text:
Levothyroxine/Oral Calcium Acetate; Carbonate; Citrate Interactions
This information is generalized and not intended as specific medical advice. Consult your healthcare professional before taking or discontinuing any drug or commencing any course of treatment.
Medical warning:
Moderate. These medicines may cause some risk when taken together. Contact your healthcare professional (e.g. doctor or pharmacist) for more information.
How the interaction occurs:
Calcium acetate, calcium carbonate, and calcium citrate decreases the amount of levothyroxine your body absorbs.
What might happen:
Your levothyroxine may not work as well. Signs and symptoms to look for include: feeling tired, dry skin and brittle nails, not being able to stand the cold, constipation, and depression.
What you should do about this interaction:
Let your healthcare professionals (e.g. doctor or pharmacist) know that you are taking these medicines together. Your doctor may want to check you thyroid function test to see if you are getting the right amount of levothyroxine. Your doctor may want you to take your levothyroxine and calcium at different times of the day.Your healthcare professionals may already be aware of this interaction and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.
- 1.Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid 2011 May;21(5):483-6.
- 2.Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000 Jun 7;283(21):2822-5.
- 3.Schneyer CR. Calcium carbonate and reduction of levothyroxine efficacy. JAMA 1998 Mar 11;279(10):750.
- 4.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM, Middleton B, Bates DW. Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Inform Assoc 2012 Sep 25.
- 5.Phoslyra (calcium acetate) US prescribing information. Fresenius Medical Care North America April, 2015.


text:
Recombination in RNA viruses,Ruzic,Kovac
Discussion of all aspects of cellular structure, physiology and communication.
Moderator: BioTeam
3 posts • Page 1 of 1
Recombination in RNA viruses,Ruzic,Kovac
Zavod za biokemiju i molekularnu biologiju
A.Kovačića 1, 10 000 Zagreb
Project: Maria – Helena Ružić, Ana Kovačević
Aspects of recombination in RNA viruses
RNA viruses deserve their reputation as Nature's swiftest evolvers. Their high rates of mutation and replication allow them to move through sequence space at a pace that often makes their DNA-based hosts ' evolution look
glacial by comparison.
Over the last two decades it has become increasingly clear that many RNA viruses add the capacity to exchange genetic material with one another, and to acquire
genes from their hosts, to this evolutionary repertoire. So, in addition to producing prodigious amounts of the raw material of evolution (mutations), these viruses also possess mechanisms that, in principle, allow them both to purge their
genomes of accumulated deleterious changes (Muller, 1964) and to create or spread bene locial combinations of mutations in an efficient manner (Fisher, 1930;Muller, 1932), two processes which are not available to clonal organisms. Two distinct but not mutually exclusive types of genetic exchange operate in RNA viruses. The first, reassortment,
occurs only in multipartite viruses and involves swapping one
or more of the discrete RNA molecules that make up the segmented viral genome. Antigenic shift in in¯uenza A virus is an example of this sort of genetic exchange and serves as a good illustration of the potential evolutionary significance of
such events.
A second process, recombination, can occur ineither segmented or unsegmented viruses when `donor'nucleotide sequence is introduced into a single, contiguous
` acceptor ' RNA molecule to produce a new RNA containing
genetic information from more than one source. In this paper
we focus on this type of genetic exchange. First, we brie¯y
review current knowledge of RNA virus recombination and
describe new methods for detecting its occurrence using gene
sequence data. We then discuss some of the evolutionary
implications of virus recombination and some of the constraints
that may shape the variety of RNA virus recombination.
Recombination in RNA viruses
In some cases of RNA virus recombination, the donor
sequence neatly replaces a homologous region of the acceptor
sequence leaving its structure unchanged. This has been
classified as `homologous recombination ' (Lai, 1992) since it
involves not just homologous parental RNAs, but also
crossovers at homologous sites. However, this is not always
the case ; hybrid sequences resulting from aberrant homologous
recombination (when similar viruses exchange sequence without
maintaining strict alignment) and nonhomologous recombination
(recombination between unrelated RNA sequences)
are also commonly observed (Lai, 1992).
Despite producing distinct kinds of hybrid RNAs, as well as
defective interfering (DI) RNAs (Lazzarini et al., 1981), the
different types of recombination appear to be variations on a
common theme. To date, almost all studies on the mechanisms
of recombination in RNA viruses have supported a copy±
choice model, originally proposed in the case of poliovirus
(Cooper et al., 1974) and now well studied in a number of
experimental systems (Duggal et al., 1997; Jarvis & Kirkegaard,
1992; Kirkegaard & Baltimore, 1986; Nagy & Bujarski, 1995,
1998; Nagy et al., 1998; Simon & Nagy, 1996; for a recent
review see Nagy & Simon, 1997). Under this model, hybrid
RNAs are formed when the viral RNA-dependent RNA
polymerase complex switches, mid-replication, from one RNA
molecule to another. This results in homologous recombination
if the replicase continues to copy the new strand precisely
where it left the old one, and aberrant or nonhomologous
recombination if it does not. This template-switching mechanism
is fundamentally different from the enzyme-driven
breakage±rejoining mechanism of homologous recombination
in DNA, not least because it invokes replication as a necessary
component of the process. Finally, Chetverin et al. (1997)
presented evidence for a splicing-like, transesterication mechanism
to explain the in vitro generation of recombinants
between RNAs associated with Qb bacteriophage ± a possible
exception to the copy±choice model of recombination in RNA
viruses. Whether such a mechanism operates in vivo remains to
be seen ; however, end-to-end joining is not regarded as a
likely mechanism for homologous recombination.
There is now a fairly rich literature documenting recombination
in RNA viruses. Many excellent recent reviews
have dealt comprehensively with aspects of recombination in
experimental and natural settings with respect to animal
viruses (Lai, 1992, 1996; Ball, 1997; Strauss & Strauss, 1997),
plant viruses (Lai, 1992; Simon & Bujarski, 1994; Roossinck,
1997; Aaziz & Tepfer, 1999) and bacteriophages (Mindich,
1996; Chetverin, 1997). Recently, reports describing homologous recombination in rotaviruses (Suzuki et al., 1998) and in hantaviruses (Sibold et al., 1999) have added doublestranded
and negative-sense RNA viruses, respectively, to the
long list of RNA viruses in which homologous recombination
has been detected. The emerging signi®cance of RNA virus
recombination is all the more fascinating given the fact that ±
until the comparatively recent publication by Cooper et al.
(1974) which showed that mutants of poliovirus could be
mapped by recombination analysis ± recombination was not
thought to be a property of RNA genomes.
New tools for detecting recombination in
The molecular revolution initiated by the development of
PCR has transformed the study of virus recombination.
Sequence analysis and phylogenetic techniques have in recent
years proven to be extremely effective methods for detecting
and characterizing recombination events among RNA viruses
both in nature (Gao et al., 1998; Hahn et al., 1988; Holmes et
al., 1999; Kusters et al., 1990; Revers et al., 1996; Sibold et al.,
1999; Suzuki et al., 1998; Worobey et al., 1999) and in the
laboratory (Banner&Lai, 1991; Greene&Allison, 1994; Kotier
et al., 1995; Mindich, 1996; Palasingam & Shaklee, 1992;
Weiss & Schlesinger, 1991). They offer a way not just to
recover information about recombination events that may
have occurred long ago or are exceedingly rare (Snijder et al.,
1991; Weaver et al., 1997), but also to probe the nest details
of the mechanism itself (Banner & Lai, 1991; Olsthoorn & van
Duin, 1996). They also provide a means to home in on the
precise location of putative crossover points and to test results
suggestive of recombination for statistical signicance.
Several methods for detecting recombination events and
locating breakpoints are graphical in nature, exploiting the fact
that many recombinant sequences are mosaics comprising
regions with quite different phylogenetic histories. One of
these, Split Decomposition analysis (Bandelt & Dress,
1992; Huson, 1998), presents con¯icting phylogenetic signal
in a single diagram. If no recombination has occurred in the
sequences tested, the splits-graph tends to resemble a
dichotomously branching phylogenetic tree, because this
adequately describes sequence relationships. However, in
datasets containing con¯icting signal due to the presence of
recombinant and hence `mosaic' sequences, the tree-like
pattern is often replaced by a more complicated `network' that
indicates a history of genetic exchange. It is worth noting that
conventional phylogenetics programs are constrained to
produce simple branching trees and can lead to serious
misinterpretation if sequence alignments are not carefully
examined for evidence of recombination prior to tree reconstruction.
Several other graphical applications, including ` bootscanning'
(Salminen et al., 1995), `PhylPro' (Weiller, 1998),
`TOPAL' (McGuire &Wright, 1998) and `DIVERT' (Gao et al.,
1998), use ` sliding windows' to detect discordant sequence
relationships suggestive of recombination. Bootscanning is an
aptly named phylogenetic approach that initially produces a
tree from a small window at one end of a sequence alignment
and assesses its robustness using bootstrapping. The window
is then incrementally shifted along the alignment and a new
bootstrap tree is produced for each resulting subset of the
alignment. Significant topological changes in the position of a
sequence in different windows indicate possible recombination.
PhylPro and TOPAL both slide a pair of adjacent windows
along the sequence alignment. Each of these methods employs
a different measure of phylogenetic signal, but in both the
phylogenetic information contained in one window is compared
to that in the neighbouring window. In the absence of
recombination all windows are expected to show similar
patterns. On the other hand, if recombination has occurred,
some adjacent windows are expected to contain con¯icting
signal and the difference between them should be greatest
when they straddle a recombination breakpoint. DIVERT, the
simplest of the sliding window graphical methods (and often
the most effective), outputs a graph of genetic distance
comparisons between a chosen sequence and comparison
sequences, which can show runs of sequence similarity and
dissimilarity suggestive of recombination. Diversity plots have
been used to great effect in the search for recombinant human
immunodeficiency virus and simian immunodeficiency virus
strains (Gao et al., 1998, 1999) and are ideally suited for
detection of RNA virus homologous recombination (Worobey
et al., 1999).
Many of these programs permit a simple qualitative
assessment of possible recombination breakpoints based on the
visual analysis of their output. However, for cases where
putative recombinants and reasonably close relatives of their
acceptor and donor sequences are available, more sophisticated
procedures exist for locating crossover points. Informative
Sites Analysis (Robertson et al., 1995), a parsimony-based
adaptation of the maximum test (Maynard Smith, 1992),
uses the distribution of polymorphic sites between a probable
recombinant and its putative ` parents ' to estimate recombination
junctions. The results can then be compared to
randomized distributions of polymorphic sites to assess their
signi®cance. A similar method, LARD (Holmes et al., 1999),
uses a maximum likelihood method to infer the optimal
breakpoints for a possible recombinant, then uses simulated
sequences to test the statistical significance of the results.
Some other methods attempt to quantify the amount of
recombination between a set of sequences, rather than
document specific recombination events, often using the
degree of linkage equilibrium. One way this can be done is
with the Index of Association. Using this statistical test, which
was designed to detect associations between alleles at different
loci, it is possible to measure the extent of linkage equilibrium
within populations (Maynard Smith et al., 1993). Another,
based on a direct phylogenetic analysis, is the Homoplasy Test
Here, the number ofhomoplasic (i.e. convergent and parallel) base changes in data
observed after construction of a maximum parsimony tree is
compared to that number expected by chance. Excessive
homoplasies are the fingerprint of recombination.
How clonal are viruses?
The impressive tally of recombinant ` hopeful monsters' ±
dramatically altered hybrid viruses that have passed the test of
natural selection and emerged as successful new viruses ±
attests to the power of recombination as an evolutionary force
in RNA viruses (Allison et al., 1989; Gibbs & Cooper,
1995; Herrewegh et al., 1998; Luytjes et al., 1988; Revers et al.,
1996; Ro$hm et al., 1996; Snijder et al., 1991; Suzuki et al.,
1998; Weaver et al., 1997). In some cases, evolutionary
evidence suggests that newly formed recombinant strains may
have initially exhibited decreased functionality, but subsequently
evolved to compensate for these effects. For
example, the Western equine encephalitis (WEE) complex
viruses are the product of a single recombination event that
occurred between Eastern equine encephalitis virus (EEEV) and
a Sindbis-like virus, probably within the last 2000 years
(Weaver et al., 1997). Sequence analysis of WEEV indicated
that, subsequent to the recombination event, its EEEV-like
capsid protein evolved to become more like a Sindbis-virus
capsid, possibly because it needs to interact with Sindbis-like
glycoproteins during virus budding (Hahn et al., 1988).
Conversely, in a sort of evolutionary compromise, almost all
the amino acid changes in the Sindbis-like glycoproteins have
been to residues that match those of EEEV. It is possible that
the new antigenic properties conferred by the Sindbis-like
glycoproteins of this predominantly EEEV-like hybrid were
sufficiently advantageous to off-set what appears to have been
a signi®cant mismatch between its recombinant structural
Whatever the circumstances of the survival and subsequent
diversi®cation of particular recombinants, it is now evident
that many pass through the narrow gates of natural selection
and contribute to the diversity seen in RNA viruses. The
production of new strains having genomes comprising regions
with different histories has important implications for the way
we think about virus evolution. For one, it means that there is
no single phylogenetic tree that can describe the evolutionary
relationships between viruses ; the recombinative nature of
viruses simply precludes the possibility of a ` true ' phylogenetic
taxonomy. Far from being an incidental process best ignored
when considering virus relationships and history, recombination
may have played a crucial role in generating many of
the taxonomic groups we recognize (Koonin & Dolja, 1993) ±
today's hopeful monster giving rise to tomorrow's genus or
family of viruses. Some studies of recombination have even led
to recommendations that higher-than-family taxonomic units
should be avoided altogether (Goldbach, 1992).
The inappropriateness of tree-like representations of evolutionary
relatedness may also apply within some virus species.
In principle, the possibility of homologous recombination
between similar strains means that the population structure in
viruses could range from completely clonal, if no recombination
has taken place, to panmictic, if recombination has
been common enough to effectively randomize loci. Although
signi®cant progress has been made studying population
structure in other organisms (Maynard Smith et al., 1993),
similar work remains to be done for RNA viruses.
Many taxonomic groupings of viruses ± for example both
the Togaviridae and the Coronaviridae ± include members that,
while clearly sharing homologous genes, differ in the order in
which these genes are organized along the genome, another
indication that recombination has been important in their
evolutionary history. Other cases ± exemplied by the haemagglutinin-
esterase gene known to be present in at least three
virus genera (Snijder et al., 1991) ± show recombination as the
engine driving modular evolution, whereby functional modules
from different sources are brought together to create new
viruses. The discovery of recombination in an increasing
number of viruses, in addition to presenting phylogenetic and
taxonomic difficulties, challenges the desirability of using short
sequence regions as markers for entire virus genomes (for
instance in molecular epidemiology studies) since they may
not accurately re¯ect true genetic or antigenic characteristics.
Evolutionary advantages of recombination
Theoretical explanations for the evolution of recombination
and hence some aspects of sexual reproduction tend to ®t into
one of two standard classes : (1) that it enables the creation and
spread of advantageous traits, and (2) that it permits the
removal of deleterious genes (for a review see Hurst & Peck,
1996). This second explanation is often linked to the notion of
`Muller's ratchet ' ± the random loss of those individuals in a
population having the fewest deleterious alleles (Muller, 1964).
Muller's ratchet predicts the gradual build-up of deleterious
alleles, asexual population. Experiments with RNA
viruses, one of only a handful of organisms in which this
hypothesis has actually been put to the test, have generally
supported its operation and shown decreased ®tness for
populations in which it occurs (Chao et al., 1992). Experimental
evidence (Chao et al., 1997) also shows that sex (in this case
reassortment) can reduce the mutational load in a population
and so help it escape from accumulated deleterious effects.
Although such direct experimental evidence has yet to
demonstrate a similar advantage for recombination, in principle
it too could serve to efficiently remove disadvantageous alleles
from a population by combining mutation-free parts of
different genomes. Indeed, suggestions have been made that
reassortment in segmented RNA viruses and recombination in
monopartite RNA viruses represent alternative evolutionary
strategies for genetic exchange in this group (Chao et al., 1992).
While this idea is fascinating, it is interesting to note that
reassortment and recombination are not mutually exclusive
and that several segmented viruses also experience recombination,
sometimes frequently. These include the bacteriophage
u6 (Mindich et al., 1992), rotaviruses (Suzuki et al., 1998),
in¯uenza A virus (Khatchikian et al., 1989), hantaviruses (Sibold
et al., 1999), ¯ock house virus (Li & Ball, 1993) and many plant
viruses (Bujarski & Kaesberg, 1986; Greene & Allison, 1994;
Robinson, 1994; Rott et al., 1991). As if to prove this point,
Masuta et al. (1998) recently reported an interspeci®c hybrid of
two cucomoviruses that arose by both reassortment and
Nonetheless, a great deal of evidence indicates that some
RNA viruses do benefit from the genome-purging effects of
recombination. A multitude of experimental studies have
shown that weak or even non-replicative mutant strains can
recombine to form viable, highly viruses. Examples include
the functional chimeras formed between nonreplicating RNAs
and DI RNAs of tombusviruses (White & Morris, 1994),
infectious recombinants produced by different combinations
of mutationally altered Sindbis virus RNAs (Raju et al.,
1995; Weiss & Schlesinger, 1991) and wild-type revertant
recombinants of Qb phage mutants (Palasingam & Shaklee,
1992) and of bromovirus mutants (Rao & Hall, 1993).
Plant viruses have also been observed to repair their
genomes by recombining with host transgene transcripts
(Borja et al., 1999; Gal-On et al., 1998; Greene & Allison,
1994; Rubio et al., 1999). Similarly, in one experiment with a
deletion mutant of mouse hepatitis virus (MHV) transfected
with a synthetic RNA that contained the deleted region
(Koetzner et al., 1992), and another with an in¯uenza A virus
mutant with a damaged neuraminidase gene (Bergmann et al.,
1992), recombination successfully repaired defective genes.
Studies of recombination in bacteriophages, too, indicate a
repair function for recombination (Mindich et al., 1994). RNA
recombination even appears to provide a telomerase-like
function by repairing the 3« ends of satellite RNAs of both
turnip crinkle virus (Burgyan & Garcõ!a-Arenal, 1998) and
cucumber mosaic virus (Simon & Nagy, 1996).
Unintentional ` natural experiments' with some viruses
point to the same conclusion. The frequent recovery of
recombinant isolates of poliovirus (Georgescu et al., 1994; Kew
& Nottay, 1984) and infectious bronchitis virus (Jia et al.,
1995; Kusters et al., 1990; Wang et al., 1994) that result from
recombination involving vaccine strains shows that recombination
has the potential to produce ` escape mutants' in
nature as well as in experiments. Recently, recombination has
also been detected in other RNA viruses for which multivalent
vaccines are in use or in trials (Holmes et al., 1999; Suzuki et al.,
1998; Worobey et al., 1999). We think the potential for
recombination to produce new pathogenic hybrid strains, and
the possible impact of such escape recombination, needs to be
carefully considered whenever multivalent live-attenuated
vaccines are used to control RNA viruses. Assumptions that
recombination either does not happen or is unimportant in
RNA viruses have a history of being proved wrong.
In addition to the evidence favouring a role for genetic
exchange in eliminating deleterious alleles, many recombinant
RNA virus strains provide ample indication that recombination
can generate beneficial new variation. In some viruses this new
variation is achieved by borrowing genetic material from their
hosts. One intriguing example of this is bovine viral diarrhoea
virus (BVDV), a pestivirus that recombines with host cellular
protein-coding RNA. As a result of virus±host recombinations,
cytopathogenic BVDVs can develop from non-cytopathogenic
ones and cause a lethal syndrome, mucosal disease, in the hosts
(Meyers et al., 1989). In¯uenza A virus has also been observed
to recombine with cellular RNA, resulting in increased
pathogenicity for the hybrid viruses (Khatchikian et al., 1989).
Recombination between virus and host genetic material
evidently occurs in plant viruses as well, as illustrated by a
luteovirus isolate with 5«-terminal sequence derived from a
chloroplast exon (Mayo & Jolly, 1991) and closteroviruses
which have acquired host cellular protein-coding genes (Dolja
et al., 1994) which are nonessential for replication and virion
production (Peremyslov et al., 1998).
A link between recombination and increased pathogenicity
has also been revealed in cases that do not involve recombination
with host genes. Template jumping during
replication in viruses infecting cats has produced, on multiple
occasions, the pathogenic strains known as feline infectious
peritonitis viruses (FIPVs) by altering asymptomatic feline
enteric coronaviruses, differing from them only by deletions of
around 100 bp in predictable locations (Vennema et al., 1998).
Another coronavirus, feline coronavirus (FCoV) type II,
appears to be a homologous (or aberrant homologous)
recombinant of FCoV type I and canine coronavirus
(Herrewegh et al., 1995). Like FIPVs, FCoV type II viruses may
have arisen on different occasions from separate recombination
events (Motokawa et al., 1996).
Experimental studies provide further signs of the ability of
recombination to generate useful, new variation. In one
particularly striking display of this, MS2 phage mutants lacking
the sequence for important stem-and-loop secondary structures
repeatedly reconstructed them via nonhomologous recombination
(Olsthoorn & van Duin, 1996).
Constraints on recombination
Recombination clearly plays a significant role in the
evolution of RNA viruses by generating genetic variation, by
reducing mutational load, and by producing new viruses. We
expect that with current advances in sequencing and sequence
analysis many more examples of hybrid viruses, produced by
recombination between different strains, will soon be found.
However, it is clearly not the case that all RNA viruses are
equally prone to recombination. It has still not been detected in
several viruses despite strenuous searches (e.g. Bilsel et al.,
1990), although some ± not otherwise known to recombine ±
nevertheless produce DI RNAs. Amongst those known to
produce hybrids, the frequency of recombinants detected in
natural or experimental studies varies markedly. Given the
potential advantages of recombination, why is there apparently
so much variation between viruses in its occurrence ? While it
is too soon to provide a de®nitive answer to this crucial
question, it is possible to dissect the process that gives rise to
recombinants and to consider the constraints that could act at
each stage to inhibit it. A simple model of recombination
between different RNA viruses, with possible constraints, is
presented in Fig. 1.
In a sense, recombinogenic viruses are all alike in that they
successfully pass through each stage outlined in the model.
Every non-recombining virus, on the other hand, is different in
its own way since constraints that block recombination could
act by breaking any link in the chain and could involve not just
viral genetic factors, but host and ecological factors particular
to that virus. The first prerequisite for successful recombination
(Fig. 1) is that an individual host must be infected by different
virus strains. [This is not quite true, of course, since (1)
recombination sometimes involves host RNA, (2) recombination
could occur between viruses that have diverged
within a clonally infected individual, and (3) evolutionarily
invisible recombination could occur between identical RNA
molecules.] Host coinfection might never occur with some
viruses simply because their divergent forms do not usually
overlap in space and time. Multivalent live-attenuated vaccines
CFDJ can be seen as potential risks in this context since they could
effectively release some viruses from this constraint. Host
factors could act at this stage too if, for instance, an immune
response reduces the window for simultaneous infection by
quickly clearing a virus, or prevents superinfection altogether
by blocking secondary infections.
Having successfully coinfected a single host, divergent
viruses must next coinfect a single cell if recombination is to
proceed. This step could be blocked by host factors, either by
an immune response that keeps virus numbers low enough to
prevent multiple infection of any individual cell, or by host cell
genetic factors that block entry of more than one virus particle
into a cell (Danis et al., 1993). Viral factors, interestingly, might
also enforce significant constraints at this stage of the model.
Recent evidence demonstrates that intracellular competition
can be costly to viruses that infect the same host cell (Turner
&Chao, 1998). Those that can keep cells to themselves
by limiting or preventing coinfection should be selectively
favoured, and many have evolved mechanisms to do just this
(Simon et al., 1990; Singh et al., 1997; Turner et al., 1999). One
of these, vesicular stomatitis virus (VSV), is an RNA virus in
which recombination between different strains has not been
detected. Might superinfection exclusion be a constraint on
recombination in VSV? Another, the segmented bacteriophage
u6, seems to limit excessive superinfection but not to the
extreme of one-virus-per-cell that would preclude genetic
exchange. Instead, it appears to have evolved an optimal
coinfection limit of two to three viruses per cell, presumably to
balance the costs of intracellular competition with the bene®ts
of reassortment (Turner et al., 1999). Since the advantage (and
cost) of recombination in any particular virus will be mediated
by such factors as the selective pressure for novel variation, the
importance of interactions between different parts of the
genome, as well as the virus mutation rate and population size,
we should expect different optima (and therefore different
degrees of constraint) in different cases.
If divergent viruses manage to infect the same cell, the next
step is simply for one of them to replicate in the presence of the
RNA of the other. This is not necessarily inevitable even in
coinfected cells. The replication of the u6 RNAs, for example,
takes place within a procapsid and it is thought that the entry
of two different RNA molecules of the same genomic segment
into this sequestered environment is impossible or at least very
rare (Mindich et al., 1992). This could explain the lack of
homologous recombination in this phage. Thus the vagaries of
RNA replication in certain viruses could impose physical
constraints on the production of hybrids.
Template switching by the viral replicase, the mechanism
whereby recombinant RNA molecules are actually created,
may also be limited by physical constraints. The negativestrand RNA viruses,
for example, whose genomes are packaged
into ribonucleoprotein structures by association
with N protein, may be less permissive than other RNA viruses
to copy±choice recombination. And perhaps the most important
physical constraint on template switching ± particularly
with respect to homologous recombination ± is simply
the extent of sequence dissimilarity between potentially
recombining genomes. Finally, genetic variation in the susceptibility
of the viral replicase to jumping (Bujarski & Nagy,
1996) no doubt plays a central role in determining how often
and by what mechanism particular viruses recombine.
Recombination occurs when these ®rst four steps are
ful®lled. Whether incipient recombinants persist, however,
depends on the fifth and final step, the selective separation of
the wheat from the chaff among hybrids. Although there is
strong evidence that genetic exchange can offer advantages in
some circumstances, random recombination no doubt destroys
more good alleles than it creates. PCR studies which have
made possible the characterization of the initial products of
recombination ± those present prior to removal by selection
(Banner & Lai, 1991; Desport et al., 1998; Jarvis & Kirkegaard,
1992) ± have produced important insights. Banner and Lai's
study of coronaviruses (1991), for example, showed that the
initial recombination events in their MHV system were almost
entirely randomly distributed along the sequence investigated.
It was only after passage through cell culture, with the
opportunity for selection to remove less variants, that
crossover sites became ` localized ' to just a small area of the
region examined. With enough passages, the recombinants
disappeared altogether. These results indicated that `recombination
hotspots ' can actually be the result of natural selection
on a pool of random recombination crossover junctions, as
opposed to elevated recombination rates in particular regions.
Crucially, they also suggested that recombination may be
more common than often assumed, but may go undetected
because of the action of strong purifying selection which will
remove new, deleterious combinations of mutations. In light of
these studies it is clear that what is meant by ` recombination
frequency' ± a term usually used without specified units ±
depends critically on whether we are assessing recombination
events before or after selection has acted. A virus which often
produces hybrid RNAs under laboratory conditions may very
rarely ± or even never ± be found to recombine in nature. This
difference is analogous to the important distinction between
the rate of mutation and the rate of substitution.
Negative selection against non-functional hybrids or those
with decreased fitness may impose the strongest constraints of
all on the appearance of recombinants. In viruses for which the
evolutionary costs of recombination outweigh the benefi ts,
though they may be mechanistically capable of genetic
exchange, strong selection will guarantee the elimination of
hybrid genomes.
Determining the constraints that operate on recombination
offers a promising path to a fuller understanding of its
importance in the evolution of RNA viruses. However, outlines
CFEA of the big picture are already clearly visible. It seems certain
that genetic exchange plays a key role in several virus groups
and that it has shaped a good deal of the diversity ± both
ancient and recent ± that exists in them. Thus, evolutionary
knowledge about recombination impacts on many aspects of
the study of RNA viruses, from the broadest investigations of
virus taxonomy, to the finest details of molecular epidemiology
and vaccine design. A ¯ood of viral gene sequence data and the
availability of new and powerful phylogenetic methods is
making the detection and characterization of recombination
ever easier, and the list of viruses showing recombination
continues to grow. The evidence for recombination, not only
between closely related viruses but also among distantly
related viruses, positive-sense and negative-sense viruses, DI
RNAs and viruses, satellite RNAs and viruses, and even with
host RNAs, suggests that almost any genetic material can be
grist for the polymerase's mill. Of all the tricks up the viral
evolutionary sleeve, surely recombination is one of the most
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Generation of DNA nucleotides
Discussion of all aspects of biological molecules, biochemical processes and laboratory procedures in the field.
Moderator: BioTeam
Generation of DNA nucleotides
My question relates to the base molecules (Adenine, Cytosine, Guanine, Thymine) in DNA.
The chromosomes are replicated in Synthesis part of cell cycle Interphase.
About 204 billion atoms are required to complement the two sides of the human genome.
There is much information about how certain things work in the cell (eg. how proteins are generated). But I'm curious about the chemical level:
How and where are the base molecules generated?
Is there a special protein or enzyme that combines the needed atoms into each molecule?
How does the polymerase obtain the needed molecules to generate the new strands?
(Does it send a message to a protein that gets the requested molecule. Or does polymerase utilize supply tanks with spigots that inject the proper molecule?)
Does the cell know in advance that there are sufficient materials available?
Any comments welcome,
Re: Generation of DNA nucleotides
From this article on Nucleotides in Wikipedia, it will tell you that nucleotides can be salvaged from other complexes, or made de novo (from scratch):
Re: Generation of DNA nucleotides
Thanks for that web page.
Method 1. "salvaged from other complexes"
In this page, it states:
"Salvage pathways are used to recover bases and nucleosides that are formed during degradation of RNA and DNA."
Question: Since DNA replication is being done in the cell cycle immediately following formation of the cell, how could there be any degradation of DNA or RNA?
Is it possible this method is used (only) later in cell life, after may genes have been expressed?
Method 2. "de novo"
I failed to mention that I'm not a chemist major; much of the web page is too technical for readers like me.
I have written computer programs; I'm accustomed to look for objects that have properties and methods (actions).
So what are the material objects needed to start the process?
Molecule x and enzyme y
What is the first method (action)? What does enzyme y do to molecule x? Perhaps the web page calls this Reaction 1?
There are many web pages that provide great drawings of transcription and translation to explain those things clearly.
I'm looking for the steps needed to generate one molecule of A, C, G, or T, in simple words.
Have you seen this kind of information?
Then, one of the other questions was: How is the newly formed molecule attracted to move when and where it is needed?
Re: Generation of DNA nucleotides
Wow, so many questions. See if I can tackle a few:
DNA replication immediately following formation of the cell is for cells that are only for reproducing themselves (such as stem cells and immune cells) when it is called for in the organism. If the cell has any function in the organism, it will only proceed onto DNA replication when it is needed to be replicated. Most cells have a function to do and perform it, and may not go on to replicating itself. Sometimes the cells just wear out or parts wear out, and the cell proceeds to salvage the parts.
Proteins in the cell do pretty much everything in the cell. If the protein is not an enzyme catalyzing a reaction to go a certain way (due to environmental conditions and the needs of the cell), it is providing transport or storage for the molecules. Nucleotides are made and transported to the nucleus where they are confined to this part of the cell and are used by the proteins when duplicating the DNA during the S phase.
Google 'Biosynthesis of Nucleotides'. It is really a complicated biochemical reaction with many steps. And yes, each step has a specific enzyme that takes a basic starting molecule (like the amino acid aspartate) and modifies it in steps, till it is a nucleotide (a nitrogenous base attached to a deoxyribose sugar, which is then phosphorylated three times). It may be too technical for you. You could possibly find it completely explained for you in a biochemistry book that would show the biochemicals and what the enzymes catalyze in each of the reaction steps. And each nucleotide is unique in their biosynthesis, so A, T, G, and C are different.
Re: Generation of DNA nucleotides
1. Are you saying that DNA replication (S phase) is done only if more cells are needed? That makes sense.
The new cell enters phase G1, then G0 in which the cell does its main job.
If more of this cell are needed, it goes into Phase S, G2 and Mitosis.
This page mentions four resources needed, under "DNA Replication"
Phase S and G2 seem to be needed only before Mitosis.
2. Until I understand more chemistry, I'm looking for an overview explanation.
"After Helicase splits the DNA, Polymerase adds about 6 billion A, T, G, or C molecules, resulting in two identical DNA strands."
Is that correct?
In a computer program, subroutines would be needed that repeat the steps needed for each nucleotide, such as:
>Read the nt. on original strand (eg. C)
>Determine its complement (eg. G)
>Obtain a new molecule of the complement (eg. G)
>Attach new molecule to new strand
3. To do DNA replication efficiently, I'm wondering if (my imagination):
There are multiple copies of Polymerase, so multiple chromosomes could be processed at the same time.
Perhaps microtubules are utilized in some way to organize the "production area".
There are "bucket brigades" of proteins carrying each type of nt. into one or more temporary dispensers connected to the Polymerase.
Polymerase causes dispenser to release a molecule of needed nt.
This would be similar to the spider releasing various types of web string material.
Have you seen any pictures of stained components to shed light on this system (like those that illustrate Mitosis)?
4. Comments about the chemical formulas for nucleotide metabolism (involving things like IMP, AMP, and GMP)
http://themedicalbiochemistrypage.org/n ... m.html#top
It's amazing to me that they discover what enzymes do in each step; this has taken much observation and testing.
Question: Is there only one occurrence of steps processed for a given amount of source material?
Or is it possible that multiple "strings" (possibly same or different nt. molecule) are being processed at different stages within the cytoplasm? This would be like various experiments being conducted at the same time in a lab or classroom.
5. I noticed this interesting statement: "Purine Nucleotide Biosynthesis, The major site of purine synthesis is in the liver."
http://themedicalbiochemistrypage.org/n ... olism.html
What products are produced in the liver; how are they transported to the cells?
Are the Final stages to produce each type of molecule always performed in the cell?
That's all for now.
Appreciate any comments on whatever.
2. well, yes, basically, that's correct
3. in bacteria, there is only one replication start, but probably there are more polymerases in the cell.
In human, there are multiple replication starts on each chromosome, which are fired consequently (several of them at a time).
4. I'm not sure, if I understand your question correctly, but there are definitelly several copies of each enzyme/protein/molecule in each cell.
5. livers are said to be the factory of the body, there is produced almost everything, what is needed in the body
Cis or trans? That's what matters.
Re: Generation of DNA nucleotides
4. Evidently many steps are needed to make the nucleotide molecules.
Note: When I first asked this question, I thought the nt. molecules were made in the cytoplasm (see next item).
I'm thinking 1.5 billion molecules of each nt. are needed. When the nt. molecules are assembled into DNA they're handled individually. But it doesn't seem plausible that they're generated individually...
So I thought there must be ways of multiple concurrent production.
I envisioned many students with there own containers doing various steps.
Does this occur in the cytoplasm? How would the reactions be "protected" from each other?
5. It's reasonable that large volumes of stuff be made in the liver.
And obviously there are all kinds of reactions happening there!
But why can't I find web pages that clearly say this? I'm looking for articles that state:
a) Liver makes what products of interest to this subject.
b) They are transported to cells how (eg. red blood cells carry oxygen).
c) Cells receive products when ready to do replication.
d) Cells do something to the products if the products from liver are not what's needed by the polymerase to do replication.
There are many web pages that clearly describe the mechanics of gene expression (transcription, mRNA, translation). Pictures with stained components help explain mitosis. Where are there similar explanations of DNA replication and nucleotide generation?
4. First of all, there are needed 3 billions of nts in EACH cell
Second of all, as kolean wrote, I think, the cells in our body do not divide usually, so you do not have to generate 3 billion × 10^14 nucleotides
d) if the cell needs 3 BILLIONS of nucleotides. Do you think, it really matter if it gets e.g. one guanine more or less?
I recommend to look for books Biochemistry by Voet & Voet or by Stryer, Tymoczko and someone... there you can find many pictures and probably also CDs with some animations
Cis or trans? That's what matters.
Re: Generation of DNA nucleotides
Yes there are many cells in my body that are NOT in the mood to divide today.
However, there are many times in the history of an organism when cells are prone to divide, correct?
And evidently, certain cells of the human do continue to divide:
"Other types of cells, such as epithelial cells, continue to divide throughout an organism's life and rarely enter G0."
Under heading "In relation to the cell cycle" at http://en.wikipedia.org/wiki/G0_phase
Obviously my question relates only to those cells that DO decide to activate Phase "Synthesis" in preparation for Mitosis.
I was thinking of the requirements of EACH cell that divides.
"two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair"
"The (human genome) is estimated to be about 3 billion base pairs long"
Doesn't that mean 6 billion nucleotides in the DNA are required for EACH dividing cell?
That comes to about 1.5 billion of each nt (A, T, C, G).
Am I looking at this incorrectly?
The article you mention
does not include the terms DNA, nucleotide, or purine.
I'm not sure how it helps at all.
A linked article mentions several proteins provided by the liver, but I don't see any devoted to exporting nt stuff.
http://en.wikipedia.org/wiki/Proteins_p ... _the_liver
I looked for book "Biochemistry" by Voet & Voet. Not in local libraries, including the Community College.
It is for sale online, so I'll need to start saving money for that.
Does anyone know if that book explains clearly in one place how:
a. the liver produces either nt molecules or things later used for nt construction
b. how those things are transported from liver to cells
c. what (if anything) the cell does to those things to enable DNA replication
There is a place for technical jargon; there is also a place for explanation in common language.
For example when writing computer programs, instructions are written in code structures of various languages (eg. Visual Basic).
It's considered a good professional thing for the programmer to insert comments WHY certain code was utilized.
The comments do not affect how the program executes, but are helpful to anyone reading the program to understand what's going on.
I'm just trying to understand "what's going on" to generate nucleotides for replication.
Thanks JackBean, for your help in this mystery.
Wanted to add that I think the liver is for the salvage pathway, or the primary processing of ingested DNA/RNA. In your first link, the article said that all nt synthesis starts with PRPP that can be made from ingested nts.
You also can not 'see' nucleotides being processed by staining slides. The chromosomes that you can see during mitosis is when the linear chromosomes are all condensed into a thick rope, and the stain shows up nicely on slides. The other visual of the 'beads-on-a-string' DNA is thru the use of the electron microscope. Crystallography and looking at the sequence of the protein is how its structure is proposed.
This is a cool animation that I found last year:
http://www.hhmi.org/biointeractive/dna/ ... n_vo2.html
I can also see that the amount of nucleotides is mind bending for you. If you think about all the cells you ingest everyday, you can see why there would even be a surplus of nts in the fluid outside of the cells. In fact you can even get a metabolic disease from the processing of purine metabolism called Gout.
from the Wikipedia on Gout . . . .
Uric acid is a product of purine metabolism, and in humans is normally excreted in the urine. Purines are generated by the body via breakdown of cells in normal cellular turnover, and also are ingested as part of a normal diet. The kidneys are responsible for approximately two-thirds of uric acid excretion, with the liver responsible for the rest.
You also have to take into account that the nitrogenous bases that make up the nts, are also used for alot of metabolic pathways (especially ATP - the energy currency of the body/organism, and it can be converted into other NTPs (nucleotide tri phosphates). There is alot going on in a system that has many checks and balances to keep it at homeostasis, with many functions to perform.
Well, you already have one strain of DNA and replicates only the second one, so divide your number by 2
Anyway, read, what kolean wrote. Also notice, that billion molecules is only 10^-15 mole, that is really, really, really just a little Notice, that in EACH living cell is every minute produced RNA of at least several thousands if not millions of nts
5. that should just show, that livers are really the factory of the body
Well, you do not have any library around? You don't have to buy Voet just because of one problem
Unfortunatelly, the nature did not provide any comments and that's why we study all these things
Asking why in science is a little problematic. You may try to answer, maybe your answer may fit the reality a little, if you're happy, but may never be sure, what is really reason and what consequence
Cis or trans? That's what matters.
You said "Well, you already have one strain of DNA and replicates only the second one, so divide your number by 2"
Could you please clarify that?
In the newly-formed daughter cell from Mitosis, what is in the DNA?
One double helix strand of DNA.
3 billion base pairs in human genome, each pair having two nucleotide molecules.
That makes 6 billion nucleotides, give or take a guanine.
Is that correct?
The nucleotides can be A, T, C, or G.
Assuming random assignments, about 1.5 billion of each.
Note: The A count equals T count, and C count equals G count.
(A+T) is probably different than (C+G).
But my focus is not in exact accounting.
(Rumor has it that there is some "junk DNA" on chromosome 22 that has final subtotals of each nt type.)
To replicate the human DNA, how many "new" nucleotides are needed?
(This is part of the job's "bill of materials".)
What number do I divide by 2?
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On July 21, President Obama signed an executive order aimed at protecting LGBT (lesbian, gay, bisexual and transgender) individuals from discrimination in the workplace. The order applies to federal employers and contractors, but employers that receive federal funding are taking a close look at the order to determine if it applies to them.
This order, explains Denise M. Visconti, office managing shareholder at Littler Mendelson P.C., solidifies trends that have been evident in the courts. "Case law is moving in the direction of greater protection under Title VII," she says, "extending federal law to cover discrimination of LGBT."
She notes that there have been different interpretations of the law, covering, for example, gender stereotyping. If a man is not acting like a "typical male" should act, or a woman is acting in a more "traditionally masculine" fashion, courts in most circuits are extending Title VII to cover matters of discrimination related to that form of stereotyping.
The executive order, says Visconti, is crystal clear. "Federal employers and contractors are prohibited from harassing employees that are part of the LGBT community, and discrimination based on gender identity or expression is explicitly prohibited," she explains.
Vault releases its 2015 ranking of best law firms for diversity
JP Morgan Chase employee survey question on LGBT alliance ruffles legal community's feathers
Of course, in many cases, companies have already started implementing policies and procedures designed to protect members of the LGBT community. This order, says Visconti, could spur companies to take a step back and see what they have been doing and what they should be doing. "Employers have said that they will follow state law and also extend protection to groups beyond what state law requires. Employers would be advised to take a look at their policies about equal employment opportunities or non-discrimination," she says. Employers should take a look at these codes of conduct and see if they include sexual identity, gender orientation and expression.
The movement toward diversity is, of course, driven at least in part by business priorities. "Employers understand and believe that a diverse workforce – whatever that means – is beneficial and cost-effective," Visconti says.
Limiting a candidate pool by mistreating individuals is bad for business, and diversity allows for a richer and deeper discussion, so there is a business case for diversity in all forms. This executive order, then, merely reinforces a trend in business, as companies look to diversify and update their policies and expectations to widen the scope of that diversity. In order to enact these policies, companies must implement proper training in order to address the widening scope of diversity.
Looking into her crystal ball, Visconti notes that it remains to be seen if there is potential backlash against this executive order. Prior to the issuance of the order, there was a series of requests of the President to add a religious exemption to the order, though it was unclear what that exemption would look like. And, whether or not companies will challenge the order, along the lines of the arguments brought by Burwell v. HobbyLobby, it is unclear how courts would rule about these federal requirements in regard to religious exemptions.


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Cancer = Mutation: Stopping Mutation Would Cure Cancer?
For discussing the functions of different structures of all organisms.
Moderator: BioTeam
8 posts • Page 1 of 1
Cancer = Mutation: Stopping Mutation Would Cure Cancer?
The other day I was feeling especially down about myself, because I want to help the world but I don't know how. Well, I mentioned cancer in a scientific debate with a friend, and I thought: Maybe I should help find the cure for cancer. Well, I looked around, and it seems that cancer is caused by mutation, when DNA doesn't know how to stop growing, or something along those lines. Well, what are some ways people stop mutation in the body? There may be a way to stop cancer(cutting it out) But not a way to prevent cancer, thoroughly. I know this may be insane to bring up "curing cancer", but someone has to do it. Are there chemicals that can stop mutation without hurting more than a specified area? I don't fully understand mutation, as well. So if you could give me some understandable links, that would be great.
It's not an easy thing to accomplish. Cells have a complex system to repair mutations, and cancer can be a problem with that or just a mutation rate that exceeds the system's abilities. Often cancer cells are "broken," cells that should just kill themselves but THAT system isn't functioning, and mutations accumulate in the cell line.
I suspect that if you did a literature search, you would find that many researchers have taken an approach similar to what you're suggesting. Who knows, you might be the one to get something useful out of it...
That would not be done as easy as it is said, because mutations arise naturally during replication and they can be induced by virtually any chemical found in the environment nowadays.
Cis or trans? That's what matters.
Mutation can be caused by many factors such as chemical (DDT, CCL4), radiation, ionizing etc. It mutate the DNA in cell. If only a single is mutated, it can be replicated as usual in mitosis. Thus, the neighbor cells which are previously normal will be affected too.
Current way to stop the cancer progression is chemotherapy. it kills the cancer cells to spread or replicate.
http://www.ask4biology.com/immunology/t ... mmunology/
Thanks for that. When I was studying mutation a couple of days ago, I saw something about radiation- I talked to one of my closest friends about it, and she told me that's what chemotherapy is. I kind of felt dumb, but at the same time sort of accomplished.
- JackBean, I know that it's easier said than done, and I sort of guessed that someone has brought on a similar approach. The more we debate it, the more I understand it. I've been researching mutation and cells(DNA and genetics, as well)- it's gotten me quite hooked on the subject of cancer and mutation, for some reason.
Darby, I understand that there are many forms of cancer, but I was simply addressing this one. I know that creating this thread was widely ambitious, but thanks for the encouragement
Re: Re:
Chemotherapy is not the same as radiation therapy, even though people often seem to think so. They are different things altogether, but achieve or aim to achieve the same end result: killing dividing cells.
Cancer cells, typically, grow faster than normal cells in the body. Many cells do not actively divide in adult humans at all, these include e.g. neurons and muscle cells. Both irradiation and chemotherapy disrupt the cell cycle and thus mainly affect fast growing cells who are constantly dividing. Irradiation does this mostly by introducing so many errors to the cell's genome that it fails the mitosis and dies. Chemotherapeutic agents have various ways of action, but they all aim to impair mitosis and thus kill fast dividing cells as well -- or force them to undergo apoptosis. So, as peculiar as it may sound, in radiotherapy cancer is fought with its own weapons: mutations.
Naturally, both these treatments come with plenty of side effects. For example, radiotherapy in itself may cause cancer, as it introduces mutations to cell genomes and some of those mutated cells may survive and become cancer cells later when its their turn. Also, since both treatments target dividing cells they are harmful to all the rapidly dividing cells in a human body, not only cancer cells. These include especially blood cells and epithelial cells, which both divide constantly and are therefore affected by irradiation and chemotherapy. Cancer patients undergoing chemotherapy often lose their hair for this precise reason: the fast-dividing cells of the hair follicle become so damaged that the hair falls off and they have gastrointestinal problems, because the gut epithelium gets damaged in the treatment. Radiotherapy is typically aimed to a very precise area (where the tumor is) and this helps to save the other tissues of the body. Chemotherapeutic agents have systemic effects since they are delivered intravenously and because of that may have wider side effects.
Because of the nature of these therapies, it is paradoxically so that often the most aggressive cancers respond best to the treatments since the cancer cells in these cases divide very rapidly. Of course, the cancer may still spread too quickly to be curable. Slow-growing, "passive" cancers, in turn, may allow the patient to live for many years without much problems, but turn out to be extremely resistant to these treatments once therapies are required.
I just wanted to give you a brief overview of these two topics, since you seemed to have confused them. Also, I hope that you notice that fighting cancer is a very tricky business and may even require introducing mutations to the patient's body to help them survive.
As others have already said, preventing cancer altogether may be next to impossible, but better treatments can most certainly be developed. If I had to guess, I would perhaps go for monoclonal antibody-based treatments to be the next big thing. The specific nature of antibodies would allow targeting only the cancer cells without harming the healthy cells, and the antibody can stimulate the body's own immune cells to kill the cancer cells or they can block vital receptors on the cancer cell's surface; or they could even be used to deliver cell-killing drugs to the exact spot where they are needed. Also, antibodies reach almost all tissues in the body. Some progress in this field has already been made, but I guess it is needless to say that also these drugs have had many difficulties along the way.
For example, because cancer cells divide quickly and they may have dysfunctional proof-reading mechanisms in the cell replication, they easily accumulate more mutations and these have a good chance to stop any one drug from working. Thus combination treatments would probably be needed for curing a cancer, making the task of developing drugs even more difficult -- you would need not just one effective drug, but several. For these and other reasons the researchers still have much to do before cancer can be treated in a similar manner as how bacterial infections are treated today (with antibiotics, or with combination of several antibiotics, because of the very same reason: acquired resistance).
Re: Re:
Woah,thank you so much for that. I honestly just entered "the realm of biology" a week or two ago(self taught), and I learned just yesterday how DNA is made out of four nucleotides; adenine, cytosine, guanine and thymine... Yeah, that's how much I don't understand cancer and DNA.
I was thinking about how radiation causes mutations in of itself, while reading up on it- so thanks for mentioning that. I never looked it up, though I should have- it seems very interesting. I'm starting to think that my idea has already been put into action, and may not be the most safe way to "cure" cancer.
Once again, thank you for clearing up the difference between chemotherapy and radiation therapy- I don't exactly love being ignorant.
Cancer cells, typically, grow faster than normal cells in the body. Many cells do not actively divide in adult humans at all, these include e.g. neurons and muscle cells. Both irradiation and chemotherapy disrupt the cell cycle and thus mainly affect fast growing cells who are constantly dividing. Irradiation does this mostly by introducing so many errors to the cell's genome that it fails the mitosis and dies. Chemotherapeutic agents have various ways of action, but they all aim to impair mitosis and thus kill fast dividing cells as well -- or force them to undergo apoptosis. So, as peculiar as it may sound, in radiotherapy cancer is fought with its own weapons: mutations.
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Elkhorn students share ideas with Wisconsin legislators at Project Lead the Way Day
MADISON — Eleven Elkhorn High School students were among students from nine districts across the state that filled the second floor of the Capitol rotunda Friday to show off their latest projects at the third Project Lead the Way Day.
The students were invited to explain the thought processes behind their latest ideas to state legislators as a means of illustrating the importance of science, technology, engineering and math education.
Project Lead the Way is the country's number one provider of STEM programs for students in kindergarten through 12th grade.
Callie Peterson, a junior at Elkhorn High School, helped build a mock 911 door alarm with three of her classmates in the school's digital electronics class. The class is one of five Project Lead the Way classes offered.
The group's alarm begins operating when the door opens and a message is sent to the alarm that switches it on, then the police are called within 15 seconds.
It took three days to build from start to finish, Peterson said.
Callie's interest in engineering was sparked when she took a technical education class in middle school. Since her freshman year she has enrolled in Project Lead the Way classes at the high school.
John Griswold, also a junior and another creator of the alarm, was hooked when he saw the school's introduction to engineering design class when he visited in middle school.
"If there had been no engineering program at our school I probably wouldn't have gotten into (engineering)," John said.�
John and Callie said they are grateful for the Project Lead the Way classes offered at the high school and were honored to attend the event at the capitol.
"It's pretty exciting (and) cool to look around and see what other people have built also from some of the same classes," Callie said. Other projects included a marble sorting machine and a robotic claw that picks up candy.
Offering hands-on classes with an emphasis on science, technology, engineering and math to high school students is one of the best ways to show students all possible career opportunities, said Steven Salter, director of Wisconsin's Project Lead the Way.
On the way to the Capitol Friday morning, Jacob Coehoorn, Elkhorn High School math and Project Lead the Way digital electronics teacher, asked the students if they were considering a career in engineering. All their hands went up, Coehoorn said.
This is the fifth year the high school has offered Project Lead the Way classes and the first time the school has been invited to attend the event that is held every two years.
"I know myself and the other instructor that's here are taking away some really cool ideas to inspire kids to try different things and make them think in different ways and learn different aspects of what we're teaching in Project Lead the Way," Coehoorn said.
About 125 students are participating in Project Lead the Way classes, Principal Chris Trottier said. Similar to Advanced Placement classes, students can receive college credit if they pass a test at the end of the year covering the material.
One class, principals of engineering, Trottier described as "physics on steroids," to explain the complexity of the courses the students are taking.
"Every student at Elkhorn High School is our best and brightest but these are the best of the best," when it comes to the Project Lead the Way classes, Trottier said.


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Elkhorn woman was among two killed after police chase
EDEN PRAIRIE, Minn.� — Family members say the Elkhorn woman killed in an officer-involved shooting on a major highway in Eden Prairie was a mother of two, while court records show the man she was with had a lengthy police record.
Dawn Marie Pfister, 34, and Matthew Vincent Serbus, 36, were killed Friday on Highway 212. Both died of multiple gunshot wounds after leading police on a chase that reached speeds of up to 90 mph during the morning rush hour.
Few details have been released about the shooting or what prompted authorities to fire their weapons. The case is being investigated and four officers — a State Patrol trooper, two Chaska police officers and one Carver County sheriff's deputy — have been placed on standard administrative leave.
Family members told the Star Tribune they are still seeking answers.
Neither Pfister nor Serbus have a permanent address.
Bridget Johnson, Pfister's stepmother, said Pfister was from Elkhorn, Wis., and has two children, ages 12 and 9. Johnson described Pfister as a "free spirit and an old soul," who loved music, dancing and her family.
Police records show Pfister was arrested in 2013 on drug-related charges, and arrest warrants in Olmsted County were pending for both Pfister and Serbus. Officials would not say when or why the warrants were issued.
Serbus, who once lived in St. Paul, had a lengthy criminal record including theft, burglary and drug-related cases. In 2006, a third-degree murder charge against Serbus was dropped in connection with the death of a 29-year-old woman who died of an overdose after Serbus and the woman had bought and used heroin and crack cocaine.


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Lack of signs at Milton bypass creating confusion
MILTON—When vacationer Lorayne Fugate drives north from Crystal Lake, Ill., to her summer cottage at Blackhawk Campground, she makes a concerted effort to avoid the new Highway 26 bypass in Milton.
She will take County M south of Milton over to Milton-Harmony Townline Road, cutting past Parkview Drive and then head straight west to South John Paul Road.
Fugate no longer sees Milton's east side downtown business district—the former main drag before the Highway 26 bypass opened a month ago—unless she has a specific reason to go there.
She said part of the problem is that, for the moment, there is hardly any directional signage around the bypass, and she's not interested in figuring out how to navigate it to get into downtown Milton.
"I'll do whatever it takes to avoid getting on that thing (the bypass). It's too confusing. Too much. I've found like five great ways to get around it," Fugate said.
Fugate was eying baby potatoes at a farm market stand in the parking lot of Milton West Elementary School on Madison Avenue. She has been coming to the stand for years, and doesn't need directions to reach it.
She just takes a totally different route through Milton to get there now—and her route basically sidesteps every business she might have stopped at prior to the Highway 26 bypass opening.�
It's a month into the bypass being open and Milton business owners and city officials say they're hearing stories similar to Fugate's from lots of motorists.
The bypass was meant to divert about 16,000 vehicles a day east of the city, in part to remove heavy truck traffic from Milton's downtown. That has caused a dearth of traffic on the east side, which city officials expected.
But what's disconcerting for business owners on the east side is that even local traffic is struggling to find its way in and out of Milton from the bypass.
Business owners say they have heard local motorists on the bypass sthat they are missing Milton entirely because of confusion over what direction to go at the new Highway 26/Highway 59 interchange, while others, includingFugate, say they are changing their daily routes to avoid the bypass.
Either way, it has spelled traffic pattern changes for businesses in the heart of Milton, and businesses are noticing it.
Jason Cowley, who owns Milton Piggly Wiggly, said he has had local customers, vacationers and commuters between Fort Atkinson and Janesville say they have had a tough time figuring out how to get to his grocery store, which is at 727 S. Janesville Street.
The bypass hasn't put a big dent in his customer base, which is primarily local, but he said it has hurt sales to people from Janesville or Fort Atkinson who would normally stop by on their work commute.
It's ironic, considering the grocery store is just north of where Highway 59 links to Janesville Street, straight west of the bypass.
"Unfortunately, the new bypass doesn't do a great job of directing people into Milton. There's nothing there to do it," Cowley said. People (who) go north-south on the Highway 26 bypass don't realize they've gotten to the Milton exit."
The most common complaint Cowley has heard? People coming from the south who want to get off the bypass to get to Milton are accidentally passing the interchange at Highway 59.
By the time the motorists realize it, they have gone all the way to County N a few miles north of Milton, where the bypass links back in with Highway 26. In order to get back to Milton, they'd have to retrace their steps four miles.
One complication: The Highway 26/Highway 59 interchange east of town, now one of the main entrances into downtown Milton, still doesn't have directional signs at the exits or its three roundabouts to point motorists into Milton.
The interchange has a series of road signs with arrows pointing to Highway 59 and Highway 26. That doesn't help motorists who haven't seen the new, reconfigured entrances and exits to Milton, which essentially has included shutting off Janesville Street to through traffic from the north and south.
City Administrator Jerry Schuetz said last week that the Wisconsin Department of Transportation, the agency in charge of putting in directional signs at the interchange, won't place signs to Milton there for at least another 4 to 6 weeks, according to an email from a DOT contractor.
Schuetz said the DOT until recently was working through protocol to decide the size of the signs and where to place them, but they have been ordered.
Schuetz said the city is now looking into the other traffic pattern issue: local commuters changing their routes to avoid the bypass or find a more convenient way to and from work.
He said the city plans to launch a traffic study in October to learn which streets in Milton are seeing heavier traffic with the bypass and its main arterial roads coming fully open in coming weeks.
"People are creatures of habit, and we're trying to learn how their driving habits may be changing with the bypass," Schuetz said.
He said the city's ad hoc sign committee will review the traffic study, which could take four to six months, to develop a plan to place directional signs around the city that officials hope will funnel drivers to the city's east and west business districts.
Now, some businesses such as Piggly Wiggly, have resorted to placing plastic directional signs along streets they know are seeing heavier traffic.
Meanwhile, the sign committee planning a Milton welcome sign at the south end of town Highway 26 splits off to the bypass, although Cowley, who is a member of the committee said discussion of the sign is still in the "community branding" phase. He said the sign could be in place early next year.
Schuetz said while the city's traffic study rolls out, the city likely will place some signs where traffic has obviously increased.
The Milton Police Department and the Rock County Sheriff's Office already has reported Parkview Drive and John Paul Road—the two main south entrances to Milton outside the bypass—as having significant increases in local and commuter traffic since the bypass opened.
Casey's General Store, a gas station and convenience mart on John Paul Road on the city's west side, is seeing the increased traffic manifest itself.�
Casey's clerk Gail Williams said gas and food sales at the store have increased significantly since the bypass opened.
"It's kind of weird, but how can you complain? We're getting new people who are now coming in every day," Williams said. "They say we're their gas station now, just because they're trying to do whatever to avoid that bypass."