the
environment would then evolve in the opposite direction after a few
generations.
"Some evolutionary theory suggests that plastic and evolutionary changes
should be in the same direction," Hughes said. "But our results indicate that
at least in the very early stages of evolution, genes that respond in the
'wrong' way to an environmental shift are those that will evolve most
quickly."
Guppies are viewed as an ideal subject for evolution research because one
year represents several generations for guppies. So, rapid evolutionary
changes are often visible in a short period of time.
That makes these results interesting to scientists and raises big questions
about how other organisms evolve in response to environmental changes.
For example, tumors face an environmental change when confronted with
chemotherapy or radiation. Plants and animals face environmental changes
with rising global temperatures. How do they change to live in these new
realities or do they ultimately not survive?

"We know that organisms respond to changes in their environment at a very

fast rate," Hughes said. "They can acclimate. That includes organisms that
are pathogens of humans and also includes things like tumors that adapt or
acclimate to, say, chemotherapy. We can measure these fast changes in
pathogens and tumors. We can measure that plasticity just the same way
we did in the brains of guppies. And then we might be able to predict how
the pathogen or tumor will respond to treatment over longer time periods.
This could help medical researchers and doctors predict and avoid
development of drug resistance in viruses, bacteria and tumors."

Story Source:
The above post is reprinted from materials provided by Florida State
University. Note: Materials may be edited for content and length.
Before nature selects, gene networks steer a course for evolution
Biologists, mathematicians work together to examine developmental
sources of variation within, between species
Date:
September 3, 2015
Source:
Carl R. Woese Institute for Genomic Biology, University of Illinois at UrbanaChampaign
Summary:
Natural selection is a race to reproduce, a competition between individuals
with varying traits that helps direct evolution. How do the structures of gene
networks determine which individuals appear on the starting line, silently
influencing evolution before competition has even begun? Researchers have
addressed this question by exploring the gene network that guides limb
development in mammals.
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This is the embryonic development of the buffy flower bat, Erophylla

sezekorni, showing the progressive growth and formation of the wings.
Credit: Courtesy of Karen Sears
Natural selection is a race to reproduce, a competition between individuals
with varying traits that helps direct the evolution of a species. As scientists
begin to explore the complex networks of genes that shape the form and
function of each individual, they can ask a new question about evolution:
How do the structures of these gene networks determine which individuals
appear on the starting line, silently influencing evolution before competition
has even begun?
University of Illinois researchers Karen Sears and Zoi Rapti, along with
collaborators at Illinois and four other institutions, have addressed this
question by exploring the gene network that guides limb development in
mammals.
They found that during early development, when limbs are first forming,
gene activity in this network varies little; later, when detailed limb structure
is beginning to emerge, the network changes in structure, and gene activity
varies more widely. This pattern may make it easier for evolution to tweak,
rather than remodel, limb structure.
"When we look at the evolutionary record of animals, we find that there are
some forms that have evolved repeatedly, and some that have never
evolved," Sears said. "I want to know the role that development has in
generating these patterns."
Sears, an associate professor of animal biology, and Rapti, an associate
professor of mathematics, led the study, which was published in PLOS
Genetics. Sears is a member of the Carl R. Woese Institute for Genomic
Biology (IGB).
Many genes encode proteins that influence or regulate each other's activity.
These functional connections, and the genes that participate in them, can
be imagined as the threads and intersections of a spider's web. Some of
these interactions are stronger or weaker than others, and in the network
they comprise, some genes have more connections than others.
Computational models can mathematically describe this network structure.

Sears, Rapti, and colleagues wanted to know what happens when a chance
event, like a mutation, changes the activity of one gene. How much will the
whole network, and the resulting course of development, be affected?
Using published data on developmental gene interactions, they created a
model of how genes interact during early and late stages of limb
development. The model allowed them to pluck at the spider web of genes,
and watch how much the rest of the web is disrupted.
The researchers found that in early limb development, the network resists
the spread of change; even when one gene's activity is altered, the network
as a whole continues to function almost as usual. Later in limb development,
however, the architecture of the network is different, and a change in one
gene's activity has a more widespread impact.
In addition, an empirical investigation of gene activity during limb develop in
four different mammals--mice, bats, opossums, and pigs--showed that
activity of developmental genes differs more in late development than in
early development. This is true when comparing individuals of the same
species, and also when comparing gene activity across species.
Together, these theoretical and empirical findings supported Sears'
strongest initial hypothesis, that genomic mechanisms restrict the degree to
which early limb development can vary in mammals. From an evolutionary
perspective, this makes sense.
"If early development is disrupted, limb development will be severely
disrupted, and it is very unlikely that the resulting limb structure will be
selectively advantageous, said Sears. "Later development, which doesn't
have as many downstream impacts, might be expected to be more free to
vary because the consequences of that variation would be less dire."

Story Source:
The above post is reprinted from materials provided by Carl R. Woese
Institute for Genomic Biology, University of Illinois at UrbanaChampaign. The original item was written by Claudia Lutz. Note: Materials
may be edited for content and length.