### The TR Prize are monthly awards for the best new research.

#### 1. SorCS1-mediated Sorting of Neurexin in Dendrites Maintains Presynaptic Function

18 February 2019 | Biorxiv link | Write review

The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The mechanisms that maintain the polarized distribution of synaptic membrane proteins are poorly understood. The sorting receptor SorCS1 is a critical trafficking regulator of neuronal receptors, including neurexin (Nrxn), a presynaptic adhesion molecule essential for synaptic transmission. We find that SorCS1 controls a balance between axonal and dendritic Nrxn1 surface levels. Newly synthesized Nrxn1 traffics to the somatodendritic surface, followed by endocytosis. SorCS1 interacts with the Rab11 effector protein Rab11FIP5/Rip11 to facilitate the transition of internalized Nrxn1 from early to recycling endosomes and bias Nrxn1 surface polarization toward the axon. In the absence of SorCS1, Nrxn1 accumulates in early endosomes and mis-polarizes to the dendritic surface, impairing presynaptic function. The axonal/dendritic balance of Nrxn1 surface distribution is activity-dependent, indicating that SorCS1-mediated sorting in somatodendritic endosomes dynamically controls Nrxn1 axonal surface polarization required for proper presynaptic function.

#### 2. Demixed principal component analysis of population activity in higher cortical areas reveals independent representation of task parameters

18 February 2019 | Arxiv link | Write review

Neurons in higher cortical areas, such as the prefrontal cortex, are known to be tuned to a variety of sensory and motor variables. The resulting diversity of neural tuning often obscures the represented information. Here we introduce a novel dimensionality reduction technique, demixed principal component analysis (dPCA), which automatically discovers and highlights the essential features in complex population activities. We reanalyze population data from the prefrontal areas of rats and monkeys performing a variety of working memory and decision-making tasks. In each case, dPCA summarizes the relevant features of the population response in a single figure. The population activity is decomposed into a few demixed components that capture most of the variance in the data and that highlight dynamic tuning of the population to various task parameters, such as stimuli, decisions, rewards, etc. Moreover, dPCA reveals strong, condition-independent components of the population activity that remain unnoticed with conventional approaches.

#### 3. Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes

18 February 2019 | Biorxiv link | Write review

Mouse embryonic stem cells (mESCs) cultured under controlled conditions occupy a stable ground state where pluripotency-associated transcriptional and epigenetic circuitry are highly active. However, mESCs from some genetic backgrounds exhibit metastability, where ground state pluripotency is lost in the absence of ERK1/2 and GSK3 inhibition. We dissected the genetic basis of metastability by profiling gene expression and chromatin accessibility in 185 genetically heterogeneous mESCs. We mapped thousands of loci affecting chromatin accessibility and/or transcript abundance, including eleven instances where distant QTL co-localized in clusters. For one cluster we identified Lifr transcript abundance as the causal intermediate regulating 122 distant genes enriched for roles in maintenance of pluripotency. Joint mediation analysis implicated a single enhancer variant ~10kb upstream of Lifr that alters chromatin accessibility and precipitates a cascade of molecular events affecting maintenance of pluripotency. We validated this hypothesis using reciprocal allele swaps, revealing mechanistic details underlying variability in ground state metastability in mESCs.

#### 4. Clueless forms dynamic, insulin-responsive bliss particles sensitive to stress

17 February 2019 | Biorxiv link | Write review

Mitochondria perform a myriad of biochemical functions in the cell that integrate ATP production and metabolism. While mitochondria contain their own genome, mtDNA, it only encodes thirteen proteins required for oxidative phosphorylation, thus well over one thousand proteins required for all mitochondrial functions are encoded in the nucleus. One such protein is Drosophila Clueless (Clu), whose vertebrate homolog is Clustered mitochondria homolog (Cluh). Clu/Cluh is a ribonucleoprotein that regulates mRNAs destined for import into mitochondria and is an essential protein that regulates cellular metabolism. Clu forms large particles in the cytoplasm, although how these particles relate to nutrition and metabolic stress is unknown. Using live-imaging, we show Clu particles are highly dynamic. Clu particles appear to be unique as they do not colocalize with many known cytoplasmic bodies. In addition, Clu particle formation is highly dependent on diet as ovaries from starved females no longer contain Clu particles although Clu protein levels remain the same and insulin is necessary and sufficient for Clu particle formation. Oxidative stress also disperses particle. Since Clu particles are only present under optimal conditions we are naming them bliss particles. These observations identify Clu particles as unique, stress-sensitive cytoplasmic ribonucleoprotein particles whose absence corresponds with altered mitochondrial function and localization.

#### 5. The value of non-motor features and genetic variants of Parkinson\'s disease for clustering Lewy body diseases

17 February 2019 | Biorxiv link | Write review

Introduction The use of non-motor Parkinson's disease (PD) features and genetic PD variants for clustering analyses may refine the phenotypic classification of idiopathic Lewy body (LB) diseases. Methods One-hundred participants [n=7 E46K-SNCA (n=5 symptomatic and n=2 asymptomatic), n=4 PARK2, n=3 LRRK2, n=8 dementia with Lewy bodies (DLB), n=48 idiopathic PD (iPD), n=30 healthy controls (HC)] underwent a comprehensive evaluation of non-motor and motor PD features. Non-motor features were used to perform a hierarchical clustering analysis with patients and HC using a Scikit-learn toolkit. Results Clustering analysis suggested three clusters of subjects including Cluster 1 or "Normal-to-mild": young iPD (< 60 years) classified together with most HC and the variable LB burden genetic PD variants (PARK2 and LRRK2) characterized by having normal-to-mild cognitive disabilities and mild-to-moderate motor disability with few axial symptoms; Cluster 2 or "Mild-to-moderate": old iPD patients (>60 years) classified together with the lowest symptomatic E46K-SNCA, PARK2 carriers and HCs, characterizing by having mild-to-moderate cognitive and motor disabilities with few axial symptoms; and Cluster 3 or "Severe": old iPD (>60 years) classified together with all DLB and the most symptomatic E46K-SNCA carriers, characterized by having severe pattern-specific cognitive disabilities (visual attention, perception, processing speed, memory and executive functions) and severe motor PD manifestations with marked axial symptoms. Conclusions Our study supports the potential value of incorporating genetic PD variants in data-driven iPD classification algorithms and the usefulness of non-motor PD features, especially visual cognition abnormalities, to facilitate the identification of aggressive LB diseases.

#### 6. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition

16 February 2019 | Biorxiv link | Write review

How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2'3'-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2'3'-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a novel therapeutic hypothesis for autoimmune syndrome treatment.

#### 7. Interplay of spatial dynamics and local adaptation shapes species lifetime distributions and species-area relationships

16 February 2019 | Arxiv link | Write review

The distributions of species lifetimes and species in space are related, since species with good local survival chances have more time to colonize new habitats and species inhabiting large areas have higher chances to survive local disturbances. Yet, both distributions have been discussed in mostly separate communities. Here, we study both patterns simultaneously using a spatially explicit, evolutionary community assembly approach. We present and investigate a metacommunity model, consisting of a grid of patches, where each patch contains a local food web. Species survival depends on predation and competition interactions, which in turn depend on species body masses as the key traits. The system evolves due to the migration of species to neighboring patches, the addition of new species as modifications of existing species, and local extinction events. The structure of each local food web thus emerges in a self-organized manner as the highly non-trivial outcome of the relative time scales of these processes. Our model generates a large variety of complex, multi-trophic networks and therefore serves as a powerful tool to investigate ecosystems on long temporal and large spatial scales. We find that the observed lifetime distributions and species-area relations resemble power laws over appropriately chosen parameter ranges and thus agree qualitatively with empirical findings. Moreover, we observe strong finite-size effects, and a dependence of the relationships on the trophic level of the species. By comparing our results to simple neutral models found in the literature, we identify the features that are responsible for the values of the exponents.

#### 8. Trends of Hospitalization in Acute Pancreatitis in Patients in the United States from 2001-2014

16 February 2019 | Biorxiv link | Write review

Background & Purpose: The prevalence of acute pancreatitis (AP) has increased over time and is one of the most important gastrointestinal causes of frequent admissions to hospital in the United States. The cost burden of AP has been steadily increasing. The primary objective of our study was to analyze patient demographics, cost burden, mortality and length of stay associated with AP hospital admissions. Methods: Nationwide inpatient sample (NIS) database was used to identify AP admissions in all patients from [≥]18 years of age from 2001 to 2014 using ICD-9-CM code 577.0 as the principal discharge diagnosis. Results: The number of hospitalizations increased from 215,238 in 2001 to 279,145 in 2014. In-hospital mortality decreased from 1.74% in 2001 to 0.66% in 2014. Mean length of hospital stay has decreased from 6.1 days to 4.6 days during the same period, but the mean hospital charges increased from $19,303 in 2001 to$35,728 in 2014. The proportion of males to females with acute pancreatitis is slowly trending up from 2001 to 2014. Conclusion: The number of hospitalizations due to acute pancreatitis has been steadily increasing, and further research needs to be done on finding out the reasons for increased causes of hospitalization and ways to decrease the cost burden on patients and hospitals.

#### 9. Humans: the hyper-dense species

16 February 2019 | Arxiv link | Write review

Humans, like all organisms, are subject to fundamental biophysical laws. Van Valen predicted that, because of zero-sum dynamics, all populations of all species in a given environment flux the same amount of energy on average. Damuth's 'energetic equivalence rule' supported Van Valen's conjecture by showing a trade off between few big animals per area with high individual metabolic rates compared to abundant small species with low energy requirements. We use established metabolic scaling theory to compare variation in densities and individual energy use in human societies to other land mammals. We show that hunter-gatherers occurred at lower densities than a mammal of our size. Most modern humans, in contrast, concentrate in large cities at densities that are up to four orders of magnitude greater than hunter-gatherers yet cities consume up to two orders of magnitude greater energy per capita. Today, cities across the globe flux greater energy than net primary productivity on a per area basis. This is possible through enormous fluxes of energy and materials across urban boundaries to sustain hyper-dense, modern humans. The metabolic rift with nature created by hyper-dense cities supported by fossil fuel energy poses formidable challenges for establishing a sustainable relationship on a rapidly urbanizing, yet finite planet.

#### 10. Genome-wide identification and analysis of A-to-I RNA editing events in the malignantly transformed cell lines from BEP2D induced by α-particles radiation

15 February 2019 | Biorxiv link | Write review

Adenosine (A) to inosine (I) RNA editing is the most prevalent RNA editing mechanism in humans and play critical roles in tumorigenesis. However, the effects of radiation on RNA editing and the mechanisms of radiation-induced cancer were poorly understood. Here, we analyzed human bronchial epithelial BEP2D cells and radiation-induced malignantly transformed cells with next generation sequencing. By performing an integrated analysis of A-to-I RNA editing, we found that genome-encoded single-nucleotide polymorphisms (SNPs) might induce the downregulation of ADAR2 enzymes, and further caused the abnormal occurrence of RNA editing in malignantly transformed cells. These editing events were significantly enriched in differentially expressed genes between normal cells and cancer cells. In addition, oncogenes CTNNB1 and FN1 were highly edited and significantly overexpressed in cancer cells, thus may be responsible for the lung cancer progression. Our work provides a systematic analysis of RNA editing from lung tumor specimens with high-throughput RNA sequencing and DNA sequencing. Moreover, these results demonstrate further evidence for RNA editing as an important tumorigenesis mechanism.

#### 11. Figuring Out Art History

15 February 2019 | Arxiv link | Write review

World population and the number of cultural artifacts are growing exponentially or faster, while cultural interaction approaches the fidelity of a global nervous system. Every day hundreds of millions of images are loaded into social networks by users all over the world. As this myriad of new artifacts veils the view into the past, like city lights covering the night sky, it is easy to forget that there is more than one Starry Night, the painting by Van Gogh. Like in ecology, where saving rare species may help us in treating disease, art and architectural history can reveal insights into the past, which may hold keys to our own future. With humanism under threat, facing the challenge of understanding the structure and dynamics of art and culture, both qualitatively and quantitatively, is more crucial now than it ever was. The purpose of this article is to provide perspective in the aim of figuring out the process of art history - not art history as a discipline, but the actual history of all made things, in the spirit of George Kubler and Marcel Duchamp. In other words, this article deals with the grand challenge of developing a systematic science of art and culture, no matter what, and no matter how.

#### 12. Identification of circadian rhythms in Nannochloropsis species using bioluminescence reporter lines

15 February 2019 | Biorxiv link | Write review

Circadian clocks allow organisms to predict environmental changes caused by the rotation of the Earth. Although circadian rhythms are widespread among different taxa, the core components of circadian oscillators are not conserved and differ between bacteria, plants, animals and fungi. Stramenopiles are a large group of organisms in which circadian rhythms have been only poorly characterized and no clock components have been identified. We have investigated cell division and molecular rhythms in Nannochloropsis species. In the four strains tested, cell division occurred principally during the night period under diel conditions, however, rhythms dampened within 2-3 days after transfer to constant light. We developed firefly luciferase reporters for long-term monitoring of in vivo transcriptional rhythms in two Nannochlropsis species, N. oceanica CCMP1779 and N. salina CCMP537. The reporter lines express free-running bioluminescence rhythms with periods of ~21-31 h that dampen within ~3-4 days under constant light. Using different entrainment regimes, we demonstrate that these rhythms are regulated by a circadian-type oscillator. In addition, the phase of free-running luminescence rhythms can be modulated pharmacologically using a CK1 {varepsilon}/{delta} inhibitor, suggesting a role of this kinase in the Nannochloropsis clock. Together with the molecular and genomic tools available for Nannochloropsis species, these reporter lines represent an excellent system for future studies on the molecular mechanisms of stramenopile circadian oscillators.

#### 13. The power of moral words: Understanding framing effects in extreme Dictator games using sentiment analysis and moral judgments

15 February 2019 | Arxiv link | Write review

Recent work suggests that people are not solely motivated by the economic consequences of the available actions, but they also have moral preferences for "doing the right thing", independently of its economic consequences. However, it remains unclear in what situations moral preferences can be activated by simply changing the framing of a decision problem. For example, earlier work proposed that moral preferences can account for framing effects in the Dictator game. However, more recent work has casted doubts on the very existence of framing effects in this game. Here we shed light on this point with two experiments. In Study 1 ($N=567$) we implement an extreme Dictator game in which dictators either get \$0.50 and another person gets nothing, or the opposite (i.e., the other person gets \$0.50 and the dictator gets nothing). We experimentally manipulate the words describing the available actions using six words, from very negative (e.g., stealing) to very positive (e.g., donating) connotations. As we predicted, we find that the rate of pro-sociality is affected by the words used to describe the available actions. In Study 2 ($N=413$, pre-registered) we collect the self-reported moral judgment and feeling associated to each of the six words used in Study 1. We show that these moral judgments and feelings can explain the framing effects in Study 1. In sum, we find that changing only one word in the instructions of an extreme Dictator game can alter people's behavior, and that behavioral changes can be explained using moral judgments and feelings associated to these words.

#### 14. Expression changes confirm predicted single nucleotide variants affecting mRNA splicing

14 February 2019 | Biorxiv link | Write review

Mutations that cause genetic diseases can be difficult to identify if the mutation does not affect the sequence of the protein, but the splice form of the transcript. However, the prediction of deleterious changes caused by genomic variants that affect splicing has been shown to be accurate using information theory-based methods. We made several such predictions of potential splicing changes that could be caused by SNPs which were found to cause natural and/or cryptic splice site strength changes. We evaluated a selected set of 22 SNPs that we predicted by information analysis to affect splicing, validated these with targeted expression analysis, and compared the results with genome-scale interpretation of RNAseq data from tumors. Abundance of natural and predicted splice isoforms were quantified by q-RT-PCR and with probeset intensities from exon microarrays using RNA isolated from HapMap lymphoblastoid cell lines containing the predicted deleterious variants. These SNPs reside within the following genes: XRCC4, IL19, C21orf2, UBASH3A, TTC3, PRAME, EMID1, ARFGAP3, GUSBP11 (F{lambda}8), WBP2NL, LPP, IFI44L, CFLAR, FAM3B, CYB5R3, COL6A2, BCR, BACE2, CLDN14, TMPRSS3 and DERL3. 15 of these SNPs showed a significant change in the use of the affected splice site. Individuals homozygous for the stronger allele had higher transcription of the associated gene than individuals with the weaker allele in 3 of these SNPs. 13 SNPs had a direct effect on exon inclusion, while 10 altered cryptic site use. In 4 genes, individuals of the same genotype had high expression variability caused by alternate factors which masked potential effects of the SNP. Targeted expression analyses for 8 SNPs in this study were confirmed by results of genome-wide information theory and expression analyses.

#### 15. Wright-Fisher construction of the two-parameter Poisson-Dirichlet diffusion

14 February 2019 | Arxiv link | Write review

The two-parameter Poisson--Dirichlet diffusion, introduced in 2009 by Petrov, extends the infinitely-many-neutral-alleles diffusion model, related to Kingman's one-parameter Poisson--Dirichlet distribution and to certain Fleming--Viot processes. The additional parameter has been shown to regulate the clustering structure of the population, but is yet to be fully understood in the way it governs the reproductive process. Here we shed some light on these dynamics by formulating a $K$-allele Wright--Fisher model for a population of size $N$, involving a uniform mutation pattern and a specific state-dependent migration mechanism. Suitably scaled, this process converges in distribution to a $K$-dimensional diffusion process as $N\to\infty$. Moreover, the descending order statistics of the $K$-dimensional diffusion converge in distribution to the two-parameter Poisson--Dirichlet diffusion as $K\to\infty$. The choice of the migration mechanism depends on a delicate balance between reinforcement and redistributive effects. The proof of convergence to the infinite-dimensional diffusion is nontrivial because the generators do not converge on a core. Our strategy for overcoming this complication is to prove \textit{a priori} that in the limit there is no "loss of mass", i.e., that, for each limit point of the sequence of finite-dimensional diffusions (after a reordering of components by size), allele frequencies sum to one.

#### 16. Optogenetic control reveals differential promoter interpretation of transcription factor nuclear translocation dynamics

14 February 2019 | Biorxiv link | Write review

The dynamic translocation of transcription factors (TFs) in and out of the nucleus is thought to encode information, such as the identity of a stimulus. A corollary is the idea that gene promoters can decode different dynamic TF translocation patterns. Testing this TF encoding/promoter decoding hypothesis requires tools that allow direct control of TF dynamics without the pleiotropic effects associated with general perturbations. In this work, we present CLASP (Controllable Light Activated Shuttling and Plasma membrane sequestration), a tool that enables precise, modular, and reversible control of TF localization using a combination of two optimized LOV2 optogenetic constructs. The first sequesters the cargo in the dark at the plasma membrane and releases it upon exposure to blue light, while light exposure of the second reveals a nuclear localization sequence that shuttles the released cargo to the nucleus. CLASP achieves minute-level resolution, reversible translocation of many TF cargos, large dynamic range, and tunable target gene expression. Using CLASP, we investigate the relationship between Crz1, a naturally pulsatile TF, and its cognate promoters. We establish that some Crz1 target genes respond more efficiently to pulsatile TF inputs than to continuous inputs, while others exhibit the opposite behavior. We show using computational modeling that efficient gene expression in response to short pulsing requires fast promoter activation and slow inactivation and that the opposite phenotype can ensue from a multi-stage promoter activation, where a transition in the first stage is thresholded. These data directly demonstrate differential interpretation of TF pulsing dynamics by different genes, and provide plausible models that can achieve these phenotypes.

#### 17. A Theoretical Study of Process Dependence for Critical Statistics in Standard Serial Models and Standard Parallel Models

14 February 2019 | Arxiv link | Write review

Critical parts of the definitions of standard serial and standard parallel modes refer to stochastic independence. Standard serial models are defined by stochastic independence and identical distributions of their processing times. Processing times in the serial models are identical to the intercompletion time statistics. Similarly, standard parallel models assume stochastically independent and identical processing times. Their processing times are equivalent to the statistic known as total completion times. Little is known about what standard serial models can predict for the total completion time or what standard parallel models can predict for the intercompletion times. Here we demonstrate that standard serial models possess a tendency to predict a positive dependence for the total completion times with that always being true in the case of a single processing order. However, with mixtures of processing orders, standard serial models may predict negative dependence of the total completion times. Comparably, standard parallel models typically predict neither independence of the intercompletion times nor identical distributions. In fact, standard parallel models predict increasing intercompletion times as the individual channels continue to finish. Nevertheless, dramatically increasing hazard functions of the channels can defeat that tendency. And, standard parallel models can predict intercompletion time independence but only when individual channel distributions are exponential. Finally, we use these and ancillary mathematical results to conclude that standard serial and standard parallel models can never perfectly mimic one another. Therefore, our findings set the stage for explicit model testing between these classes.

#### 18. Exercise twice-a-day potentiates skeletal muscle signalling responses associated with mitochondrial biogenesis in humans, which are independent of lowered muscle glycogen content

13 February 2019 | Biorxiv link | Write review

Endurance exercise begun with reduced muscle glycogen stores seems to potentiate skeletal muscle protein abundance and gene expression. However, it is unknown whether this greater signalling responses is due to low muscle glycogen per se or to performing two exercise sessions in close proximity - as a first exercise session is necessary to reduce the muscle glycogen stores. In the present study, we manipulated the recovery duration between a first muscle glycogen-depleting exercise and a second exercise session, such that the second exercise session started with reduced muscle glycogen in both approaches but was performed either two or 15 h after the first exercise session (so-called twice-a-day and once-daily approaches, respectively). We found that exercise twice-a-day increased the nuclear abundance of transcription factor EB (TFEB) and nuclear factor of activated T cells (NFAT) and potentiated the transcription of peroxisome proliferator-activated receptor-{gamma} coactivator 1 alpha (PGC-1a), peroxisome proliferator-activated receptor alpha (PPARa;) and peroxisome proliferator-activated receptor beta/delta (PPARb/d) genes, in comparison with the once-daily exercise. These results suggest that the elevated molecular signalling reported with previous train-low approaches can be attributed to performing two exercise sessions in close proximity rather than the reduced muscle glycogen content per se. The twice-a-day approach might be an effective strategy to induce adaptations related to mitochondrial biogenesis and fat oxidation.

#### 19. Mathematical Modeling of Dengue Epidemic: Control Methods and Vaccination Strategies

13 February 2019 | Arxiv link | Write review

Dengue is one of the most important infectious diseases in the world, in terms of death and economic cost. Hence, the modeling of dengue is of great importance to help us understand the dynamics disease, and interfering with its spreading mathematical by the proposition of control methods. In this work, control strategies in an attempt to eliminate the Aedes aegypti mosquito, as well as proposals for the vaccination campaign are evaluated. In our mathematical model, the mechanical control is accomplished through the environmental support capacity affected by a discrete function that represents removal of breeding. Chemical control is carried out from the use of insecticide and larvicidal. The efficacious of vaccination is studied through the removal of a fraction of individuals, proportional to the rate of vaccination, from the susceptible compartment and its transfer to the recovered compartment. Our major find is that the dengue fever epidemic is only eradicated with the use of an immunizing vaccine because control measures directed against the vector are not enough to halt disease spreading. Even where the infected mosquitoes are eliminated from the system, susceptible mosquitoes are still present, and infected humans cause dengue fever to reappear in the human population.

#### 20. The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

13 February 2019 | Biorxiv link | Write review

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to vary with behavioral state and can be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as BE-experienced animals after a two-week period of abstinence to relate the number of LH orexin cells to economic demand for cocaine. We also unilaterally knocked down LH orexin expression prior to BE with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. Animals with greater motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a two-week abstinence from BE, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual demand for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.

#### 21. Spin and Wind Directions I: Identifying Entanglement in Nature and Cognition

13 February 2019 | Arxiv link | Write review

We present a cognitive psychology experiment where participants were asked to select pairs of spatial directions that they considered to be the best example of 'Two Different Wind Directions'. Data are shown to violate the CHSH version of Bell's inequality with the same magnitude as in typical Bell-test experiments with entangled spins. Wind directions thus appear to be conceptual entities connected through meaning, in human cognition, in a similar way as spins appear to be entangled in experiments conducted in physics laboratories. This is the first part of a two-part article. In the second part we present a symmetrized version of the same experiment for which we provide a quantum modeling of the collected data in Hilbert space.

#### 22. Real-time computation of the TMS-induced electric field in a realistic head model

12 February 2019 | Biorxiv link | Write review

#### 23. Evolutionarily induced alternative states and coexistence in systems with apparent competition

12 February 2019 | Arxiv link | Write review

Predators often consume multiple prey and by mutually subsidizing a shared predator, the prey may reciprocally harm each other. When predation levels are high, this apparent competition can culminate in a prey species being displaced. Coupling quantitative genetics and Lotka-Volterra models, we study how predator evolution alters this and other ecological outcomes. These models account for a trade-off between the predator's attack rates on two prey species. We provide a mathematical characterization of a strong form of persistence--permanence--for which there is a global attractor bounded away from extinction. When the evolutionary dynamics occur at a sufficiently slower time scale than the ecological dynamics, we also characterize attractors and their basins' of attraction using singular perturbation theory and a graphical approach to the eco-evolutionary dynamics. Our results show that eco-evolutionary feedbacks can mediate permanence at intermediate trade-offs in the attack rates. However, at strong trade-offs, permanence is lost. Despite this loss of permanence, there can be attractors supporting coexistence. These attractors, however, may coincide with attractors at which the predator is excluded. Our results highlight that evo-evolutionary feedbacks can alter community structure by mediating coexistence or leading to trait-dependent alternative stable states.

#### 24. Quantifying the impact of genetically regulated expression on complex traits and diseases

12 February 2019 | Biorxiv link | Write review

About 90% of risk variants identified from genome-wide association studies (GWAS) are located in non-coding regions, highlighting the regulatory role of genetic variants. We propose a unified statistical framework, IGREX, for quantifying the impact of genetically regulated expression (GREX). This is achieved by estimating proportion of phenotypic variations that can be explained by the GREX component. IGREX only requires summary-level GWAS data and a gene expression reference panel as input. In real data analysis, using 48 tissues from the GTEx project as the reference panel, we applied IGREX to a wide spectrum of phenotypes in GWAS, and observed a significant proportion of phenotypic variations could be attributed to the GREX component. In particular, the results given by IGREX revealed tissue-across and tissue-specific patterns of the GREX effects. We also observed strong association between GREX effect and immune-related proteins, further supporting the relevance between GREX and the immune processes.

#### 25. Accelerating molecular dynamics simulations with population annealing

12 February 2019 | Arxiv link | Write review

Population annealing is a powerful tool for large-scale Monte Carlo simulations. We adapt this method to molecular dynamics simulations and demonstrate its excellent accelerating effect by simulating the folding of a short peptide commonly used to gauge the performance of algorithms. The method is compared to the well established parallel tempering approach and is found to yield similar performance for the same computational resources. In contrast to other methods, however, population annealing scales to a nearly arbitrary number of parallel processors and it is thus a unique tool that enables molecular dynamics to tap into the massively parallel computing power available in supercomputers that is so much needed for a range of difficult computational problems.

#### 26. Subject sex and partner sex modulate social touch responses across multiple cortical areas

11 February 2019 | Biorxiv link | Write review

Touch is a fundamental aspect of mammalian social, parental and sexual behavior. Human affective touch is critical for healthy child development and shows great promise as a novel therapeutic strategy for mental disorders characterized by social dysfunction, such as anxiety, depression and autism spectrum disorder. However, despite our detailed knowledge about cortical processing of non-social touch, we still know very little about how social touch modulates cortical circuits. We investigated the activity patterns of single neurons (N = 1156) across five sensory and frontal cortical areas in both male and female rats (N = 28) engaging in naturalistic social facial touch with male and female conspecifics. We found that information about social touch is widely available across cortex. Besides touch, the sex of the interaction partner (a biologically significant feature) is a major determinant of single neuron activity, and across cortex we observed 25.7% "touch" and 11.9% "sex-touch" responses. Although all areas investigated had access to social touch and partner sex information, social touch modulated different cortical areas in different ways. Finally, we found that network activity patterns during social touch depend on both subject sex and partner sex. Interestingly, these sex-differences in network activity patterns were differences in response magnitude and would not be evident without single cell resolution. Our observations suggest that socio-sexual characteristics of touch (subject and partner sex) widely modulate cortical activity and need to be investigated with cellular resolution.

#### 27. Tensor clustering with algebraic constraints gives interpretable groups of crosstalk mechanisms in breast cancer

11 February 2019 | Arxiv link | Write review

We introduce a tensor-based clustering method to extract sparse, low-dimensional structure from high-dimensional, multi-indexed datasets. This framework is designed to enable detection of clusters of data in the presence of structural requirements which we encode as algebraic constraints in a linear program. Our clustering method is general and can be tailored to a variety of applications in science and industry. We illustrate our method on a collection of experiments measuring the response of genetically diverse breast cancer cell lines to an array of ligands. Each experiment consists of a cell line-ligand combination, and contains time-course measurements of the early-signalling kinases MAPK and AKT at two different ligand dose levels. By imposing appropriate structural constraints and respecting the multi-indexed structure of the data, the analysis of clusters can be optimized for biological interpretation and therapeutic understanding. We then perform a systematic, large-scale exploration of mechanistic models of MAPK-AKT crosstalk for each cluster. This analysis allows us to quantify the heterogeneity of breast cancer cell subtypes, and leads to hypotheses about the signalling mechanisms that mediate the response of the cell lines to ligands.

#### 28. Generation of inducible SMARCAL1 knock-down iPSC to model severe Schimke immune-osseous dysplasia reveals a link between replication stress and altered expression of master differentiation genes

11 February 2019 | Biorxiv link | Write review

The Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain pathophysiology of the disease, however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Indeed, animal models of the disease are absent or useless to provide insight into the disease mechanism, since they do not recapitulate the phenotype. We generated a conditional knockdown model of SMARCAL1 in iPSCs to mimic conditions of cells with severe form the disease. Here, we characterize this model for the presence of phenotype linked to the replication caretaker role of SMARCAL1 using multiple cellular endpoints. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide data showing that, in SMARCAL1-deficient iPSCs, DNA damage response can be maintained active also after differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. In conclusion, our conditional SMARCAL1 iPSCs may represent a powerful model where studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia, thus overcoming the reported inability of different model systems to recapitulate the disease.

#### 29. Adult-born neurons inhibit developmentally-born neurons in the dentate gyrus

10 February 2019 | Biorxiv link | Write review

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. Emerging evidence from mouse models suggests that adult-born neurons exert an inhibitory influence on the dentate gyrus, which may be important for maintaining the sparse code that is needed to form precise memories. However, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, it is unclear if newborn neurons inhibit all cells equally. We therefore investigated whether adult neurogenesis in rats modulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by quantifying experience-induced Fos expression in BrdU+ cells. Consistent with an inhibitory role, enhancing neurogenesis blocked experience-dependent Fos expression in developmentally-born neurons and also in the broader granule cell population. In contrast, blocking neurogenesis did not significantly impact activity patterns. These results confirm previous work in mice and identify the developmentally-born population of neurons as a major target of neurogenesis-mediated inhibition. Treatments that target neurogenesis may therefore benefit disorders that are characterized by excitation-inhibition imbalance in the hippocampus, such as age-related memory impairments, fear and anxiety, and epilepsy.

#### 30. Exercise-induced enhancement of synaptic functiontriggered by the inverse BAR protein, Mtss1L.

10 February 2019 | Biorxiv link | Write review

The molecular mechanisms underlying the short and long-term beneficial effects of exercise on learning and memory likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked mature dentate granule cells activated specifically during exercise using conditional Fos-TRAP mice. Only a few dentate granule cells were activated at baseline, but two hours of voluntary exercise markedly increased the number of activated neurons. Activated neurons (Fos-TRAPed) showed an increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, consistent with exercise-induced structural plasticity. Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied gene in the adult brain. Overexpression of Mtss1L in neurons increased spine density, consistent with a role of its I-BAR domain in membrane curvature and spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as an effector in activity-dependent rearrangement of synapses.