Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: A comprehensive model compatible with population genetics to explain the early fate of gene duplications Taking all our results together, we formulated a comprehensive model to explain the early fate (viz. , fixation or elimination) of gene duplications (Figure 7). Notably, this model is compatible with population genetics, involving positive and neutral selective conditions (Lynch, 2007). On the one hand, a significant number of duplicates could be fixed by genetic drift only in complex organisms (i. e. higher eukaryotes; sector A in Figure 7). This would be due to their increased ability to allocate additional resources for expression (Lynch and Marinov, 2015), and their apparently reduced duplication deletion rate with respect to the inverse of the population size (Schrider et al. , 2013). However, these fixed duplications would not be stable, due to the formation-deletion balance (Reams et al. , 2010), and then, for a long-term preservation, they would require the accumulation of beneficial mutations (Han et al. , 2009), or the relocation of the second copy in the genome to prevent its deletion (Ranz et al. , 2001). This would lead to late fates of sub- or neo-functionalization (Force et al. , 1999; Conant and Wolfe, 2008). Figure 7 Download asset Open asset General model to explain the fixation of duplicated genes as a function of the degree of selection in the population and preservation in the genome for long time. Representative silhouettes correspond to bacteria (prokaryotes), yeasts (lower eukaryotes), insects, plants, and mammals (higher eukaryotes). On the other hand, positive selection could drive the fixation of duplicates in both complex and simple organisms. When the environmental changes were relatively rapid, only organisms with short generation times (i. e. , prokaryotes and lower eukaryotes) could fix duplications (sector C in Figure 7; Riehle et al. , 2001). However, such duplications would be quickly eliminated from the population afterwards (once the environment changed again), as the genome rearrangement rates are orders of magnitude higher than the per base mutation rates (Reams et al. , 2010). By contrast, when a given environmental change were prolonged, any organism, irrespective of its generation time, could fix duplications (sector D in Figure 7; Emerson et al. , 2008).

Output: corroborate


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: Such moves could reduce compliance burdens for businesses engaged in cross-border trade, especially smaller businesses. Our study shows that reductions in the costs of complying with different VAT rules in different countries could boost cross-border trade, GDP and household consumption so such efforts should be welcomed. Plans to encourage the sharing of information and best practise between national revenue authorities and to investigate the potential of a trans-national anti-fraud team also seem sensible. Another promising proposal is to abandon the long-standing objective of moving towards a VAT based upon taxing cross-border trade at the rate of VAT applicable in the exporting country (the origin principle). Doing this will allow the Commission to focus on improving the operation of the existing EU VAT system largely based on the destination principle: taxation in the importing country at the importing country's VAT rate. Such a system has real benefits. For instance, cross-country differences in rates of VAT should not distort where firms choose to source their inputs from: they pay the domestic rate of VAT whether they buy things from a domestic supplier or a supplier based in another EU country. Perhaps more controversially, the Commission envisages broadening the VAT base with efforts to reduce the extent of exemptions in the public interest (including in the public sector), and in the provision of passenger transport services. This will initially focus on areas where the distortions to the Market and competition with non-exempt firms are greatest. The report also recognises that the plethora of reduced rates of VAT increases the complexity of the system for relatively little gain. A review of the current rate structure of VAT is proposed, with the aim of abolishing reduced rates that are harmful to the Internal Market, or that apply to goods for which consumption is discouraged by other EU policies, whilst ensuring similar goods and services face the same VAT rate. This represents a step in the right direction, but will leave many exemptions and reduced rates in place. However, as stated by the Commission "the are primarily responsible for limiting as far as possible the scope of such [reduced] rates", and they also have some discretion about when to apply exemptions. Implementing a reduction in the use of exemptions and reduced rates is likely to be political difficult: those sectors benefiting from them will lobby against their abolition, and it is unlikely to be popular with national electorates either. But doing so would bring real economic gains. Exemptions, in particular, are anathema to the whole principle of VAT.

Output: pass


Input: Claim: Charred plant remains can indicate past cooking methods and food preferences. [SEP] Text: burning food, damage to cookware) was frequently reported as a perceived motivator for choosing the main household cooking oil. Specifically, respondents reported selecting an oil with a high smoke point for the style of cooking (e. g. frying) that would not damage cookware or utensils. As such, this was more frequently reported amongst participants who did not use a form of olive oil as the main oil in the household. Indeed there is a perceived perception that olive oils do not have a high smoke point and are not suitable for certain cooking methods, such as frying; however, evidence continues to mount suggesting that EVOO in particular can be heated to temperatures of 180 degrees Celsius for deep frying and up to 240 degrees Celsius for shallow frying while maintaining stability and producing less polar by-products than its polyunsaturated counterparts and in turn protecting cookware(Alzaa, Guillaume and Ravetti53–Reference Ramírez-Anaya, Castañeda-Saucedo and Olalla-Herrera56). Furthermore, there is also a common perception that heating olive oil to high temperatures may damage the properties of the oil. However, previous evidence suggests that the phenolic compounds within EVOO play a protective role in minimising oxidation during frying(Reference Servili, Sordini and Esposto57,Reference Santos, Cruz and Cunha58) and EVOO with a high oleic acid composition demonstrates a lower formation of toxic compounds during frying(Reference Procida, Cichelli and Compagnone59). Nevertheless, in the present study, EVOO continued to be the most frequently used oil for sautéing, shallow frying and stir frying which is a finding consistent with a previous cross-sectional survey of n 2234 participants in the USA which reported that 86 % of participants sautéed with olive oil despite suggestions of the proposed low smoke point associated with the oil(Reference Wang, Moscatello and Flynn60). Despite the high use of EVOO across these cooking techniques, we did observe differences between sauteing, stir frying and shallow frying. For example, we observed that a greater proportion of participants (74·3 %) used a form of olive oil for sauteing rather than for stir frying (46·3 %), which is considered a similar cooking technique albeit at a lower temperature. However, this may also reflect the interpretive differences in oil use for different cooking methods across different ethnicities.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: In this case, they would be under strong positive selection, and, consequently, they would be preserved for long time. Furthermore, all organisms could fix duplications by producing more accurate responses (sector B in Figure 7), without the need of significant environmental changes; provided the gene of interest were noisily expressed (Elowitz et al. , 2002; Raser et al. , 2004), and the duplication deletion rate were lower than the weak selective advantage. In the very long term, these weak selective conditions could also allow the exploration of novel functions, as they ensure the preservation of duplicates, without invoking fortuitous exploration in the ancestral state (Bergthorsson et al. , 2007), and with amplification when the advantage provided by the narrowed novel function were higher than the advantage by noise reduction. inherently stochastic nature of gene expression is certainly an evolutionary driver when it is linked to cell fitness to dictate the selection of particular genetic architectures (Batada and Hurst, 2007; Maamar et al. , 2007). Our results demonstrate that gene duplication can be positively selected as an architecture that allows enhancing information transfer in genetic networks (i. e. mitigation of expression errors; Rodrigo and Poyatos, 2016). Accordingly, the genetic robustness indeed observed upon the accumulation of genetic redundancy (Keane et al. , 2014) would be more a consequence than a selective trait (Kafri et al. , 2006). Certainly, by aggregating the responses of two genes, intrinsic fluctuations can be mitigated, but not fluctuations of extrinsic nature. This way, duplication would be more favorable in scenarios in which intrinsic noise is preponderant. The balance between intrinsic and extrinsic noise depends on the particular environmental conditions and the regulatory structures in which the gene in embedded. Intrinsic noise can be significant when the medium is rich in nutrients, the expression levels are low, and no further regulations affect the gene (Swain et al. , 2002). For example, competence in Bacillus is mainly governed by intrinsic noise (Maamar et al. , 2007). To follow our model, noise has to mainly impinge the regulation of the system, that is, disturb the link between the signal molecule and gene expression (Blake et al. , 2006). Moreover, our results highlight that a population genetic model with the mean selection coefficient is enough to explain the complex, stochastic evolutionary dynamics of duplication fixation.

Output: corroborate


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: Taken together, these results suggest that the topical application of new treatments targeting the proteins associated with cancer cell formation have the potential to treat cutaneous squamous cell carcinomas and other related skin conditions, and raise the possibility that topical treatments containing multiple cancer-associated protein (enzyme) inhibitors together could be more effective than utilising a single compound. ‘These innovations represent a promising and much-needed alternative to today’s topical therapies, one that directly targets the biological mechanisms driving the tumour’s growth,’ explains Dr Seykora, ‘with the number of cases of cutaneous squamous cell carcinoma steadily rising, it’s important we work to identify safer, more precise therapies to treat these cancers before they progress and spread. We believe topical kinase inhibitors are potential candidates that warrant further study. ’ E-book the researcher T. Seykoraof MedicineUniversity of. Seykora is a tenured Professor of Dermatology in the of Medicine at the University of Pennsylvania. He received his undergraduate degree in Biology with Honors and concurrently was awarded a Masters in Biochemistry from the University of Chicago. received his PhD from Rockefeller University, and then an MD qualification from Medical College. After undertaking residency and fellowship at the University of Pennsylvania, began teaching and performing research in the School of Medicine at the University of Pennsylvania, and later went on to become a tenured Professor of Dermatology, a position he still holds today. From being a Scholar at the University of Chicago in 1982 to receiving the Dean’s Award for Excellence in Teaching from the of Medicine in 2019, has received an abundance of awards and honours throughout his career. : seykora@pennmedicine. upenn. edu W: 01AR051380, RO1-CA165836, RO1-ES02811, and P30-AR069589 of Health grant P30-AR069589 Whole exome and transcriptome analysis of UV-exposed epidermis and carcinoma in situ reveals early drivers of carcinogenesis, Journal of Investigative Dermatology, 2020, 141(2), 295–307. , Voriconazole enhances UV-induced DNA damage by inhibiting catalase and promoting oxidative stress, Experimental Dermatology, 2020, 29(1), 29–38.

Output: pass


Input: Claim: Charred plant remains can indicate past cooking methods and food preferences. [SEP] Text: Additionally, the theme of minimising damage to cookware was more frequently reported as a perceived motivator for oil choice than cost. This is indeed a novel finding given that some form of olive oil was the most commonly reported oil used in Australian households, despite its high costs relative to other common cooking oils(Reference D’Adamo, Falcone and Gastaldi61,Reference Martínez, Aragonés and Poole62). Our findings are in contrast to those previously reported by Erraach et al. (Reference Erraach, Sayadi and Gomez63) and Santosa et al. (Reference Santosa, Clow and Sturzenberger47) who identified that cost was one of the main determining factors in participants’ decisions to purchase olive oil in n 439 adult consumers of olive oil (52·5 % female; 47·5 % male) in Spain and n 35 adults (82·9 % female; 17·1 % male) in the USA, respectively. However, more recent findings suggest that when choosing a household oil, factors, including sustainability, are more considered than the cost of olive oil (Reference Erraach, Jaafer and Radić64). In contrast to these findings, supporting local production of oils and environmental sustainability were not as frequently reported in the present study. Cultural background and family p10. 1017/S0007114522003798 1070. CrossRef1737. 3978. CrossRef406. CrossRef546. CrossRef605. CrossRef8. CrossRef63. CrossRef0252. CrossRef2345. 1080. CrossRef34. CrossRef11. CrossRef1130. CrossRef29. 10. 3390/foods7030029CrossRef10. 1093/advances/nmz069CrossRef2124. 10. 1080/10408398. 2018. 1438349CrossRef7675. CrossRef262. CrossRef1258. CrossRef559. CrossRef1273. CrossRef1459. CrossRef56. CrossRef1512. CrossRef122. 10. 1093/ajcn/63. 1. 116CrossRef2145. CrossRef280. CrossRef259. CrossRef31. 284. CrossRef1288. CrossRef240. 101. CrossRef114. CrossRef27. 0. Armonk, NY: IBM Corp. 1101. CrossRef2795.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Of note, the reported intrinsic adaptive value, which cannot be captured by sequence analyses, was derived from basic mathematical models of gene regulation and cell fitness (Dekel and Alon, 2005). Notably, we anticipated a series of testable results by following our theory of error buffering upon duplication. First, the gene expression level is indicative of the fixation path. The theory requires that gene expression is roughly maintained (i. e. gene dosage sharing, duplicates vs. . singletons), with the aim of minimizing deleterious fitness effects. This would hold for several fixed duplicates in different organisms (Qian et al. , 2010; Gout and Lynch, 2015; Cardoso-Moreira et al. , 2016; Lan and Pritchard, 2016), although most of the formed duplicates would be under strong purifying selection due to the cost of over-expression, as already proposed (Lynch and Conery, 2000). By contrast, those fixed duplicates showing increased gene expression levels would reflect the effect of genetic drift (Lynch and Conery, 2003) or positive selection for dosage after prolonged environmental changes (e. g. the case of flies; Emerson et al. , 2008; Cardoso-Moreira et al. , 2016). Second, noisy genes are expected to be more duplicable (e. g. as it seems to happen in yeast; Lehner (2010); Dong et al. , 2011) when noise has deleterious fitness effects. Indeed, the gain experimented by the system upon duplication is greater when gene expression inaccuracies are significant (Rodrigo and Poyatos, 2016). This would explain the TATA box enrichment in the cis-regulatory regions of duplicated genes, as these genetic motifs are associated to high plasticity (i. e. high sensitivity to multiple environmental changes) and high gene expression noise by inducing transcriptional bursts (Blake et al. , 2006; Lehner, 2010). Note that if noise were beneficial (e. g. as a survival strategy in fluctuating environments; Acar et al. , 2008), duplication would not be favored. Moreover, we might argue that essential genes would be less duplicable (He and Zhang, 2006) as a consequence of their reduced gene expression noise (Batada and Hurst, 2007). Genes under the control of regulatory structures that buffer noise (e. g.

Output: corroborate


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: The minimum level of dystrophin that might be reasonably likely to predict clinical benefit in patients with BMD remains unknown, but experts in DMD have stated that levels less than 3 percent of that of normal healthy muscle are generally associated with the typical DMD phenotype. ”The FDA also questioned whether the 13 historical controls had received the same intensity of physical therapy and steroid treatment. It stated that “performance on the 6-minute walk test could be influenced by motivation and coaching. ” The agency also expressed concern that “open-label trials are susceptible to bias on the part of investigators, patients, and parents. ”Perhaps of greatest concern, the FDA stated in its briefing document that the clinical course of the 12 patients treated with eteplirsen “appears to be within the expected natural history of DMD. ” Treated children, it stated, “experienced a sequential worsening of functional abilities and muscle weakness, as demonstrated by changes in rise times from the floor and the evolution of (NSAA) scores. ”The principal investigator of the trial, Jerry R. chair of pediatric research and professor of pediatrics and neurology at Nationwide Children's Hospital and University in Columbus, declined via email to speak with due to concerns about how such an interview might be viewed by the FDA. But the four-year data presented at AAN were seen by many as the best answer to the FDA's doubts. Still, some expressed concerns about how the challenges in seeking approval might affect enrollment for future trials seeking more definitive (and needed) blinded data. . Nelson, MD, professor of human genetics, and Carrie Miceli, PhD, professor of microbiology immunology and molecular genetics — co-directors of the Center for Dystrophy at the School of Medicine at the University of California, (UCLA) — coauthored a letter of support to the FDA to underscore the importance with which the DMD scientific community regards the drug. “We felt perplexed that the data looks good, yet has not been met with a clear path forward for approval,” Dr. Nelson said. “The data are highly supportive of the drug having a positive effect with good safety. I think the effect is substantive but not curative.

Output: contrast


Input: Claim: Charred plant remains can indicate past cooking methods and food preferences. [SEP] Text: CrossRef35. CrossRef28. CrossRef13. CrossRef2085. CrossRef1440. CrossRef2111. CrossRef1313. CrossRef873. CrossRef1833. CrossRef195. CrossRef71. CrossRef11. 9. CrossRef12. 246. CrossRef23. CrossRef2024. CrossRef229. CrossRef1911. CrossRef180. CrossRef19. 2310. CrossRef387. CrossRef7630. CrossRef12. CrossRef2840. CrossRef186. CrossRef1. Summary of questions from part B of the online survey evaluating the types of oils used in cooking and food preparation in in content Table 2. Demographic characteristics of participants (n 1248) View in content Table 3. Frequency and percentage of main household oil use differentiated by daily serve size (n 1248) View in content Table 4. Frequency n (%) of oil use for different cooking methods (n 1248) View in content Table 5. Perceived motivators of the main oil used by participants in their household (n 1248) Wilson et al. supplementary material Wilson et al. supplementary material File 33. 8 KB You have Access 1 Cited by Cited by Loading. . .

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: negative feedbacks) would not be duplicable either (Warnecke et al. , 2009). However, this consideration should be taken with caution, as genes not essential a priori could be duplicated and then, upon fixation, accumulate beneficial mutations (Han et al. , 2009) to ensure preservation for long time, resulting a posteriori in essential genes due to functional diversification (as it seems in the case of mammals; Makino et al. , 2009). Third, the local genetic context would be highly determinant of the fixation of a duplicate (Reams et al. , 2012), explaining why some genes are more duplicable than others in scenarios of apparent neutrality (hot spots; Perry et al. , 2006). Moreover, duplicates would be much shorter lived in prokaryotes than in eukaryotes (Lynch and Conery, 2003), due to the differences of orders of magnitude in the duplication deletion rates. After all, the precise experimental determination of the molecular rates of gene copy number variation would unveil to what extent natural selection has actually rivaled random genetic drift to shape complexity along the course of life history (Rodrigo, 2017). These predictions involve, nevertheless, some limitations. On the one hand, due to a simplified mathematical model not considering the many molecular/genetic attributes that impinge implicitly on gene expression, such as promoter sequence-dependent noise levels (Metzger et al. , 2015), response coupling due to genetic proximity (Becskei et al. , 2005), or recursive fitness-expression dependence (Klumpp et al. , 2009). On the other hand, due to the difficulty to provide direct empirical evidence supporting the fixation of duplicates by reducing intrinsic noise. In this regard, we expect to carry out in the future an experimental approach (Dekel and Alon, 2005; Keane et al. , 2014) complementary to this theoretical study. Despite these edges, our results complete a mechanistic model in which duplicates are fixed either by genetic drift (no selection) or by gene dosage (strong selection) with the addition of a new principle, viz. , reduction of gene expression inaccuracies upon duplication can result in a weak selective advantage. Materials and methods Fitness function Request a detailed protocol The lac operon of E.

Output: corroborate


Input: Claim: Personalized medicine uses genetic data to tailor treatments to individual patients. [SEP] Text: AbstractObjective:Response to specific depression treatments varies widely among individuals. Understanding and predicting that variation could have great benefits for people living with depression. Method:The authors describe a conceptual model for identifying and evaluating evidence relevant to personalizing treatment for depression. They review evidence related to three specific treatment decisions: choice between antidepressant medication and psychotherapy, selection of a specific antidepressant medication, and selection of a specific psychotherapy. They then discuss potential explanations for negative findings as well as implications for research and clinical practice. Results:Many previous studies have examined general predictors of outcome, but few have examined true moderators (predictors of differential response to alternative treatments). The limited evidence indicates that some specific clinical characteristics may inform the choice between antidepressant medication and psychotherapy and the choice of specific antidepressant medication. Research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the choice between medication and psychotherapy, the selection of specific medication, or the selection of a specific psychotherapy. Conclusions:While individuals vary widely in response to specific depression treatments, the variability remains largely unpredictable. Future research should focus on identifying true moderator effects and should consider how response to treatments varies across episodes. At this time, our inability to match patients with treatments implies that systematic follow-up assessment and adjustment of treatment are more important than initial treatment selection. On average, antidepressant medication and specific psychotherapies have similar success in the first-line treatment of moderate depression (1–3). And on average, different antidepressants show equal or similar efficacy (4, 5). But the fact that treatments have similar efficacy on average does not imply that treatment selection is unimportant (6, 7). Individuals vary widely in response to specific treatments, and poor response to one treatment does not necessarily imply poor response to others. For example, among patients who do not benefit from initial treatment with one antidepressant, up to one-half experience significant improvement after switching to an alternative medication (8), adding a second medication (9), or adding psychotherapy (10). Unfortunately, many patients treated in community practice, especially in primary care, have no chance to benefit from second-line treatments. After starting antidepressant treatment, nearly one-half make no follow-up visits, and only one-quarter return often enough to pursue additional treatment options (11, 12). Accurate selection of the best initial treatment could have tremendous benefits for people living with depression.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Full text Figures and data Peer review Side by side Peer review process Decision letter Author response Peer review process This 10. 7554/eLife. 02743. 017 Author response Reviewer #1: I suggest saying up front when the # of units is given that males and females were grouped together (until they're not) and how many there were of each. Good point. The legend for Figure 3 now reads: “(C) Selectivity of sensory responses for units recorded in the adult AOB (197 units from male and female animals). (D) Selectivity of sensory responses for units recorded in the adult MeA (274 units from male and female animals). ” The legend for Figure 4 now reads: “(A) Responses of AOB neurons to vomeronasal stimuli in adult male (210 units) and female (64 units) mice. (B) Responses of MeA neurons to vomeronasal stimuli in adult male (106 units) and female (91 units) mice. (C) Responses of MeA neurons to vomeronasal stimuli in juvenile male (37 units) and female (50 units) mice. Units shown in panels A-C are the same data shown in Figure 3C,D but classified according to the sex of the animal recorded. ” I think that the response selectivity description in the Results is understated and suggest it needs defining in the Results. The results now include the following statement: “To further compare the stimulus selectivity of individual neurons, we calculated a selectivity index that ranges linearly from 0 (all stimuli elicit equal responses: center of triangles in panels C,D) to 1 (only one stimulus elicits a response: vertices of triangles in panels C,D) for units recorded from the AOB (mean 0. 38; 95% CI: 0. 36 to 0. 41; see supplementary information) and from the MeA (mean 0. 54; 95% CI: 0. 50 to 0. 58). ” Single-and multi-units were classified by spike shape, separation of principal component projections, and the presence or absence of a refractory period between successive spikes – I don't understand this for multi units. Our wording was poor; this was the process to identify single units.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: The dynamics of a punctual beneficial mutant appeared in an evolutionary experiment of serial dilution passages, with maximal population size N and dilution factor D, is given by r = 2S·t ⟨N⟩, where ⟨N⟩ = N D1/2 is the geometric mean population size (also considered the effective population size; Lewontin and Cohen, 1969). The fixation probability is Pfix = 2S, and the characteristic fixation time tfix = log2(⟨N⟩2)/S. Note that the time for 50% invasion of the population is thalf-fix = log2(⟨N⟩)/S = tfix/2. However, we have Pfix = 1/⟨N⟩ and tfix = 2⟨N⟩ for a neutral mutant (Kimura, 1983). By contrast, if multiple beneficial mutants are recurrently produced at rate μb, the dynamics is given by r = μb·N·2S·t [S·log(D)·⟨N⟩] ≈ μb·2S·t S, as in each passage μb·N different mutants are generated (valid for μb·N > 1; Desai et al. , 2007). Because mutants are now recurrent, Pfix = 1, and the characteristic fixation time reads tfix = log2[⟨N⟩·S μb]/S. When m different mutations accumulate successively, tfix ≈ tfix(m) + thalf-fix(m-1) + … + thalf-fix(1), that is, a subsequent mutation can start its fixation when the preceding mutation has invaded the 50% of the population (Lang et al. , 2013). If μb·N << 1, the system can be treated as in the case of a punctual beneficial mutation, and the dynamics can be written as r = 2S·(t - T) ⟨N⟩, with a delay of T = log2(D) (μb·N), the mean number of generations required to produce a mutant, and Pfix = 2S.

Output: corroborate


Input: Claim: Personalized medicine uses genetic data to tailor treatments to individual patients. [SEP] Text: This group includes numerous cohort studies examining the associations between specific genetic variations and favorable treatment outcomes in patients treated with a single antidepressant (45–52) or class of antidepressants (53, 54). Cohort studies of this type cannot distinguish between general predictors of prognosis and true moderators that predict differential response to alternative drugs. Similarly, studies identifying genetic variations associated with better response to one active antidepressant than to placebo (55) cannot distinguish general predictors of benefit with antidepressant treatment from specific predictors of differential response to alternative medications. Because none of the aforementioned reports compare alternative active treatments, none can provide evidence to personalize antidepressant selection. Relatively few studies have examined the association between genetic variations and outcomes in patients treated with alternative antidepressants. These include both randomized comparisons of alternative antidepressants (56–59) and nonrandomized comparisons (60, 61). In some cases, the pattern of associations is consistent with presumed mechanisms of drug action. For example, Kim et al. (60) found that response to an SSRI (either fluoxetine or sertraline) was significantly associated with variation in serotonin transporter genes but not with variation in norepinephrine transporter genes. Using data from a randomized comparison of the two drugs, Szegedi et al. (56) and Tadic et al. (57) found that variations in both monoamine oxidase and catechol-O-methyltransferase genes were associated with response to mirtazapine but not with response to paroxetine. Wakeno et al. (59) found that variation in alpha 2A-adrenergic receptor genes was associated with response to milnacipran but not to paroxetine. Primary analyses in each of these studies addressed the following question: Does a specific genetic variation predict better outcome in patients treated with a specific medication? These analyses are appropriate for testing hypotheses regarding mechanisms of drug action, but they do not directly address our question regarding differential efficacy: Does a specific genetic variation identify a group of patients with significantly more favorable response to one antidepressant than to another? This question regarding differential efficacy is formally addressed by a test for interaction or moderation. Kim et al. (60) did report a post hoc subgroup analysis in which patients with a specific variation of the norepinephrine transporter gene experienced significantly higher response rates during treatment with nortriptyline than with either fluoxetine or sertraline.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: The text now reads: “Single units were classified from multi-unit activity based on spike shape, separation of principal component projections, and the presence or absence of a refractory period between successive spikes (Figure 1–figure supplement 1; Harris et al. , 2000; Hazan et al. , 2006). ” In most experiments, ∼2-6 recording sites were located dorsal to the MeA and were easily distinguished from the quiet baseline activity of the MeA. Do you mean to say that “units located dorsal to the MeA were easily distinguished from the quiet units of the MeA”? The text has been amended as follows: “In most experiments, ∼2-6 recording sites were located dorsal to the MeA and were easily distinguished from the quiet units of the MeA in the absence of vomeronasal stimulation. ” PLCO is not defined at first use and is not actually defined anywhere except in a figure legend. What does PLCO stand for? PLCO is now defined properly: “MOE stimulation elicited clear olfactory-evoked neuronal activity in the MOB and the posterolateral cortical amygdala (PLCO) in response to volatile urinary cues and odorants (Figure 1–figure supplement 3). ” In Figure 1, average histograms of the mean response (left panels) are shown with standard error (shaded region). Is this a typo and should be right panels? If not, I do not understand. Also, any SEM shading is way too small; even at 125% to see. Either increase the size of the figure or delete this. I don't see what Figure 1–figure supplement 2B adds? Our wording was unclear. The legend for Figure 2 now reads: “(Left) Each row shows the responses elicited in a single MeA unit by four different VNO stimuli, with each stimulus presented 5 times. The order of stimulus presentation was randomized during the experiment, but is shown grouped by stimulus for clarity. (Right) Histograms showing the mean response and standard error (shaded region) for each unit. Responses were aligned to the onset of stimulus presentation. All significant responses (p<0. 01; ) are indicated by an asterisk in the top right corner of the average histogram plots. Response magnitudes for each unit were normalized to the maximum response for all stimuli.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Moreover, in case of gene duplication, if multiple beneficial mutants are recurrently produced at rate μc, and deleted at rate μd, the dynamics is given by r ≈ μc·2S’·t S’, with S’ = S - μd as an effective selection coefficient (valid for μc·N > 1, and S > μd). Again, if μc·N << 1, the system can be treated as in the case of a punctual beneficial mutation, with Pfix = 2S’. << μd, the stationary solution can be approached by r ≈ μc μd for effectively neutral mutations, or by r ≈ μc (μd - S) for deleterious mutations. Genetic diversity Request a detailed protocol The per base mutation rate of E. coli is μ = 10−10 mut. /bp/gen. (Lee et al. , 2012). Cultures of this bacterium may reach population sizes up to N = 109 cells (⟨N⟩ = 2·108). This means, on average, 0. 02 (= μ·⟨N⟩) mutants of a given base pair in the population. The number of base pairs, mainly in the cis-regulatory regulatory region, whose mutation reduces in half the expression of a gene of interest can be estimated in 10 (based on data for lacZ). Thus, μb = 10·μ, which means 0. 2 (= μb·⟨N⟩) mutant of this type in the population on average. This frequency may even be higher if we not only consider the mutations in the lac promoter, but also the mutations in the coding region, or affecting the activity of its regulators (e. g. CRP; Kinney et al. , 2010). In addition, for the lacZ gene, its duplication formation rate is of μc = 3·10−4 dup. /gene/gen. , and its duplication deletion rate of μd = 4. 1·10−4–4. 4·10−2 -/gene/gen. (Reams et al. , 2010; Reams et al. , 2012). In absence of lactose, duplications are neutral (S = 0), which means, on average, a duplication frequency in the population of 0.

Output: corroborate


Input: Claim: Personalized medicine uses genetic data to tailor treatments to individual patients. [SEP] Text: Summary of Predictors of Differential ResponseRegarding initial choice between medication and psychotherapy, severity of depression does not appear to predict greater likelihood of response to medication or psychotherapy. Modest evidence suggests that personality disorder predicts more favorable response to pharmacotherapy and that negative life events (either recent stresses or childhood trauma) predict better response to psychotherapy. One trial suggests that a clear preference for either medication or psychotherapy predicts greater success with the preferred treatment. Regarding selection of a specific medication, cooccurring anxiety disorder may predict greater improvement with SSRIs than with bupropion, but this difference appears small. Biological markers (such as neuroendocrine or imaging studies) do not appear to predict differential response to specific antidepressants. Most previous studies of genetic predictors have not used appropriate designs and analyses to identify true moderators or predictors of differential efficacy. Consequently, we have no strong evidence that any genetic variation can inform antidepressant selection. Surprisingly, we also have no evidence that history of prior medication response is useful in medication selection. Regarding selection of a specific psychotherapy, moderate evidence suggests that borderline personality disorder or attachment difficulty predicts more favorable response to cognitive therapy than interpersonal therapy. Sources of Error in Research to TreatmentInadequate statistical power to detect moderator effects is a likely explanation for many of the aforementioned “negative” findings. To illustrate, in a study comparing equal numbers of patients receiving alternative treatments with average response rates of 50%, we could examine whether relative efficacy of treatments A and B varies between patients with and without characteristic X. If patients with characteristic X have a 60% response rate with treatment A and a 40% response rate with treatment B and those without characteristic X show the opposite pattern (a relatively large moderator effect), a sample of approximately 300 patients would be necessary to reliably detect this difference (assuming a 5% type I error rate and 20% type II error rate). Of the aforementioned pharmacogenetic studies (56–61), none have included more than 250 patients, and most have included fewer than 150. Research to personalize treatment, especially research focused on genetic moderators or predictors, must consider another source of error. Such research depends on the assumption (usually unstated) that an individual's response to a specific treatment will be stable across different episodes of treatment. This assumption also underlies the common clinical practice of basing medication selection on past treatment experience.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Colored bars (top and bottom) indicate the 40 second epoch following stimulus presentation that was considered for all analyses. We also agree with the second point, and Figure 1–figure supplement 2B has been removed. “Therefore, the dorsoventral topography is largely a result of quantitative biases in the numbers of 'conspecific' and 'predator' neurons located dorsal versus ventral, while only 3% of the variance is explained by a smooth transition from 'predator' selective neurons (ventral) to 'conspecific' selective neurons (dorsal). ” This is an odd statement in the sense that no quantification is given to support the quantitative biases. This is a continuation of the previous regression analysis, and a direct reference to the observed R2 value of that regression: “Regression analysis indicates a weak relationship between the dorsoventral distance and the difference in stimulus specificity for unit pairs (R2 = 0. 033, F = 8. 6, p = 0. 003; black line; light grey points omitted due to high leverage). ” Figure 2–figure supplement 2: There are no ordinate scales. Please make the insets in Figure 3C-D larger in size. They are exceptionally hard to see. The authors may want to include a recent reference on awake versus anesthetized dynamics in MOB (Cazakoff et al 2014). Both figures were amended as suggested and the Cazakoff et al 2014 reference has been added: “Sensory processing in the main olfactory system is clearly altered by anesthesia level and behavioral state (Rinberg et al. , 2006; Cazakoff et al. , 2014)…” Reviewer #2: The experimental logic, sequence, and analyses are very good; however some additional background and description of experimental details regarding the MeA would be beneficial. For example, what is known about the functions/differences of the specific MeA nuclei? What nuclei are targeted during recordings? What types of neurons are being recorded in the MeA? Also, it would be useful to include some discussion on why only ∼10% of the neurons within the MeA are responsive to stimuli presented. We have addressed each of these questions: For example, what is known about the functions/differences of the specific MeA nuclei? What nuclei are targeted during recordings?

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Genetic variability and neutral mutations: a commentary on ‘Genetic variability maintained in a finite population due to mutational production of neutral and nearly neutral isoalleles’ by Published online by Press: 29 October 2008. G. author details. G. * Affiliation: for Genome Resources, 2935 87505, USA * *e-mail: ddg@ncgr. org 0. 06 mb) View PDF [Opens in a new window] Save to to Save to An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button. Type 10. 1017/S001667230800952X [Opens in a new window] © 2008 2007, the consortium confirmed and expanded previous studies highlighting that the vast majority of the human genome is transcribed (2007). This is in marked contrast with our earlier worldview that as much as 95% of the genome is ‘junk’ and of little or dubious consequence to the everyday functioning of the cell or organism. For example, recent reviews on RNA have shown it to be ubiquitous in cellular functioning (Amaral et al. , Reference Amaral, Dinger, Mercer and Mattick2008), which, combined with the startling discovery in 2001 that there are perhaps only 30 000 human protein-coding genes, is drastically changing the way we understand genes – and ultimately – genetic variation itself. Thirty years ago, when we had a simpler view of the genome, Kimura (Reference Kimura1968b) published his work on neutral isoalleles, thereby contributing to a true upheaval in our understanding of genetic variation no less than that which we are experiencing today. Just 2 years earlier, Lewontin & Hubby (and Hubby1966) published an influential paper examining electrophoretic variation. The surprising result was that there was much more protein variation than expected, and specifically more variation than expected at individual genes or loci. This presented a paradox that sought to unravel.

Output: corroborate


Input: Claim: Personalized medicine uses genetic data to tailor treatments to individual patients. [SEP] Text: This fundamental assumption has only been examined in a single small observational study (41), and it was not supported by these data. It is remarkable that an assumption so central to clinical practice and pharmacogenetic research has so little empirical support. Addressing this gap in knowledge is a priority for future research. Because studies of depression treatment response typically consider only a single episode of treatment per person, they obscure the distinction between person-level and episode-level predictors of treatment response. Episode-level predictors are those that may vary within individuals across episodes of depression treatment. Examples of these potentially variable characteristics include pretreatment symptom severity, pretreatment episode duration, co-occurring substance abuse, and recent life stresses. In contrast, person-level predictors are expected to show no variability across treatment episodes. Examples of these stable characteristics include race or ethnicity, stable personality traits, genetic variation, family history, or the past experience of physical or sexual abuse. Traditional research designs (examining differences between individuals during a single episode of treatment) may be adequate to identify episode-level predictors of treatment response. Accurate identification of stable or person-level predictors of treatment response will require examining consistency of treatment response within individuals across multiple episodes of care. Directions for Future ResearchResearch to date has identified few clinical characteristics and no biomarkers or genetic variations that reliably predict differential effectiveness or adverse effects of specific depression treatments. We have described three conceptual difficulties that may be responsible for our failure to identify differential predictors of response. First, previous research has often conflated predictors of response to specific treatments with more general predictors of prognosis. Second, response to specific treatments may actually vary across episodes of treatment. Third, response to treatment in any episode of illness may be influenced by a mixture of episode-level (or time-varying) and patient-level (or stable) characteristics. These conceptual issues have important implications for future research to identify differential predictors of treatment response. First, research to personalize treatment for depression will probably require samples of patients considerably larger than those enrolled in traditional clinical trials. Detection of moderators or interaction effects generally requires larger samples than does detection of average or main effects, especially if a potential moderator (such as a genetic variation) influences response to one treatment but not the other. Second, research to identify person-level predictors of treatment response may need to consider response across multiple episodes of depression.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: In the methods they say that the triangular plots are generated by “projecting the normalized male, female, and predator responses on the plane,” but do not describe what exact measure of electrical activity is used responses – change in firing rate averaged across repeats? Or explain how the responses are normalized. We have expanded and clarified this description: “Triangular plots of neural responses: Triangle plots (see Figure 3C,D) of sensory responses to male female and predator stimuli were generated in three steps. First, the pre-stimulus firing rate was subtracted from the post-stimulus firing rate of each unit in order to account for differences in baseline firing rates. The absolute value of the baseline subtracted response was then taken to account for responses that consisted of a reduction in activity as compared to the pre-stimulus epoch. As can be seen in Figure 1–figure supplement 2A, such cases are an extreme minority in our data as units typically were inactive before a stimulus was presented and respond to stimuli with an increase in activity. Second, baseline adjusted firing rates were normalized by dividing by the summed responses to all stimuli such that: respMale + respFemale + respPred = 1. At this point, each unit can be plotted on an equilateral triangle with vertices at (0,0,1), (0,1,0), and (1,0,0) where the three axes represent the normalized responses to male, female and predator stimuli. Third, the plane segment defined by the intersections of this plane with the three Cartesian axes was then rotated for ease of visualization. ” 2) It is not clear if the animals are exposed to just one sample of female/male/predator urine (obtained from multiple animals) or whether in each experiment they are tested with a second independent sample. This would be important to confirm that any one response is due to chemosignals from one of the three categories. There is a discussion of principal component analysis and a supplemental figure which shows that cells responsive to a female (male or predator) stimulus are generally sensitive to an independent stimulus from the same class, but the correlation appears to hover at less than 50% for male/female odors and lower for predator.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Classical population genetics had two main classes of models to explain genetic variation: in the first model, it was known that new deleterious mutations will segregate in a population for an average of 1/s generations before they are removed by selection, where s is a measure of the selective effect, or reduction in fitness, experienced by an individual as a result of carrying the mutation. So while mutation pressure is introducing new variation, selection is removing it. If these mutations occur at a rate of μ per generation, the forces equilibrate at an average of μ/s mutations per individual – and indeed Kimura and Maruyama (Kimura & Maruyama, and Maruyama1966) had derived the entire distribution of the number of mutations per individual just 2 years earlier. Yet parameterizing μ (the genome-wide mutation rate) and s (the average selection coefficient) based on experimental studies gave values either too low to account for the observed high levels of variation or too high to be sustained under models of genetic load. Supposing new mutations to be beneficial was even more unhelpful in reconciling the data, since beneficial mutations were expected to occur at an even lower rate, and those mutations not lost due to chance when rare would sweep to fixation and in the process supplant all variants with their superior type, thereby reducing variation. The second class of models gave selection a more nuanced role in maintaining variation. Perhaps if some middle or optimal combination of variants was most fit – essentially selection for variation itself – then the observed high levels of segregating variation could be understood. For example, models on overdominance or balancing selection could indeed stably segregate large amounts of variation. The only problem was that the data were not kind to these hypotheses either. Impressive cases of heterozygote advantage and/or balancing selection could be documented in areas such as mate recognition and disease resistance, but the special nature of these examples never allowed them to shoulder the burden of a general solution. Additionally, did not the presence of an optimum generate a ‘cost’ or ‘load’ experienced by all lesser fit individuals harbouring variants displaced from the ideal? Would the underlying genetic architecture not be susceptible to invasion by load-reducing mechanisms?

Output: corroborate


Input: Claim: Personalized medicine uses genetic data to tailor treatments to individual patients. [SEP] Text: , adverse effects such as somnolence or akathisia can be mistaken for primary undertreated symptoms, and vice versa; or, even if burdensome side effects do not impede adherence, they may diminish overall well-being and patients’ global perceptions of improvement. Substance misuseAlcohol and illicit substance misuse after treatment initiation can diminish the effectiveness of any pharmacotherapy and exacerbate or perpetuate affective and other symptoms that are themselves the intended targets of treatment. Lithium: or Old Standard? Our field came to appreciate the disparity between treatment outcomes for homogeneously “ideal” patient profiles from the greater heterogeneity (and more variable prognosis) of those in real-world settings through observational studies with lithium in the 1980s. From decades of experience since lithium came into use for bipolar disorder, one can now construct a “profile” of the idealized patient best suited to respond to lithium. Rather than consider lithium to be the gold-standard mood stabilizer, as often described (as if it possessed broad universal properties for most forms of bipolar disorder), one can probably think of it more accurately as a well-studied but narrow spectrum agent. Analogous to penicillin, lithium works best in a definable, narrow subgroup of bipolar patients (<10% by some reports (32)) with a distinctly uncomplicated clinical profile, defined by the following characteristics: pure euphoric more than mixed features (33); positive family history of lithium-responsive bipolar disorder (31); introduction within the first few lifetime episodes (34); absence of rapid cycling (19); better prophylaxis against recurrent mania than depression (35); mania polarity “proneness” (16); episode patterns in which manias precede depressions (36); higher age at illness onset (36); absence of somatic comorbid condition (32); absence of substance use comorbidity (37); hyperthymic temperament (38); absence of psychosis or cognitive disorganization (39); and absence of anxiety (40). Additionally, lithium may hold a relative advantage over other mood-stabilizing agents in settings where prevention of suicidal behavior is a prominent concern (41), as a countermeasure to leukopenia (e. g. , during clozapine therapy), and in patients without psoriasis or other chronic dermatological comorbid conditions.

Output: pass


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Editorial: in the Brain – Functions and Funahashi1,2*Emmanuel Procyk3* 1Institute for Multidisciplinary Science, of Technology, Beijing, China 2of Advanced Technology, of Science, Shenzhen, China 3Univ Lyon, Université Lyon 1, Inserm, Institute U1208, Bron, on the in the Brain – Functions and Fuster and Alexander first found persistent firing in the prefrontal cortex during delayed-response performance (Fuster and Alexander, 1971), persistent neuronal activity has been observed in multiple brain areas and species, in relation to a variety of cognitive activities that require sustained processing or maintenance of states to bridge different events separated in time or to control or monitor specific functions. Persistent delay-period activity observed in the prefrontal cortex has been shown to play important roles to temporarily maintain either retrospective or prospective information necessary to perform a variety of cognitive behaviors during the delay interval, which corresponds to the function of working memory. Therefore, persistent activity has been considered as a neural correlate of working memory. Although it is an important phenomenon to understand neural mechanisms of working memory, planning or cognitive control, debates have been continued among researchers regarding its meaning, sources, and even relevance. In this Research Topic, we offered an opportunity to present research outputs carried out with various approaches including electrophysiology, behavior, and computational modeling, and to further discuss the origin and functional significance of persistent activity. The brain uses different timescales to process information. Cavanagh et al. explored the features of persistent activity based on intrinsic timescales in single neurons for information processing. As primary sensory areas process momentary sensory inputs regardless of their context, short neural timescales in turn contribute to processing and representing such information. However, neural activity in association areas that integrate various information to achieve distant goals, are characterized by longer timescale. Single neurons display different individual timescales, which predict the strength of mnemonic encoding. Neurons exhibiting longer timescales play greater roles for stable maintenance of mnemonic information and for integrating multiple pieces of task-relevant information. Although neurons exhibiting shorter timescales are also present within higher cortical areas, the presence of neurons exhibiting heterogeneous timescales could be important for adapting environmental demands dynamically.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Indeed, decades earlier, Haldane had given an elegant model of how heterozygote advantage is susceptible to gene duplication, whereby all offspring are invariant but produce the optimal intermediate genotype (one copy of the gene is fixed for one allele, while the second copy is fixed for the other allele). Against this backdrop, Kimura (Reference Kimura1968b) shows himself at the height of his powers. Kimura used the toolbox of diffusion modelling to analyse the relative forces of mutation and drift. These techniques (borrowed and expanded from their use in physics and chemistry) were well known to the great triumvirate of twentieth century population genetics: Ronald A. Fisher, and J. B. S. Haldane. raised them to a new level both in refinement of technique and as an investigative tool. Kimura (Reference Kimura1968b) first re-establishes the estimation of the effective number of allelesThe effective number of alleles (n e) in a population is the reciprocal of the average homozygosity and is a function of the effective population size and the mutation rate. Thus, n e is the number of equi-frequent alleles in an idealized population that would produce the same level of homozygosity as in an observed population. So as populations become larger, or the mutation rate increases, so does their segregating variation. Alternatively, if the population (more correctly, 4N e) falls much below the reciprocal of the mutation rate, then drift will overwhelm mutation, and most variation will be rare or lost at a locus. This result is for neutral alleles, i. e. alleles with no selection coefficient s, in a model that allows an infinite number of allelic states at a site. Equations for a finite number of possible states are also presented. Kimura then solves for the distribution of allele frequencies, again without selection, but with special consideration to loss and fixation. Because there is continual mutation, a locus is never in a permanent state of monomorphism, so Kimura's diffusion approximation on the boundary states can be seen as the probability that a locus within a population (or a single-locus population within an ensemble) transitions from zero variability at a given locus to some variability (i. e. variant frequency 1/(2N)).

Output: corroborate


Input: Claim: Gene therapy can make humans biologically immortal by halting the aging process. [SEP] Text: School of 2. 0 Journal Issue 1, 2024 Humans 2. 0: Mortal Life, Humans 2. 0: 2. 0, 1, (2024): 12-25Published online: 10 April 2024AbstractThe first ‘Humans 2. 0’ conference was held on the 1st of July 2022 at the University of Melbourne. The conference examined the current ethical dilemmas posed by emerging biomedical and technological innovation. The possible futures for humanity are uncertain, sometimes hopeful, and sometimes disturbing. In this review of Humans 2. 0, I reflect on the struggles of mortality and morality with which individuals and society are confronted as we grapple with life and legacy in the face of these uncertain futures. Keywords: Humans 2. 0, ethics, emerging technology, biomedical innovation, morality. Download PDF Image generated with PlaygroundAI using the 2. 0. Our journal’s first conference examined the current ethical dilemmas posed by emerging biomedical and technological innovation. We sought to begin unravelling the uncertain, sometimes hopeful, and sometimes disturbing futures in store for humanity. For a conference so deeply invested in exploring our path towards the future, it was perplexing that the theme to which we consistently returned throughout the day was the one theme that, without fail, stops the future in its tracks: death. At every turn it seemed that the shadow of our mortality hovered over our discussions, prodding at fear, at hope, at determination, and even at the burgeoning of wisdom. Life and LegacyIndeed, the ephemerality of human life quite literally dwelt ever over the audience. At the back of the theatre, Gary Anderson, Professor in the University of of Biochemistry and Pharmacology, positioned a television screen on which bubbles, sometimes lone and oftentimes mingling, danced in innumerable patterns. Each bubble captured in the film must now have collapsed – for bubbles, according to Anderson, are the ultimate metaphor for ephemerality – yet as we witnessed them upon the screen they lived again and perhaps will never truly die. In those bubbles also lives on a mortal being like ourselves, dancer Merce Cunningham, whose dance is metaphorically immortalised in the digital representations of the microscopic, quantum interactions of the collapsing bubbles. Though, ironically, various other such screens that once showed similar bubbles no longer work and could not be used for our conference. An apt reminder that overcoming mortality – overcoming human nature – is no simple feat.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Although persistent activity has been frequently observed in the prefrontal cortex, this activity has also been observed in many other brain areas and the function and the information represented by this activity are not always the same across different brain areas, because different brain areas participate in different information processing. Roussy et al. dissociated neural processes for visual perception from those of visual working memory based on whether the brain produces mental representations of the visual stimulus when its physical signals are available or not. In fact, neurons in early visual areas exhibit persistent activity representing perceptual signals, while neurons in association areas exhibit the activity representing working memory signals. Persistent activity has also been observed in human brain imaging studies, although not in all frontal regions observed in monkey studies. Curtis and Sprague reviewed these results obtained with fMRI signals, and showed that the content of working memory can be decoded from the pattern of neural activations in several brain areas, suggesting that these approaches find which of these brain areas contribute to working memory and what relevant features they represent. Li et al. showed that persistent activity is observed even in naïve untrained monkeys, indicating that specific local neural circuits supporting persistent activity are innately present in the prefrontal cortex. However, the operation of these circuits is flexibly modulated by the task demand, the experience, and the age and also by the effect of neuromodulators. Systemic muscarinic blockade disrupts working memory performances. Vijayraghavan and Everling reviewed such neuromodulatory effects of acetylcholine on persistent activity in the prefrontal cortex. They showed that muscarinic blockade by local iontophoretic application caused pronounced suppressive effect of persistent activity representing remembered information and that the suppressive effect of persistent activity is dose-dependent and monotonically through muscarinic M1 receptors. The observed heterogeneity of muscarinic actions also outlines unexpected modulatory effects in primate prefrontal cortex when compared with rodent studies. Recurrent neural circuit models have been proposed to explain how sustained representations are generated. Barbosa et al. , Novikov et al. , and Sarazin et al. have used such models of uni—or—multi-area networks to examine features of persistent or dynamic activity. Models are often informed by known biological elements and properties of recurrent circuits reviewed by Li et al. , Curtis and Sprague, Roussy et al. , Sarazin et al.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Kimura then closes the loop on the extended analysis by showing that in the limit of an infinite number of possible allelic states, the original estimate of n e and is recovered. An idealized number of alleles and the average number of alleles are not the same concept. The former (n e) represents the number of equi-frequent alleles in a population that could explain the observed average level of homozygosity (and therefore by extension the average level of heterozygosity or genetic variation). The latter (n a) is simply the reciprocal of the mean frequency of alleles observed in a population – very much a function of variance in allele frequencies: a locus with four alleles, each with a frequency of 0·25, will contribute to genetic variation and harbour the consequences of genetic variance much more than a locus with one allele at 0·97 and three at 0·01. The variables n e and n a capture these two concepts, respectively. Kimura solves for n e as well as n a and partakes in a number of computer simulations to check theory with implementation. This is classic Kimura; he checks his analytical derivations not just for mathematical competency, but also with independent model implementations. This uncovers a slight underestimation of the diffusion theory for both n e and n a, which he attributes to the theory's inability to completely capture the effect of rare alleles (specifically alleles represented only once in the population). The relevance of Kimura's paper in is in interpreting and supporting his even more influential paper: ‘Evolutionary rate at the molecular level’ (Kimura, Reference Kimura1968a). The elegance of the argument for neutrality espoused in Kimura (Reference Kimura1968a) was underwritten by much of the mathematics in Kimura (Reference Kimura1968b). In the latter, he ties the concept of neutral mutations together with early estimates on the prevalence of synonymous mutations and their consequences in terms of high amounts of genetic variance and low load. Kimura further expands the discussion to nearly neutral mutations (), correctly noting that for many mutations their neutrality is not an absolute property of the phenotype, but a relative property of the phenotype marginal on a given effective population size.

Output: corroborate


Input: Claim: Gene therapy can make humans biologically immortal by halting the aging process. [SEP] Text: Encephalink – a hypothetical brain-computer interface to be implanted into a person’s brain to prevent the degeneration of memory, motor, and other neurological functions – was, in our scenario, a yet untrialled, unproven technology, nonetheless offering great hope amidst the hopelessness of a devastating disease like HD. This choice represents a far larger issue facing society as we face the temptation towards rapid results and grapple with the need to ensure safety and true efficacy of emerging treatments. Munsie showed us that, like many vulnerable patients worldwide, Jordan and his parents are at risk of the “commodification of hope” and the exploitation of their desperation for vast profits. Troublingly, frustrations with often impersonal and cautious mainstream medical care and with insufficient patient support from their treatment teams as Munsie described, have only enhanced the allure of the unproven treatment market. Patients and their families are thus further exposed to emotional and financial exploitation in cycles of mainstream neglect, unproven treatment failure, and the false pretence that “the worst that could happen is nothing” (Petersen et al. , 2014), but the best could be healing and a new life. For Jordan, as we found at the Humans 2. 0 conference, with a prognosis of approximately 10-20 years more to live with juvenile-onset HD (Nance, 2007), the burden of mortality only increased this desperation to live and to die well. Amidst this frightening intermingling of dreams and deceptions, Munsie drew attention to the regulatory environments surrounding stem cell therapies and the promising new reforms to the Administration’s (TGA) regulatory authority. Already, the over 70 fraudulent stem cell clinics in Australia has been reduced to approximately 15, and new, informative publications by Australia are aiming to empower patients to make informed choices for their care (Australia, 2022). Yet disinformation and false hope persist. reminded us, such reforms often constitute a response that is “too little, too late” as in the case of Sheila Drysdale, whose tragic death caused by medical negligence and the “quack medicine” (Dillon, 2016) of unproven stem cell treatments occurred in 2013 and only precipitated reforms to the TGA from 2019. By the time of Drysdale’s death, already, reform was much too late.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: used a recurrent neural circuit model with spike timing-dependent synaptic plasticity and showed that this model can learn, memorize, and replay a large-size of continuous dynamical sequences of spiking activity under asynchronous irregular nature at different timescales, which replicates the dual dynamical and persistent aspects of working memory representations observed in the prefrontal cortex. Although persistent activity has been observed in single-neuron studies while monkeys performed delay tasks, such activity is often unstable along the delay period and heterogeneous within and across trials, which raises questions on how it contributes to working memory or to other processes putatively supported by tonic neural processing. In fact, dynamic coding and multiplexing during memory delays have been observed and are proposed to maximize the dimensionality of neural representations (Amengual and Ben Hamed; Cavanagh et al. ; Curtis and Sprague; Sarazin et al. ). Amengual and suggested that heterogeneous features of persistent activity are caused by intrinsic oscillatory dynamics working at multiple timescales and that these features allow to dynamically incorporate multiple sources of information. When subjects perform working memory tasks, an increase of gamma-band activity has been observed and is considered to reflect activation of neural populations representing the content of working memory. Novikov et al. examined functions of gamma-band oscillation on persistent activity by investigating joint effects of gamma-band oscillatory inputs and noise on the dynamics of the neural circuit with a metastable active condition. They showed that gamma-band oscillations are able to preferentially stabilize the active condition of the circuit in which information is retained in working memory, and that the synchronization of gamma oscillators affects the ability of the gamma inputs to stabilize the retention of working memory, indicating an importance of gamma-band oscillation for maintaining information in working memory. Importance of gamma-band oscillation is also shown for maintaining multiple items in working memory simultaneously. Barbosa et al. hypothesized that different features of an object (e. g. , color and position) stored in different cortical areas are bound in memory through synchrony across feature-specific neural populations and tested this hypothesis using a neural network model composed of two one-dimensional attractor networks (one for color and one for position).

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: population genetics of most range expansions is thought to be shaped by the competition between Darwinian selection and random genetic drift at the range margins. Here, we show that the evolutionary dynamics during range expansions is highly sensitive to additional fluctuations induced by environmental heterogeneities. Tracking mutant clones with a tunable fitness effect in bacterial colonies grown on randomly patterned surfaces we found that environmental heterogeneity can dramatically reduce the efficacy of selection. Time-lapse microscopy and computer simulations suggest that this effect arises generically from a local 'pinning’ of the expansion front, whereby stretches of the front are slowed down on a length scale that depends on the structure of the environmental heterogeneity. This pinning focuses the range expansion into a small number of 'lucky’ individuals with access to expansion paths, altering the neutral evolutionary dynamics and increasing the importance of chance relative to selection. eLife digest Throughout evolution, countless populations have expanded their territories by invading new areas. This invasion can happen on the scale of kilometers and millennia – such as when humans migrated out of Africa – or millimeters and months, such as the growth of a population of cells in a solid tumor. During this expansion, mutations can occur that can either increase or decrease fitness in the new territory. If a favorable mutation occurs at the edge of the population, then it has plenty of room to expand. Such a mutation has a high chance of becoming established, and so it can have a very strong impact on the genetic makeup of the population. This increase in evolutionary advantage in individuals at the front is called “gene surfing”. This phenomenon is well known in populations living in “homogeneous” territories, where the new space a population is invading is more or less the same as the one they already occupy – think of the endless flat grasslands of the Siberian steppes. But in reality, many territories are not like that. What happens if the new territory is not completely homogeneous? For instance, if a species’ expansion is impeded by a mountain range with a series of valleys. Gralka and Hallatschek investigated how such changes in landscape could affect phenomena like gene surfing. Experiments using E. coli as a model system and computer simulations showed that a varied environment – such as roughness akin to a mountain range and valleys, but on a bacterial scale – had a strong influence on the fate of mutations arising in a population.

Output: corroborate


Input: Claim: Gene therapy can make humans biologically immortal by halting the aging process. [SEP] Text: The tolls of falsely founded hopes and impotent regulatory mechanisms are unacceptable. For even amidst the turmoil and suffering of disease, moments of goodness persist. Mortality and the loss of all such goodness are bitter prices to pay for the false hope of alleviating the ailments of our mortal bodies. At the hour of death, perhaps the most powerful and painful feeling of all is that of regret; that had we chosen differently the final hour might not have come so soon. …innovation and the possibility of exploitation necessarily go hand in hand…Who are we now? Who will we become? Although death haunts us, we find ourselves preoccupied on most days not by the shade but by the concerns of life; all that we can truly hope to understand as mortals. Relative health and disease states underpin our human 1. 0 experience – whether such physical matters will remain of great import to humans 2. 0 is a matter for speculation and debate – and concerns surrounding disease and abnormality permeate our fears and our priorities as we navigate our ephemeral lives. Though the mature fruits of nascent scientific discoveries may not impact us today, once again we may have hope that the legacies of new research may beget a future where our children may be relieved of many of the disease burdens of today. Amongst such nascent research is the study of a schizophrenia risk gene; a field of study to which Bachelor of Science student recently contributed through experience at the at the University of Melbourne. Presenting on his experience characterising an alternative splice isoform and novel exon of the gene, Newnham speculated on the possibility of genetic amelioration of neuropsychiatric disorders such as schizophrenia as being a step along the pathway to our becoming humans 2. 0. Though the complexity of gene-environment interactions to generate human traits remains prohibitive, once again, the extravagance of scientific coverage in mainstream media is enough that we ought to, at the very least, be concerned that, like stem cell therapy, gene therapy or gene editing may be areas open to future experimentation and exploitation. Indeed, it seems that innovation and the possibility of exploitation necessarily go hand in hand. As progress is made in science so too are surreptitious prospects for emerging technologies revealed: for profit; for political gain; for control.

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Imaging zebrafish neural circuitry from whole brain to synapse Louis C. Leung* Gordon X. Mourrain* Department of Psychiatry and Behavioral Sciences, Center for advances in imaging tools are inspiring zebrafish researchers to tackle ever more ambitious questions in the neurosciences. Behaviorally fundamental conserved neural networks can now be potentially studied using zebrafish from a brain-wide scale to molecular resolution. In this perspective, we offer a roadmap by which a zebrafish researcher can navigate the course from collecting neural activities across the brain associated with a behavior, to unraveling molecular identities and testing the functional relevance of active neurons. In doing so, important insights will be gained as to how neural networks generate behaviors and assimilate changes in synaptic connectivity. of the major goals of neuroscience is to understand how the nervous system, as a dynamic assembly of cells and connections, generates behaviors as a suite of motor outputs. Impressive progress has been made in recent times in understanding how the nervous system develops and functions. However, with the current set of animal models, neuroscience is approaching a problem of how one can simultaneously work and integrate data across the different scales and modalities at which one can interrogate brain function. To understand a neural process across the scales–from molecules, synapses, neurons, networks to whole brain–is a bona fide frontier in the neurosciences today. Advances in functional neuroimaging are allowing us to identify with increasing precision which brain regions are correlated with a particular behavioral output. However, brain-wide visualization, permitted by electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), does not reliably approach the cellular and/or synaptic spatial resolution of brain processing (Thai et al. , 2009; Lenkov et al. , 2012). Conversely, electrophysiological or high-resolution imaging methods to record neural activity are difficult to extend beyond discrete brain regions. To understand the neural basis of behavior, a challenging goal in basic and clinical neuroscience will be to bridge the gap between these distant levels–i. e. , to be able to record and analyze the entire brain with single neuron, if not, single synapse accuracy. Here, we suggest that the recent developments in live whole brain Ca2+ imaging and super resolution array tomography (AT) can, when applied to a suitably compact brain (Figure 1), reveal and correlate whole brain activity maps down to circuit function and changes in the synaptic landscape.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: Whether the environment is favorable for expansion or not in the place where the mutation happens becomes much more important than how the mutation itself affects fitness. So, if a beneficial mutation occurs at a cliff-edge, it is not likely to get far. But if it happens at a population edge by the bacterial equivalent of gently rolling hills, there is a much better chance of the mutation taking hold. The findings suggest that the amount a population can adapt during expansion is limited, and it can even lead to the spread of harmful mutations in a population if they occur in just the right spot. Piecing together these scenarios is important in order to accurately infer the evolutionary history of a species based on mutations present in its genome now. This type of knowledge can also be useful in developing new treatments for cancers, making use of these evolutionary processes to slow or halt a tumor’s expansion. and its competition with deterministic forces plays an integral role in biology, such as in stochastic gene expression, cellular decision making, and cell differentiation (Balázsi et al. , 2011). Stochastic processes are also at the heart of evolutionary dynamics: not only do the mutations entering a population occur at random times in random individuals and at random positions in their genome, but in addition the fate of a mutation and its clonal lineage is largely stochastic and only partly determined by its effect on the individual’s fitness. The random fluctuations in the frequency of a mutant allele due to the stochasticity associated with reproduction are called genetic drift. Genetic drift is particularly strong at the front of range expansions, where only a relatively small number of individuals at the front of the expansion contributes to future growth and thus has any influence on the future genotypic composition of the population. The neutral diversity and adaptation in spatially expanding populations has been studied in computer simulations (Edmonds et al. , 2004; Klopfstein et al. , 2006; Kuhr et al. , 2011; Kuhr and Stark, 2015; Lavrentovich and Nelson, 2014; Otwinowski and Krug, 2014), in the field (Ramachandran et al. , 2005; White et al. , 2013; Louppe et al. , 2017), and in microbial colonies (Hallatschek et al. , 2007; Fusco et al. , 2016; Gralka et al. , 2016b; Korolev et al.

Output: corroborate


Input: Claim: Gene therapy can make humans biologically immortal by halting the aging process. [SEP] Text: As we navigate the frontiers of research and innovation, society must take a special interest in the vulnerable for, ultimately, it is through preying upon their suffering and corrupting their hopes that so-tempted individuals will seek to exert a god-like influence over their kin. Even as responsible, valid science mingled with considered ethics strives towards true help to the vulnerable, there will emerge at every turn those who would feign such virtuous motivation but ultimately merely use the vulnerable as test subjects or sources of income. Yet our discussion of social life after bodily death was coloured by perhaps an even more menacing fact. The frontiers of science are most frightening, not when they pursue clearly immoral paths as in the case of exploitative, profit-driven stem cell clinics, but when we follow these paths blind to, or wilfully ignorant of, the existential dangers that they pose. When, believing whole-heartedly in the notion that science will be our saviour, we pursue innovation to its utmost degree only to leave widows to weep as their artificial sons reject them and, set loose a fundamentally inhuman force unfettered by the one force that truly controls humanity: our mortality. For though qualities of innovation, creativity, hope, and determination also underpin the human condition, our mortality too, as one astute person in the audience observed, has ever been at the very heart of our nature. We are, by our nature, limited: limited by want of knowledge and by sheer lack of time. The creation of a being like “Jordan 2. 0” – the AI rendition of Jordan that might extend eternally beyond the death of “Jordan 1. 0” – removes this fundamental limitation. Without this common experience, could Jordan 2. 0 ever hope to identify with mortal beings? Without the limitations of time and physicality, the breadth and depth of knowledge that Jordan 2. 0 could hope to attain is just as unconstrained as his span of years. Why should he abide by our limited governance? Why should we hope to retain our autonomy without first and fundamentally constraining his? The emergence of such advanced AI technologies may yet open the floodgates of the singularity hypothesis such that super intelligent AI with vastly different values, goals, and conceptions of the world, will reshape that world with little heed for human concerns (Yampolskiy & Fox, 2012).

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Already an established vertebrate model for developmental biology, the zebrafish’s genetic toolbox and unique physical characteristics can now be exploited for the neurosciences. 1 1. Comparison of brain sizes of common vertebrate neuroscience models. (A) Schematic diagram of the lateral view of adult human, mouse, and zebrafish brains to scale. (B, C) Schematic diagram of the linear organization of major brain regions from olfactory bulb to spinal cord (B) and the dorsal location of telencephalic structures such as the presumptive hippocampus and amygdala (C; adapted from Mueller et al. , 2011). OB, olfactory bulb; Tel, Telencephalon; Di, Diencephalon; Mes, Mesencephalon; Rh, Rhombencephalon; sc, Spinal cord; Ctx, Neocortex; Hip, Hippocampus, pirCtx, Piriform cortex; BLA, and lot, lateral olfactory tract. can be a Model from Circuit to As with other animal models, the zebrafish will never fully recapitulate the complex psyche and behaviors of humans. However, the fundamental computational units of brain processing are likely to be conserved and are thus well-studied outside the human brain in model organisms (Sengupta and Samuel, 2009; Bellen et al. , 2010; Friedrich et al. , 2010; Rinkwitz et al. , 2011; Wang et al. , 2011). The most common mammalian model used in neuroscience is the mouse, which offers a great variety of complex behaviors, powerful genetics and excellent ex vivo brain slice electrophysiological techniques (Kullander, 2005; and Raber, 2005; Ward et al. , 2011; Kim et al. , 2013). However, attempting whole brain modeling with a mouse is a formidable challenge despite being three orders of magnitude smaller than an adult human brain, which has an estimated 1011 neurons each making around 104 connections (Figure 1). At this time, a genetic model with fewer neurons and a smaller, more accessible brain would be a more feasible option. Zebrafish, sharing conserved neurochemistry and broad brain organization with their mammalian counterparts, may help to bridge this gap and give the first insights of circuit dynamics from whole brain down to molecular changes during conserved behaviors.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: , 2011), which can serve as a useful model system because short generation times and ease of handling allow for quantitative investigations of the evolutionary dynamics of range expansions. In microbial colonies, nutrient gradients and mechanical effects limit the number of proliferating individuals to a small region close to the colony perimeter called the growth layer (Grant et al. , 2014; Gralka et al. , 2016b; Warren et al. , 2019). For mutations occurring inside the growth layer, most mutant offspring are concentrated in a relatively small number of enormously successful lineages that manage to remain at the front and 'surf’ on the expanding population wave (Excoffier and Ray, 2008). As a consequence, the evolutionary dynamics is different in microbial colonies compared with well-mixed populations. For instance, the clones (that is the collection of the initial mutant’s offspring) of spontaneous neutral mutations often reach much larger sizes (Fusco et al. , 2016), and existing beneficial variants can sweep to high frequency much faster in microbial colonies than in well-mixed populations (Gralka et al. , 2016b). Conversely, deleterious mutations are predicted to remain at the population frontier for extended periods because genetic drift is strong at the front, which prevents selection from efficiently weeding out deleterious alleles (Travis et al. , 2007; Burton and Travis, 2008; Lavrentovich et al. , 2016; Peischl et al. , 2013; Gralka et al. , 2016a). The quantitative outcome of the competition of selection and genetic drift in microbial colonies is determined by the local shape and roughness of the front (Gralka et al. , 2016b; Farrell et al. , 2017), which in turn is determined by microscopic details, such as cell-cell adhesion or cell morphology shaping the mechanical interactions between cells (Kayser et al. , 2018b; Kayser et al. , 2018a; Giometto et al. , 2018), although the direct mapping is typically unknown (Farrell et al. , 2017). The evolutionary effects of fluctuations at expanding microbial population fronts have been studied in depth, but these studies have focused only on fluctuations associated with the growth, division, and random motion of cells, whose strength may depend on intrinsic properties of the microbial species, in homogeneous environments.

Output: corroborate


Input: Claim: Gene therapy can make humans biologically immortal by halting the aging process. [SEP] Text: is a canopy term that has been used to describe the biological aging and progressive dysfunction of systemic immunity. This age-related diminution of the immune system is characterized by poor vaccine efficacy, lowered immune vigilance, and greater morbidity and mortality as a result of infectious disease (18,32). During the aging process, naïve antigen virgin T cells, which are vital for mounting immune responses to novel pathogens, are gradually replaced with expanded clones of effector and effector-memory T cells that have a late-stage differentiation phenotype and limited antigenic specificity. This "overcrowding" of the so-called immune space causes the naïve T-cell repertoire to shrink, increasing host infection risk. It is now apparent that individuals carrying latent herpesvirus infections show distinct changes within the T-cell compartment that are independent of chronological age but indicative of biological age and immunosenescence (11). Persistent reactivating herpesviruses that are prevalent among humans include herpes simplex virus (HSV-1, HSV-2), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and cytomegalovirus (CMV). Many of these viruses cause conspicuous infectious symptoms to manifest upon primary infection and also on subsequent reactivations of the virus. For instance, primary EBV infection causes infectious mononucleosis (glandular fever), whereas VZV causes chickenpox upon primary infection and shingles when reactivated in later life. Other reactivating herpesviruses such as HSV-1 and HSV-2 can cause blisters (i. e. , cold sores) to appear on mucous membranes of the labialis and genitalia. Ironically, it is persistent infection with the clinically asymptomatic and supposedly "harmless" CMV infection that is believed to have the most deleterious effects on T-cell immunity and associated immunosenescence (11,18). Indeed, CMV seropositivity is the main latent herpesvirus to be included in the immune risk profile (IRP) - an array of immune biomarkers that have been used to predict mortality in very old humans (18). Furthermore, the numbers of CMV-specific cytotoxic T cells in blood are inversely associated with survival in the elderly (18), which bolsters the intuition that persistent CMV infection is the driving force behind immunosenescence (11).

Output: contrast


Input: Claim: Certain neural circuits in the brain are dedicated to processing social cues. [SEP] Text: Five key advantages of studying the zebrafish brain are its (i) compact size, (ii) conservation of the neuropeptide pool (in contrast to invertebrates), (iii) linear organization of brain regions, (iv) structural accessibility of internal nuclei (no overlaying neocortex), and (v) optical clarity (Akanji et al. , 1990; Charonis et al. , 1990; Appelbaum et al. , 2009; Berman et al. , 2009; Friedrich et al. , 2010; Engert and Wilson, 2012). Particularly with respect to imaging dynamic processes, the zebrafish model uniquely excels as its brain is translucent and small enough that the entire volume can be captured at single cell resolution by standard microscopy magnifications. Even at 6 days old, this represents a formidable 100,000 neurons (Naumann et al. , 2010), but the linear organization of the major brain regions from olfactory bulbs to spinal cord tip further facilitates brain-wide imaging (Figure 1B). In addition, while the amygdala, hippocampus and habenula are difficult regions to scan in mammals due to their deep location beneath the neocortex, their position is inverted in zebrafish. While the anterior neural tube of mammals undergoes invagination during development, leading to their deep location beneath the neocortex, the eversion process in the development offish telencephalic makes these behaviorally important structures the most dorsal nuclei of the telencephalon (Figure 1C; Northcutt, 2008; Mueller et al. , 2011). Further, the ease of transgenesis, pharmacological studies, and conservation of behaviors (fear, anxiety, learning and memory, feeding/preying, social and sexual behavior, sleep and diurnality, etc. ), altogether makes zebrafish a powerful complement to other models used to study neural processing fundamentals likely to be conserved in humans. As we set out a roadmap below (Figure 2), we contend approaches using zebrafish could yield insights to coordinated brain activity and function that underpin the normal healthy brain and what goes awry in pathological contexts. 2 2. Roadmap of the steps a zebrafish neuroscience researcher can take to integrate the various levels of analysis within the same model organism. GECI, Genetically encoded calcium indicator; AT, Array Tomography; tol2, Tol2 transposase; -specific GCaMP sensor.

Output: pass


Input: Claim: Genetic mutations can be beneficial, neutral, or harmful depending on the context. [SEP] Text: By growing colonies on solid substrates with a weakly patterned surface with random microscopic features much bigger than individual cells, but much smaller than the whole colony, we find that environmental heterogeneity can overpower selection such that even strongly beneficial mutations are unable to establish at rates higher than expected for neutral mutations. Using a minimal computer model of populations expanding in randomly disordered environments, we show that dramatic changes in the efficacy of selection can arise from a local 'pinning’ of the expansion front, whereby stretches of the front are slowed down on a length scale that depends on the structure of the environmental heterogeneity. This pinning focuses the range expansion into a small number of individuals with access to expansion paths, increasing the importance of chance and thus limiting the efficacy of selection. We expect these results to generalize to other spatially growing populations, such as biofilms, tumors, and invasive species, when the growing population front is transiently hindered by the local environment. We grew colonies from single cells of a strain of E. coli MG1655 carrying a plasmid that is costly to produce, resulting in a 20% growth rate disadvantage s in plasmid-bearing cells compared to their plasmid-less (but otherwise isogenic) conspecifics (Figure 1). This strain loses the plasmid stochastically at a rate of about 5×10-3 per cell division (approximately independent of antibiotic concentration, see Figure 1—figure supplement 1). The plasmid codes for a fluorescence gene and confers resistance to the antibiotic doxycycline (dox, a tetracycline analog) such that when grown at increasing antibiotic concentrations, cells missing the plasmid grow more and more slowly, until they eventually grow more slowly than cells harboring the plasmid (for [dox]>0. 3μg/ml), despite the inherent cost associated with bearing the plasmid. This allowed us to treat plasmid loss effectively as a spontaneous mutation whose fitness effect s, that is the relative growth rate difference between the plasmid-bearing ('wild type’) and non-bearing ('mutant’) cells, we can finely tune from +20% to -15% by varying the amount of doxycycline in the growth media (see Figure 2—figure supplement 1), thus making the mutation either beneficial, neutral or deleterious.

Output: corroborate