3,103 Matching Annotations
  1. May 2017
    1. a 1-SD worse score is associated with a 14.6% decrease in grant-supported research publications and a 18.6% decrease in citations to those publications

      Here, the authors estimated how much a decrease of one standard deviation on the percentile score affected the number of publications and citations of a grant recipient.

    2. regression

      Regression is a measure of the relation between the mean value of one variable and corresponding values of other variables. There are different types of regression, all of which are used to identify trends in data.

    3. Poisson regressions

      A Poisson regression is a form of regression analysis where we have a random variable, which is equal to the number of events over a period of time if these events are independent and occur at a constant speed.

    4. This variation in citations underscores the potential gains from being able to accurately screen grant applications on the basis of their research potential.

      The authors found that there is a lot of variation in the research output of projects that receive grants. They conclude that it would be useful to find a way to accurately screen applications to determine their potential.

    5. institutional affiliation

      An applicant's institutional affiliation is the organization that has agreed to be the legal recipient of the grant. This organization can be a nonprofit, a university, or an employer.

    6. measure applicant-level characteristics

      The authors studied some characteristics such as the grant history or the institutional affiliation to see if the previous work of the applicant has an impact on the result of the grant application.

    7. patents that either directly cite NIH grant support or cite publications acknowledging grant support

      The last measure is the number of patents that cite those publications from (i), or acknowledge support from the grant.

    8. the total number of citations that those publications receive through 2013

      The second measure is the total number of citations the publications from (i) received through 2013.

    9. the total number of publications that acknowledge grant support within 5 years of grant approval

      The first measure of success is the number of papers a team published during the 5 years after they received the grant.

    10. funding is likely to have direct effect on research productivity

      The authors considered grants which were already funded and competing for renewal. This makes it easier to attribute differences in research productivity to the peer review process, rather than the amount of funding the project has.

    11. standard deviation (SD)

      Standard deviation is a statistical measure that is used to describe how much variation there is in a data set. A high standard deviation means that the data is very spread out.

    12. percentile score

      The percentile score is assigned by the peer review committee. It ranks all authors to determine which was the most favored by the committee. A lower score means the committee liked the application more.

    13. NIH is the world’s largest funder of biomedical research (12). With an annual budget of approximately $30 billion, it supports more than 300,000 research personnel at more than 2500 institutions (12, 13). A funding application is assigned by topic to one of approximately 200 peer-review committees (known as study sections).

      Based on an analysis conducted by the authors, biomedical research is valued highly by individuals, governments, foundations, and corporations. Research is seen as a source of more effective treatments and preventive measures and as a route to policy, new commercial products, and economic development.

      As a result, investments in biomedical research are the highest of all sectors.

    14. Because research outcomes are often skewed, with many low-quality or incremental contributions and relatively few ground-breaking discoveries

      One critique about peer reviewing is that peer review may not identify pioneering research.

      This report highlights the possible disadvantages of peer review:

      http://www.theepochtimes.com/n3/1334826-does-peer-review-pick-the-best-science/

    15. peer review has high value-added if differences in grants’ scores are predictive of differences in their subsequent research output

      If the evaluation by the peer review committee is correlated with the quality of work put out by the research group, then peer review has high value-added (meaning, it is useful for choosing research groups with the highest potential).

    16. Because NIH cannot possibly fund every application it receives, the ability to distinguish potential among applications is important for its success.

      The outcome of this study could have important implications for how the NIH evaluates and chooses who it gives money to.

    17. Whereas previous work has studied the impact of receiving NIH funds on the productivity of awardees

      These articles show that receiving a grant for postdoctoral research leads to an increase in productivity.

    18. value-added

      Value-added is the amount by which the value of the product is increased. Here, it means by how much peer review increases new insights about the quality of grant applications.

    19. Existing research in this area has focused on understanding whether there is a correlation between good peer-review scores and successful research outcomes and yields mixed results

      In these articles, the authors found out that there was no link between higher ratings from the peer-review committee and the number of citations the article eventually got.

    20. Disagreement about what constitutes important research may introduce randomness into the process

      In this article, the authors showed that getting a research grant partially depends on chance. They reviewed the same proposals with different committees, who each gave different results.

    21. Peer-review committees

      The aim of the peer-review committees is to ensure research is high-quality and to encourage innovation. However, it has been shown that peer review committees can be undermined by various factors.

    22. In 2014, the combined budgets of the U.S. National Institutes of Health (NIH), the U.S. National Science Foundation, and the European Research Council totaled almost $40 billion.

      In 2016, the combined budgets totaled $41.7 billion. The following resources indicate that the research budget continues to increase (as of December 2016).

      https://www.nih.gov/about-nih/what-we-do/budget http://www.nsf.gov/about/budget/fy2016/ https://erc.europa.eu/about-erc/facts-and-figures

    23. U.S. National Institutes of Health

      A grant is a money given to enterprises, organizations, and individuals for research, development, and education. Grants do not have to be returned, but most granting organizations require a report about the progress of the outcome.

    24. peer-review

      Peer-review is the review process for scientific articles, research, or ideas by scientific experts in the same field.

  2. Apr 2017
    1. The availability of a neuropathologically validated murine model with correspondence to human CTE is expected to open new avenues for investigation of mechanisms, biomarkers, and risk factors relevant to blast-related brain injury

      In addition to the observations and findings of this study, the physical instruments and experimental protocols that were developed will likely be very useful for further research and development of diagnostics, therapies, rehabilitation strategies, and preventative measures.

      The work here will help military service personnel and others at risk for developing neurotrauma-related disease.

    2. APOE (apolipoprotein E) genotype (77)], history of previous head trauma, innate inflammatory responsivity, neuropsychiatric comorbidity, age and gender,

      All of these are known to affect how susceptible a patient is to mild forms of neurotrauma and related effects. They can also affect how these are expressed.

    3. even greater pathogenic potential

      The authors suggest that blast exposure may be more damaging than sports-related impact because they were able to observe substantial neural abnormalities after a single blast exposure.

      In the case of impact-induced head injury, mild cases typically require repetitive impacts to cause neural abnormalities.

    4. A. H. S. Holbourn, Mechanics of head injuries. Lancet 242, 438–441 (1943).

      Holbourn compared the head to a jar containing gelatin, hypothesizing that if the jar was shaken or violently rotated it would cause a shearing effect. He believed this shearing may be the culprit behind TBI.

    5. F. W. Mott, The effects of high explosives upon the central nervous system. Lancet 187, 331–338, 441–449, 545–553 (1916). War Neuroses and Shell Shock (Frowde, Hodder &Stoughton, London, 1919).

      Mott's investigation of "shell shock" in WWI veterans was the first human clinicopathological analysis of the physical effects of blast exposure on the brain.

      The idea that an explosion could cause damage to the brain, and therefore potentially be responsible for mental deficits, led to a controversial national inquiry into blast exposure and veterans' health.

    6. D. R. Richmond, E. G. Damon, I. G. Bowen, E. R. Fletcher, C. S. White, Air-blast studies with eight species of mammals. Techn Progr Rep DASA 1854. Fission Prod. Inhal. Proj. 1–44 (1967).

      U.S. Department of Defense study that focused on blast-related lung injury and influenced thought behind blast-related injury for nearly half a century.

    7. H. Celander, C. J. Clemedson, U. A. Ericsson, H. I. Hultman, The use of a compressed air operated shock tube for physiological blast research. Acta Physiol. Scand. 33, 6–13 (1955).

      One of the first uses of a compressed gas shock tube to study blast exposure in an animal model.

    8. B. I. Omalu, S. T. DeKosky, R. L. Minster, M. I. Kamboh, R. L. Hamilton, C. H. Wecht, Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57, 128–134 (2005).

      A report of the long-term effects of repetitive head injury linked to American football.

    9. C. W. Hoge, D. McGurk, J. L. Thomas, A. L. Cox, C. C. Engel, C. A. Castro, Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N. Engl. J. Med. 358, 453–463 (2008).

      An influential paper that drew national attention to mild TBI in military veterans.

    10. Although it is possible that high-frequency components (>100 kHz) could lead to localized focusing due to reverberation and constructive interference, the pressure amplitudes we measured were far below tissue damage thresholds.

      A possible alternative hypothesis is that the structure of the head and the brain would cause the blast wave to bounce around inside the brain, causing damage.

      The authors' observations of roughly equal pressures both inside and outside the skull suggest that this is not a likely cause of injury. Furthermore, the magnitude of the pressure wave is far below the threshold that causes damage to tissues.

    11. ICP dynamics recorded during blast exposure revealed blast-induced pressure transients in the hippocampus that were coincident with and comparable in amplitude, waveform, and impulse to FFP measurements outside the cranium. This finding is consistent with the head acting as a lumped element for which the blast-induced external pressure differential equilibrates within ~100 μs.

      The results of this study suggest that pressure from the blast wave is not enough to cause brain injury. The data and calculations show that the brain rapidly adapts to the changing pressure, and that the pressure inside and outside the skull during the blast wave is comparable.

      Thus, blast wave pressure alone is not responsible for TBI.

    12. These findings suggest that genotypic determinants may be critical factors that modulate temporal and phenotypic expression of TBI and late-emerging sequelae, including CTE.

      Although the wild-type mouse model has limitations (as do all experimental models), using laboratory animals allows researchers to test things that can't be directly tested in humans.

      For example, mouse models are useful tools to study the effects of different genes. Biological research has generated thousands of genetically modified mouse strains that allow researchers to test hypotheses regarding specific genes and how these genes influence human diseases.

    13. forme fruste

      An atypical or less severe form of a disease.

      Here, the authors use the term to mean that although their mouse model replicates most of the major signs of CTE, it is limited in not developing the mature NFTs seen in human cases.

    14. contemporaneous

      Occurred at the same time.

    15. Notably, within this small controlled case series, the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.

      This statement is based on the authors' human findings from the human case studies. They observed identical paterns in head-injured athletes and blast-exposed military veterans, which has important implications for our undersetanding of traumatic brain injury and CTE.

    16. Head immobilization during blast exposure eliminated blast-related impairments in hippocampal-dependent learning acquisition (Fig. 7D; P > 0.20, repeated-measures ANOVA with post hoc Scheffe test compared to sham-blast controls) and restored blast-related memory retention deficits to normal levels (Fig. 7E; P > 0.20, one-way ANOVA with post hoc Scheffe test), supporting the conclusion that head acceleration is necessary for behavioral learning impairments.

      To test the "bobblehead effect," the authors performed the same experiments on mice whose heads had been held still during blast exposure and mice whose heads were allowed to move freely.

      Mice whose heads were allowed to move freely were exposed to both the blast wave (the pressure of the blast) and the blast wind (the wind following a blast wave). Mice whose heads were restrained were only exposed to the blast wave.

      The authors hypothesized that blast neurotrauma and the resulting cognitive deficits were the result of the acceleration of the head during a blast (i.e., the blast wind), meaning that mice whose heads were restrained would not show any abnormalities.

      The results reported here support the authors' hypothesis that head acceleration is a major contributor to traumatic brain injury following blast exposure.

    17. escape latencies

      The length of time it takes to escape the maze.

    18. Barnes maze

      A tool used to study spatial learning and memory. The fact that blast-exposed mice took longer to escape and had poorer memories of the maze suggests a cognitive deficit due to blast exposure.

    19. blast exposure did not impair gross neurological functioning with respect to locomotion, exploratory activity, and thigmotaxis (an indicator of murine anxiety assessed by movement close to the wall of the experimental apparatus)

      It was important to assess locomotion (movement) because the behavioral cognition test used relies on locomotion for its results.

      If locomotion were impaired, then the results of the behavioral test could not be linked to cognition alone.

      The authors did not detect any abnormalities in locomotion in either the control or experimental group, meaning that any cognitive abnormalities they observed were not due to locomotor defects. This strengthens the argument that any of the abnormalities they saw were due to blast-related interference with brain functions affecting learning and memory.

    20. candidate mechanisms

      Although we understand a lot about the hippocampus and its function, there is still a lot of active research into the exact way that learning and memory work. Because of this, the word "candidate" is used to qualify this statement.

    21. We found marked impairments of stimulus-evoked LTP in mouse slices prepared 2 weeks and 1 month after blast exposure

      As above, the authors found impairments in a neuronal process thought to be involved in memory storage.

    22. significantly slowed 2 weeks after blast exposure, an effect that persisted for at least 1 month

      Following blast exposure, the authors observed a slowing of axonal conduction in structures of the hippocampus that are important for long-term potentiation (LTP).

    23. long-term potentiation

      Long-term potentiation (LTP) is a measure of synaptic plasticity, or the ability of synapses to adapt and change. LTP is important to learning and memory. If it is impaired, it can cause cognitive deficits, specifically in processes important to memory.

    24. axonal conduction

      The movement of electrophysiological signals along the axon. Slowed (or prolonged) conduction is a sign of a defect in the relaying of signals between different parts of the brain.

    25. bilaterally

      On both sides of the brain.

    26. inclusion bodies

      Clumps of stable molecules found in the nuclei and cytoplasm of cells. They are usually a sign of viral infection and are the site of viral multiplication, but they can also indicate neurological disease.

    27. dystrophic myelinated nerve fibers

      Some axons are surrounded by a layer of myelin, a fatty, white substance that helps regulate signal transmission.

    28. Pathologically swollen, edematous, and often highly vacuolated astrocytic end-feet were observed in association with dysmorphic capillaries marked by pathologically thickened, tortuous basal lamina and abnormal endothelial cells with irregularly shaped nuclei (Fig. 4L and figs. S11 to S16)

      Astrocytes support blood vessels and interact with other types of brain cells to control the blood-brain barrier (BBB), a membrane that protects the brain from disruptive changes in the blood.

      Using the electorn microscopic images in Figure 4 and Supplementary Figures 11 to 16, the authors saw that a single blast exposure can damage not only are the smallest blood vessels but the astrocytic "feet" that wrap around and encase these blood vessels.

      Because these blood vessels are critical for gas and fluid exchange, damage to them can disrupt many metabolic processes.

    29. stratum radiatum

      A region of the hippocampus.

    30. paucity

      Scarcity.

    31. stratum pyramidale

      A region of the hippocampus.

    32. pathology

      Abnormalities.

    33. Ultrastructural

      Refers to a scale that is beyond detection by light microscopy, requiring a magnification that can only be achieved by electron microscope.

    34. However, blast-exposed mice did show decreased choline acetyltransferase immunoreactivity in motor neurons in the cervical cord (fig. S10D) and cranial nerve XII (fig. S10F) when compared to sham-blast controls (fig. S10, C and E), suggesting loss of central cholinergic inputs.

      Choline acetyltransferase (ChAT) is an enzyme that produces the neurotransmitter acetylcholine.

      Reduced ChAT concentrations are associated with Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

      Decreased ChAT following blast TBI suggests similarities between Alzheimer's, ALS, and TBI.

    35. Purkinje cells

      Cells that help regulate nerve impulses.

    36. Activated perivascular microglia were observed throughout the brain in blast-exposed mice and were especially notable in the cerebellum

      The authors also observed other key signs of CTE, such as the presence of activated microglia near small blood vessels (perivascular microgliosis).

      This finding is consistent with traumatic microvascular injury and reactive microgliosis, which are signs of chronic inflammation in the brain.

    37. dystrophic axons

      Axons that are wasting away.

    38. pyknotic

      Neurons whose nuclear chromatin has condensed and gathered within the nucleus. This is a step that cells undergo during apoptosis or necrosis, two methods of cell death. Pyknotic neurons are either dead or dying.

    39. chromatolytic

      Dead or dying neurons. These neurons have suffered a breakdown of Nissl bodies, large granular bodies that are the site of protein synthesis.

    40. We hypothesized that blast forces exerted on the skull would result in head acceleration-deceleration oscillation of sufficient intensity to induce persistent brain injury (“bobblehead effect”)

      In this section, the authors sought to find out if their mouse model of blast neurotrauma caused similar brain abnormalities as those observed in human CTE cases.

      If so, it would mean there is a causal linkage between blast exposure and development of CTE later in life.

    41. Kinematic analysis of high-speed videographic records of head movement during blast exposure confirmed rapid oscillating acceleration-deceleration of the head in the horizontal and sagittal planes of motion (Fig. 2, D to G, and video S1).

      The authors used high-speed video cameras (which capture 100,000 frames per second) to record mouse head movements during blast exposure.

      The videos showed violent winds pushing and pulling on the head during the blast, which the authors measured as the kinematics (motions over time) of the head.

      These pushing and pulling forces during blast exposure were similar to sport-related impacts leading to injury.

    42. blast wind velocity was 150 m/s (336 miles/hour)

      After investigating the effects of blast waves on the skull and brain, the authors turned their attention to the effects of blast wind.

      See the following video for a look at the destructive nature of these blast winds during a 1955 atomic weapons test:

      https://www.youtube.com/watch?v=ztJXZjIp8OA

    43. brain parenchyma

      "Parenchyma" refers to the bulk component of a tissue. The brain parenchyma includes the dense network of brain cells and their processes, but does not include membranes, vascular elements, etc.

    44. Although the reflected and transmitted shock waves are large (~2.5 times greater than the 77-kPa incident overpressure), the ~7-μs traversal time of the skull-brain transmitted wave is short enough to allow rapid equilibration across the skull. Thus, the head acts acoustically as a “lumped element”

      The authors also calculated how the blast pressure wave would travel through the brain tissue. They found that, as with the skull, the pressure wave moved too quickly through the brain to cause injury.

      The authors conclude that the head may be treated as a "lumped element," meaning that the blast pressure wave travels through it as if it were a single body.

    45. The pressure differential associated with this traversal has an insignificant effect on skull displacement due to the short time interval.

      The authors next investigated how the blast pressure wave interacted with the mice's skulls. They calculated the speed of the shockwave by taking pressure measurements with multiple sensors at different locations and measuring the time delay between recordings. Using the distance between sensors and the time delay, they were able to record the "speed" of the wave as it traveled down the shock tube.

      By comparing the wave speed with the width of the mice's heads, the authors concluded that the wave traveled too quickly to create a pressure gradient large enough to cause injury. Based on these results, they were able to rule out skull compression as a cause of TBI.

    46. dynamic pressure

      Dynamic pressure is more complex than static pressure. It includes not only the pressure that results from particles in natural, random motion, but collisions of particles that result from movement in the flow direction.

    47. To investigate possible thoracic contributions to blast-induced ICP transients,

      A common hypothesis for the way blast waves cause traumatic brain injury is that the pressure from the blast compresses the thorax (chest region) and part of the circulatory system. It is thought that this creates vascular pressure, which forces blood into the brain and increases intracranial pressure. This is known as the "water hammer effect."

    48. To investigate intracranial pressure (ICP) dynamics during blast exposure, we inserted a needle hydrophone into the hippocampus of living mice and monitored pressure dynamics during blast exposure.

      The first potential injury source the authors investigated was the interaction of the blast wave with the brain. The authors tested whether this interaction was destructive to the brain. To do this, they measured the pressure of the brain in living mice using a small needle hydrophone (a microphone used to detect sound waves underwater).

    49. static (incident) pressure profile

      Like all moving fluids, blast shockwaves have two different pressure measures: static and dynamic. Static pressure is the pressure exerted on one particle of the fluid when it is at rest. Dynamic pressure incorporates the movement of the fluid (or gas), and is a measure of the kinetic energy of the fluid.

      Static pressure can be measured with a "side-on" sensor.

    50. allowed free movement of the head and cervical spine to model typical conditions associated with military blast exposure

      The majority of previous studies did not allow free movement of the head during blast exposure in shock tubes. Because of this, these studies showed minimal or no brain injury from blast exposure, contributing to the long-held belief that blast exposure is not linked to brain injury.

      By allowing free movement of the head, the authors obtained results that proved otherwise, i.e., blast exposure can cause brain injury and have long-term neurological consequences.

    51. murine

      Mouse.

    52. U-fibers

      A type of fiber that connects different gyri (ridges) in the brain.

    53. multifocal axonopathy

      Damage to axons in multiple locations.

    54. astrocytosis

      An increase in the number of astrocytes that is due to damage to the nervous system and a sign of neurodegenerative disease.

    55. Evidence of axon degeneration, axon retraction bulbs, and axonal dystrophy were observed in the subcortical white matter subjacent to cortical tau pathology

      In areas of the cortex where the authors saw irregular tau proteins, they saw damage to the axons in the white matter beneath.

    56. cardiac arrhythmia

      An irregular heartbeat (too fast, too slow, or the wrong rhythm).

    57. OxyContin

      An opioid pain medication with a high risk of addiction. If too high of a dose is taken, it can be fatal.

    58. exacerbation

      Worsening.

    59. psychomotor speed

      Reduced reaction time in movements related to mental processes.

    60. posttraumatic stress disorder (PTSD)

      A disorder that develops in some people who have a terrifying or dangerous experience. There are many symptoms, but the major signs are increased anxiety, flashbacks, nightmares, and uncontrollable thoughts about the event.

    61. analgesics

      Pain relievers.

    62. aspiration pneumonia

      An infection that occurs after inhaling food, liquid, or vomit into the lungs.

    63. four young-adult normal control subjects

      Although not shown in the figure below, the authors also examined the brains of healthy controls that matched the age and sex of the experimental subjects. They used the same IHC technique.

      No abnormalities were observed in the control cases.

    64. Neuropathological comparison to brains from young-adult amateur American football players (Fig. 1, C, D, G, and H) with histories of repetitive concussive and subconcussive injury exhibited similar CTE neuropathology marked by perivascular NFTs and glial tangles with sulcal depth prominence in the dorsolateral and inferior frontal cortices.

      The abnormalities seen in the brains of head-injured athletes and blast-exposed military veterans were similar, so the authors hypothesized that the cause of CTE in these two groups must also be similar. However, it is currently not possible to diagnose CTE until after a patient has died and their brain can be autopsied.

      The authors identified a correlation between neurotrauma and CTE, but in order to test their hypothesis and prove a causal connection, they had to perform controlled experiments. They used a mouse model for this.

    65. microglia

      Microglia are immune cells in the brain that are related to the cells in our peripheral immune system. Cells from our peripheral immune system cannot enter the brain, so the brain has to develop its own innate immune system. Microglia are a key component of this.

    66. NFTs and dystrophic axons immunoreactive for monoclonal antibody CP-13 (Fig. 1, A to I, L, Q, R, and U, and fig. S1) directed against phosphorylated tau protein at Ser202 (pS202) and Thr205 (pT205), monoclonal antibody AT8 (Fig. 1S) directed against phosphorylated tau protein at Ser202 (pS202) and Thr205 (pT205)

      Monoclonal antibodies are used in immunohistochemical staining to detect abnormal phosphorylated tau proteins. In this study, several different antibodies were used to detect various forms of tau proteins in different places in the brain.

      If the specific set of abnormalities is detected in the postmortem brain of someone who had a history of neurotrauma, the diagnosis is CTE.

    67. perivascular foci

      Spaces around blood vessels.

    68. inferior frontal, dorsolateral frontal, parietal, and temporal cortices with predilection for sulcal depths

      The unique neuropathological lesion of CTE is an irregular accumulation of NFTs and glial tangles around the small blood vessels deep in the sulci (grooves) of the cortex.

    69. glial tangles

      Similar to NFTs but in glial cells instead of neurons. These tangles are also associated with abnormal tau protein accumulation and, when they are observed in the brain, are an indicator of disease.

    70. intracerebral hemorrhage

      Bleeding in the brain.

      An intracerebral hemorrhage can disrupt blood flow and deprive the brain of oxygen, put pressure on brain tissue around the hemorrhage, and introduce toxins into the brain.

      Intracerebral hemorrhage can be fatal.

    71. basilar aneurysm

      Weakness in the walls of the basilar artery at the base of the brain, resulting in ballooning. Rupture of this blood vessel can cause sudden onset of neurological symptoms and is often lethal.

    72. repetitive concussive injury

      Repetitive concussive injury means that the athlete had multiple reported concussions. Recent research suggests that repeated impacts to the head (but not necessarily concussions) are related to an increased risk of developing neurodegenerative diseases including CTE.

      Thus, the number of head impacts, regardless of how many resulted in concussion, is a more accurate measure of risk of long-term neurological consequences, including CTE.

    73. normal controls of comparable ages without a history of blast exposure

      A control is a group or individual that is used as a standard of comparison in experiments.

    74. compared these neuropathological analyses

      The authors used neuropathological analysis to compare the brains of military veterans who were exposed to blasts with young American football players, a professional wrestler, and normal controls.

    75. clinicopathological correlation

      The relationship between the sequence of events that led up to the death of the patient or subject and the findings from an autopsy.

    76. Clinical symptoms of CTE include progressive affective lability, irritability, distractability, executive dysfunction, memory disturbances, suicidal ideation, and in advanced cases, cognitive deficits and dementia.

      Recently, scientists have recognized that blast-related traumatic brain injury suffered during military service can have a negative impact on veterans' lives. It has been shown to impair many brain functions (concentration, memory, cognition) and negatively affect mood (irritability, suicidal ideation).

      In 2012, President Barack Obama signed an Executive Order to improve access to mental health care for veterans: https://www.whitehouse.gov/the-press-office/2012/08/31/executive-order-improving-access-mental-health-services-veterans-service

    77. Head immobilization during blast exposure prevented blast-induced learning and memory deficits.

      If a mouse's head was prevented from moving when it was exposed to a blast, the learning and memory deficits described above did not occur.

    78. oscillation

      Back and forth movement.

    79. persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission.

      Mice that were exposed to blasts had memory and learning problems. Additionally, axons in their brain showed reduced function and they had defective activity-dependent long-term potentiation, which is thought to be important to learning and memory.

      In this case, these defects were all correlated but not necessarily caused by one another.

    80. hemorrhage

      Occurs when blood vessels are punctured and blood begins to flow out of them.

    81. neuropsychiatric spectrum disorder

      A group of psychiatric disorders with underlying neurological causes.

    82. Given the overlap of clinical signs and symptoms in military personnel with blast-related TBI and athletes with concussion-related CTE, we hypothesized that common biomechanical and pathophysiological determinants may trigger development of CTE neuropathology and sequelae in both trauma settings.

      A common format of experimental design in medical research is to formulate a hypothesis based on findings in human patients and test the hypothesis in an animal model.

    83. the mechanisms of injury

      How exposure to blasts injures the brain.

    1. In most vertebrate appendages, the density of innervation is lower than in salamanders, and Singer suggested that this is a primary determinant for the loss of regenerative ability, for example in mammals (9, 39). This hypothesis now seems unlikely because there are other variables apparently curtailing regeneration

      Connects to Next Generation Science Standards Science and Engineering Practice 6: Constructing explanations (for science) and designing solutions (for engineering).

    2. nerve sheath

      Nerves do not very often just hang out by themselves; they usually are part of a nerve sheath, a collection of nerves bundled together.

      A major type of cell responsible for "bundling" or ensheathing these cells are Schwann cells. These cells are discussed below.

      You can think of these as the cords connecting to your computer, most of you likely have all of your cords nicely wrapped and bound together. You don't have single cords going everywhere.

      http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2121/images/neurium.jpg

    3. axons

      The "fingerlike" extensions from the body of a nerve cell. For a diagram of a nerve cell, see:

      http://www.bbc.co.uk/staticarchive/5d3d66ef622165ae607b3c02f6e603c524eececf.gif

    4. peripheral nerves

      Nerves of the peripheral nervous system that innervate the limb. Does not include nerves found solely in the spinal cord or brain.

    5. glycosylphosphatidylinosotol (GPI)–anchored protein

      You have very likely heard of transmembrane proteins, proteins that integrate into the plasma membrane of a cell. A glycosylphosphatidylinosotol (GPI)-anchored protein is a very similar idea.

      In the case of GPI-anchored protein, GPI is what actually integrates into the plasma membrane as opposed to the protein itself as in in a transmembrane protein. Because GPI is bonded to the protein it becomes anchored along with GPI. Now, a protein that was once free-floating and cytoplasmic is now bound to the plasma membrane.

      Although it does have the same structure as GPI, the following diagram does show conceptually what is happening:

      http://www.sigmaaldrich.com/content/dam/sigma-aldrich/articles/biology/Glycobiology/structure-of-gpi-anchored-proteins.jpg

    6. Distal blastemal cells are converted to more proximal cells by exposure to retinoic acid or other retinoids

      Retinoic acid (a major component of vitamin A) and derived compounds are often used to treat acne. Many of these drugs, however, are known to cause major birth defects at the dosages effective for treating acne. The drug isotretnoin (brand name Accutane®) is in particular known to cause severe birth defects.

      As a result, there is heavy regulation of this drug including mandatory birth control. This, unfortunately, was not always the case and resulted in many children born with birth defects. See this article in The New York Times for more:

      http://www.nytimes.com/1984/10/11/us/acne-drug-accutane-linked-to-severe-birth-deformities.html

      Although development is not regeneration, retinoic acid's role in causing defects in both these processes does highlight shared similarities. Retinoic acid does not disrupt every biology process, you need vitamin A to live of course!

      Because retinoic acid is capable of disrupting both these processes this does suggest some link between the two.

    7. limb blastema

      The limb blastema is the site of regeneration. It is the region where the salamander's limb has been damaged and/or removed and the limb will regrow.

      The limb blastema is composed of mesenchymal progenitor cells. These cells are able to become mesenchymal tissue such as cartilage, muscle, and connective tissue.

      The blastema is formed after "healing," which ensures there isn't serious blood loss. For a picture, see:

      http://openi.nlm.nih.gov/imgs/512/397/2656220/2656220_jbiol105-1.png

    8. Limb regeneration occurs in various species of salamander and offers important insights into the possibilities for regenerating a complex structure in adult vertebrates

      Connects to AP Science Practice 1:

      The student can use representations and models to communicate scientific phenomena and solve scientific problems.

    9. electroporation

      A method for making cells permeable to macromolecules by passing electric current though them.

    10. denervation

      Removal of the limb nerve supply.

    11. distal

      Away from the point of attachment. For example, your fingers are distal to your shoulder.

      For a picture, see:

      https://www.geol.umd.edu/~jmerck/geol431/images/directions.jpg

    12. limb blastemal cells

      The limb blastema is the site of regeneration. It is the region where the salamander's limb has been damaged and/or removed and the limb will regrow. The limb blastema cells are composed of specialized cells that are able to regenerate structures of the limb.

      The blastema is formed after "healing," which ensures there isn't serious blood loss. For a picture see:

      [http://openi.nlm.nih.gov/imgs/512/397/2656220/2656220_jbiol105-1.png] (http://openi.nlm.nih.gov/imgs/512/397/2656220/2656220_jbiol105-1.png)

  3. Mar 2017
  4. Feb 2017
    1. G2

      This is the second gap phase of the cell cycle, between DNA replication (S phase) and mitosis (M phase). During G2, the cell prepares to divide.

      To move on to the next phase (the M phase), a checkpoint ensures that all chromosomes are fully replicated and have no other types of damage.

    2. DNA complements of 2n or 4n

      The number of full chromosome sets in a cell is indicated as a multiple of n. A eukaryotic cell with two complete sets of chromosomes is therefore described as being "2n" (or "diploid").

      After DNA replication in the S phase, the cell's DNA content doubles, and it now contains four complete copies of the genome, making it "4n." Then, after the cell divides in the M phase, there are two daughter cells, each with two complete sets of chromosomes (2 x 2n cells).

      Most cells cycle between being 2n and 4n. Sperm and egg cells (gametes), however, are special cases: They are "haploid" and contain only one set of chromosomes, making them 1n or simply n. Gametes therefore cycle between being 1n and 2n.

    3. cell cycle

      Each time the cell divides into two, it goes through a sequence of events that may include growth, DNA replication, preparation to divide, and finally division. We collectively refer to these events as the "cell cycle," and to the four major events as "phases" (G1, S, G2, and M phase).

      Specialized proteins called "cell cycle regulators" or "checkpoint proteins" regulate the progression from one phase to the next. The progression through these checkpoints is a strictly regulated process that usually works without errors. When errors do occur, they can have catastrophic consequences, including the development of cancer.

      Use this interactive tutorial to learn more: http://www.hhmi.org/biointeractive/eukaryotic-cell-cycle-and-cancer

    1. segregation analyses

      A technique used to determine how a trait is inherited, and if it is inherited in a standard (Mendelian) way.

    2. autosomal

      Refers to the autosomes, or the 22 numbered chromosomes (which do not include the sex chromosomes).

    3. The accumulating number of distinct, individually rare genetic causes in autism (5, 10, 11) suggests that the genetic architecture of autism resembles that of mental retardation and epilepsy, with many syndromes, each individually rare, as well as other cases potentially reflecting complex interactions between inherited changes

      Studies have shown that there are many unique combinations of mutations that can cause autism, similar to the case of mental retardation and epilepsy. Unfortunately, given that there are so many ways for autism to occur, it is difficult to track which changes can lead to symptoms.

    4. syndromic autism

      Here, "syndromic" means common varities of autism.

    5. monogenic neurological disorders

      Disorders caused by a single gene.

    6. neuropsychiatric

      A mental disorder that is caused by the nervous system.

    7. homozygosity mapping

      A method for mapping genes that are involved in rare, recessive disorders. It is used in inbred populations (populations where many individuals are related to each other). Because these populations are very highly related, individuals will share large areas of their chromosomes surrounding target genes.

    8. autism-spectrum disorders

      Autism-spectrum disorders (ASD), sometimes referred to collectively as "autism," are a family of developmental disorders that have different symptoms and intensities.

    1. E. Y. Chiang, A. Hidalgo, J. Chang, P. S. Frenette, Nat. Methods 4, 219–222 (2007).

      This 2007 paper from Chiang et al. presented a new method for looking at the recruitment of different types of white blood cells to the site of an injury, while simultaneously identifying clusters of ligand-receptor couplings.

      All of this can be visualized in live mice!

      From this initial study, PSGL-1 was identified as a promising neutrophil ligand protein.

    2. PSGL-1

      P-selectin glycoprotein ligand 1 interacts with the P-selectin found on platelets.

      For reference, P-selectin functions as a cell adhesion molecule on activated platelets. Ligands are molecules that produce a signal by binding to a site on a target protein (in this case, the P-selectin on platelets).

    3. segregates to the uropod of polarized neutrophils

      Previous research presented a new method for looking at the recruitment of different types of white blood cells to the site of an injury, while simultaneously identifying clusters of ligand-receptor couplings. This can be done in live mice.

      From this initial study, PSGL-1 was identified as a promising neutrophil ligand protein.

  5. Jan 2017
    1. The fabrication of these microlattices is enabled by projection microstereolithography

      Can you, based on the procedure described in the text, explain how the different microlattices are manufactured?

      The Common Core English and Language Arts Standards

      • 11-12.3: Follow precisely a complex multistep procedure when carrying out experiments, taking measurements, or performing technical tasks; analyze the specific results based on explanations in the text.

    2. nanoscale

      Nanoscale relates to objects whose characteristic dimensions lie between 1 and 999 nm (=10<sup>-9</sup> m). It is the scale below the microscopic scale.

    1. nonprimate

      Any animal that is not a member of the group of animals that includes human beings, apes, and monkeys.

    1. eudaimonic

      Eudaimonic well-being, as compared with hedonic well-being, relates more to the achievement/fulfillment of meaning in life.

      It relates to happiness/well-being that is achieved through a virtuous or transcendent life.

    2. 2013 U.S. Congressional Record

      You can browse through daily issues of the Congressional Record here.

    1. V. Vähätalo, M. Salkinoja-Salonen, P. Taalas, K. Salonen, Spectrum of the quantum yield for photochemical mineralization of dissolved organic carbon in a humic lake. Limnol. Oceanogr. 45, 664–676 (2000).

      This study measured sunlight driven conversion of DOC to CO<sub>2</sub> in a lake in southern Finland. They measured lower quantum yields than the authors found in the paper you just read.

    2. autotrophs

      Organisms such as plants and algae that use sunlight to produce their own energy source. They do not need to eat.

    3. which is 25 to 40% of the estimated CO2 released to the atmosphere from arctic fresh waters (4, 9). The remaining CO2 released to the atmosphere is likely generated in soil waters and transferred directly to surface waters (3, 4) or is respired by bacteria

      The carbon dioxide (CO<sub>2</sub>) released from surface water as calculated in this paper only accounts for 20% to 40% of the estimated CO<sub>2</sub> release from all arctic freshwater.

      Other possible sources of CO<sub>2</sub> include CO<sub>2</sub> released directly from water in the ground and CO<sub>2</sub> produced by organisms living in the sediment at the bottom of lakes, rivers, and streams.

    4. moieties

      Sections of a molecule

    5. zenith angle

      How high in the sky the sun will get during the day

    6. (i) photomineralization of DOC (N = 97), (ii) partial photo-oxidation of DOC (N = 97)

      Measurement methods are summarized here and provided in detail in the supplemental information.

      Photomineralization and partial photo-oxidation were measured for each water sample by first filtering the bacteria out of the samples and then putting them in ultraclean, air-tight, transparent vials.

      Vials were exposed to sunlight for 12 hours. Control vials were wrapped in foil, and placed alongside the sunlight-exposed vials.

      After the sunlight exposure, carbon dioxide (CO<sub>2</sub>) production and oxygen (O<sub>2</sub>) consumption were measured for each sample, as in the dark bacterial respiration experiment.

      The amount of complete and partial oxidation that occurred were calculated based on the ratio of O<sub>2</sub> use to CO<sub>2</sub> production. This is possible because complete oxidation uses one molecule of O<sub>2</sub> for every CO<sub>2</sub> produced, whereas partial oxidation uses O<sub>2</sub> but does not produce any CO<sub>2</sub>.

    7. We quantified dark bacterial respiration

      The details of how this was done are in the supplemental information. The method is summarized below:

      The authors measured dark bacterial respiration by putting unfiltered water samples in extremely clean, air-tight vials and allowing them to sit for 5–7 days at 6°C to 7°C (the average temperature of nonfrozen water at the sampling sites).

      As a control, the authors used water samples where all of the bacteria had been killed using mercury.

      At the end of the 5–7 days, the authors measured how much carbon dioxide (CO<sub>2</sub>) had been produced in each sample. In some samples, the amount of oxygen (O<sub>2</sub>) decrease was also measured as a way of validating the results. Bacterial respiration uses one molecule of O<sub>2</sub> for each molecule of CO<sub>2</sub> produced. The two methods returned the same results, indicating high-quality data.

    8. photomineralization

      Breakdown of organic carbon to carbon dioxide driven by sunlight

    9. quantified concurrently

      Measured at the same time

    10. water column

      From the surface of the water to the bottom

    11. photodegradation

      Breakdown by sunlight

    12. chromophoric

      Light-absorbing (yes, this word is redundant)

    13. photostimulated

      Sunlight-driven

    14. permafrost soils contain twice as much C as there is in the atmosphere (7), and they are thawing (8) and releasing C to surface waters and the atmosphere

      This link discusses some possible implications of thawing permafrost.

    15. C cycling

      Carbon "cycling" happens when carbon changes forms in the environment, for example, when dissolved organic carbon oxidizes to form carbon dioxide (CO<sub>2</sub>), or when plants use CO<sub>2</sub> for photosynthesis. Carbon is not destroyed in the environment, but it frequently changes forms.

      Image Description Image from globecarboncycle.unh.edu

    16. flux

      Amount transfered

    17. flocculated

      Clumped together in particles

    18. carbon budget

      The carbon budget is the amount of carbon dioxide that can be emitted before the earth starts to experience the most dangerous impacts of climate change.

    19. partial oxidation

      Partial oxidation is when organic carbon is broken down, but not all the way. Partially oxidized carbon is not released into the atmosphere. Partial oxidation still requires oxygen (not as much as complete oxidation), though no carbon dioxide is produced.

      An example would be "fading" of a colored fabric that you leave out in the sun, like a favorite blue hat that you wear all the time. The dye (which is made of organic carbon) gets broken down by light and fades in color, but it isn't converted into CO<sub>2</sub>.

    20. CO2

      Carbon dioxide (CO<sub>2</sub>), is the main form of carbon in the atmosphere.

      CO<sub>2</sub> is a “greenhouse gas,” which means that extra CO<sub>2</sub> in Earth’s atmosphere contributes to global warming.

      It is made when other forms of carbon are completely oxidized.

    21. complete oxidation

      Complete oxidation is when organic carbon is broken down as much as possible to form inorganic carbon in the form of carbon dioxide (CO<sub>2</sub>).

      Oxidation of organic carbon to CO<sub>2</sub> requires oxygen (O<sub>2</sub>) and is an important piece of the carbon cycle, that is, the cycling of carbon between its organic forms (organic carbon, DOC), and inorganic carbon (CO<sub>2</sub>).

      One molecule of oxygen (O<sub>2</sub>) is required for each molecule of CO<sub>2</sub> that is produced from the oxidation of organic carbon.

    22. Carbon

      Carbon is an element that is found in all living things and in many other substances in the environment, such as carbon dioxide (CO<sub>2</sub>). It can also be found in soil and can be dissolved in lakes, rivers, and oceans.

  6. Nov 2016
    1. peer-review

      Peer-review is the review process for scientific articles, research, or ideas by scientific experts in the same field.

  7. Sep 2016
    1. J. J. Palop, J. Chin, L. Mucke, Nature 443, 768 (2006).

      This review was written by members of the same lab in which Dr. Roberson did the work described in this paper.

      It outlines how the symptoms experienced by Alzheimer's patients seem to fluctuate constantly, suggesting that these symptoms cannot just be caused by dying neurons (which would result in symptoms that would get progressively worse).

      The authors discuss known changes in other proteins in the brains of Alzheimer’s patients and how these protein networks might work together to mediate symptoms of Alzheimer’s disease in the brain.

    2. K. SantaCruz et al., Science 309, 476 (2005).

      Santa Cruz and colleagues studied genetically modified mice that had a mutation in the human version of the tau gene, which caused those mice to get tau tangles like those seen in Alzheimer’s disease.

      Knocking out this tau gene allowed the mice to avoid memory and cognitive problems, although the tangles still formed.

    3. A. J. Myers et al., Hum. Mol. Genet. 14, 2399 (2005).

      Myers and colleagues examined patients that had died of progressive supranuclear palsy, a disease caused by a mutation in the tau gene.

      They found that these patients also had an increased risk for Alzheimer’s disease, pointing to an important connection between tau and Alzheimer’s.

    4. J. Lewis et al., Science 293, 1487 (2001).

      Lewis and colleagues made a genetically modified mouse with a mutated APP gene and a mutated tau gene.

      These double mutants had plaques like other hAPP mice, but they also had tangles that were more severe than in other mice, showing that problems with amyloid and tau can interact and cause symptoms of Alzheimer’s disease.

    5. R. Tanzi, L. Bertram, Cell 120, 545 (2005).

      Tanzi and Bertram review the "amyloid hypothesis," which is the idea that a build-up of amyloid-β into plaques causes problems in tau, which then form tangles, causing the symptoms of Alzheimer’s disease.

    6. We found no adverse effects of tau reduction on health or cognition in mice, and the evidence that even partial tau reduction robustly protected mice from Aβ and excitotoxic agents highlights its potential benefits.

      This work started as a side project and eventually became a pillar of Dr. Roberson’s later work on mouse models of Alzheimer’s disease. It has been credited with "sparking the research community’s interest in the role of tau in the pathogenesis of Alzheimer’s disease.”

      Read more in Neurology Today:

      http://journals.lww.com/neurotodayonline/_layouts/15/oaks.journals.mobile/post.aspx?blogId=1&postId=520

    7. microdeletions of chromosome 17q21 encompassing the tau gene are associated with learning disabilities in humans

      It might be difficult to recreate this mouse model in humans because previous research has shown that removing the gene that encodes tau in humans leads to serious learning impairments.

    8. Our findings raise the possibility that tau reduction could protect against AD and other neurological conditions associated with excitotoxicity

      This work was covered by AlzForum, a leading advocacy group for Alzheimer’s research and patients.

      Read more at AlzForum:

      http://www.alzforum.org/news/research-news/app-mice-losing-tau-solves-their-memory-problems

    9. tau modulates sensitivity to excitotoxins and may be involved in regulating neuronal activity

      Lowering tau even in normal mice (those without the hAPP gene, who would not get Alzheimer’s disease) was beneficial in making mice less prone to seizures when injected with an seizure-inducing drug.

      This means that in healthy mice, normal tau may be involved in modulating excitation in neurons, reducing the overall risk of seizures.

      (Seizures are a result of abnormally high electrical activity in the brain that occurs when certain neurons are excessively excited.)

    10. intraperitoneal

      An injection into the belly of a mouse that avoids hitting any internal organs.

    11. hAPP-nontransgenic mice

      Mice that do not have the hAPP gene (normal mice).

    12. at a dose that was not lethal to mice without hAPP (P < 0.05). Tau reduction prevented this effect, as no hAPP/Tau+/– or hAPP/Tau–/– mice died. Seizures in hAPP/Tau+/– and hAPP/Tau–/– mice were less severe and occurred at longer latencies than in hAPP/Tau+/+ mice

      Like humans with Alzheimer’s disease, many mice used as models of the disease have a tendency to get seizures, including the hAPP mice used in this study.

      However, hAPP mice without tau or with reduced tau had fewer seizures than those with the normal amount of tau.

    13. Excitotoxicity is implicated in the pathogenesis of AD

      During the course of Alzheimer’s disease, excess stimulation can occur in neurons, causing problems in the brain (including seizures).

      http://www.medscape.com/viewarticle/813029

    14. aberrant

      Wrong or deviating from the norm.

    15. Given that tau reduction prevented behavioral deficits but not neuritic dystrophy, these may represent parallel, rather than causally linked, disease manifestations, or tau reduction may act downstream of neuritic dystrophy.

      Eliminating tau in hAPP mice prevented memory and cognitive problems, but it didn’t prevent the neurons from becoming damaged and impaired.

      The removal of tau must therefore work in an unrelated way to improve cognition in these mice.

    16. Despite the differences in their behavior, hAPP/Tau+/+, hAPP/Tau+/–, and hAPP/Tau–/– mice had similar amounts of neuritic dystrophy

      All hAPP mice, independent of the amount of tau, had neurons whose axons and dendrites were withering away in regions near amyloid plaques.

      These results show that this type of damage in Alzheimer’s disease can happen even without tau being present.

    17. neurites

      Any extension of a neuron, like an axon or a dendrite.

    18. dystrophic

      Wasting away.

    19. punctae

      Dots or points.

    20. In our study, reduction of endogenous, wild-type tau protected hAPP mice against Aβ-dependent cognitive impairments, and this did not involve the elimination of a large pool of tau with typical AD-associated modifications

      Reducing tau in hAPP mice protected those mice against the cognitive impairments seen in Alzheimer’s disease.

      The authors looked at hAPP mice with normal amounts of tau to see how the tau became abnormal later in life. They compared these changes with abnormal tau measured in other mouse models of Alzheimer’s disease.

      The connection between tau and amyloid-β in this model isn’t clear and may involve multiple types of tau or tau stored in various locations (or pools) within the cell.

    21. proteolysis

      The breakdown of a protein by enzymes.

    22. Generation of neurotoxic tau fragments has also been implicated as a mechanism of Aβ toxicity (21). Tau-deficient primary neurons are resistant to Aβ-induced degeneration (3,22), apparently because Aβ toxicity in vitro involves production of a 17-kD tau fragment

      Previous research has shown that fragments of abnormal tau are toxic and may also play a role in how toxic amyloid-β is to neurons. In fact, neurons lacking tau seem immune to damage by amyloid-β.

      This may be the reason why, in this study, the researchers found that the reduction of tau had improved memory, even though amyloid-β or plaque levels remained unchanged.

      http://www.ncbi.nlm.nih.gov/pubmed/15930385

    23. hippocampal homogenates

      Ground up or processed tissue.

    24. Major AD-related phosphorylation sites in human tau are conserved in murine tau, including those phosphorylated by proline-directed kinases, such as glycon synthase kinase (GSK)–3β and cdk5, or by microtubule affinity–regulating kinase (MARK)

      Phosphorylation adds a phosphate group to a molecule. When proteins (like enzymes) are phophorylated, their function and activity changes.

      Abnormal tau that is more phosphorylated than normal is a hallmark of Alzheimer’s disease.

      In mice, tau is phosphorylated similarly to tau in humans, which makes comparisons feasible and simple.

    25. effectors

      A molecule that binds to a protein and changes its function.

    26. Thus, the beneficial effects of reducing tau were observed without detectable changes in Aβ burden, suggesting that tau reduction uncouples Aβ from downstream pathogenic mechanisms

      The authors examined the brains of hAPP mice with different levels of tau. They found that, at all levels of tau, the amount of amyloid plaques and the amount of floating amyloid-β were the same in all hAPP mice.

      Thus, the reduction of tau, which had improved memory, didn’t alter the amyloid-β or plaque levels, suggesting that amyloid-β or plaque levels alone are not responsible for memory loss.

    27. Thus, tau reduction prevented major Aβ-dependent adverse effects in hAPP mice

      hAPP mice are known to die young, as a result of the induced Alzheimer’s disease. But if hAPP mice had a reduced amount of tau, they lived much longer.

      Additionally, hAPP mice with normal levels of tau were hyperactive even into middle age, whereas hAPP mice with no tau were not.

    28. etiology

      Cause or origin.

    29. To determine whether the benefits afforded by tau reduction were sustained, we examined older mice

      By examining older hAPP mice with and without tau, the authors could test how tau causes Alzheimer’s disease to progress as an animal ages.

    30. Increased exploratory locomotor activity is seen after entorhinal cortex lesions and may reflect deficits in spatial information processing (16); hAPP mice show similar hyperactivity

      Previous research has shown that damaging an area of the brain (the entorhinal cortex) that sits next to the hippocampus can make an animal hyperactive.

      Damage to the entorhinal cortex is common in Alzheimer’s disease. Using the same methodology as in previous studies, the authors therefore tested their mice for increased hyperactivity to see whether there was any evidence of damage to this brain area.

    31. tau reduction gene dose-dependently ameliorates Aβ-dependent water maze learning and memory deficits.

      Mice with the hAPP gene usually do poorly in the water maze because of their impaired memory. However, hAPP mice that have only half the amount of normal tau did remember where the platform was after additional training.

      hAPP mice with no tau performed similar to normal, healthy mice, showing good memory on this test.

      Thus, removal of all the normal tau seems to prevent memory problems. Even removing just half the normal tau already has some memory benefits.

    32. Probe trials, in which the platform was removed and mice were given 1 min to explore the pool, confirmed the beneficial effect of tau reduction

      After the researchers trained all mice to swim to a platform hidden under the water surface, the authors removed the platform to see how much time they spent in the area where the platform used to be. This way the researchers were able to test the memory of the mice.

    33. spatial learning

      Learning (and remembering) where something is in 3D space.

      In this case, the mouse cannot see the platform hidden under the surface of the water. It has to remember from previous trials where it's located.

    34. hAPP/Tau+/+mice took longer to master this task (Fig. 1A; P < 0.001). In contrast, hAPP/Tau+/– and hAPP/Tau–/– mice performed at control levels

      Alzheimer’s mice (with hAPP) that had normal amounts of tau (Tau+/+) took longer to learn to swim to a visible platform than the other five types of mice.

    35. Morris water maze

      A maze in which mice learn the location of a platform. The platform is visible at first and then hidden under the water surface once the mice learn its location.

      This type of maze requires the hippocampus, one of the first parts of the brain to become damaged in Alzheimer’s disease.

      See a video about the Morris Water maze here:

      http://www.jove.com/video/897/morris-water-maze-experiment

      https://youtu.be/leHLL4vcbCc

    36. To test learning and memory

      Next Generation Science Standards: Connects to Practice 2: Developing and using models

      The authors developed and used an animal model to study how different levels of tau might interact with amyloid-β to cause the symptoms of Alzheimer’s disease.

      www.nap.edu/openbook.php?record_id=13165&page=42A

    37. We crossed hAPP mice (11) with Tau–/– mice (12) and examined hAPP mice with two (hAPP/Tau+/+), one (hAPP/Tau+/–), or no (hAPP/Tau–/–) endogenous tau alleles, compared with Tau+/+, Tau+/–, and Tau–/– mice without hAPP (13)

      The authors used mice that were genetically engineered to express a human copy of the amyloid precursor protein (called hAPP mice). hAPP mice are a common animal model of Alzheimer’s disease. They develop amyloid plaques and severe memory and cognitive problems later in life, just like humans with the disease.

      The authors bred these hAPP mice with other mice that were missing both their genes for the tau protein (called Tau-/- mice). From this breeding plan, the authors produced hAPP mice with normal amounts of tau (hAPP/Tau+/+), with half the normal amount of tau (hAPP/Tau+/-), and with no tau (hAPP/Tau-/-).

      They also produced mice without the human APP gene that had normal, half, and no tau.

    38. familial AD mutations

      Specific genetic mutations that cause Alzheimer’s disease.

      These mutations are very rare and only account for about 2% of all cases of Alzheimer’s disease. If an individual has one of these rare mutations s/he is destined to get Alzheimer’s disease (100% chance of developing Alzheimer's).