bluuebunny/crossref_metadata_2025 huggingface dataset:
Metastable attractors explain the variable timing of stable behavioral action sequences
Authors: Recanatesi Stefano , Pereira Ulises , Murakami Masayoshi , Mainen Zachary , Mazzucato Luca
Published: January 2020

Natural animal behavior displays rich lexical and temporal dynamics, even in a stable environment. The timing of self-initiated actions shows large variability even when they are executed in reliable, well-learned sequences. To elucidate the neural mechanism underlying this mix of reliability and stochasticity, we trained rats to perform a stereotyped sequence of self-initiated actions and recorded neural ensemble activity in secondary motor cortex (M2), known to reflect trial-by-trial action timing fluctuations. Using hidden Markov models, we established a dictionary between ensemble activity patterns and actions. We then showed that metastable attractors, with a reliable sequential structure yet high transition timing variability, could be produced by coupling a high-dimensional recurrent network and a low-dimensional feedforward one. Transitions between attractors in our model were generated by correlated variability arising from the feedback loop between the two networks. This mechanism predicted aligned, low-dimensional noise correlations that were empirically verified in M2 ensembles. Our work establishes a novel framework for investigating the circuit origins of self-initiated behavior based on correlated variability.
New distribution records and range extensions of mosquitoes in British Columbia and the Yukon Territory
Authors: Peach Daniel AH. , Poirier Lisa M.
Published: January 2020

We report the first records ofAedes euedesHoward, Dyar, and Knab, andCoquillettidia perturbans(Walker) from Canada’s Yukon Territory, and the first record ofAe. decticusHoward, Dyar, and Knab from British Columbia. We also report range extensions in northern BC for the western treehole mosquito,Aedes sierrensis(Ludlow), the common house mosquito,Culex pipiensL., and the cool weather mosquitoCuliseta incidens(Thomson).
Characterization of a novel NDM-5-harboring plasmid from a carbapenem-resistantEscherichia coliisolate from China
Authors: Yin Dongdong , Lin Yanfeng , Li Zhonghong , Ma Hui , Lu Lanfen , Wang Kaiying , Yang Lang , Du Xinying , Song Hongbin , Li Peng , Qi Kezong
Published: January 2020

A carbapenem-resistantEscherichia coli(sequence type 5415) strain was isolated from a male patient. S1-PFGE and Southern blotting showed that theblaNDM-5gene was located on a novel 66-kb IncFII [F2:A-:B-] plasmid. Conjugation assays revealed that theblaNDM-5-bearing plasmid was self-transferrable. Genomic sequencing and comparative analysis suggested that plasmid p2947-NDM5 likely originated from a combination of an IncFII-type backbone and theblaNDM-5flanking genetic elements. This study highlights the genetic complexity of an NDM-5 carbapenemase and the urgent need for continuous active monitoring.

IMPORTANCE

Carbapenem resistance due to the NDM enzyme has become a serious clinical problem in medical care and public health. We here identified ablaNDM-5-positiveE. colistrain ST5414. TheblaNDM-5gene was located on a novel self-transferrable IncFII type plasmid p2947-NDM5. Genomic sequencing and comparative analysis suggested that plasmid p2947-NDM5 likely originated from a combination of an IncFII-type backbone and the blaNDM-5 flanking genetic elements. The genetic context of NDM-5 is highly similar to that of animal origins, and we speculate that theblaNDM-harboring IncFII plasmid has a potential risk of being transmitted from animals to humans and should be paid more attention. Our findings highlight the threat of NDM-5 carbapenemase circulation and the urgency of stringent surveillance and control measures.
Human stem cell derived sensory neurons are positioned to support varicella zoster virus latency
Authors: Sadaoka Tomohiko , Rajbhandari Labchan , Shukla Priya , Jagdish Balaji , Lee Hojae , Lee Gabsang , Venkatesan Arun
Published: January 2020

The neuropathogenesis of varicella-zoster virus (VZV) has been challenging to study due to the strict human tropism of the virus and the resultant difficulties in establishing tractable experimental models.In vivo, sensory neurons of the dorsal root ganglia and trigeminal ganglia serve as cellular niches that support viral latency, and VZV can subsequently reactivate from these cells to cause disease. Whether sensory neurons possess intrinsic properties that position them to serve as a reservoir of viral latency remains unknown. Here, we utilize a robust human sensory neuron system to investigate lytic infection and viral latency. We find that sensory neurons exhibit resistance to lytic infection by VZV. On the other hand, latent infection in sensory neurons is associated with an episomal-like configuration of viral DNA and expression of the VZV latency-associated transcript (VLT), thus closely mirroring thein vivostate. Moreover, despite the relative restriction in lytic infection, we demonstrate that viral reactivation is possible from latently infected sensory neurons. Taken together, our data suggest that human sensory neurons possess intrinsic properties that serve to facilitate their role as a latent reservoir of VZV.

IMPORTANCE

Varicella-zoster virus (VZV) has infected over 90% of people worldwide. Following primary infection, the virus can remain dormant in the nervous system and may reactivate later in life, with potentially severe consequences. Here, we develop a model of VZV infection in human sensory neurons in order to determine whether these cells are intrinsically positioned to support latency and reactivation. We find that human sensory neurons are relatively resistant to lytic infection, but can support latency and reactivation. Moreover, duringin vitrolatency human sensory neurons, but not other neurons, express the newly discovered VZV latency-associated transcript (VLT), thus closely mirroring thein vivolatent state. Taken together, these data indicate that human sensory neurons are uniquely positioned to support latency. We anticipate that this human sensory neuron model will serve to facilitate further understanding of the mechanisms of VZV latency and reactivation.
Gut Microbiota Mediates the Protective Effects of Andrographolide Inhibits Inflammation and Nonalcoholic Fatty Liver Disease(NAFLD) in High-Fat Diet induced ApoE(-/-) Mice
Authors: Shi Shuai , Ji Xin-Yu , Shi Jing-Jing , Shi Shu-Qing , Jia Qiu-Lei , Yuan Guo-Zhen , Zhang Qiu-Yan , Dong Yu , Lu Ying-Dong , Cui Han-Ming , Hu Yuan-Hui
Published: January 2020

Mechanisms relating the gut bacteria to Nonalcoholic Fatty Liver Disease (NAFLD) have been proposed containing the dysbiosis-induced dysregulation of hepatic lipid metabolism that allows for the translocation of microbial components and leads to hepatic inflammation and steatosis. Andrographolide (AG) regulates inflammation mediated by NF-κB pathway which also play a key role in reduction of inflammation and fibrosis in experimental nonalcoholic steatohepatitis (NASH), yet the mechanisms linking this effect to gut microbiota remain obscure. Here we show that ApoE knockout (Apoe -/-) mice fed a high-fat diet (HFD) supplemented with AG regulates levels of biochemical index and inflammatory cytokines associated with gut microbe. Moreover, HEPG2 cells induced by ox-LDL were used as validation in vitro. H&E staining and Oil-Red staining were respectively used for tissue and cells morphology. Gut microbiota were examined by 16S rRNA sequencing. Expression of NF-κB, C/EBPβ and PPAR-γ in liver and HEPG2 cells were detected by western blot and qRT-PCR. The results showed, among others, that AG alleviate hepatic steatosis and fat content in HEPG2 cells, while it induced decreased levels of Bacteroides, and increased levels of Faecalibaculum, Akkermansia. We further identified that inhibition of NF-κB/C/EBPβ/PPAR-γ pathway of hepatic steatosis model in vivo and vitro by AG also contributes to prevention of HFD-induced inflammation and dislipidemia. Importantly, as result of pearson correlation, Bacteroides may be the most relevant one fundamentally involved in the mechanism of AG attenuates NAFLD. Together, our findings uncover an interaction between AG and gut microbiota as a novel mechanism for the anti-NAFLD effect of AG acting through prevention of microbial dysbiosis, dislipidemia and inflammation.

Importance

HFD due to gut microbial dysbiosis is a major contributor to the pathogenesis of dislipidemia and inflammation, which primarily mediates the development of NAFLD. A treatment strategy to reduce both dislipidemia and inflammation appears to be an effective approach for addressing the issue of NAFLD. Andrographolide (AG) is the major effect component in traditional Chinese medicine Chuan-xin-lian (Andrographis). Little is known about the role of gut microbiota in the anti-NAFLD effect of AG. 16S rRNA gene sequencing revealed that AG significantly decreased Bacteroides and increased Faecalibaculum, Akkermansia. By using vivo and vitro experiment, we prove that gut microbiota plays a key role in AG-induced protective against high-fat-diet-induced dislipidemia and inflammation. Moreover, NF-κB/C/EBPβ/PPAR-γ pathway inhibition was partially involved in the beneficial effect of AG. Together, these data suggest that the gut microbiome is a critical factor for the anti-NAFLD effects of AG.
A susceptibility locus on chromosome 13 profoundly impacts the stability of genomic imprinting in mouse pluripotent stem cells
Authors: Swanzey Emily , McNamara Thomas F. , Apostolou Effie , Tahiliani Mamta , Stadtfeld Matthias
Published: January 2020

Cultured pluripotent cells accumulate detrimental epigenetic alterations, including DNA methylation changes at imprinted genes known as loss-of-imprinting (LOI). Despite the substantial biomedical relevance of this phenomenon, the molecular cause of this epigenetic instability in pluripotent cells remains unknown. While the occurrence of LOI is generally considered a stochastic phenomenon, here we document a strong genetic determinant that segregates mouse pluripotent cells into epigenetically stable and unstable cell lines. Unstable lines exhibit hypermethylation atDlk1-Dio3and select other imprinted loci, which is associated with impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and can preserve developmental potential. Susceptibility to LOI greatly differs between commonly used mouse strains, which we utilize to map a causal region on chromosome 13 with Quantitative Trait Locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific epigenetic abnormalities in pluripotent cells and provide a non-invasive way to suppress them. This highlights the importance of considering genetics in conjunction with culture conditions for assuring the quality of pluripotent cells for biomedical applications.
Time dependent stress relaxation and recovery in mechanically strained 3D microtissues
Authors: Walker Matthew , Godin Michel , Harden James L. , Pelling Andrew E.
Published: January 2020

Characterizing the time-dependent mechanical properties of cells is not only necessary to determine how they deform, but also to fully understand how external forces trigger biochemical-signaling cascades to govern their behavior. Presently mechanical properties are largely assessed by applying local shear or compressive forces on single cells in isolation grown on non-physiological 2D surfaces. In comparison, we developed the microfabricated vacuum actuated stretcher to measure tensile loading of 3D multicellular ‘microtissue’ cultures. With this approach, we assessed here the time-dependent stress relaxation and recovery responses of microtissues, and quantified the spatial remodeling that follows step length changes. Unlike previous results, stress relaxation and recovery in microtissues measured over a range of step amplitudes and pharmacological treatments followed a stretched exponential behavior describing a broad distribution of inter-related timescales. Furthermore, despite a performed compendium of experiments, all responses led to a single linear relationship between the residual elasticity and degree of stress relaxation, suggesting that these mechanical properties are coupled through interactions between structural elements and the association of cells with their matrix. Lastly, although stress relaxation could be quantitatively and spatially linked to recovery, they differed greatly in their dynamics; while stress recovery behaved as a linear process, relaxation time constants changed with an inverse power law with step size. This assessment of microtissues offers insights into how the collective behavior of cells in a 3D collagen matrix generate the dynamic mechanical properties of tissues, which is necessary to understanding how cells deform and sense mechanical forces in the body.
Mechanical stretch sustains myofibroblast phenotype and function in microtissues through latent TGF-β1 activation
Authors: Walker Matthew , Godin Michel , Pelling Andrew E.
Published: January 2020

Fibrosis is a leading cause of death in developed countries that is characterized by a progressive deterioration of tissue mechanical behavior. Developing methods to study tissue mechanics and myofibroblast activation may lead to new targets for therapeutic treatments that are urgently needed. Microtissue arrays are a promising approach to conduct relatively high throughput research into fibrosis as they recapitulate key biomechanical aspects of the disease through a relevant 3D extracellular environment. In early work, our group developed a device called the MVAS-force to stretch microtissues while enabling simultaneous assessment of their dynamic mechanical behavior. Here we investigated TGF-β1 induced fibroblast to myofibroblast differentiation in microtissue cultures using our MVAS-force device through assessing α-SMA expression, contractility and stiffness. By doing so, we linked cell-level phenotypic changes to functional changes that characterize the clinical manifestation of fibrotic disease. As expected, TGF-β1 treatment promoted a myofibroblastic phenotype and microtissues became stiffer and possessed increased contractility. Furthermore, these changes were partially reversible upon TGF-β1 withdrawal. In contrast, however, long-term cyclic stretching maintained myofibroblast activation. Furthermore stretching had no effect compared static cultures when TGF-β1 receptors were inhibited and stretching promoted myofibroblast differentiation when given latent TGF-β1. Together these results suggest that external mechanical stretch may activate latent TGF-β1 and might be a powerful stimulus for continued myofibroblast activation to progress fibrosis. Further exploration of this pathway with our approach may yield new insights into myofibroblast activation and more effective therapeutic treatments for fibrosis.

Insight box

Using a novel high-throughput approach, we quantified the effects of dynamic mechanical stretching on the phenotype and function of cells in 3D microtissue cultures during myofibroblast activation with TGF-β1 treatment and subsequent withdrawal. Our findings show that mechanical stretch may activate endogenously produced latent TGF-β1 to maintain the presence and activity of myofibroblasts after tissue injury. Importantly, through this feed forward mechanism, mechanical stretch might be a powerful stimulus that directs tissues away from recovery and towards the development of fibrosis.
Atomistic Molecular Dynamics Simulations of Trioleoylglycerol – Phospholipid Membrane Systems
Authors: Hammad Mirza Ahmed , Akram Hafiza Minal , Raza Muhammad Sohail
Published: January 2020

Adiposomes are phospholipid coated triacylglyceride particles that serve as structural models of the fat storage compartments of cells, known as lipid droplets (LDs); however, unlike LDs, they do not carry proteins. There is a deficit of available methods and experimental data regarding the internal packing of the adiposomes, and computer simulations offer a promising way to pinpoint the molecular arrangements within these structures. However, in the absence of a triacylglycerol-specific atomic forcefield, thus far, all adiposome/LD simulations have been performed with the coarse grained/united atom forcefields. Yet it is desirable to model the phospholipid/triacylglycerol interface with atomic resolution. In the present study, we first prepared a 2-monooleoylglycerol (MOG) forcefield which was then used to build a trioleoylglycerol (TOG) forcefield by the modular approach of the AMBER software suite. TOG bilayer membrane (2L) systems were modelled from two different initial conformations; TOG3 and TOG2:1. The simulations revealed that TOG2:1 is the most populated conformation in TOG membranes, irrespective of the starting conformation. Some other parameter optimizations were performed for TOG membranes based on which adiposome mimicking tetralayer membrane system (4L) was prepared with a TOG bilayer at core surrounded by two DOPC leaflets. The 4L membranes were stable throughout the simulations, however it was observed that a small amount of cations and water diffused from surface to the TOG core of the membrane. Based on these results a TAG-packing model was also developed. It is expected that the availability of MOG forcefield will equip future studies with a framework for molecular dynamics simulations of adiposomes/LDs.
A theory of the use of information by enemies in the predator-prey space race
Authors: Patin Rémi , Fortin Daniel , Chamaillé-Jammes Simon
Published: January 2020

We currently lack a comprehensive theory about how behaviourally responsive predators and prey use the information they acquire about the environment and each other’s presence while engaged in the ‘space race’. This limits our understanding of the role of behaviour in trophic relationships and our ability to predict predators and prey distributions. Here we combined a simulation model with a genetic algorithm to discover how predators and prey behaving optimally should use information in environments with different levels of heterogeneity in prey forage distribution and prey vulnerability. Our results demonstrate the key role of movement unpredictability in successful strategies for both predators and prey, supporting the ‘shell-game’ hypothesis. We however reveal striking differences between predators and prey in the magnitude of this unpredictability, and in how it varies with the environment. Our work offers a robust theoretical framework to better understand predator-prey space use and interpret empirical studies.
Functional diversity metrics using kernel densityn-dimensional hypervolumes
Authors: Mammola Stefano , Cardoso Pedro
Published: January 2020

The use ofn-dimensional hypervolumes in trait-based ecology is rapidly increasing. By representing the functional space of a species or community as a Hutchinsonian niche, the abstract Euclidean space defined by a set of independent axes corresponding to individuals or species traits, these multidimensional techniques show great potential for the advance of functional ecology theory.

In the panorama of existing methods for delineating multidimensional spaces, the R packagehypervolume[Glob. Ecol. Biogeogr.(2014) 23:595–609] is currently the most used. However, functions for calculating the standard set of functional diversity (FD) indices—richness, divergence, and regularity—have not been developed within thehypervolumeframework yet. This gap is delaying its full exploitation in functional ecology, meanwhile preventing the possibility to compare its performance with that of other methods.

We develop a set of functions to calculate FD indices based onn-dimensional hypervolumes, including alpha (richness), beta (and respective components), dispersion, evenness, contribution, and originality. Altogether, these indices provide a coherent framework to explore the primary mathematical components of FD within a multidimensional setting. These new functions can work either with hypervolume objects or raw data (species presence or abundance and their traits) as input data, and are versatile in terms of input parameters and options.

These functions are implemented withinBAT(Biodiversity Assessment Tools), an R package for biodiversity assessments. As a coherent corpus of functional indices based on a common algorithm, it opens the possibility to fully explore the strengths of the Hutchinsonian niche concept in community ecology research.
Logarithmic encoding of ensemble time intervals
Authors: Ren Yue , Allenmark Fredrik , Müller Hermann J. , Shi Zhuanghua
Published: January 2020

Although time perception is based on the internal representation of time, whether the subjective timeline is scaled linearly or logarithmically remains an open issue. Evidence from previous research is mixed: while the classical internal-clock model assumes a linear scale with scalar variability, there is evidence that logarithmic timing provides a better fit to behavioral data. A major challenge for investigating the nature of the internal scale is that the retrieval process required for time judgments may involve a remapping of the subjective time back to the objective scale, complicating any direct interpretation of behavioral findings. Here, we used a novel approach, requiring rapid intuitive ‘ensemble’ averaging of a whole set of time intervals, to probe the subjective timeline. Specifically, observers’ task was to average a series of successively presented, auditory or visual, intervals in the time range 300-1300 ms. Importantly, the intervals were taken from three sets of durations, which were distributed such that the arithmetic mean (from the linear scale) and the geometric mean (from the logarithmic scale) were clearly distinguishable. Consistently across the three sets and the two presentation modalities, our results revealed subjective averaging to be close to the geometric mean, indicative of a logarithmic timeline underlying time perception.
Systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets
Authors: Piran Mehran , Piran Mehrdad , Sepahi Neda , Ghanbariasad Ali , Rahimi Amir
Published: January 2020

Colorectal cancer (CRC) is one of the major causes of cancer deaths across the world. Patients survival time at time of diagnosis depends largely on stage of the tumor. Therefore, understanding the molecular mechanisms promoting cancer progression from early stages to high-grade stages is essential for implementing therapeutic approaches. To this end, we performed a unique meta-analysis flowchart by identifying differentially expressed genes (DEGs) between normal, primary and metastatic samples in some test datasets. DEGs were employed to construct a protein-protein interaction (PPI) network. Then, a smaller network containing 39 DEGs were extracted from the PPI network whose nodes expression induction or suppression alone or in combination with each other would inhibit tumor progression or metastasis. A number of these DEGs were then verified by gene expression profiling, survival analysis and a number of validation datasets from different genomic repositories. They were involved in cell proliferation, energy production under hypoxic conditions, epithelial to mesenchymal transition (EMT) and angiogenesis. Multiple combination targeting of these DEGs were proposed to have high potential in preventing cancer progression. Some genes were also presented as diagnostic biomarkers for colorectal cancer. Finally, TMEM131, DARS and SORD genes were identified in this study which had never been associated with any kind of cancer neither as a biomarker nor curative target.
Functional specialization of the medial temporal lobes in human recognition memory: dissociating effects of hippocampal vs parahippocampal damage
Authors: Argyropoulos Georgios P. D. , Dell’Acqua Carola , Butler Emily , Loane Clare , Roca-Fernandez Adriana , Almozel Azhaar , Drummond Nikolas , Lage-Martinez Carmen , Cooper Elisa , Henson Richard N. , Butler Christopher R.
Published: January 2020

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes or material-types in recognition memory. We tested a rare patient (Patient MH) with a perirhinal lesion that appeared to spare the hippocampus, using two recognition memory paradigms, each run separately with faces, scenes and words. Replicating reports of a previous case, Patient MH showed impaired familiarity and preserved recollection, relative to controls, with no evidence for any effect of material-type. Moreover, when compared with other amnesic patients, who had hippocampal lesions that appeared to spare the perirhinal cortex, Patient MH showed greater impairment on familiarity and less on recollection, forming a double dissociation. However, when replacing this traditional, binary categorization of patients with a parametric analysis that related memory performance to continuous measures of brain damage across all patients, we found a different pattern: while hippocampal damage predicted recollection, it was parahippocampal instead of perirhinal (or entorhinal) cortex volume that predicted familiarity. Furthermore, there was no evidence that these brain-behavior relationships were moderated by material-type, nor by laterality of damage. Thus, while our data provide the most compelling support yet for dual-process models of recognition memory, in which recollection and familiarity depend on different MTL structures, they suggest that familiarity depends more strongly upon the parahippocampal rather than perirhinal cortex. More generally, our study reinforces the need to go beyond single-case and group studies, and instead examine continuous brain-behavior relationships across larger patient groups.
Cold tolerance in rice plants is partially controlled by root responses
Authors: Rativa Angie Geraldine Sierra , Junior Artur Teixeira de Araújo , Friedrich Daniele da Silva , Gastmann Rodrigo , Lamb Thainá Inês , Vargas Igor de , Silva Alexsander dos Santos , Pozzebon-Silva Ândrea , Adamski Janete Mariza , Fett Janette Palma , Ricachenevsky Felipe Klein , Sperotto Raul Antonio
Published: January 2020

Rice (Oryza sativaL.) ssp.indicais the most cultivated species in the South of Brazil. However, these plants face low temperature stress from September to November, which is the period of early sowing, affecting plant development during the initial stages of growth, and reducing rice productivity. This study aimed to characterize the root response to low temperature stress during the early vegetative stage of two rice genotypes contrasting in their cold tolerance (CT, cold-tolerant; and CS, cold-sensitive). Root dry weight and length, as well as number of root hairs, were higher in CT than CS when exposed to cold treatment. Histochemical analyses indicated that roots of CS genotype present higher levels of lipid peroxidation and H2O2accumulation, along with lower levels of plasma membrane integrity than CT under low temperature stress. RNAseq analyses revealed that the contrasting genotypes present completely different molecular responses to cold stress. The number of over-represented functional categories was lower in CT than CS under cold condition, suggesting that CS genotype is more impacted by low temperature stress than CT. Several genes might contribute to rice cold tolerance, including the ones related with cell wall remodeling, cytoskeleton and growth, signaling, antioxidant system, lipid metabolism, and stress response. On the other hand, high expression of the genesSRC2(defense),root architecture associated 1(growth),ACC oxidase,ethylene-responsive transcription factor, andcytokinin-O-glucosyltransferase 2(hormone-related) seems to be related with cold sensibility. Since these two genotypes have a similar genetic background (sister lines), the differentially expressed genes found here can be considered candidate genes for cold tolerance and could be used in future biotechnological approaches aiming to increase rice tolerance to low temperature.
A neural correlate of visual discomfort from flicker
Authors: Gentile Carlyn Patterson , Aguirre Geoffrey K.
Published: January 2020

The theory of “visual stress” holds that visual discomfort results from overactivation of the visual cortex. Despite general acceptance, there is a paucity of empirical data that confirm this relationship, particularly for discomfort from visual flicker. We examined the association between neural response and visual discomfort using flickering light of different temporal frequencies that separately targeted the magnocellular, parvocellular, and koniocellular post-receptoral pathways. Given prior work that has shown larger cortical responses to flickering light in people with migraine, we examined 10 headache free people and 10 migraineurs with visual aura. The stimulus was a uniform field, 50 degrees in diameter, that modulated with high-contrast flicker between 1.625 and 30 Hz. We asked subjects to rate their visual discomfort while we recorded steady state visually evoked potentials (ssVEP) from primary visual cortex. The peak temporal sensitivity ssVEP amplitude varied by post-receptoral pathway, and was consistent with the known properties of these visual channels. Notably, there was a direct, linear relationship between the amplitude of neural response to a stimulus and the degree of visual discomfort it evoked. No substantive differences between the migraine and control groups was found. These data link increased visual cortical activation with the experience of visual discomfort.
Hydropathy patterning complements charge patterning to describe conformational preferences of disordered proteins
Authors: Zheng Wenwei , Dignon Gregory , Brown Matthew , Kim Young C. , Mittal Jeetain
Published: January 2020

Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is of great interest due to its relevance to critical intracellular functions and diseases. It is now well established that the polymer scaling behavior can provide a great deal of information about the conformational properties as well as liquid-liquid phase separation of an IDP. It is, therefore, extremely desirable to be able to predict an IDP’s scaling behavior from the protein sequence itself. The work in this direction so far has focused on highly charged proteins and how charge patterning can perturb their structural properties. As naturally occurring IDPs are composed of a significant fraction of uncharged amino acids, the rules based on charge content and patterning are only partially helpful in solving the problem. Here, we propose a new order parameter, sequence hydropathy decoration (SHD), which can provide a near quantitative understanding of scaling and structural properties of IDPs devoid of charged residues. We combine this with a charge patterning parameter, sequence charge decoration (SCD), to obtain a general equation, parameterized from extensive coarse-grained simulation data, for predicting protein dimensions from the sequence. We finally test this equation against available experimental data and find a semi-quantitative match in predicting the scaling behavior. We also provide guidance on how to extend this approach to experimental data, which should be feasible in the near future.

Graphical TOC Entry
Heterozygous mutation of Sonic Hedgehog receptor (Ptch) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice
Authors: Jackson Thomas W. , Bendfeldt Gabriel A. , Beam Kelby A. , Rock Kylie D. , Belcher Scott M.
Published: January 2020

Sonic hedgehog (SHH) signaling is essential for the differentiation and migration of early stem cell populations during cerebellar development. Dysregulation of SHH-signaling can result in cerebellar overgrowth and the formation of the brain tumor medulloblastoma. Treatment for medulloblastoma is extremely aggressive and patients suffer life-long side effects including behavioral deficits. Considering that other behavioral disorders including autism spectrum disorders, holoprosencephaly, and basal cell nevus syndrome are known to present with cerebellar abnormalities, it is proposed that some behavioral abnormalities could be inherent to the medulloblastoma sequalae rather than treatment. Using a haploinsufficient SHH receptor knockout mouse model (Ptch1+/-), a partner preference task was used to explore activity, social behavior and neuroanatomical changes resulting from dysregulated SHH signaling. Compared to wild-type,Ptch1+/-females displayed increased activity by traveling a greater distance in both open-field and partner preference tasks. Social behavior was also sex-specifically modified inPtch1+/-females that interacted more with both novel and familiar animals in the partner preference task compared to same-sex wild-type controls. Haploinsufficency of PTCH resulted in cerebellar overgrowth in lobules IV/V and IX of both sexes, and female-specific decreases in hippocampal size and isocortical layer thickness. Taken together, neuroanatomical changes related to deficient SHH signaling may alter social behavior.
Pathway mining in functional genomics: An integrative approach to delineate boolean relationships between Src and its targets
Authors: Piran Mehran , Sepahi Neda , Piran Mehrdad , Fernandes Pedro L , Ghanbariasad Ali
Published: January 2020

Motivation: There are important molecular information hidden in the ocean of big data could be achieved by recognizing true relationships between different molecules. Human mind is very limited to find all molecular connections. Therefore, we introduced an integrated data mining strategy to find all possible relationships between molecular components in a biological context. To demonstrate how this approach works, we applied it on proto-oncogene c-Src. Results: Here we applied a data mining scheme on genomic, literature and signaling databases to obtain necessary biological information for pathway inference. Using R programming language, two large edgelists were constructed from KEGG and OmniPath signaling databases. Next, An R script was developed by which pathways were discovered by assembly of edge information in the constructed signaling networks. Then, valid pathways were distinguished from the invalid ones using molecular information in articles and genomic data analysis. Pathway inference was performed on predicted pathways starting with Src and ending with the DEGs whose expression were affected by c-Src overactivation. Moreover, some positive and negative feedback loops were proposed based on the gene expression results. In fact, this simple but practical flowchart will open new insights into interactions between cellular components and help biologists look for new possible molecular relationships that have not been reported neither in signaling databases nor as a signaling pathway.
A Synergism Between Dimethyl Trisulfide And Methyl Thiolacetate In Attracting Carrion-Frequenting Beetles Demonstrated By Use Of A Chemically-Supplemented Minimal Trap
Authors: Trumbo Stephen T. , Dicapua John A.
Published: January 2020

Microbially-derived volatile organic compounds recruit insects to carrion, shaping community assembly and ecological succession. The importance of individual volatiles and interactions between volatiles are difficult to assess in the field because of (1) the myriad compounds from decomposing animals, and (2) the likelihood that complex component blends are important for the final approach to carrion. On the assumption that searching insects may use simpler volatile cues to orient at a distance, we employed a chemically-supplemented minimal trap that uses test chemicals to attract from a distance and a minimal carrion bait to induce trap entry. Traps supplemented with dimethyl trisulfide (DMTS) attracted more individuals than controls, while traps supplemented only with methyl thiolacetate (MeSAc) did not. Traps supplemented with both chemicals, however, attracted statistically greater numbers of adult silphids (Necrophila americanaandOiceoptoma noveboracense), and the histeridEuspilotus assimilisthan the combined totals of DMTS-only and MeSAc-only traps, demonstrating a synergism. The attraction ofNecrophila americanalarvae to traps left in the field for less than 24 h suggests that this species sometimes moves between carrion sources; a follow-up experiment in the laboratory demonstrated that larvae have the ability to feed on non-carrion insects and to survive without food while moving between carcasses. The use of such species for forensic applications requires caution.
Finding A Fresh Carcass: Bacterially-Derived Volatiles And Burying Beetle Search Success
Authors: Trumbo Stephen T. , Steiger Sandra
Published: January 2020

When burying beetles first emerge as adults, they search for well-rotted carcasses with fly maggots on which to feed. After attaining reproductive competence, they switch their search and respond to a small, fresh carcass to prepare for their brood. Because the cues used to locate a feeding versus a breeding resource both originate from carrion, the beetles must respond to subtle changes in volatiles during decomposition. We investigated cues used to locate a fresh carcass in the field by (1) a general subtractive method, applying an antibacterial or antifungal to reduce volatiles, and (2) a specific additive method, placing chemicals near a fresh carcass. Five sulfur-containing compounds were studied: dimethyl sulfide (DMS), dimethyl disulfide (DMDS), dimethyl trisulfide (DMTS), methyl thiolacetate (MeSAc) and methyl thiocyanate (MeSCN). For the sulfides, we predicted that DMS would be the most attractive and DMTS the least attractive because of differences in the timing of peak production. We made noa prioripredictions for MeSAc and MeSCN. Antibacterial treatment of a carcass aged for 48 h resulted in a 59% decrease in beetles discovering the resource. The addition of MsSAc had no effect on discovery of a fresh carcass, while DMS and DMDS had a limited ability to attract breeding beetles. The chemical that was least well known, MeSCN, had a remarkable effect, increasing beetle numbers by 200-800% on a fresh carcass and almost guaranteeing discovery. DMTS, which is known to attract a variety of carrion insects, was the only compound to significantly reduce beetle presence at a fresh carcass. A laboratory experiment demonstrated that DMTS does not directly inhibit breeding, suggesting that DMTS deters breeding beetles while they fly.
SCANNER: A Web Resource for Annotation, Visualization and Sharing of Single Cell RNA-seq Data
Authors: Cai Guoshuai , Xiao Feifei
Published: January 2020

Motivation

In recent years, efficient scRNA-seq methods have been developed, enabling the transcriptome profiling of single cells massively in parallel. Meanwhile, its high dimensionality brought challenges in data modeling, analysis, visualization and interpretation. Available analysis tools require extensive knowledge and training of data properties, statistical modeling and computational skills. It is challenging for biologists to efficiently view, browse and interpret the data.

Results

Here we developed SCANNER, as a public webserver resource to equip the biologists and bioinformatician to share and analyze scRNA-seq data in a comprehensive and collaborative manner. It is effort-less and host-free without requirement on software setup or coding skills, and enables a user-friendly way to compare the activation status of gene sets on single cell basis. Also, it is equipped with multiple data interfaces for easy data sharing and currently provide a database for studying the smoking effect on single cell gene expression in lung. Using SCANNER, we have identified larger proportions of cancer-associated fibroblasts cells and activeness of fibroblast growth related genes in melanoma tissues in females compared to males. Moreover, we foundACE2is mainly expressed in pneumocytes, secretory cells and ciliated cells with disparity in gene expression by smoking behavior.

Availability and implementation

SCANNER is available athttps://www.thecailab.com/scanner/.

Supplementary information

Supplementary data are available online.

Contact

GCAI@mailbox.sc.eduorXIAOF@mailbox.sc.ecu

Key Points

SCANNER provides a new web server resource for promoting scRNA-seq data analysis

SCANNER enables comprehensive and dynamic analysis and visualization, novel functional annotation and activeness inference, online databases and easy data sharing.

SCANNER bridges the data analysis and the biological experiment units.
Recombinant protein production and purification of SiiD, SiiE and SiiF - components of the SPI4-encoded type I secretion system fromSalmonellaTyphimurium
Authors: Klingl Stefan , Kordes Sina , Schmid Benedikt , Gerlach Roman G. , Hensel Michael , Muller Yves A.
Published: January 2020

In humans,Salmonella entericainfections are responsible for a pleiotropy of medical conditions. These include intestinal inflammation and typhoid fever. The initial contact betweenSalmonellaand polarized epithelial cells is established by the SPI4-encoded type I secretion system (T1SS), which secrets SiiE, a giant non-fimbrial adhesin. We have recombinantly produced various domains of this T1SS fromSalmonella entericaserovar Typhimurium inEscherichia colifor further experimental characterization. We purified three variants of SiiD, the periplasmic adapter protein spanning the space between the inner and outer membrane, two variants of the SiiE N-terminal region and the N-terminal domain of the SiiF ATP-binding cassette (ABC) transporter. In all three proteins, at least one variant yielded high amounts of pure soluble protein. Proper folding and cooperative unfolding were investigated by circular dichroism (CD) spectroscopy. Secondary structure content estimations from CD spectra were in good agreement with the values derived from SiiD and SiiF homology models or, in case of the SiiE N-terminal region, a secondary structure prediction. For one SiiD variant, protein crystals could be obtained that diffracted X-rays to approximately 4 Å resolution.
Transcription factor enrichment analysis (TFEA): Quantifying the activity of hundreds of transcription factors from a single experiment
Authors: Rubin Jonathan D. , Stanley Jacob T. , Sigauke Rutendo F. , Levandowski Cecilia B. , Maas Zachary L. , Westfall Jessica , Taatjes Dylan J. , Dowell Robin D.
Published: January 2020

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Detecting differential activation of transcription factors (TFs) in response to perturbation provides insight into cellular processes. Transcription Factor Enrichment Analysis (TFEA) is a robust and reliable computational method that detects differential activity of hundreds of TFs given any set of perturbation data. TFEA draws inspiration from GSEA and detects positional motif enrichment within a list of ranked regions of interest (ROIs). As ROIs are typically inferred from the data, we also introducemuMerge, a statistically principled method of generating a consensus list of ROIs from multiple replicates and conditions. TFEA is broadly applicable to data that informs on transcriptional regulation including nascent (eg. PRO-Seq), CAGE, ChIP-Seq, and accessibility (e.g. ATAC-Seq). TFEA not only identifies the key regulators responding to a perturbation, but also temporally unravels regulatory networks with time series data. Consequently, TFEA serves as a hypothesis-generating tool that provides an easy, rigorous, and cost-effective means to broadly assess TF activity yielding new biological insights.
MISTR: A conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict
Authors: Sorouri Mahsa , Chang Tyron , Jesudhasan Palmy , Pinkham Chelsea , Elde Nels C. , Hancks Dustin C.
Published: January 2020

Host-pathogen conflicts leave genetic signatures of variation in homologous host genes. Using these “molecular scars” as a guide, we discovered a vertebrate-specificMItochondrialSTressResponse circuit (MISTR). MISTR proteins are associated with electron transport chain factors and activated by stress signals such as interferon-gamma and hypoxia. Upon stress, ultraconserved miRNAs downregulate MISTR1 followed by replacement with paralogs MISTRAntiViral (MISTRAV) or MISTRHypoxia (MISTRH), depending on the insult. While cells lacking MISTR1 are more sensitive to apoptotic triggers, cells lacking MISTRAV or expressing the poxvirus-encoded vMISTRAV exhibit resistance to the same insults. Rapid evolution signatures across primate genomes forMISTR1andMISTRAVindicate ancient and ongoing conflicts with pathogens. MISTR proteins are also found in plants, yeasts, and an algal virus indicating ancient origins and suggesting diverse means of altering mitochondrial function under stress. The discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal fundamental biological processes.
Preservation of cognition in hypertension-treated South Indian rural population
Authors: Rajkumar Radhika , Merciline Alex Divya , Muthukrishnan Suresh Kumar , Subhashree Murali , Duraimurugan Muniswamy , JanakiDevi Velmurugan , Datta Manjula , Subramaniam Jamuna R.
Published: January 2020

Change in diet, life style and increased life expectancy has led to the dramatic escalation in old age related complication like cognitive decline leading to dementia. Cardiovascular diseases (CVD) are huge risk factors for dementia, including Alzheimer disease (AD). Hypertension is very well known to cause cognitive impairment. Control of CVD could provide protection against dementia. Earlier, in the mouse model of AD, reserpine, an antihypertensive and antipsychotic drug could elicit improvement in the working memory in AD model mice and enhance the same in normal mice. Hence, Cognitive protection in the patients on chronic antihypertensive drug which contains reserpine was evaluated. Cognition in a cohort (in the South Indian rural population) of hypertensive patients (majority age group – 50-70 years) who have been chronically treated with a combinatorial drug, (adelphane/adelphane esidrex-Novaritis, Switzerland) consisting of reserpine and hydrazine for years was compared with controls without hypertension. The cohorts were age, sex, socio-economic, education background matched. Cognition was scored using the Tamil version of: Addenbrooke’s Cognitive Examination-III (T-ACEIII) and Tamil-Montreal Cognitive Assessment (T-MoCA) scales. The composite T-ACEIII score of control and treated groups were 53.6 and 53.2, respectively. T-MoCA scores (Control-15.1 and Treated-14.7) did not show much alteration. Further, the mean scores of the control and treated groups’ individual components of cognition in ACE, namely, Attention, Memory, Fluency, Language and visuospatial – cognitive skills also did not reveal significant difference. Thus, controlling blood pressure or hypertension with chronic antihypertensive medication like adelphane/adelphane esirdex (reserpine containing drugs) has retained normal cognition in both genders.