bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-Invariant Working Memory Representations in the Presence of Code-Morphing in the Lateral Prefrontal Cortex
Authors: Parthasarathy Aishwarya , Tang Cheng , Herikstad Roger , Cheong Loong Fah , Yen Shih-Cheng , Libedinsky Camilo
Published: March 2019

Endogenous processes allow the maintenance of working memories. These processes presumably involve prefrontal networks with strong recurrent connections. Distractors evoke a morphing of the population code, even when memories are stable. But it is unclear whether these dynamic population responses contain stable memory information. Here we show that dynamic prefrontal activity contains stable memory information, and the stability depends on parallel movement of trajectories associated with different memories in state space. We used an optimization algorithm to find a subspace with stable memory information. In correct trials the stability extended to periods that were not used to find the subspace, but in error trials the information and the stability were reduced. A bump attractor model was able to replicate these behaviors. The model provided predictions that could be confirmed with the neural data. We conclude that downstream regions could read memory information from a stable subspace.
A conserved requirement forFbxo7during male germ cell cytoplasmic remodelling
Authors: Rathje Claudia C , Randle Suzanne J , Rawi Sara Al , Skinner Benjamin M , Johnson Emma EP , Bacon Joanne , Vlazaki Myrto , Affara Nabeel A , Ellis Peter J , Laman Heike
Published: March 2019

Summary statement

Fbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here we show that in addition to the previously-known Parkinsonian and haematopoietic phenotypes, Fbxo7-deficient male mice are completely sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the cells undergo cytoplasmic remodelling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7-deficient males. Mutation of theDrosophilaFbxo7 orthologue,nutcracker(ntc) was previously shown to cause sterility at a similar stage of germ cell development, indicating that the requirement for Fbxo7 is conserved. Thentcphenotype was attributed to proteasome mis-regulation via an interaction with the proteasome regulator, DmPI31. Our data suggest rather that in mice, the requirement for Fbxo7 is either independent of its interaction with PI31, or relates specifically to cytoplasmic proteasome activity during spermiogenesis.
Heart development in the lizards (Varanidae) with the greatest extent of ventricular septation
Authors: Hanemaaijer Jermo , Gregorovicova Martina , Nielsen Jan M. , Moorman Antoon FM , Wang Tobias , Planken R. Nils , Christoffels Vincent M , Sedmera David , Jensen Bjarke
Published: March 2019

Among lizards, only monitor lizards (Varanidae) have a functionally divided cardiac ventricle. This enables them to sustain higher systemic blood pressures and higher metabolic rates than other reptiles of similar size. The division results from the concerted action of three partial septa, which may have homology to the full ventricular septum of mammals and archosaurs. Homology, however has only been inferred from anatomical comparisons of hearts of adult monitors whereas gene expression during heart development has not been studied. We show in developing monitors that the partial septa that separate the left and right ventricle, the ‘muscular ridge’ and ‘bulbuslamelle’, express the evolutionary conserved transcription factorsTbx5, Irx1andIrx2, orthologues of which mark the full ventricular septum. Compaction of embryonic trabeculae contributes to the formation of these septa. The septa are positioned, however, to the right of the atrioventricular junction and they do not partake in the separation of incoming atrial blood streams. Instead, the ‘vertical septum’ within the left ventricle separates the atrial blood streams. It expressesTbx3andTbx5, which orchestrate the formation of the electrical conduction axis of the full ventricular septum. These patterns of expression are more pronounced in monitors than in other lizards, and are associated with a deep electrical activation near the vertical septum, contrasting the primitive base-to-apex activation of other lizards. We conclude that current concepts of ventricular septum formation apply well to the monitor septa and that there is evolutionary conservation of ventricular septum formation among amniote vertebrates.
Definitely saw it coming? An ERP study on the role of article gender and definiteness in predictive processing
Authors: Fleur Damien S. , Flecken Monique , Rommers Joost , Nieuwland Mante S.
Published: March 2019

People sometimes anticipate specific words during language comprehension. Consistent with word anticipation, pre-nominal articles elicit differential neural activity when they mismatch the gender of a predictable noun compared with when they match. However, the functional significance of this pre-nominal effect is unclear: Do people only predict the noun or do they predict the entire article-noun combination? We addressed this question in an event-related potential study (N=48) with pre-registered data acquisition and analyses, capitalizing on gender-marking on Dutch definite articles and the lack thereof on indefinite articles. Participants read mini-story contexts that strongly suggested either a definite or indefinite noun phrase (e.g., ‘het/een boek’, the/a book) as its best continuation, followed by a definite noun phrase with the expected noun or an unexpected, different gender noun (‘het boek/de roman’, the book/the novel). We observed an enhanced negativity (N400) for articles that were unexpectedly definite or mismatched the expected gender, with the former effect being strongest. Pre-registered analyses and exploratory Bayesian analyses did not yield convincing evidence that the effect of gender-mismatch depended on expected definiteness. While prediction of article form cannot be excluded, it may not be required to elicit pre-nominal effects.
EMULSION: transparent and flexible multiscale stochastic models in epidemiology
Authors: Picault Sébastien , Huang Yu-Lin , Sicard Vianney , Arnoux Sandie , Beaunée Gaël , Ezanno Pauline
Published: March 2019

Stochastic mechanistic models are essential to predictive epidemiology, to better explore biological assumptions and anticipate effects of control measures on pathogen spread. Their development is usually long and iterative, involving multi-disciplinary knowledge integration. However, knowledge often becomes lost in model code, hindering late changes in assumptions and often making models appearing as black boxes to end-users. We introduce here EMULSION, an artificial intelligence-based software intended to help modellers focus on model design rather than programming. EMULSION defines a domain-specific language to make all components of an epidemiological model (structure, processes, parameters…) explicit as a structured text file. This file is readable by scientists from other fields (epidemiologists, biologists, economists), who can contribute to validate or revise assumptions at any stage of model development. It is then automatically processed by EMULSION generic simulation engine, preventing any discrepancy between model description and implementation. The modelling language and simulation architecture both rely on the combination of advanced artificial intelligence methods (knowledge representation and multi-level agent-based simulation), allowing several modelling paradigms (from compartment- to individual-based models) at several scales (up to metapopulations). The flexibility of EMULSION and its capability to support iterative modelling are illustrated here through examples of progressive complexity, including late revisions of core model assumptions. EMULSION is also currently used to model the spread of several diseases in real pathosystems (zoonoses such as Q fever or the vector-borne Rift Valley fever; or bovine respiratory diseases, with a focus on detection and treatment protocols). EMULSION provides a command-line tool for checking models, producing model diagrams, running simulations, and plotting outputs. Implemented in Python 3, EMULSION runs on Linux, MacOS, and soon Windows. It is released under Apache-2.0 license. A comprehensive documentation with installation instructions, tutorial and examples is available from:https://sourcesup.renater.fr/emulsion-public.
Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment
Authors: Leo Federica De , Quilici Giacomo , Tirone Mario , Mannella Valeria , Marchis Francesco De , Preti Alessandro , Gori Alessandro , Casalgrandi Maura , Mezzapelle Rosanna , Bianchi Marco E. , Musco Giovanna
Published: March 2019

Extracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.
Transcriptome Profiling of Mouse Brain and Lung under Dip2A Regulation Using RNA-Sequencing
Authors: sah Rajiv kumar , Yang Anlan , Bah Fatoumata Binta , Adlat Salah , Bohio Ameer Ali , Oo Zin Mar , Wang Chenhao , Myint May zun Zaw , Bahadar Noor , Zhang Luqing , Feng Xuechao , Zheng Yaowu
Published: March 2019

Disconnected interacting 2 homolog A (DIP2A) gene is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systemically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a-/- mice. Total RNAs were extracted from brain and lung of E19.5 embryos for RNA-Seq. Clean reads were mapped to mouse reference sequence (mm9) using Tophat and assembled into transcripts by Cufflinks. Edge R and DESeq were applied to identify differentially expressed genes (DEGs) and annotated under GO, COG, KEGG and TF. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes ‘DNA-templated transcription and Transcription from RNA polymerase II promoter’, ‘multicellular organism development’, ‘cell differentiation’ and ‘apoptotic process’. In addition, COG classification showed that both were mostly involved in ‘Replication, Recombination and Repair’, ‘Signal transduction and mechanism’, ‘Translation, Ribosomal structure and Biogenesis’ and ‘Transcription’. KEGG enrichment analysis showed that brain was mainly enriched in ‘Thryoid cancer’ pathway whereas lung in ‘Complement and Coagulation Cascades’ pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, Hapln1, Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation and survival; genes Hoxa5, Eya1, Ctsh, Erff1, Lama1, Lama2, Rspo2, Sox11, Spry4, Shh, Igf1 and Wnt7a from lung are important in lung development and morphogenesis. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.
Repeatability of adaptive radiation depends on spatial scale: regional versus global replicates of stickleback in lake versus stream habitats
Authors: Paccard Antoine , Hanson Dieta , Stuart Yoel E. , von Hippel Frank A. , Kalbe Martin , Klepaker Tom , Skúlason Skúli , Kristjánsson Bjarni K. , Bolnick Daniel I. , Hendry Andrew P. , Barrett Rowan D.H.
Published: March 2019

The repeatability of adaptive radiation is expected to be scale dependent, with determinism decreasing as greater spatial separation among “replicates” leads to their increased genetic and ecological independence. Threespine stickleback (Gasterosteus aculeatus) provide an opportunity to test whether this expectation holds for the early stages of adaptive radiation - their diversification in freshwater ecosystems has been replicated many times. To better understand the repeatability of that adaptive radiation, we examined the influence of geographic scale on levels of parallel evolution by quantifying phenotypic and genetic divergence between lake and stream stickleback pairs sampled at regional (Vancouver Island) and global (North America and Europe) scales. We measured phenotypes known to show lake-stream divergence and used reduced representation genome-wide sequencing to estimate genetic divergence. We assessed the scale-dependence of parallel evolution by comparing effect sizes from multivariate models and also the direction and magnitude of lake-stream divergence vectors. At the phenotypic level, parallelism was greater at the regional than the global scale. At the genetic level, putative selected loci showed greater lake-stream parallelism at the regional than the global scale. Generally, the level of parallel evolution was low at both scales, except for some key univariate traits. Divergence vectors were often orthogonal, highlighting possible ecological and genetic constraints on parallel evolution at both scales. Overall, our results confirm that the repeatability of adaptive radiation decreases at increasing spatial scales. We suggest that greater environmental heterogeneity at larger scales imposes different selection regimes, thus generating lower repeatability of adaptive radiation at larger spatial scales.
scds: Computational Annotation of Doublets in Single Cell RNA Sequencing Data
Authors: Bais Abha S , Kostka Dennis
Published: March 2019

Motivation

Single cell RNA sequencing (scRNA-seq) technologies enable the study of transcriptional heterogeneity at the resolution of individual cells and have an increasing impact on biomedical research. Specifically, high-throughput approaches that employ micro-fluidics in combination with unique molecular identifiers (UMIs) are capable of assaying many thousands of cells per experiment and are rapidly becoming commonplace. However, it is known that these methods sometimes wrongly consider two or more cells as single cells, and that a number of so-calleddoubletsis present in the output of such experiments. Treating doublets as single cells in downstream analyses can severely bias a study’s conclusions, and therefore computational strategies for the identification of doublets are needed. Here we present single cell doublet scoring (scds), a software tool for thein silicoidentification of doublets in scRNA-seq data.

Results

Withscds, we propose two new and complementary approaches for doublet identification: Co-expression based doublet scoring (cxds) and binary classification based doublet scoring (bcds). The co-expression based approach,cxds, utilizes binarized (absence/presence) gene expression data and employs a binomial model for the co-expression of pairs of genes and yields interpretable doublet annotations.bcds, on the other hand, uses a binary classification approach to discriminate artificial doublets from the original data. We apply our methods and existing doublet identification approaches to four data sets with experimental doublet annotations and find that our methods perform at least as well as the state of the art, but at comparably little computational cost. We also find appreciable differences between methods and across data sets, that no approach dominates all others, and we believe there is room for improvement in computational doublet identification as more data with experimental annotations becomes available. In the meanwhile,scdspresents a scalable, competitive approach that allows for doublet annotations in thousands of cells in a matter of seconds.

Availability and Implementation

scdsis implemented as an R package and freely available athttps://github.com/kostkalab/scds.

Contact

kostka@pitt.edu
The FluPRINT dataset: A multidimensional analysis of the influenza vaccine imprint on the immune system
Authors: Tomic Adriana , Tomic Ivan , Dekker Cornelia L. , Maecker Holden T. , Davis Mark M.
Published: March 2019

Recent advances in machine learning have allowed identification of molecular and cellular factors that underly successful antibody responses to influenza vaccines. Results of these studies have revealed the high level of complexity necessary to establish influenza immunity, and many different cellular and molecular components involved. However, identified correlates of protection fail to account for the majority of vaccinated cases across ages, cohorts, and influenza seasons. Major challenges arise from small sample sizes and from analysis of only one aspect of the biology such by using transcriptome data. The objective of the current study is to create a unified database, entitled FluPRINT, to enable a large-scale study exploring novel cellular and molecular underpinnings of successful immunity to influenza vaccines. Over 3,000 parameters were considered, including serological responses to influenza strains, serum cytokines, cell subset phenotypes, and cytokine stimulations. FluPRINT, thus facilitates application of machine learning algorithms for data mining. The data are publicly available and represent a resource to uncover new markers and mechanisms that drive successful influenza vaccination.
Keratin-Based Epidermal Green Autofluorescence is a Common Biomarker of Organ Injury
Authors: Zhang Mingchao , Li Yujia , Wang Jiucun , Tang Huiru , Yang Zhong , Wu Danhong , Tao Yue , He Hao , Wang Sijia , Chen Xingdong , Yin Shankai , Shi Haibo , Wei Xunbin , Chu Tianqing , Tang Wanzhi , Maharjan Dhruba Tara , Yang Zhaoxia , Wang Yu , Jin Li , Ying Weihai
Published: March 2019

It is critical to discover biomarkers for non-invasive evaluation of the levels of inflammation and oxidative stress in human body - two key pathological factors in numerous diseases. Our study has indicated keratin 1-based epidermal autofluorescence (AF) as a biomarker of this type: Inducers of both inflammation and oxidative stress dose-dependently increased epidermal green AF with polyhedral structure in mice, with the AF intensity being highly associated with the dosages of the inducers. Lung cancer also induced increased epidermal green AF of mice, which was mediated by inflammation. Significant and asymmetrical increases in green AF intensity with polyhedral structure were found in the Dorsal Index Fingers’ skin of acute ischemic stroke (AIS) patients. While the AF intensity of the subjects with high risk for developing AIS, ischemic stroke patients in recovery phase and lung cancer patients was significantly higher than that of healthy controls, both AF intensity and AF asymmetry of these four groups were markedly lower than those of the AIS patients, which have shown promise for AIS diagnosis. Several lines of evidence have indicated K1 as an origin of the AF, e.g., K1 siRNA administration attenuated the oxidative stress-induced AF increase of mice. Collectively, our study has indicated K1-based epidermal AF as a biomarker for non-invasive evaluation of the levels of inflammation and oxidative stress in the body. These findings have established a basis for novel keratin’s AF-based biomedical imaging technology for non-invasive, efficient and economic diagnosis and screening of such inflammation- and oxidative stress-associated diseases as AIS.
Ticks Home in on Body Heat: A New Understanding of Ectoparasite Host-Seeking and Repellent Action
Authors: Carr Ann L. , Salgado Vincent L.
Published: March 2019

Ticks are second only to mosquitoes as vectors of disease to humans and animals. Commercial insect repellents reduce or prevent potentially infectious tick bites by disrupting tick host-seeking behavior. Tick host-seeking is mainly ascribed to the Haller’s organ, a complex sensory structure on the tick foreleg that detects odors, carbon dioxide and heat4–7, but these host-seeking mechanisms and the mechanism of their disruption by repellents are not well understood1,2. There is anecdotal evidence that ticks and other ectoparasites are attracted to heat, but it has never been demonstrated that they use radiant heat to detect hosts at a distance. In fact, previous attempts to do this have concluded that radiant heat is not used by ticks. Here we show thatAmblyomma americanumandDermacentor variabilisticks can sense and home in on a human from several meters away, guided by radiant heat sensed by the Haller’s organ, and specifically the capsule, a covered spherical pit organ. An aperture in the capsule cover confers directionality and highly reflective interior surfaces of the capsule provide high sensitivity. Low concentrations of the insect repellents DEET, picaridin, 2-undecanone, citronellal and nootkatone eliminate thermotaxis without affecting olfactory-stimulated host-seeking behavior. Our results demonstrate that the tick Haller’s organ capsule is a radiant heat sensor used in host-finding and that repellents disrupt this sense at concentrations that do not disrupt olfaction. We anticipate this discovery to significantly aid insect repellent research and development of innovative strategies for protection against ectoparasites and vector-borne disease.
Differential effects of diet and weight on taste responses in diet-induced obese mice
Authors: Ahart Zachary C. , Martin Laura E. , Kemp Bailey R. , Banik Debarghya Dutta , Roberts Stefan G.E. , Torregrossa Ann-Marie , Medler Kathryn F
Published: March 2019

The ever growing obesity epidemic has created a need to develop a better understanding of the underlying mechanisms responsible for this condition. Appetite and consumption are directly influenced by the taste system which determines if potential food items will be ingested or rejected. While previous studies have reported that obese individuals have reduced taste perception, the relationship between these processes is still poorly understood. Earlier work has demonstrated that diet-induced obesity (DIO) directly impairs taste responses, particularly for sweet stimuli. These deficits occurred in the cells located in the oral cavity as well as in the behavioral responses. However, it is not clear if these changes to the taste system are due to obesity or to the high fat diet exposure. The goal of the current study was to determine if diet or excess weight is responsible for the DIO induced taste deficits. Using a combination of live cell imaging, brief-access licking, immunohistochemistry and real-time PCR, we have found that diet and weight gain can each selectivity affect taste. Follow up experiments determined that two key signaling proteins, gustducin and phospholipase Cβ2, are significantly reduced in the high fat diet without weight gain and obese mice, identifying a potential mechanism for the reduced taste responsiveness to some stimuli. Our data indicate that the relationship between obesity and taste is complex and reveal that for some stimuli, diet alone can cause taste deficits, even without the onset of obesity.
Allele frequency distribution of SNPs associated with levels of Vitamin D-binding protein and 25-hydroxyvitamin D
Authors: Nizamutdinov Igor , Popov Yaroslav , Ilinsky Valery , Rakitko Alexander
Published: March 2019

Haplotypes defined by rs7041/rs4588 in GC gene modulate 25-hydroxyvitamin D (25(OH)D) and vitamin D-binding protein (DBP) levels. To investigate the distributions of GC polymorphisms, the rs7041 and rs4588 allele and haplotypes frequencies were analyzed in samples from different Eurasian regions. The GC1S haplotype associated with high level of serum 25(OH)D had the maximum frequency in European populations (except Finish population). Such frequency distributions may be a result of adaptation to low solar insolation rate. Besides, there was a strong trend of increasing GC1F haplotype frequency from Europe (10-15%) to Siberia and Easter Asia (40-45%).
Human lung organoids develop into adult airway-like structures directed by physico-chemical biomaterial properties
Authors: Dye Briana R. , Youngblood Richard L. , Oakes Robert S. , Kasputis Tadas , Clough Daniel W. , Nagy Melinda S. , Spence Jason R. , Shea Lonnie D.
Published: March 2019

Tissues derived from human pluripotent stem cell (hPSC) often represent early developmental time points. Yet, when transplanted into immunocompromised mice, these hPSC-derived tissues further mature, which has been enhanced with biomaterial scaffolds, gaining tissue structure and cell types similar to the native adult lung. Our goal was to define the physico-chemical biomaterial properties, including the polymer type, degradation, and pore interconnectivity of the scaffolds. Transplantation of human lung organoids (HLOs) on microporous poly(lactide-co-glycolide) (PLG) scaffolds or polycaprolactone (PCL) produced organoids that formed tube-like structures that resembled both the structure and cellular diversity of an adult lung airway. Microporous scaffolds formed from poly(ethylene glycol) (PEG) hydrogel scaffolds inhibit maturation and the HLOs remain as lung progenitors. The structures formed from cells that occupy multiple pores within the scaffold, and pore interconnectivity and polymer degradation contributed to the maturation. Finally, the overall size of the generated airway structure and the total size of the tissue was influenced by the material degradation rate. Collectively, these biomaterial platforms provide a set of tools to promote maturation of the tissues and to control the size and structure of the organoids.
The alternative reality of plant mitochondrial DNA
Authors: Kozik Alexander , Rowan Beth A. , Lavelle Dean , Berke Lidija , Eric Schranz M. , Michelmore Richard W. , Christensen Alan C.
Published: March 2019

Plant mitochondrial genomes are usually assembled and displayed as circular maps based on the widely-held assumption that circular genome molecules are the primary form of mitochondrial DNA, despite evidence to the contrary. Many plant mitochondrial genomes have one or more pairs of large repeats that can act as sites for inter- or intramolecular recombination, leading to multiple alternative genomic arrangements (isoforms). Most mitochondrial genomes have been assembled using methods that were unable to capture the complete spectrum of isoforms within a species, leading to an incomplete inference of their structure and recombinational activity. To document and investigate underlying reasons for structural diversity in plant mitochondrial DNA, we used long-read (PacBio) and short-read (Illumina) sequencing data to assemble and compare mitochondrial genomes of domesticated(Lactuca sativa)and wild(L. salignaandL. serriola)lettuce species. This allowed us to characterize a comprehensive, complex set of isoforms within each species and to compare genome structures between species. Physical analysis ofL. sativamtDNA molecules by fluorescence microscopy revealed a variety of linear, branched linear, and circular structures. The mitochondrial genomes forL. sativaandL. serriolawere identical in sequence and arrangement, and differed substantially fromL. saligna,indicating that the mitochondrial genome structure did not change during domestication. From the isoforms evident in our data, we inferred that recombination occurs at repeats of all sizes at variable frequencies. The differences in genome structure betweenL. salignaand the two other lettuce species can be largely explained by rare recombination events that rearrange the structure. Our data demonstrate that representations of plant mitochondrial DNA as simple, genome-sized circular molecules are not accurate descriptions of their true nature and that in reality plant mitochondrial DNA is a complex, dynamic mixture of forms.

Data Availability

BioProject: Organellar genomes of cultivated and wild lettuce(Lactuca)varieties PRJNA508811https://www.ncbi.nlm.nih.gov/bioproject/508811and other accessions as indicated through the text and supplemental data.

Funding

NSF grant MCB-1413152 to ACC and support from UC Davis to RWM.
Comparing Time Series Transcriptome Data Between Plants Using A Network Module Finding Algorithm
Authors: Lee Jiyoung , Heath Lenwood S. , Grene Ruth , Li Song
Published: March 2019

Comparative transcriptome analysis is the comparison of expression patterns between homologous genes in different species. Since most molecular mechanistic studies in plants have been performed in model species including Arabidopsis and rice, comparative transcriptome analysis is particularly important for functional annotation of genes in other plant species. Many biological processes, such as embryo development, are highly conserved between different plant species. The challenge is to establish one-to-one mapping of the developmental stages between two species. In this protocol, we solve this problem by converting the gene expression patterns into a co-expression network and then apply network module-finding algorithms to the cross-species co-expression network. We describe how to perform such analysis using bash scripts for preliminary data processing and R programming language, which implemented simulated annealing method for module finding. We also provide instructions on how to visualize the resulting co-expression networks across species.
Return of an apex predator to a suburban preserve triggers a rapid trophic cascade
Authors: Leempoel Kevin , Meyer Jordana , Hebert Trevor , Nova Nicole , Hadly Elizabeth A.
Published: March 2019

Absence of apex predators simplifies food chains, leading to trophic degradation of ecosystems and diminution of the services they provide1. However, most predators do not coexist well with humans, which has resulted in a decline of carnivores and functional ecosystems worldwide2. In some instances, cryptic carnivores manage to survive amidst human settlements, finding refuge in small biological islands surrounded by urban landscapes. In such a system, we used two non-invasive data collection methods (camera trapping and fecal sampling) to investigate the multiannual relationship between predators and prey, and between competitors, through analysis of: (1) relative abundance and detection probability of species over time, (2) causal interactions via empirical dynamic modeling, (3) diet, and (4) diel activity patterns. All approaches show concordance in the results: the natural return of an apex predator, the puma (Puma concolor), triggered a trophic cascade, affecting the abundance and behavior of its main prey, subordinate predators and other prey in the studied system. Our study demonstrates that trophic recovery can occur rapidly following the return of a top predator, even in small protected areas in increasingly urbanized landscapes.
Principles and characteristics of biological assemblies in experimentally determined protein structures
Authors: Xu Qifang , Dunbrack Roland L.
Published: March 2019

More than half of all structures in the PDB are assemblies of two or more proteins, including both homooligomers and heterooligomers. Structural information on these assemblies comes from X-ray crystallography, NMR, and cryo-EM spectroscopy. The correct assembly in an X-ray structure is often ambiguous, and computational methods have been developed to identify the most likely biologically relevant assembly based on physical properties of assemblies and sequence conservation in interfaces. Taking advantage of the large number of structures now available, some of the most recent methods have relied on similarity of interfaces and assemblies across structures of homologous proteins.
Nanotubes effectively deliver siRNA to intact plant cells and protect siRNA against nuclease degradation
Authors: Demirer Gozde S. , Zhang Huan , Goh Natalie S. , Chang Roger , Landry Markita P.
Published: March 2019

Post-transcriptional gene silencing (PTGS) is a powerful tool to understand and control plant metabolic pathways, which is central to plant biotechnology. PTGS is commonly accomplished through delivery of small interfering RNA (siRNA) into cells. While siRNA delivery has been optimized for mammalian systems, it remains a significant challenge for plants due to the plant cell wall. Standard plant siRNA delivery methods (Agrobacteriumand viruses) involve coding siRNA into DNA vectors, and are only tractable for certain plant species. Herein, we develop a nanotube-based platform for direct delivery of siRNA, and show high silencing efficiency in intact plant cells. We demonstrate that nanotubes successfully deliver siRNA and silence endogenous genes owing to effective intracellular delivery and nanotube-induced protection of siRNA from nuclease degradation. This study establishes that nanotubes, which are below the size exclusion limit of the plant cell wall, could enable a myriad of plant biotechnology applications that rely on RNA delivery.
Decreasing Serine Levels During Growth Transition Triggers Biofilm Formation inBacillus subtilis
Authors: Greenwich Jennifer , Reverdy Alicyn , Gozzi Kevin , Cecco Grace Di , Tashjian Tommy , Godoy-Carter Veronica , Chai Yunrong
Published: March 2019

Biofilm development inBacillus subtilisis regulated at multiple levels. While a number of known signals that trigger biofilm formation do so through the activation of one or more sensory histidine kinases, it was recently discovered that biofilm activation is also coordinated by sensing intracellular metabolic signals, including serine starvation. Serine starvation causes ribosomes to pause on specific serine codons, leading to a decrease in the translation rate ofsinR, which encodes a master repressor for biofilm matrix genes, and ultimately biofilm induction. How serine levels change in different growth stages, howB. subtilisregulates intracellular serine levels in response to metabolic status, and how serine starvation triggers ribosomes to pause on selective serine codons remain unknown. Here we show that serine levels decrease as cells enter stationary phase and that unlike most other amino acid biosynthesis genes, expression of serine biosynthesis genes decreases upon the transition into stationary phase. Deletion of the gene for a serine deaminase responsible for converting serine to pyruvate led to a delay in biofilm formation, further supporting the idea that serine levels are a critical intracellular signal for biofilm activation. Finally, we show that levels of all five serine tRNA isoacceptors are decreased in stationary phase compared to exponential phase. Interestingly, the three isoacceptors recognizing UCN serine codons are reduced to a much greater extent than the two that recognize AGC and AGU serine codons. Our findings provide evidence for a link between serine homeostasis and biofilm development inB. subtilis.

IMPORTANCE

InBacillus subtilis, biofilm formation is triggered in response to various environmental and cellular signals. It was previously proposed that serine limitation acts as a proxy for nutrient status and triggers biofilm formation at the onset of biofilm entry through a novel signaling mechanism caused by global ribosome pausing on selective serine codons. In this study, we revealed that serine levels decrease at the biofilm entry due to catabolite control and a shunt mechanism. We also show that levels of five serine tRNA isoacceptors are differentially decreased in stationary phase compared to exponential phase; three isoacceptors recognizing UCN serine codons are reduced much greater than the two recognizing AGC and AGU codons. This indicates a possible mechanism for selective ribosome pausing.
Emotion Modulation of the Body-Selective Areas in the Developing Brain
Authors: Ross Paddy , Gelder Beatrice de , Crabbe Frances , Grosbras Marie-Hélène
Published: March 2019

Emotions are strongly conveyed by the human body and the ability to recognize emotions from body posture or movement is still developing through childhood and adolescence. To date, there are very few studies exploring how these behavioural observations are paralleled by functional brain development. Furthermore, there are currently no studies exploring the development of emotion modulation in these areas. In the current study, we used functional magnetic resonance imaging (fMRI) to compare the brain activity of 25 children (age 6-11), 18 adolescents (age 12-17) and 26 adults while they passively viewed short videos of angry, happy or neutral body movements. We observed that when viewing bodies generally, adults showed higher activity than children bilaterally in the body-selective areas; namely the extra-striate body area (EBA), fusiform body area (FBA), posterior superior temporal sulcus (pSTS) and amygdala (AMY). Adults also showed higher activity than adolescents, but only in right hemisphere body-selective areas. Crucially, however, we found that there were no age differences in the emotion modulation of activity in these areas. These results indicate, for the first time, that despite activity selective to body perception increasing across childhood and adolescence, emotion modulation of these areas in adult-like from 7 years of age.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
In vivostudy of gene expression with an enhanced dual-color fluorescent transcriptional timer
Authors: He Li , Binari Richard , Huang Jiuhong , Falo-Sanjuan Julia , Perrimon Norbert
Published: March 2019

Fluorescent transcriptional reporters are widely used as signaling reporters and biomarkers to monitor pathway activities and determine cell type identities. However, a large amount of dynamic information is lost due to the long half-life of the fluorescent proteins. To better detect dynamics, fluorescent transcriptional reporters can be destabilized to shorten their half-lives. However, applications of this approachin vivoare limited due to significant reduction of signal intensities. To overcome this limitation, we enhanced translation of a destabilized fluorescent protein and demonstrate the advantages of this approach by characterizing spatio-temporal changes of transcriptional activities inDrosophila. In addition, by combining a fast-folding destabilized fluorescent protein and a slow-folding long-lived fluorescent protein, we generated a dual-color transcriptional timer that provides spatio-temporal information about signaling pathway activities. Finally, we demonstrate the use of this transcriptional timer to identify new genes with dynamic expression patterns.
A Novel Ensemble-Based Machine Learning Algorithm To Predict The Conversion From Mild Cognitive Impairment To Alzheimer’s Disease Using Socio-demographic Characteristics, Clinical Information And Neuropsychological Measures
Authors: Grassi Massimiliano , Rouleaux Nadine , Caldirola Daniela , Loewenstein David , Schruers Koen , Perna Giampaolo , Dumontier Michel ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2019

Background

Despite the increasing availability in brain health related data, clinically translatable methods to predict the conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) are still lacking. Although MCI typically precedes AD, only a fraction of 20-40% of MCI individuals will progress to dementia within 3 years following the initial diagnosis. As currently available and emerging therapies likely have the greatest impact when provided at the earliest disease stage, the prompt identification of subjects at high risk for conversion to full AD is of great importance in the fight against this disease. In this work, we propose a highly predictive machine learning algorithm, based only on non-invasively and easily in-the-clinic collectable predictors, to identify MCI subjects at risk for conversion to full AD.

Methods

The algorithm was developed using the open dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), employing a sample of 550 MCI subjects whose diagnostic follow-up is available for at least 3 years after the baseline assessment. A restricted set of information regarding sociodemographic and clinical characteristics, neuropsychological test scores was used as predictors and several different supervised machine learning algorithms were developed and ensembled in final algorithm. A site-independent stratified train/test split protocol was used to provide an estimate of the generalized performance of the algorithm.

Results

The final algorithm demonstrated an AUROC of 0.88, sensitivity of 77.7%, and a specificity of 79.9% on excluded test data. The specificity of the algorithm was 40.2% for 100% sensitivity.

Discussion

The algorithm we developed achieved sound and high prognostic performance to predict AD conversion using easily clinically derived information that makes the algorithm easy to be translated into practice. This indicates beneficial application to improve recruitment in clinical trials and to more selectively prescribe new and newly emerging early interventions to high AD risk patients.
Active role of free RNA during the early phase of proteostasis stress
Authors: Alriquet Marion , Martínez-Limón Adrían , Hanspach Gerd , Hengesbach Martin , Tartaglia Gian G. , Calloni Giulia , Vabulas R. Martin
Published: March 2019

Transient sequestration of proteins and RNA is an essential principle of cellular reaction to stress. Compared to polypeptides, less is known about the role of RNA released from polysomes during acute proteostasis stress. Using quantitative mass spectrometry, we identified a set of proteins assembled by free RNA in the heat-shocked mammalian cytosol. RNA-associated proteins displayed higher disorder and larger size, which supports the role of multivalent interactions during the initial phase of the RNA granule formation. Structural features of the free RNA interactors defined them as a subset of RNA-binding proteins. The interactome contained preferentially the active form of eIF2α. The interaction between assembled proteinsin vivorequired RNA. The reconstitution of the association processin vitroindicated to the multimolecular basis for the increased binding to RNA upon heat shock in the cytosol. Our results reveal how free RNA can participate in reorganization of cellular functions during proteostasis stress.
Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study
Authors: Tuisku Jouni , Plavén-Sigray Pontus , Gaiser Edward C. , Airas Laura , Al-Abdulrasul Haidar , Brück Anna , Carson Richard E. , Chen Ming-Kai , Cosgrove Kelly P. , Ekblad Laura , Esterlis Irina , Farde Lars , Forsberg Anton , Halldin Christer , Helin Semi , Kosek Eva , Lekander Mats , Lindgren Noora , Marjamäki Päivi , Rissanen Eero , Sucksdorff Marcus , Varrone Andrea ,   HRRT [11C]PBR28 study group, Rinne Juha , Matuskey David , Cervenka Simon ,   Members of HRRT [11C]PBR28 study group
Published: March 2019

Purpose

To investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28.

Methods

[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; n=78 with HAB and n=62 MAB genotype; age range 19-80 years; BMI range 17.6 - 36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (n=53), Turku PET centre (n=62) and Yale University PET Center (n=25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts.

Results

There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.

Conclusion

These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
Effective Public Apologies
Authors: Kim Hoh , Kralik Jerald D. , Yun Kyongsik , Chung Yong-an , Jeong Jaeseung
Published: March 2019

Communicating with the public after corporate crises is often necessary, yet little evidence provides guidance. To address this, our theoretical and content analyses of public apologies revealed 12 key content elements. From these, we developed a basic apology, and tested its effectiveness alone, and with additional content. In two experiments involving river contamination, the basic apology was effective and improved with additional content. In Experiment 1, effectiveness involved actions taken to reduce harm and reoccurrence. Experiment 2 increased the hazard to carcinogenic chemicals, and one apology was superior: the basic apology plus statements of recovery efforts and defense of company actions. The two experiments show that crisis severity influences apology effectiveness. Experiment 3 found that clarifying causality helps convince people that the crisis source is identified and the problem resolved. Our findings show that an optimal public apology is comprehensive, and details the causes and actions taken to prevent reoccurrence.
Help from my friends—cooperation of BMAL1 with noncircadian transcription factors
Authors: Shostak Anton , Brunner Michael
Published: March 2019

The circadian clock in the suprachiasmatic nucleus (SCN) of mammals drives 24-h rhythms of sleep/wake cycles. Peripheral clocks present in other organs coordinate local and global physiology according to rhythmic signals from the SCN and via metabolic cues. The core circadian clockwork is identical in all cells. However, there is only a small amount of overlap of the circadian transcriptomes in different organs and tissues. A novel study by Beytebiere and colleagues (pp. 294–309) indicates that the regulation of tissue-specific rhythmic gene expression involves the cooperation of the circadian transcription factor (TF) BMAL1:CLOCK with tissue-specific TFs (ts-TFs) and correlates with the potential of BMAL1:CLOCK to facilitate rhythmic enhancer–enhancer interactions.
Preparation of Polymerase Chain Reaction Templates from Embryonic and Adult Mouse Tissue Samples
Authors: Rossant Janet , Nagy Andras
Published: March 2019

A simple cell or tissue lysate can provide a sufficient quality and amount of template DNA for polymerase chain reaction (PCR). This protocol can be used to prepare embryonic tissues, yolk sac, ear punch, toe, or 1- to 2-mm (maximum 5 mm) tail samples for PCR analysis.