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

Below is this month's biology research from Biorxiv and Arxiv. TR Prizes based on your donations and peer reviews of these works are given at the end of each month.

1. Semi-supervised identification of cell populations in single-cell ATAC-seq

20 November 2019 | Biorxiv link | Write review

Identifying high-confidence cell-type specific open chromatin regions with coherent regulatory function from single-cell open chromatin data (scATAC-seq) is difficult due to the complexity of resolving cell types given the low coverage of reads per cell. In order to address this problem, we present Semi-Supervised Identification of Populations of cells in scATAC-seq data (SSIPs), a semi-supervised approach that integrates bulk and single-cell data through a generalizable network model featuring two types of nodes. Nodes of the first type represent cells from scATAC-seq with edges between them encoding information about cell similarity. A second set of nodes represents "supervising" datasets connected to cell nodes with edges that encode the similarity between that data and each cell. Via global calculations of network influence, this model allows us to quantify the influence of bulk data on scATAC-seq data and estimate the contributions of scATAC-seq cell populations to signals in bulk data. Using simulated data, we show that SSIPs successfully separates distinct cell types even when they differ in very few mapped scATAC-seq reads, with a significant improvement over unsupervised cell type identification. We apply SSIPs to scATAC-seq data from the developing human brain and show that supervising with just 25 differentially expressed genes from scRNA-seq enables the identification of two subtypes of interneurons not identifiable from scATAC-seq data alone. SSIPs opens the door to identifying high resolution cell types in single-cell open chromatin data, enabling the study of cell-type specific regulatory elements.

2. Infinite graphs in systematic biology, with an application to the species problem

20 November 2019 | Arxiv link | Write review

We argue that C. Darwin and more recently W. Hennig worked at times under the simplifying assumption of an eternal biosphere. So motivated, we explicitly consider the consequences which follow mathematically from this assumption, and the infinite graphs it leads to. This assumption admits certain clusters of organisms which have some ideal theoretical properties of species, shining some light onto the species problem. We prove a dualization of a law of T.A. Knight and C. Darwin, and sketch a decomposition result involving the internodons of D. Kornet, J. Metz and H. Schellinx. A further goal of this paper is to respond to B. Sturmfels' question, "Can biology lead to new theorems?"

3. Inhibitory effects of β-caryophyllene on Helicobacter pylori infection in vitro and in vivo

19 November 2019 | Biorxiv link | Write review

The human specific bacterial pathogen Helicobacter pylori (H. pylori) is a Gram-negative microaerophilic bacterium and associated with severe gastric diseases such as peptic ulceration and gastric cancer. Recently, the increasing resistance and the emergence of adverse effects make the usage of antibiotics less effectively. Therefore, development of new antimicrobial agent is required to control H. pylori infection. In the current study, it has been demonstrated the inhibitory effect of {beta}-caryophyllene on H. pylori growth and the protective effect against H. pylori infection as well as antibacterial therapeutic effect. {beta}-caryophyllene inhibited H. pylori growth via down-regulation of dnaE, dnaN, holB and gyrA and also down-regulated virulence factors such as CagA, VacA and SecA proteins. {beta}-caryophyllene inhibited expression of several type IV secretion system (T4SS) components including virB2, virB4 and virB8, so that CagA translocation into H. pylori-infected AGS cells was decreased by {beta}-caryophyllene treatment. {beta}-caryophyllene also inhibited VacA toxin entry through down-regulation of type IV secretion system (T5SS). In vivo experiments using Mongolian gerbils demonstrated antibacterial therapeutic effects of {beta}-caryophyllene. After {beta}-caryophyllene administration, immunohistochemistry (IHC) stain using anti-H. pylori antibody showed the antibacterial effect and H&E stain showed the therapeutic effect in treated groups. Hematological data which conformed with histological data support the therapeutic effect of {beta}-caryophyllene administration. Such a positive effect of {beta}-caryophyllene on H. pylori infection potently substantiate that this natural compound could be used as a new antimicrobial agent or functional health food to help the patients whom suffering from gastroduodenal diseases due to H. pylori infection.

4. Law of the Minimum Paradoxes

19 November 2019 | Arxiv link | Write review

The "Law of the Minimum" states that growth is controlled by the scarcest resource (limiting factor). This concept was originally applied to plant or crop growth (Justus von Liebig, 1840) and quantitatively supported by many experiments. Some generalizations based on more complicated "dose-response" curves were proposed. Violations of this law in natural and experimental ecosystems were also reported. We study models of adaptation in ensembles of similar organisms under load of environmental factors and prove that violation of Liebig's law follows from adaptation effects. If the fitness of an organism in a fixed environment satisfies the Law of the Minimum then adaptation equalizes the pressure of essential factors and therefore acts against the Liebig's law. This is the the Law of the Minimum paradox: if for a randomly chosen pair "organism-environment" the Law of the Minimum typically holds, then, in a well-adapted system, we have to expect violations of this law. For the opposite interaction of factors (a synergistic system of factors which amplify each other) adaptation leads from factor equivalence to limitations by a smaller number of factors. For analysis of adaptation we develop a system of models based on Selye's idea of the universal adaptation resource (adaptation energy). These models predict that under the load of an environmental factor a population separates into two groups (phases): a less correlated, well adapted group and a highly correlated group with a larger variance of attributes, which experiences problems with adaptation. Some empirical data are presented and evidences of interdisciplinary applications to econometrics are discussed.

5. Temporally-precise disruption of prefrontal cortex informed by the timing of beta bursts impairs human action-stopping

19 November 2019 | Biorxiv link | Write review

Human action-stopping is widely considered to rely on a prefronto-basal ganglia-thalamocortical network, with right inferior frontal cortex (rIFC) posited to play a critical role in the early stage of implementation. Here we sought causal evidence for this idea in experiments involving healthy human participants (male/female). We first show that action-stopping is preceded by bursts of electroencephalographic activity in the beta band over prefrontal electrodes, putatively rIFC, and that the timing of these bursts correlates with the latency of stopping at a single-trial level: earlier bursts are associated with faster stopping. From this we reasoned that the integrity of rIFC at the time of beta bursts might be critical to the successful implementation of the stop process. We then used fMRI-guided transcranial magnetic stimulation (TMS) to disrupt rIFC at the approximate time of beta bursting. Stimulation prolonged stopping latencies and, moreover, the prolongation was most pronounced in individuals for whom the pulse appeared closer to the presumed time of beta bursting. These results help validate a prominent model of the neural architecture of action stopping, whereby the process is initiated early by the rIFC (~80-120 ms after a stop signal) and is then implemented via basal ganglia and primary motor cortex, before affecting the muscle at about 160 ms. The results also highlight the usefulness of prefrontal beta bursts to index an apparently important sub-process of stopping, the timing of which might help explain within- and between-individual variation in impulse control.

6. Spatial eco-evolutionary feedbacks mediate coexistence in prey-predator systems

19 November 2019 | Arxiv link | Write review

Eco-evolutionary frameworks can explain certain features of communities in which ecological and evolutionary processes occur over comparable timescales. Here, we investigate whether an evolutionary dynamics may interact with the spatial structure of a prey-predator community in which both species show limited mobility and predator perceptual ranges are subject to natural selection. In these conditions, our results unveil an eco-evolutionary feedback between species spatial mixing and predators perceptual range: different levels of mixing select for different perceptual ranges, which in turn reshape the spatial distribution of prey and its interaction with predators. This emergent pattern of interspecific interactions feeds back to the efficiency of the various perceptual ranges, thus selecting for new ones. Finally, since prey-predator mixing is the key factor that regulates the intensity of predation, we explore the community-level implications of such feedback and show that it controls both coexistence times and species extinction probabilities.

7. Endocrine autoimmune disease as a fragility of immune-surveillance against hypersecreting mutants

18 November 2019 | Biorxiv link | Write review

Many endocrine organs show prevalent autoimmune diseases (AID) such as type-1-diabetes and Hashimoto's-thyroiditis. The fundamental origins of these diseases is unclear. Here we address AID from the viewpoint of feedback control. Endocrine tissues maintain their mass by feedback-loops that balance cell proliferation and removal according to input signals related to the hormone function. Such feedback is unstable to mutant cells that mis-sense the signal, and therefore hyper-proliferate and hyper-secrete the hormone. We hypothesize that in order to prevent these mutants from expanding, each organ has a dedicated 'autoimmune surveillance of hyper-secreting mutants' (ASHM), in which hyper-secreting cells are preferentially eliminated, at the cost of a fragility to AID. ASHM correctly predicts the identity of the self-antigens and the presence of T-cells against these self-antigens in healthy individuals. It offers a predictive theory for which tissues get frequent AID, and which do not and instead show frequent mutant-expansion disease (e.g. hyperparathyroidism).

8. Feed-forward approximations to dynamic recurrent network architectures

18 November 2019 | Arxiv link | Write review

Recurrent neural network architectures can have useful computational properties, with complex temporal dynamics and input-sensitive attractor states. However, evaluation of recurrent dynamic architectures requires solution of systems of differential equations, and the number of evaluations required to determine their response to a given input can vary with the input, or can be indeterminate altogether in the case of oscillations or instability. In feed-forward networks, by contrast, only a single pass through the network is needed to determine the response to a given input. Modern machine-learning systems are designed to operate efficiently on feed-forward architectures. We hypothesised that two-layer feedforward architectures with simple, deterministic dynamics could approximate the responses of single-layer recurrent network architectures. By identifying the fixed-point responses of a given recurrent network, we trained two-layer networks to directly approximate the fixed-point response to a given input. These feed-forward networks then embodied useful computations, including competitive interactions, information transformations and noise rejection. Our approach was able to find useful approximations to recurrent networks, which can then be evaluated in linear and deterministic time complexity.

9. Different mechanisms for modulation of the initiation and steady-state of smooth pursuit eye movements

18 November 2019 | Biorxiv link | Write review

Smooth pursuit eye movements are used by primates to track moving objects. They are initiated by sensory estimates of target speed represented in the middle temporal (MT) area of extrastriate visual cortex and then supported by motor feedback to maintain steady-state eye speed at target speed. Here, we show that reducing the coherence in a patch of dots for a tracking target degrades the eye speed both at the initiation of pursuit and during steady-state tracking, when eye speed reaches an asymptote well below target speed. The deficits are quantitatively different between the motor-supported steady-state of pursuit and the sensory-driven initiation of pursuit, suggesting separate mechanisms. The deficit in visually-guided pursuit initiation could not explain the deficit in steady-state tracking. Pulses of target speed during steady-state tracking revealed lower sensitivities to image motion across the retina for lower values of dot coherence. However, sensitivity was not zero, implying that visual motion should still be driving eye velocity towards target velocity. When we changed dot coherence from 100% to lower values during accurate steady-state pursuit, we observed larger eye decelerations for lower coherences, as expected if motor feedback was reduced in gain. A simple pursuit model accounts for our data based on separate modulation of the strength of visual-motor transmission and motor feedback. We suggest that reduced dot coherence creates less reliable target motion that impacts pursuit initiation by changing the gain of visual-motor transmission and perturbs steady-state tracking by modulation of the motor corollary discharges that comprise eye velocity memory.

10. Photoproximity profiling of protein-protein interactions in cells

17 November 2019 | Biorxiv link | Write review

We report a novel photoproximity protein interaction (PhotoPPI) profiling method to map protein-protein interactions in vitro and in live cells. This approach utilizes a bioorthogonal, multifunctional chemical probe that can be targeted to a genetically encoded protein of interest (POI) through a modular SNAP-Tag/benzylguanine covalent interaction. A first generation photoproximity probe, PP1, re-sponds to 365 nm light to simultaneously cleave a central nitroveratryl linker and a peripheral diazirine group, resulting in diffusion of a highly reactive carbene nucleophile away from the POI. We demonstrate facile probe loading, and subsequent interaction- and light-dependent proximal labeling of a model protein-protein interaction (PPI) in vitro. Integration of the PhotoPPI workflow with quantita-tive LC-MS/MS enabled unbiased interaction mapping for the redox regulated sensor protein, KEAP1, for the first time in live cells. We validated known and novel interactions between KEAP1 and the proteins PGAM5 and HK2, among others, under basal cellular condi-tions. By contrast, comparison of PhotoPPI profiles in cells experiencing metabolic or redox stress confirmed that KEAP1 sheds many basal interactions and becomes associated with known lysosomal trafficking and proteolytic proteins like SQSTM1, CTSD and LGMN. Together, these data establish PhotoPPI as a method capable of tracking the dynamic sub-cellular and protein interaction social network of a redox-sensitive protein in cells with high temporal resolution.

11. An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans

17 November 2019 | Biorxiv link | Write review

While many diseases of aging have been linked to the immunological system, immune metrics with which to identify the most at-risk individuals are lacking. Here, we studied the blood immunome of 1001 individuals age 8-96 and derived an inflammatory clock of aging (iAge), which tracked with multi-morbidity and immunosenescence. In centenarians, iAge was on average, 40 years lower than their corresponding chronological age. The strongest contributor to this metric was the chemokine CXCL9, which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule. Thus, our results identify an important link between inflammatory molecules and pathways known to govern lifespan.

12. Mutation analysis of multiple pilomatricomas in a patient with myotonic dystrophy type 1 suggests a DM1-associated hypermutation phenotype

16 November 2019 | Biorxiv link | Write review

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease which results from an expansion of repetitive DNA elements within the 3' untranslated region of the DMPK gene. Some patients develop multiple pilomatricomas as well as malignant tumors in other tissues. Mutations of the catenin-{beta} gene (CTNNB1) could be demonstrated in most non-syndromic pilomatricomas. In order to gain insight into the molecular mechanisms which might be responsible for the occurrence of multiple pilomatricomas and cancers in patients with DM1, we have sequenced the CTNNB1 gene of four pilomatricomas and of one pilomatrical carcinoma which developed in one patient with molecularly proven DM1 within 4 years. We further analyzed the pilomatrical tumors for microsatellite instability as well as by NGS for mutations in 161 cancer-associated genes. Somatic and independent point-mutations were detected at typical hotspot regions of CTNNB1 (S33C, S33F, G34V, T41I) while one mutation within CTNNB1 represented a duplication mutation (G34dup.). Pilomatricoma samples were analyzed for microsatellite instability and expression of mismatch repair proteins but no mutated microsatellites could be detected and expression of mismatch repair proteins MLH1, MSH2, MSH6, PMS2 was not perturbed. NGS analysis only revealed one heterozygous germline mutation c.8494C>T; p.(Arg2832Cys) within the ataxia telangiectasia mutated gene (ATM) which remained heterozygous in the pilomatrical tumors. The detection of different somatic mutations in different pilomatricomas and in the pilomatrical carcinoma as well as the observation that the patient developed multiple pilomatricomas and one pilomatrical carcinoma over a short time period strongly suggest that the patient displays a hypermutation phenotype. This hypermutability seems to be tissue and gene restricted. Co-translation of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might constitute an explanation for the observed tissue and gene specificity of hypermutability observed in DM1 patients. Elucidation of putative mechanisms responsible for hypermutability in DM1 patients requires further research.

13. Relaxed random walks at scale

16 November 2019 | Arxiv link | Write review

Relaxed random walk (RRW) models of trait evolution introduce branch-specific rate multipliers to modulate the variance of a standard Brownian diffusion process along a phylogeny and more accurately model overdispersed biological data. Increased taxonomic sampling challenges inference under RRWs as the number of unknown parameters grows with the number of taxa. To solve this problem, we present a scalable method to efficiently fit RRWs and infer this branch-specific variation in a Bayesian framework. We develop a Hamiltonian Monte Carlo (HMC) sampler to approximate the high-dimensional, correlated posterior that exploits a closed-form evaluation of the gradient of the trait data log-likelihood with respect to all branch-rate multipliers simultaneously. Our gradient calculation achieves computational complexity that scales only linearly with the number of taxa under study. We compare the efficiency of our HMC sampler to the previously standard univariable Metropolis-Hastings approach while studying the spatial emergence of the West Nile virus in North America in the early 2000s. Our method achieves an over 300-fold speed-increase over the univariable approach. Additionally, we demonstrate the scalability of our method by applying the RRW to study the correlation between five mammalian life history traits in a phylogenetic tree with 3650 tips.

14. IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

16 November 2019 | Biorxiv link | Write review

Aberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRIS's utility for expanding targeted cancer immunotherapy.

15. Topology, Landscapes, and Biomolecular Energy Transport

16 November 2019 | Arxiv link | Write review

While ubiquitous, energy redistribution remains a poorly understood facet of the nonequilibrium thermodynamics of biomolecules. At the molecular level, finite-size effects, pronounced nonlinearities, and ballistic processes produce behavior that diverges from the macroscale. Here, we show that transient thermal transport reflects macromolecular energy landscape architecture through the topological characteristics of molecular contacts and the nonlinear processes that mediate dynamics. While the former determines transport pathways via pairwise interactions, the latter reflects frustration within the landscape for local conformational rearrangements. Unlike transport through small-molecule systems, such as alkanes, nonlinearity dominates over coherent processes at even quite short time- and length-scales. Our exhaustive all-atom simulations and novel local-in-time and space analysis, applicable to both theory and experiment, permit dissection of energy migration in biomolecules. The approach demonstrates that vibrational energy transport can probe otherwise inaccessible aspects of macromolecular dynamics and interactions that underly biological function.

16. Immunocapture of dsRNA-bound proteins provides insight into Tobacco rattle virus replication complexes

15 November 2019 | Biorxiv link | Write review

Plant RNA viruses form highly organized membrane-bound virus replication complexes (VRCs) to replicate their genome and multiply. VRCs contain both virus- and host-encoded proteins, and have been investigated through a number of experimental approaches, including genetic screens on surrogate model experimental hosts and pull-down of viral replicase proteins. Double-stranded RNA (dsRNA) is an obligate intermediate of the replication process of all RNA viruses and is the trigger of potent antiviral defenses in all eukaryotes. In this work, we describe the use of a GFP-tagged dsRNA-binding protein (B2:GFP) to pull down viral replicating RNA and associated proteins in planta . Following infection of A. thaliana constitutively expressing B2:GFP with tobacco rattle virus (TRV), we were able through GFP immunoprecipitation to pull down dsRNA. Mass spectrometry analysis of the dsRNA-B2:GFP-bound proteins from TRV-infected plants revealed the presence of (i) viral proteins such as the replicase, which attested to the successful isolation of VRCs, and (ii) a number of host proteins, some of which have previously been involved in virus infection. To verify whether the identified host proteins localized at TRV replication complexes, we selected nine candidates, generated genetic fusions with RFP, and transiently expressed them in healthy and TRV-infected N. benthamiana stably expressing B2:GFP. Confocal microscopy analysis revealed that eight out of nine candidates showed dramatic re-localization upon infection, and seven of these co-localized with B2-labeled TRV replication complexes, providing ample validation for the immunoprecipitation results. We therefore propose B2:GFP-mediated pull down of dsRNA to be a novel and robust method to explore the proteome of VRCs in planta .

17. 3D spatial exploration by E. coli echoes motor temporal variability

15 November 2019 | Arxiv link | Write review

Unraveling bacterial strategies for spatial exploration is crucial for understanding the complexity in the organization of life. Bacterial motility determines the spatio-temporal structure of microbial communities, controls infection spreading and the microbiota organization in guts or in soils. Most theoretical approaches for modeling bacterial transport rely on their run-and-tumble motion. For Escherichia coli, the run time distribution was reported to follow a Poisson process with a single characteristic time related to the rotational switching of the flagellar motors. However, direct measurements on flagellar motors show heavy-tailed distributions of rotation times stemming from the intrinsic noise in the chemotactic mechanism. Currently, there is no direct experimental evidence that the stochasticity in the chemotactic machinery affect the macroscopic motility of bacteria. In stark contrast with the accepted vision of run-and-tumble, here we report a large behavioral variability of wild-type \emph{E. coli}, revealed in their three-dimensional trajectories. At short observation times, a large distribution of run times is measured on a population and attributed to the slow fluctuations of a signaling protein triggering the flagellar motor reversal. Over long times, individual bacteria undergo significant changes in motility. We demonstrate that such a large distribution of run times introduces measurement biases in most practical situations. Our results reconcile the notorious conundrum between run time observations and motor switching statistics. We finally propose that statistical modeling of transport properties currently undertaken in the emerging framework of active matter studies, should be reconsidered under the scope of this large variability of motility features.

18. Cell type and cortex-specific RNA editing in single human neurons informs neuropsychiatric disorders

15 November 2019 | Biorxiv link | Write review

Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This process, known as 'RNA editing', is dysregulated in many neuropsychiatric diseases, but is little understood at the level of individual neurons. We examined full-length nuclear transcriptomes of 3,055 neurons from six cortical regions of a neurotypical post-mortem female donor and identified 40,861 high-confidence edited sites. The majority of sites were located within Alu repeats in introns or 3' UTRs, and were present in previously published RNA editing databases. We identified 15,784 putative novel RNA editing sites, 30% of which were also detectable in independently generated neuronal transcriptomes from unrelated donors. The strongest correlates of global editing rates were expression levels of small nucleolar RNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2, one of three known RNA editing enzymes in humans. As expected, expression of DNA and RNA binding proteins were negatively associated with editing. We present evidence for dysregulated RNA editing in six rare genetic conditions; and report 117 differentially edited sites between cortical regions and neuronal subtypes. These results provide spatial and neurophenotypic context for 1,871 and 998 sites that are differentially edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts.

19. Optimal stimulation protocol in a bistable synaptic consolidation model

15 November 2019 | Arxiv link | Write review

Consolidation of synaptic changes in response to neural activity is thought to be fundamental for memory maintenance over a timescale of hours. In experiments, synaptic consolidation can be induced by repeatedly stimulating presynaptic neurons. However, the effectiveness of such protocols depends crucially on the repetition frequency of the stimulations and the mechanisms that cause this complex dependence are unknown. Here we propose a simple mathematical model that allows us to systematically study the interaction between the stimulation protocol and synaptic consolidation. We show the existence of optimal stimulation protocols for our model and, similarly to LTP experiments, the repetition frequency of the stimulation plays a crucial role in achieving consolidation. Our results show that the complex dependence of LTP on the stimulation frequency emerges naturally from a model which satisfies only minimal bistability requirements.

20. Comparative Genomics and Full-Length TprK Profiling of Treponema pallidum subsp. pallidum Reinfection

14 November 2019 | Biorxiv link | Write review

Developing a vaccine against Treponema pallidum subspecies pallidum, the causative agent of syphilis, remains a public health priority. Syphilis vaccine design efforts have been complicated by lack of an in vitro T. pallidum culture system, prolific antigenic variation in outer membrane protein TprK, and lack of functional annotation for nearly half of the genes. Understanding the genetic basis of T. pallidum reinfection can provide insights into variation among strains that escape cross-protective immunity. Here, we present comparative genomic sequencing and deep, full-length tprK profiling of two T. pallidum isolates from blood from the same patient that were collected six years apart. Notably, this patient was diagnosed with syphilis four times, with two of these episodes meeting the definition of neurosyphilis, during this interval. Outside of the highly variabletprK gene, we identified 14 coding changes in 13 genes. Nine of these genes putatively localized to the periplasmic or outer membrane spaces, consistent with a potential role in serological immunoevasion. Using a newly developed full-length tprK deep sequencing protocol, we profiled the diversity of this gene that far outpaces the rest of the genome. Intriguingly, we found that the reinfecting isolate demonstrated less diversity across each tprK variable region compared to the isolate from the first infection. Notably, the two isolates did not share any full-length TprK sequences. Our results are consistent with an immunodominant-evasion model in which the diversity of TprK explains the ability of T. pallidum to successfully reinfect individuals, even when they have been infected with the organism multiple times.

21. Implementing robust neuromodulation in neuromorphic circuits

14 November 2019 | Arxiv link | Write review

We introduce a methodology to implement the physiological transition {between distinct neuronal spiking modes} in electronic circuits composed of resistors, capacitors and transistors. The result is a simple neuromorphic device organized by the same geometry {and exhibiting the same input--output properties as} high-dimensional electrophysiological neuron models. {Preliminary} experimental results highlight the robustness of the approach in real-world applications.

22. Inter-subject phase synchronization differentiates neural networks underlying physical pain empathy

14 November 2019 | Biorxiv link | Write review

Recent approaches for understanding the neural basis of pain empathy emphasize the dynamic construction of neural networks underlying this multifaceted social cognitive process. Inter-subject phase synchronization (ISPS) is an approach for exploratory analysis of task-based fMRI data that reveals brain networks dynamically synchronized to task-features across subjects. We applied ISPS to task-fMRI data assessing vicarious pain empathy in healthy subjects (n=238). The task employed physical (limb) and affective (faces) painful and corresponding non-painful visual stimuli. ISPS revealed two distinct networks synchronized during physical pain observation, one encompassing anterior insula and midcingulate regions strongly engaged in (vicarious) pain, and another encompassing parietal and inferior frontal regions associated with social cognitive processes which may further modulate and support the pain empathic response. No robust network synchronization was observed while processing facial expressions of pain, possibly reflecting high inter-individual variation in response to socially transmitted pain experience. ISPS also revealed networks related to task onset or general processing of physical (limb) or affective (face) stimuli which encompassed networks engaged in object manipulation or face processing, respectively. Together, the ISPS approach permits segregation of networks engaged in different psychological processes, providing additional insight into shared neural mechanisms of empathy for physical pain across individuals.

23. Chern-Simons-Higgs Model as a Theory of Protein Molecules

14 November 2019 | Arxiv link | Write review

In this paper we discuss a one-dimensional Abelian Higgs model with Chern-Simons interaction as an effective theory of one-dimensional curves embedded in three-dimensional space. We demonstrate how this effective model is compatible with the geometry of protein molecules. Using standard field theory techniques we analyze phenomenologically interesting static configurations of the model and discuss their stability. This simple model predicts some characteristic relations for the geometry of secondary structure motifs of proteins, and we show how this is consistent with the experimental data. After using the data to universally fix basic local geometric parameters, such as the curvature and torsion of the helical motifs, we are left with a single free parameter. We explain how this parameter controls the abundance and shape of the principal motifs (alpha helices, beta strands and loops connecting them).

24. Effect of arbuscular mycorrhizal fungi (AMF) and plant growth promoting rhizobacteria (PGPR) on microbial community structure of phenanthrene and pyrene contaminated soils using Illumina HiSeq sequencing.

13 November 2019 | Biorxiv link | Write review

In order to determine the influence of arbuscular mycorrhizal fungi (AMF , Glomus versiforme ) and plant growth promoting rhizobacteria (PGPR, Pseudomonas fluorescens , PS2-6) on degradation of phenanthrene (PHE) and pyrene (PYR) and the change of microbial community structure in soils planted with tall fescue ( Festuca elata ), four treatments were set up in phenanthrene (PHE) and pyrene (PYR) contamined soil: i.e., tall fescue (CK), AMF + tall fescue (GV), PGPR + tall fescue (PS) and AMF + PGPR + tall fescue (GVPS), PHE and PYR dissipation in the soil and accumulated in the tall fescue were investigated. Our results showed that highest removal percentage of PHE and PYR in contaminated soil as well as biomass of tall fescue were observed in GVPS. PHE and PYR accumulation by tall fescue roots were higher than shoots, the mycorrhizal status was best manifested in the roots of tall fescue inoculated with GVPS, and GVPS significantly increased the number of PGPR colonization in tall fescue rhizosphere soil. And paired-end Illumina HiSeq analysis of 16S rRNA and Internal Transcribed Spacer (ITS) gene amplicons were also employed to study change of bacterial and fungal communities structure in four treatments. GVPS positively affected the speices and abundance of bacteria and fungi in PHE and PYR contaminated soil, an average of 71,144 high quality bacterial 16S rDNA tags and 102,455 ITS tags were obtained in GVPS, and all of them were assigned to 6,327 and 825 operational taxonomic units (OTUs) at a 97% similarity, respectively. Sequence analysis revealed that Proteobacteria was the dominant bacterial phylum, Ascomycota was the dominant fungal phylum in all treatments, whereas Proteobacteria and Glomeromycota were the most prevalent bacterial and fungal phyla in GVPS, respectively. And in the generic level, Planctomyces is the richest bacterial genus , and Meyerozyma is the richest fungal genus in all treatments, whereas Sphingomona was the dominant bacterial genus, while the dominant fungi was Fusarium in GVPS. Overall, our findings revealed that application of AMF and PGPR had an effective role in improving the growth characteristics, root colonization of F. elata and soil microbial community structure in PHE and PYR contaminated soils, but no obvious in degradation efficiencies of PAHs as compared to the control.

25. Predicting Earth's Carrying Capacity of Human Population as the Predator and the Natural Resources as the Prey in the Modified Lotka-Volterra Equations with Time-dependent Parameters

13 November 2019 | Arxiv link | Write review

We modified the Lotka-Volterra Equations with the assumption that two of the original four constant parameters in the traditional equations are time-dependent. In the first place, we assumed that the human population (borrowed from the T-Function) plays the role as the prey while all lethal factors that jeopardize the existence of the human race as the predator. Although we could still calculate the time-dependent lethal function, the idea of treating the lethal factors as the prey was too general to recognize the meaning of them. Hence, in the second part of the modified Lotka-Volterra Equations, we exchanged the roles between the prey and the predator. This time, we treated the prey as the natural resources while the predator as the human population (still borrowed from the T-Function). After carefully choosing appropriate parameters to match the maximum carrying capacity with the saturated number of the human population predicted by the T-Function, we successfully calculated the natural resources as a function of time. Contrary to our intuition, the carrying capacity is constant over time rather than a time-varying function, with the constant value of 10.2 billion people.

26. Prioritization of abiotic and biotic stress responses by direct linkage of ABI1 phosphatase and CPK5 calcium-dependent protein kinase

13 November 2019 | Biorxiv link | Write review

In nature plants are constantly challenged by simultaneous abiotic and biotic stresses, and under conflicting stress scenarios prioritization of stress responses is required for plant survival. Calcium-dependent protein kinase CPK5 is a central hub in local and distal immune signaling, required upstream of hormone salicylic acid (SA)-dependent systemic acquired resistance (SAR). Here we show that CPK5 signaling-dependent immune responses are effectively blocked and pathogen resistance is reverted either upon treatment of plants with abscisic acid (ABA) or in genetic mutant backgrounds lacking PP2C phosphatase activities including abi1-2. Consistently, enhanced immune responses occur upon co-expression of CPK5 kinase with active variants of ABI1 phosphatase ABI1G180S and ABI1G181A. Biochemical studies and mass spectrometry-based phosphosite analysis reveal a direct ABI1 phosphatase-catalyzed de-phosphorylation of CPK5 at T98, a CPK5 auto-phosphorylation site. CPK5T98A, mimicking continuous de-phosphorylation through ABI1, correlates with an increase in kinase activity and CPK5 function in ROS production. CPK5T98D, mimicking a CPK5 auto-phosphorylated status under ABA-induced phosphatase inhibition, leads to inactivated CPK5 causative to an immediate stop of immune responses. Our work reveals an elegant mechanism for plant stress prioritization, where the ABA-dependent phosphatase ABI1, negative regulator of abiotic responses, functions as positive regulator of biotic stress responses, stabilizing CPK5-dependent immune responses in the absence of ABA. This mechanism allows continuous immune signaling during pathogen survey in environmentally non-challenging conditions. Under severe abiotic stress, immune signaling is discontinued via a direct biochemical intersection through a phosphatase/kinase pair recruiting two key regulatory enzymes of these antagonistic signaling pathways.

27. Dynamical learning of dynamics

13 November 2019 | Arxiv link | Write review

The ability of humans and animals to quickly adapt to novel tasks is difficult to reconcile with the standard paradigm of learning by slow synaptic weight modification. Here we show that already static neural networks can learn to generate required dynamics by imitation. After appropriate weight pretraining, the networks quickly and dynamically adapt to learn new tasks and thereafter continue to achieve them without further teacher feedback. We explain this ability and illustrate it with a variety of target dynamics, ranging from oscillatory trajectories to driven and chaotic dynamical systems.

28. Purification and molecular characterization of phospholipase, antigen 5 and hyaluronidases from the venom of the Asian hornet (Vespa velutina)

12 November 2019 | Biorxiv link | Write review

The aim of this study was to purify potential allergenic components of Vespa velutina venom, the yellow legged Asian Hornet, and perform a preliminary characterization of the purified proteins. Starting from the whole venom of V.velutina, several chromatographic steps allowed to purify the phospholipase (named Vesp v 1), as well as the antigen 5 (Vesp v 5, the only allergenic component described as such so far). The two hyaluronidase isoforms found (Vesp v 2A and Vesp v 2B) cannot be separated from each other, but they are partially purified and characterized. Purity of the isolated proteins in shown by SDSPAGE, as well as by the results of the N-terminal sequencing. This characterization and nLC-MS/MS data provide most of the sequence for Vesp v 1 and Vesp v 5 (72 and 84% coverage, respectively), confirming that the whole sequences of the isolated natural components match with the data available in public transcriptomic databases. It is of particular interest that Vesp v 1 is a glycosylated phospholipase, a fact that had only described so far for the corresponding allergen components of Dolichovespula maculata and Solenopsis invicta. The availability of the complete sequences of Vespa velutina components permits comparison with homologous sequences from other Hymenoptera. These data demonstrate the higher similarity among the species of the genera Vespa and Vespula, in comparison to Polistes species, as it is especially observed with the hyaluronidases isoforms: the isoform Vesp v 2A only exists in the former genera, and not in Polistes; in addition, the most abundant isoform (Vesp v 2B) exhibits 93% sequence identity with the Ves v 2 isoform of Vespula vulgaris. Finally, the isolated components might be useful for improving the diagnosis of patients that could be allergic to stings of this invasive Asian hornet, as it has been the case of an improved diagnosis and treatment of other Hymenoptera-sensitized patients.

29. Network structure of cascading neural systems predicts stimulus propagation and recovery

12 November 2019 | Arxiv link | Write review

Many neural systems display cascading behavior characterized by uninterrupted sequences of neuronal firing. This gap precludes an understanding of how variations in network structure manifest in neural dynamics and either support or impinge upon information processing. Here, we develop a theoretical understanding of how network structure supports information processing through network dynamics, and we validate our theory with empirical data. Using a generalized spiking model and mathematical tools from linear systems theory, network control theory, and information theory, we show how network structure can be designed to temporally extend the propagation and recovery of certain stimulus patterns. Moreover, we observe cycles as structural and dynamic motifs that are prevalent in such networks. Broadly, our results demonstrate how cascading neural networks could contribute to cognitive faculties that require lasting activation of neuronal patterns, such as working memory or attention.

30. Mechanical Suppression of Breast Cancer Cell Invasion and Paracrine Signaling Requires Nucleo-Cytoskeletal Connectivity

12 November 2019 | Biorxiv link | Write review

Exercise benefits the musculoskeletal system and reduces the effects of cancer. The beneficial effects of exercise are multifactorial, where metabolic changes and tissue adaptation influence outcomes. Mechanical signals, a principal component of exercise, are anabolic to the musculoskeletal system and restrict cancer progression. We examined the mechanisms through which cancer cells sense and respond to mechanical signals. Low-magnitude, high-frequency signals were applied to human breast cancer cells in the form of low-intensity vibration (LIV). LIV decreased invasion through matrix and impaired secretion of osteolytic factors PTHLH, IL-11, and RANKL. Furthermore, paracrine signals from mechanically stimulated cancer cells, reduced osteoclast differentiation resorptive capacity. Physically disconnecting the nucleus by knockdown of SUN1 and SUN2 impaired the ability of LIV to suppress invasion and production of osteolytic factors. LIV also increased cell stiffness; an effect dependent on an intact LINC complex. These data show that mechanical signals alter the metastatic potential of human breast cancer cells, where the nucleus serves as a mechanosensory apparatus to alter cell structure and intercellular signaling.