Thursday, June 16, 2011

Wnt signalling in stem cells and cancer. Xanya Sofra Weiss

The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

Stem cells are cells that have the unique ability to self- renew as well as to generate more differentiated progeny. The most primitive stem cell is the embryonic stem cell, which is derived from the inner cell mass of the blasto- cyst. This cell is pluripotent and can thus generate all the tissues of the body. Following the pioneering work on haemato- poietic stem cells over the last five decades, a multitude of recent studies have indicated that most other adult tissues also harbour stem cells. These adult stem cells are normally involved in homeo- static self-renewal processes but can also be rapidly recruited to repair tissues upon injury. With the study of adult stem cell biology, recurring roles of a limited set of signalling cascades are rapidly being uncovered. One of these is the canonical Wnt cascade. Notably, in many of the same tissues where the Wnt cascade controls stem cells, cancer ensues upon dysregulated activation of this pathway. Conceptually, this indicates that an efficient road to cancer involves the hijacking of physiological regulators of stem cell function in these particular tissues. Below, we first outline the canonical Wnt cascade, and then describe its mirror image roles in the biology of stem cells and cancer.

vertebrate genome encodes four highly similar Tcf/Lef proteins. In the absence of a Wnt signal, Tcf/Lef proteins repress target genes through a direct association with co-repressors such as Groucho. The interaction with b-catenin transiently converts Tcf/Lef factors into transcriptional activators. Drosophila genetics has recently identified two additional nuclear components, Pygopus and Bcl9 (also known as legless), conserved in vertebrates. Pygopus is essential for transcriptional activation of Tcf/Lef target genes, whereas Bcl9 seems to bridge Pygopus to Tcf-bound b-catenin. In sum, the canonical pathway translates a Wnt signal into the transient transcription of a Tcf/Lef target gene programme.


Xanya Sofra Weiss

Xanya Sofra Weiss

THE INSIDE STORY OF CELL COMMUNICATION. Xanya Sofra Weiss

Cells communicate by sending and receiving signals. Signals may come from the environment, or they may come from other cells. In order to trigger a response, these signals must be transmitted across the cell membrane. Sometimes the signal itself can cross the membrane. Other times the signal works by interacting with receptor proteins that contact both the outside and inside of the cell. In this case, only cells that have the correct receptors on their surfaces will respond to the signal.


Xanya Sofra Weiss

Xanya Sofra Weiss

Collagen synthesis of articular cartilage explants in response to frequency of cyclic mechanical loading. Xanya Sofra Weiss

Articular cartilage in vivo experiences the effects of both cell-regulatory proteins and mechanical forces. This study has addressed the hypothesis that the frequency of intermittently or continuously applied mechanical loads is a critical parameter in the regulation of chondrocyte collagen biosynthesis. Cyclic compressive pressure was applied intermittently to bovine articular cartilage explants by using a sinusoidal waveform of 0.1–1.0 Hz frequency with a peak stress of 0.5 MPa for a period of 5–20 s followed by a load-free period of 10–1,000 s. These loading protocols were repeated for a total duration of 6 days. In separate experiments, cyclic loading was continuously applied by using a sinusoidal waveform of 0.001–0.5 Hz frequency and a peak stress of 1.0 MPa for a period of 3 days. Unloaded cartilage discs of the same condyle were cultured in identically constructed loading chambers and served as controls. We report quantitative data showing that (1) no correlation exists between the relative rate of collagen synthesis expressed as the proportion of newly synthesized collagen among newly made proteins and either the frequency of intermittently or continuously applied loads or the overall time cartilage is actively loaded, and (2) individual protocols of intermittently applied loads can reduce the relative rate of collagen synthesis and increase the water content, whereas (3) continuously applied cyclic loads always suppress the relative rate of collagen synthesis compared with that of unloaded control specimens. The results provide further experimental evidence that collagen metabolism is difficult to manipulate by mechanical stimuli. This is physiologically important for the maintainance of the material properties of collagen in view of the heavy mechanical demands made upon it. Moreover, the unaltered or reduced collagen synthesis of cartilage explants might reflect more closely the metabolism of normal or early human osteoarthritic cartilage.

Xanya Sofra Weiss

Xanya Sofra Weiss

Signaling Pathways for Glycated Human Serum Albumin-Induced IL-8 and MCP-1 Secretion in Human RPE Cells. Xanya Sofra Weiss

PURPOSE.

To determine the signal mediators involved in glycated human serum albumin (GHSA) stimulation of interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 secretion in human retinal pigment epithelium (hRPE) cells.


METHODOS:

hRPE cells were stimulated by GHSA in the presence or absence of a series of kinase inhibitors. The induced IL-8 and MCP-1 mRNA and proteins were determined by reverse transcription–polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot analysis, electrophoretic mobility shift assay, and immunohistochemical staining were used to analyze activation of signaling mediators and transcription factors.


RESULT:

IncubatioSn of hRPE cells with GHSA resulted in rapid activation of Raf-1, extracellular signal-regulated protein kinases (ERK) 1/2, p38, and the transcription factor nuclear factor (NF)-κB. Coincubation of hRPE cells with the mitogen-activated protein (MAP) kinase (MEK) inhibitor U0126; NF-κB inhibitors BAY11-7085, caffeic acid phenethyl ester (CAPE), parthenolide, and curcumin; protein kinase (PK)C inhibitor Ro318220; and protein tyrosine kinase (PTK) inhibitor genistein largely eliminated most of the stimulated production of IL-8 and MCP-1. Combined inhibition of MEK by U0126, p38 by SB202190, and Janus kinase (jak) by AG490 revealed that GHSA stimulation of IL-8 production was predominately mediated by MEK and to a lesser extent by p38 pathways, whereas activation of MEK, p38, and jak was required for maximal MCP-1 induction. Moreover, GHSA-stimulated IL-8 secretion was more sensitive to U0126 (50% inhibitory concentration[ IC ] = 0.5 μM) than MCP-1 (IC = 10μ M)



CONCLUSIONS:

GHSA stimulates hRPE IL-8 and MCP-1 production through divergent and overlapping, but not identical, intracellular signaling cascades. GHSA induces activation of a series of kinases including PKC, PTK, MAPK, p38, and jak and the transcription factor NF-κB. The Raf/MAPK pathway plays an essential role in GHSA signaling.


Xanya Sofra Weiss

Xanya Sofra Weiss

Selective Loss of Sertoli Cell and Germ Cell Function Leads to a Disruption in Sertoli Cell-Germ Cell Communication During Aging in the Brown Norway

We investigated the effects of aging on Sertoli cell-germ cell interactions from Brown Norway rats using the induction of four specific mRNAs as markers. The testes from aging (24 mo old) Brown Norway rats can be normal size or regressed. One marker, a von Ebner's-like protein, is expressed in coculture and “in vivo” in germ cells from normal testes of 6- and 24-mo-old rats but not in germ cells from regressed testes of 24-mo-old rats. A second germ cell marker, the Huntington disease protein, is expressed in all germ cells. Two Sertoli cell markers, a serotonin receptor and a novel gene, are induced in Sertoli cells by meiotic germ cells. The serotonin receptor mRNA is expressed in Sertoli cells from 20-day, 6-mo, and 24-mo normal testes but not in those from 24-mo regressed testes. The novel gene is induced in Sertoli cells from all testes. We conclude that Sertoli cells from aged regressed testes are unable to respond to selective signals from germ cells from young rats, and germ cells from regressed testes show a similar selective loss. Such disruptions in communication between Sertoli cells and germ cells likely contribute to germ cell loss during aging.

Xanya Sofra Weiss

Xanya Sofra Weiss


Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors.

STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related recep- tor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the ��- and ��-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signal- ing, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic my- elogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.

Xanya Sofra Weiss

Xanya Sofra Weiss

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Xanya Sofra Weiss

Identification of protein–protein interactions often provides insight into protein function, and many cellular processes are performed by stable protein complexes. We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae. Each preparation was analysed by both matrix-assisted laser desorption/ ionization–time of flight mass spectrometry and liquid chromatography tandem mass spectrometry to increase coverage and accuracy. Machine learning was used to integrate the mass spectrometry scores and assign probabilities to the protein–protein interactions. Among 4,087 different proteins identified with high confidence by mass spectrometry from 2,357 successful purifications, our core data set (median precision of 0.69) comprises 7,123 protein–protein interactions involving 2,708 proteins. A Markov clustering algorithm organized these interactions into 547 protein complexes averaging 4.9 subunits per complex, about half of them absent from the MIPS database, as well as 429 additional interactions between pairs of complexes. The data (all of which are available online) will help future studies on individual proteins as well as functional genomics and systems biology.



Xanya Sofra Weiss

Xanya Sofra Weiss

Thursday, June 9, 2011

Protein turnover plays a key role in aging. Xanya Sofra Weiss

Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of damaged macromolecules, especially proteins, is likely to play a central role in senescent decline. In this paper, we discuss evidence that the progressive decrease in protein synthesis and turnover can be the primary cause of the increase in the concentration of damaged proteins with age. Conversely, protein damage itself is likely to be the cause of the decrease in protein turnover. This could establish a positive feedback loop where the increase in protein damage decreases the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The establishment of such a feedback loop should result in an exponential increase in the amount of protein damage—a protein damage catastrophe—that could be the basis of the general deterioration observed in senescent organisms. © 2002 Published by Elsevier Science Ireland Ltd.


Xanya Sofra Weiss

Xanya Sofra Weiss

Parasympathetic nerve-evoked protein synthesis, mitotic activity and salivary secretion in the rat parotid gland and the dependence on NO-generation.

Incorporation of radiolabelled leucine and thymidine into trichloroacetic acid-insoluble material of the parotid gland was used as indices of protein synthesis and mitotic activity, respectively, following electrical stimulation of the parasympathetic auriculo-temporal nerve for 30 min in pentobarbitone-anaesthetized rats under adrenoceptor blockade (phentolamine and propranolol, 2 mg/kg intravenous of each) in the absence or presence of atropine (2 mg/kg intravenous) and without or with nitric oxide synthase inhibitors. In atropinized rats, the parasympathetic non-adrenergic, non-cholinergic (NANC) nerve-evoked mean increases in protein synthesis at a frequency of 10 Hz (142%) and 40 Hz (200%) were not affected in a statistically significant way (124 and 275%, respectively) by the neuronal type NO-synthase inhibitor Nwpropyl-L-arginine (N-PLA) (30 mg/kg intravenous). Neither were the increase (175%) in protein synthesis at 10 Hz in non-atropinized animals affected by N-PLA (180%). The increase (65%) in mitotic activity, 19 h after the end of stimulation at 40 Hz, in the presence of atropine, was not affected by N-PLA (55%). Neither were the increase (95%) in gland content of amylase at this point of observation statistically significant affected by N-PLA (144%). The secretion of fluid and output of amylase from the parotid gland upon nerve stimulation was not affected by N-PLA. When examining the non-selective NO-synthase inhibitor L-NAME (30 mg/kg intravenous) in atropinized rats subjected to stimulation at 10 Hz, neither the increase in protein synthesis nor the evoked fluid response or amylase outputs were affected. Hence, in contrast to an NO-dependent sympathetic-induced protein synthesis and mitosis in the parotid gland, involving the activity of the neuronal type NO-synthase, no support for a parasympathetic-induced protein synthesis (and gain in gland amylase) and mitosis, depending on NO-generation, was found.


Xanya Sofra Weiss

Xanya Sofra Weiss

Non-neuronal cholinergic system and signal transduction pathways mediated by band 3 in red blood cells. Xanya Sofra Weiss

BACKGROUND: Non-neuronal acetylcholine (ACh) and acetylcholinesterase (AChE) have been recognized in t Vascular ACh has been associated by us with the regulation of microcirculatory flow by modulating nitric oxide ( intracellular mobilization, metabolism (NOx) and release from erythrocytes, as well as the glycolytic flux. Velnacri maleate is a well-known AChE inhibitor which plays a competitive role by decreasing NO-mediated erythrocyte responses. A plausible hypothesis to explain the mechanisms underlying those events hinges on the NO translo among nitrosylated molecules and phosphorylated/dephosphorylated states of band 3 protein, processed by maj tyrosine-kinases (PTK: p72syk, p53/56lyn and p59/61hck) and phosphotyrosine-phosphatases (PTP).

METHODS: To assess this hypothesis under the influence of AChE effectors (acetylcholine/velnacrine), blood sa from healthy donors were harvested and Western blot analysis was subsequently used to determine the degree phosphorylation, in the presence and absence of PTK/PTP inhibitors. NO and nitrites/nitrates were quantified usi amperometric method and the Griess Reaction, respectively, in erythrocyte suspensions. Measurements of eryth metabolites (2,3-bisphosphoglycerate; glyceraldehyde 3-phosphate dehydrogenase; glucose-6-phosphodehydro lactate), hemoglobin and cyclic nucleotides were conducted afterwards.

RESULTS: Increased levels of phosphorylated-band 3 obtained upon p72syk inhibition suggest p59/61hck and as secondary involved kinases. As to NO/NOx quantification, in the presence of PTKi we reported higher levels velnacrine-AChE, as opposed to acetylcholine-AChE. Calpeptin, a PTP inhibitor which triggers full band 3-phosphorylation, led to the opposite NO mobilization, being reinforced by ACh. Oxy-hemoglobin, glyceraldehy 3-phosphate dehydrogenase and glucose-6-phosphodehydrogenase were found to decrease with ACh, whereas lactate and both cGMP/cAMP happened to increase.

CONCLUSION: Changes on human erythrocyte NOx mobilization and metabolic fluxes occur under influence of non-neuronal ACh/AChE, in turn dependent on the degree of band 3-phosphorylation. Since these vascular eve potentially change under pathological conditions, coadjuvant drugs could become accessible in the setting of microcirculation disease.


Xanya Sofra Weiss

Xanya Sofra Weiss

SEX AND AGING. Xanya Sofra Weiss

In nearly every culture on earth women outlive men — significantly so in the oldest years. But the men who do survive to become elderly are hardier than the women. A US National Institute of Aging study showed that 44% of men over age 80 are "robust and independent" compared with only 28% of women. And the percentage of surviving males increases from 15% at age 100 to 40% at age 105 in the United States.
If aging has been programmed by evolutionary forces, sex could be a very important contributor to the program. The reproductive organs of the human female exhibits a rate of aging that is among the most rapid of body systems. The complete shutdown of female fertility at menopause may be of value in preventing the birth of deformed children or death in childbirth of a mother who has several dependent children. For a species with a lengthy parenting period, it makes sense for fertility to cease long before the debilities of advancing age begin. Gonadotropin hormones from the pituitary gland are controlled by gonadotropin-releasing hormone, a 10-amino-acid peptide originating in neurons located in the arcuate nucleus of the hypothalamus. The two gonadotropin hormones (FSH & LH) are the same for females as for males, although their function is very different. Simplistically, FSH stimulates egg production in females & sperm production in males, whereas LH stimulates estrogen production in females & testosterone
production in males.
In fertile females FSH (Follicle-Stimulating Hormone) accelerates the growth of 6−12 primary follicles in the ovary each month — one of which may become a mature ovum. The follicles secrete estrogens, the most powerful of which is estradiol. A sudden increase in LH (Luteinizing Hormone) usually triggers ovulation (follicle rupture with discharge of the ovum) and the conversion of the follicle to the corpus luteum ("yellow body") — which also secretes estrogen, but primarily secretes progesterone. Progesterone stimulate the walls of the uterus to prepare it for implantation of the fertilized ovum. If pregnancy occurs, progesterone inhibits ovulation (by suppressing FSH & LH) and promotes uterine development until the placenta becomes more mature. (Progesterone is so-named because it promotes gestation, ie, the growth of offspring in the womb).
Aside from their role in the monthly cycle, estrogens are responsible for the development and maintenance of the female sexual organs, cause the deposition of fat in the breast&buttocks (which contributes to the feminine figure) and have a potent effect on bone development.
Menopause is the event in a woman's life when her ovary literally runs out of eggs. The loss of follicles to produce estradiol causes an end to menstrual cycling and production of estrogen & progesterone by the ovary. At age 30, a woman's period is normally 28−30 days, but by age 40 her period is typically closer to 25 days and her rate of egg-loss has accelerated. Further shortening (accompanied by periods when no ovulation occurs) eventually leads to menopause at an average age of 50 (plus or minus 10 years). The menopausal woman often experiences anxiety, irritability and fatigue. Beginning before menopause most women experience "hot flashes", ie, 3 minute surges of blood to the skin of the chest, shoulders & face leading to sudden hotness & sweating. Hot flashes are associated with a pulsatile release of LH from hypothalamic neurons associated with body temperature elevation. Estrogen therapy eliminates hot flashes. The rate of loss of ovarian follicles doubles around age 35, raising the suspicion that a hypothalamic mechanism may be the ultimate cause of menopause [SCIENCE 273:67-70 (1996)].
Graph of Female Hormonal Cycles
The most serious complications of menopause are osteoporosis and a decline in cardiovascular health. The Framingham Heart Study demonstrated that between ages 35 to 65 men have 10 times the incidence of heart attack as women — probably because estrogen protects against heart disease. Estrogen elevates HDL cholesterol and reduces LDL cholesterol in the bloodstream.
After menopause, nipples decrease in size and the surrounding alveolar tissue shrinks. Erection of these tissues with external stimulation is more difficult. Vaginal contractions during orgasm is reduced to 4−5 at 0.8-second intervals from 8−12 in young adults.
The testes have been regarded as the source of maleness at least since ancient Rome, where eunuchs & women were not permitted to "testify" (testis is Latin for "witness"). In the male, LH stimulates secretion of testosterone by the interstitial cells of Leydig in the testes. FSH stimulates spermatogenesis in the seminiferous tubules of the testes. Testosterone promotes development of male sexual organs in the foetus. At puberty testosterone stimulates hair growth on the face & pubis, causes enlargement of the larynx to deepen the voice, increases skin thickness, causes a 50% increase in muscle mass, promotes bone growth, increases basal metabolism up to 15% and increases red blood cell concentration.
There is no sudden "andropause" event in males that is comparable to the menopause event of females. Instead, testosterone levels tend to decline gradually with age. This decline occurs most dramatically in those with cardiovascular disease or a predisposition to adult-onset diabetes. Although sperm count declines, fatherhood has been verified for a male as old as 94. Semen production declines in the prostate as a man ages — and the smooth muscle is replaced by overgrowing connective tissue that enlarges the prostate, blocks urine and can lead to cancer. 85% of men over age 50 have symptoms arising from benign prostatic hyperplasia — a noncancerous overgrowth of prostate tissue possibly caused by excessive expression of the anti-apoptosis protein bcl−2 [HUMAN PATHOLOGY 27:668-675 (1996)]. In some tissues testosterone must be converted to dihydrotestosterone (by the enzyme 5−α reductase) in order to act. This occurs most notably in the prostate gland, which produces semen (a mixture of sugars, protein and water). Dihydrotestosterone has also been implicated in baldness. The European drug Permixon (an extract of the saw palmetto berry) inhibits 5−α reductase, and is used to prevent prostate hypertrophy and prostate cancer. The Life Extension Foundation sells saw palmetto berry extracts as a dietary supplement for this purpose.
Testosterone has been used in elderly men for "rejuvenation" — to restore virility & muscle strength. Testosterone increases the risk of cardiovascular disease — by increasing blood pressure, by lowering HDL cholesterol and by elevating LDL cholesterol. These same dangerous side effects are also seen in athletes who attempt to use androgens or other anabolic steroids to improve athletic performance. Eunuchs reportedly live longer, although there have been no controlled clinical trials to prove this
observation. Sterilization of a dog or cat (male or female) adds a couple of years to its lifespan. Any reduction in sex hormones would be expected to reduce cell proliferation and hence reduce the probability of cancer.
Male libido peaks in mid-adolescence, and does not correlate exactly with testosterone blood levels. In elderly men it may take from 10 seconds to several minutes to get an erection, in contrast to 3−5 seconds in young men. Contractions of the penile urethra during orgasm is reduced to 1−2 contractions per 0.8-seconds from 3−4 in young adults. Ejaculatory distance is reduced from 12−24 inches to 3−5 inches.

Xanya Sofra Weiss

Xanya Sofra Weiss

EVOLUTION THEORY AND SPECIES-SPECIFIC AGING. Xanya Sofra Weiss

Russell Wallace, who with Charles Darwin discovered natural selection, speculated that longevity much beyond the age of procreation would be a disadvantage for a species. Parents would threaten their children by competition for resources. This would imply an evolutionary advantage to genetically programmed aging. The programmed self-destruction with corticosteroids by Pacific salmon after spawning — and whose decaying bodies provide nutrient for their offspring — may be severe example indicating the possiblity of programmed senescence. But as biologist Herman Medawar noted, there is circular reasoning in claiming that senescence evolved so that non-senescent individuals could more readily survive. If there were no senescent, poorly-reproducing individuals, there would be no need for replacement.

If aging were the product of evolutionary forces, aging could reasonably be expected to result from programming. But since most animals in the wild die of accident, attack or disease it seems questionable that evolutionary forces determine aging. Robins in the wild, for example, have an

estimated 12-year maximum lifespan and a 40% chance of surviving any given year. With a (0.4)12 — or 1 in 60,000 — chance that a robin can avoid accident, attack or disease for 12 years, there would seem to be little opportunity for natural selection to play a role in the evolution of senescence. Against this argument is evidence that early stages of senescence reduce the ability of an animal to survive — thereby causing earlier selection against older animals.

An alternative to the view that senescence is the product of evolution compares genetic programming to the engineering of a fly-by satellite designed to gather data about a planet. The engineering is focused on ensuring that the satellite reaches its destination and performs its data gathering/transmission when passing the planet. Beyond the planet it is a matter of indifference to the engineers how long the satellite continues to function — random decay occurs. Applying the analogy, the satellite passing the planet is like an organism passing its reproductive period. Once the objectives of reproduction & parenting have been achieved the organism decays by random malfunction.

The vast range of maximum lifespan differences between species provides convincing evidence that longevity is genetically influenced. An elephant lives about 10−20 times longer than a mouse, yet both animals have roughly the same number of lifetime heartbeats — the elephant at 30 per minute and the mouse at 300 per minute. Both species take about 200 million breaths in a lifetime. And both species have a metabolic potential (total kilocalories used per gram of body weight per lifetime) of about 200 kcal. This figure is much the same for other mammals, but humans are exceptional with a metabolic potential of 800 kcal. Brains use more energy than any other human organ. (Basal metabolic rate for humans is about 80 watts = 70 Calories per hour.) Birds have a metabolic potential of 1,000 to 1,500 kcal.

Gerontologists who compare the longevity of species explain this discrepancy by saying that while body weight correlates well with longevity, there is a better correlation with brain weight for primates. For other species brain size may be more related to motor function than to cognitive capacity.

Flight, like brain weight, also confers a longevity advantage. Finches & robins live about 3 times as long as rodents the same size. Flying squirrels live twice as long as their close relatives the chipmunks. Parrots have a maximum lifespan in excess of 90 years. The Andean condor may be the most long-lived of any bird, but its maximum lifespan has not been confirmed.

Gross attributes of species typically associated with greater longevity are: large size, ability to yfl, brainy, a spiny or shelled encasement, and cold-blooded. All but the last attribute reduce vulnerability to predators. Porcupines are the longest-lived rodents. Naked mole rats, by living underground, are also safer from predators and live significantly longer than similarly-sized rats. All adaptations that afford protection from predators and other hazards justify greater developmental resources to build a more durable animal with a longer maximum lifespan.Opossums evolving on an island free of predators have been shown to have substantially longer lifespans and smaller litters than opossums living on the nearby mainland [JOURNAL OF ZOOLOGY; 229:695-708 (1993)]. Where competition between individuals of a species for mates & resources is more important than survival against predators and other hazards, evolution causes more investment in making a more hardy & durable animal — which includes having fewer offspring on each birthing (but more total offspring over the lifetime) — with each offspring receiving more care and resources. Gene survival can be better promoted (up to a point) by extending lifespan and reproductive period of reproductively successful adults than by creating many more offspring, a signficant number of whom will not survive to become reproductive adults.

Large size also confers protection against predators and confers an improved ability to escape dangerous environments. Metabolic rate decreases proportionally with increases in body size, which allows larger animals to survive longer when food & water are scarce. [For a sphere, surface area

S = 4πr2 and volume V = (4/3)πr3, which means that S/V varies inversely with r (radius). Because heat is generated in the volume and dissipates in the surface area, relative dissipation decreases with an increase in radius because of the decrease in S/V.] Large animals are better able to withstand extreme temperatures because of greater body mass. Large animals and birds are more easily able to travel long distances to find food or less harsh environments.

Cold-blooded animals needn't expend energy to maintain body temperature and therefore generate fewer free-radicals. Also, the rate of chemical reactions more than doubles for each 10oC increase in temperature. Cold-blooded animals may use one-tenth as much energy as warm-blooded animals of the same body weight. The alligator, Galapagose tortoise and lake sturgeon combine large size with cold-bloodedness. Turtles live longer than other reptiles because of the shell which protects against predators. With the combination of hard shell, large size and cold-bloodedness, it is not surprising that the Galagose turtle is probably the most long-lived vertebrate. Hard shell, cold-bloodedness and the ability to reduce metabolic rate allow some bivalves to live nearly four centuries [GERONTOLOGY; Philipp,EER; 56(1):55-65 (2010)].

A short-lived organism would waste metabolic energy by over-investing in anti-oxidant or DNA-repair enzymes when the energy could be spent on rapid growth and reproduction. When a species has fewer predators, evolution invests fewer resources into speedy reproduction and more genetic resources (DNA repair, etc.) into a longer reproductive period (longer life). In the case of birds, the mitochondrial membranes contain more unsaturated fat making them less vulnerable to lipid peroxidation. And the protein complexes of the respiratory chain of mitochondria generate fewer free radicals in birds than in mammals. It is conceivable that an animal with well-engineered cells could live many centuries. Human germ cells have arguably lived for millions of years through an investment in DNA-repair enzymes, antioxidant enzymes and telomerase.

Evolutionary biologists are able to use artificial selection in the laboratory experimentally (rather than passively studying natural selection in the wild) to seek the evolutionary determinates of longevity. Michael Rose at the University of California has shown that Drosophila(fruit-flies) bred for 15 generations by disposing of eggs laid early in life and only using eggs that were laid toward the end of reproductive life achieved maximum lifespans 30% greater than that of controls. The long-lived strains had increased levels of SOD, CAT and xanthine dehydrogenase as well as increased levels of heat shock proteins conferring stress resistance [JOURNALS OF GERONTOLOGY

55A(11):B552-B559 (2000)]. Hsp22 heat shock protein expression was 2−10 times greater in the long-lived strains as compared to controls. Transgenic Drosophila (ie, fruit flies with artificially altered genes) with extra copies of hsp70 genes live nearly 8% longer than controls following heat treatment [NATURE; Tatar,M; 390:30 (1997)].

Dr. Rose has also observed the experimental increase in mortality associated with aging ceases late in life [PHYSIOLOGICAL AND BIOCHEMICAL ZOOLOGY; Rose;MR; 78(6):869-878 (2005)]. Although mortality rates remain very high in late-life, they plateau. Studies of inbred Drosophila indicate that the plateauing cannot be due to genetic variation. From his evolutionary biology perspective Dr. Rose associates this phenomenon with a late-life end of the force of natural selection. This would imply that senescence is genetically programmed and that studying the genetics of the plateau could be the key to understanding the genetics of longevity.


Xanya Sofra Weiss

Xanya Sofra Weiss

AN OVERVIEW OF AGING AND OF AGING THEORIES. Xanya Sofra Weiss

Many scientists have wondered whether a single cause (probably cellular or hormonal) lies behind all aging phenomena — or whether aging is inherently multi-faceted. Differences in lifespan between species raise critical questions, in this regard. Why is a rodent old at 3 years, a horse old at 35 years and a human old at 80 years? Aren't the cells much the same? Why is it that at age 3 about 30% of rodents have had cancer, whereas at age 85, about 30% of humans have had cancer? Some species (such as lobsters, alligators and sharks) show few signs of aging. Cancer cells, stem cells and human germ cells seem "immortal" when compared to other cells.

When discussing aging it is important to distinguish two points on survival curves. Mean lifespan (average lifespan) corresponds to the age at which the horizontal line for 50% survival intersects the survival curve. Maximum lifespan corresponds to the age at which the survival curves touch the age-axis (0% survival) — and this represents the age at which the oldest known member of the species has died. (In animal studies, maximum lifespan is typically taken to be the mean lifespan of the most long-lived 10%.) Curve A as shown is a pure exponential decay curve. Curve B corresponds to the survival of small animals, such as mice or squirrels in a natural environment. Human survival was still close to curve B in ancient Rome when average lifespan was 22 years, but by the mid−1800s the typical North American lived to be 40 — more like curve C. Today, people in the most developed countries have an average lifespan of about 80 — resembling curve D. Reduction of infant mortality has accounted for most of the increased longevity, but since the 1960s mortality rates among those over 80 years has been decreasing by about 1.5% per year. Maximum lifespan for humans, however, has remained about 115−120 all through known history. The longest documented human lifespan has been for Frenchwoman Jean Calment who lived 122.3 years.

Curing specific diseases such as heart disease or cancer can do no more than further "square" the survival curve (toward curve E), with no effect on maximum lifespan. Curing cancer would add about 2 years to human life, whereas eliminating heart disease would add 3 or 4 years. Mean lifespan varies with susceptibility to disease, accident & homicide/suicide, whereas maximum lifespan is determined by "rate of aging". In aging research, maximum lifespan is regarded as a proxy for aging. Chemicals, calorie restriction with adequate nutrition, or other interventions which increase maximum lifespan are said to have slowed the aging process.

If human beings were free of disease & senescence the only causes of death would be accident, suicide & homicide. Under such conditions it is estimated that from a population of one billion, a 12-year-old would have a median lifespan of 1,200 years and a maximum lifespan of 25,000 years.In 1825 an English actuary named Benjamin Gompertz discovered that likelihood of dying increases exponentially with age after maturity — an empirical observation that has stood the test of time. A 35-year-old is twice as likely to die as a 25-year-old and a 25-year-old is twice as likely to die as a 15-year-old. The exponential increase does not continue past age 80 and death rate may even decline after age 110 [SCIENCE 280:855-860 (1998)]. (Medflies — Mediterranean fruit flies — show a plateau of linear rather than exponential death rate when 20-25% of the population remains). Similarly, the risk of getting Alzheimer's Disease doubles every 5 years past the age of 60 — probably plateauing after age 90 (when over half the population is already demented). Cancer rate increases exponentially with age, but also seems to plateau in the very elderly. One explanation might be that subsets of the population that are considerably more hardy due to genetics or behavior may remain after the more heterogenous majority have died. Another explanation suggests the complete elimination of the forces of natural selection at the oldest ages — which causes subsequent survival to be completely the result of genetic "random drift" [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA) 93:15249-15253 (1996)]. Causes of death in middle-age tend to be due to diseases affecting high-risk individuals (cancer, diabetes, hypertension, etc.), whereas the elderly are more vulnerable to multiple pathologies due to vulnerability of aging organs &

tissues [JOURNALS OF GERONTOLOGY 58A(6):B495-B507 (2003)].

Attempts to classify theories of aging have led to the two major classifications programmed aging and wear&tear aging. Programmed aging would be aging due to something inside an organism's control mechanisms that forces elderliness & deterioration — similar to the way genes program other life-stages such as cell differentiation during embryological development or sexual maturation at adolescence. By contrast aging due to wear&tear is not the result of any specific controlling program, but is the effect of the sum effect of many kinds of environmental assaults — ie, damage due to radiation, chemical toxins, metal ions, free-radicals, hydrolysis, glycation, disulfide-bond cross- linking, etc. Such damage can affect genes, proteins, cell membranes, enzyme function, blood vessels, etc.

When Pacific salmon have lived in the ocean for 2 or 3 years, they make an arduous upstream journey against a raging riverswim until they find a place suitable for spawning. After spawning, the adrenal gland releases massive amounts of corticosteroids — leading to rapid deterioration. It would be costly for the species to have salmon that could live another year and repeat the journey — or compete with the offspring for food. Although this process is obviously "programmed", it is inaccurate to describe it as "aging". Programmed death, rather than programmed aging, is a common phenomenon among animals that reproduce only once.

Grazing animals show wear-and-tear to their teeth to the point where they can no longer eat, and they die of starvation. Again, it stretches the point to say the teeth are aging. The teeth of rabbits (like human fingernails) continue to grow as wearing occurs — and in this sense are "programmed" to compensate for "wear&tear". Why don't grazing animals have teeth that continue to grow? Human beings can replace tissue, capillaries and bone in wound-healing, yet cannot regrow a severed limb the way a salamander can. Why isn't human DNA "programmed" to re-grow kidney or liver tissue as it ages? Planarians (flatworms) have a pool of stem cells which can replace any of their fully differentiated cells. Programming that compensates for wear & tear should be distinguished from programming that causes deterioration.


Xanya Sofra Weiss

Xanya Sofra Weiss

SYMPTOMS OF AGING. Xanya Sofra Weiss

One can catalog changes that typically occur with age. For people of developed countries age changes include: A loss of hearing ability, particularly for higher frequencies. There is a decline in the ability to taste salt&bitter (sweet&sour are much less affected). There is a reduction of the thymus gland to 5−10% of its original mass by age 50. Levels of antibodies increase with aging. One third of men and half of women over 65 report some form of arthritis. About half of those aged 65 have lost all teeth. The elderly require twice as much insulin to achieve the glucose uptake of the young. There is reduced sensitivity to growth factors & hormones due to fewer receptors and dysfunctional post-receptor pathways. The temperature needed to separate DNA strands increases with age. Weight declines after age 55 due to loss of lean tissue, water and bone (cell mass at age 70 is 36% of what it is at age 25). Body fat increases to age 60. Muscle strength for men declines 30−40% from age 30 to age 80. Reaction time declines 20% from age 20 to 60. Elderly people tend to sleep more lightly, more frequently and for shorter periods — with a reduction in rapid eye-movement (REM) sleep. Neurogenesis in the hippocampus declines with age. Degree of saturation of fats drops by 26% in the brains of old animals. Presbyopia (reduced ability to focus on close-up objects) occurs in 42% of people aged 52−64, 73% of those 65−74 and 92% of those over age 75. Most people over age 75 have cataracts. About half of those over 85 are disabled (defined as the inability to use public transportation). Over 75% of people over 85 have 3−9 pathological conditions, and the cause of death for these people is frequently unknown.
Aging changes are frequently associated with an increase in likelihood of mortality, but this is not necessarily the case. For example, graying of hair is a symptom of aging, but graying does not increase likelihood of mortality. Aging changes which are not associated with a specific disease, but which are associated with a generalized increase in mortality would qualify as biomarkers of aging — and would distinguish biological age from chronological age. Biomarkers would be better predictors of the increased likelihood of mortality (independent of specific disease) than the passage of time (chronological age). Cross-linking of collagen, insulin resistance and lung expiration capacity have been proposed as candidates but, as yet, no biomarkers of aging have been validated and universally accepted.

Xanya Sofra Weiss

Xanya Sofra Weiss


Mechanisms of Aging DEFINITION OF AGING. Xanya Sofra Weiss

DEFINITION OF AGING
Aging is a syndrome of changes that are deleterious, progressive, universal and thus far irreversible. Aging damage occurs to molecules (DNA, proteins, lipids), to cells and to organs. Diseases of old age (diseases which increase in frequency with age, such as arthritis, osteoporosis, heart disease, cancer, Alzheimer's Disease, etc.) are often distinguished from aging per se. But even if the aging process is distinct from the diseases of aging, it is nonetheless true that the damage associated with the aging process increases the probability that diseases of old age will occur.
Some gerontologists prefer to use the word senescence because "aging" implies that the passage of time necessarily results in deterioration (biological entropy) — which is certainly not true during the early, developmental, time of life (before the age of 10 or 12 in humans). I will retain the word "aging" because I believe the association between aging & deterioration is universal as adult years progress and because the distinction between aging & development is very strongly established in conventional language. Also, shorter words make for slightly faster reading.

Xanya Sofra Weiss

Xanya Sofra Weiss

Cell communication secrets revealed at SBC. Xanya Sofra Weiss

A method that cells use to communicate and coordinate activities has been confirmed by researchers from Cornell University, Monsanto Co. and Argonne.

This work could lead to new drugs to fight such diseases as cystic fibrosis and the bubonic plague, or to new technologies that perform useful environmental tasks, such as filtering water.

Biologists have theorized that bacteria communicate by releasing and sensing chemical pheromones to detect their population densities. This activity is termed "quorum sensing."

Using Argonne's

Structural Biology Center (SBC), the researchers confirmed this theory. They determined the molecular structure of a key protein - TraR - in this interbacterial communication

and witnessed how TraR acts as a relay to sense pheromones and then activate genes to create biofilms. A common example of a biofilm is the scum found on ponds.

More than 70 types of organisms are believed to use this molecular "census-taking" process including Yersinia pestis - the bubonic plague bacterium.

"We believe the quorum-sensing process signals bacteria to create biofilms - mats of bacterial cells over a solid surface," said Argonne biophysicist Rong-guang Zhang.

Zhang is lead author of an article describing their results in the June 27 issue of Nature.

"To see how these cells communicate, we crystallized and studied the structure of the TraR protein complexed with pheromone and DNA of the well-known Agrobacterium tumefaciens,

an agricultural pathogen that causes tumors in plants," said Zhang.

Researchers got a microsecond snapshot of quorum sensing in progress.

Knowing the structure of this important quorum-sensing protein may permit researchers to treat bacterial biofilm-related diseases, such as cystic fibrosis, by creating drugs to block the chemical signals that form biofilms.

Conversely, scientists could stimulate the formation of useful biofilms to filter water or perform other useful environmental tasks.

The structural information comes from shining X-rays from the Advanced Photon Source – the nation's most brilliant source of X-rays – onto tiny, frozen protein crystals.

The X-ray images are captured by a quick, electronic camera. Advanced software converts the data into 3-D images biologists use to infer how these proteins work and interact with other molecules.

"The structure," Zhang said, "is the most asymmetrical we have seen for a protein-DNA complex. It is shaped liked a butterfly with its wings bent back."

Pheromones lie fully embedded within the protein. To activate the pheromones, several amino acid residues critical to RNA polymerase activation, or gene copying, make contact with the "butterfly body" of TraR. – Evelyn Brown


Xanya Sofra Weiss

Xanya Sofra Weiss

Intercellular Communication. Xanya Sofra Weiss

Cell-to-cell Communication (Cell Signaling)

Almost without exception, whenever two or more living cells interact in a specific way, cell surface carbohydrates will be involved.

- Dr. John Hodgson[1]

Cellular communication is a hot topic in the science industry as there are many links to cell signaling

errors and degenerative and autoimmune diseases.[2] Cell communication (cell signaling) is a new field of study which is supported by very little information. This is rapidly changing, however.

There are different ways in which a cell communicates:

Cell to Cell Contact Proteins Hormones Electrical and Chemical Signals Others...

Cell to Cell Contact

Cells respond to cell-to-cell or extracellular-matrix-cell contact.[3] These interactions are mostly done

through glycoproteins[4] (a protein coated with glyconutrients[5]). Through contact, cells can receive structural and functional signals. Through contact, a skin cell, for example, “knows” that it’s on the surface of your body and not inside, like a heart cell. Through contact, cells can even instruct cells to

undergo apoptosis.[3]

Proteins

Proteins are secreted from a cell, travel a short distance to a a neighboring cell where they are recognized and interpreted. These signals can tell one cell to become a skin cell and a nearby cell to

become a hair cell.[6]Hormones

Hormones are considered long range signals. These are created by the endocrine system, put in the

blood stream and distributed to the necessary organs.[6][7] Hormones are responsible for development, sexual development in puberty, sexual appetite, sleep, and just about every major function in your body. There exist long range proteins that are sometimes thought of as hormones, insulin is a good

example.[8]

Electrical and Chemical Signals

Electrical and chemical signals are responsible for communicating very complex messages between neurons or between neurons and muscles cells.[9] The point of contact between two cells, called synapses,[10] is where electrical signals are converted into a chemical signal and then back into an electrical signal in the other cell.[11] These signals are very interesting and may be responsible for learning, memory[12] and ultimately consciousness.


Xanya Sofra Weiss

Xanya Sofra Weiss

Elaine Fuchs Honored with Albany Medical Center Prize. Xanya Sofra Weiss

Howard Hughes Medical Institute investigator Elaine Fuchs is one of three scientists who have been awarded the 2011 Albany Medical Center Prize in Medicine and Biomedical Research. Fuchs, James A.

Thomson of the University of Wisconsin-Madison, and Shinya Yamanaka of Kyoto University, were honored for pioneering work in isolating human stem cells.

The Albany Prize, which is awarded annually, recognizes extraordinary and sustained contributions to improving health care and promoting biomedical research with translational benefits applied to improved patient care. Fuchs,

Thomson, and Yamanaka are being recognized for work that has moved scientists closer to realizing the regenerative and potentially healing properties of stem cells, as well as helping illuminate how human tissues develop and function.

The scientists will receive the prize on May 13 during a celebration in Albany, New York. The $500,000 prize is the largest award in medicine and science in the United States.

The science of stem cell research focuses on the earliest stage of cellular development. These remarkable cells have the ability to become any tissue in the body and to reproduce indefinitely.

Researchers hope to harness the power of these cells to one day repair or replace damaged tissue in patients, possibly building new spinal cords or growing new limbs.

Fuchs, whose lab is at Rockefeller University, studies skin and hair—two distinct structures that develop from the same skin stem cell. To use stem cells therapeutically, she says,

it is essential to first understand how the cells function on the molecular level. By unraveling the biology of skin stem cells, she hopes to answer a question that has intrigued her for more than two decades:

How does a skin stem cell decide to become skin or hair?

Understanding skin stem cells' normal behavior is also helping Fuchs learn what happens when their growth goes awry. Her studies have already uncovered the genetic basis of blistering skin diseases and clues to the way skin cancers and inflammatory skin disorders develop.

Her research may also hold clues for deciphering the extraordinary characteristics that enable stem cells to develop into distinct tissues and organs. "While there is much promise for stem cells in revolutionizing medicine, we must first learn more about stem cells before we can know whether this might be possible," she contends.

Unlike most other adult stem cells, skin stem cells can be easily grown in the laboratory. Fuchs's research has shown that multiple signaling pathways, including the Wnt and BMP pathways,

influence how stem cells are coaxed to develop into hair follicles. Together, positive Wnt signals and antagonistic BMP signals lead to activation of transcription factors, which induce the formation of a hair follicle bud.

In the absence of these signals, stem cells develop into skin epidermis. This line of research may eventually lead to new ways to restore or inhibit hair growth.

By exploring how the stem cell reservoir (niche) forms and how stem cells are activated to proliferate and differentiate, Fuchs's work is having an impact on understanding how defective stem cells can cause cancers.

Fuchs is the recipient of numerous prizes and awards, including the National Medal of Science (2009), the FASEB Excellence in Science Award (2006), the Dickson Prize in Medicine (2004) from the University of Pittsburgh,

and the Lounsbery Award (2001) from the National Academy of Sciences. She is a member of the Institute of Medicine, the National Academy of Sciences, the American Philosophical Society, and the American Academy of Arts and Sciences.


Xanya Sofra Weiss

Xanya Sofra Weiss

G Protein Coupling and Signaling Pathway Activation by M1 Muscarinic Acetylcholine Receptor Orthosteric and Allosteric Agonists. Xanya Sofra Weiss

Rachel L. Thomas, Rajendra Mistry, Christopher J. Langmead, Martyn D. Wood, and R. A. John Challiss


The M1 muscarinic acetylcholine (mACh) receptor is among a growing number of G protein-coupled receptors that are able to activate multiple signaling cascades.

AC-42 (4-n-butyl-1-[4-(2- methylphenyl)-4-oxo-1-butyl] piperidine) is an allosteric agonist that can selectively activate the M1 mACh receptor in the ab- sence of an orthosteric ligand.

Allosteric agonists have the potential to stabilize unique receptor conformations, which may in turn cause differential activation of signal transduction path- ways. In the present study,

we have investigated the signaling pathways activated by AC-42, its analog 77-LH-28-1 (1-[3-(4- butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone),

and a range of orthosteric muscarinic agonists [oxotremorine-M (oxo-M), arecoline, and pilocarpine] in Chinese hamster ovary cells recombinantly expressing the human M1 mACh receptor.

Each agonist was able to activate G��q/11-dependent signaling, as demonstrated by an increase in guanosine 5��-O-(3-thio-triphosphate) ([35S]GTP��S) binding to G��q/11 proteins and total [3H]inositol phosphate accumulation assays in intact cells.

All three orthosteric agonists caused significant enhancements in [35S]GTP��S binding to G��i1/2 subunits over basal; however, neither allosteric ligand produced a significant response.

In contrast, both orthosteric and allosteric agonists are able to couple to the G��s/cAMP pathway, enhancing forskolin-stimu- lated cAMP accumulation.

These data provide support for the concept that allosteric and orthosteric mACh receptor agonists both stabilize receptor conformations associated with G��q/11- and G��s-dependent signaling; however,

AC-42 and 77-LH- 28-1, unlike oxo-M, arecoline, and pilocarpine, do not seem to promote M1 mACh receptor-G��i1/2 coupling, suggesting that allosteric agonists have the potential to activate distinct sub- sets of downstream effectors.


Xanya Sofra Weiss

Xanya Sofra Weiss

Monday, June 6, 2011

Electrical cues regulate the orientation and frequency of cell division and the rate of wound healing in vivo. Xanya Sofra Weiss

Controlling cell division is fundamental. One environmental cue that exerts profound control over both the orientation and fre- quency of cell division in vivo is a naturally occurring, wound- induced electric field (EF). Wounds in rat corneas generate endog- enous EFs in the plane of the epithelial sheet because the transcorneal potential difference (TCPD; ��40 mV internally posi- tive) collapses at the wound edge, but is maintained at normal levels at 0.5 mm back from the wound. We manipulated the endogenous EF this creates by using drugs with differing actions. The wound-induced EF controlled the orientation of cell division; most epithelial cells divided with a cleavage plane parallel to the wound edge and perpendicular to the EF vector. Increasing or decreasing the EF pharmacologically, respectively increased or decreased the extent of oriented cell division. In addition, cells closest to the wound edge, where the EF was highest, were oriented most strongly by the EF. Remarkably, an endogenous EF also enhanced the frequency of cell division. This also was regu- lated by enhancing or suppressing the EF pharmacologically. Be- cause the endogenous EF also regulated the wound healing rate, it may act as one control of the interplay between cell migration and cell division during healing.


Xanya Sofra Weiss

Xanya Sofra Weiss

Music of the Spheres. Xanya Sofra Weiss

Notes in music are related to each other by specific ratios.
These ratios determine the 'space' between each tone, and in turn define the notes.
Although to the human ear the notes sound as if they are equally spaced,
the following chart shows that in fact the ratios are more complex.
Several years ago, astronomer Gerald S. Hawkins, former Chairman of the astronomy department at Boston University, noticed that some of the most visually striking of the crop-circle patterns embodied geometric theorems that express specific numerical relationships among the areas of various circles, triangles, and other shapes making up the patterns (Science News: 2/1/92, p. 76). In one case, for example, an equilateral triangle fitted snugly between an outer and an inner circle. It turns out that the area of the outer circle is precisely four times that of the inner circle.
Three other patterns also displayed exact numerical relationships, all of them involving a diatonic ratio, the simple whole-number ratios that determine a scale of musical notes. "These designs demonstrate the remarkable mathematical ability of their creators," Hawkins comments.
Hawkins found that he could use the principles of Euclidean geometry to prove four theorems derived from the relationships among the areas depicted in crop circles. He also discovered a fifth, more general theorem, from which he could derive the other four (see recent work, here). "This theorem involves concentric circles which touch the sides of a triangle, and as the [triangle] changes shape, it generates the special crop-circle geometries," he says.
Hawkins' fifth crop-circle theorem involves a triangle and various concentric circles touching the triangle's sides and corners. Different triangles give different sets of circles. An equilateral triangle produces one of the observed crop-circle patterns; three isoceles triangles generate the other crop- circle geometries.
What is most surprising is that all geometries give diatonic (musical) ratios. Never before (to my knowledge) have geometric theorems been linked with music.
Curiously, Hawkins could find no reference to such a theorem in the works of Euclid or in any other book that he consulted. When he challenged readers of Science News and The Mathematics Teacher to come up with his unpublished theorem, given only the four variations, no one reported success.
In July 1995, however, "the crop-circle makers . . . showed knowledge of this fifth theorem," Hawkins reports. Among the dozens of circles surreptitiously laid down in the wheat fields of England, one pattern fit Hawkins' theorem based on the stringent definitions, on the rules established by the circles over the period 1980 to the present.

Xanya Sofra Weiss

Xanya Sofra Weiss


The evolution of cell communication: The Road not Taken. Xanya Sofra Weiss

In the post-genomic era the complex problem of evolutionary biology can be tackled from the top-down, the bottom-up, or from the middle-out. Given the emergent and contingent nature of this process, we have chosen to take the latter approach, both as a mechanistic link to developmental biology and as a rational means of identifying signaling mechanisms based on their functional genomic significance. Using this approach, we have been able to configure a working model for lung evolution by reverse-engineering lung surfactant from the mammalian lung to the swim bladder of fish. Based on this archetypal cell-molecular model, we have reduced evolutionary biology to cell communication, starting with unicellular organisms communicating with the environment, followed by cell-cell communication to generate metazoa, culminating in the communication of genetic information between generations, i.e. reproduction. This model predicts the evolution of physiologic systems-including development, homeostasis, disease, regeneration/ repair, and aging- as a logical consequence of biology reducing entropy. This approach provides a novel and robust way of formulating refutable, testable hypotheses to determine the ultimate origins and first principles of physiology, providing candidate genes for phenotypes hypothesized to have mediated evolutionary changes in structure and/or function. Ultimately, it will form the basis for predictive medicine and molecular bioethics, rather than merely showing associations between genes and pathology, which is an unequivocal Just So Story. In this new age of genomics, our reach must exceed our grasp.

Xanya Sofra Weiss

Xanya Sofra Weiss