rc7

Locusts (1). Many ancient scripts, like The Old Testament and the works of Plato, have several references to locusts and their behavior, specifically to the spectacular phenomenon of marching locust hopper bands. Part of our fascination with locust swarms is due to the fact that they always have been and still are a major threat to agriculture. Locusts are described as a pest of unusually destructive powers. A desert locust adult can consume roughly its own weight, about two grams, in fresh food per day. The notorious 1915 locust attack in the Middle East, for example, resulted in the destruction of 536,000 tons of food. According to the Food and Agriculture Organization of the United Nations, in modern days, a typical African nation spends around $30 million in anti-locust campaigns. (2). The coordinated activity of crowds consisting of millions of individuals, while not unique to locusts, has been and still is a challenge to laymen and scientists alike. Despite considerable progress in understanding the mechanisms underlying the emergence and synchronization among moving crowds of animals as well as humans, locust swarming still presents several fundamental open questions. These include key questions regarding locust biology as well as more theoretical aspects. Some of the open questions include: what are the principle interactions between locusts in a swarm; what are the evolutionary advantages to swarming; how do local dynamics within a swarm translate to macroscopic dynamics of large swarms consisting of millions of individuals; and are there quantifiable traits unique to locust swarms compared to other animal crowds, such as fish, birds, or humans? (3). Locusts are short-horned grasshoppers that exhibit density-dependent phase-polymorphism, or polyphenism, the phenomenon in which two or more distinct phenotypes are produced by the same genotype. They appear in two forms or phases. Crowding of the grasshopper induces the gregarious phase, most notorious for its tendency to aggregate and form massive swarms. However, isolation of the grasshopper leads to the solitary phase, in which individuals actively avoid other locusts. The differences between the gregarious and solitary phases are collectively termed phase characteristics, extending from behavior and ecology, through morphology and anatomy, to physiology and biochemistry. (4). Locust phase polyphenism is continuous, and many intermediate forms can be found between the extreme gregarious and solitary phases. The phase transformation is reversible and not developmental-stage or age-specific. Full-scale phase transformation takes several generations, and presumably occurs only in the field. In the laboratory, locusts kept either under crowding or under isolation, respectively approach the characteristics of the gregarious and the solitary phases. (5). Some 15 locust species, belonging to several phylogenetic groups, are considered true locusts, because they express density-dependent polyphenism, swarming, and migration. The most notorious and studied is the desert locust, which inhabits dry grasslands and deserts. This species of locust has threatened agricultural production in Africa, the Middle East, and Asia for centuries. The migratory locust species has a wider range than that of any other species. It is found in grasslands throughout Africa, major parts of Eurasia, the East Indies, tropical Australia, and New Zealand. The Australian plague locust is the most important pest species of locust in Australia, due to the large areas infested, the frequency of outbreaks, and its ability to produce several generations in a year. (6). These species may differ in their ability to express the phase phenomenon in its entirety and in the dynamics and magnitude of their response to changes in population density. As knowledge of diverse species increases, key species-specific differences in the dynamics of the phase phenomenon may emerge. The intricate phylogeny of locusts also offers a challenge to any attempt at explaining the evolution of the locust phenomenon. (7). As mentioned, locust behavior is a prominent phase characteristic. The major behavioral characteristic of locusts in the gregarious phase is their strong attraction to other locusts, which translates to active aggregation behavior. Gregarious locusts are also generally more active, including their strong propensity to march in huge bands of hoppers or to form flying swarms as adults. In contrast, solitary-reared locusts actively avoid contact with other locusts. They are more sedentary and cryptic in behavior, do not march, and fly less. (8). The behavioral phase transformation is a positive-feedback process. Solitary-reared locusts have been reported to acquire most of the behavioral characteristics of the gregarious phase within four to eight hours of crowding, including the propensity to aggregate, and thus reinforce the gregarious behavior provided by other locusts. Recently, it has been shown that even a 30-minute exposure of a solitary-reared nymph to a small crowd of locusts is sufficient for the induced change in behavior to persist, even after re-isolation of the locust for 24-72 hours. Details of the dynamics of phase transformation and its interactions with the environment are still far from being fully resolved. (9). Swarming is a hallmark of locust behavior. Swarming is a result of the attraction and aggregation tendency of locusts in the gregarious phase. Locust-coordinated mass movement includes the flight of adult swarms, but even more conspicuous is the marching of nymphs or hopper bands. Both swarming and marching start very early on in the locust life cycle, a few days after hatching. Desert locust nymphs have a diurnal pattern of behavior. The locust bands will normally have one period of marching in the forenoon and another in the afternoon, strongly dependent on weather conditions such as temperature, but also on clouds obscuring the sun, as well as on rain or cold wind. In our own observations of the desert locust, marching usually took place from just before noon to two hours before sunset. The marching hopper bands can cover very different areas, from a few hundred square meters up to several kilometers. As reported for different locust species, their shape can also vary, ranging from columnar to frontal structures. During marching of the hoppers, bands may meet, merge, or fuse, and the coordinated movement will thereby further enhance the swarming. (10). Undisturbed nymphs within marching bands will advance predominantly by very consistent walking rather than by jumping or hopping. This behavior is most typical to the desert and migratory locusts and may be less so in other species. Regarding the speed of marching, it has been noted that the actual speed of individual hoppers bears only a remote and uncertain relation to the marching rate of the bands. The reason for this is that the proportion of hoppers marching at any given moment can be as low as 10%. Individual marching locusts very often stop for periods of various durations. Locusts at the front of a large band will slow down or simply turn more often, reducing their net displacement in comparison to those behind them. These behaviors will serve to maintain the integrity of the marching bands. They often result in bands comprising an extremely dense front followed by an exponential decay of density, with a consequent loss of cohesion toward the back. What the major factors are that affect the direction of marching is still an open question. (11). The cannibalistic propensity of locusts has been recently associated with marching behavior and was even suggested as a major driving force for the formation of collective motion in locust nymphs. Cannibalism is very well documented in locusts. However, it is accepted that cannibalism is mainly directed toward hatchlings, freshly molted, injured, or dead animals, and is rarely directed toward active, healthy individuals. Moreover, the documented dynamics within the marching band as described above are not consistent with the nymphs escaping predation or trying to cannibalize on their marching companions. (12). Even though the connection to cannibalism may be tenuous, it is well established that the nutritional state of the hoppers does have an important impact on the amount of marching, its speed, and the distance traveled. Hence, it may be suggested that in addition to possible species-specific differences, different interactions among locust nymphs may occur at different behavioral contexts, and maybe also at different times of the day. (13). Flying swarms of adult locusts will migrate predominantly downwind. Within a given section of the swarm, locusts were observed to generally fly with their bodies parallel, separated by as little as 10 cm. The integrity of the swarm is maintained by the fact that, similar to the marching hoppers, upon reaching the edges of the swarm locusts will turn back to re-join it. (14). Locusts have much to offer with respect to our general understanding of coordinated movement in nature. One of the major remaining challenges in the growing field of collective animal movement lies in relating the similarities and differences between the behavioral modes of motion of different organisms to the observed large-scale coordinated behavior they exhibit. (15). With the increasing accumulation of biological knowledge, it is becoming clear that only a combined interdisciplinary, biological, and theoretical effort can advance our understanding of the locust phenomenon in general and of locust collective movement in particular. There is great importance in performing further controlled empirical experiments to test the hypotheses of locust phase transformation, hopper behavior, and swarming behavior in order to better understand collective motion of multiple organisms.

1-17

Evolution Through Teeth (1). A complex hierarchy of interrelated factors has contributed to the evolution of primate development, growth and lifespan. While much of this evolutionary history is unknowable, given only the fossil record of bones and teeth, teeth have to grow within whatever period of development is available. As such their growth is a reflection of the time determined by natural selection acting on key life-history variables. (2). Because a time-scale for dental development can be retrieved from the internal structure of teeth, we can discover more than might be imagined about fossil primates and more, in particular, about fossil hominids and our own evolutionary history. Some insights into the evolutionary processes underlying changes in dental development are emerging from a better understanding of the mechanisms controlling enamel and dentin formation. (3). The developmental processes that control the rates of enamel and dentin formation ultimately hold the key to a better understanding of how the timing of dental development comes to track evolutionary change in life-history timing. Enamel and dentin, while fundamentally different tissues, are both extremely hard and never remodel. Dentin is secreted by odontoblasts. These differentiate from the mesenchymal neural crest cells of the dental papilla. Odontoblasts secrete a proteoglycan-rich organic matrix, part of whose function is to delay mineralization for several days until collagen fiber growth and orientation within the matrix is complete, and then to induce hydroxyapatite formation. Hydroxyapatite is the primary mineral that gives enamel and dentin its strength. Several growth factors, including Insulin-like Growth Factor (IGF-1), Fibroblast Growth Factor (FGF-1) and members of the Transforming Growth Factor beta family (TGF-βs and Bone Morphogenetic Protein, BMP-2) may act synergistically to induce odontoblast differentiation, which stimulates the synthesis of dentin matrix formation. More importantly, some of these growth factors remain sequestered and potentially active throughout life within mineralized dentin. (4). Enamel matrix is secreted by ameloblasts that differentiate from the inner enamel epithelium of the tooth. Unlike dentin, enamel contains no collagen and is even harder due to a higher mineral content. IGF-1 is known to increase rates of enamel matrix secretion and is associated with increased expression of genes for the enamel matrix proteins involved in mineralization, such as enamelin and amelogenin. The onset of enamel matrix secretion is triggered by dentin matrix secretion. However, unlike dentin, mineralization begins almost immediately. (5). Permanent molar teeth develop in sequence between birth and adulthood. In particular, their emergence into the mouth is in each case a developmental milestone that can be used as a proxy to determine the pace of life history in fossil primates. Modern human permanent molars (first molar or M1, second molar or M2, and third molar or M3) emerge roughly 6 years apart at ages 6, 12 and 18 years. Modern chimpanzee permanent molars emerge roughly at 3.5, 6.5 and 10.5 years and those of macaque monkeys at roughly 1.3, 3.5 and 5.5 years of age. The tooth eruption of M1 correlates best with several life-history traits. For example, completion of 90% of brain growth occurs at M1 tooth eruption in all primates, and skeletal maturity correlates broadly with M3 eruption. Thus, many of the crucial questions about the pace of life history in fossil hominoids depend on being able to reconstruct the timing of tooth eruption in molar teeth. (6). Many Miocene apes were a morphological mosaic of characters that we recognize today as specific to either modern apes or monkeys. Great apes have a prolonged life-history profile compared with Old World monkeys. They have reduced rates of mortality, longer gestation periods (longer period of embryonic development), and mature more slowly. They also reproduce at a much later age. Recent evidence also suggests that besides studying their morphological attributes, M1 eruption times in Miocene fossil apes might also identify the first evidence of a shift to a modern ape-like life history profile. (7). Modern humans have big brains, walk on two feet and have small teeth and jaws. The earliest bipedal fossil hominids from Chad and Kenya are dated about 6 million years ago, but for at least the first 4 million years of hominid evolution there is little evidence for an increase in brain size, after which brain size and body proportions seem to have changed significantly with the emergence of the genus Homo. Changes in brain size are closely linked with many life-history traits. Initially, it was thought, almost by definition, that the earliest hominids would show evidence of a human-like life-history profile, but it is now generally accepted this cannot be substantiated. There are several lines of evidence that allow us to track the evolution of life-history traits among fossil hominids. Various incremental markings in enamel have been used to estimate an age at M1 eruption, as have their relatively small cranial capacities, and both approaches conclude these ages fall within the range known for living great apes. However, within this generally ape-like picture, we should expect as much variation among early hominids as we see today among living apes and there may be hints of this in the fossil record. (8). Despite similar infant diets, great ape deciduous (non-permanent) tooth wear patterns vary with early or late first intake of supplementary food during the weaning period and also seem to reflect their longer or shorter inter-birth intervals. Clearly, early hominids had diverse diets and this is reflected in the thinner or thicker enamel of some australopithecines. It is difficult to attribute all of these differences in deciduous tooth wear to their infant diets and equally likely there were contrasting life-history strategies among australopithecines that mirrored both the availability and quality of food and their evolutionary history. In some late surviving australopithecines, heavy deciduous tooth wear early in life may have been linked to early first intake of supplementary food, early weaning and shorter inter-birth intervals. Significant adaptive changes in reproductive strategy and life history may have kept up with pressure to survive over millions of years. After 2 million years, only the robust australopithecines remain in the fossil record and these were extinct by 1 million years ago. (9). The link between brain size, tooth development and a slower life-history profile is a clear one but a curious one. Some researchers have argued that the whole changing life-history profile during primate evolution has influenced brain growth and that it is this that has ultimately facilitated cognitive evolution. Longer periods of embryonic development have extended many phases of human brain growth, including glial cell mitosis, dendritic growth, synaptogenesis, dendritic pruning and myelination. Just three or four extra days of embryonic development result in three or four more rounds of founder cell mitosis in the brain, which is enough to account for the 10-fold larger human cortex than of a macaque monkey. Brain size as well as brain complexity is, therefore, time dependent as is dental development and simply yet another part of the life-history package. Brain size might not then have been driven solely by selection for cognitive ability. The sequence of events may have begun with a shift in life-history strategy and growth of a bigger more complex brain, which then increased the likelihood of selection for increased cognitive ability. And in the end, increased cognitive ability is bound to contribute towards a further reduction in adult mortality rates. (10). What then of Neanderthals whose brains were bigger than modern humans, but whose life-history profile is described either as at the lower limit of the modern human range on the basis of shorter enamel formation times and patterns of molar tooth wear or as being distinct and 15% shorter than modern humans? Clearly, the late surviving Neanderthals were under considerable demographic pressure from both sudden colder, drier climatic conditions and from incoming biologically and behaviorally modern human populations. Neanderthals are likely to have experienced high levels of infant and adult mortality due to these factors. It makes no biological sense for any primate to take 18-20 years to grow up only to die as a young adult, but then again the Neanderthals did not survive. Understanding the demise of the Neanderthals may ultimately come from a better understanding of our own survival.

18-34

Antipsychotic Treatment (1). Schizophrenia and psychotic disorders are estimated to affect 1% of the population and are one of the highest causes of global disability. They place a considerable burden on individuals, families, and society, with costs amounting to $62.7 billion in the United States in 2002. The highest costs are related to unemployment, and one study found that more than 80% of people diagnosed with schizophrenia have some ongoing social disability. (2). Long-term antipsychotic treatment has been the norm for people diagnosed with schizophrenia and other recurrent psychotic disorders since the introduction of these drugs in the 1960s. Recent data from the United Kingdom indicate that 97.5% of mental health service patients diagnosed with schizophrenia are prescribed at least one antipsychotic. The practice is based on research believed to have established that continuous antipsychotic treatment reduces the risk of relapse. Interpreting the evidence is not straightforward, though, and other data are beginning to emerge that suggest that long-term treatment may have an adverse impact on levels of social functioning. (3). Evidence for the benefits of long-term antipsychotic treatment consists of trials comparing antipsychotic maintenance with antipsychotic discontinuation. In other words, a group of patients already stabilized on antipsychotics are randomly allocated either to continue drug treatment, or to have it withdrawn and, in most cases, replaced by placebo. As a whole, these trials show that patients who have medication withdrawn are more likely to have increased symptoms, usually defined as relapse. However, several commentators have pointed to issues that complicate the interpretation of these "discontinuation" trials. (4). Firstly, the fact that antipsychotics, like other drugs, have withdrawal effects has not been adequately acknowledged in trial design or interpretation. Patients allocated to antipsychotic discontinuation are vulnerable to experiencing antipsychotic withdrawal symptoms like anxiety and agitation, which may be mistaken for a relapse of the underlying condition. This possibility is exacerbated by the fact that there are no agreed-on criteria for relapse. Many studies rely on clinical judgment and others use definitions that include non-specific items, such as agitation and hostility, likely to be exaggerated by antipsychotic withdrawal effects. Although withdrawal symptoms would be expected to be less prolonged than a genuine relapse, we know little about their course. It is possible they might persist for long periods following long-term treatment. (5). Moreover, the experience of antipsychotic withdrawal may, in itself, make a relapse of the underlying condition more likely. The phenomenon of withdrawal-induced relapse has been shown convincingly in patients taking lithium to treat bipolar disorder. Patients who stop long-term lithium treatment are more at risk of having a relapse than they were before they started it. There is some evidence of a similar effect following antipsychotic withdrawal in people with schizophrenia. Relapses cluster around the point of withdrawal in most studies, for example, and one study found that gradual withdrawal reduced the risk of relapse. However, it may be the case that withdrawal over an average of four weeks is not gradual enough for people who have been on medication for many years. Alternatively, withdrawal-related effects may occur however carefully treatment is withdrawn. (6). Therefore, antipsychotic discontinuation studies may partially, or even wholly, reflect the adverse effects of antipsychotic withdrawal, rather than the benefits of initiating maintenance treatment. Further problems with existing studies include the fact that most focus on relapse as their principle outcome, with few providing data on other outcomes such as functioning, quality of life, work performance, aggressive behavior, and violence. In a recent analysis, for example, only three studies provided data on quality of life, only two studies reported data on employment, and only five studies reported on aggressive behavior. No study lasted longer than eight months, and most involved abrupt discontinuation instead of including both a discontinuation group and a maintenance group. (7). We also know little about how patients balance the risk of relapse against other outcomes. If relapse is not severe, for example, and the side effects of drugs are experienced as disabling, patients may accept relapse as a price worth paying. Although some commentators have suggested that relapses worsen long-term outcomes, evidence from discontinuation trials indicates that symptoms return to normal when drug treatment is re-instated. (8). Long-term antipsychotic therapy is associated with common and potentially serious complications, so any uncertainty about the benefits of such treatment is a major concern. Tardive dyskinesia, a neurological condition involving involuntary movements associated with cognitive impairment, remains common. Recent studies find it affects approximately five percent of people per year who take antipsychotics. It is known to be irreversible in some cases and can occur after a few months of treatment. Tardive dyskinesia has been recognized for many years, but recent studies have revealed that long-term antipsychotic treatment is associated with reduced brain weight and volume, and most studies suggest that brain volume reduction is associated with reduced cognitive performance. (9). Antipsychotics are cardio-toxic and associated with sudden cardiac death. Some studies report an increased risk of mortality, even after controlling for other risk factors. Most antipsychotics cause weight gain of some degree, and some of the "atypical" antipsychotics can cause extreme weight gain, glucose and lipid abnormalities, and diabetes. Metabolic abnormalities develop within days of drug initiation and have occasionally been reported to be irreversible. Antipsychotics are also reported to be unpleasant to take, causing emotional blunting and sexual dysfunction, among other undesired effects. (10). Fifteen- and twenty-year outcomes from a long-term cohort study involving people with early psychosis have recently been published. The data suggest that people who take antipsychotics on a continual basis have poorer outcomes than people who have periods of not taking antipsychotics. The effect persisted after controlling for early prognostic factors. (11). The results are supported by data from a seven-year follow-up of an antipsychotic discontinuation study. This study represents the first really long-term follow-up of a randomized cohort. It consisted of a comparison between maintenance treatment and a flexible and gradual antipsychotic reduction and discontinuation strategy. At the 18-month follow up, relapses were more frequent in the group randomized to the discontinuation strategy, in line with other studies. At seven-year follow-up, however, relapses had equalized between the groups, and participants originally randomized to antipsychotic reduction and discontinuation were twice as likely to show a full social recovery as those allocated to the maintenance group. Symptomatic remission, however, did not differ between the groups. At follow-up, use of antipsychotics in the antipsychotic reduction and discontinuation group was lower. The analysis demonstrated that antipsychotic discontinuation or reduction to very low doses, regardless of the randomized group, was associated with higher rates of recovery. (12). The majority of people who experience more than one episode of psychosis are currently recommended to remain on long-term antipsychotic treatment, with little guidance about whether the treatment should ever be stopped, and if so, how this should be done. Many patients find this approach unacceptable, and stop of their own accord without support, which likely leads to the complications of sudden medication withdrawal, including relapse. (13). The studies used to justify current clinical practice do not provide reliable data about the costs and benefits of long-term antipsychotic therapy. In particular, questions remain about how continuous treatment affects people's overall functioning over the long term, with some indications that it may be detrimental. There is abundant evidence that long-term antipsychotic treatment is associated with serious and disabling adverse effects. (14). We need to do more research to establish the pros and cons of long-term antipsychotic treatment for people with one or more episodes of psychosis or schizophrenia. Further studies that evaluate a gradual and individualized approach to antipsychotic discontinuation are particularly important, both in people with first episode psychosis, and more challengingly, in people with recurrent conditions. Such studies need to include an assessment of outcomes other than relapse and assess what alternative treatments might facilitate patients in successfully reducing their antipsychotic burden. Longer-term follow-up of five to ten years is required to reflect the duration of treatment in clinical practice. Also, there has so far been little success in identifying factors that might predict successful discontinuation among heterogeneous patients. (15). While we await the results of further long-term discontinuation studies, some researchers suggest we need to reconsider antipsychotic maintenance treatment as the default strategy for people with recurrent psychotic disorders. In 1976, two leading psychiatrists felt that the cost-benefit ratio of long-term antipsychotic medication was often not favorable for patients and recommended that every chronic schizophrenic outpatient maintained on antipsychotic medication should have the benefit of an adequate trial without drugs. Recent evidence suggests that, when risks allow, modern-day clinicians and patients could also consider this option.

35-50

1

Choice [E] is correct. The term "phenotype" refers to an organism's expressed traits (like hair color, eye color, etc.). Genotype, on the other hand, refers to an organism's genetic makeup. Paragraph 3 refers to the fact that locusts have multiple phenotypes. It states that: Locusts are short-horned grasshoppers that exhibit density-dependent phase-polymorphism, or polyphenism, the phenomenon in which two or more distinct phenotypes are produced by the same genotype. They appear in two forms or phases. In other words, although some locusts may share the same genetic makeup (genotype), they may express a different phenotype. In the case of locusts, the two phenotypes refer to either gregarious or solitary behavior. Choice [A] is incorrect. The quote above from paragraph 3 explicitly states that the genotypes are the same, but the phenotypes differ. Choice [B] is incorrect. Fathering behaviors are not mentioned in this passage. Choice [C] is incorrect. The question stem is asking about phenotypes, not genotypes. Choice [D] is incorrect. Paragraph 4 states that the phase change is reversible, not permanent: The phase transformation is reversible and not developmental-stage or age-specific.