bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased expression of MCPIP1 in HIV-1 controllers is correlated with overexpression of p21
Authors: de Azevedo Suwellen S. D. , Ribeiro-Alves Marcelo , Côrtes Fernanda H. , Delatorre Edson , Hoagland Brenda , Grinsztejn Beatriz , Veloso Valdilea G. , Morgado Mariza G. , Souza Thiago Moreno L. , Bello Gonzalo
Published: April 2019

Some multifunctional cellular proteins, as the monocyte chemotactic protein-induced protein 1 (MCPIP1) and the cyclin-dependent kinase inhibitor p21, have also shown to be able to modulate the cellular susceptibility to the human immunodeficiency virus type 1 (HIV-1). Several studies described that p21 is expressed at high levelsex vivoin cells from individuals who naturally control HIV-1 replication (HIC). The expression level of MCPIP1 in HIC was never described before, but a recent study in a model of renal carcinoma cells showed that MCPIP1 overexpression was associated with an increase of both p21 transcripts and proteins levels. Here, we explored the potential associations between MCPIP1 and p21 expression, as well as with cellular activation in HIC, sustaining undetectable (elite controllers – EC) or low (viremic controllers – VC) viral loads. We found a selective upregulation of MCPIP1 and p21 mRNA levels in PBMC from HIC compared with both ART– suppressed and HIV–negative control groups (P ≤ 0.02) and a strong positive correlation (r ≥ 0.57; P ≤ 0.014) between expressions of both transcripts independently of the VL, treatment condition and HIV status. The mRNA levels of p21, but not of MCPIP1, were positively correlated with activated CD4+T cells levels in HIC and EC (r ≥ 0.53; P ≤ 0.017). In relation to the monocyte activation, the mRNA levels of both p21 (r = 0.74; P = 0.005) and MCPIP1 (r = 0.58; P = 0.040) were positively correlated with plasmatic levels of sCD14 only in EC. Multivariate analysis confirmed the association between MCPIP1 and p21 mRNA levels, and between the latter with the frequency of activated CD4+T cells. These data show for the first time the simultaneous overexpression and positive correlation of MCPIP1 and p21 transcripts in the setting of natural suppression of HIV-1 replicationin vivo. The positive correlation between MCPIP1 and p21 transcripts supports a common regulatory pathway connecting these multifunctional host factors and a possible synergistic effect on HIV-1 replication control. Pharmacological manipulation of these cellular proteins may open novel therapeutic perspectives to prevent HIV-1 replication and disease progression.
Modeling in an oral health study through two statistical methods in Uruguay
Authors: Massa Fernando , Berberian Natalia , Álvarez-Vaz Ramón
Published: April 2019

In epidemiological studies it is common practice to work with binary variables that reflect the presence of certain diseases, which in turn may be associated with another set of variables, that in general are assumed as risk factors of the former. In the field of epidemiological studies referred to oral health, it is common to inquire about the relationship between the presence of some pathologies and certain characteristics of the study participants through generalized linear models (GLM). However, this type of analysis is usually carried out for each variable of interest separately and at no time is a measure obtained that summarizes the status of each participant. The objective was to apply and compare two methodologies; one applying classical approach of explaining each oral disease separately from a set of explanatory variables and another using item response theory (IRT) models (specifically the Rasch model) since they allow the joint analysis of a set of variables obtaining an individual assessment as a by-product, which in this case is interpreted as “sickness proneness”. On the other hand, the analysis presented here extends the Rasch model including a linear predictor that allows to investigate about the possible effect of several factors on the propensity of the individuals to suffer the different pathologies. Our results found evidence of an effect of gender, insufficient physical activity (IPhA) and age on general proneness to oral diseases.
Haplotype-based genome wide association study using a novel SNP-set method : RAINBOW
Authors: Hamazaki Kosuke , Iwata Hiroyoshi
Published: April 2019

Background

Diffculty in detecting rare variants is one of the problems in conventional genome wide association studies (GWAS). The problem is closely related to the complex gene compositions comprising multiple alleles, such as haplotypes. Several single nucleotide polymorphism (SNP) set approaches have been proposed to solve this problem. These methods, however, have been rarely discussed in connection with haplotypes. In this study, we developed a novel SNP-set GWAS method named “RAINBOW” and applied the method to haplotype-based GWAS by regarding a haplotype block as a SNP-set. Combining haplotype block estimation and SNP-set GWAS, haplotype-based GWAS can be conducted without prior information of haplotypes.

Results

We prepared 100 datasets of simulated phenotypic data and real marker genotype data ofOryza sativasubsp.indica, and performed GWAS of the datasets. We compared the power of our method, the conventional single-SNP GWAS, the conventional haplotype-based GWAS, and the conventional SNP-set GWAS. The results of the comparison indicated that the proposed method was able to better control false positives than the others. The proposed method was also excellent at detecting causal variants without relying on the linkage disequilibrium if causal variants were genotyped in the dataset. Moreover, the proposed method showed greater power than the other methods, i.e., it was able to detect causal variants that were not detected by the others, especially when the causal variants were located very close to each other and the directions of their effects were opposite.

Conclusion

The proposed method, RAINBOW, is especially superior in controlling false positives, detecting causal variants, and detecting nearby causal variants with opposite effects. By using the SNP-set approach as the proposed method, we expect that detecting not only rare variants but also genes with complex mechanisms, such as genes with multiple causal variants, can be realized. RAINBOW was implemented as the R package and is available athttps://github.com/KosukeHamazaki/RAINBOW.
Differential network analysis of human tissue interactomes highlights tissue-selective processes and genetic disorder genes
Authors: Basha Omer , Argov Chanan M. , Artzy Raviv , Zoabi Yazeed , Hekselman Idan , Alfandari Liad , Chalifa-Caspi Vered , Yeger-Lotem Esti
Published: April 2019

Motivation

Differential network analysis, designed to highlight interaction changes between conditions, is an important paradigm in network biology. However, network analysis methods have been typically designed to compare between few conditions, were rarely applied to protein interaction networks (interactomes). Moreover, large-scale benchmarks for their evaluation have been lacking.

Results

Here, we assess five network analysis methods by applying them to 34 human tissues interactomes. For this, we created a manually-curated benchmark of 6,499 tissue-specific, gene ontology biological processes, and analyzed the ability of each method to expose these tissue-process associations. The four differential network analysis methods outperformed the non-differential, expression-based method (AUCs of 0.82-0.9 versus 0.69, respectively). We then created another benchmark, of 1,527 tissue-specific disease cases, and analyzed the ability of differential network analysis methods to highlight additional disease-related genes. Compared to a non-differential subnetworks surrounding a known disease-causing gene, the extremely-differential subnetwork (top 1%) was significantly enriched for additional disease-causing genes in 18.6% of the cases (p≤10e-3). In 5/10 tissues tested, including Muscle, nerve and heart tissues (p = 2.54E-05, 2.71E-04, 3.63E-19), such enrichments were highly significant.

Altogether, our study demonstrates that differential network analysis of human tissue interactomes is a powerful tool for highlighting processes and genes with tissue-selective functionality and clinical impact. Moreover, it offers expansive manually-curated datasets of tissue-selective processes and diseases that could serve for benchmark and for analyses in many other studies.

Contact

estiyl@bgu.ac.il
High-fat diet enhances starvation-induced hyperactivity via sensitizing hunger-sensing neurons in Drosophila
Authors: Huang Rui , Song Tingting , Su Haifeng , Wang Liming
Published: April 2019

Proper regulation of food intake can be disrupted by sustained metabolic challenges such as high-fat diet (HFD), which may result in various metabolic disorders. Previously, we showed that starvation induced sustained hyperactivity, an exploratory component of food-seeking behavior, via a specific group of octopamingeric (OA) neurons (Yu et al., 2016). In the present study, we found that HFD greatly enhanced starvation-induced hyperactivity. HFD increased the excitability of these OA neurons to a hunger hormone named adipokinetic hormone (AKH), via increasing the accumulation of AKH receptor (AKHR) in these neurons. Upon HFD, excess dietary lipids were transported by a lipoprotein LTP to enter these OA neurons via the cognate receptor LpR1, which activated AMPK-TOR signaling and suppressed autophagy-dependent degradation of AKHR. Taken together, we uncovered a mechanism that linked HFD and starvation-induced hyperactivity, providing insight in the reshaping of neural circuitry under metabolic challenges and the progression of metabolic diseases.
Sustained dechlorination of vinyl chloride to ethene inDehalococcoides-enriched cultures grown without addition of exogenous vitamins and at low pH
Authors: Puentes Jácome Luz A. , Wang Po-Hsiang , Molenda Olivia , Li Yi Xuan (Jine-Jine) , Islam M. Ahsanul , Edwards Elizabeth A.
Published: April 2019

Trichloroethene (TCE) is a ubiquitous groundwater pollutant. Successful TCE bioremediation has been demonstrated at field sites using specialized microbial consortia harboring TCE-respiringDehaloccocoideswhose growth is cobalamin (vitamin B12)-dependent. Bioaugmentation cultures grown ex situ with ample exogenous vitamins in the medium and at neutral pH may become vitamin-limited or inhibited by acidic pH once injected into field sites, resulting in incomplete TCE dechlorination and accumulation of more toxic vinyl chloride (VC). Here, we report growth of theDehalococcoides-containing bioaugmentation culture KB-1 in a TCE-amended mineral medium devoid of vitamins and in a VC-amended mineral medium at low pH (6.0 and 5.5). In cultures grown without exogenous vitamins or cobalamin,Acetobacterium, which can synthesize 5,6-dimethylbenzimidazole (DMB), the lower ligand of cobalamin, andSporomusaare the dominant acetogens. At neutral pH, a growingAcetobacteriumpopulation supports complete TCE dechlorination byDehalococcoidesat millimolar levels with a substantial increase in the amount of measured cobalamin (~20-fold). Sustained dechlorination of VC to ethene was achieved at a pH as low as 5.5, yet at low pHAcetobacteriumis less abundant, potentially affecting the production of DMB and/or cobalamin. However, dechlorination activity at very low pH (< 5.0) was not stimulated by DMB supplementation, but was restored by raising pH to neutral. Assays in cell extracts revealed that vinyl chloride reductase (VcrA) activity declines significantly below pH 6.0 and is undetectable below pH 5.0. This study highlights the roles of and interplay between vitamin-producing populations and pH in microbial dechlorinating communities, and their importance for successful chlorinated ethenes bioremediation at field sites.
Estradiol modulates gut microbiota in femaleob/obmice fed a high fat diet
Authors: Acharya Kalpana D , Gao Xing , Bless Elizabeth P , Chen Jun , Tetel Marc J
Published: April 2019

Estrogens protect against diet-induced obesity in women and female rodents. In support of these anorectic effects, lack of estrogens in postmenopausal women is associated with weight gain, increasing their risk for cardiovascular diseases and cancer. Estrogens act with leptin, a satiety hormone encoded by theobgene, to regulate energy homeostasis in females. Leptin-deficient mice (ob/ob) exhibit morbid obesity and insulin resistance. In addition to estrogens and leptin, the gut microbiome (gut microbes and their metabolites), is critical in regulating energy metabolism. The present study investigates whether estrogens and leptin modulate gut microbiota in ovariectomizedob/ob(obese) or heterozygote (lean) control mice fed a high-fat diet (HFD) that received either 17β-Estradiol (E2) or vehicle implants. E2 attenuated weight gain in both genotypes compared to vehicle counterparts. Moreover, both obesity (ob/obmice) and E2 reduced gut microbial diversity.ob/obmice exhibited lower species richness than control mice, while E2-treated mice had reduced evenness compared to vehicle mice. Regarding taxa, E2 treatment was associated with higher abundances of the family S24-7. Leptin was associated with higher abundances of Coriobacteriaceae,ClostridiumandLactobacillus. E2 and leptin had overlapping effects on relative abundances of some taxa, suggesting that interaction of these hormones is important in gut microbial homeostasis. Taken together, these findings suggest that E2 and leptin profoundly alter the gut microbiota of HFD-fed female mice. Understanding the function of E2 and leptin in regulating gut microbiota will allow the development of therapies targeting the gut microbiome for hormone-dependent metabolic disorders in women.
Adverse childhood experiences: associations with educational attainment and adolescent health, and the role of family and socioeconomic factors. Analysis of a prospective cohort study
Authors: Houtepen Lotte C , Heron Jon , Suderman Matthew J , Fraser Abigail , Chittleborough Catherine R , Howe Laura D
Published: April 2019

Background

Experiencing multiple adverse childhood experiences (ACE) is a risk factor for many adverse outcomes. However, the role of family and socioeconomic factors in these associations is often overlooked.

Methods and findings

Using data from the Avon Longitudinal Study of Parents and Children, we assess associations of ACE between birth and 16 years (sexual, physical or emotional abuse, emotional neglect, parental substance abuse, parental mental illness or suicide attempt, violence between parents, parental separation, bullying, and parental criminal conviction) with educational attainment at 16 years (n=9,959) and health at age 17 years (depression, obesity, harmful alcohol use, smoking and illicit drug use, n=4,917). We explore the extent to which associations are robust to adjustment for family and socioeconomic factors, whether associations differ according to socioeconomic factors, and estimate the proportion of adverse educational and health outcomes attributable to ACE, family or socioeconomic measures.

There were strong associations of ACE with lower educational attainment and higher risk of depression, drug use and smoking. Associations with educational attainment attenuated after adjustment but remained strong. Associations with depression, drug use and smoking were not altered by adjustment. Associations of ACE with harmful alcohol use and obesity were weak. We found no evidence that associations differed by socioeconomic factors. Between 5-15% of the cases of adverse educational and health outcomes occur amongst people experiencing 4+ ACE, and between 1-19% occur in people whose mothers have a low level of education.

Conclusions

This study demonstrates strong associations between ACE and lower educational attainment and worse health that are independent of family and socioeconomic factors. Our findings imply that interventions that focus solely on ACE or solely on socioeconomic deprivation, whilst beneficial, would miss most cases of adverse educational and health outcomes. Intervention strategies should therefore target a wide range of relevant factors, including ACE, socioeconomic deprivation, parental substance use and mental health.
Spatiotemporal restriction ofFUSCA3expression by class I BPC promotes ovule development and coordinates embryo and endosperm growth
Authors: Wu Jian , Petrella Rosanna , Dowhanik Sebastian , Gregis Veronica , Gazzarrini Sonia
Published: April 2019

Spatiotemporal regulation of gene expression plays an important role in developmental timing in plants and animals. FUSCA3 regulates the transition between different phases of development by acting as a link between different hormonal pathways in Arabidopsis. However, the mechanisms governing its spatiotemporal expression patterns are poorly understood. Here, we show thatFUS3is expressed in the chalaza and funiculus of the mature ovule and seed, but is repressed in the embryo sac, integuments and endosperm.FUS3repression requires class I BASIC PENTACYSTEINE (BPC) proteins, which directly bind to theFUS3locus and restrict its expression pattern. During vegetative and reproductive development, derepression ofFUS3inbpc1/2orpML1:FUS3misexpression lines results in dwarf plants carrying defective flowers and aborted ovules. Post-fertilization, ectopicFUS3expression in the endosperm increases endosperm nuclei proliferation and seed size and delays or arrests embryo development. These phenotypes are rescued inbpc1/2 fus3-3. Lastly, class I BPCs interact with FIS-PRC2 (FERTILIZATION-INDEPENDENT SEED-Polycomb Repressive Complex 2), which repressesFUS3in the endosperm. We propose that BPC1/2 promotes the transition from reproductive to seed development by repressingFUS3in ovule integuments. After fertilization, BPC1/2 and FIS-PRC2 repress FUS3 in the endosperm to coordinate endosperm and embryo growth.
Structure and functional implications of WYL-domain-containing transcription factor PafBC involved in the mycobacterial DNA damage response
Authors: Müller Andreas U. , Leibundgut Marc , Ban Nenad , Weber-Ban Eilika
Published: April 2019

In mycobacteria, transcriptional activator PafBC is responsible for upregulating the majority of genes induced by DNA damage. Understanding the mechanism of PafBC activation is impeded by a lack of structural information on this transcription factor that contains a widespread, but poorly understood WYL domain frequently encountered in bacterial transcription factors. Here, we determined the crystal structure ofArthrobacter aurescensPafBC. The protein consists of two modules, each harboring an N-terminal helix-turn-helix DNA binding domain followed by a central WYL and a C-terminal extension (WCX) domain. The WYL domains exhibit Sm-folds, while the WCX domains adopt ferredoxin-like folds, both characteristic for RNA binding proteins. Our results suggest a mechanism of regulation in which WYL domain-containing transcription factors may be activated by binding RNA molecules. Using anin vivomutational screen inMycobacterium smegmatis, we identify potential co-activator binding sites on PafBC.
Does diversity beget diversity in microbiomes?
Authors: Madi Naïma , Vos Michiel , Murall Carmen Lia , Legendre Pierre , Shapiro B. Jesse
Published: April 2019

Microbes are embedded in complex communities where they engage in a wide array of intra- and inter-specific interactions. The extent to which these interactions drive or impede microbiome diversity is not well understood. Historically, two contrasting hypotheses have been suggested to explain how species interactions could influence diversity. ‘Ecological Controls’ (EC) predicts a negative relationship, where the evolution or migration of novel types is constrained as niches become filled. In contrast, ‘Diversity Begets Diversity’ (DBD) predicts a positive relationship, with existing diversity promoting the accumulation of further diversity via niche construction and other interactions. Using high-throughput amplicon sequencing data from the Earth Microbiome Project, we provide evidence that DBD is strongest in low-diversity biomes, but weaker in more diverse biomes, consistent with biotic interactions initially favoring the accumulation of diversity (as predicted by DBD). However, as niches become increasingly filled, diversity hits a plateau (as predicted by EC).

Impact statement

Microbiome diversity favors further diversity in a positive feedback that is strongest in lower-diversity biomes (e.g. guts) but which plateaus as niches are increasingly filled in higher-diversity biomes (e.g. soils).
Maternal antibodies provide partial protection from postnatal Zika viremia in nonhuman primates
Authors: Maness Nicholas J , Schouest Blake , Singapuri Anil , Dennis Maria , Gilbert Margaret H. , Bohm Rudolf P. , Schiro Faith , Aye Pyone P. , Baker Kate , Van Rompay Koen K. A. , Lackner Andrew A. , Bonaldo Myrna C. , Blair Robert V. , Permar Sallie R. , Coffey Lark L. , Panganiban Antonito T. , Magnani Diogo
Published: April 2019

Zika virus (ZIKV) will remain a public health threat until effective vaccines and therapeutics are made available in the hardest hit areas of the world. Recent data in a nonhuman primate model showed that infants postnatally infected with ZIKV were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. We addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with Zika virus during pregnancy. Passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while binding, possibly non-neutralizing antibodies remained detectable until viral infection at 5 months of age. Post-infection acute serum viremia was substantially reduced relative to adults infected with the same dose of the same stock of a Brazilian isolate of ZIKV (n=11 pregnant females) and another stock of the same isolate (n=4 males and 4 non-pregnant females). Virus was never detected in cerebrospinal fluid nor in neural tissues at necropsy two weeks after infection, suggesting reduced viral burden relative to adults and published data from infants. However, viral RNA was detected in lymph nodes, confirming some tissue dissemination. Though protection was not absolute, our data suggest infants born healthy to infected mothers may harbor a modest but important level of protection from postnatally acquired ZIKV for several months after birth, an encouraging result given the potentially severe infection outcomes of this population.
Optimal Mass Transport Kinetic Modeling for Head and Neck DCE-MRI: Initial Analysis
Authors: Elkin Rena , Nadeem Saad , LoCastro Eve , Paudyal Ramesh , Hatzoglou Vaios , Lee Nancy Y. , Shukla-Dave Amita , Deasy Joseph O. , Tannenbaum Allen
Published: April 2019

Current state-of-the-art models for estimating the pharmacokinetic parameters do not account for intervoxel movement of the contrast agent (CA). We introduce an optimal mass transport (OMT) formulation that naturally handles intervoxel CA movement and distinguishes between advective and diffusive flows. Ten patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in the study between June 2014 and October 2015 and under-went DCE MRI imaging prior to beginning treatment. The CA tissue concentration information was taken as the input in the data-driven OMT model. The OMT approach was tested on HNSCC DCE data that provides quantitative information for forward flux (ΦF) and backward flux (ΦB). OMT-derived ΦF was compared with the volume transfer constant for CA, Ktrans, derived from the Extended Tofts Model (ETM). The OMT-derived flows showed a consistent jump in the CA diffusive behavior across the images in accordance with the known CA dynamics. The mean forward flux was 0.0082 ± 0.0091 (min-1) whereas the mean advective component was 0.0052±0.0086 (min-1) in the HNSCC patients. The diffusive percentages in forward and backward flux ranged from 8.67–18.76% and 12.76–30.36%, respectively. The OMT model accounts for intervoxel CA movement and results show that the forward flux (ΦF) is comparable with the ETM-derived Ktrans. This is a novel data-driven study based on optimal mass transport principles applied to patient DCE imaging to analyze CA flow in HNSCC.
Population differences in aggression are shaped by cyclone-induced selection
Authors: Little Alexander G. , Fisher David N. , Schoener Thomas W. , Pruitt Jonathan N.
Published: April 2019

Surprisingly little is known about the evolutionary impacts of rare but extreme black swan events, like tropical cyclones. By intercepting three cyclones in fall 2018, we evaluated cyclone-induced selection on collective behavior in a group-living spider. We further examined whether historic frequencies of cyclone landfalls are correlated with geographic variation in group behavior. Cyclones consistently selected for more aggressive spider societies. Furthermore, sites where cyclones have historically been more common also harbor more aggressive groups. Thus, two corroborative lines of evidence convey that that cyclone-induced selection can drive the evolution of colony behavior, and suggest that extreme black swan events can shape within-species diversity and local adaptation.

One Sentence Summary

Tropical cyclones drive the evolution of more aggressive spider societies.
Scalable, FACS-Free Genome-Wide Phenotypic Screening
Authors: Mair Barbara , Aldridge Peter M. , Atwal Randy S. , Masud Sanna N. , Zhang Meng , Philpott David , Tong Amy H.Y. , Sargent Edward H. , Angers Stéphane , Moffat Jason , Kelley Shana O.
Published: April 2019

Genome-scale functional genetic screens can identify key regulators of a phenotype of interest, such as determinants of protein expression or modification. Here, we present a rapid, high-throughput approach to phenotypic CRISPR-Cas9 screening. To study factors that modulate the display of CD47 on the cell surface, we processed an entire genome-wide screen containing more than 108cells in under one hour and maintained high levels of cell viability using a highly scalable cell sorting technology. We robustly identified modulators of CD47 function including QPCTL, an enzyme required for formation of the pyroglutamyl modification at the N-terminus of this protein.
baerhunter: An R package for the discovery and analysis of expressed non-coding regions in bacterial RNA-seq data
Authors: Ozuna A. , Liberto D. , Joyce R. M. , Arnvig K.B. , Nobeli I.
Published: April 2019

Standard bioinformatics pipelines for the analysis of bacterial transcriptomic data commonly ignore non-coding but functional elements e.g. small RNAs, long antisense RNAs or untranslated regions (UTRs) of mRNA transcripts. The root of this problem is the use of incomplete genome annotation files. Here, we present baerhunter, a method implemented in R, that automates the discovery of expressed non-coding RNAs and UTRs from RNA-seq reads mapped to a reference genome. The core algorithm is part of a pipeline that facilitates downstream analysis of both coding and non-coding features. The method is simple, easy to extend and customize and, in limited tests with simulated and real data, compares favourably against the currently most popular alternative.

Availability

The baerhunter R package is available from: https://github.com/irilenia/baerhunter

Contact

i.nobeli@bbk.ac.uk
Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling
Authors: Alvarez-Dominguez Juan R. , Donaghey Julie , Kenty Jennifer H. R. , Rasouli Niloofar , Helman Aharon , Charlton Jocelyn , Straubhaar Juerg R. , Meissner Alexander , Melton Douglas A.
Published: April 2019

Investigating pancreatic islet differentiation from human stem cells in vitro provides a unique opportunity to dissect mechanisms that operate during human development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from pluripotent stem cells to mature pancreatic islet cells, uncovering widespread epigenome remodeling upon endocrine commitment. Key lineage-defining loci are epigenetically primed before activation, foreshadowing cell fate commitment, and we show that priming of α-cell-specific enhancers steers polyhormonal cells toward an α-cell fate. We further dissect pioneer factors and core regulatory circuits across islet cell differentiation and maturation stages, which identify LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural β-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation.
ChIA-DropBox: a novel analysis and visualization pipeline for multiplex chromatin interactions
Authors: Tian Simon Zhongyuan , Capurso Daniel , Kim Minji , Lee Byoungkoo , Zheng Meizhen , Ruan Yijun
Published: April 2019

ChIA-Drop is a new experimental method for mapping multiplex chromatin interactions with single-molecule precision by barcoding chromatin complexes inside microfluidics droplets, followed by pooled DNA sequencing. The chromatin DNA reads with the same droplet-specific barcodes are inferred to be derived from the same chromatin interaction complex. Here, we describe an integrated computational pipeline, named ChIA-DropBox, that is specifically designed for reconstructing chromatin reads in each droplet and refining multiplex chromatin complexes from raw ChIA-Drop sequencing reads, and then visualizing the results. First, ChIA-DropBox maps and filters sequencing reads, and then reconstructs the “chromatin droplets” by parsing the barcode sequences and grouping together chromatin reads with the same barcode. Based on the concept of chromosome territories that most chromatin interactions take place within the same chromosome, potential mixing up of chromatin complexes derived from different chromosomes could be readily identified and separated. Accordingly, ChIA-DropBox refines these “chromatin droplets” into purely intra-chromosomal chromatin complexes, ready for downstream analysis. For visualization, ChIA-DropBox converts the ChIA-Drop data to pairwise format and automatically generates input files for viewing 2D contact maps in Juicebox and viewing loops in BASIC Browser. Finally, ChIA-DropBox introduces a new browser, named ChIA-View, for interactive visualization of multiplex chromatin interactions.
Elav-mediated exon skipping and alternative polyadenylation of the Dscam1 gene is required for axon outgrowth
Authors: Zhang Z. , So K. , Peterson R. , Bauer M. , Ng H. , Zhang Y. , Kim J.H. , Kidd T. , Miura P.
Published: April 2019

Many metazoan genes express alternative long 3′ UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3′ UTR isoforms due to alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3′ UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3′ UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon growth in Drosophila. The Dscam1 long 3′ UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing.

Graphical Abstract

Highlights

Elav regulates Dscam1 long 3′ UTR (Dscam1-L) biogenesis

Long-read sequencing reveals connectivity of long 3′ UTR to skipping of upstream exon 19

Loss of Dscam1-L impairs axon outgrowth

Dscam1 long 3′ UTR is required for correct splicing of exon 19
Early urine proteome changes in an implanted bone cancer rat model
Authors: Wang Ting , Li Lujun , Qin Weiwei , Huan Yuhang , Gao Youhe
Published: April 2019

In this study, Walker 256 cells were implanted into rat tibiae. Urine samples were then collected on days 3, 5, 7, and 13 and were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). With label-free quantification, 25 proteins were found to change significantly in the urine of the tumor group mice compared with the proteins in the urine of the control group mice; this was even the case when there were no significant lesions identified in the Computed Tomography(CT) examination. Among these differentially proteins, 7 were reported to be associated with tumor bone metastasis. GO analysis shows that the differential proteins on day 3 were involved in several responses, including the acute phase response, the adaptive immune response and the innate immune response. The differentially proteins on day 7 were involved in the mineral absorption pathway. The differentially proteins on day 13 were involved in vitamin D binding and calcium ion binding. These processes may be associated with bone metastasis. Our results demonstrate that urine could sensitively reflect the changes in the early stage of implanted bone cancer; this provides valuable clues for future studies of urine biomarkers for tumor bone metastasis.
Single Cortical Neurons as Deep Artificial Neural Networks
Authors: Beniaguev David , Segev Idan , London Michael
Published: April 2019

We introduce a novel approach to study neurons as sophisticated I/O information processing units by utilizing recent advances in the field of machine learning. We trained deep neural networks (DNNs) to mimic the I/O behavior of a detailed nonlinear model of a layer 5 cortical pyramidal cell, receiving rich spatio-temporal patterns of input synapse activations. A Temporally Convolutional DNN (TCN) with seven layers was required to accurately, and very efficiently, capture the I/O of this neuron at the millisecond resolution. This complexity primarily arises from local NMDA-based nonlinear dendritic conductances. The weight matrices of the DNN provide new insights into the I/O function of cortical pyramidal neurons, and the approach presented can provide a systematic characterization of the functional complexity of different neuron types. Our results demonstrate that cortical neurons can be conceptualized as multi-layered “deep” processing units, implying that the cortical networks they form have a non-classical architecture and are potentially more computationally powerful than previously assumed.
Microeconomics of metabolism: Overflow metabolism as Giffen behaviour
Authors: Yamagishi Jumpei F. , Hatakeyama Tetsuhiro S.
Published: April 2019

Biological systems such as intracellular metabolism are rationally regulated to maximize the cellular growth rate through evolution (1–4), whereas microeconomics investigates the behaviour of consumers assumed to rationally maximize their utility (5, 6). Despite this analogy as optimization problems, the link between biology and economics has not been fully established (7, 8). Here, we developed an exact mapping between the regulation of metabolism and the theory of consumer choice, thereby revealing the correspondence between long-standing mysteries in both fields: overflow metabolism and Giffen behaviour. Overflow metabolism, particularly known as the Warburg effect in cancer (9, 10), is a seemingly wasteful but ubiquitous strategy where cells utilize aerobic glycolysis instead of the more energetically-efficient oxidative phosphorylation (9–16), whereas Giffen behaviour is the unexpected consumer behaviour where a good is demanded more as its price rises (17, 18). We revealed that the general conditions for these phenomena are trade-off and complementarity, i.e., impossibility of substitution for different goods. This correspondence implies that oxidative phosphorylation is counterintuitively stimulated when its efficiency is decreased by metabolic perturbations like drug administration. Therefore, Giffen behaviour bridges the Warburg effect and the reverse and inverse Warburg effect (19–22). This highlights that application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
Nanoscale subcellular architecture revealed by multicolor 3D salvaged fluorescence imaging
Authors: Zhang Yongdeng , Schroeder Lena K. , Lessard Mark D. , Kidd Phylicia , Chung Jeeyun , Song Yuanbin , Benedetti Lorena , Li Yiming , Ries Jonas , De Camilli Pietro , Rothman James E. , Baddeley David , Bewersdorf Joerg
Published: April 2019

Combining the molecular specificity of fluorescent probes with three-dimensional (3D) imaging at nanoscale resolution is critical for investigating the spatial organization and interactions of cellular organelles and protein complexes. We present a super-resolution light microscope that enables simultaneous multicolor imaging of whole mammalian cells at ~20 nm 3D resolution. We show its power for cell biology research with fluorescence images that resolved the highly convoluted Golgi apparatus and the close contacts between the endoplasmic reticulum and the plasma membrane, structures that have traditionally been the imaging realm of electron microscopy.

One Sentence Summary

Complex cellular structures previously only resolved by electron microscopy can now be imaged in multiple colors by 4Pi-SMS.
Translocation of dense granule effectors across the parasitophorous vacuole membrane inToxoplasma-infected cells requires the activity of ROP17, a rhoptry protein kinase
Authors: Panas Michael W. , Ferrel Abel , Naor Adit , Tenborg Elizabeth , Lorenzi Hernan A. , Boothroyd John C.
Published: April 2019

Toxoplasma gondiitachyzoites co-opt host cell functions through introduction of a large set of rhoptry- and dense granule-derived effector proteins. These effectors reach the host cytosol through different means: direct injection for rhoptry effectors and translocation across the parasitophorous vacuolar membrane (PVM) for dense granule (GRA) effectors. The machinery that translocates these GRA effectors has recently been partially elucidated, revealing 3 components, MYR1, MYR2 and MYR3. To determine if other proteins might be involved, we returned to a library of mutants defective in GRA translocation and selected one with a partial defect, suggesting it might be in a gene encoding a new component of the machinery. Surprisingly, whole-genome sequencing revealed a missense mutation in a gene encoding a known rhoptry protein, a serine/threonine protein kinase known as ROP17. ROP17 resides on the host-cytosol side of the PVM in infected cells and has previously been known for its activity in phosphorylating and, thereby, inactivating host immunity-related GTPases. Here, we show that null or catalytically dead mutants of ROP17 are defective in GRA translocation across the PVM, but that translocation can be rescued “intrans"by ROP17 delivered by other tachyzoites infecting the same host cell. This strongly argues that ROP17’s role in regulating GRA translocation is carried out on the host-cytosolic side of the PVM, not within the parasites or lumen of the parasitophorous vacuole. This represents an entirely new way in which the different secretory compartments ofToxoplasmatachyzoites collaborate to modulate the host-parasite interaction.

Importance

WhenToxoplasmainfects a cell it establishes a protective parasitophorous vacuole surrounding it. While this vacuole provides protection, it also serves as a barrier to the export of parasite effector proteins that impact and take control of the host cell. Our discovery here that the parasite rhoptry protein, ROP17, is necessary for export of these effector proteins provides a distinct, novel function for ROP17 apart from its known role in protecting the vacuole. This will enable future research into ways in which we can prevent the export of effector proteins thereby preventingToxoplasmafrom productively infecting its animal and human hosts.
The genome of the endangered Dryas monkey provides new insights into the evolutionary history of the vervets
Authors: van der Valk T. , Gonda C. M. , Silegowa H. , Almanza S. , Sifuentes-Romero I. , Hart T. , Hart J. , Detwiler K. , Guschanski K.
Published: April 2019

Genomic data can be a powerful tool for inferring ecology, behaviour and conservation needs of highly elusive species, particularly when other sources of information are hard to come by. Here we focus on the Dryas monkey (Cercopithecus dryas), an endangered primate endemic to the Congo Basin with cryptic behaviour and possibly less than 250 remaining individuals. Using whole genome sequencing data we show that the Dryas monkey represents a sister lineage to the vervets (Chlorocebus sp.) and has diverged from them around 1.4 million years ago with additional bi-directional gene flow ∼750,000 – ∼500,000 years ago that has likely involved the crossing of the Congo River. Together with evidence of gene flow across the Congo River in bonobos and okapis, our results suggest that the fluvial topology of the Congo River might have been more dynamic than previously recognised. Despite the presence of several homozygous loss-of-function mutations in genes associated with sperm mobility and immunity, we find high genetic diversity and low levels of inbreeding and genetic load in the studied Dryas monkey individual. This suggests that the current population carries sufficient genetic variability for long-term survival and might be larger than currently recognised. We thus provide an example of how genomic data can directly improve our understanding of highly elusive species.
Sensorimotor peak alpha frequency is a reliable biomarker of pain sensitivity
Authors: Furman Andrew J. , Prokhorenko Mariya , Keaser Michael L. , Zhang Jing , Chen Shuo , Mazaheri Ali , Seminowicz David A.
Published: April 2019

Previous research has observed that individuals with chronic pain demonstrate slower alpha band oscillations (8-12 Hz range) during resting electroencephalography (EEG) than do age-matched, healthy controls. While this slowing may reflect pathological changes within the brain that occur during the chronification of pain, an alternative explanation is that healthy individuals with slower alpha frequencies are more sensitive to prolonged pain, and by extension, more susceptible to developing chronic pain. To formally test this hypothesis, we examined the relationship between the pain-free, resting alpha frequency of healthy individuals and their subsequent sensitivity to two experimental models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two testing visits separated by 8 weeks on average (n = 61 Visit 1, n = 46 Visit 2). We observed that the speed of an individual’s pain-free alpha oscillations was negatively correlated with sensitivity to both prolonged pain tests and that this relationship was reliable across short (minutes) and long (weeks) timescales. Furthermore, we used the speed of pain-free alpha oscillations to successfully identify those individuals most sensitive to prolonged pain, which we also validated on data from a separate, independent study. These results suggest that alpha oscillation speed is a reliable biomarker of prolonged pain sensitivity with the potential to become a tool for prospectively identifying pain sensitivity in the clinic.
Iron is a ligand of SecA-like metal-binding domainsin vivo
Authors: Cranford-Smith Tamar , Jamshad Mohammed , Jeeves Mark , Chandler Rachael A. , Yule Jack , Robinson Ashley , Alam Farhana , Dunne Karl A. , Aponte Angarita Edwin H. , Alanazi Mashael , Carter Cailean , Henderson Ian R. , Lovett Janet E. , Winn Peter , Knowles Timothy , Huber Damon
Published: April 2019

The ATPase SecA is an essential component of the bacterial Sec machinery, which transports proteins across the cytoplasmic membrane. Most SecA proteins contain a long C-terminal tail (CTT). InEscherichia coli, the CTT contains a structurally flexible linker domain and a small metal-binding domain (MBD). The MBD coordinates zinc via a conserved cysteine-containing motif and binds to SecB and ribosomes. In this study, we screened a high-density transposon library for mutants that affect the susceptibility ofE. colito sodium azide, which inhibits SecA-mediated translocation. Results from sequencing this library suggested that mutations removing the CTT makeE. coliless susceptible to sodium azide at subinhibitory concentrations. Copurification experiments suggested that the MBD binds to iron and that azide disrupts iron binding. Azide also disrupted binding of SecA to membranes. Two otherE. coliproteins that contain SecA-like MBDs, YecA and YchJ, also copurified with iron, and NMR spectroscopy experiments indicated that YecA binds iron via its MBD. Competition experiments and equilibrium binding measurements indicated that the SecA MBD binds preferentially to iron and that a conserved serine is required for this specificity. Finally, structural modelling suggested a plausible model for the octahedral coordination of iron. Taken together, our results suggest that SecA-like MBDs likely bind to ironin vivo.
Spatially and temporally distinct encoding of muscle and kinematic information in rostral and caudal primary motor cortex
Authors: Kolasinski James , Dima Diana C. , Mehler David M. A. , Stephenson Alice , Valadan Sara , Kusmia Slawomir , Rossiter Holly E.
Published: April 2019

Hand movements are controlled by neuronal networks in primary motor cortex (M1). The organising principle in M1 does not follow an anatomical body map, but rather a distributed representational structure in which motor primitives are combined to produce motor outputs. Both electrophysiological recordings in primates and human imaging data suggest that M1 encodes kinematic features of movements, such as joint position and velocity. However, M1 exhibits well-documented sensory responses to cutaneous and proprioceptive stimuli, raising questions regarding the origins of kinematic motor representations: are they relevant in top-down motor control, or are they an epiphenomenon of bottom-up sensory feedback during movement? Moreover, to what extent is information related to muscle activity encoded in motor cortex? Here we provide evidence for spatially and temporally distinct encoding of kinematic and muscle information in human M1 during the production of a wide variety of naturalistic hand movements. Using a powerful combination of high-field fMRI and MEG, a spatial and temporal multivariate representational similarity analysis revealed encoding of kinematic information from data glove recordings in more caudal regions of M1, over 200ms before movement onset. In contrast, patterns of muscle activity from EMG were encoded in more rostral motor regions later in the cycle of movement. Our spatial and temporal analysis provide compelling evidence that top-down control of dexterous movement engages kinematic representations in caudal regions of M1 prior to movement production; an area with direct cortico-motorneuronal connections. Muscle information encoded more rostrally in M1 was engaged later, suggestive of involvement in bottom-up signalling.