Exploration of the tumorigenic, metabolic, and cognitive consequences of tau protein removal

Background: Tau accumulation causes tauopathies and drives cellular senescence, which can lead to inflammation, neurodegeneration, and cognitive impairment. The association between intracellular tau deposition and pathogenesis has prompted therapeutic strategies that reduce tau expression. However, tau is also critical in microtubule stabilization, synaptic plasticity, and maintaining DNA integrity. We investigated the impact of tau removal on brain cell senescence and associated neurocognitive behaviors in aged tau knockout (Mapt0/0) and wild type control (Mapt+/+) mice. We also assessed physical, metabolic, histological, and biochemical outcomes in Mapt0/0 and Mapt+/+ mice and in response to high fat diet (HFD), a stressor that drives DNA damage. Method: 20-month-old female Mapt0/0 and Mapt+/+ mice were subjected to the Elevated Plus Maze to assess anxiety-like behavior. Mice were then fed control (CTL) or HFD (60% kcal fat) for 9 weeks. Behavioral and physical measures were then assessed, and brain tissue was further analyzed via gene expression, biochemistry, and histological assays. Result: Tau knockout and HFD, separately and additively, caused weight gain and insulin resistance. Removing tau primed cells to proliferate, as Mapt0/0 mice had increased body size, organ size, and tumor burden compared to Mapt+/+. We observed no difference in senescence between genotypes on CTL diet. The HFD increased senescence only in Mapt+/+ mice, whereas Mapt0/0 mice displayed increased tumor burden. Mapt0/0 mice displayed anxiety- and depressive-like behaviors on both diets. Transcriptomic and protein expression data revealed that several molecules responded similarly to tau removal and HFD exposure, but Mapt+/+ and Mapt0/0 mice responded differently to HFD. Genotype differences in DNA damage and cell cycle dysregulation were also observed. Conclusion: Mapt0/0 mice did not accumulate senescent cells but demonstrated anxiety-like behaviors in the presence of elevated DNA damage; thus tau knockout may drive neuropsychiatric phenotypes which can be dissociated from obesity and senescence. Mapt0/0 mice also developed tumors, suggesting that tau plays a critical role in cell fate decisions, including senescence versus cancer. Overall, we found that tau removal prevents senescent cell accumulation with the tradeoff of tumorigenic, metabolic, and cognitive consequences. We caution against removing tau until a better understanding of its physiological roles are defined

Learning and CRF-Induced Indecision during Escape and Submission in Rainbow Trout during Socially Aggressive Interactions in the Stress-Alternatives Model

Socially stressful environments induce a phenotypic dichotomy of coping measures for populations in response to a dominant aggressor and given a route of egress. This submission- (Stay) or escape-oriented (Escape) dichotomy represents individual decision-making under the stressful influence of hostile social environments. We utilized the Stress-Alternatives Model (SAM) to explore behavioral factors which might predict behavioral phenotype in rainbow trout. The SAM is a compartmentalized tank, with smaller and larger trout separated by an opaque divider until social interaction, and another divider occluding a safety zone, accessible by way of an escape route only large enough for the smaller fish. We hypothesized that distinctive behavioral responses during the first social interaction would indicate a predisposition for one of the behavioral phenotypes in the subsequent interactions. Surprisingly, increased amount or intensity of aggression received had no significant effect on promoting escape in test fish. In fact, during the first day of interaction, fish that turned toward their larger opponent during attack eventually learned to escape. Escaping fish also learn to monitor the patrolling behavior of aggressors, and eventually escape primarily when they are not being observed. Escape per se, was also predicted in trout exhibiting increased movements directed toward the escape route. By contrast, fish that consistently remained in the tank with the aggressor (Stay) showed significantly higher frequency of swimming in subordinate positions, at the top or the bottom of the water column, as well as sitting at the bottom. In addition, a corticotropin-releasing factor (CRF)-induced behavior, snap-shake, was also displayed in untreated fish during aggressive social interaction, and blocked by a CRF1 receptor antagonist. Especially prevalent among the Stay phenotype, snap-shake indicates indecision regarding escape-related behaviors. Snap-shake was also exhibited by fish of the Escape phenotype, showing a positive correlation with latency to escape. These results demonstrate adaptive responses to stress that reflect evolutionarily conserved stress neurocircuitry which may translate to psychological disorders and decision-making across vertebrate taxa

Genetic Architecture of a Reinforced, Postmating, Reproductive Isolation Barrier between Neurospora Species Indicates Evolution via Natural Selection

A role for natural selection in reinforcing premating barriers is recognized, but selection for reinforcement of postmating barriers remains controversial. Organisms lacking evolvable premating barriers can theoretically reinforce postmating isolation, but only under restrictive conditions: parental investment in hybrid progeny must inhibit subsequent reproduction, and selected postmating barriers must restore parents' capacity to reproduce successfully. We show that reinforced postmating isolation markedly increases maternal fitness in the fungus Neurospora crassa, and we detect the evolutionary genetic signature of natural selection by quantitative trait locus (QTL) analysis of the reinforced barrier. Hybrid progeny of N. crassa and N. intermedia are highly inviable. Fertilization by local N. intermedia results in early abortion of hybrid fruitbodies, and we show that abortion is adaptive because only aborted maternal colonies remain fully receptive to future reproduction. In the first QTL analysis of postmating reinforcement in microbial eukaryotes, we identify 11 loci for abortive hybrid fruitbody development, including three major QTLs that together explain 30% of trait variance. One of the major QTLs and six QTLs of lesser effect are found on the mating-type determining chromosome of Neurospora. Several reinforcement QTLs are flanked by genetic markers showing either segregation distortion or non-random associations with alleles at other loci in a cross between N. crassa of different clades, suggesting that the loci also are associated with local effects on same-species reproduction. Statistical analysis of the allelic effects distribution for abortive hybrid fruitbody development indicates its evolution occurred under positive selection. Our results strongly support a role for natural selection in the evolution of reinforced postmating isolation in N. crassa

A comprehensive analysis of autocorrelation and bias in home range estimation

Home range estimation is routine practice in ecological research. While advances in animal tracking technology have increased our capacity to collect data to support home range analysis, these same advances have also resulted in increasingly autocorrelated data. Consequently, the question of which home range estimator to use on modern, highly autocorrelated tracking data remains open. This question is particularly relevant given that most estimators assume independently sampled data. Here, we provide a comprehensive evaluation of the effects of autocorrelation on home range estimation. We base our study on an extensive data set of GPS locations from 369 individuals representing 27 species distributed across five continents. We first assemble a broad array of home range estimators, including Kernel Density Estimation (KDE) with four bandwidth optimizers (Gaussian reference function, autocorrelated-Gaussian reference function [AKDE], Silverman´s rule of thumb, and least squares cross-validation), Minimum Convex Polygon, and Local Convex Hull methods. Notably, all of these estimators except AKDE assume independent and identically distributed (IID) data. We then employ half-sample cross-validation to objectively quantify estimator performance, and the recently introduced effective sample size for home range area estimation ((Formula presented.)) to quantify the information content of each data set. We found that AKDE 95% area estimates were larger than conventional IID-based estimates by a mean factor of 2. The median number of cross-validated locations included in the hold-out sets by AKDE 95% (or 50%) estimates was 95.3% (or 50.1%), confirming the larger AKDE ranges were appropriately selective at the specified quantile. Conversely, conventional estimates exhibited negative bias that increased with decreasing (Formula presented.). To contextualize our empirical results, we performed a detailed simulation study to tease apart how sampling frequency, sampling duration, and the focal animal´s movement conspire to affect range estimates. Paralleling our empirical results, the simulation study demonstrated that AKDE was generally more accurate than conventional methods, particularly for small (Formula presented.). While 72% of the 369 empirical data sets had >1,000 total observations, only 4% had an (Formula presented.) >1,000, where 30% had an (Formula presented.) <30. In this frequently encountered scenario of small (Formula presented.), AKDE was the only estimator capable of producing an accurate home range estimate on autocorrelated data.Fil: Noonan, Michael J.. National Zoological Park; Estados Unidos. University of Maryland; Estados UnidosFil: Tucker, Marlee A.. Senckenberg Gesellschaft Für Naturforschung; . Goethe Universitat Frankfurt; AlemaniaFil: Fleming, Christen H.. University of Maryland; Estados Unidos. National Zoological Park; Estados UnidosFil: Akre, Thomas S.. National Zoological Park; Estados UnidosFil: Alberts, Susan C.. University of Duke; Estados UnidosFil: Ali, Abdullahi H.. Hirola Conservation Programme. Garissa; KeniaFil: Altmann, Jeanne. University of Princeton; Estados UnidosFil: Antunes, Pamela Castro. Universidade Federal do Mato Grosso do Sul; BrasilFil: Belant, Jerrold L.. State University of New York; Estados UnidosFil: Beyer, Dean. Universitat Phillips; AlemaniaFil: Blaum, Niels. Universitat Potsdam; AlemaniaFil: Böhning Gaese, Katrin. Senckenberg Gesellschaft Für Naturforschung; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Cullen Jr., Laury. Instituto de Pesquisas Ecológicas; BrasilFil: de Paula, Rogerio Cunha. National Research Center For Carnivores Conservation; BrasilFil: Dekker, Jasja. Jasja Dekker Dierecologie; Países BajosFil: Drescher Lehman, Jonathan. George Mason University; Estados Unidos. National Zoological Park; Estados UnidosFil: Farwig, Nina. Michigan State University; Estados UnidosFil: Fichtel, Claudia. German Primate Center; AlemaniaFil: Fischer, Christina. Universitat Technical Zu Munich; AlemaniaFil: Ford, Adam T.. University of British Columbia; CanadáFil: Goheen, Jacob R.. University of Wyoming; Estados UnidosFil: Janssen, René. Bionet Natuuronderzoek; Países BajosFil: Jeltsch, Florian. Universitat Potsdam; AlemaniaFil: Kauffman, Matthew. University Of Wyoming; Estados UnidosFil: Kappeler, Peter M.. German Primate Center; AlemaniaFil: Koch, Flávia. German Primate Center; AlemaniaFil: LaPoint, Scott. Max Planck Institute für Ornithologie; Alemania. Columbia University; Estados UnidosFil: Markham, A. Catherine. Stony Brook University; Estados UnidosFil: Medici, Emilia Patricia. Instituto de Pesquisas Ecológicas (IPE) ; BrasilFil: Morato, Ronaldo G.. Institute For Conservation of The Neotropical Carnivores; Brasil. National Research Center For Carnivores Conservation; BrasilFil: Nathan, Ran. The Hebrew University of Jerusalem; IsraelFil: Oliveira Santos, Luiz Gustavo R.. Universidade Federal do Mato Grosso do Sul; BrasilFil: Olson, Kirk A.. Wildlife Conservation Society; Estados Unidos. National Zoological Park; Estados UnidosFil: Patterson, Bruce. Field Museum of National History; Estados UnidosFil: Paviolo, Agustin Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Ramalho, Emiliano Esterci. Institute For Conservation of The Neotropical Carnivores; Brasil. Instituto de Desenvolvimento Sustentavel Mamirauá; BrasilFil: Rösner, Sascha. Michigan State University; Estados UnidosFil: Schabo, Dana G.. Michigan State University; Estados UnidosFil: Selva, Nuria. Institute of Nature Conservation of The Polish Academy of Sciences; PoloniaFil: Sergiel, Agnieszka. Institute of Nature Conservation of The Polish Academy of Sciences; PoloniaFil: Xavier da Silva, Marina. Parque Nacional do Iguaçu; BrasilFil: Spiegel, Orr. Universitat Tel Aviv; IsraelFil: Thompson, Peter. University of Maryland; Estados UnidosFil: Ullmann, Wiebke. Universitat Potsdam; AlemaniaFil: Ziḝba, Filip. Tatra National Park; PoloniaFil: Zwijacz Kozica, Tomasz. Tatra National Park; PoloniaFil: Fagan, William F.. University of Maryland; Estados UnidosFil: Mueller, Thomas. Senckenberg Gesellschaft Für Naturforschung; . Goethe Universitat Frankfurt; AlemaniaFil: Calabrese, Justin M.. National Zoological Park; Estados Unidos. University of Maryland; Estados Unido

Moving in the anthropocene: global reductions in terrestrial mammalian movements

Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effects of two neuromuscular training programs on running biomechanics with load carriage: a study protocol for a randomised controlled trial

Background In recent years, athletes have ventured into ultra-endurance and adventure racing events, which tests their ability to race, navigate, and survive. These events often require race participants to carry some form of load, to bear equipment for navigation and survival purposes. Previous studies have reported specific alterations in biomechanics when running with load which potentially influence running performance and injury risk. We hypothesize that a biomechanically informed neuromuscular training program would optimize running mechanics during load carriage to a greater extent than a generic strength training program. Methods This will be a two group, parallel randomized controlled trial design, with single assessor blinding. Thirty healthy runners will be recruited to participate in a six weeks neuromuscular training program. Participants will be randomized into either a generic training group, or a biomechanically informed training group. Primary outcomes include self-determined running velocity with a 20 % body weight load, jump power, hopping leg stiffness, knee extensor and triceps-surae strength. Secondary outcomes include running kinetics and kinematics. Assessments will occur at baseline and post-training. Discussion To our knowledge, no training programs are available that specifically targets a runner’s ability to carry load while running. This will provide sport scientists and coaches with a foundation to base their exercise prescription on

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme