bluuebunny/crossref_metadata_2025 huggingface dataset:
Family-based quantitative trait meta-analysis implicates rare noncoding variants inDENND1Ain pathogenesis of polycystic ovary syndrome
Authors: Dapas Matthew , Sisk Ryan , Legro Richard S. , Urbanek Margrit , Dunaif Andrea , Hayes M. Geoffrey
Published: November 2018

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young women. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. To test the hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants inDENND1A(P=5.31×10−5,Padj=0.019) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants inDENND1Ahave previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated thatDENND1Ais an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence thatDENND1Aplays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.
Cytokit: A single-cell analysis toolkit for high dimensional fluorescent microscopy imaging
Authors: Czech Eric , Aksoy Bulent Arman , Aksoy Pinar , Hammerbacher Jeff
Published: November 2018

Background

Multiplexed in-situ fluorescent imaging offers several advantages over single-cell assays that do not preserve the spatial characteristics of biological samples. This spatial information, in addition to morphological properties and extensive intracellular or surface marker profiling, comprise promising avenues for rapid advancements in the understanding of disease progression and diagnosis. As protocols for conducting such imaging experiments continue to improve, it is the intent of this study to provide and validate software for processing the large quantity of associated data in kind.

Results

Cytokit offers (i) an end-to-end, GPU-accelerated image processing pipeline; (ii) efficient input/output (I/O) strategies for operations specific to high dimensional microscopy; and (iii) an interactive user interface for cross filtering of spatial, graphical, expression, and morphological cell properties within the 100+ GB image datasets common to multiplexed immunofluorescence. Image processing operations supported in Cytokit are generally sourced from existing deep learning models or are at least in part adapted from open source packages to run in a single or multi-GPU environment. The efficacy of these operations is demonstrated through several imaging experiments that pair Cytokit results with those from an independent but comparable assay. A further validation also demonstrates that previously published results can be reproduced from a publicly available multiplexed image dataset.

Conclusion

Cytokit is a collection of open source tools for quantifying and analyzing properties of individual cells in large fluorescent microscopy datasets that are often, but not necessarily, generated from multiplexed antibody labeling protocols over many fields of view or time periods. This project is best suited to bioinformaticians or other technical users that wish to analyze such data in a batch-oriented, high-throughput setting. All source code, documentation, and data generated for this article are available under the Apache License 2.0 at https://github.com/hammerlab/cytokit.
Coccinellid host morphology dictates morphological diversity of the parasitoid waspDinocampus coccinellae
Authors: Vansant Hannah , Vasquez Yumary M , Obrycki John J , Sethuraman Arun
Published: November 2018

Pararsitoid-host interactions involving host species that are newly introduced into the range of a generalist parasitoid provide systems that can be examined for phenotypic plasticity and evolutionary changes in parasitoid-host dynamics. The solitary Braconid parasitoid wasp,Dinocampus coccinellae, has a cosmopolitan distribution and parasitizes approximately 50 species of predatory lady beetles (ladybirds) in the family Coccinellidae. In this study we quantified the effect of six (4 native North American and 2 non-native North American) host species on the morphometrics ofD. coccinellae. Adult lady beetles were collected from 13 locations in the United States and reared in the laboratory untilD.coccinellaeexited from their adult beetle hosts. Eighty-nine individualD. coccinellaefemales and their associated host were weighed and morphometric measurements were taken. The smallest lady beetle hostHippodamia parenthesisproduced the smallest adult wasps; the largest host species,Coccinella septempunctata, produced the largest female wasps. A directional cline in morphology of wasps and their coccinellid hosts was also observed in a dry-weight regression (R2= 0.4066, p-value < 0.0001). Two underlying mechanisms may explain the results of our study: (1) morphometric variation inD. coccinellaeis governed by phenotypic plasticity with the size of the emerging offspring contingent on the size of the coccinellid host, and/or (2) that morphometric variation inD. coccinellaeis governed by genomic adaptation to coccinellid host populations.
Killer meiotic drive and dynamic evolution of thewtfgene family
Authors: Eickbush Michael T. , Young Janet M. , Zanders Sarah E.
Published: November 2018

Natural selection works best when the two alleles in a diploid organism are transmitted to offspring at equal frequencies. Despite this, selfish loci known as meiotic drivers that bias their own transmission into gametes are found throughout eukaryotes. Drive is thought to be a powerful evolutionary force, but empirical evolutionary analyses of drive systems are limited by low numbers of identified meiotic drive genes. Here, we analyze the evolution of thewtfgene family ofSchizosaccharomyces pombethat contains both killer meiotic drive genes and suppressors of drive. We completed assemblies of allwtfgenes for two S.pombestrains, as well as a subset ofwtfgenes from over 50 strains. We find thatwtfcopy number can vary greatly between strains, and that amino acid substitutions, expansions and contractions of DNA sequence repeats, and nonallelic gene conversion between family members all contribute to dynamicwtfgene evolution. This work demonstrates the power of meiotic drive to foster rapid evolution and identifies a recombination mechanism through which transposons can indirectly mobilize meiotic drivers.
On-site integrated production of cellulases and β-glucosidases by Trichoderma reesei Rut C30 using steam-pretreated sugarcane bagasse
Authors: Fernandes de Souza Marcella , Pinto da Silva Bon Elba , Ana da Silvab Ayla Sant’
Published: November 2018

The high cost of commercial cellulases still hampers the economic competitiveness of the production of fuels and chemicals from lignocellulosic biomasses. This cost may be decreased by the on-site production of cellulases with the integrated use of the lignocellulosic biomass as carbon source. This integrated approach was evaluated in the present study whereby steam-pretreated sugarcane bagasse (SPSB) was used as carbon source for the production of cellulases by Trichoderma reesei Rut C30 and the produced enzymes were subsequently used for SPSB hydrolysis. An enzyme preparation with a high cellulase activity, of 1.93 FPU/mL, was obtained, and a significant β-glucosidase activity was achieved in buffered media, indicating the importance of pH control during enzyme production. The hydrolysis of SPSB with the laboratory-made mixture resulted in a glucose yield of 80%, which was equivalent to those observed for control experiments using commercial enzymes. Even though the supplementation of this mixture with external β-glucosidase from Aspergillus awamori was found to increase the initial hydrolysis rates, it had no impact on the final hydrolysis yield. It was shown that SPSB is a promising carbon source for the production of cellulases and β-glucosidases by T. reesei Rut C30 and that the enzyme preparation obtained is effective for the hydrolysis of SPSB, supporting the on-site integrated approach to decrease the cost of the enzymatic hydrolysis of lignocellulosic biomass.
Basal stem cell fate specification is mediated by SMAD signaling in the developing human lung
Authors: Miller Alyssa J. , Yu Qianhui , Czerwinski Michael , Tsai Yu-Hwai , Conway Renee F. , Wu Angeline , Holloway Emily M. , Walker Taylor , Glass Ian A. , Treutlein Barbara , Camp J. Gray , Spence Jason R.
Published: November 2018

Basal stem cells (basal cells), located in the bronchi and trachea of the human lung epithelium, play a critical role in normal airway homeostasis and repair, and have been implicated in the development of diseases such as cancer1-4. Additionally, basal-like cells contribute to alveolar regeneration and fibrosis following severe injury5-8. However, the developmental origin of basal cells in humans is unclear. Previous work has shown that specialized progenitor cells exist at the tips of epithelial tubes during lung branching morphogenesis, and in mice, give rise to all alveolar and airway lineages9,10. These ‘bud tip progenitor cells’ have also been described in the developing human lung11-13, but the mechanisms controlling bud tip differentiation into specific cell lineages, including basal cells, are unknown. Here, we interrogated the bud tip-to-basal cell transition using human tissue specimens, bud tip progenitor organoid cultures11, and single-cell transcriptomics. We used single-cell mRNA sequencing (scRNAseq) of developing human lung specimens from 15-21 weeks gestation to identify molecular signatures and cell states in the developing human airway epithelium. We then inferred differentiation trajectories during bud tip-to-airway differentiation, which revealed a previously undescribed transitional cell state (‘hub progenitors’) and implicated SMAD signaling as a regulator of the bud tip-to-basal cell transition. We used bud tip progenitor organoids to show that TGFT1 and BMP4 mediated SMAD signaling robustly induced the transition into functional basal-like cells, and thesein vitro-derived basal cells exhibited clonal expansion, self-renewal and multilineage differentiation. This work provides a framework for deducing and validating key regulators of cell fate decisions using single cell transcriptomics and human organoid models. Further, the identification of SMAD signaling as a critical regulator of newly born basal cells in the lung may have implications for regenerative medicine, basal cell development in other organs, and understanding basal cell misregulation in disease.
First Osteosarcoma Reported from a New World Elapid Snake and Review of Reptilian Bony Tumors
Authors: Hall Alexander S. , Jacobs Justin L. , Smith Eric N.
Published: November 2018

Cancer chiefly occurs in vertebrates. Rare in amphibians, and perhaps common in reptiles, various neoplasms and malignant cancers have been reported with erratic frequency by museums, paleontologists, veterinarians, and pet hobbyists. Unsurprisingly, most herpetofaunal diversity has never been systematically surveyed for the presence of neoplasms owing to the extreme rarity or obscurity of many species. Museum collections can fill these gaps in knowledge, especially when researchers use non-destructive techniques. In this study, we used X-ray computed tomography to discover and characterize an osteosarcoma of the spine in a rare South American coralsnake, Micrurus ancoralis. Two spinal vertebrae were completely fused and adjacent vertebrae showed evidence of corruption. The fused vertebrae contained a hollow inner network thought to be vascular tissue. We also review previous reports of tumors in the Elapidae and all bony tumors in non-avian reptiles. The rarely reported technique of X-ray CT for tumor discovery could greatly improve our understanding of the species diversity and perhaps underlying causes of neoplasia.
Perturbations of transcription and gene expression-associated processes alter distribution of cell size values inSaccharomyces cerevisiae
Authors: Maitra Nairita , Anandhakumar Jayamani , Blank Heidi M. , Kaplan Craig D. , Polymenis Michael
Published: November 2018

The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild typeSaccharomyces cerevisiaecells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains inSaccharomyces cerevisiae.We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population.
ENvironmental Dynamics Underlying Responsive Extreme Survivors (ENDURES) of Glioblastoma: a Multi-disciplinary Team-based, Multifactorial Analytical Approach
Authors: Johnston Sandra K. , Whitmire Paula , Massey Susan Christine , Kumthekar Priya , Porter Alyx B. , Raghunand Natarajan , Gonzalez-Cuyar Luis F. , Mrugala Maciej M. , Hawkins-Daarud Andrea , Jackson Pamela R. , Hu Leland S. , Sarkaria Jann N. , Wang Lei , Gatenby Robert A. , Egan Kathleen M. , Canoll Peter , Swanson Kristin R.
Published: November 2018

Although glioblastoma is a fatal primary brain cancer with a short median survival of 15 months, a small number of patients survive more than 5 years after diagnosis; they are known as extreme survivors (ES). Due to their rarity, very little is known about what differentiates these outliers from other glioblastoma patients. For the purpose of identifying unknown drivers of extreme survivorship in glioblastoma, we developed the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of glioblastoma). This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histological parameters. Leveraging our combined resources, the goals of the ENDURES consortium are two-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with glioblastoma and (2) to leverage the ENDURES repository for new insights on tumor behavior and novel targets for prolonging survival for all glioblastoma patients. In this article, we review the available literature and discuss what is already known about ES. We then describe the creation of our consortium and some of our preliminary results.

Funding

This review was financially supported by a grant from the James S. McDonnell Foundation

Conflicts of Interest

The authors have declared that no conflicts of interest exist.

Authorship

Conceptualized consortium: LW, RG, KME, PC, and KRS. Built consortium: SKJ, PK, NR, JS, KME, PC, and KRS. Wrote the manuscript: SKJ, PW, SCM, PK, AP, and KME. Reviewed and edited the manuscript: LFGC, MMM, AHD, PRJ, and LSH. Contributed to writing, provided feedback, and approved of final manuscript: All authors.

Link to website for ENDURES

http://mathematicalneurooncology.org/?page_id=2125
Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype
Authors: Laurent Jon M , Fu Xin , German Sergei , Maurano Matthew T , Zhang Kang , Boeke Jef D
Published: November 2018

Age-related Macular Degeneration (AMD) is a leading cause of blindness in the developed world, especially in aging populations, and is therefore an important target for new therapeutic development. Recently, there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci, including a highly significant association at 10q26. The 10q26 risk region contains two genes, HTRA1 and ARMS2, both of which have been separately implicated as causative for the disease, as well as dozens of sites of non-coding variation. To date, no studies have successfully pinpointed which of these variant sites are functional in AMD, nor definitively identified which genes in the region are targets of such regulatory variation. In order to efficiently decipher which sites are functional in AMD phenotypes, we describe a general framework for combinatorial assembly of large ‘synthetic haplotypes’ along with delivery to relevant disease cell types for downstream functional analysis. We demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type ‘assemblon’ covering the HTRA1/ARMS2 risk region. We further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region, delivery and analysis of which will identify functional sites and their effects, leading to an improved understanding of AMD development. We anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.
AVADA Enables Automated Genetic Variant Curation Directly from the Full Text Literature
Authors: Birgmeier Johannes , Tierno Andrew P. , Stenson Peter D. , Deisseroth Cole A. , Jagadeesh Karthik A. , Cooper David N. , Bernstein Jonathan A. , Haeussler Maximilian , Bejerano Gill
Published: November 2018

Purpose

The primary literature on human genetic diseases includes descriptions of pathogenic variants that are essential for clinical diagnosis. Variant databases such as ClinVar and HGMD collect pathogenic variants by manual curation. We aimed to automatically construct a freely accessible database of pathogenic variants directly from full-text articles about genetic disease.

Methods

AVADA (Automatically curated VAriant DAtabase) is a novel machine learning tool that uses natural language processing to automatically identify pathogenic variants and genes in full text of primary literature and converts them to genomic coordinates for rapid downstream use.

Results

AVADA automatically curated almost 60% of pathogenic variants deposited in HGMD, a 4.4-fold improvement over the current state of the art in automated variant extraction. AVADA also contains more than 60,000 pathogenic variants that are in HGMD, but not in ClinVar. In a cohort of 245 diagnosed patients, AVADA correctly annotated 38 previously described diagnostic variants, compared to 43 using HGMD, 20 using ClinVar and only 13 (wholly subsumed by AVADA and ClinVar’s) using the best automated abstracts-only based approach.

Conclusion

AVADA is the first machine learning tool that automatically curates a variants database directly from full text literature. AVADA is available upon publication at http://bejerano.stanford.edu/AVADA.
Virulence gene profiles and phylogeny of Shiga toxin-positiveEscherichia colistrains isolated from FDA regulated foods during 2010-2017
Authors: Gonzalez-Escalona Narjol , Kase Julie Ann
Published: November 2018

Illnesses caused by Shiga toxin-producingEscherichiacoli (STECs) can be life threatening, such as hemolytic uremic syndrome (HUS). The STECs most frequently identified by USDA’s Microbiological Data Program (MDP) carried toxin gene subtypesstx1aand/orstx2a. Here we describe the genome sequences of 331 STECs isolated from foods regulated by the FDA 2010-2017, determining their genomic identity, serotype, sequence type, virulence potential, and prevalence of antimicrobial resistance. Isolates were selected from the MDP archive, routine food testing by field labs (ORA), food testing by a contract company, and our laboratory (ORS). Only 276 (83%) were confirmed as STECs byin silicoanalysis. Foods from which STECs were recovered included cilantro (6%), spinach (25%), lettuce (11%), and flour (9%). Phylogenetic analysis using core genome MLST revealed these STEC genomes were highly variable, with some clustering associated with ST types and serotypes. We detected 95 different sequence types (ST); several ST were previously associated with HUS: ST21 and ST29 (O26:H11), ST11 (O157:H7), ST33 (O91:H14), ST17 (O103:H2), and ST16 (O111:H-).in silicovirulome analyses showed ~ 51% of these strains were potentially pathogenic [besidesstxgene they also carriedeae(25%) or 26%subA(26%)]. Virulence gene prevalence was also determined:stx1 only (19%) -variants a and c;stx2 only (66%) – variants a, b, c, d, e, and g; andstx1/sxt2 (15%). Our data form a new WGS database that can be used to support food safety investigations and monitor the recurrence/emergence ofE. coliin foods.

Importance

Shiga toxin-producingEscherichiacoli (STECs) are associated with foodborne outbreaks worldwide; however, surveillance has not previously included genomic analyses for phylogenetics, prevalence, or potential virulence. We constructed the first genomic database of isolates from FDA-regulated foods to help monitor the emergence of new pathogenic STECs. Although only ~30 STECs were isolated per year, 50% of these carried markers associated with pathogenesis either a combination ofeaeplusstx, orsubAplusstx. Moreover, those strains also carried virulence genes associated with severe illnesses. Here we showed that WGS enabled comparisons across isolates to establish phylogeny, help in identification of antibiotic resistance by monitoring the presence of antimicrobial resistance genes, and determined the presence of known virulence genes that have been linked with illnesses. Future food safety investigations will benefit from improved source tracking and risk assessments made possible by these analyses and new WGS database.
Personalization of hybrid brain models from neuroimaging and electrophysiology data
Authors: Sanchez-Todo R. , Salvador R. , Santarnecchi E. , Wendling F. , Deco G. , Ruffini G.
Published: November 2018

Personalization is rapidly becoming standard practice in medical diagnosis and treatment. This study is part of an ambitious program towards computational personalization of neuromodulatory interventions in neuropsychiatry. We propose to model the individual human brain as a network of neural masses embedded in a realistic physical matrix capable of representing measurable electrical brain activity. We call this ahybrid brain model (HBM)to highlight that it encodes both biophysical and physiological characteristics of an individual brain. Although the framework is general, we provide here a pipeline for the integration of anatomical, structural and functional connectivity data obtained from magnetic resonance imaging (MRI), diffuse tensor imaging (DTIconnectome) and electroencephalography (EEG). We personalize model parameters through a comparison of simulated cortical functional connectivity with functional connectivity profiles derived from cortically-mapped, subject-specific EEG. We show that individual information can be represented in model space through the proper adjustment of two parameters (global coupling strength and conduction velocity), and that the underlying structural information has a strong impact on the functional outcome of the model. These findings provide a proof of concept and open the door for further advances, including the model-driven design of non-invasive brain-stimulation protocols.
Habitat loss and fragmentation increase realized predator-prey body size ratios
Authors: Hillaert Jasmijn , Vandegehuchte Martijn L. , Hovestadt Thomas , Bonte Dries
Published: November 2018

In the absence of predators, habitat fragmentation favors large body sizes in primary consumers with informed movement due to their high gap-crossing ability. However, the body size of primary consumers is not only shaped by such bottom-up effects, but also by top-down effects as predators prefer prey of a certain size. Therefore, higher trophic levels should be taken into consideration when studying the effect of habitat loss and fragmentation on size distributions of herbivores.

We built a model to study the effect of habitat loss and fragmentation within a simple food web consisting of (i) a basal resource that is consumed by (ii) a herbivore that in turn is consumed by (iii) a predator. Our results highlight that predation may result in local accumulation of the resource via top-down control of the herbivore. As such, the temporal and spatial variation of the resource distribution is increased, selecting for increased herbivore movement. This results in selection of larger herbivores than in the scenario without predator. As predators cause herbivores to be intrinsically much larger than the optimal sizes selected by habitat fragmentation in the absence of predators, habitat fragmentation is no longer a driver of herbivore size. However, there is selection for increased predator size with habitat fragmentation as herbivores become less abundant, favoring gap-crossing ability of the predator. Since herbivore and predator body size respond differently to habitat loss and fragmentation, realized predator-herbivore body size ratios increase along this fragmentation gradient. Our model predicts the dominance of top-down forces in regulating body size selection in food webs and helps to understand how habitat destruction and fragmentation affect overall food web structure.
A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP
Authors: Goldblatt Jenny , Lawrenson Richard Ashley , Muir Luke , Dattani Saloni , Tsuchiya Tomoko , Kanegasaki Shiro , Sriskandan Shiranee , Pease James Edward
Published: November 2018

To evade the immune system, the lethal human pathogenStreptococcus pyogenesproduces SpyCEP, an enzyme that cleaves the C-terminalα-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage.

We examined thein vitromigration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N-terminus and preserved disulphide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C terminalα-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whilst navigation of an fMLP gradient remained largely intact.

We conclude therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation due to a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
Delays, behaviour and transmission: modelling the impact of effective private provider engagement on tuberculosis control in urban India
Authors: Arinaminpathy Nimalan , Deo Sarang , Singh Simrita , Khaparde Sunil , Rao Raghuram , Vadera Bhavin , Kulshrestha Niraj , Gupta Devesh , Rade Kiran , Nair Sreenivas Achuthan , Dewan Puneet
Published: November 2018

In India, the country with the world’s largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of India’s recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing.

We found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0 – 32.5%) and 15.8% (95% CrI 7.8 – 28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0 – 55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.
Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity
Authors: Kirby Leslie , Jin Jing , Cardona Jaime Gonzalez , Smith Matthew D. , Martin Kyle A. , Wang Jingya , Strasburger Hayley , Herbst Leyla , Alexis Maya , Karnell Jodi , Davidson Todd , Dutta Ranjan , Goverman Joan , Bergles Dwight , Calabresi Peter A.
Published: November 2018

Oligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10+oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.
Timing polymerase pausing with TV-PRO-seq: dissecting the interplay of pausing duration and location, and gene expression
Authors: Zhang Jie , Cavallaro Massimo , Hebenstreit Daniel
Published: November 2018

Transcription of many genes in metazoans is subject to polymerase pausing, which is the transient stop of transcriptionally-engaged polymerases. This is known to mainly occur in promoter proximal regions but it is not well understood. In particular, a genome-wide measurement of pausing times at high resolution has been lacking. We present here the time-variant precision nuclear run-on and sequencing (TV-PRO-seq) assay, an extension of the standard PRO-seq that allows us to estimate genome-wide pausing times at single-base resolution. Its application to human cells demonstrates that, proximal to promoters, polymerases pause more frequently but for shorter times than in other genomic regions. Pausing release by the detergent sarkosyl, previously believed to be linked to the factor NELF at the promoter proximal region only, is independent of the latter. Comparison with single-cell gene expression data reveals that the polymerase pausing times are longer in highly expressed genes, while transcriptionally noisier genes have higher pausing frequencies and slightly longer pausing times. Analyses of histone modifications suggest that the marker H3K36me3 is related to the polymerase pausing.
De novo transcriptome assembly of the Italian white truffle (Tuber magnatum Pico)
Authors: Vita Federico , Alpi Amedeo , Bertolini Edoardo
Published: November 2018

The Italian white truffle (Tuber magnatum Pico) is a gastronomic delicacy that dominates the worldwide truffle market. Despite its importance, the genomic resources currently available for this species are still limited. Here we present the first de novo transcriptome assembly of T. magnatum. Illumina RNA-seq data were assembled using a single-k-mer approach into 22,932 transcripts with N50 of 1,524 bp. Our approach allowed to predict and annotate 12,367 putative protein coding sequences, reunited in 6,723 loci. In addition, we identified 2,581 gene-based SSR markers. This work provides the first publicly available reference transcriptome for genomics and genetic studies providing insight into the molecular mechanisms underlying the biology of this important species.
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm
Authors: Qian Hongwu , Cao Pingping , Hu Miaohui , Gao Shuai , Yan Nieng , Gong Xin
Published: November 2018

The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of oligomeric Hh receptor Patched (Ptch) by the secreted and post-translationally modified ligand Hh relieves suppression of the signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp). The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers and each dimer binds to one ShhNp through two distinct inhibitory interfaces. Ptch1-A binds to ShhNp through the well-characterized Ca2+-mediated interface on the globular domain of ShhNp, and Ptch1-B primarily interacts with the N-terminal peptide and the palmitoyl moiety. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1-B. Our structure elucidates the tetrameric assembly of Ptch1 and suggests asymmetric mode of actions of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.
Distinguishing multiple-merger from Kingman coalescence using two-site frequency spectra
Authors: Fenton Eliot F. , Rice Daniel P. , Novembre John , Desai Michael M.
Published: November 2018

Demographic inference methods in population genetics typically assume that the ancestry of a sample can be modeled by the Kingman coalescent. A defining feature of this stochastic process is that it generates genealogies that are binary trees: no more than two ancestral lineages may coalesce at the same time. However, this assumption breaks down under several scenarios. For example, pervasive natural selection and extreme variation in offspring number can both generate genealogies with “multiple-merger” events in which more than two lineages coalesce instantaneously. Therefore, detecting multiple mergers (and other violations of the Kingman assumptions) is important both for understanding which forces have shaped the diversity of a population and for avoiding fitting misspecified models to data. Current methods to detect multiple mergers in genomic data rely primarily on the site frequency spectrum (SFS). However, the signatures of multiple mergers in the SFS are also consistent with a Kingman coalescent with a time-varying population size. Here, we present a new statistical test for determining whether the Kingman coalescent with any population size history is consistent with population data. Our approach is based on information contained in the two-site joint frequency spectrum (2-SFS) for pairs of linked sites, which has a different dependence on the topologies of genealogies than the SFS. Our statistical test is global in the sense that it can detect when the genome-wide genetic diversity is inconsistent with the Kingman model, rather than detecting outlier regions, as in selection scan methods. We validate this test using simulations, and then apply it to demonstrate that genomic diversity data fromDrosophila melanogasteris inconsistent with the Kingman coalescent.
Neural Population Control via Deep Image Synthesis
Authors: Bashivan Pouya , Kar Kohitij , DiCarlo James J
Published: November 2018

Particular deep artificial neural networks (ANNs) are today’s most accurate models of the primate brain’s ventral visual stream. Here we report that, using a targeted ANN-driven image synthesis method, new luminous power patterns (i.e. images) can be applied to the primate retinae to predictably push the spiking activity of targeted V4 neural sites beyond naturally occurring levels. More importantly, this method, while not yet perfect, already achieves unprecedented independent control of the activity state of entire populations of V4 neural sites, even those with overlapping receptive fields. These results show how the knowledge embedded in today’s ANN models might be used to non-invasively set desired internal brain states at neuron-level resolution, and suggest that more accurate ANN models would produce even more accurate control.
Ventral hippocampal projections to the medial prefrontal cortex regulate social memory
Authors: Phillips Mary L. , Robinson Holly A. , Pozzo-Miller Lucas
Published: November 2018

Inputs from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) have been implicated in several neuropsychiatric disorders. Here, we show that the long-range vHIP-mPFC projection is hyperactive in the Mecp2 knockout (KO) mouse model of the autism spectrum disorder Rett syndrome, which has deficits in social memory. Chronically mimicking vHIP-mPFC hyperexcitability in wild-type mice impaired social memory, whereas chronic inhibition of mPFC-projecting vHIP neurons in Mecp2 KO mice rescued social memory deficits; the extent of memory rescue was negatively correlated with the strength of vHIP input to the mPFC. Acute manipulations of the vHIP-mPFC projection also affected social memory in a specific and selective manner, suggesting that proper vHIP-mPFC signaling is necessary to recall social memories. In addition, we identified an altered vHIP-mPFC innervation pattern and increased synaptic strength onto layer 5 pyramidal neurons as contributing factors in aberrant vHIP-mPFC signaling in Mecp2 KO mice.
Multiple mechanisms link prestimulus neural oscillations to sensory responses
Authors: Iemi Luca , Busch Niko A , Laudini Annamaria , Haegens Saskia , Samaha Jason , Villringer Arno , Nikulin Vadim V
Published: November 2018

Spontaneous fluctuations of neural activity may explain why sensory responses vary across repeated presentations of the same physical stimulus. To test this hypothesis, we recorded electroencephalography in humans during stimulation with identical visual stimuli and analyzed how prestimulus neural oscillations modulate different stages of sensory processing reflected by distinct components of the event-related potential (ERP). We found that strong prestimulus alpha- and beta-band power resulted in a suppression of early ERP components (C1 and N150) and in an amplification of late components (after 0.4 s), even after controlling for fluctuations in 1/f aperiodic signal and sleepiness. Whereas functional inhibition of sensory processing underlies the reduction of early ERP responses, we found that the modulation of non-zero-mean oscillations (baseline shift) accounted for the amplification of late responses. Distinguishing between these two mechanisms is crucial for understanding how internal brain states modulate the processing of incoming sensory information.
Loss of cytoplasmic incompatibility and minimal fecundity effects explain relatively lowWolbachiafrequencies inDrosophila mauritiana
Authors: Meany Megan K. , Conner William R. , Richter Sophia V. , Bailey Jessica A. , Turelli Michael , Cooper Brandon S.
Published: November 2018

Maternally transmittedWolbachiabacteria infect about half of all insect species. ManyWolbachiacause cytoplasmic incompatibility (CI), reduced egg hatch when uninfected females mate with infected males. Although CI produces a frequency-dependent fitness advantage that leads to high equilibriumWolbachiafrequencies, it does not aidWolbachiaspread from low frequencies. Indeed, the fitness advantages that produce initialWolbachiaspread and maintain non-CIWolbachiaremain elusive.wMauWolbachiainfectingDrosophila mauritianado not cause CI, despite being very similar to CI-causingwNo fromD. simulans(0.068% sequence divergence over 682,494 bp), suggesting recent CI loss. Using draftwMau genomes, we identify a deletion in a CI-associated gene, consistent with theory predicting that selection within host lineages does not act to increase or maintain CI. In the laboratory,wMau shows near-perfect maternal transmission; but we find no significant effect on host fecundity, in contrast to published data. IntermediatewMau frequencies on the island Mauritius are consistent with a balance between unidentified small, positive fitness effects and imperfect maternal transmission. Our phylogenomic analyses suggest that group-BWolbachia, includingwMau andwPip, diverged from group-AWolbachia, such aswMel andwRi, 6–46 million years ago, more recently than previously estimated.
A novel olfactometer for efficient and flexible odorant delivery
Authors: Burton Shawn D. , Wipfel Mia , Guo Michael , Eiting Thomas P. , Wachowiak Matt
Published: November 2018

Understanding how sensory space maps to neural activity in the olfactory system requires efficiently and flexibly delivering numerous odorants within single experimental preparations. Such delivery is difficult with current olfactometer designs, which typically include limited numbers of stimulus channels and are subject to inter-trial and inter-channel contamination of odorants. Here, we present a novel olfactometer design that is easily constructed, modular, and capable of delivering an unlimited number of odorants with temporal precision and no detectable inter-trial or inter-channel contamination. The olfactometer further allows for flexible generation of odorant mixtures and flexible timing of odorant sequences. Odorant delivery from the olfactometer is turbulent but reliable from trial-to-trial, supporting operant conditioning of mice in an odorant discrimination task and permitting odorants and concentrations to be mapped to neural activity with a level of precision equivalent to that obtained with a flow dilution olfactometer. This novel design thus provides several unique advantages for interrogating olfactory perception and for mapping sensory space to neural activity in the olfactory system.
Focus on the breath: Brain decoding reveals internal states of attention during meditation
Authors: Weng H.Y. , Lewis-Peacock J.A. , Hecht F.M. , Uncapher M.R. , Ziegler D.A. , Farb N.A.S. , Goldman V. , Skinner S. , Duncan L.G. , Chao M.T. , Gazzaley A.
Published: November 2018

Meditation practices are used to cultivate internally-oriented attention to bodily sensations, which may improve health via cognitive and emotion regulation of bodily signals. However, it remains unclear how meditation impacts internal attention states due to lack of measurement tools that can objectively assess mental states during meditation practice itself, and produce time estimates of internal focus at individual or group levels. To address these measurement gaps, we tested the feasibility of applying multi-voxel pattern analysis (MVPA) to single-subject fMRI data to (1) learn and recognize internal attentional (IA) states relevant for meditation during a directed IA task, and (2) decode or estimate the presence of those IA states during an independent meditation session. Within a mixed sample of experienced meditators and novice controls (N=16), we first used MVPA to develop single-subject brain classifiers for 5 modes of attention during an IA task in which subjects were specifically instructed to engage in one of five states (i.e., meditation-related states: breath attention, mind wandering, and self-referential processing, and control states: attention to feet and sounds). Using standard cross-validation procedures, MVPA classifiers were trained in five of six IA blocks for each subject, and predictive accuracy was tested on the independent sixth block (iterated until all block volumes were tested, N=2160). Across participants, all five IA states were significantly recognized well above chance (>41% vs. 20% chance). At the individual level, IA states were recognized in most participants (87.5%), suggesting that recognition of IA neural patterns may be generalizable for most participants, particularly experienced meditators. Next, for those who showed accurate IA neural patterns, the originally trained classifiers were then applied to a separate meditation run (10-min) to make an inference about the percentage time engaged in each IA state (breath attention, mind wandering, or self-referential processing). Preliminary group-level analyses demonstrated that during meditation practice, participants spent more time attending to breath compared to mind wandering or self-referential processing. This paradigm established the feasibility of using MVPA classifiers to objectively assess mental states during meditation at the participant level, which holds promise for improved measurement of internal attention states cultivated by meditation.