Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: We calibrated the setup by aligning the position of the stylus with the location of five projected dots. This calibration allowed us to accurately display a cursor that represented the location of the stylus above the graphic tablet. The projected background was black (depicted as gray in Fig 1A). The feedback had a systematic delay of approximately 40 ms with relation to the hand movement. This value was determined before the start of the study with an interception task (similar to the one described below), in which we compared the stylus position and the target location on trials in which participants indicated they had hit the target. The system delay will have been corrected for in all of the future display and analysis of the data. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 1. Set-up and procedure. A. Set-up of the task: The task image was projected onto a screen that was visible for the subject through a mirror. Recorded movements with a stylus were made on a graphic tablet. The hand and hand-held stylus were blocked from view by the mirror. B. Task procedure: (1) A white dot at the bottom of the screen (diameter = 6 mm) indicated the start location. A red cursor represented the movements made by the stylus (diameter = 6 mm). The trial initiated when the participant moved the cursor to the start location. The goal of the task was to intercept a ball (diameter = 10 mm) moving from left to right or vice versa with a straight ballistic movement. (2) During the adaptation phase there was a temporal perturbation (delay) of 100 ms between the hand and cursor. (3) (TE) was defined as the temporal lead or lag of the stylus (hand) crossing the target’s trajectory line in relation to the target. A lead was denoted by a positive TE, and a lag with a negative TE. (4) In the area within the dashed lines, vision of the cursor was obstructed from view. 1 shows the setup and the procedure for the experiment. The goal of the task was to intercept a target (white dot) on the screen with the cursor (red dot), that followed the movement of the hand. In order to start a trial, the participant had to move the cursor to the starting position (Fig 1B-1). A high-pitched sound marked the start of the trial.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Due to their unpaired electron, free radicals are very reactive species and their overproduction can cause damage to all biological macromolecules (DNA, proteins, lipids), resulting in cell alteration. Polyphenols can also act as antioxidants through their capacity to chelate metal ions such as iron. Some of them have antioxidant activity stronger than the reference water soluble vitamin E analogue Trolox, (Fauconneau et al. , 1997). There are increasing evidences that polyphenols may protect cell constituents against oxidative damage and limit various disease associated with oxidative stress. Number of in vitro and in vivo studies have demonstrated that polyphenols intake limits the incidence of coronary heart diseases, in particular atherosclerosis in which low density lipoprotein (LDL) oxidation play a key mechanism in the development of this pathology. Likewise, studies provide evidence for a protective role of a diet rich in polyphenols against chronic diseases including cancers (Anantharaju et al. , 2016) and diabetes (Jung et al. , 2007). In more recent works, polyphenols may provide protection in neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) (Figure 1). Figure 1: Classification of representative natural polyphenols reported in this 42. Moreover, these polyphenols dose-dependently destabilized preformed fAβs, with overall activity of the molecules examined in the order of: myricetin = morin = quercetin > kaempferol > (+)-catechin = (–)-epicatechin. The same authors demonstrated similar effects for tannic acid on the formation, extension and destabilization of fAβ (Ono et al. , 2004). Rivière et al. (2007) examined the effects of stilbenes on Aβ25–35 fibril formation, using UV-visible measurements and electron microscopy. The inhibitory properties of resveratrol, piceid, resveratrol diglucoside, piceatannol, astringin and viniferin were characterized and compared. Resveratrol and piceid were shown to be the most efficient to inhibit Aβ polymerization (Rivière et al. , 2007).

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: We believe that the lipid distribution experiments as suggested by the reviewer will be of critical importance in our next manuscript but is beyond the scope of this manuscript, specifically highlighting the unified importance of ether lipid machinery in both metformin and phenformin-mediated lifespan extension. 5. One naturally wonders whether the over-expression of enzymes ads-1 and/or acl-7 would also be bioactive. I do not think these are essential studies to add, but if the authors have the information they should add it to the paper. We thank the reviewer for this insightful suggestion. We are currently working on developing these genetic reagents for future studies that will finely delineate the specific nodes during ether lipid biosynthesis that may confer pro-longevity and healthspan benefits in the nematode. 6. Figure 1-B-D; E-G seems to share the same WT control for all presented data, authors should indicate that all tests run in the same control experiment if this is the case, and should confirm in methods that same-day WT controls are run in the same experimental test of each study. We apologize for the oversight in clearly highlighting that the lifespan analyses shown in Figure 1B-D;E-G are representative of results from 1 replicate run in the same batch with same-day wildtype controls. We amend in the figure legends for Figure 1 and Materials and methods sections that this is the case (lines 179 to 180) and note that additional replicates with independent wild type controls and all appropriate statistics for comparisons are included as Supplementary file 1. 7. ads-1 and acl-7 mutants exhibit modest increases in longevity with metformin treatment; acl-7 + phen might be different at end stages. Authors do comment that the response is blunted but some note that not all impact of the drug is eliminated should be added. We thank the reviewer for their careful interpretation of our lifespan analyses. We have amended the text in lines 153 to 155 to note that ads-1 and acl-7 mutants may display a modest increase in lifespan with metformin administration, but with a percentage median lifespan increase significantly reduced in comparison to wildtype controls (Supplementary file 1). We also note that although these mutations result in a loss of function of the protein, they are missense mutations, and thus a small amount of residual ether lipid biosynthetic capacity cannot be completely ruled out (see the following comment in the response to point 8 below).

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Randomly across trials, the target would move from left to right or vice versa at one of 3 different speeds (17. 5, 22. 5 or 27. 5 cm/s). The three different speeds were used to prevent participants from learning were to intercept at what time, without taking the movement of the target into account. The target path was +20 cm in the y-direction from the starting position. Participants were instructed to intercept the target with a smooth straight movement, and to end their movement well beyond the target’s trajectory line. There were no points rewarded, only when the center of the cursor hit the target, an acoustic signal would sound. After the explanation of the task and a familiarization phase of 10 trials, the experiment started. The experiment consisted of a baseline phase followed by an adaptation phase. During the baseline phase of 80 trials, no additional delays were added to the system. During the adaptation phase, the cursor movement was delayed with an additional 100 ms compared to the hand movement (Fig 1B-2). As participants could not see their own hand, they were unaware of these additional delays. This was verified by verbal confirmation at the end of the experiment. To discourage online corrections we blocked the cursor’s path from view between 0. 5 and 16 cm (see Fig 1B-4) along the y-axis from the starting location. During the baseline this led to an average of 126 ms (95% bootstrapped CI [124-128 ms]) visibility of the cursor before it would reach the trajectory line. As a result, participants could see the cursor cross the target’s trajectory line, but online corrections were minimized. Analysis of responses The data was prepared for analysis with the aid of the R-program [41]. In order to account for any deficient recordings and missing data, the raw position data for the hand and cursor in the x and y direction were interpolated by steps of 0. 008 s and filtered with a bidirectional Butterworth filter (cut-off = 6Hz, sampling rate = 125 Hz). The velocity and acceleration of the hand were computed by calculating the first and second order derivatives of the filtered position data with respect to time. The derivatives were calculated for each time point by dividing the change in position by the change in time over the past two time points (average Δt = 0. 016s).

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: The ability of multiple polyphenolic glycosides and their esterified derivative to interact with metal ions and metal-free/-associated Aβ, and further control both metal-free and metal-induced Aβ aggregation was investigated through western blot assay, transmission electron microscopy, ultraviolet (UV)-visible spectroscopy, fluorescence spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy by Korshavn et al. (2015) The cytotoxicity of the compounds and their ability to mitigate the toxicity induced by both metal-free and metal-bound Aβ were also examined. Thus, verbascoside, natural product present in olive tree and its esterified derivative was shown to regulate the aggregation and cytotoxicity of metal-free and/or metal-associated Aβ to different extents (Korshavn et al. , 2015). A recent study demonstrated that trans ε-viniferin disaggregated Aβ1–42 with better efficiency than resveratrol (Vion et al. , 2017). These effects can be partially explained by interaction of polyphenols with amyloid peptide. Thus, a non-covalent complex between ε-viniferin glucoside and Aβ was observed by electrospray ionization mass spectrometry (Richard et al. , 2011). Moreover, in a recent review, rosmarinic acid was described to also directly interact with Aβ1–42 (Taguchi et al. , 2017). These molecules interfere with β-sheet to exert their activity (Francioso et al. , 2015). But polyphenols effects on metal ions contribute also to their properties. An assay using 2-(5-Bromo-2-pyridylazo)-5-[N-propyl-N-(3-sulfopropyl)amino]phenol disodium salt dihydrate (5-Br-PAPS) allowing the examination of Zn(II) and Cu(II) complexation showed that gallic acid, EGCG, and curcumin are multifunctional agents (Chan et al. , 2016). Many in vivo studies demonstrated in different AD models that polyphenols inhibited amyloid deposits in brain mice.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: The authors show that expression of ether lipid biosynthesis genes does not increase with biguanide treatment (Figure 2 —figure supplement 2; Results lines 305 – 313), and FARD-1::RFP levels decrease with phenformin treatment (Figure 2 —figure supplement 2M) and suggest that "post-translational negative feedback of ether lipids on the ether lipid biosynthetic pathway, as has been previously reported" (Results lines 311 – 313)--a citation for these results should be added. We apologize for this oversight and have included the citation for Honsho, et al. 2010 in lines 312 and 6481. 12. These data argue against phenformin and fard-1 overexpression triggering downstream pathways in the same way. Although fard-1 oe increases lifespan in a manner that is not additive with phenformin treatment (Figure 5 A and B), fard-1 overexpression evidently does not trigger the same negative feedback mechanism, as overexpressed FARD-1 levels shown in Figure 2 —figure supplement 2 M appear to be high in vehicle controls, and are lowered with phenformin treatment. If both fard-1 overexpression and phenformin treatment signal similarly to trigger a post-translational negative feedback mechanism (which would presumably be important for lifespan extension), one would expect similar FARD-1 levels in fard-1 oe animals with and without phenformin treatment. It is possible that fard-1 overexpression simply overwhelms – or is insufficient to trigger – negative feedback mechanisms. Data showing overexpressed fard-1 mRNA and FARD-1 protein levels vs. endogenously expressed fard-1 and FARD-1, with and without biguanide treatment, would help clarify these seemingly paradoxical results. We thank the reviewer for this important suggestion, and we have performed the experiment as suggested. We include in Figure 5G-H qRT-PCR analysis of wild type and fard-1(oe3) animals treated with phenformin, evaluating the RNA expression levels of endogenous fard-1 (using qRT-PCR primers probing for the native 3’ UTR of fard-1, Figure 5D).

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Of the 20 participants, one was excluded from the study due to recording issues with the graphic tablet. For the remaining 19 participants (3040 trials), we inspected the movement speed during the movement before the target’s trajectory line was reached. As we had instructed participants to move through the target’s trajectory line, we discarded trials in which subjects moved through it with very low speeds (v < 20 cm/s). Two other participants were removed from the study because the systematically failed to comply with these instructions of the task (in >25% of their trials). For the 17 included participants we removed the trials in which this was the case (2. 1% of the remaining trials discarded). We calculated the Error (TE) on each trial. TE was defined as the temporal difference between the hand and the target reaching the same point on the target’s trajectory line (Fig 1B-3). The TE was baseline-corrected by subtracting the average TE of the last 30 baseline trials for each participant in order to make sure any biases within subjects were removed. Positive values denoted the hand leading the target and negative values denoted the hand lagging behind the target. In order to hit the target when a temporal perturbation was applied, subjects would have to start leading the target with their hand. The TE was used to calculate the for each participant. Score was calculated by fitting a two-state line through the TE data points of the adaptation phase (see Fig 2), with intercept 0. The slope (a) and asymptote (b) that resulted in a minimum residuals were each first normalized across subjects and then summed. Score gave us the ability to reward both speed and final level of adaptation. High values of the score meant that participants were relatively fast and had more complete levels of adaptation. Low values meant that participants adapted slowly and incomplete. Although we had the possibility to analyze slope and asymptote separately (to see if speed or final level of adaptation was affected differently) we only had a few participants with higher slopes, which made this analysis more difficult (see Table 1). We therefore decided only to focus on the Adaptation Score. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 2. Adaptation score examples. The dots represent the moving averages (window = 4 trials) of two example participants.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Thus, it was shown that curcumin, injected peripherally into aged APPsweTg2576 mice crossed the blood brain barrier (BBB) and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively (Yang et al. , 2005). Another study, using in vivo multiphoton microscopy, demonstrated that curcumin crossed the BBB and labeled senile plaques and cerebrovascular amyloid angiopathy in another model of AD, APP(Swe)/PS1dE9 mice. Moreover, systemic treatment on these mice with curcumin for 7 days cleared and reduced existing plaques (Garcia-Alloza et al. , 2007). When these same mice were fed during 6 months, between 3 and 9 months of age, with polyphenol-rich grape seed extract, containing gallic acid, catechin, epicatechin and proanthocyanidins or with curcumin, a decrease of Aβ deposition was observed (Wang et al. , 2009). In the same way, when APPsweTg2576 were fed with myricetin, nordihydroguaiaretic acid (NDGA) or rosmarinic acid for 10 months from the age of 5 months, amyloid plaques in mice brains were significantly decreased (Hamaguchi et al. , 2009). Resveratrol administrated by food at AD Tg19959 mice during 45 days also diminished plaque formation in a region specific manner, in medial cortex, striatum and hypothalamus (Karuppagounder et al. , 2009). Polyphenols and tau Some polyphenols were also shown to inhibit phosphorylation and aggregation of tau. For example, EGCG was described to bind tau in this phosphorylation site with high affinity and to modify tridimensional structure of tau, leading to inhibition of its aggregation (Gueroux et al. , 2017). A recent study showed that, by direct interaction with tau, rosmarinic acid prevented β-sheet assembly (Cornejo et al. , 2017). Grape seed-derived polyphenol extract seems to potentially interfere with the assembly of tau peptides into neurotoxic aggregates (Wang et al. , 2010).

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: These results indicate that FARD-1 overexpression indeed reduces native fard-1 expression by ~40%, and that biguanide treatment does not additively reduce fard-1 expression even further. Interestingly, biguanide treatment appears to reduce the expression of exogenously overexpressed fard-1 by about ~60%, consistent with the reduction in RFP-tagged protein levels shown in Figure 2 —figure supplement 2M. We speculate that the discrepancy in feedback mechanisms between the endogenous and exogenous fard-1 transcripts is likely due to the design of the overexpressor, as the fard-1(oe) strains in this manuscript all utilize a synthetic unc-54 3’ UTR to enhance permissive expression in all C. elegans somatic cells, and likely maintain expression as a multicopy integrant in the genome, thus overwhelming negative feedback mechanisms. Indeed, several studies have suggested that the 3’ UTR structure of several mRNAs mediate negative feedback loops to finely tune protein expression patterns12,13. Combined, these results suggest that FARD-1 overexpression and biguanide treatment regulate endogenous fard-1 levels through similar mechanisms, but the differential UTR utilization and potential for multicopy integration may explain their distinct lifespan promoting dependencies. We discuss the significance of these results in lines 650 through 655. 13. Figure 3D (D-H) RNAi of three fatty acid desaturases (D-F) two fatty acid elongases (G and H) …blunt phenformin-mediated lifespan extension in wild type worms. fat-1 RNAi extends lifespan, phen treatment brings this close to wt +phen, and there is no significant difference wt+phen vs. fat-1(RNAi) + phen; it might be technically reasonable to indicate the response is blunted (percent increase) but fat-1 does not appear to be all that impactful on longevity. These data do not impress regarding the importance of fat-1 in phenformin outcome; the discussion should be toned down or eliminated. We thank the reviewer for their careful interpretation of the lifespan results for fat-1 RNAi. We agree that there does not appear to be a meaningful or interpretable interaction between fat-1 and biguanide action in longevity, and so we have removed the fat-1 data and reference to it from this version of the text.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: In order to calculate the Adaptation Score, the slope (a) and asymptote (b) were normalized across subjects and then summed for each participant. For P1 we were able to fit an exponential function, while for P2 the adaptation an exponential could not be fit. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageTable 1. Pre-normalized slopes (a) and Asympotes (b) and adaptation scores for all the subjects. is often quantified by fitting the exponential function (exp(−τ ⋅ trial)) and calculating the time constant τ of this function. However, our pilot data showed we could not fit this function for each participant, as some participants adapted in a non-exponential way. There were 11 participants for which we were able to calculate the exponential function. In order to verify our method of quantifying adaptation, we compared τ of this exponential to our and confirmed our main finding (see below) using τ instead of the Adaptation Score. Movement onset was calculated according to algorithm A as proposed by [42] on the tangential velocity of the hand (tolerance range = 10%). The average movement speed (Mv) between the time of movement onset and the crossing of the target’s trajectory line was calculated. We also calculated the absolute movement angle (Ma) from the y-axis, calculated between movement onset and movement onset + 200 ms. In order to identify the relationship between different kinematic variables and Error, we analyzed the relationship between Mv, Ma, movement time (T), absolute target velocity (tv), (σMv)2- group (LOW = 0; HIGH = 1) and their interactions on TE. We did this with a for both the baseline and adaptation phase (lambda = 0. 6). can be used with multicollinear variables. We calculated bootstrapped confidence intervals (95%). LASSO regression includes a penalization. Confidence intervals can therefore only provide information about the variability regarding β for each predictor, but they should be interpreted with caution when it comes to the significance of the predictors. Additionally, we performed another analysis with this technique in order to verify the respective contributions of movement speed variability ((σMv)2) and movement angle ((σMa)2) and their interaction on the Adaptation Score.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Same authors showed that oral administration of this extract significantly decreased the development of AD type tau neuropathology in the brain of Thy-1 mutated human tau (TMHT) mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain (Wang et al. , 2010). Moreover, polyphenols induce disaggregation of aggregated tau (Duff et al. , 2010) and modify ultrastructure of paired helical filaments isolated from AD brains, decreasing enlargement of filaments (Ksiezak-Reding et al. , 2012). Both daily intraperitoneal injections between 12 and 14 months and oral treatment between 8 and 14 months by green tea EGCG induced decrease of insoluble hyperphosphorylated tau in brain of APPswe Tg2576 mice (Rezai-Zadeh et al. , 2005, 2008). Moreover, a systemic treatment with curcumin during 7 days, partially restored distorted neurites in APP(Swe)/PS1dE9 mice (Garcia-Alloza et al. , 2007). Polyphenols and PD Polyphenols and α-syn In vitro, α-syn has been shown to form amyloid fibrils and these fibrils have been detected in patient with PD in the form of plaques in the brain. However, autopsies have shown that there is no correlation between the amount of fibrils and the severity of PD (Goldberg and Lansbury, 2000). A prominent hypothesis is that the soluble β-oligomers which are formed prior to the formation of mature fibrils are the cause of cytotoxicity, probably by membrane pore formation (Sivanesam and Andersen, 2016). Therefore, the prevention of protein aggregation and oligomerization is an attractive strategy in combating the neurodegeneration because it acts on the very beginning of the proposed cellular pathway leading to cell death. In order to modulate amyloidogenesis pathways, common strategies are (i) to prevent α-syn from forming toxic oligomers, (ii) to increase the amyloidogenesis so that α-syn spends very little time in the presumably toxic oligomers state, and (iii) to direct α-syn to form off-pathway non¬toxic aggregates (Sivanesam and Andersen, 2016).

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Compellingly, metabolically inactivating the bacterial food source does not impair the ability of the ether lipid machinery to abrogate biguanide-mediated lifespan extension (Figure 2 —figure supplement 4). Additionally, our previously published study interrogating the role of CeACAD10 in regulation of metformin action in growth and cancer highlights that UV-mediated inactivation of OP50-1 growth does not affect metformin-mediated growth inhibition, and that direct injection of metformin into the animal is sufficient to drive CeACAD10 biguanide response activation14. Combined, these data rigorously exclude the possibility that biguanides alter ether lipid levels or the activity of the machinery via indirect effects through bacterial metabolism. We include a new section in Results to highlight this important statement (lines 509 to 547) and include a brief description of these results in the Discussion (lines 577 to 580). 21. Finally, as the authors point out, identification of the specific lipids necessary for promoting healthy aging is not feasible here; with which I totally agree. The actual mechanism by which ether lipid synthesizing enzymes modulate extended survival for the isp-1, eat-2, and raga-1 backgrounds or +phenformin is not really defined by this work. Still, the highlight of a critical biosynthetic pathway in biguanide outcomes and the implication of SKN-1/NRF2 in the biology is of sufficient importance in the field to merit high-profile publication. We again thank the reviewer for their support of our work and for their excellent feedback, which greatly strengthened the mechanistic underpinnings of our work. Reviewer #2 (Recommendations for the authors): Key points to address: 1. Address the impact of biguanides on bacterial growth (OP50, HT115) experimentally e. g. bacterial growth, the impact of heat-killed bacteria on key biguanide phenotypes, and their relationship to ether lipids. The impact of biguanide concentration should also be considered in this regard. We thank the reviewer for this important suggestion, and we have performed the experiment as suggested. As indicated in 3 and 22, we have performedMS of adult day 1 nematodes treated with or without phenformin and grown on live or metabolically dead OP50-1 E. coli food sources using a rigorously established 1% PFA treatment protocol 3.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: As expected with regards to our hypothesis, we found the only included predictor of the to be the (σMv)2 (see Results). The remainder of our analysis was therefore focused on the role of Mv on Adaptation. The correlation between Mv variability across baseline trials ((σMv)2) and the was calculated using the rcorr- function from the Hmisc-package [43]. We used Spearman, in addition to Pearson, because Spearman (based on ranks) captures monotonic relation better than Pearson (which requires linear relations). We also calculated this relationship for τ calculated for the 11 participants that showed exponential adaptation curves. We examined if the predictive capacity of (σMv)2 was due to the sequential effects of the TE on Mv by dividing the participants in a LOW (n = 9) and HIGH (n = 8) (σMv)2 group based on the size of their movement speed variability. In order to verify if there were group differences in variances for Mv and TE, we did F-tests on the results from the baseline phase (var. test-function for R). As we suspected that the benefit of (σMv)2 came from error correction rather than exploration, we expected sequential effects of TEt on Mvt+1. The sequential effects can show us if the error on one trial had an effect on the movement speed of consecutive trials. We verified this idea in two different ways: First, we fit a linear mixed model (lmer-function of the lme4-package [44] that examined the slopes of the HIGH and LOW (σMv)2 group, with subject as a nested random effect. We found significant effect for the HIGH (σMv)2 group, indicating that movement speed was used to account for previous encountered errors. In order to examine this effect in more detail, we calculated the cross correlation (ccf-function for R) between the TE and Mv for lag 0 through 3 for each subject individually to capture the corrective pattern. This way we could examine the effects of the movement speed on the error (lag 0) and the effect of the error on the movement speed over the next 3 trials (lag 1-3).

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Effects of natural polyphenols on α-syn aggregation/disaggregation are studied and described (Figure 2B and 1). Using fluorescence spectroscopy with thioflavin S and electron microscopy, Ono and Yamada (2006) examined the effects of 13 antioxidants on the formation and destabilization of preformed α-syn fibrils. Their anti fibrillogenic and fibril-destabilizing activity was in the order: tannic acid = nordihydroguaiaretic acid = curcumin = rosmarinic acid = myricetin > kaempferol = ferulic acid > catechin = epi-catechin. Thus, they concluded that these antioxidants could prevent the development of α-synucleinopathies, not only through scavenging reactive oxygen species, but also through directly inhibiting the deposition of fibrils in the brain. Masuda et al. (2006) tested 39 polyphenols and 14 from them are strong inhibitors of α-syn filament assembly. Baicalein, delphinidin, gallocatechin gallate, and rosmarinic acid seem to be of particular interest for their properties to inhibit α-syn filament formation. They formed soluble, non cytotoxic (on human neurons SH-SY5Y cells), oligomeric α-syn, probably by binding to the C-terminal region, suggesting that this may be the mechanism by which filament formation is inhibited. 48 different flavonoids belonging to several classes were tested by Meng et al. (2010) for their ability to inhibit the aggregation of α-syn by stabilizing non-pathogenic protein conformation. Majority of the flavonoids inhibit α-syn polymerization either delaying or completely abolishing fibril formation and disaggregate the preformed fibrils into monomer and non¬pathogenic oligomers. Molecule such as baicalein tightly bind to the protein and greatly stabilize its native unfold conformation. The mechanism of the strong inhibition is mostly due to the formation of Schiff base (Meng et al. , 2009). Hong et al. (2008) specified that baicalein-stabilized oligomers are β-sheet-enriched according to analysis. They did not form fibrils even after very prolonged incubation. Oligomers were extremely stable.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: This PFA treatment protocol, as opposed to heat or UV killing protocols, both completely kill and metabolically inactivate the food source (Figure 6 —figure supplement 2A), making this a more reliable, uniformly consistent strategy to eliminate bacterial growth and metabolism as confounding variables in lipidomic and lifespan analyses 3. These analyses rigorously show that biguanides increase relative nematode ether lipid levels independent of any indirect effects on bacterial growth, proliferation, or metabolism (Figure 6 —figure supplement 2D-G). Compellingly, metabolic inactivation of the bacterial food source neither impairs the lifespan extending effects of biguanides nor impairs the ability of the ether lipid machinery to abrogate biguanide-mediated lifespan extension (Figure 6 —figure supplement 3A-F). Combined, these data rigorously exclude the possibility that biguanides alter ether lipid levels or the activity of the machinery via indirect effects through bacterial growth or metabolism. We performed experiments utilizing a final dosage of 4. 5 mM phenformin and 50 mM metformin, both of which are minimally required to robustly and reproducibly extend C. elegans lifespan, as corroborated and utilized by several independent laboratories7-10. Thus, these data strengthen the conclusion that phenformin and metformin prompt ether lipid-dependent increases in lifespan via direct effects on the worm, i. e. independently of biguanide effects on bacteria. Given that these results contrast with previously published work by others, and the importance to the field, we plan a whole separate manuscript about biguanide effects directly on nematode lifespan versus indirectly through the bacteria. As such we do not dwell extensively on the subject herein. 2. Address whether different amounts of biguanide cause the same effect on ether lipids. We thank the reviewer for this suggestion. We again wish to clarify to the reviewer that the intention of this study is to illuminate the requirements for ether lipid biosynthesis on the pro-longevity mechanism of biguanides. As such, we utilized doses of metformin and phenformin that minimally robustly extend C. elegans lifespan (4. 5 mM phenformin and 50 mM metformin) without resulting in negative pleiotropies, as utilized by multiple independent laboratories to identify genetic regulators of the drug7-10.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: In order to decrease the effect of any auto-correlation or common trends within the time-series we prewhitened the TE and Mv for each participant with the prewhiten-function of the psd-package. Bootstrapped confidence intervals (95%) were calculated. The results were correlated with the individual results, in order to examine if sequential effects of TE on Mv could predict differences in adaptation. ResultsWe first analyzed the behavior or participants within a trial for both phase 1 and 2 (see Table 2). A negative TE denoted being late, and a positive TE denoted being early. Both phases included (σMv)2-group and movement time (T) as predictors of TE. Larger movement times led to a more negative TE. The HIGH (σMv)2 group had on average more positive TE. None of the other main effects were included as predictors, although there seemed to be some small interaction effects. As movement time was one of the main predictors of error, it is likely that participants use Mv to account for errors. However, another way to account for errors is by varying the movement angle (Ma). We found a significant correlation between Mv and Ma (R = 0. 62, p < 0. 001), and (σMv)2 and (σMa)2 (R = 0. 67, p < 0. 005). The results of the (λ = 0. 37) showed us that only (σMv)2 was a significant predictor of the (β = 0. 01; 95% CI[0. 008–0. 020]), while (σMa)2 and (σMa)2 ⋅ (σMv)2 were dropped. The remainder of the analysis will therefore only focus on Mv. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageTable 2. Predictors for temporal hand error within a trial for Phase 1 and 2. λ = 0. 6 for both models. regression includes a penalization, caution is required when interpreting Confidence Intervals. experiment was designed to study the relationship between (σMv)2 and the Adaptation score. Fig 2 shows two example subjects and their responses during the experiment. Participants showed various degrees of adaptation. Adaptation scores varied between -1. 49 and +1. 67 (Table 1).

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: These baicalein-stabilized oligomers, being added to the solution of the aggregating α-syn, were able to noticeably inhibit its fibrillation. Using confocal single-molecule fluorescence spectroscopy, Caruana et al. (2011) used the structural diversity of 14 polyphenols to define key molecular scaffolds most effective in inhibiting oligomer formation by α-syn and disaggregating pre-formed oligomers. They found that baicalein, EGCG, nordihydroguaiaretic acid, morin, myricetin, quercetin and tannic acid have strong effects. They conclude that the best candidate required: (1) aromatic recognition elements that would allow non-covalent binding to the α-syn monomer/oligomer and (2) hydroxyl groups (especially the presence of three > two > one –OH group on the same ring structure) that would hinder the progress of the self-assembly process and/or destabilize its structure. In another work, Caruana confirmed the ability of α-syn oligomers to permeabilise phospholipids membranes, potentially via pore-forming mechanism resembling the mechanism of neuronal toxicity in vivo (Caruana et al. , 2012). They found that a group of small-molecule polyphenols (Nordihydroguaiaretic acid, Morin, Baicalein and Apigenin) strongly protect against membrane perturbation induced by aggregated wild-type and mutant (A30P, A53T) α-syn. Some studies focused more specifically on one polyphenol and drew attention. Curcumin has been extensively studied on different models of neurodegenerative diseases and the results suggested that it could be of interest in the treatment of these pathologies. However, the potential efficacy of curcumin is limited owing to its poor potency and bioavailability. For this reason, Ahsan et al. (2015) screened different curcumin derivatives and they found that curcumin pyrazole derivatives inhibit α-syn aggregation and reduce α-syn associated neurotoxicity by employing several biophysical, imaging techniques, dot blot and cell based assays. EGCG bind to the natively unfolded polypeptides, forming complexes and preventing their conversion into toxic, on-pathway aggregation intermediates.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: The supraphysiological 160 mM dosage of metformin used in our prior genetic screens was only initially utilized to identify biguanide response elements. Given that the prior literature shows that higher doses of biguanides do not positively influence C. elegans lifespan5,7, even if additive effects on ether lipids were evident, we argue that they are not relevant to the major thrust of this manuscript on longevity-promoting effects of biguanides and ether lipids. 3. Address the direct genetic connections between skn-1 and fard-1 (etc) e. g. by creating a fard-1; skn-1 gof double and examining fat +/- Phenformin. Alternatively, could this be examined using fat measurements from aak-2 and daf-16 +/- fard-1? It would be interesting to see if the mechanism is the same for all of these longevity processes and make the study of even broader relevance. We thank the reviewer for this suggestion. To clarify, we believe that SKN-1 is the transcription factor operating downstream of the ether lipid machinery to induce somatic lipid depletion, metabolic stress defenses, and pro-longevity outcomes. We have multiple lines of evidence to support this conclusion: (1) A skn-1 RNAi targeting all isoforms of SKN-1 completely abrogates the pro-longevity effects of fard-1 (oe1) animals (Figure 5D), (2) a total SKN-1 loss-of-function mutant completely prevents both biguanide-mediated lifespan extension4 and somatic lipid depletion phenotypes (Figure 6D-E), and (3) skn-1gf animals displaying depleted somatic lipid content elevate 18:0 DMA levels (1), in contrast to changes in 16:0 DMA and 18:1 DMA in fard-1 (oe3) animals, suggesting that skn-1gf alone does not mirror FARD-1 overexpression mediated changes in ether lipid levels. As such, we do not believe that a fard-1lf,skn-1gf animal will suppress the skn-1gf Asdf phenotype.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Fig 3A displays the moving average (window = 4 trials) of TE throughout the task. The blue line shows the mean of the nine participants with below-average (σMv)2, and the orange line depicts the mean of the eight participants with above-average (σMv)2. The spread around these lines represent the standard deviation of the data across subjects. When the temporal perturbation of 100 ms is introduced, subjects account for this delay by reaching the target’s trajectory earlier with their hand in relation to the target. This is depicted by a more positive TE in Fig 3. Upon visual inspection there seemed to be a slightly faster adaptation for the HIGH group than for the LOW group (see Fig 3B). In order to verify this notion, we calculated an adaptation score for each participant. We found a significant correlation between (σMv)2 and the adaptation score (Pearson r = 0. 51, p = 0. 037). We found an even higher Spearman correlation (r = 0. 61, p = 0. 009), indicating that the relationship might be better described by a logarithmic curve (dashed line in Fig 3B). These findings imply that there is a strong positive relationship between (σMv)2 and the adaptation. We confirmed this result by finding a negative correlation between (σMv)2 and τ (r = -0. 63, p = 0. 038) (Fig 4A). This was as expected, as the had a negative (albeit not significant) correlation with τ as calculated by the exponential (r = -0. 54, p = 0. 088) (Fig 4B). Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 3. The relationship between (σMv)2 and adaptation score. (A) The moving average data (+- SD) of the LOW (blue) and HIGH (orange) variability group. (B) The relationship between (σMv)2 and the Adaptation Score. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 4. Verification of the adaptation score. A. The relation between movement speed variability and τ of the exponential function. B. The relationship between the and τ of the exponential function.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: The stimulation of this off-pathway led to the reduced cytotoxicity (Ehrnhoefer et al. , 2008). It has also been suggested that EGCG is capable of binding to the oligomeric state of α-syn, destabilizing it and preventing it from interacting with membranes that would ultimately lead to cytotoxicity (Lorenzen et al. , 2014). In a recent study, Yang et al. (2017) showed that EGCG exhibited its protective effect against α-syn mediated cytotoxicity, not only by producing the off-pathway compact oligomers, but also by facilitating the conversion of “active” oligomers into fibrils, thus accelerating the removal of active oligomers which could exert the membrane disruption and subsequent cellular degeneration. Gallic acid potently inhibited the formation of fibrils of α-syn and reduced the rate of formation of oligomers (Liu et al. , 2014). It binds to soluble, non-toxic oligomers and stabilize their structure. Additionally, by using structure activity relationship, data obtained from 14 structurally similar benzoic acid derivatives showed that the inhibition of α-syn fibrillation was related to the number of hydroxyl moieties and their position on the phenyl ring (Ardah et al. , 2014). Piceatannol inhibited the formation of α-syn fibrils and was able to destabilize preformed filaments. Furthermore, it protected PC12 (neuron like) cells against α-syn-induced toxicity (Temsamani et al. , 2016). Albani et al. (2009) showed that resveratrol pre-treatment protect SK-N-BE cells from the toxicity arising from aggregation-prone protein (α-syn(A30P), mutated α-syn in familial Parkinsonism). In animal models of PD, several studies clearly demonstrated that various polyphenols possess neuroprotective effects, but no study provided information on interaction between polyphenols and α-syn and on fibrils formation. Polyphenols and synphilin-1 Few studies described the role of polyphenols in aggregation of synphilin-1.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Skip to Content eLife home page your research Search by keyword or author Reset form my search to Genetics and 10. 7554/eLife. 82210 Open access Copyright information Version of RecordAugust 22, 2023 Open annotations (there are currently 0 annotations on this page). 1,990 views 271 downloads 15 2210. Copy to clipboard Download BibTeX Download. RIS Full text Figures and data Peer review Side by side Abstract Editor's evaluation eLife digest and methods Data availability 10. 7554/eLife. 82210. sa0 Decision letter Reviews on Sciety eLife's review process eLife digest Metformin is the drug most prescribed to treat type 2 diabetes around the world and has been in clinical use since 1950. The drug belongs to a family of compounds known as biguanides which reduce blood sugar, making them an effective treatment against type 2 diabetes. More recently, biguanides have been found to have other health benefits, including limiting the growth of various cancer cells and improving the lifespan and long-term health of several model organisms. Epidemiologic studies also suggest that metformin may increase the lifespan of humans and reduce the incidence of age-related illnesses such as cardiovascular disease, cancer and dementia. Given the safety and effectiveness of metformin, understanding how it exerts these desirable effects may allow scientists to discover new mechanisms to promote healthy aging. The roundworm Caenorhabditis elegans is an ideal organism for studying the lifespan-extending effects of metformin. It has an average lifespan of two weeks, a genome that is relatively easy to manipulate, and a transparent body that enables scientists to observe cellular and molecular events in living worms. To discover the genes that enable metformin’s lifespan-extending properties, Cedillo, Ahsan et al. systematically switched off the expression of about 1,000 genes involved in C. elegans metabolism. They then screened for genes which impaired the action of biguanides when inactivated. This ultimately led to the identification of a set of genes involved in promoting a longer lifespan. Cedillo, Ahsan et al. then evaluated how these genes impacted other well-described pathways involved in longevity and stress responses. The analysis indicated that a biguanide drug called phenformin (which is similar to metformin) increases the synthesis of ether lipids, a class of fats that are critical components of cellular membranes.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: expected, the F-test revealed a significant difference between the HIGH and LOW variability groups in baseline Mv (F(1, 1315) = 2. 5, p < 0. 001). However, no differences were found for TE (F(1,1315) = 1. 1, p = 0. 35). This is important because it ensures that differences in sequential effects that are found between groups are not the result of differences in errors that were made. We examined the relationship between the TE on a certain trial, and the change in Mv on the next trial for participants in the HIGH and in the LOW (σMv)2 group (see Fig 5). The mixed linear model revealed that, when the error was zero, neither of the groups significantly changed their Mv (p = 0. 69 (LOW); p = 0. 59 (HIGH)). The effect of TE on the next trial’s Mv was significant for the HIGH (σMv)2 group (slope = -15. 9 cm/s2; p = 0. 02). The LOW (σMv)2 group did not show a significant effect (slope = 6. 3 cm/s2; p = 0. 68). revealed a significant difference between groups (F(1, 1263) = 5. 2, p = 0. 02). This suggests that participants with a higher (σMv)2 increased their speed when encountering a negative error and vice versa, while the participants with lower (σMv)2 did not. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 5. The relationship between the baseline TE on trial t-1 and the subsequent change in Mvel. Dots represent individual trials for subjects within the HIGH (orange) and LOW (blue) (σMv)2 group. The lines indicate the predicted slope of the model. order to examine if this difference can predict adaptation on an individual level, we calculated the cross correlation (ccf) between Mv at different t+lag and TE (Fig 6). A negative ccf indicates that a negative error (arriving too late) leads to increased velocities, and a more positive error (earlier) leads to decreased velocities. Consequently, a positive ccf indicates the opposite (negative error → decreased velocities; positive error → increased velocities).

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: However, Pal et al demonstrated that a curcumin analogue, the 3,5-bis(2-flurobenzylidene)piperidin-4-one induced a marked decrease in synphilin-1 aggregation in the dopaminergic SHSY-5Y cells (Pal et al. , 2011). This curcumin analog prevents this aggregation by preventing covalent modifications and by maintaining the expression of the protein disulfide isomerase. paper reviews the significant papers that demonstrated beneficial effects of natural polyphenols against protein aggregates found in AD an PD. These properties can be explained by the capacity of polyphenols to inhibit aggregation of major components of pathological aggregates, i. e. , Aβ in amyloid plaques, tau in NTF, α-syn and synphilin-1 in LB and LNs and to partially disaggregate them. Many mechanisms are implicated, such as direct interaction of polyphenols with β-sheets of these proteins, leading to inhibition of abnormal conformational changes or hyperphosphorylation, but also by interaction with metal ions promoting aggregation. These effects are particularly interesting because polyphenols possess other beneficial properties, such as antioxidative, anti-inflammatory, pro-autophagic and neuroprotective activities. These properties, by themselves, may participate in the reduction in protein aggregation and deposition, without a direct effect of polyphenols on the process of protein aggregation and deposition. As multi-targeting drugs, polyphenols may lead to the development of therapeutic agents that could prove useful in combating AD and PD. However, it is difficult to predict nontoxic efficient doses for in vivo studies and clinical trials, because there is not necessarily a conversion relationship between in vitro and in vivo doses, notably because in vivo experiments are influenced by complex factors such as neuroendocrine system and immunity (Chen et al. , 2018). Moreover, the doses between humans and animals are usually converted by body surface area calculation method, but this result may be not reliable because of the differences in drug metabolism between these two species. To our knowledge, no clinical trial studied the role of polyphenols in the formation of protein aggregates in prion-like diseases. The only clinical studies investigating polyphenols effects in neurodegenerative diseases evaluated their role to prevent or treat cognitive impairment associated with neurodegeneration.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Indeed, genetically mutating the three major enzymes required for ether lipid production stopped the biguanide from extending the worms’ lifespans. Critically, inactivating these genes also prevented lifespan extension through other known strategies, such as dietary restriction and inhibiting the cellular organelle responsible for producing energy. Cedillo, Ahsan et al. also showed that increasing ether lipid production alters the activity of a well-known longevity and stress response factor called SKN-1, and this change alone is enough to extend the lifespan of worms. These findings suggest that promoting the production of ether lipids could lead to healthier aging. However, further studies, including clinical trials, will be required to determine whether this is a viable approach to promote longevity and health in humans. is the first line therapy for type 2 diabetes and the most frequently prescribed oral hypoglycemic medication worldwide (Inzucchi et al. , 2012). Human epidemiologic studies note an association between metformin use and decreased incidence of cancer (Evans et al. , 2005; Yuan et al. , 2013). In addition, metformin extends lifespan in invertebrate and vertebrate models (Cabreiro et al. , 2013; Martin-Montalvo et al. , 2013; Onken and Driscoll, 2010), and therefore may reduce aging-related diseases in humans (Barzilai et al. , 2016). Nonetheless, our understanding of the molecular pathways governing the health-promoting effects of metformin is only just beginning to emerge. Our previous work identified a conserved signaling axis connecting mitochondria, the nuclear pore complex, and mTORC1 inhibition that is required for metformin-mediated extension of lifespan in Caenorhabditis elegans and inhibition of growth in worms and human cancer cells (Wu et al. , 2016). The energy sensor AMP-activated protein kinase (AMPK) is not necessary for metformin-induced growth inhibition in C. elegans but is required for the drug’s pro-longevity effects (Cabreiro et al. , 2013; Onken and Driscoll, 2010; Chen et al. , 2017).

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: In congruence with Fig 6, participants with higher (σMv)2 scores seemed to have a trend towards more negative ccfs, while the participants with low (σMv)2 scores had ccfs near zero. The high (σMv)2 group showed a positive ccf(0) (i. e. the cross correlation between Mv and TE within a trial). Slower hand movements led to more negative TE and fast hand movement to positive TE. It shows that for this group there is some dependency of the TE on the Mv within a trial. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 6. Serial ccf for each (σMv)2 group. The serial ccf for lag 0-3 for the HIGH (orange) and LOW (blue) (σMv)2 groups. The error bars represent the 95% bootstrapped confidence intervals. see if this difference could explain the differences in adaptation, we calculated the correlation between the different lags and the (Fig 7). The correlation between Mv and TE within a trial (lag0), i. e. how the Mv affected the TE, seemed to not be able to explain differences in adaptation. Although there is also no correlation for ccf(1), the lag2 and lag3 ccf seem to predict the in this experiment. This suggests that errors might not be corrected right away, or only partially from trial to trial. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 7. The relationship between the ccf score and the adaptation score. The ccf is shown for lags 0-3 (A-D). The color of the data-points (blue-orange) indicates the size of the (σMv)2. The dotted line indicates a ccf of zero. DiscussionThis study found a positive relationship between variability of movement speed during the baseline phase, and the adaptation to a temporal perturbation. Our results indicate that this variability might be a result of error correction strategies, rather than exploration. Participants that corrected their movement velocity after encountering an error on average adapted more than participants who did not. To our knowledge, we are the first ones to reveal such a relationship in temporal adaptation. The role of noise in adaptation has recently received a lot of attention. A study by Wu et al.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: 2017;32:945–953. The role of tau kinases in Alzheimer's disease Devel. 2010;13:595–603 Dong W, Wang R. Effects of resveratrol-induced cellular autophagy in control of neurodegenerative diseases Xue Bao. 2016;51:18–22. Disaggregation of tau as a therapeutic approach to tauopathies Res. 2010;7:235–240. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers Mol Biol. 2008;15:558–566 Fauconneau B, Waffo-. Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests Life Sci. 1997;61:2103–2110 ’Erme M, Mosca L. β-sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis Chem. 2015;23:1671–1683. Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice J Neuroinflammation. 2014;11:139. Targeting oligomers in neurodegenerative disorders: lessons from alpha-synuclein, tau, and amyloid-beta peptide J 24 Suppl. 2011;2:223–232 Garcia-. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model J Neurochem. 2007;102:1095–1104. Is there a cause-and-effect relationship between alpha¬synuclein fibrillization and Parkinson's disease? Biol. 2000;2:E115–119 Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation Structure. 2010;18:1244–1260 Greenwald J, Riek R. On the possible amyloid origin of protein folds J Mol Biol. 2012;421:417–426. Epigallocatechin 3-gallate as an inhibitor of tau phosphorylation and aggregation: a molecular and structural insight J Dis. 2017;4:218–225.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Consistently, mechanistic studies indicate that the longevity-promoting transcription factor SKN-1/nuclear factor erythroid 2-related factor (Nrf) is required for biguanide-mediated lifespan extension (Cabreiro et al. , 2013; Onken and Driscoll, 2010). The relationship of these metformin longevity response elements to each other and their hierarchy in the biological response to biguanides remains unknown. Thus, the mechanisms by which metformin exacts its beneficial effects on health are likely to be branching and complex. The importance of ether lipids, a major structural component of cell membranes, to aging and longevity is not fully established. Ether lipids are involved in the maintenance of general membrane fluidity and in the formation of lipid rafts within microdomains, which are important for promotion of membrane fusion and cellular signaling (Glaser and Gross, 1994; Komljenovic et al. , 2009; Marrink and Mark, 2004). Ether lipids have broad roles in the regulation of cell differentiation (Davies et al. , 2001; Facciotti et al. , 2012; Rodemer et al. , 2003; Teigler et al. , 2009), cellular signaling (Thukkani et al. , 2002; Albert et al. , 2003), and reduction of oxidative stress through their action as antioxidants (Morand et al. , 1988; Zoeller et al. , 1988; Reiss et al. , 1997; Maeba et al. , 2002). Humans deficient in ether lipid biogenesis suffer from rhizomelic chondrodysplasia punctata (RCDP), a rare genetic disorder, which results in skeletal and facial abnormalities, psychomotor retardation, and is uniformly fatal typically before patients reach their teenage years (White et al. , 2003). Thus, current evidence linking alterations in ether lipid levels to aging and longevity in humans is strictly correlative (Gonzalez-Covarrubias et al. , 2013; Pradas et al. , 2019). Ether lipids, which are structurally distinct from canonical phospholipids, have a unique biosynthetic pathway through which a fatty alcohol is conjugated to the glycerol backbone at the sn-1 position via an ether linkage.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: [32] suggested that there might be a positive influence of variability on adaptation through reinforcement learning, revealed by an increased baseline variability for fast adapters. In line with these results, we found a benefit of increased baseline variability on the adaptation for temporal perturbations. However, our results suggest that participants with higher variability use their velocity more as a way to correct for errors. Our results are therefore more in line with the idea that motor noise from different types of processes can have either a positive, negative or neutral effect on adaptation [13]. Two types of noise that are relevant for adaptation are sensory noise and motor noise. Sensory noise can influence adaptation by influencing the uncertainty of the error [22, 45]. More sensory noise can lead to higher variability. However, error correction actually decreases with more uncertain sensory information. It is therefore unlikely that sensory noise was the source of the increased adaptation. Motor noise can roughly be divided into planning noise and execution noise [16]. A recent study by Vliet et al. [46] found that execution noise correlated negatively with adaptation rate, while planning noise revealed the opposite trend. Execution noise increases the uncertainty of the feedback that is received. Contrarily, more noise in the planning process can lead to more uncertain forward predictions, with a higher rate of error correction as a result. In the current study, we did not measure noise in the system directly. We therefore cannot determine the direct effect of planning noise and/or execution noise on the adaptation. However, it has been suggested that planning noise, in the form of stochastic resonance, could have a positive effect on signal detection by enhancing sub-threshold signals to supra-threshold [47–49]. Enhanced error-detection could lead to more error correction. Our results are in line with the idea that higher planning noise could increase the reliance on error feedback and lead to larger trial-to-trial corrections [46]. The question remains: why did we find a positive relationship between baseline variability and adaptation, while many other studies did not [13, 50–53]? It is likely that differences in design, such as variability measure or feedback provided, trigger variations in the accumulation of the different types of noise. In this study, we defined the average movement speed as an indicator of task-relevant variability, instead of the movement speed at the moment of interception, or the error at interception.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Recent advances in alpha¬synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease Mol Neurobiol. 2013;47:525–536. ATP13A2 regulates mitochondrial bioenergetics through macroautophagy Neurobiol Dis. 2012;45:962–972 Habtemariam S. Molecular pharmacology of rosmarinic and salvianolic acids: potential seeds for Alzheimer's and vascular dementia drugs Mol Sci. 2018;19:E458. Phenolic compounds prevent Alzheimer's pathology through different effects on the amyloid-beta aggregation pathway Pathol. 2009;175:2557–2565. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases Neuromolecular Med. 2003;4:21–36. Structural characteristics of alpha-synuclein oligomers stabilized by the flavonoid baicalein J Mol Biol. 2008;383:214–223. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles Biochem Pharmacol. 2014;88:631–639 -. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity J Neurol. 1998;57:334–337. Hypoglycemic effects of a phenolic acid fraction of rice bran and ferulic acid in C57BL/KsJ-db/db mice J Chem. 2007;55:9800–9804. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease Neurochem Int. 2009;54:111–118. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science. 2003;300:486–489. Reactivity of metal-free and metal-associated amyloid-beta with glycosylated polyphenols and their esterified derivatives Sci Rep. 2015;5:17842 Kroemer G, Levine B. Autophagic cell death: the story of a misnomer Biol. 2008;9:1004–1010 Ksiezak-Reding H, Ho L, Santa-Maria I, Diaz-.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Interestingly, requirement for the ether lipid biosynthetic genes extends to multiple genetic longevity paradigms, including defective mitochondrial electron transport function (isp-1), defective pharyngeal pumping/caloric restriction (eat-2), and compromises in mTOR complex 1 activation (raga-1). We show that overexpressing fard-1, the enzyme that produces fatty alcohols for ether lipid biogenesis in C. elegans, extends lifespan, supportive of the idea that alterations in the ether lipid landscape alone is sufficient to promote healthy aging. Mechanistically, ether lipids promote longevity downstream of biguanide action through activation of metabolic stress defenses and somatic lipid redistribution driven by the transcription factor SKN-1/Nrf. These data suggest that a heretofore unappreciated role for ether lipids is to enable organismal-level, longevity-promoting stress defenses. responsible for ether lipid biosynthesis are necessary for biguanide-induced lifespan extension A prior screen of ~1000 metabolic genes for RNA interference (RNAi) knockdowns that interfere with the growth-inhibitory properties of a high, 160 mM dose of metformin in C. elegans (utilized to maximize the sensitivity and specificity of our assay to identify true epistatic candidates) (Wu et al. , 2016), yielded fard-1 and acl-7, which are required for ether lipid biosynthesis. Ether lipids are distinguished from canonical phospholipids as the latter contain exclusively fatty acids conjugated to glycerol, whereas ether lipids contain a fatty alcohol conjugated to the glycerol backbone at the sn-1 position via an ether linkage (Figure 1A). Confirming our screen results, granular, quantitative analysis following RNAi knockdown of fard-1 and acl-7 reveals significant resistance to biguanide-induced growth inhibition (Figure 1—figure supplement 1A). Our lab has previously demonstrated that biguanide effects on growth in C. elegans share significant overlap mechanistically with the machinery by which metformin extends lifespan in the worm, thus suggesting that modulation of ether lipid biosynthesis may also be responsible for the lifespan-extending properties of the drug (Wu et al. , 2016).

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: We theorized that movement velocity would provide the richest information about the temporal contingencies of the sensorimotor system, and therefore could be more beneficial for exploration. By averaging the movement speed on each trial we believe to have filtered out a large part of the execution noise. This could have highlighted the effect of planning noise on adaptation. Similarly, Wu et al. [32] calculated the variability of deflection of a rewarded hand path throughout the movement, while He et al. [13] looked at the endpoint error. It is likely that endpoint error is more susceptible to execution noise. On the other hand, Dhawale et al. [54] suggested in a recent review that differences in results between studies might be inherent to differences in feedback. et al. [32], feedback was absent during the baseline, which may have led to an accumulation of planning noise (drift) that could not be corrected trial-to-trial [55]. et al. [13], feedback was provided throughout the movement, which means the variability measure might be dominated by execution noise. In the current study, we did provide error feedback in the baseline, which might be taken as evidence against the latter idea. However, these ideas together support the hypothesis that experimental designs that promote planning noise over execution noise are more likely to reveal a positive relationship between variability and adaptation. Next, we need to consider the effect of generalization on the results. The term generalization refers to how the mapping between action and consequence generalizes to other tasks and target speeds. Research has shown that generalization of temporal perturbations is limited to tasks that are very similar to the learned task [39]. We used three different target speeds in two directions in this study. Some participants might had a better generalization from one speed to the other than others. It is possible that at the moment the perturbation was applied, some participants were able to generalize the changing consequences better for all target speeds and, as a result, adapt faster. For generalization to have an effect on our results there would need to be a relationship between movement speed variability and generalization. More variable people might develop broader tuning curves, and as a result adapt faster. We think this idea is captured well within the notion of exploration that is part of our original hypothesis: higher variability due to exploration might broaden the brain’s knowledge on the temporal contingencies over a broader range of target speeds and situations.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Ultrastructural alterations of Alzheimer's disease paired helical filaments by grape seed-derived polyphenols Neurobiol Aging. 2012;33:1427–1439. EGCG-mediated autophagy flux has a neuroprotection effect via a class III histone deacetylase in primary neuron cells Oncotarget. 2015;6:9701–9717 -. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations Cell. 2010;141:1146–1158. Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy Mol Sci. 2014;15:1625–1646 Liu F, Iqbal K, Grundke-. Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease J Biol Chem. 2005;280:1790–1796. Gallic acid interacts with alpha-synuclein to prevent the structural collapse necessary for its aggregation Acta. 2014;1844:1481–1485. How epigallocatechin gallate can inhibit alpha-synuclein oligomer toxicity in vitro J Biol Chem. 2014;289:21299–21310 Lynch-. The role of autophagy in Parkinson's disease Med. 2012;2:a009357. Understanding the broad-spectrum neuroprotective action profile of green tea polyphenols in aging and neurodegenerative diseases J Alzheimers Dis. 2011;25:187–208. Small molecule inhibitors of alpha-synuclein filament assembly Biochemistry. 2006;45:6085–6094 Mazzanti G, S. Curcumin and resveratrol in the management of cognitive disorders: What is the clinical evidence? Molecules. 2016;21:E1243. Molecular mechanisms underlying the flavonoid-induced inhibition of alpha-synuclein fibrillation Biochemistry. 2009;48:8206–8224. Effects of various flavonoids on the alpha-synuclein fibrillation process Parkinsons Dis. 2010;2010:650794 Mietelska-. Tau protein modifications and interactions: their role in function and dysfunction Mol Sci. 2014;15:4671–4713 -.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Indeed, loss-of-function mutations in any of three genes encoding enzymes required for ether lipid biosynthesis, fard-1, acl-7, or ads-1, significantly abrogate lifespan extension induced by lifespan-extending doses of metformin (50 mM) and the related biguanide phenformin (4. 5 mM) (Figure 1B–G). Loss-of-function of ads-1 and acl-7 may display a modest increase in lifespan with metformin administration but display a percentage median lifespan increase significantly reduced in comparison to wild-type controls (Figure 1B–G, and throughout manuscript see Supplementary file 1 for all tabular survival statistics and biological replicates). Confirming that these mutations confer resistance to metformin by compromising ether lipid synthetic capacity, RNAi knockdowns of fard-1 and acl-7 in wild-type worms also partially impair lifespan extension promoted by phenformin (Figure 1—figure supplement 1B–C). This dependency is not confounded by chemical inhibition of reproduction, as lifespan analyses performed without the use of the thymidylate synthase inhibitor 5-fluoro-2′-deoxyuridine (FUdR) reveal similar abrogation of biguanide-mediated lifespan extension with inactivation of the ether lipid synthetic machinery (Figure 1—figure supplement 2A–F; and Hekimi, 2011). Studies from this point forward are presented predominantly with phenformin because phenformin is more readily absorbed without need for a specific transporter, unlike metformin (Wu et al. , 2016; Sogame et al. , 2009; Segal et al. , 2011), and our experience indicates more consistent lifespan extension with phenformin in C. elegans. Figure 1 with 2 supplements see all Download asset Open asset Genes responsible for ether lipid biosynthesis are necessary for biguanide-induced lifespan extension. (A) C. elegans ether lipid synthesis is catalyzed by three enzymes: fatty acyl reductase FARD-1, acyltransferase ACL-7, and alkylglycerone phosphate synthase ADS-1 (adapted from Figure 1 of Shi et al. , 2016 and Dean and Lodhi, 2018). The latter two are localized to the peroxisomal lumen.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Unfortunately our current dataset cannot give a definitive answer to the question of generalization. Throughout the study, we mainly focused on how participants change their movement speed from trial-to-trial. However, in this task subjects were free to change their interception location or movement angle and onset time in order to account for prediction errors. This leads to a variety of strategies that participants can use to perform the task and correct for errors. These strategies are not independent of the target speed, nor independent of each other. For example, faster targets can lead to faster movements, earlier onset times and/or to broader hitting positions [56–58]. Furthermore, we found a correlation between the movement angle and the movement speed. These interconnections between movement features make it challenging to examine the participants’ strategies. However, it has been proposed that, in order to successfully hit a target, people benefit more from estimating the time it takes to reach the target’s trajectory, followed by fine-tuning the point of interception throughout the movement (online correction), as opposed to estimating when the target will reach the interception location [2]. As a result, errors are likely attributed to incorrect estimations of the time it takes to reach the target’s trajectory, rather than an incorrect estimations of interception location. As online correction was discouraged in our experiment, the reliance on error correction through changing the predicted temporal features of the movement was enhanced even further. During this experiment, successful participants used their movement speed as a control agent for trial-to-trial error correction in interception, and to a lesser extend their interception location or movement angle. This does not mean that low adapters do not have useful strategies of error correction. However, if the source of an error is temporal, using movement speed as a corrective strategy can be beneficial. Vice versa, if an error is spatial, corrections in movement angle would be more favorable. It is therefore possible that the difference in adaptation is rooted in the interpretation of the error. Ccf(0) seemed to be slightly higher in the high variability group compared to the low variability group. This shows that participants with higher variability had a higher cross-correlation between the speed of movement and the temporal hand error in the same trial. This suggests that the temporal hand errors that participants with higher variability make are more dependent on the movement speed. This is not a surprising feature, given that more variability can more easily reveal a dependency of the temporal hand error on the movement speed.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration Biotechnol Adv. 2017 doi: 10. 1016/j. biotechadv. 2017. 12. 001 Naczk M, Shahidi F. Phenolics in cereals, fruits and vegetables: occurrence, extraction and analysis J Anal. 2006;41:1523–1542 Ono K, Yamada M. Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro J Neurochem. 2006;97:105–115. Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro Acta. 2004;1690:193–202. Potent anti¬amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease J Neurochem. 2003;87:172–181. Nitrosative stress-induced Parkinsonian Lewy-like aggregates prevented through polyphenolic phytochemical analog intervention Res Commun. 2011;404:324–329. Plant polyphenols as dietary antioxidants in human health and disease Cell Longev. 2009;2:270–278 Rezai-. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice Brain Res. 2008;1214:177–187 Rezai-. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice J Neurosci. 2005;25:8807–8814 -. Protective effect of epsilon-viniferin on beta-amyloid peptide aggregation investigated by electrospray ionization mass spectrometry Chem. 2011;19:3152–3155 Rivière. Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro Chem. 2007;15:1160–1167.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Each of these mRNAs decreased or remain unchanged in abundance upon treatment with biguanide via quantitative RT-PCR (Figure 2—figure supplement 2G–L), suggesting that ether lipids are not increased in phenformin treatment through a transcriptional mechanism. A parallel decrease in overall levels of FARD-1::RFP protein of fard-1(oe1) transgenics was seen with phenformin treatment (Figure 2—figure supplement 2M). These seemingly paradoxical data are likely consistent with post-translational negative feedback of ether lipids on the ether lipid biosynthetic pathway, as has been previously reported (Honsho et al. , 2010). To affirm that the peroxisome is an essential site of ether lipid production in biguanide action, we disrupted peroxisomal protein targeting and examined phenformin-stimulated lifespan extension. Indeed, either prx-5 or prx-19 RNAi impair lifespan extension prompted by phenformin fully or partially, respectively (Figure 3A–B). PRX-5 is involved in protein import into the peroxisomal matrix and PRX-19 is involved in proper sorting of proteins for peroxisomal biogenesis. Thus, either disruption of ether lipid biosynthetic machinery or of a principal site of ether lipid biosynthesis impairs phenformin’s pro-longevity benefit. Figure 3 Download asset Open asset Peroxisomal protein import, fatty acid elongases, and fatty acid desaturases are required for the pro-longevity effects of biguanides. (A–B) Knockdown of prx-5 (A) and prx-19 (B) by RNA interference (RNAi) eliminates or significantly suppresses phenformin-mediated lifespan extension. (C) Schematic representation of the mono- (MUFA) and polyunsaturated fatty acid (PUFA) synthesis pathway in C. elegans (adapted from Figure 1 of Watts, 2016). (D–G) RNAi of two fatty acid desaturases (D–E) and two fatty acid elongases (F and G) involved in the synthesis of 18- and 20-carbon PUFAs blunt phenformin-mediated lifespan extension in wild-type worms. Colored symbols for elo and fat genes (vs.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Another reason why ccf(0) is higher in the HIGH variability group is that participants with more dependency of temporal hand error on movement speed use their movement speed more as a way to correct for error and as a result, adapt more. We need to consider the possibility that this positive ccf(0) could have had an effect on the negative ccfs found in later lags. When a slow hand movement is made and a negative error occurs, it is more likely that the next movement will be faster. This therefore can lead to negative ccfs in consecutive lags. However, these differences in ccf(0) were not able to explain differences in adaptation. Therefore it seems unlikely that dependencies between Mv and TE within a trial alone could have explained more negative ccfs for consecutive lags. To conclude, we found a correlation between movement speed variability and adaptation to a temporal perturbation. Further analysis of this relationship indicated that this is likely the result of error correction strategies that also benefited the adaptation, although the results are not conclusive. More research is needed to examine the contributions of movement speed, interception location and movement angle and the differences between temporal and spatial perturbations. Furthermore, it would be interesting to know how these error correction strategies are related to different types of noise and how the how the brain regulates these processes. 1. Regan D. Visual factors in hitting and catching. J Sports Sci. 1997;15(6):533–58. pmid:9486432 View 2. . How people achieve their amazing temporal precision in interception. J Vis. 2015;15(3). View 3. Adams JA. A closed-loop theory of motor learning. J Mot Behav. 1971;3(2):111–49. pmid:15155169 View 4. . Is the cerebellum a smith predictor? J Mot Behav. 1993;25(3):203–16. pmid:12581990 View 5. López-. Catching a gently thrown ball. Res. 2010;206(4):409–17. pmid:20862460 View 6. López-Moliner J, Keil MS. People favour imperfect catching by assuming a stable world. PLoS One. 2012;7(4):e35705. pmid:22558205 View 7. . Forward models: Supervised learning with a distal teacher. Cognitive science.

Output: pass


Input: Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Challenges for research on polyphenols from foods in Alzheimer's disease: bioavailability, metabolism, and cellular and molecular mechanisms J Chem. 2008;56:4855–4873 Sivanesam K, Andersen NH. Modulating the amyloidogenesis of α-synuclein Curr Neuropharmacol. 2016;14:226–237. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. 1998;95:6469–6473 Stefani M, Rigacci S. Beneficial properties of natural phenols: highlight on protection against pathological conditions associated with amyloid aggregation Biofactors. 2014;40:482–493. Structure-activity relations of rosmarinic acid derivatives for the amyloid beta aggregation inhibition and antioxidant properties Med Chem. 2017;138:1066–1075 Temsamani H, Krisa S, Decossas-. Piceatannol and other wine stilbenes: a pool of inhibitors against α-synuclein aggregation and cytotoxicity Nutrients. 2016;8:E367. Metal dyshomeostasis and their pathological role in prion and prion-like diseases: the basis for a nutritional approach Front Neurosci. 2017;11:3. Natural product-based amyloid inhibitors Biochem Pharmacol. 2017;139:40–55. Trans ε-viniferin is an amyloid-β disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer's disease Neurosci. 2017;88:1–6. Synphilin-1 is present in Lewy bodies in Parkinson's disease Ann Neurol. 2000;47:521–523 Wang J, Santa-Maria I, Ho L, Ksiezak-. Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease J Alzheimers Dis. 2010;22:653–661. Curcumin protects neuronal cells against status-epilepticus-induced hippocampal damage through induction of autophagy and inhibition of necroptosis Physiol Pharmacol. 2017;95:501–509. Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases J Ethnopharmacol. 2016;194:861–876.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: those in black and white) in (C) indicates those that inhibit phenformin lifespan extension when knocked down by RNAi. For (A, B) and (D–G), results are representative of two to three biological replicates. **, p<0. 01; ***, p<0. 001; ****, p<0. 0001 by log-rank analysis. Note that (D–G) contain the same wild-type controls as they are visualized from the same replicate of the study. See also Supplementary file 1 for tabular survival data and biological replicates. Fatty acid elongases and desaturases are positive effectors of biguanide-mediated lifespan extension Most mature ether lipid species contain a fatty acid in the sn-2 position linked by an ester bond (Dean and Lodhi, 2018). The majority of fatty acids conjugated in ether lipids are largely synthesized endogenously in C. elegans by fatty acid desaturases and fatty acid elongases (Perez and Van Gilst, 2008; Perez and Watts, 2021; Figure 3C). Thus, we hypothesized that some of these desaturases and elongases may also contribute mechanistically to biguanide-mediated lifespan extension. Indeed, RNAi knockdown of two fatty acid desaturases and two fatty acid elongases in phenformin-treated C. elegans blunted phenformin-stimulated lifespan extension relative to empty vector controls (Figure 3D–G). Notably, these four genes all contribute to the production of fatty acids 18–20 carbons in length with three or more double bonds. Although knockdown of fatty acid desaturases and elongases in C. elegans results in inherent lifespan extension on vehicle relative to wild-type controls on empty vector RNAi as has been previously reported (et al. , 2011; Horikawa et al. , 2008), RNAi knockdown of fat-3, fat-4, elo-1, and elo-2 mitigate phenformin-driven lifespan extension (Figure 3D–G). These results suggest the tantalizing possibility that specific fatty acid desaturases and elongases promote biguanide-mediated lifespan extension through contribution of long and polyunsaturated fatty acids (PUFAs) to the synthesis of ether lipids, though a mechanistically distinct role is also possible.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: 1992;16(3):307–354. View 8. . for Control. Neural Netw. 1996;9(8):1265–1279. pmid:12662535 View 9. . Effects of muscle fatigue and temperature on electromechanical delay. Neurophysiol. 1998;38(2):67–73. pmid:9553743 View 10. Wei K, Körding K. Relevance of error: what drives motor adaptation? J Neurophysiol. 2009;101(2):655–64. pmid:19019979 View 11. . Rethinking motor learning and savings in adaptation paradigms: model-free memory for successful actions combines with internal models. Neuron. 2011;70(4):787–801. pmid:21609832 View 12. . Noise in the nervous system. Nature reviews neuroscience. 2008;9(4):292. pmid:18319728 View 13. . Determinants of the Speed of Motor Learning. PLoS Comput Biol. 2016;12(9):e1005023. pmid:27606808 View 14. . A central source of movement variability. Neuron. 2006;52(6):1085–96. pmid:17178410 View 15. . Neural variability in premotor cortex provides a signature of motor preparation. J Neurosci. 2006;26(14):3697–712. pmid:16597724 View 16. van Beers RJ. Motor learning is optimally tuned to the properties of motor noise. Neuron. 2009;63(3):406–17. pmid:19679079 View 17. . Motor variability arises from a slow random walk in neural state. J Neurosci. 2014;34(36):12071–80. pmid:25186752 View 18. . by Variability. J Neurosci. 2017;37(37):9076–9085. pmid:28821678 View 19. . Signal-dependent noise determines motor planning. Nature. 1998;394(6695):780–4. pmid:9723616 View 20. . Sources of signal-dependent noise during isometric force production. J Neurophysiol. 2002;88(3):1533–44. pmid:12205173 View 21. van.

Output: pass


Input: Claim: Magnetic resonance imaging (MRI) is an example of a biophysical technology used in medical diagnosis. [SEP] Text: Log in or new issue alertsGet alerts Enter your Email address: Subscribe to e2017. | DOI: 10. 1097/RMR. 0000000000000140 published studies have revealed that magnetic resonance imaging (MRI) is by far the most effective imaging modality for cancer detection, it is currently considered cost-ineffective for screening women at an intermediate risk for breast cancer. The concept of an “abbreviated MRI” protocol has recently emerged as a possible solution for reducing the cost of MRI. The abbreviated MRI is a shortened version of the standard MRI, consisting of a single early phase dynamic contrast enhanced (DCE) series. Several clinical studies have shown that this MRI protocol would not affect sensitivity or specificity for breast MRI screening purposes. In clinical practice, morphologic evaluation and kinetic assessment are 2 major components of the interpretation process. However, kinetic assessment cannot be performed with the abbreviated protocol, because multiple sets of post-contrast images are necessary for the generation of kinetic curves. “Accelerated MRI” is a collective term for imaging techniques that acquire DCE-MR images in a very short time. Published studies suggest that the kinetic assessment during the very early post-contrast phase obtained with the accelerated MRI techniques is comparable to that with the standard MRI techniques. Applying accelerated MR techniques could potentially enhance the abbreviated MRI protocol in terms of diagnostic potential, while maintaining the shorter study time. Thus, the abbreviated MRI protocol associated with accelerated MRI techniques may provide value for screening and for diagnostic purposes. Screening mammography has been shown to be associated with reduction of breast cancer mortality. However, the ability of mammography to detect cancers is reduced significantly when the breast tissue is dense. 1–7 Therefore, supplemental screening has been recommended for women with dense breasts. Currently, more than 25 states in the US require mammography facilities to inform women with dense breasts to discuss supplemental screening tests with their providers. Automated breast ultrasonography (ABUS) has gained popularity as a supplemental screening method. However, the first multi-institutional study of breast cancer screening using ABUS (the SomoInsight study) revealed a very high recall rate (28. 5%). 8 Thus, ultrasonography might not be considered as the sole method of supplemental screening for these women.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Genes involved in ether lipid biosynthesis are required in multiple longevity paradigms Given the critical role of ether lipids in the response to biguanides, we hypothesized that these molecules may also play a broader role in diverse longevity paradigms involving metabolic or nutrient-sensing pathways. C. elegans mutant strains that exhibit (1) reduced mitochondrial function (isp-1), (2) disrupted mTORC1 signaling (raga-1), (3) abnormal pharyngeal pumping resulting in a dietary restricted-like state (eat-2), or (4) inhibition of insulin/insulin-like growth factor-1 signaling (daf-2), all result in extension of lifespan (Apfeld et al. , 2004; Curtis et al. , 2006; Senchuk et al. , 2018; Schreiber et al. , 2010). To determine whether requirement for the ether lipid biosynthetic machinery in aging generalizes to these other lifespan extension paradigms, we knocked down all three ether lipid biosynthetic enzymes by RNAi in wild-type C. elegans and four long-lived genetic mutants: raga-1, isp-1, eat-2, and daf-2. Knockdown of fard-1, acl-7, and ads-1 by RNAi results in suppression of lifespan extension in isp-1, raga-1, and eat-2 mutants (Figure 4A–C). However, knockdown of ether lipid synthesis genes by RNAi did not impact lifespan extension in daf-2 mutants (Figure 4—figure supplement 1). Thus, the ether lipid biosynthetic machinery plays a broad role in lifespan extension, and, importantly, does not non-selectively shorten lifespan by making animals generally unfit. Figure 4 with 1 supplement see all Download asset Open asset Genes involved in ether lipid biosynthesis are required for lifespan extension in multiple longevity paradigms. (A–C) isp-1, raga-1, and eat-2 mutants display extended lifespan relative to wild-type animals that is dependent upon the three members of the ether lipid biosynthetic pathway. Results are representative of three biological replicates. **, p<0. 01; ***, p<0. 001; ****, p<0. 0001 by log-rank analysis.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: The role of execution noise in movement variability. J Neurophysiol. 2004;91(2):1050–63. pmid:14561687 View 22. . A sensory source for motor variation. Nature. 2005;437(7057):412–6. pmid:16163357 View 23. . Post-Activity in in the Estimations from Internal Models. J Neurosci. 2016;36(5):1516–28. pmid:26843635 View 24. Mazzoni P, Krakauer JW. An implicit plan overrides an explicit strategy during visuomotor adaptation. J Neurosci. 2006;26(14):3642–5. pmid:16597717 View 25. . Error correction, sensory prediction, and adaptation in motor control. Neurosci. 2010;33:89–108. pmid:20367317 View 26. Körding KP, Wolpert DM. Bayesian integration in sensorimotor learning. Nature. 2004;427(6971):244–7. pmid:14724638 View 27. Todorov E, Jordan MI. Optimal feedback control as a theory of motor coordination. Nat Neurosci. 2002;5(11):1226–35. pmid:12404008 View 28. Wei K, Körding K. Uncertainty of feedback and state estimation determines the speed of motor adaptation. Neurosci. 2010;4:11. pmid:20485466 View 29. . Reinforcement learning: A survey. Journal of artificial intelligence research. 1996;4:237–285. View 30. Introduction to reinforcement learning. vol. 135. MIT press Cambridge; 1998. 31. . Principles of sensorimotor learning. Neurosci. 2011;12(12):739–51. pmid:22033537 View 32. Ölveczky BP, Smith MA. Temporal structure of motor variability is dynamically regulated and predicts motor learning ability. Nat Neurosci. 2014;17(2):312–21. pmid:24413700 View 33. . A memory of errors in sensorimotor learning. Science. 2014;345(6202):1349–53. pmid:25123484 View 34. . Prospective errors determine motor learning Nat Commun. 2015;6: 5925.

Output: pass


Input: Claim: Magnetic resonance imaging (MRI) is an example of a biophysical technology used in medical diagnosis. [SEP] Text: Multiple clinical studies have shown that breast magnetic resonance imaging (MRI) is effective for the detection of breast cancer in women at an increased risk for breast cancer9–16; the efficacy of MRI is by far the highest when compared with mammography and ultrasound in the detection of breast cancer. 10,11,15,16 (ACS) recommends MRI screening every year in addition to annual screening mammography for women who have a lifetime risk of breast cancer of 20% to 25% or greater, according to risk assessment tools that are based mainly on family history, women with a known BRCA1 or BRCA2 mutation, women who have a first-degree relative with a BRCA mutation, women with a clinical history of radiation to the chest between ages 10 and 30 years, women who have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have first-degree relatives with one of these syndromes. 17 MRI screening for these women is reportedly cost-effective. 18,19 Although there are data suggesting that breast MRI might be useful for the detection of breast cancer in women at moderately increased risk for breast cancer, the ACS is not for or against yearly MRI screening for these women due to insufficient evidence. 9,20–23 Women at moderately increased risk for breast cancer with a lifetime risk of 15% to 20% include women who have a personal history of breast cancer, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH), or atypical lobular hyperplasia (ALH), or who have dense breasts (“extremely” or “heterogeneously” dense) as seen on a mammogram. MRI for non-high-risk women is not cost-effective in the US, and this might be one of the reasons why MRI screening is limited to women at the greatest risk for developing breast cancer. 24 The idea of an “abbreviated breast MRI” protocol was established in an effort to lower the MRI cost predicated on the extended image acquisition table time and also on the radiologists’ interpretation time.

Output: corroborate


Input: Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: See also Figure 4—figure supplement 1 and Supplementary file 1 for tabular survival data and biological replicates. Overexpression of fard-1 is sufficient to promote lifespan extension To determine whether stimulation of ether lipid biosynthesis is sufficient to prompt lifespan extension, we tested the effect of overexpression (oe) of the sole C. elegans fatty acid reductase that synthesizes fatty alcohols for ether lipid biogenesis, fard-1, on lifespan. Strikingly, fard-1(oe1) alone significantly extends lifespan (Figure 5A). This result is similar in a second, independent fard-1(oe2) transgenic line (Figure 5B). To confirm that fard-1(oe) lifespan extension is dependent upon ether lipid biosynthesis, we knocked down fard-1, acl-7, and ads-1 by RNAi in the fard-1(oe1) transgenic strain. As predicted, knockdown of three ether lipid biosynthetic enzymes leads to significant suppression of fard-1(oe1) lifespan extension (Figure 5C and Figure 5—figure supplement 1A–B). Figure 5 with 1 supplement see all Download asset Open asset fard-1 overexpression is sufficient to extend lifespan by modulating ether lipid synthesis. (A–B) Two independently generated fard-1 overexpression (fard-1 oe1 and fard-1 oe2) transgenic strains exhibit lifespan extension that is not further extended by concomitant phenformin treatment. (C) RNA interference (RNAi) knockdown of ads-1 fully suppresses fard-1(oe1) lifespan extension, indicating that the fard-1(oe)-mediated lifespan extension is dependent upon ether lipid synthesis. (D) qRT-PCR analysis of wild-type and fard-1(oe3) animals treated with vehicle or phenformin until adult day 1 reveals that both biguanide treatment and fard-1 exogenous overexpression results in an equivalent reduction of native fard-1 gene expression, as indicated by primers targeting the native 3’ UTR of fard-1, a sequence not represented in the fard-1 overexpression transgene (n=3 biological replicates).

Output: contrast