bluuebunny/crossref_metadata_2025 huggingface dataset:
scRMD: Imputation for single cell RNA-seq data via robust matrix decomposition
Authors: Chen Chong , Wu Changjing , Wu Linjie , Wang Yishu , Deng Minghua , Xi Ruibin
Published: November 2018

Motivation

Single cell RNA-sequencing (scRNA-seq) technology enables whole transcriptome profiling at single cell resolution and holds great promises in many biological and medical applications. Nevertheless, scRNA-seq often fails to capture expressed genes, leading to the prominent dropout problem. These dropouts cause many problems in down-stream analysis, such as significant noise increase, power loss in differential expression analysis and obscuring of gene-to-gene or cell-to-cell relationship. Imputation of these dropout values thus becomes an essential step in scRNA-seq data analysis.

Results

In this paper, we model the dropout imputation problem as robust matrix decomposition. This model has minimal assumptions and allows us to develop a computational efficient imputation method scRMD. Extensive data analysis shows that scRMD can accurately recover the dropout values and help to improve downstream analysis such as differential expression analysis and clustering analysis.

Contact

ruibinxi@math.pku.edu.cn
Metabolite composition of sinking particles reflects a changing microbial community and differential metabolite degradation
Authors: Johnson Winifred M. , Longnecker Krista , Kido Soule Melissa C. , Arnold William A. , Bhatia Maya P. , Hallam Steven J. , Van Mooy Benjamin A. S. , Kujawinski Elizabeth B.
Published: November 2018

Marine sinking particles transport carbon from the surface and bury it in deep sea sediments where it can be sequestered on geologic time scales. The combination of the surface ocean food web that produces these particles and the particle-associated microbial community that degrades these particles, creates a complex set of variables that control organic matter cycling. We use targeted metabolomics to characterize a suite of small biomolecules, or metabolites, in sinking particles and compare their metabolite composition to that of the suspended particles in the euphotic zone from which they are likely derived. These samples were collected in the South Atlantic subtropical gyre, as well as in the equatorial Atlantic region and the Amazon River plume. The composition of targeted metabolites in the sinking particles was relatively similar throughout the transect, despite the distinct oceanic regions in which they were generated. Metabolites possibly derived from the degradation of nucleic acids and lipids, such as xanthine and glycine betaine, were an increased mole fraction of the targeted metabolites in the sinking particles relative to surface suspended particles, while algal-derived metabolites like the osmolyte dimethylsulfoniopropionate were a smaller fraction of the observed metabolites on the sinking particles. These compositional changes are shaped both by the removal of metabolites associated with detritus delivered from the surface ocean and by production of metabolites by the sinking particle-associated microbial communities. Further, they provide a basis for examining the types and quantities of metabolites that may be delivered to the deep sea by sinking particles.
Absence of pathogenic mutations in CD59 in chronic inflammatory demyelinating polyradiculoneuropathy
Authors: Duchateau Lena , Martin-Aguilar Lorena , Lleixà Cinta , Cortese Andrea , Dols-Icardo Oriol , Cervera-Carles Laura , Pascual-Goñi Elba , Diaz-Manera Jordi , Calegari Ilaria , Franciotta Diego , Rojas-Garcia Ricard , Illa Isabel , Clarimon Jordi , Querol Luis
Published: November 2018

Objective

Mutations inCD59cause CIDP-like polyneuropathy in children with inherited chronic hemolysis. We hypothesized that mutations inCD59might be found in a subset of sporadic CIDP patients.

Methods

5 patients from two centers, fulfilling the EFNS/PNS diagnostic criteria for CIDP were included.CD59coding region was amplified by PCR and Sanger sequenced.

Results

One rare variant was detected in a patient which resulted in a synonymous change and predicted to be neutral. Pathogenic variants were absent in our cohort.

Interpretation

Our pilot study suggests that mutations inCD59are absent in adult-onset sporadic CIDP.
In vivo widefield calcium imaging of the mouse cortex for analysis of network connectivity in health and brain disease
Authors: Cramer Julia V , Gesierich Benno , Roth Stefan , Dichgans Martin , Düring Marco , Liesz Arthur
Published: November 2018

The organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations. Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter- and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease.
Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice
Authors: Chowdhury Sumaiya , Song Sunmi , Zhang Hui Emma , Wang Xin Maggie , Gall Margaret G. , Tse Yu Denise Ming , Lay Angelina J. , Wen Xiang Michelle Sui , Evans Kathryn A. , Wetzel Stefanie , Liu Yolanda , Yau Belinda , Coppage Andrew L. , Lo Lisa , Stokes Rebecca A. , Hawthorne Wayne J. , Cooney Gregory J. , McLennan Susan V. , Gunton Jenny E. , Bachovchin William W. , Turner Nigel , Kebede Melkam A. , McCaughan Geoffrey W. , Twigg Stephen M. , Gorrell Mark D.
Published: November 2018

Background & Aims

Fibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.

Methods

Wildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.

Results

FAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic β-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and β-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic β-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.

Conclusion

This is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.
Accurate sequence variant genotyping in cattle using variation-aware genome graphs
Authors: Crysnanto Danang , Wurmser Christine , Pausch Hubert
Published: November 2018

Background: The genotyping of sequence variants typically involves as a first step the alignment of sequencing reads to a linear reference genome. Because a linear reference genome represents only a small fraction of sequence variation within a species, reference allele bias may occur at highly polymorphic or diverged regions of the genome. Graph-based methods facilitate to compare sequencing reads to a variation-aware genome graph that incorporates non-redundant DNA sequences that segregate within a species. We compared accuracy and sensitivity of graph-based sequence variant genotyping using the Graphtyper software to two widely used methods, i.e., GATK and SAMtools, that rely on linear reference genomes using whole-genomes sequencing data of 49 Original Braunvieh cattle. Results: We discovered 21,140,196, 20,262,913 and 20,668,459 polymorphic sites using GATK, Graphtyper, and SAMtools, respectively. Comparisons between sequence variant and microarray-derived genotypes showed that Graphtyper outperformed both GATK and SAMtools in terms of genotype concordance, non-reference sensitivity, and non-reference discrepancy. The sequence variant genotypes that were obtained using Graphtyper had the lowest number of mendelian inconsistencies for both SNPs and indels in nine sire-son pairs with sequence data. Genotype phasing and imputation using the Beagle software improved the quality of the sequence variant genotypes for all tools evaluated particularly for animals that have been sequenced at low coverage. Following imputation, the concordance between sequence- and microarray-derived genotypes was almost identical for the three methods evaluated, i.e., 99.32, 99.46, and 99.24 % for GATK, Graphtyper, and SAMtools, respectively. Variant filtration based on commonly used criteria improved the genotype concordance slightly but it also decreased sensitivity. Graphtyper required considerably more computing resources than SAMtools but it required less than GATK. Conclusions: Sequence variant genotyping using Graphtyper is accurate, sensitive and computationally feasible in cattle. Graph-based methods enable sequence variant genotyping from variation-aware reference genomes that may incorporate cohort-specific sequence variants which is not possible with the current implementations of state-of-the-art methods that rely on linear reference genomes.
let-7controls the transition to adulthood by releasing select transcriptional regulators from repression by LIN41
Authors: Aeschimann Florian , Neagu Anca , Rausch Magdalene , Großhans Helge
Published: November 2018

Development of multicellular organisms relies on faithful temporal control of cell fates. InCaenorhabditis elegans, the heterochronic pathway governs temporal patterning of somatic cells. This function may be phylogenetically conserved as several heterochronic genes have mammalian orthologues, and as the heterochroniclet-7miRNA and its regulator LIN28 appear to time the onset of puberty in mice and humans. Here, we have investigated howlet-7promotes the transition to adulthood inC. elegans. We find thatlet-7controls each of three relevant processes, namely male and female sexual organ morphogenesis as well as changes in skin progenitor cell fates, through the same single target,lin-41. LIN41 in turn silences two pairs of targets post-transcriptionally, by binding and silencing their mRNAs. The EGR-type transcription factor LIN-29a and its co-factor, the NAB1/2 orthologous MAB-10, mediate control of progenitor cell fates and vulval integrity. By contrast, male tail development depends on regulation of the DM domain-containing transcription factors DMD-3 and MAB-3. Our results provide mechanistic insight into an exemplary temporal patterning pathway, demonstrate thatlet-7– LIN41 function as a versatile regulatory module that can be connected to different outputs, and reveal how several levels of post-transcriptional regulation ultimately achieve effects through controlling transcriptional outputs.
Systems approaches provide new insights into Arabidopsis thaliana root growth under mineral nutrient limitation
Authors: Bouain Nadia , Korte Arthur , Satbhai Santosh B. , Rhee Seung Y. , Busch Wolfgang , Rouached Hatem
Published: November 2018

The molecular genetic mechanisms by which plants modulate their root growth rate (RGR) in response to nutrient deficiency are largely unknown. Using a panel of Arabidopsis thaliana natural accessions, we provide a comprehensive combinatorial analysis of RGR variation under macro- and micronutrient deficiency, namely phosphorus (P), iron (Fe), and zinc (Zn), which affect root growth in opposite directions. We found that while -P stimulates early RGR of most accessions, -Fe or -Zn reduces it. The combination of either -P-Fe or -P-Zn leads to suppression of the growth inhibition exerted by -Fe or -Zn alone. Surprisingly, Arabidopsis reference accession Columbia (Col-0) is not representative of the species under -P and -Zn. Using a genome wide association study, we identify candidate genes that control RGR under the assayed nutrient deficiency conditions. By using a network biology driven search using these candidate genes, we further identify a functional module enriched in regulation of cell cycle, DNA replication and chromatin modification that possibly underlies the suppression of root growth reduction in -P-Fe conditions. Collectively, our findings provide a framework for understanding the regulation of RGR under nutrient deficiency, and open new routes for the identification of both large effect genes and favorable allelic variations to improve root growth.
The evolution of egg trading in simultaneous hermaphrodites
Authors: Peña Jorge , Nöldeke Georg , Puebla Oscar
Published: November 2018

Egg trading, whereby simultaneous hermaphrodites exchange each other’s eggs for fertilization, constitutes one of the few rigorously documented and most widely cited examples of direct reciprocity among unrelated individuals. Yet how egg trading may initially invade a population of non-trading simultaneous hermaphrodites is still unresolved. Here, we address this question with an analytical model that considers mate encounter rates and costs of egg production in a population that may include traders (who provide eggs for fertilization only if their partners also have eggs to reciprocate), providers (who provide eggs regardless of whether their partners have eggs to reciprocate), and withholders (“cheaters” who only mate in the male role and just use their eggs to elicit egg release from traders). Our results indicate that a combination of inter-mediate mate encounter rates, sufficiently high costs of egg production, and a sufficiently high probability that traders detect withholders (in which case eggs are not provided) is conducive to the evolution of egg trading. Under these conditions traders can invade—and resist invasion from—providers and withholders alike. The prediction that egg trading evolves only under these specific conditions is consistent with the rare occurrence of this mating system among simultaneous hermaphrodites.
Functional heterogeneity within the developing zebrafish epicardium
Authors: Weinberger Michael , Simões Filipa C. , Patient Roger , Sauka-Spengler Tatjana , Riley Paul R.
Published: November 2018

The epicardium is essential during cardiac development, homeostasis and repair and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA-sequencing uncovered three epicardial subpopulations with specific genetic programmes and distinctive spatial distribution within the developing heart. Perturbation of unique gene signatures uncovered distinct functions associated with each subpopulation and established novel epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. This work elucidates the mutual spatiotemporal relationships between different epicardial subpopulations and assigns unique function to each during cardiac development. Understanding which mechanisms cells employ to establish a functional epicardium and to communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.
Systematic identification of human SNPs affecting regulatory element activity
Authors: van Arensbergen Joris , Pagie Ludo , FitzPatrick Vincent , de Haas Marcel , Baltissen Marijke , Comoglio Federico , van der Weide Robin , Teunissen Hans , Võsa Urmo , Franke Lude , de Wit Elzo , Vermeulen Michiel , Bussemaker Harmen , van Steensel Bas
Published: November 2018

Most of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help pinpoint SNPs that underlie human traits.
Co-culture and biogeography of Prochlorococcus and SAR11
Authors: Becker Jamie W. , Hogle Shane L. , Rosendo Kali , Chisholm Sallie W.
Published: November 2018

Prochlorococcus and SAR11 are among the smallest and most abundant organisms on Earth. With a combined global population of about 2.7 x 1028 cells, they numerically dominate bacterioplankton communities in oligotrophic ocean gyres and yet they have never been grown together in vitro. Here we describe co-cultures of Prochlorococcus and SAR11 isolates representing both high- and low-light adapted clades. We examined: (1) the influence of Prochlorococcus on the growth of SAR11 and vice-versa, (2) whether Prochlorococcus can meet specific nutrient requirements of SAR11, and (3) how co-culture dynamics vary when Prochlorococcus is grown with SAR11 compared with sympatric copiotrophic bacteria. SAR11 grew as much as 70% faster in the presence of Prochlorococcus, while the growth of the latter was unaffected. When Prochlorococcus populations entered stationary phase, SAR11 abundances decreased dramatically. In parallel experiments with copiotrophic bacteria however, the heterotrophic partner increased in abundance as Prochlorococcus densities leveled off. The presence of Prochlorococcus was able to meet SAR11’s central requirement for organic carbon, but not reduced sulfur. Prochlorococcus strain MIT9313, but not MED4, could meet the unique glycine requirement of SAR11, likely due to production and release of glycine betaine by MIT9313. Evidence suggests that Prochlorococcus MIT9313 may also compete with SAR11 for the uptake of 3-dimethylsulfoniopropionate (DMSP). To place our results in context, we assessed the relative contribution of Prochlorococcus and SAR11 genome equivalents to those of identifiable bacteria and archaea in over 800 marine metagenomes. At many locations, more than half of the identifiable genome equivalents in the euphotic zone belonged to Prochlorococcus and SAR11 – highlighting the biogeochemical potential of these two groups.
Convergent recruitment of life cycle regulators to direct sporophyte development in two eukaryotic supergroups
Authors: Arun Alok , Coelho Susana M. , Peters Akira F. , Bourdareau Simon , Peres Laurent , Scornet Delphine , Strittmatter Martina , Lipinska Agnieszka P. , Yao Haiqin , Godfroy Olivier , Montecinos Gabriel J. , Avia Komlan , Macaisne Nicolas , Troadec Christelle , Bendahmane Abdelhafid , Cock J. Mark
Published: November 2018

Three amino acid loop extension homeodomain transcription factors (TALE HD TFs) act as life cycle regulators in green algae and land plants. In mosses these regulators are required for the deployment of the sporophyte developmental program. We demonstrate that mutations in either of two TALE HD TF genes,OUROBOROSorSAMSARA, in the brown algaEctocarpusresult in conversion of the sporophyte generation into a gametophyte. The OUROBOROS and SAMSARA proteins heterodimerise in a similar manner to TALE HD TF life cycle regulators in the green lineage. These observations demonstrate that TALE-HD-TF-based life cycle regulation systems have an extremely ancient origin, and that these systems have been independently recruited to regulate sporophyte developmental programs in at least two different complex multicellular eukaryotic supergroups, Archaeplastida and Chromalveolata.
Modulation ofrpoSfitness by loss ofcpdAactivity during stationary-phase inEscherichia coli
Authors: Chib Savita , Seshasayee Aswin SaiNarain
Published: November 2018

Experimental evolution ofEscherichia coliin one month long stationary-phase in lysogeny broth batch cultures repeatedly selected mutations in the genes for the stationary-phase sigma factor RpoS and the cAMP phosphodiesterase CpdA. The founder strain carried a previously identified allele ofrpoS, referred to asrpoS819,a partially functional variant that confers growth advantage in stationary-phase (GASP). The 46 base duplication at the 3’ end ofrpoS819produces a longer protein present at very low levels compared to wild type RpoS. A newrpoSvariantrpoS92, carrying a re-duplication of the original duplication inrpoS819,arose during the first week of our evolution experiment. InrpoS92, an in-frame stop codon truncated RpoS819 creating a shorter RpoS92 whose levels are restored to that of wild type RpoS. Transcription profiling ofrpoS92indicated a shift in gene-expression to that of wild-typerpoS, reversing some of the expression trends ofrpoS819. Δ3cpdA, carrying an in-frame three base deletion, had arisen late in our evolution experiment. It is a loss of function mutation, which elevates cAMP levels. Using mixed culture competition experiments, we demonstrate thatrpoS92confers GASP, whereas Δ3cpdAconfers relatively modest GASP in comparison to the ancestralrpoS819. Δ3cpdAmediates epistatic repression ofrpoS92GASP. The original survivor carrying both rpoS92 and Δ3cpdAbesides other mutations displays robust GASP, highlighting the role of these additional mutations in reversing the epistatic interaction between Δ3cpdAandrpoS92.In 10- and 20-day old spent media, there is a reduction in the competitive fitness ofrpoS92,which is arrested by Δ3cpdA.Thus the activity of RpoS fluctuates via genetic mutations in deep stationary phase, and additional mutations in CpdA helps modulate the competitive fitness of RpoS variants.
Automagic: Standardized Preprocessing of Big EEG Data
Authors: Pedroni Andreas , Bahreini Amirreza , Langer Nicolas
Published: November 2018

Electroencephalography (EEG) recordings have been rarely included in large-scale studies. This is arguably not due to a lack of information that lies in EEG recordings but mainly on account of methodological issues. In many cases, particularly in clinical, pediatric and aging populations, the EEG has a high degree of artifact contamination and the quality of EEG recordings often substantially differs between subjects. Although there exists a variety of standardized preprocessing methods to clean EEG from artifacts, currently there is no method to objectively quantify the quality of preprocessed EEG. This makes the commonly accepted procedure of excluding subjects from analyses due to exceeding contamination of artifacts highly subjective. As a consequence, P-hacking is fostered, the replicability of results is decreased, and it is difficult to pool data from different study sites. In addition, in large-scale studies, data are collected over years or even decades, requiring software that controls and manages the preprocessing of ongoing and dynamically growing studies. To address these challenges, we developed Automagic, an open-source MATLAB toolbox that acts as a wrapper to run currently available preprocessing methods and offers objective standardized quality assessment for growing studies. The software is compatible with the Brain Imaging Data Structure (BIDS) standard and hence facilitates data sharing. In the present paper we outline the functionality of Automagic and examine the effect of applying combinations of methods on a sample of resting EEG data. This examination suggests that applying a pipeline of algorithms to detect artifactual channels in combination with Multiple Artifact Rejection Algorithm (MARA), an independent component analysis (ICA)-based artifact correction method, is sufficient to reduce a large extent of artifacts.
NKX2.1 is critical for melanocortin neuron identity, hypothalamicPomcexpression and body weight
Authors: Orquera Daniela P. , Tavella M. Belén , de Souza Flavio S. J. , Nasif Sofía , Low Malcolm J. , Rubinstein Marcelo
Published: November 2018

Food intake is tightly regulated by a group of neurons present in the mediobasal hypothalamus which activate satiety by releasingPomc-encoded melanocortins. Although the relevance of hypothalamic POMC neurons in the regulation of energy balance and body weight is well appreciated, little is known about the transcription factors that establish their cellular fate, terminal differentiation and phenotypic maintenance. Here, we report that the transcription factor Nkx2.1 activates hypothalamicPomcexpression from early development to adulthood by binding to conserved canonical NKX motifs present in the neuronalPomcenhancers nPE1 and nPE2. Transgenic and mutant mouse studies showed that the NKX motifs present in nPE1 and nPE2 are essential for their transcriptional enhancer activity. Early inactivation ofNkx2.1in the ventral hypothalamus prevented the onset ofPomcexpression and selectiveNkx2.1ablation from POMC neurons impairedPomcexpression and increased body weight and adiposity. These results demonstrate that NKX2.1 is critical in the early establishment of arcuate melanocortin neurons and the regulation ofPomcexpression and body weight in adulthood.
Opto-activation of cortical somatostatin interneurons alleviates parkinsonian symptoms
Authors: Vandecasteele Marie , Valverde Sébastien , Piette Charlotte , Gangarossa Giuseppe , Derousseaux Willy , Aristieta Arbelaiz Asier , Touboul Jonathan , Degos Bertrand , Venance Laurent
Published: November 2018

Deep brain stimulation of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics and modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A mathematical model highlights how the decrease in pyramidal neurons activity can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.

One-sentence Summary

Deep brain stimulation recruits cortical somatostatin interneurons, and their opto-activation is beneficial in Parkinson’s.
Oxytocin and vasotocin receptor variation sheds light into the evolution of human prosociality
Authors: Theofanopoulou Constantina , Andirkó Alejandro , Boeckx Cedric , Jarvis Erich D.
Published: November 2018

Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the full genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and that have associated literature. We performed variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency and selection analyses on data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, the OTR-rs6770632 was predicted to be the most functional. We found two sites where alleles (OTR: rs59190448 and rs237888)1 present only in modern humans and archaic humans are under positive selection in modern humans, with rs237888 predicted to be a highly functional site. We identified three sites of convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking very highly in terms of functionality and being under balancing selection in modern humans. Our findings shed light on evolutionary questions of modern human and hominid prosociality, as well as on similarities in the social behavior between modern humans and bonobos.
Neural Sampling Strategies for Visual Stimulus Reconstruction fromTwo-photon Imaging of Mouse Primary Visual Cortex
Authors: Garasto Stef , Nicola Wilten , Bharath Anil A. , Schultz Simon R.
Published: November 2018

Deciphering the neural code involves interpreting the responses of sensory neurons from the perspective of a downstream population. Performing such a read-out is an important step towards understanding how the brain processes sensory information and has implications for Brain-Machine Interfaces. While previous work has focused on classification algorithms to identify a stimulus in a predefined set of categories, few studies have approached a full-stimulus reconstruction task, especially from calcium imaging recordings. Here, we attempt a pixel-by-pixel reconstruction of complex natural stimuli from two-photon calcium imaging of mouse primary visual cortex. We decoded the activity of 103 neurons from layer 2/3 using an optimal linear estimator and investigated which factors drive the reconstruction performance at the pixel level. We find the density of receptive fields to be the most influential feature. Finally, we use the receptive field data and simulations from a linear-nonlinear Poisson model to extrapolate decoding accuracy as a function of network size. We find that, on this dataset, reconstruction performance can increase by more than 50%, provided that the receptive fields are sampled more uniformly in the full visual field. These results provide practical experimental guidelines to boost the accuracy of full-stimulus reconstruction.
A new species in theAnopheles gambiaecomplex reveals new evolutionary relationships between vector and non-vector species
Authors: Barron Maite G , Paupy Christophe , Rahola Nil , Akone-Ella Ousman , Ngangue Marc F. , Wilson-Bahun Theodel A. , Pombi Marco , Kengne Pierre , Costantini Carlo , Simard Frédéric , Gonzalez Josefa , Ayala Diego
Published: November 2018

Complexes of closely related species provide key insights about the rapid and independent evolution of adaptive traits. Here, we described and studied a presumably new species in theAnopheles gambiaecomplex,Anopheles fontenillei, recently discovered in the forested areas of Gabon, Central Africa. Our analysis placed the new taxon in the phylogenetic tree of theAn. gambiaecomplex, revealing important introgression events with other members of the complex. In particular, we detected recent introgression withAn. gambiaeandAn. coluzziiof genes directly involved in vectorial capacity. Moreover, genome analysis of the new species also allowed us to resolve the evolutionary history of inversion 3La. Overall,Anopheles fontenilleihas implemented our understanding about the relationship of species within thegambiaecomplex and provides insight into the evolution of vectorial capacity traits, relevant for the successful control of malaria in Africa.
Non-invasive ultrasound quantification of Scar Tissue Volume predicts functional changes during tendon healing
Authors: Ackerman Jessica E. , Studentsova Valentina , Loiselle Alayna E.
Published: November 2018

Tendon injuries are very common and disrupt the transmission of forces from muscle to bone, leading to impaired function and quality of life. Successful restoration of tendon function after injury is a challenging clinical problem due to the pathological, scar-mediated manner in which tendons heal. Currently, there are no standard treatments to modulate scar tissue formation and improve tendon healing. A major limitation to the identification of therapeutic candidates has been the reliance on terminal end-point metrics of healing in pre-clinical studies, which require a large number of animals and result in destruction of the tissue. To address this limitation, we have identified quantification of Scar Tissue Volume (STV) from ultrasound imaging as a longitudinal, non-invasive metric of tendon healing. STV was strongly correlated with established endpoint metrics of gliding function including Gliding Resistance (GR) and Metatarsophalangeal (MTP) Flexion Angle. However, no associations were observed between STV and tensile mechanical properties. To define the sensitivity of STV to identify differences between functionally discrete tendon healing phenotypes, we utilized S100a4 haploinsufficient mice (S100a4GFP/+), which heal with improved gliding function relative to wildtype (WT) littermates. A significant decrease in STV was observed in S100a4GFP/+repairs, relative to WT at day 14. Taken together, these data suggest US quantification of STV as a means to facilitate the rapid screening of biological and pharmacological interventions to improve tendon healing, and identify promising therapeutic targets, in an efficient, cost-effective manner.
Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice
Authors: Simon Matthew , Meter Michael Van , Ablaeva Julia , Ke Zhonghe , Gonzalez Raul S. , Taguchi Taketo , Cecco Marco De , Leonova Katerina I. , Kogan Valeria , Helfand Stephen L. , Neretti Nicola , Roichman Asael , Cohen Haim Y. , Antoch Marina , Gudkov Andrei , Sedivy John M. , Seluanov Andrei , Gorbunova Vera
Published: November 2018

Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6 deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA which triggers massive type I interferon response via activation of cGAS. Remarkably, nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number and type I interferons were elevated in the wild type aged mice. As sterile inflammation is a hallmark of aging we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.

Highlights

SIRT6 KO mice accumulate L1 cDNA triggering type I interferon response via cGAS pathway

Wild type aged mice accumulate L1 cDNA and display type I interferon response

Reverse transcriptase inhibitors rescue type I interferon response and DNA damage

Reverse transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice
The WT1-BASP1 complex is required to maintain the differentiated state of taste receptor cells
Authors: Gao Yankun , Banik Debarghya Dutta , Roberts Stefan G. E. , Medler Kathryn F.
Published: November 2018

The WT1-BASP1 complex is a transcriptional repressor that is involved in cell differentiation; however, the mechanisms underlying its effects are not well-characterized in vivo. In the peripheral taste system which endogenously expresses these proteins, BASP1 co-expression with WT1 begins at the end of development, suggesting a role for the WT1-BASP1 complex in terminal cell differentiation within this system. Using a conditional BASP1 mouse, we demonstrate that BASP1 is critical to maintain the differentiated state of adult cells by inhibiting the activation of WT1-dependent target genes. Our results uncover a central role for the WT1-BASP1 complex in maintaining cell differentiation.
Homologous Recombination as an Evolutionary Force in African Swine Fever Viruses
Authors: Zhu Zhaozhong , Xiao Chao-Ting , Fan Yunshi , Cai Zena , Lu Congyu , Zhang Gaihua , Jiang Taijiao , Tan Yongjun , Peng Yousong
Published: November 2018

Recent outbreaks of African swine fever virus (ASFV) in China severely influenced the swine industry of the country. Currently, there is no effective vaccine or drugs against ASFVs. How to effectively control the virus is challenging. In this study, we have analyzed all the publicly available ASFV genomes and demonstrated that there was a large genetic diversity of ASFV genomes. Interestingly, the genetic diversity was mainly caused by extensive genomic insertions and/or deletions (indels) instead of the point mutations. The genomic diversity of the virus resulted in proteome diversity. Over 250 types of proteins were inferred from the ASFV genomes, among which only 144 were observed in all analyzed viruses. Further analyses showed that the homologous recombination may contribute much to the indels, as supported by significant associations between the occurrence of extensive recombination events and the indels in the ASFV genomes. Repeated elements of dozens of nucleotides in length were observed to widely distribute and cluster in the adjacent positions of ASFV genomes, which may facilitate the occurrence of homologous recombination. Moreover, two enzymes, which were possibly related to the homologous recombination, i.e., a Lambda-like exonuclease with a YqaJ-like viral recombinase domain, and a DNA topoisomerase II, were found to be conservative in all the analyzed ASFVs. This work highlighted the importance of the homologous recombination in the evolution of the ASFVs, and helped with the strategy development of the prevention and control of the virus.
Pluripotent Stem Cell-derived Cerebral Organoids Reveal Human Oligodendrogenesis with Dorsal and Ventral Origins
Authors: Kim Hyosung , Xu Ranjie , Ragunathan Padmashri , Dunaevsky Anna , Liu Ying , Dreyfus Cheryl F. , Jiang Peng
Published: November 2018

The process of oligodendrogenesis has been relatively well delineated in the rodent brain. However, it remains unknown whether analogous developmental processes are manifested in the human brain. Here, we report oligodendrogenesis in forebrain organoids, generated by using OLIG2-GFP knockin human pluripotent stem cell (hPSC) reporter lines. OLIG2/GFP exhibits distinct temporal expression patterns in ventral forebrain organoids (VFOs) vs. dorsal forebrain organoids (DFOs). Interestingly, oligodendrogenesis can be induced in both VFOs and DFOs after neuronal maturation. Assembling VFOs and DFOs to generate fused forebrain organoids (FFOs) promotes oligodendroglia maturation. Furthermore, dorsally-derived oligodendroglial cells outcompete ventrally-derived oligodendroglia and become dominant in FFOs after long-term culture. Thus, our organoid models reveal human oligodendrogenesis with ventral and dorsal origins. These models will serve to study the phenotypic and functional differences between human ventrally- and dorsally-derived oligodendroglia and to reveal mechanisms of diseases associated with cortical myelin defects.
Fast and accurate shared segment detection and relatedness estimation in un-phased genetic data using TRUFFLE
Authors: Dimitromanolakis Apostolos , Paterson Andrew D. , Sun Lei
Published: November 2018

Relationship estimation and segment detection between individuals is an important aspect of disease gene mapping. Existing methods are either tailored for computational efficiency, or require phasing to improve accuracy. We developed TRUFFLE, a method that integrates computational techniques and statistical principles for the identification and visualization of identity-by-descent (IBD) segments using un-phased data. By skipping the haplotype phasing step and, instead, relying on a simpler region-based approach, our method is computationally efficient while maintaining inferential accuracy. In addition, an error model corrects for segment break-ups that occur as a consequence of genotyping errors. TRUFFLE can estimate relatedness for 3.1 million pairs from the 1000 Genomes Project data in a few minutes on a typical laptop computer. Consistent with expectation, we identified only three second cousin or closer pairs across different populations, while commonly used methods identified a large number of such pairs. Similarly, within populations, we identified much fewer related pairs. Compared to methods relying on phased data, TRUFFLE has comparable accuracy but is drastically faster and has fewer broken segments. We also identified specific local genomic regions that are commonly shared within populations, suggesting selection. When applied to pedigree data, we observed 99.6% accuracy in detecting 1st to 5th degree relationships. As genomic datasets become much larger, TRUFFLE can enable disease gene mapping through implicit shared haplotypes by accurate IBD segment detection.
NeuroRoots, a bio-inspired, seamless Brain Machine Interface device for long-term recording
Authors: Ferro Marc D. , Proctor Christopher M. , Gonzalez Alexander , Zhao Eric , Slezia Andrea , Pas Jolien , Dijk Gerwin , Donahue Mary J. , Williamson Adam , Malliaras Georges G. , Giocomo Lisa , Melosh Nicholas A.
Published: November 2018

Minimally invasive electrodes of cellular scale that approach a bio-integrative level of neural recording could enable the development of scalable brain machine interfaces that stably interface with the same neural populations over long period of time.

In this paper, we designed and created NeuroRoots, a bio-mimetic multi-channel implant sharing similar dimension (10µm wide, 1.5µm thick), mechanical flexibility and spatial distribution as axon bundles in the brain. A simple approach of delivery is reported based on the assembly and controllable immobilization of the electrode onto a 35µm microwire shuttle by using capillarity and surface-tension in aqueous solution. Once implanted into targeted regions of the brain, the microwire was retracted leaving NeuroRoots in the biological tissue with minimal surgical footprint and perturbation of existing neural architectures within the tissue. NeuroRoots was implanted using a platform compatible with commercially available electrophysiology rigs and with measurements of interests in behavioral experiments in adult rats freely moving into maze. We demonstrated that NeuroRoots electrodes reliably detected action potentials for at least 7 weeks and the signal amplitude and shape remained relatively constant during long-term implantation.

This research represents a step forward in the direction of developing the next generation of seamless brain-machine interface to study and modulate the activities of specific sub-populations of neurons, and to develop therapies for a plethora of neurological diseases.
Graphlet Laplacians: graphlet-based neighbourhoods highlight topology-function and topology-disease relationships
Authors: Windels Sam F. L. , Malod-Dognin Noël , Pržulj Nataša
Published: November 2018

Motivation

Laplacian matrices capture the global structure of networks and are widely used to study biological networks. However, the local structure of the network around a node can also capture biological information. Local wiring patterns are typically quantified by counting how often a node touches different graphlets (small, connected, induced sub-graphs). Currently available graphlet-based methods do not consider whether nodes are in the same network neighbourhood.

Contribution

To combine graphlet-based topological information and membership of nodes to the same network neighbourhood, we generalize the Laplacian to the Graphlet Laplacian, by considering a pair of nodes to be ‘adjacent’ if they simultaneously touch a given graphlet.

Results

We utilize Graphlet Laplacians to generalize spectral embedding, spectral clustering and network diffusion. Applying our generalization of spectral clustering to model networks and biological networks shows that Graphlet Laplacians capture different local topology corresponding to the underlying graphlet. In biological networks, clusters obtained by using different Graphlet Laplacians capture complementary sets of biological functions. By diffusing pan-cancer gene mutation scores based on different Graphlet Laplacians, we find complementary sets of cancer driver genes. Hence, we demonstrate that Graphlet Laplacians capture topology-function and topology-disease relationships in biological networks