bluuebunny/crossref_metadata_2025 huggingface dataset:
Dosimetric effect of respiration‐gated beam on IMRT delivery
Authors: Duan Jun , Shen Sui , Fiveash John B. , Brezovich Ivan A. , Popple Richard A. , Pareek Prem. N.
Published: August 2003

Intensity modulated radiation therapy (IMRT) with a dynamic multileaf collimator (DMLC) requires synchronization of DMLC leaf motion with dose delivery. A delay in DMLC communication is known to cause leaf lag and lead to dosimetric errors. The errors may be exacerbated by gated operation. The purpose of this study was to investigate the effect of leaf lag on the accuracy of doses delivered in gated IMRT. We first determined the effective leaf delay time by measuring the dose in a stationary phantom delivered by wedge‐shaped fields. The wedge fields were generated by a DMLC at various dose rates. The so determined delay varied from 88.3 to 90.5 ms. The dosimetric effect of this delay on gated IMRT was studied by delivering wedge‐shaped and clinical IMRT fields to moving and stationary phantoms at dose rates ranging from 100 to 600 MU/min, with and without gating. Respiratory motion was simulated by a linear sinusoidal motion of the phantom. An ionization chamber and films were employed for absolute dose and 2‐D dose distribution measurements. Discrepancies between gated and nongated delivery to the stationary phantom were observed in both absolute dose and 2‐D dose distribution measurements. These discrepancies increased monotonically with dose rate and frequency of beam interruptions, and could reach 3.7% of the total dose delivered to a ion chamber. Isodose lines could be shifted by as much as 3 mm. The results are consistent with the explanation that beam hold‐offs in gated delivery allowed the lagging leaves to catch up with the delivered monitor units each time that the beam was interrupted. Low dose rates, slow leaf speeds and low frequencies of beam interruptions reduce the effect of this delay‐and‐catch‐up cycle. For gated IMRT it is therefore important to find a good balance between the conflicting requirements of rapid dose delivery and delivery accuracy.
Clinical implementation of x‐ray phase‐contrast imaging: Theoretical foundations and design considerations
Authors: Wu Xizeng , Liu Hong
Published: August 2003

Theoretical foundation and design considerations of a clinical feasible x‐ray phase contrast imaging technique were presented in this paper. Different from the analysis of imaging phase object with weak absorption in literature, we proposed a new formalism for in‐line phase‐contrast imaging to analyze the effects of four clinically important factors on the phase contrast. These are the body parts attenuation, the spatial coherence of spherical waves from a finite‐size focal spot, and polychromatic x‐ray and radiation doses to patients for clinical applications. The theory presented in this paper can be applied widely in diagnostic x‐ray imaging procedures. As an example, computer simulations were conducted and optimal design parameters were derived for clinical mammography. The results of phantom experiments were also presented which validated the theoretical analysis and computer simulations.
Cortical Basal Ganglionic Degeneration
Authors: Scarmeas Nikolaos , Chin Steven S. , Marder Karen
Published: August 2003

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a retired mason’s assistant with cortical basal ganglionic degeneration (CBGD). CBGD is an extremely rare neurodegenerative disease that is categorized under both Parkinsonian syndromes and frontal lobe dementias. It affects men and women nearly equally, and the age of onset is usually in the sixth decade of life. CBGD is characterized by Parkinson’s-like motor symptoms and by deficits of movement and cognition, indicating focal brain pathology. Neuronal cell loss is ultimately responsible for the neurological symptoms.
Alzheimer’s Disease
Authors: Honig Lawrence S. , Chin Steven S.
Published: August 2003

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with Alzheimer’s disease (AD). AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than was memory impairment. Throughout the limbic system and neocortex of the patient were large numbers of senile plaques and neurofibrillary tangles, the pathological hallmarks of AD.
Life Extension--Our Salvation or Our Ruin?
Authors: Barinaga Marcia
Published: August 2003

Extending the human life-span will have far-reaching political and sociological implications and presents countless ethical conundrums. In an economy based on scarcity, who will receive life-extension treatment? Will treatments be considered therapeutic necessities or mere enhancements for those who can pay? Is life extension a social good or a luxury? Will it be acceptable for an individual to refuse life extension, or would that be akin to suicide? Some experts say we would be wise to consider these questions now, before life-extending therapies become a reality.
Of Hyperaging and Methuselah Genes
Authors: Strauss Evelyn
Published: August 2003

Work on rare genetic disorders that mimic some aspects of aging may have implications far beyond finding cures for rare diseases. It might also provide clues about the normal human aging process and yield insight into diseases common to old age, such as atherosclerosis, which could lead to new avenues of research for treatments that prolong life. In addition, the discovery of hormones that apparently control life-span hints at a general biological mechanism for health and longevity that extends beyond any single organism.
Immune System Resuscitation: T cells from old mice get vitamin E’s personal attention
Authors: Davenport R. John
Published: August 2003

Vitamin E might counteract aging’s impact on the immune system by breathing new life into waning T cells, according to new work. Scientists had previously ascribed the positive effect of vitamin E on T cells to a reduction in the amounts of an intermediary: a lipid-soluble hormone called prostaglandin E
2
(PGE
2
) that suppresses T cell function. Adolfsson and colleagues purified T cells from a mixture of spleen cells to get rid of macrophages, which produce PGE
2
. Then they added vitamin E, activated the T cells with antigen, and incubated them to allow the cells to respond. Next, the team assessed cell proliferation and production of the immune system protein IL-2, two indicators of healthy T cell function. By these measures, vitamin E enhanced the behavior of naïve T cells--T cells that had not been exposed to antigen before the experiment--from old mice: With treatment, they reproduced better and produced more IL-2 than did controls. In contrast, vitamin E did not boost function of mature T cells--those previously exposed to antigen--from old mice, nor T cells of either type from young mice. These data shed light on how vitamin E revives T cells and might help researchers understand how best to use vitamin E therapy to bolster the immune systems of the elderly.

--R. John Davenport; suggested by Jennifer Fuller

O. Adolfsson, B. T. Huber, S. N. Meydani, Vitamin E-enhanced IL-2 production in old mice: Naive but not memory T cells show increased cell division cycling and IL-2-producing capacity.
J. Immunol.
167
, 3809-3817 (2001).
[Abstract]
[Full Text]
Protecting the Heart: Will studying the young save the old?
Authors: Strauss Evelyn
Published: August 2003

A little bit of a bad thing can be good for you--but this truism might not apply equally to the old and the young. A variety of minor biochemical and physical assaults on cells and organs can protect them later from more severe forms of the same--or even different--insults. Some drugs that exploit this phenomenon to protect animals and potentially people from permanent heart damage might not work as well in old organisms as in young ones, according to a new study. Schulman and colleagues subjected old rats to one of three drugs that shield younger ones from subsequent heart damage. Afterward, the team blocked blood supply to the heart for 35 minutes before allowing it to flow again. This treatment mimics heart attack and open-heart surgery, where physicians chemically stop the heart while working on it. The drugs significantly reduced the degree of destruction--as measured by the amount of dead heart tissue--in the young animals but not in the old ones. No one yet knows if these results apply to humans, but they raise questions about the wisdom of a common practice: proceeding from promising results in young animals to clinical studies in old humans, the population most affected by heart attacks and open-heart surgery.

--Evelyn Strauss; suggested by Kathy Rosewell

D. Schulman, D. S. Latchman, D. M. Yellon, Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury.
Am. J. Physiol. Heart Circ. Physiol.
281
, H1630-H1636 (2001).
[Abstract]
[Full Text]
Aiming for Ames: Test promises to ease breeding task
Authors: Strauss Evelyn
Published: August 2003

Ames dwarf mice might be small, but they promise to wield great power--at least in the field of aging. These animals live 49% to 64% longer than their normal littermates; studying them is already hinting at physiological mechanisms that underlie longevity. A newly published method to rapidly identify the Ames defect at the DNA level should facilitate the ability to breed this strain and to distinguish affected individuals from their siblings even before they start to exhibit the hallmark characteristics: Ames dwarf mice carry two defective copies of the
Prop-1
gene, which causes defects in the growth hormone signaling pathway and consequent dwarfism. In addition, the animals are sterile or near-sterile; hormone treatments partially counteract this condition, but it’s not easy to produce offspring from two subfertile Ames dwarf mice. Although the
Prop-1
gene was isolated in 1996, no one had published a method by which to detect the DNA lesion in animals until now. Dollé and colleagues have developed a standard polymerase chain reaction-based test that allows investigators to distinguish animals that carry zero, one, or two copies of defective
Prop-1
by detecting diagnostic bands of DNA on a gel. This ability will allow researchers to identify animals suitable for breeding: ones that look normal yet harbor a single copy of the defective gene. In addition, the technique offers a way to distinguish Ames dwarf mice even when they are very young, before the growth differences become apparent. That capability could facilitate studies of these animals at the beginning--as well as the end--of their very long lives.

--Evelyn Strauss; suggested by James M. Harper

M. E. T. Dollé, W. K. Snyder, J. Vijg, Genotyping the
Prop-1
mutation in Ames dwarf mice.
Mech. Ageing Dev.
122
, 1915-1918 (2001).
[Abstract]
[Full Text]
Dangerous Liaisons
Authors: Chicurel Marina
Published: August 2003

More often than not, cancer appears hand in hand with old age. Cancer is wedded to the progression of time through its need to accumulate multiple mutations. But some studies suggest a potentially deeper relation in which aging supplies cancer with a unique terrain where it can thrive. Although unresolved questions abound about the relation between cancer and aging, basic scientific insights are emerging, as are new ideas for keeping the lethal disease at bay.
More Than a Sum of Our Cells
Authors: Hopkin Karen
Published: August 2003

Cells in the body grow and die, cells in lab dishes grow and die, and individual organisms grow and die. The parallels seem maddeningly obvious, but scores of scientists still labor to draw the correct connections, to uncover the mechanisms that underlie aging in cell culture flasks and in whole animals. Do our cells stop growing, quit working, cease dividing, or start dying as we age? Do we die when our cells do, or are we somehow more than the sum of our cells? For decades, scientists have searched for evidence that links changes in cell growth, cell function, cell division, and cell death to the phenomenon we call aging. Although definitive proof eludes them, researchers continue to conduct experiments in tissue culture and in animal models, amassing information that points us toward a greater understanding of what aging is--and is not.
The Two Faces of Oxygen
Authors: Tuma Rabiya
Published: August 2003

Scientists have suspected for half a century that reactive oxygen species (ROS) are major instigators of aging. These byproducts of metabolism batter a wide variety of molecules within cells, and an organism’s ability to repair the damage declines with age. Now, some researchers say they’re wrapping up the case against ROS, at least for lower organisms. By counteracting this destruction with protective enzymes, researchers have extended the average lifetime of some invertebrates. But the verdict isn’t in yet, because recent studies have revealed that ROS also make key contributions to normal cell signaling.
Hard Times Teach Life-Extending Lessons
Authors: Davenport R. John
Published: August 2003

A network of genes controls whether worm larvae hibernate during tough times. Some long-lived worms co-opt elements of the network to extend their lives during good times as well. Now, two groups of scientists have identified a gene that seems to make a hormone that is crucial for propelling worms toward adulthood--and it influences longevity as well.
Survivor!
Authors: Hechtel Sibylle
Published: August 2003

Plants, animals, and bacteria boast varied mechanisms to resist extreme environmental conditions. Many of these strategies seal an organism in an inactive form: The creature diverts energy from routine life activities to build robust defenses. But emerging evidence suggests that parts of these survival pathways can lengthen life-span without also triggering hibernation.
Working Out the Kinks: Fly enzyme reverses protein damage, extends life-span (Protein damage)
Authors: Davenport R. John
Published: August 2003

Getting bent out of shape isn't good for a person's blood pressure--or for proteins. Over time, cellular proteins accumulate chemical changes that can distort their shapes and disrupt their functions. Keeping these alterations at bay might help an aging organism maintain its youthful vigor. New results support that idea by indicating that extra doses of a protein-repairing enzyme help flies live longer, at least under certain conditions.

Two amino acids--aspartate and asparagine--can spontaneously undergo changes that convert them to another chemical form, called isoaspartate. The transformation reshuffles the carbon atoms in the amino acids. This perturbation puts a kink in the backbone of a protein that contains the amino acids, which distorts the shape of the protein and can prevent it from performing its cellular duties. To combat this affront, organisms carry an enzyme called protein carboxyl methyltransferase (PCMT), which converts isoaspartate back to aspartate and restores the backbone to its proper line.

Because isoaspartates accumulate as organisms age, Chavous and colleagues wondered whether supplementary PCMT would increase an animal's life-span. To find out, the researchers manipulated amounts of PCMT in the fruit fly
Drosophila melanogaster.
They engineered some flies to produce large amounts of PCMT all the time and other flies to produce extra protein only at higher than normal temperatures. They grew both sets of flies, along with a control group, at either room temperature or the elevated temperature and waited for the flies to die.

At the elevated temperature, both types of experimental flies lived about 35% longer on average than did control flies. At room temperature, however, neither set of test flies lived longer than normal. The results suggest that enhanced protein-repairing power can help flies endure, but only at elevated temperatures. It's not clear why supplemental PCMT doesn't extend the life-span of flies grown at room temperature. PCMT might require the assistance of heat shock proteins, whose amounts shoot up with temperature and which help cells maintain protein integrity. These proteins--which unfold and refold other proteins to help them maintain their proper shape--might help PCMT gain access to the altered amino acids. Alternatively, extra PCMT might make a measurable difference only when isoaspartates accumulate rapidly, as they do at higher temperatures. The work hints that keeping the kinks out of proteins--especially under stressful conditions such as high temperature--might stretch out an animal's life-span.

--R. John Davenport; suggested by Amir A. Sadighi Akha

D. A. Chavous, F. R. Jackson, C. M. O'Connor, Extension of the
Drosophila
lifespan by overexpression of a protein repair methyltransferase.
Proc. Natl. Acad. Sci. U.S.A.
98
, 14814-14818 (2001).
[Abstract]
[Full Text]
If You Build It, Will They Come?
Authors: Toy Jennifer
Published: August 2003

Richard Sprott has a dream: to circumvent the cumbersome process of supplying labs with specialized research animals by moving people rather than animals. His brainchild, the International Biogerontology Resources Institute (IBRI) in Friuli, Italy, intends to attract researchers by offering access to an extensive collection of strains from around the world, superb veterinary care, and, of course, a business trip to Italy. Unique to IBRI is a research agenda dedicated to developing animal models--a task some view as a relatively unsexy side of science.
Napoleonic Demons: Short telomeres trigger trouble for everyone
Authors: Strauss Evelyn
Published: August 2003

Like mischievous teenagers on a train, small numbers of telomeres can pull an emergency cord and stop the cell that carries them. These repeated stretches of DNA and associated proteins cap chromosome ends and play a key role in cellular life and death. When telomeres decay, chromosomes fuse with each other and spark genetic havoc that can lead to cancer (see
"Intimate Liaisons"
) or induce a cell to commit suicide (see
"More Than a Sum of Our Cells"
). The consequences of telomere dysfunction are well established, but the exact trigger remains unknown. Several groups have studied the relation between cell survival and average telomere length. As a result, some investigators have concluded that telomeric length does not solely govern its function, because the cell can act up even when the average length remains generous. But new work shows that cells respond to individual chromosome ends rather than the average: Even a small number of shrunken telomeres can spur lethal events.

Hemann and colleagues generated mice with very short telomeres by inbreeding for six generations animals that lack telomerase, the enzyme that replenishes the short repeated sequences that compose telomeric DNA. Then they mated individuals from this strain with those with normal telomeres. The resulting offspring have long telomeres on half of their chromosomes and short ones on the other half. If average telomere length determines survival, the extent of cell suicide--or apoptosis--in these mice should fall halfway between that of the two parents. To probe this issue, the team analyzed cell death and found instead that the degree of apoptosis resembles that of the parent with short telomeres. This result suggests that the most diminutive telomeres--not the whole population--sabotage cells.

To find out whether the shriveled ends instigate global telomere trouble--inducing normal ends to inappropriately stick together, for example--the researchers assessed the relation between telomere length and misconduct. They used a fluorescent probe consisting of dye-labeled DNA that binds to the repeated sequences and emits a signal whose intensity is proportional to telomere length. Using this technique, they showed that chromosomes that most frequently fuse carry the shortest telomeres; chromosomes with long telomeres tend to behave properly.

Together, the results suggest that small numbers of miscreant telomeres set off the cellular alarms that lead to death. Apparently, although most telomeres are good passengers, a few deviants can slam on the brakes for the entire cell.

--Evelyn Strauss

M. T. Hemann, M. A. Strong, L.-Y. Hao, C. W. Greider, The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.
Cell
107
, 67-77 (2001).
[Abstract]
[Full Text]
Passing the Baton: New gene might get the handoff from growth hormone
Authors: Davenport R. John
Published: August 2003

In a relay race, the lead and anchor legs get the glory. But the middle runners are crucial for propelling the team from start to finish. A newly identified gene might run the second stretch in a cellular signaling race by taking the stick from growth hormone (GH). Mounting evidence suggests that a cellular signaling pathway triggered by GH in mammals can influence life-span in fruit flies, worms, and possibly mice: Some animals that carry mutations in the insulin/insulin-like growth factor 1 (IGF-1) pathway live significantly longer than normal. Although the binding of GH to cells eventually stimulates IGF-1, the genes that respond directly to GH remain mysterious. New work points to a potential target.

Lu and colleagues engineered rat heart muscle cells to produce the GH receptor and then added growth hormone to half of the cells. Using microarrays, the team analyzed messenger RNA (mRNA) from treated and untreated samples to identify genes that ramped up or down in response to the hormone. The amount of one gene's transcript increased fourfold. When the researchers injected mice with GH, mRNA production from the mouse version of this gene--which they called
Grtp1
, for GH-regulated TBC protein-1--increased in testes (where the gene is most highly expressed, even at base levels). The amount of
Grtp1
mRNA decreased in kidney and liver. This result suggests that GH controls expression of
Grtp1
in intact animals as well as in isolated cells.

No one knows the function of
Grtp1
, but its predicted amino acid sequence contains a so-called TBC motif. This domain lies in activators of GTPases, proteins that use the small signaling molecule GTP to turn on and off cellular signaling pathways. Together, these proteins flip molecular switches to control processes such as cell division. The team found genes that resemble
Grtp1
in humans and fruit flies in addition to rats and mice. This observation hints that
Grtp1
's function--whatever it might be--is well conserved. It also gives researchers multiple systems in which to test whether
Grtp1
runs a leg in the aging race.

C. Lu, J. Kasik, D. A. Stephan, S. Yang, M. A. Sperling, R. K. Menon,
Grtp1
, a novel gene regulated by growth hormone.
Endocrinology
142
, 4568-4571 (2001).
[Abstract]
[Full Text]

--Suggested by James M. Harper
Get Some Glasses, Ump!
Authors: Miller Katharine
Published: August 2003

No National Institutes of Health (NIH) study sections are dedicated to aging-related grant proposals; as a result, flawed evaluations abound, according to many researchers in the field. In fall 2002 NIH will introduce two new study sections to evaluate grant proposals on aging. But the study sections still face turf wars with other new--and potentially overlapping--study sections.
Faustian Bargain: Cellular senescence at first prevents, later promotes, cancer
Authors: Davenport R. John
Published: August 2003

What seems like a good idea can sometimes backfire later. A mechanism that foils cancer in young animals might induce it in older ones, according to a new study.

Most mammalian cells, whether in animals or culture dishes, don't divide forever; instead, they eventually undergo cellular senescence, which permanently arrests cell division (see
"More Than a Sum of Our Cells"
). In animals, that process might prevent cells with DNA damage or shortened telomeres from growing into tumors (see
"Dangerous Liaisons"
). Senescent cells, however, remain in the body--dormant but perhaps not benign.

To investigate how senescent cells affect the tissue in which they reside, Krtolica and colleagues grew cultures that contained either presenescent or senescent fibroblasts--cells that compose connective tissue--and then layered test cultures of various epithelial cell types on top of the fibroblasts. The researchers measured proliferation of the epithelial cells by tagging their DNA with fluorescent labels. Senescent, but not presenescent, fibroblasts provoked duplication of cell lines that had previously acquired mutations known to predispose them to cancer, the team found. Neither senescent nor presenescent fibroblasts promoted the growth of normal human epithelial cells. Cell-to-cell contact isn't required for the stimulation: Material secreted by senescent cells induced precancerous cells to grow approximately three times faster than did material secreted by presenescent cells. Senescent cells also appear to promote tumor growth in vivo: Tumors were more prevalent and grew larger in mice injected with precancerous epithelial cells and senescent fibroblasts than in those injected with precancerous cells and presenescent fibroblasts.

Senescent cells apparently create a rich environment for tumor growth. This phenomenon, combined with the increased incidence of cancer-causing mutations as time passes, could partially explain the exponential increase in cancer rates as we age. Identifying exactly how senescent cells create fertile ground for cancer might well shed light on how a good deal in youth turns sour with age.

--R. John Davenport; suggested by Nick Bishop

A. Krtolica, S. Parrinello, S. Lockett, P.-Y. Desprez, J. Campisi, Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging.
Proc. Natl. Acad. Sci. U.S.A.
98
, 12072-12077 (2001).
[Abstract]
[Full Text]
Keeping the Bad Guy Down: New potential tumor-suppressor gene
Authors: Beckman Mary
Published: August 2003

In the good guy-bad guy world of cancer, shifty proteins often run afoul of cellular law, prompting molecular sheriffs to action. One cellular citizen--the protein Akt--normally lives a quiet life, performing its civic duty in the insulin-like growth factor-1 (IGF-1) and insulin mammalian signaling pathways. These pathways manage cell growth in mammals, and related ones regulate aging in organisms that include worms, flies, and possibly mice (see
"Growing Old Together"
).

To do its job, Akt slips on a phosphate group. If the protein dons this black hat for too long, however, it triggers a molecular stampede in the IGF-1 signaling pathway, which promotes a half-dozen cancers. Mutations in Akt or its handlers can turn Akt to a permanent life of crime. A corrupt form of the protein, found in many cancers, never removes its phosphate; this version transforms innocuous cell lines into deadly tumor inducers in mice. In healthy cells, a white-hatted cellular cowboy--a tumor-suppressor gene known as
PTEN
--keeps Akt in check. Research has now uncovered a second marshal in the mammalian struggle against unrestrained Akt that keeps the phosphate hat away from the potential scoundrel, preventing it from suiting up in its gunslinger garb.

To seek regulators of Akt, Hemmings and colleagues used a technique to fish out molecules that bind to a bait protein--in this case, a piece of Akt--from a pool of human proteins. Using a variety of biochemical techniques, they showed that one protein--which they named CTMP--prevents Akt from acquiring the phosphate group that leads to its hyperactivity. They then produced CTMP in a cell line made cancerous by the delinquent Akt. CTMP quashed the ability of these cells to grow uncontrolled in culture dishes and reduced the speed at which they induce tumors in mice. These results suggest a rationale for new cancer therapies: Perhaps a drug that mimics CTMP could wrangle in a lawless Akt. The researchers also found that the amount of CTMP in cells mirrored that of PTEN and propose that the two might be regulated in parallel. If so, CTMP could be partly responsible for Akt lawlessness that is now blamed on a slacking PTEN.

CTMP provides a new focus for labs that are trying to discover how IGF-1-like signaling pathways control life-span. Perhaps this molecular desperado plays a role not just in cancer but also in longevity: It might help decide whether to send cells--or organisms--riding off into the sunset.

--Mary Beckman

S.-M. Maira, I. Galetic, D. P. Brazil, S. Kaech, E. Ingley, M. Thelen, B. A. Hemmings, Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane.
Science
294
, 374-380 (2001).
[Abstract]
[Full Text]
Death and Aging, Together at Last
Authors: Hopkin Karen
Published: August 2003

Researchers may have discovered the missing link between cell death and aging, pathways that until now have seemed not to overlap. In two papers in the 19 October issue of
Cell
, they show that Sir2, a protein that promotes longevity in yeast and worms, counteracts the destructive tendencies of p53, a protein that determines whether cells with mutilated DNA will undergo apoptosis. The findings raise the possibility that Sir2 increases life-span by keeping cells from offing themselves and support the theory that programmed cell death might be involved in aging.
Emergency Response Teams Share Strategies: Human and rat brains reorganize similarly after stroke
Authors: Miller Katharine
Published: August 2003

The human brain behaves like a close-knit community. When natural disaster destroys a few houses, friends across town as well as those next door lend a hand. Similarly, in a stroke-damaged human brain, the uninjured hemisphere tries to help, and later the neighborhood around the hardest hit region recovers enough to pitch in as well. Now, researchers have used functional magnetic resonance imaging (fMRI)--the same technique that uncovered this behavior in human brains--to show that rats' brains reorganize similarly after stroke. Functional magnetic resonance imaging of rat brains after stroke offers a new experimental model for studying how the brain repairs itself and for evaluating therapies.

Dijkhuizen and colleagues induced a stroke in rats by tying off an artery in the right side of the animals' brains; as a result, the left side of the body became temporarily clumsy. They then exploited fMRI to assess how the brains changed as the rats' disabled left limbs recovered. This technique measures blood flow, a reflection of metabolic activity; fMRI generates information about which regions of the brain respond when the subject performs a task. While the animals slept inside the fMRI machine, the researchers gently shocked the rats' left paws to simulate the task of tapping fingers. Three days after the stroke, the brains of sham-operated rats responded on the side opposite the injured limb, but the damaged rats' brains lit up on the unharmed left side. After 14 days, when the animals had regained some control over their left paws, the brightness of the unaffected hemisphere dwindled; the edges of the lesion, however, glowed for the first time.

Functional magnetic resonance imaging provides a noninvasive way to pinpoint sites of physiological change that occur during recovery from a stroke. Because rat and human brains appear to share healing strategies, researchers are optimistic that the new system will provide an experimental model in which to study stroke and its potential treatments. They hope to develop new approaches, because the two therapies currently available are not always effective: Clot-busting drugs work only if used in the first few hours after the mishap, and physical therapy doesn't succeed in all patients. For the approximately 4 million Americans who live with stroke-related disabilities, innovative therapies offer hope of regaining control over their bodies and minds--and toward that end, neighborly rats might now lend a paw.

--Katharine Miller

R. M. Dijkhuizen, J. Ren, J. B. Mandeville, O. Wu, F. M. Ozdag, M. A. Moskowitz, B. R. Rosen, S. P. Finklestein, Functional magnetic resonance imaging of reorganization in rat brain after stroke.
Proc. Natl. Acad. Sci. U.S.A.
98
, 12766-12771 (2001).
[Abstract]
[Full Text]
Protective Pas de Deux? A new partner might help Werner syndrome protein safeguard the genome during replication
Authors: Davenport R. John
Published: August 2003

The protein that causes the premature aging disorder Werner syndrome (see
"Of Hyperaging and Methuselah Genes"
) has picked up a fresh dance partner. The Werner syndrome protein (WRN) apparently enhances the moves of an enzyme that plays a role in DNA replication and repair. WRN was already known to bind to other proteins involved in these processes, and on its own, it unwinds and chews up DNA. But exactly what WRN does in the cell--and how its defective versions lead to premature aging--remains mysterious.

A protein called FEN-1 trims DNA tails that crop up during DNA replication and repair. In addition, the yeast version of FEN-1 helps maintain genetic stability; a defective form of it provokes genetic mayhem, such as large deletions, also seen in cells with faulty WRN. Because FEN-1 and WRN seem to inspire similar choreography, Brosh and colleagues wondered whether the two ever engage in a molecular tango. To find out, the researchers used a fragment of the WRN protein as bait to fish associated proteins out of material from human cell nuclei. Employing antibodies, they hauled WRN from the mixture and discovered that FEN-1 came along for the ride.

They then probed whether the union between the proteins affects their respective enzymatic activities. Although FEN-1 does not alter WRN's capacity to unwind DNA, WRN stimulates FEN-1's ability to cleave DNA: FEN-1 nibbles DNA faster when WRN is present than when FEN-1 tackles the chore by itself. Whether FEN-1 and WRN perform this duet in intact cells--and whether disrupting this collaboration is a critical trigger for Werner syndrome--remains to be seen. But the result offers a glimpse at some new variations in the Werner protein's repertoire.

--R. John Davenport; suggested by Matt Kaeberlein

R. M. Brosh Jr., C. von Kobbe, J. A. Sommers, P. Karmakar, P. L. Opresko, J. Piotrowski, I. Dianova, G. L. Dianov, V. A. Bohr, Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity.
EMBO J.
20
, 5791-5801 (2001).
[Abstract]
[Full Text]
Bye-bye Birdie: Short-lived fryers less resistant to molecular pecking than long-lived fliers
Authors: Davenport R. John
Published: August 2003

Our feathered friends might be hiding a few antiaging tricks under their wings: New results suggest that long-lived birds withstand damage caused by reactive oxygen molecules better than either mammals or short-lived birds do.

Pound for pound, birds survive much longer than do mammals, but they also break down food for energy at higher rates. Those observations seem paradoxical because metabolic activity produces reactive oxygen species (ROS)--destructive molecules that likely contribute to aging (see
"The Two Faces of Oxygen"
). Recent studies indicate, however, that compared to mammals, long-lived birds produce fewer ROS per molecule of oxygen processed. And those birds also appear more adept at preventing ROS from causing cellular damage. But no one had established whether all birds or only long-lived ones carry these traits.

To investigate this issue, Ogburn and colleagues cultured cells from two species of birds: quail, which live about 4 years, and budgerigars (common pets fondly known as budgies), whose longevity can top 20 years. They also tested short- and long-lived mammals: mice, with a life-span of 3 years, and humans, who can survive to ages greater than 100. The researchers subjected the cell cultures to oxidative stress by exposing them to high concentrations of oxygen or hydrogen peroxide, and then they counted the cells that persisted. A higher percentage of budgie cells survived the assault than did those from the other three species. Additional experiments indicate that the budgies' superior defenses require active genes: When the researchers added chemical inhibitors of either messenger RNA or protein synthesis to the cells, budgie cell survival after treatment dropped to the level measured in the other three species. The results indicate that long-lived birds fend off oxidative damage better than do their less-robust cousins.

It's unclear if the cell culture model accurately reflects the response of cells in vivo. But the system does give scientists a controlled way to compare species and flush out budgies' possible secrets to a longer life. Budgies could boast a greater quantity of the same antioxidant enzymes that shorter-lived species employ, or they might have developed unique strategies for dealing with oxidative injury. Pinpointing the genes responsible for the difference between species might reveal the answer. Such information could enhance our understanding of possible connections between oxidative damage and aging and hint at ways to give wings to our own defenses.

--R. John Davenport

C. E. Ogburn, K. Carlberg, M. A. Ottinger, D. J. Holmes, G. M. Martin, S. N. Austad, Exceptional Cellular Resistance to Oxidative Damage in Long-Lived Birds Requires Active Gene Expression.
J. Gerontol. A Biol. Sci. Med. Sci.
56
, B468-B474 (2001).
[Abstract]
[Full Text]
They're Alive! Protein potion brings senescent cells back from the (un)dead
Authors: Davenport R. John
Published: August 2003

Like zombies, senescent cells join the ranks of the undead. They no longer divide, but they don't die either. Now it turns out that these cellular freaks possess the resources for resurrection to a more vigorous existence: The right brew of normal proteins can kick-start DNA replication in the stalled cells.

Until now, scientists needed deviant proteins to shock senescent cells back to life: Cancer-causing molecules activate two cellular pathways that stimulate division. In the new work, Sarraj and colleagues mixed and matched benign proteins, looking for a combination that spurs senescent cells to start reproducing again. They tested Mdm2, which distracts the p53 protein from one of its usual jobs: inhibiting cell proliferation. Other candidates were three E2F proteins, which boost the production of molecules that encourage cells to multiply. Because senescent cells contain more p53 and less E2F than do normal cells, the researchers reasoned that providing additional Mdm2 or E2F might trigger cell duplication. To test this idea, they infected senescent human fibroblasts--cells that compose connective tissue--with various combinations of viruses, each of which is engineered to produce one of these proteins. By looking for incorporation of a tagged molecule into DNA, they were able to determine what fraction of cells copied their DNA--an indication that cell division had started up again. Serving up extra Mdm2 or E2F individually had a modest effect: 10% to 30% of the cells showed signs of replicative life. But Mdm2 plus any one of the three E2Fs jolted 50% to 70% of the cells back into action.

Scientists have suspected that the right blend of cellular proteins could recharge senescent cells, but they hadn't shown that experimentally until now. The results provide evidence that supplying certain proteins lacking in senescent cells can indeed reverse the process. The study enhances our knowledge about possible links between senescence and cancer or aging. In animals, senescence might fight cancer by stunting the growth of damaged cells before they start dividing unchecked (see
"Dangerous Liaisons"
). And accumulation of senescent cells might be to blame for some of the effects of aging (see
"More Than a Sum of Our Cells"
). But no one's likely to start receiving antiaging E2F/Mdm2 injections any time soon: The treated cells might retain the harmful characteristics that sparked senescence in the first place and rejuvenating them might just produce more of a bad thing. But knowing how to bring senescent cells back to life will undoubtedly shed light on the spell that makes them zombies in the first place.

--R. John Davenport; suggested by Chang-Su Lim

S. Sarraj, R. Farb, R. Martell, Reconstitution of DNA synthetic capacity in senescent normal human fibroblasts by expressing cellular factors E2F and Mdm2.
Exp. Cell Res.
270
, 268-276 (2001).
[Abstract]
[PDF]
Drugs Protect Mice From Pernicious Forms of Oxygen
Authors: Tuma Rabiya S.
Published: August 2003

Oxygen fuels cellular processes, but burning it creates reactive molecules that zap cellular machinery. To neutralize these cellular bullets, organisms produce an arsenal of enzymes. Animals that lack one of these enzymes--mitochondrial superoxide dismutase (SOD2)--die shortly after birth. Now new work has shown that several drugs that mimic SOD2 in the brain can prolong the lives of the mutant mice--probably by reversing some of the neurological damage that normally kills them--indicating their potential as life-extension treatments.
Ebb Tide: Brain center linked to decrease in egg-producing waves
Authors: Davenport R. John
Published: August 2003

As mammals age, one of the first things to go is reproductive capacity. Ovulation becomes irregular, because waves of luteinizing hormone (LH) don't crest as high as before. New results indicate that a reduction in nerve impulses from a particular part of the brain is partly responsible for lowering the levels of the hormone that triggers LH production.

Release of luteinizing hormone-releasing hormone (LH-RH) from neurons in the hypothalamus, a part of the brain that governs a host of hormone-controlled bodily functions, spurs the pituitary gland to produce waves of LH. These so-called LH surges stimulate egg release from the ovaries, but they diminish during aging because production of LH-RH by hypothalamic neurons decreases. Exactly what causes this decline is unknown, but some suspect that neurons from elsewhere in the hypothalamus might be to blame. Previous work implicated a region known as the AVPv: AVPv nerve cells connect to LH-RH-producing neurons, and damaging the AVPv blocks LH surges. But it hasn't been clear if a decrease in AVPv activity with advancing years prevents LH-RH synthesis.

In search of a missing link, Le and colleagues looked for activity in AVPv and LH-RH neurons in the brains of young and middle-aged rats sacrificed in the midst of an LH surge. The team used antibodies to detect the presence of the Fos protein, an indicator of neuron activity. A smaller percentage of LH-RH neurons in middle-aged rat brains contained Fos as compared with young rat brains. In addition, a similarly reduced fraction of neurons in the AVPv region of middle-aged brains lit up with Fos. The researchers then damaged AVPv in young rats and monitored LH-RH neuron activity. LH-RH neurons on the same side of the brain as the lesion took a hit, expressing no Fos; LH-RH neurons on the uninjured side of the brain carried on normally. The results add to evidence that nerves in the AVPv stimulate LH-RH production. They also suggest that reduced AVPv firing accounts in part for the waning LH-RH production--and, in turn, the declining LH and loss of ovulation--that comes with age.

Why AVPv activity falls over time is unclear, and the answer is not likely to be simple. The AVPv takes in signals from multiple hormones and neurons, so the change probably involves more than one trigger. And other brain centers could play roles as well. Further elucidating this pathway will help researchers understand how once-swelling hormonal seas flatten.

--R. John Davenport

W.-W. Le, P. M. Wise, A. Z. Murphy, L. M. Coolen, G. E. Hoffman, Parallel declines in Fos activation of the medial anteroventral periventricular nucleus and LHRH neurons in middle-aged rats.
Endocrinology
142
, 4976-4982 (2001).
[Abstract]
[Full Text]
Does Caloric Restriction in the Laboratory Simply Prevent Overfeeding and Return House Mice to Their Natural Level of Food Intake?
Authors: Austad Steven N.
Published: August 2003

Some researchers have speculated that the senescence-retarding effect of caloric restriction on laboratory rodents is an artifact of overfeeding under captive conditions. The argument posits that mice in nature are chronically calorically restricted; therefore, the typical laboratory protocol of restricting animals to 60% of their ad lib food intake more realistically replicates life in the field: the conditions under which the animals' physiology has been designed by natural selection to thrive. The hypothesis concludes that instead of comparing control animals with restricted animals, we are in fact comparing overfed animals with adequately fed ones, and, not surprisingly, the overfed ones die younger. In this Perspective, the author discusses the merits and drawbacks of this hypothesis in light of energy consumption data for various types of mice.
Parkinson's Disease
Authors: Constantino Anne E. A. , Honig Lawrence S.
Published: August 2003

In this case study, we describe the symptoms, neurological examination, test results, and brain pathology of a man with Parkinson's disease (PD). PD commonly presents with tremor or changes in one's ability to walk or move. Other major difficulties caused by this disease include rigidity of the body, slowness of movement, and postural imbalance. The disease symptoms principally result from the degeneration of a specific population of neuronal cells in the brain stem, in a region called the pars compacta of the substantia nigra. Pathology shows the loss of these cells and the appearance of characteristic neuronal cytoplasmic inclusions called Lewy bodies, which are composed principally of aggregated α-synuclein protein.
U.K. Researchers Mind the Gap: New collaboration patches cracks in research on aging
Authors: Miller Katharine
Published: August 2003

To address quality-of-life issues related to aging--many of which lie in the spaces between traditional scientific disciplines--four British research councils launched the National Collaboration on Ageing Research (NCAR) at a conference held in Birmingham on 12 November. These agencies, each of which runs its own program on aging, will now collaborate to identify and eventually sponsor joint projects. "It is imperative that we bring together the different research efforts," says Alan Walker, a social scientist and director of NCAR. "The U.K. is simply not getting the maximum impact from researchers who are locked in disciplinary pigeonholes." The councils--which fund research on biotechnology and biology; medicine; economics and social science; and engineering and physical sciences--will also team up with governmental agencies "to shorten the time it takes to translate research output into policy and practice," says Walker.

The impetus for the collaboration flowed from AgeNet, a U.K. governmental initiative that established a Web site and held workshops to stimulate research in the field of aging. When funding for AgeNet ended in March 2000, the research councils and the Department of Health decided to keep the AgeNet Web site alive and develop a coordinated approach to research on aging. During the next year and a half, Walker, as director of the Growing Older Programme for the Economic and Social Research Council, gained backing from the British government and the financial support to manage the collaboration--although there is still no pot of money to fund specific projects. "It's been a long time coming, and it's taken a lot of backroom effort to convince key players, but we've had an absolutely massive response from scientists," he says.

Some possible ideas for joint projects include using medical, engineering, and social science expertise to improve access to transportation or design better living environments for seniors; using biological, health care, and social science resources to help older people regain independence after a stroke or major injury; and getting biotechnologists, engineers, doctors, and social scientists to explore high-tech solutions to the needs of homebound people.

As these ideas develop, the research councils will prepare for the next step: creating a funding route to make the projects happen. This phase of the project will require that councils commit some of their money to NCAR programs, an act that might meet some resistance. But if NCAR succeeds, the potential payback in quality of life for Britain's elderly should be worth the effort.

--Katharine Miller

Further Reading

UK National Collaboration on Ageing Research
http://www.shef.ac.uk/ukncar