The authors first checked how many replications "worked" by analyzing how many replication studies showed a significant effect with the same direction (positive or negative) as the original studies.

Of the 100 original studies, 97 showed a significant effect. Based on their ability to replicate the original studies, the authors expected around 89 successful replications. However, results showed that only 35 studies were successfully replicated.

Last, the authors wanted to know if successfully reproducible studies differed from studies that could not be replicated in a systematic way.

For this, they checked if a number of differences in the original studies, such as the size of the effect originally reported, was systematically related to successfully replicated studies.

They also checked if a number of differences in the replication studies themselves, such as the size of the effect of the replication study, related systematically to successful replications.

The authors combined the results of each original and replication study to determine if the cumulative joint effect size was significantly different from zero. If the overall effect was significantly different from zero, this could be treated as an indication that the effect exists in reality, and that the original or replication did not erroneously pick up on an effect that did not actually exist.

The authors hypothesized that in half the replication studies, the effect would be stronger in the original than the replication.

The reason for choosing this null hypothesis here is that this is the expectation we would have if chance alone determined the effect sizes. There are two likely outcomes for each replication study: (1) that its effect size is bigger than that of the original study, and (2) that its effect size is smaller than that of the original study.

If chance alone determined the effect size of the replication, we would see each possible outcome realized in 50% of the cases. If the proportion of replication effects that are bigger than the effect of the original study was significantly different from 50%, it could be concluded that this difference was not random.

The null hypothesis is the assumption that a certain effect does not exist in reality, and that any observations of this effect in data is due to unsystematic error.

Predictors are variables that the researchers identified as potentially correlated with reproducibility.

After completing their replication attempt, independent reviewers checked that each team's procedure was well documented, that it followed the initial replication protocol, and that the statistical analysis on the effects selected for replication were correct.

Then, all the data were compiled to conduct analyses not only on the individual studies, but about all replication attempts made. The authors wanted to know if studies that replicated and those that did not replicate would be different.

For instance, they investigated if studies that replicated would be more likely to come from one journal than another, or if studies that did not replicate would be more likely to have a level of statistical significance than studies which could be replicated.

A correlation coefficient describes the statistical relationship between two variables. It shows both the direction (positive coefficient: as A increases, B increases as well; negative coefficient: as A increases, B decreases), and the strength of the relationship (coefficient close to zero: weak relationship; coefficient close to +/- 1: strong relationship).

For example, there might be a positive correlation between years of attendance to school and general knowledge: the longer people have attended school, the more knowledge they acquire. On the other hand, there could be a negative correlation between hours spent watching TV and enjoyment of outdoor activities: the more time people spend watching TV, the less they might enjoy going for a hike.

Importantly, correlation coefficients do not tell us anything about causation.

Ioannidis conducted computer simulations to show that for most studies, it is more likely for a finding to be a false positive than a true identification of an effect.

Among the factors that make it more likely for research findings to be false are small sample size or the underlying effect, and when designs, definitions, and analyses are more flexible rather than rigorously objective.

Sufficient conditions are one set of circumstances under which a specific effect can be found, but there could be many other circumstances under which the effect would occur.

For example, if a person asks you for money and you give it to them, asking for money is a sufficient condition. It's enough to make you give the person money. But there are other circumstances in which you would have done the same. For example, you may have given them money in exchange for a bouquet of flowers.

Necessary conditions are the circumstance that must be met in order to find a specific effect. If these conditions are not met, the effect cannot be found.

For example, to find the effect that prosocial people are more likely than selfish people to give change to someone asking for money, a necessary condition would be studying human subjects, not penguins.

The strength of an effect.

Results are referred to as statistically significant when we find the result convincing because it is extremely unlikely that the observed effects are due to random chance.

Reproducibility is a characteristic of a scientific study, stating that it can be run and run repeatedly, and will in its repetitions yield the same result.

If an experiment has been reproduced successfully, it has been conducted more than once with similar results each time. Subsequent studies are called reproducing studies, replication studies, or replications.

Goreau describes the species of corals found in Jamaica's reefs and the patterns of their distributions. He notes that the northern and southern coasts look different from each other and hypothesizes that these differences are driven by differences in storm frequencies.

Fecundity refers to the ability of an organism to produce offspring. If an organism is more fecund, this means it produces more offspring

Sea stars from the class Ophiuroidea. Brittle stars are named so for their fragile, thin arms.

Diadema antillarum is commonly known as the long-spined sea urchin. Before populations of D. antillarum died off in 1983 in massive numbers, they were a common sight in Caribbean reefs and played an important role in controlling the growth of macroalgae.

Gorgonians are part of a group of corals often called "soft corals" due to their lack of a rigid calcified skeleton. Arborescent means "treelike," referring to gorgonians that specifically have upright treelike forms.

Agaricia is a genus of corals that form flat leaf-like or plate-like structures. The "spp." means "multiple species of." So Agaricia spp. means "species of the genus Agaricia."

Acropora palmata is commonly known as Elkhorn coral for its antlerlike appearance. As a result of its complex 3D shape, A. palmata adds significant structure to coral reefs and forms an important habitat for many other marine organisms.

Since this study was published, hurricanes have been increasing in both frequency and intensity in the North Atlantic. We may begin to see shifts in coral reef communities toward something more like Port Royal.

Read more from the U.S. Global Change Research Program:

http://nca2014.globalchange.gov/report/our-changing-climate/changes-hurricanes

Homologous properties in biology have the same evolutionary origins, but not necessarily the same function. A common example is the human arm and a bat's wing.

Bumps found in the area of tissue that joins the epidermal (outer) layer and the dermal (middle) layers of the skin.

Test

A technique that stimulates a small population of neurons by passing an electrical current through a nearby microelectrode.

The cortex is divided into layers from the surface of the brain inward. The deep-layer levels of the trunk cortex are closer the the center of the brain.

Diagram of the cortical layers of a human brain: https://www.ncbi.nlm.nih.gov/books/NBK10870/figure/A1798/

The part of the brain that detects touch happening in certain places in the body.

The trunk region of the somatosensory cortex specifically activates when the trunk, or the main body, of the rat is stimulated.

Diagram of the human somatosensory cortex: https://www.ncbi.nlm.nih.gov/books/NBK11153/figure/A641/?report=objectonly

Reverse transcriptase polymerase chain reaction is a variation of polymerase chain reaction (PCR). RT-PCR begins with an "extra" step in which RNA is reverse transcribed into its DNA complement and then amplified using traditional PCR.

It is commonly used to analyze the expression patterns of infections and diseases.

When natural events (i.e. fires, hurricanes, or other disturbances) happen to only some areas, scientists can study the effects by comparing affected and unaffected sites.

This is a natural experiment.

Various studies describe the aftermath of tropical cyclones on coral reefs. Effects of storms seem to vary depending on the structure, form, and composition of the affected reef.

None of the studies cited had intimate knowledge of the impacted reefs immediately before the disturbance.

A community is a group of interacting organisms that live in the same location. Community composition is the makeup of a community.

Disturbances in the environment, such as storms and fires, can affect the state of an ecological community.

For example, traditional ecological knowledge dictates that when disturbances are frequent or intense, all species in the affected area may become locally extinct. But when disturbances are rare, the community may become dominated by only the most competitive species.

Counterintuitively, an intermediate level of disturbance may maintain the highest level of biodiversity.

Corals are a group of colonial marine animals that form hard calcium skeletons. They have stinging cells that can be used to catch and kill small prey, but they also often carry symbiotic algae inside that they can use to convert sunlight into cellular energy.

When corals live together in large groups, they can form a buildup of sediment and minerals in the ocean called a reef. The complex structures of reefs create habitats for many other ocean animals.

https://www.sciencedaily.com/releases/2016/07/160728110501.htm

The Institute for Basic Science research team explained the use of a technique, mTAIL-seq, to study the regulation of translation through the presence and length of the poly-A tail.

A basic background of the process of transcribing DNA into RNA and translating RNA into proteins is given in the article to show the importance of each step of the central dogma.

The IBS research team was able to use their technique to show that the regulation of the messenger RNAs controls what proteins are being expressed in the cell controlling the phenotype of the individual: hair color, height, etc.

http://science.sciencemag.org/content/352/6292/1430

Bin Wu lead a group of researchers in developing molecular techniques which would allow translation elongation and initiation rates to be observed and quantified. Form Wu’s research, the SunTag epitope was developed and combined with MS2 tagging, which was the first experiment that allowed movement of mRNA, translation, and protein migration to be observed in a living cell.

Wu’s research on translation kinetics helped lay the foundation for Morisaki’s research and the development of nascent chain tracking.

System of tagging RNA so the movement of mRNA in the cell can be seen.

This paper is in the same issue of Science and describes a different way to visualize translation in the cell using fluorescent markers.

The biggest molecule, in this experiment KDM5B, took the longest to translate.

Most polysomes translated the FLAG tagged and HA tagged proteins independently; however, a few interacted with one another, suggesting that translation of some proteins might be co-regulated.

To determine whether multiple polysomes can interact with one another to translate multiple mRNAs, the authors transfected two KDM5B genes into the cell, one containing the HA SM tag and one containing the FLAG SM tag. These two tags can be detected by different antibodies bound to different color fluorochromes.

A protein used by influenza virus to enter cells and infect them. Here it is used to as a tag to label proteins as they are translated so that translation and protein movement can be seen.

The translational elongation rate was consistent for each of the translated proteins and was between 8-12 amino acids per second.

Like the process of transcription, the start of the translation process is random and there is no memory of previous initiations.

An organic compound that interferes with protein synthesis

https://upload.wikimedia.org/wikipedia/commons/4/48/Cycloheximide.png

Fading of the fluorophore to stop the fluorescence of the protein

Photobleaching or FRAP uses laser light to quench the fluorescence being emitted by the fluorescent tag. The fluorescence can be recovered by Fab antibodies leaving the translated proteins and being replaced by new antibodies. Thus, this experiment can determine how length of time that the Fab antibodies can bind to the newly translated proteins. These experiments were used to gather baseline data to determine the rate of transcriptional elongation.

This experiment measured how quickly the Fab antibodies bound to the polysomes by injecting the antibodies into cells containing the KDM5B gene and the MCP fluorescent marker.

Procedure that compares the fluorescent intensity between different molecules

Polysomes used for translation are constructed like a big ball rather than an elongated structure.

A statistical method used to show the normal distribution of data

A restricted area that is seen through the lens of a microscope

Untranslated region of the mRNA at the 3’ end

Polysomes showed a lot variation in movement through the cell. Proteins that were moving into the nucleus generally moved by diffusion while beta actin polysomes showed a slower pattern of movement, suggesting that the newly translated protein might be interacting with other cellular proteins.

https://www.sciencedaily.com/releases/2016/08/160804102311.htm

It is traditionally thought that proteins that are involved in the regulation of translation and transcription are in two different categories. However, researchers at Umea University in Sweden and Inserm in France have now discovered that there is a gray area when discussing regulation of genetic expression at different levels.

The researchers have discovered that some proteins, specifically p53, have the ability to control the expression of the MDMX gene at both transcription and translation. By mutating the region of the p53 gene that encodes the DNA binding domain of the protein (making the translated p53 protein unable to bind to DNA) researchers observed that the control MDMX gene expression was still being regulated by p53 during translation.

From this discovery we can draw the conclusion that protein regulation of genetic expression is even more complex than previously thought.

Using the FLAG tag described above, the authors measured how quickly the ribosomes translated the proteins by determining when the ribosomes left the mRNA after translation.

After tracking the mRNA going through translation, it was concluded that polysomes are variable.There can be one ribosome present for on average every 200 mRNA bases, but a ribosome can be present every 900 mRNA bases.

The results suggested that there are multiple ribosomes per RNA being translated. The number of ribosomes/mRNA varied from 3-5 and seemed to correlate with the length of the mRNA.

To determine how many proteins are being translated at any one time from a single molecule of mRNA, beta actin was labelled with only one FLAG tag (rather than 10). Multiple proteins can be translated from one mRNA using polysomes.

Using a system to track mRNA during translation, scientists were able to visualize the size of translation sites, the mobility of the molecules, and how bright each molecule appeared after being tagged with fluorescence.

Procedure used to identify proteins by separating the proteins by length

Histone protein that is part of the core, or the part of the histone the DNA wraps around

Nonmuscular cytoskeleton protein involved in movement and structure of the cell

To further test the abilities of identifying translation dynamics using the previously identified system, experiments were conducted using smaller proteins, beta-actin and H2B, rather than KDM5B.

Because the spots became brighter after addition of cycloheximide (which allows more ribosomes to load onto each mRNA) and because their were fewer spots after addition of puromycin, it can be concluded that the fluorescent spots in the cell are sites of translation.

A fourth experiment was conducted in order to positively identify that the co-located protein-mRNA spots were sites of translation, 4 micrograms of cycloheximide were added. The addition of the cycloheximide caused translation to slow down while also allowing for more ribosomes to attach to a single transcript.

With the addition of puromycin, the number fluorescent spots decreased, suggesting that the spots were sites of translation.

http://www.pnas.org/content/70/12/3866.full.pdf

Puromycin is an inhibitor of protein synthesis. This article explains why the researchers were unable to see the KDM5B protein after the addition of puromycin. Puromycin causes a premature release of protein chains. The ribosome falls off of the mRNA before translation is complete. The ribosome dissociates into its subunits.

To test the co-moving protein-mRNA spots (areas/spots in the images taken, Fig. 1, C and D, where a red and green dots were co-located) were locations of translation, 50 micrograms of puro-mycin was added to U2OS cells containing the transiently transferred plasmid. The puromycin leads to the inhibition of translation while mRNAs are still present.

A process in which neurons are damaged or die as a result of too much stimulation (or excitation, hence "excito-toxicity").

For example, excitotoxicity can occur from a seizure.

Originating from within the body. In this case, "endogenous" refers to the tau proteins that occur naturally in the body of the mice.

Tau proteins are primarily found in neurons of the central nervous system.

They stabilize the neuron's microtubules, which are components of the cell's cytoskeleton, the inner stabilizing network of filaments and tubules.

A protein that is bound to microtubules.

Microtubules are part of a neuron’s inner cytoskeleton that maintains the structure and stability of the cell.

A small protein.

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.

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

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.

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

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.)

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

This paper illustrates the Science Practices standards (SP.1-SP.4).

The authors take observed phenomena, note that they have yet to be fully explored, and carefully form testable hypotheses about their role in the development of Alzheimer’s disease.

In their study, the researchers combine knowledge from earlier research using mouse models to study the molecular basis of the disease with two main observations:

(1) Tau is known to build up in Alzheimer’s disease patients, and

(2) a higher than normal level of tau protein results in a higher risk for developing the disease.

They hypothesize that changing the level of tau will result in less severe disease symptoms, which they carefully test in well-designed experiments, choosing powerful methods to collect and analyze data and to control for as many variables as possible.

Finally, they incorporate their findings into a general model for tau working together with amyloid-β to cause the symptoms of Alzheimer’s disease.

http://apcentral.collegeboard.com/apc/public/repository/cbscs-science-standards-2009.pdf (Page iii)

Although the sequence of molecular events that causes Alzheimer's disease was and still is unclear, it is generally believed that, as a first step, amyloid-β proteins build up into plaques; then, abnormal tau proteins kill neurons and build up into tangles.

Targeting plaques as a treatment therefore made sense, because, if successful, it would affect the disease earlier in the process of neural destruction.

When this paper was published in 2007, virtually all experimental treatments for Alzheimer’s disease targeted the amyloid-β proteins, either to stop their production, to help the brain get rid of them better, or to stop them from building up into plaques.

The plaques formed from built-up amyloid-β were easy to see in tissue samples from Alzheimer’s patients and it seemed like an obvious target.

Evidence from this study and following studies showing the importance of lowering tau has led researchers to target tau with their experimental new treatments, including vaccines that use the body’s own immune system to fight off the problematic tau proteins.

http://www.medicaldaily.com/alzheimers-disease-tau-protein-vaccine-391883

Almost 10 years after this paper was published, no good treatments for Alzheimer’s disease exist, but more and more of the new drugs in clinical trials are targeting the tau protein, as a result of early laboratory research such as this.

http://www.bloomberg.com/news/articles/2016-06-27/after-190-tries-are-we-any-closer-to-a-cure-for-alzheimer-s

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.

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.

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.

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.

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

Wrong or deviating from the norm.

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

Wasting away.

Dots or points.

The breakdown of a protein by enzymes.

Ground up or processed tissue.

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

Cause or origin.

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.

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

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).

Mice that have been genetically engineered to produce the amyloid precursor protein, which is thought to give rise to amyloid-β.

A set of genes inherited together.

In this case, the authors discuss the idea that several genes related to the tau protein seem to affect the probability that a person will develop Alzheimer’s disease later in life.

This means that molecular changes are made to tau proteins after they are being made.

Some types of abnormal tau appear in cases of Alzheimer’s disease.

Alzheimer's disease is the most common type of dementia. It's a disease of aging in which the proteins amyloid-β and tau build up or aggregate in the brain, causing neurons to die.

Amyloid-β proteins build up into clumps called plaques, and abnormal tau proteins fall off of their microtubules, which kills the neurons. These tau proteins later aggregate into clumps called tangles.

Symptoms of Alzheimer’s disease include memory and cognitive problems, and patients eventually die from the disorder.

This peptide consists of a strand of up to about 40 amino acids that are the main component of the amyloid plaques found in the brains of Alzheimer's patients.

These papers investigate axonal injury in the context of TBI. Strich et al. focused on the clinical neuropathology of axonal injury, and Gennarelli et al. focused on the biomechanics.

These works support the idea that head acceleration during injury leads to stress that causes damage to nerve fibers and impairs the brain postinjury.

Omalu et al. presented a single case of CTE in a military veteran. The authors of the present study investigated a controlled case series comparing blast-exposed military veterans and athletes

Dr. Omalu is perhaps best known as the subject of the movie Concussion, starring Will Smith.

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

This paper provides a thorough case study of CTE in athletes and characterizes some of the key features of the disease. The motivation behind the present study came from identifying similar CTE pathology in the brains of military veterans.

McKee et al. also published a follow-up that includes the largest case series of CTE to date.

This study provided evidence for structural brain injury in blast-exposed military veterans. This brought attention to the reality of blast TBI, which was the signature injury of the Operation Enduring Freedom and Operation Iraqi Freedom conflicts.

A book by RAND corporation that brought the concept of the "invisible injury[should this be "wounds"?] of war" to a broader audience both in the United States and abroad.

This study received a lot of attention not only in the scientific community, but from the media, veterans advocacy groups, military medicine decisionmakers, and policymakers. It has brought new life to the debate surrounding connections between blast exposure, traumatic brain injury, and the long-term health outcomes and risks for military veterans exposed to blasts.

For some selected news coverage, see the Related science news tab in the sidebar.

The negative phase of a blast wave follows the initial shock, and sucks items back toward the center of the blast source. Here, the authors consider the possibility that this negative phase could contribute to injury.

They use underwater sonar as a standard. Tissue damage results from repeated negative pressure of ~100 kilopascal generated by sonar waves. Because the blast pressure wave used in this experiment is only a single compressive wave and the negative pressure is far below the positive pressure, the authors discount negative pressure as a possible cause of injury.

Lithotripsy is a procedure that uses sound waves to break apart kidney stones without damaging normal tissue. These waves have positive pressures of around 40 megapascal. Because the waves created by blast pressure are much smaller in amplitude than those used in lithotripsy, it is unlikely they would cause damage.

Mouse tau protein is resistant to pathogenic aggregation like that seen in humans. Therefore, it is not surprising that the authors did not observe neurofibrillary tangles (NFTs) in the brains of blast-exposed mice).

However, the authors were surprised to see pretangles (early-stage NFTs) and elevated levels of abnormally phosphorylated tau protein in the brains of blast-exposed mice. The observation of both of these abnormalities in wild-type mice strongly supports the link between blast exposure and CTE.

Alternatively, the authors could have used genetically modified (transgenic) mice that overexpress human tau protein. These mouse strains show aggressive tau protein aggregation leading to mature NFTs.

Regardless of the magnitude of the signal immediately after the blast, the post-tetanic response in the blast-exposed mice falls off sharply over the 1-hour period following the stimulus. This means that the brain pathway and processes by which new memories are formed is impaired in blast-exposed mice.

Post-tetanic potentiation (PTP) is the change in potential that occurs after a tetanus, or a series of stimuli that occur in a short period. It is thought to be involved in synaptic plasticity, which is important to learning and memory.

The authors observed that blast-exposed mice had a reduced potential that is consistent with impaired hippocampal function. The deficit remained for at least 1 month.

A specific type of branch given off by axons that is important to learning and memory.

The hippocampus is a part of the brain that is critical to learning and memory. Because of this, it is one of the most often studied and well-understood structures and there are established experimental methods to study it.

The authors investigated the hippocampus because their results indicated that damage occurs to it during blast exposure.

ELISA is a common test used to identify and quantify a protein in a sample. It is similar to immunoblotting in tissues, but is performed in a solution.

To learn about ELISA, see the Journal of Visualized Experiments:

https://www.jove.com/science-education/5061/the-elisa-method

This is an unexpected and important finding. Wild-type C57BL/6 mice with murine tau protein do not normally develop the neurofibrillary pretangles seen in this figure panel. The authors confirmed this finding in Figure 5.

The authors saw an increase in total tau protein in blast-exposed mice. To confirm that this increase was also true for phosphorylated tau, they computed the ratio of phosphorylated tau to total tau.

Glial fibrillary acid protein (GFAP) is a naturally ocurring protein expressed in the astrocytes of the brain.

After blast TBI or other forms of brain injury, GFAP expression is increased, indicating astrocytic activation. This increase in GFAP expression can be seen in the figure by comparing Panel G with Panel H, or by comparing the right side of the blast-exposed brain with the left side (Panel H).

The authors used western blotting to detect abnormal phosphorylated tau and confirm their electron microscopy observations. They confirmed that levels of phosphorylated tau were elevated in the brains of blast-exposed mice as compared to the control group.

For more on western blotting, see the Journal of Visualized Experiments:

http://www.jove.com/science-education/5065/the-western-blot

Neurons that stain darker than surrounding neurons.

Dark neurons are controversial in neuropathology because there is evidence that rough handling of tissue samples can cause them. However, the dark neurons that the authors observed are not uniform [AND THEREFORE?] could not be the result of improper handling. The presence of dark neurons in blast-exposed mice suggests dead or dying neurons.

Pigment granules associated with wear and tear on a cell. Abnormal accumulation can be a sign of disease.

Perivascular astrocytes have feetlike structures that interact with blood vessels in the brain. Hydropic means that these "feet" are filled with fluid.

The authors also observed this in the human cases in Figure 1. This is a surprising result, because the CP13 antibody detects hyperphosphorylated human tau protein (not mouse), and phosphorylated tau abnormalities had not been observed in nontransgenic mouse models.

Because the authors saw CTE-linked tau abnormalities in the mouse model but not in mice in the control group, they concluded that blast exposure is linked to brain abnormalities associated with CTE.

To explore these regions of the brain, see the Allen Brain Atlas.

Using more sensitive methods (light microscopy, electron microscopy, protein immunoblotting, neurophysiology, and behavioral testing), the authors found that a single blast exposure was sufficient to cause significant brain injury, CTE-related abnormalities, and cognitive deficits in mice.

This is an important "negative" finding that is reported in almost all cases of blast exposure. There is a lack of gross (visible to the naked eye) brain injury in the brains of people that have been exposed to a nonpenetrating blast.

The fact that this finding is replicated in this study encouraged the authors to explore whether there were "invisible injuries" in the brains of blast-exposed mice.

When transmitting a signal (using light, sound, electricity, etc), transmission is most efficient when the two objects have similar impedance (like resistance). If the impedance values between the objects is different, the signal is both transmitted and at least partially reflected.

A blast pressure wave traveling through air behaves similarly to a signal transmission. In this case, the difference in impedance led to a back reflection of part of the shock wave.

There were no significant differences between the pressure in the brains of living mice compared to decapitated mice. This led the authors to reject the hypothesis that there is a thoracic-vascular contribution to TBI (the water hammer effect).

This result also suggested there must be a different way that blast exposure causes brain injury, which motivated the authors' investigation of other hypotheses.

To test the water hammer effect, the authors compared the pressure resulting from a blast wave both inside and outside the head of a living mouse. They then compared these measurements to similar measurements performed on a decapitated mouse head.

Because the disembodied mouse head had no vascular system or thorax, the water hammer could not contribute to the shock wave pressure inside the head. However, the authors observed similar shock wave pressures in both the live mouse and the mouse head, showing that the water hammer effect cannot be the primary source of brain damage.

Explosion simulation software based on a large data base of experimentally obtained blast data. ConWep enables comparative analysis of blasts. The authors used the software to verify that their simulated blasts closely matched explosions that would happen in the field.

In animal studies (especially those using mice) it is important for the researchers to identify the genotype of the species they're studying. This helps other researchers either replicate the findings or identify errors in the authors' reasoning due to the genetic makeup of the model organism.

C57BL/6 mice are the most commonly used nontransgenic mouse in biomedical research. They are called "wild-type" because their genetics have not been changed by humans.

Mouse colonies like this are inbred to make sure the mice are as genetically identical as possible. This helps eliminate extra, unexpected variables in an experiment that could affect the results in unknown ways.

The authors designed a "shock tube" to create controlled blasts. A shock tube is basically a wind tunnel: Pressure is built up on one side and suddenly released, creating a shock wave that travels down the tube.

Source: Fraunhofer CMI

After finding identical CTE-linked problems in the brains of military veterans with blast exposure and athletes who suffered head injuries, the authors investigated how blast exposure might cause brain injury using a mouse model.

Mice are commonly used to model human diseases.

In this figure, the authors look at the CTE neuropathology (neurological abnormalities) in blast-exposed military veterans and young American football athletes.

Through postmortem analysis (still the only way to identify CTE), they found the same disease in both groups.

From these findings, the authors were motivated to investigate whether blast injury would cause the same disease as sport-related head injuries.

Immunohistochemistry (IHC) is a technique used to identify the biochemical and cellular cause of disease in a tissue.

First, a tissue is treated with a primary antibody. This antibody binds to the target protein in the tissue.

Next, the sample is treated with a second antibody that will bind to and detect the primary antibody. This second antibody has a colored or fluorescent tagged [is there a word missing here?] so that it can be detected with a microscope or other tool.

Question: Why do scientists use a second, additional antibody instead of just tagging the primary antibody and using that for analysis?

Traumatic brain injury (TBI) is a known risk factor for cognitive decline, dementia, and neurodegenerative diseases (such as Alzheimer's) later in life.

However, the diagnosis of CTE in teenagers and young adults is important because they do not have some of the indicators of Alzheimer's disease. This suggests a different disease mechanism.

Tau-46 is a "pan-tau" stain, meaning it detects all (or many) forms of tau protein, both normal and abnormal.

In normal control cases, nonphosphorylated tau immunostaining would be diffuse and light. In pathologic cases, phosphorylated tau immunostaining would be present in neurons and glia.

Executive function refers to specific cognitive functions carried out in the frontal lobes. They include things such as making decisions, setting and planning for multistep goals, controlling our emotions, moral reasoning, and our working memory (part of our short-term memory).

Activities like writing a paper use many cognitive tasks that depend on executive function. Damage to the prefrontal cortex can impair executive function and interfere with tasks that rely on it.

The authors report several findings linking blast exposure to CTE:

-A correlation between blast exposure and CTE in human brains (identical to the CTE seen in athletes' brains).

-A causal link between blast exposure and CTE in a mouse model.

-A causal link between blast exposure and cognitive problems commonly seen in blast-exposed military veterans.

-Cognitive problems can be prevented by restricting head movement during a blast.

"-pathy" comes from the Greek pathos and means disease. Words that end in -pathy indicate disease.

For example, myelinated axonopathy refers to disease of the myelinated axons.

A medical condition that is the result of a previous disorder or disease.

Pronounced "seh kweh lay."

Damage to the brain caused by a strong outside force, such as a football tackle or an explosion.

Related to thinking, understanding, learning, and memory.

Brains that came from people who had already died.

A brain disease often found in athletes with a history of repeated head injuries and military veterans with a history of blast exposure.

Replicated.

Damage to the brain caused by a strong outside force, such as a football tackle or an explosion.

In February 2015, the National Institutes of Health NIH organized a meeting of pathologists in Boston to come up with criteria for postmortem diagnosis of CTE.

Read the report from the meeting here: https://www.ninds.nih.gov/Current-Research/Focus-Research/Traumatic-Brain-Injury/NIH-Chronic-Traumatic-Encephalopathy

Cause.

A protein found in the brain that is important to the structure of neurons. Functional tau protein is important to proper intracellular communication and healthy neurons.

Diseases caused by defective tau protein are called tauopathies. Examples of tauopathies include chronic traumatic encephalopathy (CTE) and Alzheimer's disease.

routines

The e coli strain engineered by the authors is behaving as they predicted.

Exogenous refers to something originating outside the organism.

Endogenous refers to something originating within the organism.

Chimeric refers to something composed of two different elements

The authors built a specific strain of E. coli that they could easily trace throughout these next experiments.

The receptor protein tsr undergoes post-translation modifications in the form of methylation of some of its glutamine residues to attain the active form. It's called a chemotactic protein since it controls swimming behavior of E.Coli by generating signals by sensing ribose and galactose that influence the direction of flagellar rotation.

To construct the E. coli strain expressing the Tsr-Venus fusion protein, they used the previously published λRED recombination system, in which the chimeric tsr-venus gene had the coding sequence of tsr gene fused to the N-terminus of venus and a kanamycin drug resistance marker. The chimeric gene was incorporated into the lacZ locus.

Autofluorescence is the fluorescence emitted by cellular structures when they have absorbed light. This often obscures signals from proteins of interests in microscopy especially when signal is week.

Some authors like to state exactly what they have shown early on in the paper. In this case, the authors prepare the reader for a methods type paper.

Copy number here refers to the number of protein molecules existing in the cell at any instant of time.

A Temporal change refers to change as a function of time.

Genes exist in genome as either single copy or duplication. The efficiency of gene expression ranges from low (producing few proteins) to very high (producing many proteins).

Mechanical property of single DNA molecule, assays of biomolecules with nanoscale control, single-molecule detection of ribosomes binding with other proteins, etc. add to our current understanding of transcriptional and translational events at molecular levels.

Lac Operon is a collection of adjacent bacterial genes responsible for the entry and metabolism of lactose. It contains the genes coding for three enzymes and is flanked by a repressor and a promoter region to control expression.

The central dogma of molecular biology states that biological information flows in only one direction, from DNA to RNA to proteins.

Exceptions have since been found, however: for example, reverse transcriptase is an enzyme that uses RNA as a template to form DNA --- so information, as known now, can flow in the wrong direction too (from RNA to DNA).

Not all genes in the cell are expressed in equal amount; some are expressed much lesser than others. Studying such genes requires methods to probe one or very few molecules at a time.

A stochastic process is one involving a random variable. It used as a counterpart of the word "deterministic".

Yellow fluorescent protein (GFP) and homologous fluorescent proteins must undergo chemical reactions after translation in order to become fluorescent.

Going from the translated polypeptide to the fluorescent form of the protein is called "maturation. The variant of YFP used here (Venus) has a short maturation time.

Errors during DNA replication or the invasion by viral DNA can lead to the duplication of a gene. Over time, the two copies of the genes differentiate. Three scenarios are known: Neofunctionalization: One gene develops a new function

Subfunctionalization: The two copies of the gene split the functionality between them

Loss: One gene loses its functionality.

In this context, dynamic rewiring refers to the change of interactions over time after a gene duplication event.

The representation of all interactions in an organism (molecular interactome network). The molecules are mostly visualized as nodes and the interactions as edges.

A representation of interactions between different entities. The interactions are often visualized as lines or arrows.

A small plant that occurs in many different parts. It's genome is small compared to other plants, therefore it is widely used as a model organism for plants.

The proteome is all proteins of an organism at a given time point and under clearly specified conditions. The proteome differs with time and condition.

The term “cumulative process” here refers to taking an approach to research in which we try to gain insight not by interpreting strongly the results of one individual study at a time, but by integrating the results of several studies and broader research programs to gain an overview of the overall evidence.

Validity refers to the degree to which a certain result or conclusion in research corresponds with reality. There are different aspects of a study which can improve or decrease its validity.

For example, a study has high ecological validity if its results can be directly applied to real-life situations outside of the lab.

Innovation refers to coming up with new ideas for research, in other words to generating new hypotheses.

Verification refers to checking if a certain idea holds up in subsequent research, in other words to confirming hypotheses.

This refers to results of studies that cover a wide range of different topics, without going into detail on a specific area.

A preregistration is a document in which researchers compile information on how their study will be run and analyzed before it is conducted.

The document often contains information on which research question will be pursued, which hypothesis will be tested, how the data is collected and how the sample is generated, which data is excluded, and how the data will be prepared for analysis and ultimately analyzed.

Documenting in advance helps separate confirmatory hypothesis testing from exploratory research.

Here, upwardly biased means that the effect sizes reported in the literature are distorted to appear bigger than they really are.