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No birds sing on the island of Guam. Sometime in the 1940s the brown tree snake, native to Australia and New Zealand, arrived there, probably in the cargo hold of a passing ship. It had no natural predators, and was let loose on an island rich in wildlife. It proliferated madly, causing the extinction of numerous vertebrate species as it spread.
Something very similar is happening in Florida. The Burmese python, introduced by the pet trade, was first sighted in the Everglades in the 1980s. By 2000 or so there were well-established reproductive populations, and between 2000 and 2010 these grew exponentially. There are now estimated to be somewhere between 30,000 and 300,000 Burmese pythons in southern Florida, with effects on wildlife similar to those in Guam, writ large. These pythons are now genetically distinct from the pythons of Burma, but remarkable in their own lack of diversity: a clonal population run wild.
Or, if you appreciate unintended irony, take the case of Darwin's frogs, the Chilean amphibian first described by the great evolutionary biologist during his voyage of discovery on HMS Beagle. Darwin's frogs (Rhinoderma rufum is the proper scientific name) have likely gone extinct, the result of the introduction of a toxic fungal species, Batrachochytrium dendrobatidis.
Batrachochytrium dendrobatidis causes chytridiomycosis, a disease characterized by the inability to breathe, hydrate, osmoregualte, or thermoregulate correctly. It is sweeping around the globe, wiping out amphibian species wherever it lands: as many as 30 percent of amphibian species worldwide may be affected. Amphibians have been around for 365 million years, but their biodiversity is collapsing due to an invasive species.
The brown tree snake and the Burmese python and chytridiomycosis are part of a growing, and global problem: the spread, through human agency, of invasive species. These invasive species are an important part of what has been labeled "the sixth extinction."
The previous five great extinctions (such as the meteor that wiped out the dinosaurs) were caused by cataclysmic natural events. The sixth extinction is on us: the species have spread sometimes through intent (the Burmese python) and sometimes by mistake (the brown tree snake), but always through human intervention.
The results have been devastating, with loss of biodiversity on a worldwide scale. They are also very expensive: one estimate puts the economic burden of the 6500 harmful invasive species in the United States at $100 billion per year. Not too different from the cost of cancer care in the U.S., I would guess, or at least the same order of magnitude.
Analogies are always dangerous, because biology is so particular and contextual, but the invasive species studied by wildlife ecologists seem, well, almost like cancer. They spread from their initial ecosystem, establish themselves at a distant site, proliferate madly, and push aside the normal hosts, in the process reconfiguring the microenvironment of the distant site. Uncontrolled, they eliminate their hosts.
This connection has not been lost on either ecologists or cancer researchers, both of whom now make use of each other's scientific approaches. It is one of the delights of science that we can make important contributions through repurposing insights from one field to another, and the cancer-wildlife ecology connection is a good example of this phenomenon.
Shannon Index
Take the Shannon index. Claude Shannon was one of the greatest, and least recognized, 20th century scientists. He is, for practical purposes, the father of information theory, and his work underlies much of the computer technology we take for granted. Shannon was interested in entropy (information loss) in strings of transmitted text, and his Shannon index was designed to measure the degree of that entropy.
Wildlife ecologists use the Shannon index to measure species biodiversity. A big issue surrounding the introduction of invasive species involves its effects on the overall biodiversity of an ecosystem. If the brown tree snake assassinates Guam's birdlife, the biodiversity of the island diminishes, an impoverishment that ultimately affects us all. One can measure biodiversity using the Shannon index, the equation for which, for those who are interested, is as follows:
The Shannon index has been applied to cancer ecosystems as well. Intratumor diversity differs among cancers. For instance, among breast cancers, triple negative breast cancers are more genotypically diverse than luminal breast cancers, and their "biodiversity," as measured by the Shannon Index, may predict patient survival. Distant metastatic deposits (the true "invasive species") tend to have a greater degree of diversity than the primary tumor, perhaps a reflection of the treatments they have been exposed to. Vanessa Alemendro's recent Cancer Research paper (Cancer Res; 74(5); 1338-48, 2014) is a nice starting point on this topic. Similar results have been seen in Barrett's esophagus, where the Shannon index of a lesion predicts progression to frank esophageal cancer.
Evolutionary Imbalance Hypothesis
A colleague recently referred to Charles Darwin as "the first and best oncologist." The Shannon index/biodiversity story is further evidence that this is true. Recently two evolutionary biologists, Dov Sax of Brown University and Jason Fridley of Syracuse University, have proposed what they call the Evolutionary Imbalance Hypothesis of invasive species.
The EIH goes something like this: species from regions with deep and diverse evolutionary histories are more likely to be successful invaders of regions with less deep, less diverse evolutionary histories.
Sax and Fridley have put EIH to the test through statistical analysis of multiple "host" and "recipient" ecosystems, looking both in the plant and animal kingdoms, and the hypothesis always appears to ring true. Humans have created several unintended experimental tests of EIH: digging the Suez and Panama canals exposed, in each case, a more evolutionarily diverse ecosystem to a less well-developed ecosystem. Guess who invaded whom?
EIH is nothing new, the authors point out: Darwin proposed it in 1859, saying that better tested species have "consequently been advanced through natural selection and competition to a higher stage of perfection or dominating power." When I think of a nice, well-behaved tubular breast cancer, each cell looking like its neighbor, each with a low mutational load, and compare it with a high-grade, genomically diverse basal breast cancer, and the subsequent fate of their hosts, I can only repeat, "Darwin was the first and best oncologist."
Ken Pienta's group at Hopkins has taken the connection even further, explicitly making the link between metastasizing cancers and invasive species. Invasive species, they point out in a recent paper (Journal of Cellular Biochemistry 115:1478–1485, 2014), are ecosystem engineers, reconfiguring their microenvironment "as they construct a niche that is favorable to their own survival."
This niche construction results in ecologic inheritance, "the inheritance, via an external environment, of one or more natural selection pressures previously modified by niche-constructing organisms." Pienta's group has championed the use of mathematical approaches derived from the ecology literature (the Tilman equations for modeling the invasion of two species into a defined space) to describe bone marrow metastasis.
Tumors are great ecosystem engineers, through the secretion of cytokines and growth factors that permanently alter the neighborhood they live in, making life easier for their progeny. But whereas many invasive species eventually reach some sort of homeostasis with their new ecosystem, cancers rarely do so. Their ecosystem engineering, successful in the short term, ultimately results in environmental collapse, and the death of the host.
So are they "successful" invasive species, or not? It's all a matter of perspective, and the duration of the perspective. They are successful invaders right up to the patient's last breath.
And, at the need of the day, so what? Both of the groups mentioned above have suggested that we might use ecologic principles as part of a therapeutic attack on metastatic lesions. One wonders whether the recent immunologic approaches using checkpoint inhibitors (anti-PD1 and PDL-1) are a partial answer to the ecologic observations regarding tumor biodiversity: the more genomically and antigenically diverse a cancer (think melanoma and smoking-induce lung cancer), the more sensitive to immunotherapy? Is the Shannon index as a predictor of immunotherapy benefit? It's a thought.
Wildlife ecologists are just beginning to draw on the cancer experience, if my cursory review of their literature is correct. While they regularly refer to invasive species as a form of ecosystem cancer, they are just beginning to think about what it takes to wipe out these "cancerous" species. A recent press release by the US Geological Survey pointed out that the cancer model of "prevention, early detection, diagnosis, treatment options and rehabilitation" made perfect sense, and this combined approach is being used to combat invasive American bullfrogs in the Yellowstone River of the Northern Rockies. I just hope invasive American bullfrogs are easier targets than triple negative breast cancer.
Humans are the ultimate invasive species, and the one that allowed all the others to spread. We're responsible for the extinction (outside of 1.5% of our own genome) of our closest relatives, the Neanderthals, as well as the many other large mammalian and avian species that have disappeared since we conquered the world. We've provided the conduits for all the other invasive species that are performing ecosystem engineering on a global scale.
It would be easy to say that we are the ultimate cancer, the one doing its level best to foul its global environment. Indeed, many have said something like this. But if so, we are surely the first cancer with a conscience, and perhaps the only one ultimately capable of reining itself in before it kills its host.
Let's hope that the fields of wildlife ecology and cancer biology continue to cross-fertilize, to the benefit of both planetary and human ecosystems. Let's pray that we continue to be a "successful" invasive species.
Recently I was dining with friends, enjoying a pleasant Palo Alto evening on their porch. We noticed a family of quail walking on the ledge of the wooden fence that enclosed the yard, a mother and her brood of children. They hopped down into the yard. A peregrine falcon was sitting atop a tall tree, off in the distance. To me it was a thin smudge, featureless and motionless, perhaps a football field away. I suspect the falcon saw every minor blemish on my face. A falcon's vision is considerably better than that of an aging medical oncologist: they can see prey three kilometers away.
At some intellectual level I was aware that falcons were predators, capable of swift, violent action. My hostess even mentioned that she hoped the falcon had not seen the covey of quail. But we gave the falcon little thought until it fell from the sky, talons out, into the gathering of quail: a large, close blur, shocking in its suddenness, striking just feet from where we sat. I could have sworn I had seen it on that distant tree just seconds before, and that was in fact probably the case: falcons have been clocked at speeds as high as 242 miles per hour during their hunting stoop. They are, as I now know, the fastest animals on the planet.
One of the memes running through oncology right now is that of "cancer as a chronic disease." If you enter it as a search term in Google you get 54,100 hits. The idea taking hold is that we are entering a time when the average patient's cancer will be held in check through the judicious use of systemic targeted agents. Years will pass, the patient in generally good health.
I must admit that the phrase "chronic disease" always gives me pause when I hear it in relation to cancer. Historically, physicians separated acute illnesses such as pneumonia from chronic illnesses such as rheumatoid arthritis or diabetes. Prior to the advent of antibiotic therapies in the 1940's it was the acute illnesses that tended to kill; afterwards there was a progressive shift to chronic disease as a cause of death.
From a definitional standpoint, the standard definition of a "chronic disease" is "a long-lasting condition that can be controlled but not cured." Most human solid tumors meet this definition, and are recognized as such by the CDC.
But I think that when we talk about "cancer as a chronic disease" we are usually thinking of something else: basically, the cancer goes into the stasis field of modern medicine and does not emerge to kill you. My patients certainly think in those terms.
There are, of course, some real candidates for what I might consider true chronic disease status, the oncoequivalent of "take your insulin and it won't kill you": chronic myelogenous leukemia, controlled with imatinib, or an ER-positive breast cancer held in check with an aromatase inhibitor for prolonged periods. Or, to a somewhat lesser degree, metastatic HER2-positive breast cancer, or metastatic colorectal cancer, or renal carcinoma, all diseases where survival has significantly improved through the application of targeted therapies.
Scientifically this rapidly brings us to the question of treatment duration. Here we are trapped in empiricism. Mother Nature selected a year of HER2-targeted adjuvant therapy with trastuzumab as optimum. Not six months, not two years, but the time it takes the earth to circle the sun. Or maybe not: adding a year of adjuvant neratinib to your year of trastuzumab may improve disease-free survival. Three years of adjuvant imatinib is better than one year for GIST tumors post-surgery. How about five?
For early stage ER-positive breast cancer, ten years of tamoxifen is better than five years is better than three years is better than one year: every time we have studied duration, longer is better. Though, of interest, the disease-free survival curves never quite plateau: are we are just delaying the inevitable?
And if so, is it really a chronic disease? If you stop treating rheumatoid arthritis and your joints get hot again, you may be miserable but you probably will not die, and have a good chance of going back into remission with the same old drug: joints don't mutate. If you have metastatic breast cancer you are walking around under the cloud of a death sentence, any temporary stay of execution provided by fulvestrant or T-DM1 notwithstanding. Part of my problem with "cancer as a chronic disease" is exactly this: I know few individuals who would trade RA for metastatic cancer. Equating them seems somehow disingenuous.
I keep thinking of that peregrine falcon and the quail family. I have had a number of patients who I have sheparded along for years, occasionally decades, with either estrogen receptor-targeted or HER2-targeted treatments. It is easy to contract and propagate the "cancer as a chronic disease" meme with such patients. The clinic visits become celebrations of the doctor's therapeutic virtuosity and the patient's family anniversaries, with drugs being switched in and out every now and then when the CAT scan demonstrates modest progression.
You can almost fool yourself into believing that the patient doesn't have a lethal disease. And then the falcon swoops in. "Chronic disease" can turn into "acute and lethal" in a shockingly brief period. One clinic visit you are discussing an upcoming high school graduation, and then the next you are having an end of life discussion.
I do not know why it is--perhaps because the patients have transitioned from being patients to old friends--but the death of a patient whom I have treated for a decade usually hits me harder than one who dies quickly. There is no intellectual reason for this: the death of a long-term survivor suggests I was actually doing my job, and I should be delighted that I have added many years of high quality life rather than just a few. But it always leaves a bitter taste in my mouth. I doubt it is an experience a rheumatologist deals with very often.
Like some old soldier looking over the parapets at a distant enemy, I have learned to respect my foe's endless ingenuity, its treachery, its patient evil, and its almost maniacal drive to escape the barriers I try and throw up around it. We have, again and again, seen the ultimate failure of kinase-based approaches that have dominated the last decade, the consequence of smart tumor's ability to mutate and evade.
The real "chronic disease" possibilities may lie within the realm of immune checkpoint inhibitors, where some (though certainly not all) melanomas appear to go into stasis for years and years, the body's immune system unleashed to keep the wolves at bay. The idea of metastatic melanoma as a chronic disease still boggles the imagination, but it certainly looks to be a real possibility for many patients. Whether I want my T regulatory system ramped up for the next decade or two remains to be seen. I suspect we will be keeping the immunologists and rheumatologists very busy: more chronic disease.
Are there any other approaches that might turn human cancer into a true chronic disease?
I present for your edification the naked mole rat. These are probably the ugliest mammals on the planet, almost disgustingly so. They are also the longest-lived rodents we have, clocking in at 30 years, a good life if living in total darkness underground in what one leading student of the species has described as a "dictatorship" is your cup of tea.
But here is the really interesting thing: they never die of cancer. I don't mean rarely, I mean never.
It doesn't matter how hard you try, either. Pump them full of carcinogens, and they just go on their merry, repulsive way, burrowing through the earth as if nothing had ever happened. And why is this? It turns out that the naked mole rat produces generous amounts of a high molecular weight form of hyaluronic acid, an evolutionary adaption that changes their skin to something quite stretchy and allows them to easily traverse underground passages. This form of hyaluronic acid has the pleasant side effect of walling off individual cancer cells before they can gain mass or metastasize. The naked mole rat buries the cancer cell in concrete. This is a spectacular example of a microenvironmental approach to cancer.
Cancer cells live in neighborhoods, and for the past decade or so we have been enlisting the neighbors (blood vessels, T cells) in the neighborhood watch. These microenvironmental approaches have started to take off, and I suspect (based partly, but not entirely, on the naked mole rat story) that we just at the beginning of such interventions. Hopefully we will not end up looking like naked mole rats.
Naked mole rats also have exceptional transcriptional fidelity. This error-free life also protects them from cancer. So taken are laboratory researchers with the naked mole rat that Science magazine declared it the "Vertebrate of the Year" in 2013, and there has been an explosion of scientific articles plumbing the rodent's exceptional longevity and freedom from cancer. And, of course, a naked mole rat genome project.
But back to the falcon and the quail. For a brief second after the falcon struck, we were unsure of the outcome. We couldn't see whether the falcon had succeeded in snatching one of the young covey. Then there was an explosion of quail, noisy, vectored in multiple contradictory directions, their panic reigning supreme. And then, much more quietly than the quail and more slowly than he had arrived, the falcon took off, talons empty: not today. Not today. Not today!
The crickets in my back yard have been particularly noisy these last few days, louder than they have been all summer, so loud they have kept me awake with their chirping. But I enjoy listening to them. Sometimes I just hear one, sometimes a veritable orchestra, or at least a robust string section. It is, for reasons I cannot explain, a deeply comforting sound.
I have had warm feelings towards them since my youth. I grew up as part of a generation raised on Walt Disney's Pinocchio, where a charming Jiminy Cricket served as (somewhat ineffective) conscience for the long-nosed wooden boy. Hollywood anthropomorphism favored crickets, and why not? Unlike mosquitoes and lice, these insects never mean us any harm.
As a child I was fascinated with their amazing ability to tell me the temperature. Maybe you learned this as I did. Count the chirps in 15 seconds, add 40, and you have the temperature in degrees Fahrenheit. This observation was formulated as Dolbear's Law in 1897, and it still works, more or less. More or less, because there are over 900 cricket species worldwide, and they do not all chirp, and do not chirp at the same rate for a given temperature. So Dolbear's law is not exactly a law of nature.
I was taught that these living thermometers rubbed their hind legs together to create the chirps, and believed it for decades, but it just isn't so: the crickets have something called a stridulatory organ, a large vein running along the bottom of each wing. In fact, the scientific name for chirping is stridulation; I'll stick with chirping. Crickets run the top of one wing along the bottom of the other to create the sound. And, in case you are wondering, crickets have a tympanic membrane to hear the chirps--though oddly enough it is located just below the knee.
Why crickets chirp is another matter: largely this is mating behavior, the male of the species announcing himself to potential mates. Entomologists distinguish four separate chirping behaviors, including a calling song that attract females and repels other males, a quiet courting song used when a female is near, an aggressive song triggered by the near presence of other males, and a brief copulatory song produced after a successful mating. You can't make this stuff up.
The timekeeping aspect of the chirping has nothing to do with its underlying reproductive purposes. Crickets are, like all insects, cold-blooded, and their chirpings heat up along with their bodies. The thermometer is coincidence, an artifact of physicochemical design, albeit a happy one for a six-year-old boy on a warm summer's night in a field in Wisconsin.
Living Thermometers
Nature is full of living thermometers. Measuring temperature must be something basic to all living organisms, for even lowly bacteria are capable of it: they contain temperature-sensing RNA sequences, known as RNA Thermometers, or RNATs, in their mRNAs. RNATs control virulence, heat shock, and cold shock genes in E. coli.
Their two structures are simple but clever: a zipper-like structure that gradually melts as temperature increases, and a switch mode, where two mutually exclusive structures depend on ambient temperature. RNATs are such a clever natural design that they are now being co-opted by biotechnologists.
Sometimes these internal thermometers can have seemingly bizarre purposes. Red-eared slider turtles (and many other reptiles) lack sex chromosomes. Turtle gender is determined by the temperature at which their eggs are incubated, with colder temperatures producing males and warmer temperatures females. The cut point is right around 29oC.
How this occurs has been partially elucidated in recent years. Aromatase (which, as all good medical oncologists know, converts androgens to estrogens) is under epigenetic control, so that, in the words of a recent PLOS paper, "female-producing temperature allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development." And, in case the breast cancer docs are wondering, you can change the turtle's gender by exposing its egg to letrozole. And you thought it was just a breast cancer drug.
But mammals are the ultimate living thermometers. If you are a warm-blooded animal whose edge over crocodiles and snakes involves continuous thermoregulation (and we live within a very narrow temperature range), then you need to have some means of measuring your degree with precision.
And we are quite good at it, we humans. The skin at the base of our thumbs can perceive temperature differences of 0.02-0.07o C. I find this little short of amazing: our fingers are thermometers. The explanation for this impressive ability is an evolutionary masterpiece. Temperature-sensitive transient receptor potential channels (or thermoTRPs) are a family of ion channels, activated at different temperature thresholds, each exquisitely sensitive to a particular temperature range. One of them, TRPV1, is also activated by capsaicin, which is why those red-hot chili peppers make your throat feel like it is burning up.
We rarely think of this internal thermometer, perhaps because it is hidden in the background, unlike the more showy, in-your-face senses of sight and hearing and taste and smell. It gets lumped in with "sense of touch" and promptly forgotten. And, since the invention of thermometers in the 17th century, we have rarely felt the need to rely on it, or even recognize its existence.
We are the only species on the planet to have an external thermometer--two if you count our cricket biothermometers. But the old thermometer is still there, sitting quietly in the back.
Temperature Metaphors
This temperature sense is hard-wired into our psyche, as our language (indeed, every human language) commemorates. We speak of "an icy stare" or say that a relationship is "heating up" or that someone has a "burning desire" or of a lawman being "in hot pursuit" of a criminal, only to discover that "the trail has gone cold." We live by metaphors, and temperature metaphors are exceptionally common.
It goes even deeper than language. Psychological studies have shown that the simple act of handing someone a warm cup increases interpersonal warmth, and that someone excluded from a conversation will judge a room to be cooler than one who is included. Our subconscious is deeply invested in temperature, and it is wired into our internal thermometer.
The oncologist in me always wonders whether such things affect cancers. Temperature dysregulation is, of course, common in cancers such as Hodgkin's disease, and a rare complication of treatment for Hodgkin's is prolonged hypothermia (lasting up to 10 days) following chemotherapy administration. I'm sure there is some interesting biology there, perhaps involving thermoTRP's, but at the end of the day it probably doesn't matter all that much.
Thermoregulation has not been a huge therapeutic player in the cancer field, despite half-hearted attempts at cryosurgery and hyperthermia. Are cancers essentially cold-hearted, or do they burn with the desire to harm? Or both at the same time? Metaphor only carries you so far, and attributing emotions to lethal Darwinian machines is pointless. But when I lay my hand on an inflammatory breast cancer I am always impressed, sometimes even shocked, by its malignant heat, its angry redness. Perhaps ion channels are irrelevant to their darker purpose, or perhaps like so many other things we haven't looked closely enough.
As it turns out, there is a growing literature on capsaicin as an anti-cancer agent: the active agent in chili peppers induces necrotic cell death in cancer cells, and does so in direct relation to TRPV1 expression levels. Is that cool, or what? Or a hot research area? Whichever.
So I sit on my back porch pondering all this as the evening proceeds, the temperature gradually falling, the symphony of chirps slowing bit by bit, and eventually dying out. Perhaps the crickets have found their special ones tonight. Is that a celebratory chirp I hear?
Recently, in preparation for a lecture I gave on writing scientific papers, I had the opportunity to re-read Watson and Crick's original 1953 Nature paper, "Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid." It is not just the most important scientific paper in biology written in the last century, it is also one of the most beautifully written: concise, clear, jargon-free, and with the greatest punch line for any paper in the scientific literature: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." Try and top that for a discussion section.
I downloaded the paper from the Nature website, which required me to go to the actual April 25, 1953 issue. My eyes wandered for a few seconds over the table of contents for the issue, and suddenly I had a thought: I wonder what it was like to publish a paper in that issue of Nature if your name wasn't Watson or Crick? To be remembered, forever in the annals of science, as one of the also-rans.
There are many equivalents, both inside and outside science: giving a talk at the Linnaean Society in 1858 in the same session where Darwin and Wallace's first papers on evolution were presented. Or, perhaps, being the back-up act on the 1964 Ed Sullivan Show for the Beatles. A wonderful trivia question, by the way: Las Vegas entertainers Allen & Rossi, and the impressionist Frank Gorshin, in case you want to wow someone at a dinner party.
6 Articles, 23 Letters
So who were the also-rans? There were six articles and 23 letters in the issue. Of the six articles, three were about the structure of DNA. In addition to the Watson and Crick article, there was Maurice Wilkins' "Molecular Structure of Nucleic Acids: Molecular Structure of Deoxypentose Nucleic Acids" and Rosalind Franklin's "Molecular Configuration in Sodium Thymonucleate."
Franklin's paper includes the beautiful x-ray crystallography that has become a commonplace for biology texts ever since, a ghostly X of salmon DNA.
The Wilkins and Franklin papers represented important support to the Watson-Crick modeling paper, which is why the two Cambridge researchers had encouraged their King's College colleagues to submit papers at the same time.
The interaction of Watson and Crick with Wilkins and Franklin (both of King's College. London), and for that matter the fraught relationship of Wilkins and Franklin, are part of the lore of molecular biology. Watson and Crick ran no experiments, relying instead on the work of others, most prominently Rosalind Franklin's X-ray diffraction studies of DNA, which they correctly interpreted as evidence in favor of a double helix. It was a crucial piece of experimental data, and one that both Wilkins and Franklin had misinterpreted. Watson's classic memoir, The Double Helix, describes the interactions in picturesque detail, and his description of Franklin in particular struck many then and later as both petty and sexist.
The Nobel Prize can be given out to a maximum of three investigators, and in 1962 Wilkins was investigator number three. Franklin had, in the intervening years, developed ovarian cancer, and died at the age of 37, some four years before the prize was awarded. She spent some of her final months with Crick and his wife, receiving chemotherapy. The oncologist in me has always wondered whether the Jewish Franklin carried an Ashkenazi BRCA mutation.
Would she have been awardee number three had she lived? This is an unanswerable question, but her premature death doomed her to permanent also-ran status, making her a feminist icon in the process. Could she have come up with the double helix structure on her own, given sufficient time? Perhaps. But her Nature article concludes with a sad, might-have-been-but-wasn't, admission: "Thus our general ideas are not inconsistent with the model proposed by Watson and Crick in the preceding communication." Not inconsistent with: a grudging admission that she had failed to see what her own data supported.
Impact Factor
Editors of scientific journals, and contributors to those journals, scrutinize the impact factor. The impact factor is quite simple: add up the total number of citations for a journal in the first two years after publication, and divide by the number of citable items (usually articles and reviews). The best journals (Science, Nature, Lancet, New England Journal of Medicine) usually have the highest impact factors. The vast remainder are decidedly mediocre: a sea of journals with an impact factor of 2 or thereabouts. Most published science is unmemorable, rapidly forgotten even by the authors. Citations do not have a Gaussian distribution; instead they follow a power law distribution, with a few 900-pound gorillas followed by a long tail. And seldom has the power law been so severe as that issue of Nature.
Impact factor is a way of keeping score, though not without its own issues. One problem with it is that it cannot measure the long-term impact of a paper. With 60-plus years of follow-up, however, we can look at the long-term impact of the work published in that April 25, 1953 issue of Nature. Watson and Crick are the huge winners, of course: Google Scholar says their paper has been cited 9866 times, and we hardly need the citation numbers to realize the revolutionary importance of that paper. The Wilkins and Franklin papers clock in at 618 and 833 citations, marking them as important contributions. But what of the others?
Let's begin with the other three articles. They are, in order of presentation, "Refractometry of Living Cells"; "Microsomal Particles of Normal Cow's Milk"; and "Measurement of Wind Currents in the Sea by the Method of Towed Electrodes." None is particularly remembered today, I think it is safe to say. Google Scholar reports the three articles as having had, respectively, 172, 41, and 15 citations. OK citation numbers, even today, but definitely in the also-ran category. Interestingly, the refractometry paper was cited by a 1991 Science paper on optical adherence tomography that itself has been cited 8400 times.
The letters range from 0 to 235 citations, according to Google Scholar. The most recognized is W.R. Davis's "An Unusual Form of Carbon", which has been cited 235 times, most recently in 2010. The story here is interesting. Davis and his colleagues worked at the British Ceramic Research Association in Stoke on Trent in England, where they studied the carbon deposited on the brickwork of blast furnaces. They identified what they described as tiny "carbon vermicules," some as small as 100 angstroms. In retrospect (hence the 235 citations) they were early discoverers of carbon nanotubes, members of the fullerene structural family, now actively studied for their fascinating physicochemical properties. Three researchers received Nobel prizes in the 1996 for fullerene studies, so one can feel for Davis and his fellow Stoke on Trent ceramicists. They were dual also-rans, publishing in the same issue as Watson and Crick, and coming along a few decades too early in the as-yet-unnamed fullerene field.
Of the other papers published as letters, what is there to say? I love the title of K.A. Alim's "Longevity and Production in the Buffalo," though R. Hadek's "Mucin Secretion in the Ewe's Oviduct" runs a close second for my affections.
But is easy to understand why such articles are poorly cited and long forgotten, given the relative obscurity of the topics. One of the keys to success in science is choosing the right problem to work on, and mucin secretion in the ewe's oviduct probably cannot compete with decoding the key to life on earth.
Least Cited, But...
The least cited paper (I could not find any citations using Google Scholar) is my favorite: Monica Taylor's "Murex From the Red Sea". Taylor wrote from Notre Dame College in Glasgow, where she curated a natural history collection. Sir John Graham Kerr had collected some 300 Murex tribulus shells from the Great Bitter Lake in Egypt. Murex was what would now be called an alien invasive species, introduced following the completion of the Suez Canal, and Sir John (would a 2014 letter to Nature ever refer to a Sir John?) and Monica wondered whether the species had altered its presentation, "relieved of the shackles of environment." The letter was a plea for specimens from the Red Sea so that the comparison might be made. Wikipedia informs me that Murex tribulus is a large predatory sea snail, with a distribution from the Central Indian Ocean to the Western Pacific Ocean.
Did Monica Taylor ever get her Red Sea specimens? Life is full of small mysteries. Taylor herself is a fascinating soul. Born in 1877, the daughter of a science teacher and the cousin of Sir Hugh Taylor, one-time Dean of the Princeton Graduate School, she trained as a teacher prior to becoming a nun. So Monica Taylor was actually Sister Monica, and Sister Monica dearly wanted to become a scientist. But the road was not smooth for a woman, let alone a nun, wishing to be a scientist in the early twentieth century. She was refused permission to attend the University of Glasgow, and was unable to complete an external degree from the University of London due to Notre Dame's inadequate laboratory facilities.
After several thwarted attempts, according to the University of Glasgow website, "She was eventually granted permission to do laboratory work in the Zoology Department of the University of Glasgow, provided she did not attend lectures and was chaperoned by another Sister at all times." There she impressed Professor Graham Kerr, who encouraged her to pursue an advanced degree, and obtained permission for her to attend classes. After receiving a DSc from the University of Glasgow in 1917, she headed the Science Department at Notre Dame College until her retirement in 1946, all the while conducting significant research in amoebic zoology.
In 1953, the year of her Murex letter, she was awarded an honorary doctorate from the University of Glasgow for being "a protozoologist of international distinction." She died in 1968; six years after Watson and Crick got their Nobel prizes. No citations, and no Nobel, but perhaps you will remember this also-ran, a woman of courage and fortitude.
Most of us are also-rans, if judged against those carved into science's Mount Rushmore. Glory would not be glorious if it was common. But maybe we have it wrong if we think the also-rans felt demeaned by their also-ranness. Maybe Dr. Alim or Dr. Hadek or Sister Dr. Taylor enjoyed their brush with greatness. And maybe, just maybe, they were satisfied with lives well lived in service to science and mankind.
I recently read Dave Eggers' brilliant and frightening novel The Circle, his modern take on Orwell. In 1984 the totalitarian state was the enemy of freedom, a hard tyranny motivated by the state's desire to crush all opposition. Eggers thinks we are headed for a much softer tyranny, one dominated by do-gooder Silicon Valley business types determined to eliminate—indeed, undermine the justification for—any attempt at privacy. 1984 has come and gone; the world of The Circle careens towards us at high speed.
The sphere of privacy continues to shrink. If it even is a sphere anymore; sometimes it seems shriveled to a point that is no longer three dimensional, almost a bodiless mathematical concept. Hardly a day goes by without some new assault, or potential assault, finding its way into the news. Some examples are from the scientific literature, and some from current politics, but the vector is always the same: towards an era where privacy ceases to exist.
Much of this is technology-driven. That technology affects privacy rights is nothing new. Previous generations had to deal with wiretapping and listening devices, after all. But this seems both quantitatively and qualitatively different.
Here are a few I've collected in the last year. What impresses is the sheer variety of attacks on privacy, coming from every degree of the compass:
· An article in PNAS demonstrates that your Facebook "likes" could do a pretty good job of defining your sexual orientation (85% predictive ability for male homosexuality), race, and political identity.
· The FBI recently announced that it had deployed drones on American soil four times in recent years. Police departments are considering doing the same in American cities, supplementing the now ubiquitous CCTV cameras.
· A group of Harvard engineers recently created a quarter-sized "fly", a robotic insect capable of controlled flight (for a first look at the future look at http://www.youtube.com/watch?feature=player_embedded&v=cyjKOJhIiuU). Give it some "eyes", deploy a few hundred, and then imagine some hovering outside your bedroom window. Flutter, flutter, buzz, buzz. Is that a mosquito I just slapped, or some investigator's eyeballs?
And while I could not exist anymore without Google, the company has been the great destroyer of privacy. If you want to know someone's life history, it is probably out there somewhere on a server farm. Try a little experiment: Starting with a colleague's name, see how much personal information you can find in an hour. Next, imagine how much of that information you could have found in an hour a decade or two ago. You would be amazed.
Maybe that's a good thing: it depends on who's searching, and why. If you don't want to date a convicted felon, going online is a good way to avoid that particular mishap. But it is, of course, much more than just that. Every little thing about you can end up out there. When I was a teenager we used to laugh at school administrators who claimed that some minor infraction would "become part of your permanent record." Not anymore: the record is not only permanent, it is global. In some important way there are no second chances anymore.
Google (don't be evil) is responsible for other transgressions. We now know that Google StreetView collected more than pictures of your front door: they went behind the door to collect passwords, email, and medical and financial records, as the company admitted in court. The court fined the company a half-day of its profits, which I suppose tells you how much the courts value your privacy. Google also promised to go and sin no more, which I know will reassure us all. And they will now require employees to take the computer industry equivalent of a HIPAA course. All right, I admit, cruel and unusual punishment.
These Internet assaults are layered on top of other privacy intrusion: ubiquitous CCTV's following you down city streets, your cell phone movements describing where you have travelled with great precision, your credit card history demonstrating a financial phenotype, your checkout at the grocery story generating targeted advertising on the back of the receipt, and your web history now the technological equivalent of a trash can, to be sorted through by private investigators digging for dirt. Sometime in the last decade privacy became a fossil word. The expectation of privacy is disappearing from public discourse.
About the only data that doesn't want to be free is personal health information, and that only because accessing it is a felony. How long before technology effectively eliminates medical privacy? For the moment, at least, medicine remains Privacy Island. Sort of, anyway: all around us the sharks circle, waiting to strike. Don't step too far off the shore.
· An article in Science showed that one could, by merging publically available "de-identified" data from the 1000 Genomes project with popular online genealogy data, re-identify the source individuals.
· If a patient accesses a free online health website for information on "cancer" or "herpes" or "depression", according to Marco Huesch of USC, that information will, on average, be shared with six or seven third-party elements.
I used to think that conspiracy theorists were crackpots, with their ideas of the government tracking us via RFID-encoded greenbacks through airport security checkpoints. It turns out that the crackpots were right, though wrong about the purveyor (the TSA? Seriously? The dysfunctional guys who still can't stop people from carrying box cutters through security checkpoints?).
It's much closer to home than that, as I've recently discovered. Hospitals are taking a deep dive into something called RTLS, or Real Time Location Services. I found out about this technology (as usual, I am the last to know) through service on a committee overseeing the building of a new hospital. RTLS places RFIDs on every large object (in RTLS-speak, "assets") as well as on patients and hospital employees. It can then localize all of these to within three feet, via carefully placed receivers scattered throughout the building. Several companies (Versus, CenTrak) have sprung up to commercialize this technology.
These devices have real uses. They keep large, expensive pieces of equipment from walking out the door, or at least allow you to track which door they walked through. Recently a hospital in Munster, Indiana suffered an outbreak of MERS. Because hospital employees were tracked through Versus RTLS technology, the hospital was able to hand CDC investigators a list of everyone who had come in contact with the patient. Sounds great, right? An epidemiologist's dream.
Perhaps. The cynic in me says that sometime in the near future some hospital administrator will use the technology to decide, and chastise, employees who spend too much time in the bathroom. Administrators just can't help themselves.
RTLS is part of the larger "Internet of Things", or IoT as it has come to be called. A recent article in The Economist suggests that by 2020 some 26 billion devices will be connected to the Cloud. Consider IoT's potential. Will I end up with a brilliant toaster, one that knows exactly how long to brown my bread? A mattress that diagnoses sleep apnea? A lawn mower whose handles sends my pulse and blood pressure to my internist? A microwave oven that refuses to zap hot dogs when I go over my fat gram budget for the day? Maybe I'll be healthier. I'll certainly be crankier: the soft tyranny of the IoT will drive me off the deep end in a hurry.
The bottom line, though, is this: we are entering an era of ubiquitous monitoring, and it is here to stay. I wish I was (just) being paranoid. Here are the words of a recently released government report entitled Big Data: Seizing Opportunities, Preserving Values: "Signals from home WiFi networks reveal how many people are in a room and where they are seated. Power consumption data collected from demand-response systems show when you move about your house. Facial recognition technologies can identify you in pictures online and as soon as you step outside. Always-on wearable technologies with voice and video interfaces and the arrival of whole classes of networked devices will only expand information collection still further. This sea of ubiquitous sensors, each of which has legitimate uses, make the notion of limiting information collection challenging, if not impossible."
Discussions on privacy are frequently cadged in terms of crime or terrorism: wouldn't you prefer to give up another bitty little piece of your soul, a loss you would hardly notice, to avoid another 9/11 or even an armed robbery? The security state, adept at guarding or criminalizing the release of information harmful to its reputation, cannot imagine its citizens deserving or even wanting the same protections. One is reminded of Ben Franklin's prescient statement: "They who would give up essential Liberty, to purchase a little temporary Safety, deserve neither Liberty nor Safety."
But government intrusions are becoming almost irrelevant. I doubt the TSA or NSA or FBI or CIA or any other of the alphabet soup of government agencies really cares very much about my Internet history. It is, rather, the Pacific ocean of data being collected, and the certainty that it will be shared with, well, everyone. Remember the words of that government report? "This sea of ubiquitous sensors, each of which has legitimate uses, make the notion of limiting information collection challenging, if not impossible." Challenging, if not impossible: I'll opt for impossible.
And will we care? I doubt it, so long as the data theft remains quietly in the background, being used for purposes no more nefarious than designing advertising strategy or predicting sales.
George W. Sledge, Jr., MDGEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of "Regular Departments & Columns."
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London Welsh head coach Justin Burnell was a satisfied man after seeing the Exiles kick-off their pre-season with a 64-0 win over Henley Hawks at Dry Leas.
But Burnell is acutely aware that there are tougher tests to come.
Giving debuts to a number of the Club's summer signings, Welsh ran in ten tries and now face Wasps next Sunday at Adams Park.
"I thought it was a good blow out," said Burnell. "Wherever you go, to score ten tries is always pleasing, but the most important factor was keeping the opposition to nil.
"It's the start of the pre-season process, the first step on the ladder, and a bigger challenge next week in Wasps.
"To come away with minimum injuries, ten tries and a clean sheet is pleasing, but there is still a lot to work on in respect of the skill aspect.
"I thought we dropped too many balls and some of the passing just wasn't accurate enough.
"When we go in to these bigger games that's going to be the difference between winning and losing."
Eight of those tries came in a clinical first-half display which saw Ben West and Rhys Crane both cross twice, with Adam Field, Elliot Kear, Nic Reynolds and Chris Elder all touching down.
"Rhys Crane looked really sharp and I thought James Down was man of the match today – I was really impressed with him," added Burnell.
"As for some of the other new signings, Chris Elder looked confident and safe under the high ball and has a big physical presence.
"And some of those performances will now be rewarded and go in to the squad to play Wasps."
Welsh's second half tries came from Elder and James Lewis, but the Aviva Premiership new boys certainly didn't have it all their own way in the second half as Henley grew in to the game and asked plenty of questions of the Welsh defence.
"It was scrappy in the second half. There were a lot of changes and it took the third batch of players that bit more time to get in to it," said Burnell.
"In games like this when you get to a 50 point margin and all everyone can see is the 100 point margin, but you've got to give respect to Henley.
"They were outstanding. They worked hard and it was a great advert for the relationship between the two clubs."
The Exiles now head to Adams Park next Sunday for what is sure to be a far sterner challenge.
"That will be a true indication of where we're actually at," said Burnell "We'll be putting out the best team available as well as some of the boys who played today, and we're really looking forward to the challenge."
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Pax Christi marks 70 years of pursuing peaceOct. 11, 2014 Peace & Justice
Benedictine Sr. Christine Vladimiroff diesSep. 30, 2014 Sisters' Stories
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Global summit helps break the silence on war and womenJun. 28, 2014 Global, People
Australian church's quiet revolution 'had to happen'Mar. 24, 2014 Global
Deacons help to expand church's welcomeJan. 28, 2014 Faith & Parish
Sociologist has kept his eye on CatholicismDec. 11, 2013 People
Letter signed by interfaith leaders urges Congress to pass gun control lawsDec. 9, 2013 People, Politics
Bourgeois disinvited from SNAP Philadelphia fundraiserOct. 16, 2013 People
A church that requires a different kind of bishopSep. 7, 2013 Global
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I have not purchased or read this book. This is the comment I was going to post to Ms. Glaser's article at "The Daily Beast" entitled "Elizabeth Peña and the... Read morePublished 25 days ago by Tv Food and Drink
I really enjoyed reading about the history of alcohol use in America as it pertains to women and how modern day over-consumption can be addressed beyond AA.Published 25 days ago by Susan Schubert
The AA's Deniers are closing Ranks here doing What They doing best that are Denying, Denying and Dennying. Read morePublished 1 month ago by Steven M. Morris
This book is profoundly ignorant about alcohol and addiction. Do not believe its unwarranted attack on 12 step programs. Nothing else works for most people, and it does work. Read morePublished 1 month ago by Peter Byrne
This is a well researched book and the history of women and booze is fascinating. Her analysis of why women drink more in the 21st c. Read morePublished 1 month ago by Thrilled Mama
I thought it a good book the covers a great deal of information about how women have evolved into a drinking society and how we might discern what it is to be an alcoholic. Read morePublished 1 month ago by Sheryl A. Oconnortaylor


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All Schools
(27) All Schools
(27) High Schools
(2) High Schools
(2) Elementary Schools
(25) Elementary Schools
(25) Preschools
(16) Preschools
(27) All Schools
(27) High Schools
(2) High Schools
(2) Elementary Schools
(25) Elementary Schools
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There are 27 private schools in California belonging to the National Association of Episcopal Schools (NAES), serving 5,979 students.
National Association of Episcopal Schools (NAES) Private Schools
- School Location Students Grades
RiversideAll Saints Carden Academy
3847 Terracina Dr
Riverside, CA, 92506
(951)682-8122(Episcopal)98 students | Gr. K-8
CarmelAll Saints' Day School
8060 Carmel Valley Road
Carmel, CA, 93923
(831)624-9171(Episcopal)204 students | Gr. PK-8
San FranciscoCathedral School For Boys
1275 Sacramento Street
San Francisco, CA, 94108
(415)771-6600273 students | Gr. K-8
All-boys (Episcopal)
San GabrielChilds Garden Center
535 W Roses Rd
San Gabriel, CA, 91775
(626)282-2731Daycare / Preschool (Episcopal)18 students | Gr. K-1
CoronadoChrist Church Day School
1114 9th St
Coronado, CA, 92118
(619)435-6393(Episcopal)122 students | Gr. KG-6
SaratogaSaint Andrew's Episcopal School
13601 Saratoga Ave.
Saratoga, CA, 95070
(408)867-3785(Episcopal)375 students | Gr. PK-8
Chula VistaSaint John's Episcopal School
760 1st Ave
Chula Vista, CA, 91910
(619)422-4141(Episcopal)277 students | Gr. PK-8
PortervilleSt Anne School
385 N F St
Porterville, CA, 93257
(559)784-4096(Roman Catholic)173 students | Gr. KG-8
DowneySt Mark''s Episcopal School
10354 Downey Ave
Downey, CA, 90241
(562)869-7213(Episcopal)101 students | Gr. PK-8
UplandSt Marks Episcopal School
330 E 16th St
Upland, CA, 91784
(909)920-5565(Episcopal)165 students | Gr. KG-8
Apple ValleySt Timothy''s Preparatory School
15757 Saint Timothy Rd
Apple Valley, CA, 92307
(760)242-4256(Episcopal)67 students | Gr. PK-6
ComptonSt Timothys Episcopal School
312 S Oleander Ave
Compton, CA, 90220
(310)638-6319(Episcopal)38 students | Gr. PK-8
San MateoSt. Ambrose Sea Breeze School
900 Edgewater Blvd
San Mateo, CA, 94404
(650)574-5437Daycare / Preschool (Episcopal)n/a students | Gr. NS-PK
South PasadenaSt. James Parish Day School & Kindergarten
1325 Monterey Rd
South Pasadena, CA, 91030
(626)799-6906Daycare / Preschool (Episcopal)15 students | Gr. K
Rancho Santa MargaritaSt. John's Episcopal School
30382 Via Con Dios
Rancho Santa Margarita, CA, 92688
(949)858-5144(Episcopal)356 students | Gr. NS-8
RosevilleSt. John's School
4501 Bob Doyle Drive
Roseville, CA, 95747
(916)786-5400(Episcopal)194 students | Gr. PK-8
Palm DesertSt. Margaret's Episcopal School
47-535 Highway #74
Palm Desert, CA, 92260
(760)346-6268(Episcopal)118 students | Gr. PK-8
San Juan CapistranoSt. Margaret's Episcopal School
31641 La Novia
San Juan Capistrano, CA, 92675
(949)661-0108(Episcopal)1099 students | Gr. PK-12
WinnetkaSt. Martin Fields Parish School
7136 Winnetka Avenue
Winnetka, CA, 91306
(818)340-5144(Episcopal)100 students | Gr. PK-8
San MateoSt. Matthew's Episcopal Day School
16 Baldwin Ave
San Mateo, CA, 94401
(650)342-5436(Episcopal)198 students | Gr. NS-8
Pacific PalisadesSt. Matthew's Parish School
1031 Bienveneda Avenue
Pacific Palisades, CA, 90272
(310)454-1350(Episcopal)294 students | Gr. NS-8
CarmichaelSt. Michael's Episcopal Day
2140 Mission Ave
Carmichael, CA, 95608
(916)485-3418(Episcopal)211 students | Gr. PK-8
Thousand OaksSt. Patrick's Episcopal Day School
1 Church Rd
Thousand Oaks, CA, 91362
(805)497-1416(Episcopal)132 students | Gr. K-6
OaklandSt. Paul's Episcopal School
116 Montecito Ave
Oakland, CA, 94610
(510)285-9600(Episcopal)360 students | Gr. K-8
La JollaThe Bishop's School
7607 La Jolla Blvd
La Jolla, CA, 92037
(858)459-4021(Episcopal)797 students | Gr. 6-12
IrvineThe Children's Center Of St. An
4400 Barranca Pkwy
Irvine, CA, 92604
(949)651-0198Daycare / Preschool (Episcopal)25 students | Gr. NS-PK
Sierra MadreThe Gooden School
192 N Baldwin Ave
Sierra Madre, CA, 91024
(626)355-2410(Episcopal)169 students | Gr. KG-8
State Statistics
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Updated October 26, 2014
What do you do when you are dissatisfied with your local public schools? Homeschool your children? Send them to private school? Let's look at your options.
Your religion matters to you. You want your child to attend a school which will combine academics and religious education. Here is an overview of what is available together with some links to denominational web sites.
Add things up and you'll quickly find the answer- math is crucial both in academics and the real world. By following these strategies and following personal training programs, students can uncover their weaknesses and conquer math.
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HoopsHype Andrea Bargnani rumors
And it was CAA, according to sources, that persuaded Dolan to make the ill-fated trade for its client Andrea Bargnani—over the concerns of the Knicks' front office. "If (Jackson's hiring) breaks the stranglehold of CAA, I want it to happen," said an agent who does business with the Knicks. "I can't see him in a million years working with them." Bleacher Report
Andrea Bargnani says he has no timetable for his return and is unsure if he will be back this season. Bargnani suffered an elbow injury on Jan. 24. Kenyon Martin (ankle) hasn't resumed basketball activities. He has been out since Feb. 3 with a sore left ankle. ESPN.com
The torn ligament in Andrea Bargnani's left elbow won't require surgery, but the Knicks aren't sure how long they'll be without the 7-footer. "He's out indefinitely," Woodson said before Friday's game against Charlotte. Wall Street Journal
Chandler then was asked if he was surprised Woodson took out a unit that had built a five-point lead early in the fourth quarter spearheaded by Pablo Prigioni and Andrea Bargnani. "A little,'' Chandler said. "It is what it is.'' New York Post
The Knicks are expecting Pablo Prigioni (broken toe) to return after missing 16 games, and Woodson indicated the veteran point guard might start alongside Raymond Felton in the backcourt. A return to that smaller alignment likely would push Andrea Bargnani to the bench, with Anthony manning the power forward spot. New York Daily News
Carmelo Anthony scored 29 points, Andrea Bargnani had 19, and the Knicks beat the Heat 102-92 on Thursday night for their season-high third straight victory. "You can tell it's different than one month ago," Bargnani said. "Our faces are different, our body language is different." USA Today Sports
Chris Herring: Fewbother guys I was statistically curious abt: David Lee & Carlos Boozer. Both guys, like Bargnani, shoot WAY better when gms aren't close. Twitter @HerringWSJ
Andrea Bargnani had trouble moving his neck after the game and said he's been playing with a stiff neck for the last eight to 10 days. He played only 4:16 in the second half, but making no impact on defense or the boards had more to do with that than his neck did. Newsday
Al Iannazzone: Bargnani was booed during intros, louder than in the preseason but still nothing like Vince Carter's return here. Not even close. Twitter @Al_Iannazzone
This would be the ballgame. The shot clock was off, and the Bucks would have to foul, and the Knicks could win the game at the foul line, and — AND HOLY HELL, DID HE JUST SHOOT A 3-POINTER?!?!?!?!?!?!?!? "Maybe he thought I shot an airball and he had to shoot," Anthony would say later. "Maybe he thought we were behind," Mike Woodson said. "I made a mistake," Bargnani said. New York Post
In fact, this past summer, the Knicks originally wanted to trade for Portland Trail Blazers power forward LaMarcus Aldridge, but "Andrea Bargnani was pushed onto the Knicks because of CAA," according to a source close to the Knicks. Bleacher Report
Dolan became livid over the public disclosure of the deal terms and became aware over some segments of reaction that deemed the package a third straight debacle in dealing with Raptors general manager Masai Ujiri, sources said. Ujiri, the NBA's Executive of the Year with the Denver Nuggets a year ago, negotiated deals that brought the Knicks Carmelo Anthony and Andrea Bargnani in recent years. Yahoo! Sports
Chris Herring: Woodson, on Bargnani: "His teammates were excited to see him show some emotion." Twitter @HerringWSJ
Thursday night he was on the receiving end, even if he wasn't sure what language he was being yelled at when Andrea Bargnani earned his first career ejection in the fourth quarter of the Knicks' slump-busting rout of the Nets at Barclays Center. "I don't speak Italian," Garnett barked when asked what Bargnani said to him. New York Daily News
"I wasn't speaking Italian, but that's not important," said Bargnani, who finished with 16 points to help the Knicks finally halt their nine-game losing streak. "The game was important. I'm happy we won. "I don't want to talk about referees and what happened. I got ejected, and that's OK. We got the game and that's what counts." New York Daily News
As Howard made his way down the floor, Bargnani lunged for him in an attempt to Hack-a-Dwight again. His teammates shouted at him not to do it; an intentional foul away from the ball with less than two minutes left would have resulted in one shot plus the ball. CBSSports.com
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Comprehensive DescriptionRead full entry
Nominate race has forehead, crown and ear-coverts to upperparts bright yellowish-green, uppertail-coverts slightly more yellow; very narrow white eyering (almost lacking); chin and throat to upper breast orange-yellow, remainder of underparts grayish-white, undetail-coverts yellow; iris chestnut-brown to grey-brown; vill blackish; legs bluish-grey. Differs from Z. novaeguineae in generally brighter coloration, mich narrower white eyering. Sexes alike. Juvenile apparently undescribed. Races differ mainly in coloration of head and prominence of eyering, nominate being brightest and almost lacking eyering, other three having black forehead and broad eyering: chrysolaemus has greener upperparts than nominate, and very conspicuous greenish edges on tail feathers; gregarius is more yellow and duller on back, with narrower eyering than previous and slightly more orangeish-yellow on throat, thus approaching nominate; delicatulus has whole forehead, loral line and area under eye black, very broad white eyering, greener bach than chrysolaemus, distinctly less orange throat (closely resembles race sulaensis of Z atrifons).


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It's a simple law of doing business. If one location is making a lot of money, then imagine what several locations could do. Everyone is familiar with the concept of chain businesses. You can find examples of them in just about every type of industry working today. There are chain hardware stores, florists, and even massage clinics. The most popular and familiar type of chain business is restaurants. Restaurant chains are available from concession stand style establishments to fast food chains, on up the ladder to five star dining options. Anyone can choose to run a restaurant of this type with the appropriate corporate support.
There are several reasons to consider adding one of the restaurant chains to your company's resume. The corporate company provides almost all of your needs including food, menu selections, packaging, policies, and management support. Local owners typically supply the staff and may have some flexibility in how the restaurant is run, though this varies according to corporate headquarters' policies. Many people and companies choose to enter the restaurant business with a chain location because it usually offers a well- known name brand that almost sells itself.
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Working behind the scenes at the Royal Opera House
16 October 2014
In preparation for TheatreCraft 2014 careers fair, a selection of our favourite backstage films and resources.
Listen: Antonio Pappano - 'Every note must be theatrical. Every note is important'
13 October 2014
The Music Director of The Royal Opera on opera in cinemas, the pressure on singers, and his thoughts on concept-led 'Regietheater'.
Vicky Featherstone, Artistic Director of the Royal Court Theatre, to open TheatreCraft 2014
19 September 2014
The acclaimed theatre director will open this year's event at the ROH on Friday 17 October.
Follow in the footsteps of Royal Ballet dancers: Applications for Genée Ballet Competition 2014 are now open
14 August 2014
Previous medalists include Lauren Cuthbertson and Steven McRae.
New apprenticeships offered at the ROH
6 May 2014
We're currently recruiting for eight new apprentices, with opportunities across our backstage and technical departments.
National Apprenticeship Week 2014: How you can gain vital working experience at the ROH
3 March 2014
Apprenticeships are available in a range of departments, from Technical Theatre to Scenic Art.
Apprentices successfully complete training after two years at ROH
7 August 2013
Four apprentices celebrated after working on everything from Rigoletto to the BAFTAs.
500 primary school children from around England come together to perform at Covent Garden
31 July 2013
Children and teachers share new-found dance experience, developed through Dance Dynamic.
ROH staff visit National Centre for the Performing Arts in Beijing
17 June 2013
Royal Opera House delivering training courses in China.
ROH Thurrock looking into new costume facility
4 June 2013
New building would be a home for costume making, storage and learning.


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John Redwood
MP, Wokingham
MP, Wokingham
See our much more detailed, easier-to-read analysis of votes on health, welfare, foreign policy, social issues, taxation and more.
John Redwood quite often rebelled against their party in this parliament
Can the hon. Gentleman explain why he, as someone who wants Scottish independence and to be completely independent of the United Kingdom Government, wants to put himself completely under the government of the European Union?
Does that not mean that we need a new relationship? Does the right hon. Gentleman not see that, according to his logic, we cannot be in the room when a lot of financial matters are discussed because we are not part of the compacts relating to the euro?
Will the right hon. Gentleman give way?
More of John Redwood's recent appearancesRSS feed (?)
Conservative MP for Wokingham
Entered House of Commons on 11 June 1987 — General election
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This data was produced by TheyWorkForYou from a variety of sources. Voting information from Public Whip.


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Special Boat ServiceLine breaks: Spe¦cial Boat Ser|vice
Entry from British & World English dictionary
(abbreviation: SBS)
Definition of Special Boat Service in English:
(In the UK) a nautical counterpart of the SAS, provided by the Royal Marines.
Definition of Special Boat Service in:
- British & World English dictionary
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Pronunciation: ˈSHpräkɡəˌf(y)o͞ol
intuitive understanding of a language's natural idiom…


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Originally published Saturday, December 21, 2013 at 3:51 PM
Man gets 8 years for child's accidental gun death
A Sedro-Woolley man pleaded guilty Friday to first-degree manslaughter for the July 21 shooting death of his girlfriend's 4-year-old son.
Skagit Valley Herald
MOUNT VERNON — A Sedro-Woolley man pleaded guilty Friday to first-degree manslaughter for the July 21 shooting death of his girlfriend's 4-year-old son.
Trevor Braymiller, 25, was sentenced to almost eight years in prison — almost twice as long as Dwayne Kerrigan was alive. The child accidentally shot himself with Braymiller's gun, prosecutors said.
About 15 members of Dwayne's family were in the Skagit County Superior courtroom, at least one wearing a T-shirt with the child's name and face on it. They cried and held each other after Judge Dave Needy handed down the 95-month sentence.
"It's a very difficult case for all the family to deal with," senior deputy prosecutor Trisha Johnson said.
After the shooting, which took place in the family home, Braymiller took the gun and fled to Big Lake. Hours later, a State Patrol dog found the gun at a church near the house.
Braymiller surrendered to police the next day, after an autopsy determined the boy had shot himself in the head.
In court Friday, defense lawyer Keith Tyne called the case "utterly heartbreaking ... the saddest kind of case I can think of." His client is overcome with remorse and never meant to hurt anyone, he said.
"Mr. Braymiller made very bad decisions in the days before this tragedy," he said.
Although Tyne advised him to go to trial, calling the manslaughter case "defensible," Braymiller refused to force Dwayne's family to relive the trauma of the boy's death during a trial, Tyne said.
Braymiller had been with Dwayne's mother, Heather Brittain, for 3½ years and was a father figure to Dwayne, Tyne said. He and Brittain have a daughter together, who was also in the house during the shooting.
The manslaughter conviction is Braymiller's first strike under Washington's three-strikes law for serious offenses. His only other criminal history is drug-related: possession of marijuana with intent to deliver and possession of methamphetamine. He was on probation for that case when the shooting occurred and was not allowed to have the gun, which turned out to have been stolen.
The guilty plea to manslaughter dropped the two other counts against Braymiller: unlawful possession of a firearm and possession of a stolen firearm.
Needy ruled that drug addiction contributed to what had happened, which will allow Braymiller to seek chemical-dependency treatment in prison. After his release, Braymiller must serve three years in community custody. He also must pay $6,339 in restitution, mostly to cover Dwayne's funeral costs.
In victim-impact statements, some members of Dwayne's family said Braymiller should not get any "breaks." Needy said that although the 95-month manslaughter sentence is at the low end for someone with Braymiller's criminal history, he doesn't see it as a break because Braymiller will have to live with what happened for the rest of his life.
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Adam Lambert to Teens: I Get Bullied, Tooby Hilton Hater at . Comments
There's so much more to me than who I choose to sleep with. You are so much more than your orientation. Be strong. Pay attention to the positive.
It's hard to imagine a better role model for confused, at-risk youths than Adam Lambert.
This well-spoken, talented singer is unafraid and unashamed to be true to who he is, yet he refuses to simply be labeled as a gay singer. How come?
Because, as Lambert explains in the video below, one's sexual orientation is such a small part of who one actually is. Yes, it gets better, he tells bullied teens around the world... but only if you stay strong, stay focused and never let the ignorant win.
Absolutely wonderful! A great human being.
I applaud Adam for his honesty and not trying to hide who he is. It shouldn't matter what someone's sexual preferences are only who they are. So many people in this country (America) are full of hate and ignorance. It makes me cringe when I hear someone say something derogatory toward a gay person. They are not just "gay" they are a person with feelings and that is only a small part of who they are. I am a "straight" female and I would hate to be labled that because that does not describe WHO I am as a person. Stay strong Adam, you are a beautiful person!
The stupid homophobes in this world are the ones killing the poor gay children. So sad!!! Thumbs up to Adam for helping them!!
true idol.
Love you brave Adam, we just love you!!
I love you Adam. You're my idol, realy. Like you sead it doesn't mean whit who you sleep or how do you dress, you just have to be your self. Be difrend. Whene you become fameous I heard your music and is osome. And they sead to me why you listen to him, he's gay and bla bla bla... And I sead to the thath it doesn't mean if he is gay, all it mathers in the kind of person you are and not how you dress and thath things. And thene they think you're crazy because you listen to them. What a losers. And just thath you know thise is writen by 13 year old girl from Slovenia.


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Not Quite Dating
Posted December 6, 2012
My Review:*happy sigh* Another great book by Catherine Bybee. Th
My Review:*happy sigh* Another great book by Catherine Bybee. This is only the second I've read by her, but she is quickly establishing herself as a favorite contemporary romance author. I become completely immersed within the stories of her books and I love that. Seriously, I never even think about the fact that I am reading a book when I am reading one of her's. I simply become part of the story and don't want it to end. That's some great writing there!
The story line in this one isn't new... rich guy who hides his wealth to find a girl who likes him for who he really is... but Catherine Bybee did it so well. I loved these characters!
Jessie is on the edge. She lives in a 2 bedroom apartment with her 5 yo son and her 21 yo sister. Her sister is in Nursing school and Jessie works nights at the local Denny's so that she or her sister is always around to care for her son. She grew up with a mother who was constantly falling in love with losers and Jessie, herself, hasn't had the best of luck choosing guys. This next time, she's determined she's going to choose a guy who isn't going to mooch off her for the rest of his life.
Jack has had it with shallow arm-candy. He wants a girl to like him for who he is.... not for the size of his very hefty bank account. When he meets Jessie, he thinks he has to hide who he is, so he acts like he has a temporary holiday job at the local upscale motel (that he actually owns). Jessie sees him as someone a bit flakey... so she agrees to be friends with him... friends only, although Jack never hides the fact that he wants more.
I liked the way that this was all set up...*Jack's family who owns the upscale chain of motels and a ranch in Texas...I can't wait for his sister, Katie's story.*When Jack comes into the book, he's with his 3 best friends for a bachelor weekend in Vegas. I liked the friendship between these guys....and again look forward to seeing more of them.... especially Drew, after his heartbreak in this book.*I loved Jessie's son and sister and what they added to this story. * I loved that the book took place during Christmas. I truly wasn't expecting it to be a holiday read, but it made a GREAT one!This is book #1 in the Not Quite series...I am excited to read the rest of them because this was a great start!I received a complimentary copy of this book in return for an honest review.
1 out of 1 people found this review helpful.Was this review helpful? Yes NoThank you for your feedback. Report this reviewThank you, this review has been flagged.
Posted November 29, 2012
Loved it! You will too!
This is a great book with a real feel. Catherine has created well developed characters. I fell in love with Jessie (no, not because we share a name) and her fierce love for her son, Danny. Jack is the kind of guy we all want to magically take interest in us and rescue us from our boring lives.
I loved the character arcs. This wasn't just another typical romance novel. Not that it isn't a romance novel. I just feel like Catherine spent more time focusing on building the story, developing the characters, and creating a great book than just thinking about the next steamy scene.
I'd recommend this book for the romance lovers out there, but then also to those that enjoy a good read with a realer take on romance- not that I've ever heard of a millionaire randomly taking it on himself to woo over the Denny's waitress, but hey, it could happen.
1 out of 1 people found this review helpful.Was this review helpful? Yes NoThank you for your feedback. Report this reviewThank you, this review has been flagged.
Posted May 15, 2013
Jessie Mann is a single mom. She's worked hard for everything s
Jessie Mann is a single mom. She's worked hard for everything she has. She and her sister work to see her son Danny has all he needs. Jessie keeps hoping someday her prince will arrive with enough money so she doesn't have to worry every day. Until he does, she works at a waitress on the graveyard shift.Was this review helpful? Yes NoThank you for your feedback. Report this reviewThank you, this review has been flagged.
Jack Morrison is an heir to a luxury hotel empire. He and his buddies are just back from a bachelor party to end all parties. Jack has been wondering if he'll ever find a woman who loves him and not his back account. Then Jessie walks into his life.
This book is fantastic! It's the first in the "Not Quite" series. I can't wait to read the others. The characters are well developed and fun to follow. The story one you'll enjoy again and again. Tender, fun and the fairy tale ending is all you could ever want in a book. You'll get hooked on this one from page one.
I found no issues.
I gave this one 5 cheers out of 5 because it's such a fantastic read. ~Copy of book provided by author in exchange for a fair review~


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Savor: Mindful Eating, Mindful Life (Paperback)
Not currently in the store – Usually ships in 1-5 days
End Your Struggle with Weight.
Your Path Begins Here.
With the scientific expertise of Dr. Lilian Cheung in nutrition and Thich Nhat Hanh's experience in teaching mindfulness the world over, Savor not only helps us achieve the healthy weight and well-being we seek, but also brings to the surface the rich abundance of life available to us in every moment.
About the Author
Thich Nhat Hanh is a Vietnamese Buddhist Zen Master, poet, scholar, and peace activist who was nominated for the Nobel Peace Prize by Dr. Martin Luther King, Jr. He is the author of many books, including the classics Peace Is Every Step and The Art of Power. Hanh lives in Plum Village, his meditation center in France, and leads retreats worldwide on the art of mindful living.
Praise for Savor: Mindful Eating, Mindful Life…
"Among Buddhist leaders influential in the West, Thich Nhat Hanh ranks second only to the Dalai Lama."
-New York Times
"Hanh and Cheung explore the convergence of nutritional science with Buddhist teaching and find complementary insights. Together, they provide approaches that help to heal both the individual and societal illness that is being manifested as an epidemic of obesity. Everyone can learn from this book."
-Walter Willett, M.D., author of Eat, Drink, and Be Healthy and Chair, Department of Nutrition Harvard School of Public Health
"Authored by an eminent spiritual leader and a renowned nutritionist, this work infuses science into wisdom and wisdom into science. It is a practical guide to eating mindfully and points the way to attain a healthier weight and a more satisfying life."
-From the foreword by Harvey V. Fineberg, M.D., Ph.D. President, Institute of Medicine
"Zen Buddhist monk Thich Nhat Hanh and Dr. Lilian Cheung, in Savor, have brought us a profoundly beautiful and powerful guide to mindful eating and living. Please savor it."
-David S. Ludwig, MD, PhD, Director of the Optimal Weight for Life (OWL) Program, Children's Hospital Boston and author, Ending the Food Fight: Guide your Child to a Healthy Weight in a Fast Food/Fake Food World.
"This is a uniquely insightful and positive program for wellness; a book of tested wisdom; practical action; and intellectual, emotional, and spiritual nutriments."
"...Not your average healthy-eating guide. 'Savor' may have us rethinking every bite, but maybe that's just what we need.."
-Tricycle Magazine
"In their new book, "Savor: Mindful Eating, Mindful Life," Lilian Cheung, a nutritionist at Harvard, and Thich Nhat Hanh, a Buddhist teacher, give important advice to dieters about using Buddhist techniques of mindfulness to control overeating."
-New York Times
"Even if you already have your weight under control, implementing the exercises in this book is bound to enhance the presence and sensuous pleasure of your eating."
-Basil & Spice
"The book is recommended not only for those seeking practical advice on how to control excesses leading to overweight but also to anyone wishing to bring balance into his or her everyday life."
-New Age Retailer
"Together, Cheung and Hanh offer a primer on psychological and spiritual health, as well as a practical nutritional guide to healthier eating."
-Harvard Magazine


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Spotlight on the Library of Michigan
- "Faster Broadband for Schools and Libraries" A Sunday New York Times editorial supporting the growth of the E-Rate program via a modest increased tax on phone lines to provide an increased spending cap that will provide and improve broadband services for schools and libraries, particularly those in poor and rural areas.
- 2014 Friends of Michigan Libraries (FOML) Outstanding Friends Group Merit Award Did your Friends of the Library carry out an outstanding project or a number of successful activities in your community during 2014 that had a significant impact on your library's services to the community? FOML encourages you to apply for this award. Applications must be postmarked by Friday, January 16, 2015. Go to the link above for more information and an application form.
- School Libraries in the 21st Century The SL 21 program is a tool to help measure the quality of School Library programs within individual school buildings in Michigan. A set of criteria based on leadership, learning environment and teaching are used to evaluate school library media programs. The measures were developed by the Library of Michigan and the Michigan Association of Media in Education.
Goals, Mission & Performance
- The Mission of the Library of Michigan The Michigan Legislature created The Library of Michigan to guarantee the people of this State and their government one perpetual institution to collect and preserve Michigan publications, conduct reference and research and support libraries statewide.
- Scorecard for the Library of Michigan - October 2014
Michigan eLibrary
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Find It Here!
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The Library will be closed Thursday and Friday, November 27 and 28, in observance of Thanksgiving. Normal business hours will resume Monday, December 1.
The Library of Michigan is open Monday - Friday 10 a.m. to 5 p.m. and the second Saturday of every month from 10:00 to 4:00. Parking is a dollar an hour in our convenient lot. See the link above to contact departments or individuals.