Cell Backup Systems Challenge Evolution, Show Design Principles

first_imgHas an intelligent design paper been published in the Proceedings of the National Academy of Sciences?1  Read the abstract and decide whether this research supports Darwinism or design:Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes.  One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses.  Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime.  In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods.  More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated.  By manual inspection of the literature, we have compiled a list of such “responsive backup circuits” in a diverse list of species.  Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation.  We then apply modeling approaches to explore further their dynamic properties.  Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precision.  We thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation.  In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.The three authors, all from the Weizmann Institute in Rehovot, Israel, speak freely of the evolution of this phenomenon in their paper; they also, interestingly, refer to design and design principles just as often:In particular, we suggest the existence of regulatory designs that exploit redundancy to achieve functionalities such as control of noise in gene expression or extreme flexibility in gene regulation.  In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.    Clues for regulatory designs controlling redundancy were obtained first in a recent study…They call these cases of functional redundancy responsive backup circuits (RBCs).  Interestingly, they found some cases where one RBC is regulated by another RBC.  Though often the two backup copies were differently regulated, they could become coregulated under certain environmental conditions.  The team also found that some of these functionally redundant genes are found all the way from yeast to mammals; this is sometimes called “evolutionary conservation” but actually describes stasis, not evolution.    The authors do not deny that these backup systems evolved somehow: “For a single cell, the ability to quickly and efficiently respond to fluctuating environments is crucial and offers an obvious evolutionary advantage,” they postulate, suggesting that accidental duplication of genes was co-opted for this purpose.  They do not get into any details of how this might have happened, however, and their analysis seems more interested on the complexity and design benefit of the systems.    Their criteria for functional backups were stated thus: “Two lines of evidence could indicate a function’s direct benefit from existing redundancy: first is the evolutionary conservation of the functional overlap, and second is a nontrivial regulatory design that utilizes it.”  How many such systems exist in nature they could not say, because there have not been enough studies.  Many functionally equivalent copies of enzymes (isozymes) are known.  The genes that produce them are often regulated by different pathways.  Under stress, however, some can become coregulated to provide robustness against environmental irregularities or damaging mutations.The model that emerges is that although many isozymes are specialized for different environmental regimes, alarm signals induced by particular stress stimuli may call for their synergistic coexpression.  Here, RBCs provide functional specialization together with extreme flexibility in gene control that could be activated when sufficient stress has been applied.  For example, in yeast, glucose serves as a regulatory input for alternating between aerobic and anaerobic growth.  Its presence is detected by two separate and independent signaling pathways, one probing intracellular glucose concentrations and the other probing extracellular concentrations.They searched the literature and found several interesting ones that are described in detail in the paper.  “In all these cases, the common denominator is that one of the two duplicates is under repression in wild type and that that repression is relieved upon its partner’s mutation.”    This raises an interesting question – one that could have been asked by someone in the intelligent design movement.  They even answer a possible objection with a design principle:The extent to which genomic functional redundancies have influenced the way we think about biology can be appreciated simply by inspecting the vast number of times the word “redundancy” is specifically referred to in the biomedical literature (Fig. 5, which is published as supporting information on the PNAS web site).  Particularly interesting is the abundance with which it is addressed in studies of developmental biology (Fig. 5).  In fact, it is here that concepts such as “genetic buffering” and “canalization” first had been suggested.  Furthermore, the robustness of the developmental phenotypes such as body morphologies and patterning have been repeatedly demonstrated.  So the question is, are these redundancies simply leftovers of ancient duplications, or are they an additional component to the sophisticated machinery of cellular regulation?    In criticism, one may argue that many of the reported redundancies do not actually represent functionally equivalent genes but rather reflect only partial functional overlap.  In fact, knockout phenotypes have been described for a number of developmental genes that have redundant partners.  For these reasons, it has been suggested to define redundancy as a measure of correlated, rather than degenerate, gene functions.  Although these facts may suggest that redundancies have not evolved for the sake of buffering mutations, it has, in our opinion, little relevance to the question of whether they serve a functional role.  The interesting question is, then, can such a functional role for the duplicated state be inferred from the way the two genes are regulated?Along that line, they found that the amount of upregulation of one gene was often dependent on the regulation of the other.  This suggested to them that the sum of the expression of the two copies is nearly constant as a buffer against noise in the system.  When one line gets noisy, due to a mutation, the other responds with more signal.  They call this “dosage-dependent linear response.”  In some cases during development, the responsive overlap decreases as the organism grows.  In short, “The abundance of redundancies occurring in genes related to developmental processes, and their functional role as master regulators (Fig. 5) may be taken to suggest their utilization in either the flexibility or robustness of regulatory control.”    Some examples they give are even more complex.  RBCs may also be implicated in the resistance of some organisms to multiple drugs.  In some cases, each isoform can compensate equally for the other; in others, one of the forms is the main (the controller) and the other acts as the backup (the responder), only coming into play when the primary goes sour.  “One of the most profound and insightful of these recurring regulatory themes,” they exclaim, “is that, although both genes are capable of some functional compensation, disruption of the responder produces a significantly less deleterious phenotype than disruption of the controller”.  In evolutionary terms, why would the backup copy be better?A simple potential interpretation may suggest that although the controller is the key player performing some essential biological role, the responder is merely a less efficient substitute.  Yet, accepting the notion that redundancy could not have evolved for the sake of buffering mutations, this interpretation still is severely lacking.    A different, and more biologically reasonable, hypothesis accounting these asymmetries is that one of the functions of the responder is to buffer dosage fluctuations of the controller.  This buffering capacity requires a functional overlap that also manifests itself in compensations against the more rare event of gene loss.  Other models accounting for this assymetry are discussed further in this work, but our main point of argument is that this complex regulation of functionally redundant, yet evolutionarily conserved genes, strongly indicates utilization of redundancy.Their next subsection is called “Regulatory Designs.”  What emerges from their discussion of how each gene can regulate its partner is a complex picture: in one case, “redundancy is embedded within a more complex interaction network that includes a unidirectional responsive circuit in which the controller (dlx3) also represses its own transcription, whereas the responder (dlx7) is a positive autoregulator.”  More examples like this are described.  They predicted, and found, that RBCs could also regulate “downstream processes from variation and fluctuations arising from nongenetic noise.”  The net result is that by using these functional backup systems, the organism has more robustness against perturbations, yet more flexibility in a dynamic environment.    What is the fruit of this research?  Why should scientists look for these “regulatory designs” in the cell?  They offer an intriguing example.  It is known that one form of human muscular dystrophy occurs when a member of an RBC suffers a mutation.  Studies of this pair in mice, however, shows that the other member can respond by upregulating its expression.  It is thought a similar response might occur in humans.  “Inspired by the compensatory effect demonstrated by this RBC in mice, its artificial induction in humans by means of gene therapy has been suggested.  Although such modalities have not yet been realized, they suggest a fruitful possibility.”1Kafri, Levy and Pilpel, “The regulatory utilization of genetic redundancy through responsive backup circuits,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0604883103, published online before print July 21, 2006This is really a remarkable paper filled with inspiring possibilities.  If we can just think design instead of years of mindless mutations, we might find cures for debilitating diseases.  This paper has much of the obligatory evolutionspeak, but what does Darwinian thinking really contribute?  Nothing.  Although the researchers paid lip service to the evolutionary explanation that members of RBC pairs might have arisen through gene duplication, and that the coregulation might have provided a selectable fitness advantage, such language is really nothing more than the usual aftermarket sales pitch on the designed product.  The real heart of their argument was that design exists, it is functional, and we can learn from it in ways that could help mankind.  The future of design-theoretic science looks bright.(Visited 8 times, 1 visits today)FacebookTwitterPinterestSave分享0last_img read more

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N.Y. Fantasy Football Stays Shut

first_imgTweetPinShare0 Shares NEW YORK — A New York judge on Nov. 16 rejected the requests of daily fantasy sports operators DraftKings and FanDuel for temporary restraining orders to block the state attorney general’s attempt to shut them down.In separate complaints filed Nov. 13 in state Supreme Court in Manhattan, FanDuel and DraftKings first asked a judge for an injunction, arguing that Attorney General Eric Schneiderman wrongly characterized their businesses as illegal gambling operations.On Nov. 16, Boston-based DraftKings and New York-based FanDuel asked Justice Manuel Mendez for an immediate restraining order to stop Schneiderman until they can present their case. Each said they face irreparable damage otherwise.DraftKings said it has 375,000 New Yorkers among some 2.5 million players, and that the attorney general told its vendors in letters that it was at risk of not doing business in New York anymore.FanDuel said it has over 1 million users, with “hundreds of thousands” in New York whose deposits it has been unable to process since Nov. 13.The company blamed that on Schneiderman’s office, saying it has already contacted the bank and payment processors handling FanDuel’s customer deposits and withdrawals, deterring them from continuing.Schneiderman’s lawyers told Mendez at a hearing late Nov. 16 that they hadn’t done anything to actually prevent the companies from doing business in New York, and therefore he couldn’t issue an order to stop it.Mendez agreed. “They have not taken action yet to somehow enjoin the plaintiff from continuing to engage in their business here in New York,” he said. He ordered them back to court on Nov. 25.The case began with cease and desist letters sent by the attorney general last week, warning DraftKings and FanDuel they should stop conducting illegal gambling in New York.DraftKings and FanDuel argue that they offer games of skill, not of chance, as defined New York’s gambling laws.DraftKings said it was “confident in our legal position” and intended to keep operating in the state.____By Deepti Hajela. AP writer Michael Virtanen in Albany, New York, contributedlast_img read more

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TFA Annual Report

first_imgThe TFA Annual Report that will be put out for membership is now available to view.TFA will send an original to every TFA affiliate and some to each State office.The report will be presented at the TFA AGM which will occur on Sunday, 14 December 2008 in Canberra.Related Filestfa_annual_report_200708-pdflast_img

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10 months agoVan Dijk: Liverpool will ask me about De Ligt if we want him

first_imgVan Dijk: Liverpool will ask me about De Ligt if we want himby Paul Vegas10 months agoSend to a friendShare the loveLiverpool defender Virgil van Dijk admits there’s little talk about Matthijs de Ligt.The Ajax stopper is expected to leave for a major European power, though Van Dijk says there’s been little talk of his Holland teammate at Melwood.He told AD: “It does not work like that. A big club like Liverpool has so many scouts looking around, they will keep an eye on him. “If they want to know something, I’ll hear about it.”Asked how much he would pay for De Ligt, Van Dijk laughed: “Well, less than that for me, hahaha. But Ajax is in a luxurious position. We will see.” TagsTransfersAbout the authorPaul VegasShare the loveHave your saylast_img read more

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a month agoTottenham legend Ardiles insists title push remains on

first_imgAbout the authorPaul VegasShare the loveHave your say Tottenham legend Ardiles insists title push remains onby Paul Vegasa month agoSend to a friendShare the loveTottenham legend Ossie Ardiles insists a title push remains on.Tottenham are third in the Premier League table after five matches, just two points behind Manchester City but seven adrift of leaders Liverpool.”[It’s been] very positive. I believe that there are two teams to beat – Liverpool and Manchester City – but I think we are one of the teams that can beat them and we are going to try and fight with them all the way,” Ardiles told Sky Sports.”We have a very, very strong squad. That showed last season and in the Champions League as well. “We do have a very strong squad but we have to be a little bit better and I hope we will do it this year.” last_img read more

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a month agoDONE DEAL? Cowley making Simpson his first signing as Huddersfield manager

first_imgTagsTransfersAbout the authorPaul VegasShare the loveHave your say DONE DEAL? Cowley making Simpson his first signing as Huddersfield managerby Paul Vegasa month agoSend to a friendShare the loveDan Cowley has made Danny Simpson his first signing as Huddersfield Town manager.The Sun says the former Leicester City fullback has agreed a deal with Huddersfield until the end of the season.Cowley wanted experience in his squad to get the Terriers out of trouble and turned to 32-year-old to provide competition at right-back.Huddersfield currently sit bottom of the Championship with just one point from eight games and are six points adrift of safety already.Jan Siewert was axed in August after a run of one win in 19 matches – which included relegation from the Premier League – before Cowley and brother Nicky joined from Lincoln earlier this month. last_img read more

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Federalprovincial funding gives early childhood educators wage boosts

first_img“Early childhood educators are the heart of B.C.’s child care system, and their passion and dedication are key to setting B.C. kids on the path to future success,” said Katrine Conroy, B.C.’s Minister of Children and Family Development. “As we build new licensed child care spaces, we know that we also need to build the ECE workforce. Our government appreciates the important work early childhood educators do every day, and with this strategy, we aim to support ECEs throughout their career – because when we invest in child care, everyone benefits.”Through the new strategy, the B.C. government aims to encourage more people to become or stay on career paths as early childhood educators. By improving recruitment and retention, the government said that more B.C. families will have access to stable child care programs. Child care providers have cited lack of qualified early childhood educators as a key hiring challenge in recent years.Under the new strategy childcare workers at licensed facilities that have been approved for the Child Care Fee Reduction Initiative will be getting a $1-per-hour raise early next year, with another $1-per-hour raise in April 2020.A $10-million investment to fund an expanded ECE Education Support Fund was also announced to provide increased ECE Student bursaries and a new payment schedule to reimburse students sooner.Under ChildCare BC, the government says it will be spending more than $1 billion on child care over the next three years. VANCOUVER, B.C. – The provincial government announced today that thousands of childcare workers across B.C. will be getting wage boosts and new supports through the Province’s ChildCare BC plan.The B.C. government said today that it will be spending $136 million to support the new Early Care and Learning Recruitment and Retention Strategy, which will help support early childhood educators by providing wage enhancements, on-the-job training opportunities and other measures.The federal government announced that it would be providing $16.3 million in funding for bursaries and professional development.last_img read more

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TMC registers complaint against Arjun

first_imgKolkata: Trinamool Congress leaders from North 24-Parganas have registered a complaint with the District Election Officer (DEO) against Arjun Singh, who is contesting the forthcoming Lok Sabha elections from the Barrackpore constituency on BJP’s ticket.A separate complaint was also lodged at the Titagarh police station in this regard. The district Trinamool Congress leaders have alleged that Singh had called up a Trinamool Congress leader in Barrackpore and threatened him with dire consequences. Also Read – Bengal family worships Muslim girl as Goddess Durga in Kumari PujaThey also termed the incident as a desperation move after Singh was removed from the post of chairman of Bhatpara Municipality through secret ballot on Monday. The district TMC leaders are also of the view that Singh is making threat calls after apprehending defeat in the upcoming elections. It may be mentioned here that Singh has recently joined BJP from Trinamool Congress. After he joined BJP, the Trinamool Congress leaders decided to issue a no-confidence motion in the 34-member Bhatpara Municipality in North 24-Parganas. The no-confidence motion was passed against Singh through a secret ballot, where he lost 21-11. The DEO of North 24-Parganas, who also happens to be the District Magistrate, will carry out a probe into the alleged threat call and may submit a report to the office of the Chief Electoral Officer (CEO) in the state. The CEO’s office had also sought a report from the DEO on Monday, after a BJP party office was allegedly ransacked in Bhatpara.last_img read more

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Morocco ranks 78th in list of best countries for business

first_imgRabat- American Magazine published its list of the best countries for business in 2013. According to the list, which was published last December, Morocco ranks 78th worldwide for doing business. Morocco ranks second country in the North Africa behind Tunisia, which ranked 77. In the Arab world, Morocco is ranked 9th after the United Arab Emirates (30th), Qatar (40th), Saudi Arabia (56), Oman (58), Bahrain (59), Jordan (65), Kuwait (76) and Tunisia (77). Algeria ranked 131, while Libya ranked 136.Ireland tops the list of best countries for business followed by New Zealand, Hong Kong, Denmark, Sweden, Finland, Singapore, Canada, Norway and the Netherlands. The American famous magazine based its assessment on data made public by a number of think tanks and international organizations, such as the Freedom House, the Heritage Foundation, the Property Rights Alliance, Transparency International, the World Bank and the World Economic Forum.© Morocco World News. All Rights Reserved. This material may not be published, rewritten or redistributedlast_img read more

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Hines Ward Moves From NFL To TV Job

Hines Ward on the mic.Former Pittsburgh Steelers receiver Hines Ward showed his moves on the football field in arguably a Hall of Fame career and he showed his deft footwork in winning ABC’s Dancing With The Stars last year. Now, Ward takes on a new challenge: television analyst.The former Georgia Bulldog has been signed on by NBC Sports to work as an analyst for its NFL and college football coverage — a nice gig for Ward, who retired from the NFL in March after 14 years with the Steelers.The four-time Pro Bowl participant has a multi-year deal and will be a regular contributor to the NBC’s Football Night In America on Sundays and will be part of NBC Sports Network’s college football studio show on Saturdays. read more

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