bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactobacillus suantsaicola sp. nov. and Lactobacillus suantsaiihabitans sp. nov., isolated from suan-tsai, a traditional fermented mustard green product of Taiwan
Authors: Lin Shih-Ting , Wang Li-Ting , Wang Hsing-Min , Tamura Tomohiko , Mori Koji , Huang Lina , Watanabe Koichi
Published: June 2019

Four Gram-stain-positive strains, R7T, R11, R19T and R27, were isolated from suan-tsai, a traditional fermented mustard green product of Taiwan. Cells were rod-shaped, non-motile, non-haemolytic, asporogenous, facultatively anaerobic, heterofermentative, and did not exhibit catalase and oxidase activities. Comparative analyses of 16S rRNA, pheS and rpoA gene sequences demonstrated that these novel strains were members of the genus

Lactobacillus

. 16S rRNA and the concatenated pheS and rpoA gene sequence similarities between strains R7T and R11, and strains R19T and R27 were very high (>99.8 % similarity), respectively. On the basis of 16S rRNA gene sequence similarities, the type strains of

Lactobacillus paralimentarius

(98.5 %),

Lactobacillus kimchii

(98.5 %),

Lactobacillus alimentarius

(98.1 %) and

Lactobacillus bobalius

(98.1 %) were the closest neighbours to strains R7T and R11, and the type strains of

Lactobacillus brevis

(98.9 %),

Lactobacillus cerevisiae

(98.4 %), Lactobacillus hammesii (98.4 %),

Lactobacillus koreensis

(98.4 %) and

Lactobacillus yonginensis

(98.0 %) were the closest neighbours to strains R19T and R27, respectively. The average nucleotide identity values of R7T and R19T with the closely related type strains were 78.9–80.1% and 75.7–80.5 %, respectively. The digital DNA–DNA hybridization values were 22.8–23.6% and 21.0–23.1 %, respectively. Phenotypic and genotypic test results demonstrated that these strains represent two novel species of the genus

Lactobacillus

, for which the name

Lactobacillus
suantsaicola sp. nov. (R7T=BCRC 81127T=NBRC 113530T) and

Lactobacillus
suantsaiihabitans sp. nov. (R19T=BCRC 81129T=NBRC 113532T) are proposed.
Demultiplexing overlapping signaling scaffold functions to probe lipid messenger coupling to cytoskeletal dynamics
Authors: Trenton Nicholaus J. , McLaughlin R. Tyler , Bellamkonda Satya K. , Tsao David S. , Mace Emily M. , Orange Jordan S. , Schweikhard Volker , Diehl Michael R.
Published: June 2019

The coordination of lipid messenger signaling with cytoskeletal regulation is central to many organelle-specific signaling and regulatory processes. While central to many aspects of cell physiology, this coupling often depends on the function of multi-domain scaffolds that orchestrate transient interactions and dynamic feedback among a spectrum of signaling intermediates and regulatory proteins on organelles. Understanding scaffold protein functions has remained challenging given this complexity. This work employs live-cell imaging and statistical analyses to deconvolve (demultiplex) how the multi-domain scaffold IQGAP1 coordinates phosphoinositide signaling with organelle-specific actin regulation and membrane processing events. Using actin-ensconced endosomes that localize to the basal cortex of polarized epithelial cells as a model system, we demonstrate abilities to dissect how IQGAP1 transitions between different actin and endosomal-membrane tethered states. We provide evidence IQGAP1 functions as a transient inhibitor of actin growth around the endosomes in at least one of these states. While not easily distilled via standard (static) colocalization analyses or traditional pathway perturbations methods, this negative regulation was revealed via a series of dynamic correlation and multiple regression analyses. These methods also uncovered that the negative actin regulation is linked to GTPase-dependent tethering to the endosomal membrane. Moreover, the scaffold transitions underlying this control are shown to depend on the production of PIP3 lipid messengers by the lipid kinase PI3K. Overall, these methods and results provide new insights in to how IQGAP1 act as a signaling hub by orchestrating time-dependent membrane and cytoskeletal protein interactions and provide new routes to dissect scaffold-mediated pathway regulation in a variety of settings.
scRecover: Discriminating true and false zeros in single-cell RNA-seq data for imputation
Authors: Miao Zhun , Li Jiaqi , Zhang Xuegong
Published: June 2019

High-throughput single-cell RNA-seq (scRNA-seq) data contains excess zero values, including those of genes not expressed in the cell, and those produced due to dropout events. Existing imputation methods do not distinguish these two types of zeros. We present a modest imputation method scRecover to only impute the dropout zeros. It estimates the zero dropout probability of each gene in each cell, and predicts the number of truly expressed genes in the cell. scRecover is combined with other imputation methods like scImpute, SAVER and MAGIC to fulfil the imputation. Down-sampling experiments show that it recovers dropout zeros with higher accuracy and avoids over-imputing true zero values. Experiments on real data illustrate scRecover improves downstream analysis and visualization.
Modified covariance beamformer for solving MEG inverse problem in the environment with correlated sources
Authors: Kuznetsova Aleksandra , Nurislamova Yulia , Ossadtchi Alexei
Published: June 2019

Abstract

Magnetoencephalography (MEG) is a neuroimaging method ideally suited for non-invasive studies of brain dynamics. MEG’s spatial resolution critically depends on the approach used to solve the ill-posed inverse problem in order to transform sensor signals into cortical activation maps. Over recent years non-globally optimized solutions based on the use of adaptive beamformers (BF) gained popularity.

When operating in the environment with a small number of uncorrelated sources the BFs perform optimally and yield spatial super-resolution. However, the BFs are known to fail when dealing with correlated sources acting like poorly tuned spatial filters with low signal-to-noise ratio (SNR) of the output timeseries and often meaningless cortical maps of power distribution.

This fact poses a serious limitation on the broader use of this promising technique especially since fundamental mechanisms of brain functioning, its inherent symmetry and task-based experimental paradigms result into a great deal of correlation in the activity of cortical sources. To cope with this problem, we developed a novel beamformer approach that preserves high spatial resolution in the environments with correlated sources.

At the core of our method is a projection operation applied to the vectorized sensor-space covariance matrix. This projection does not remove the activity of the correlated sources from the sensor-space covariance matrix but rather selectively handles their contributions to the covariance matrix and creates a sufficiently accurate approximation of an ideal data covariance that could hypothetically be observed should these sources be uncorrelated. Since the projection operation is reciprocal to the PSIICOS method developed by us earlier (Ossadtchi et al. (2018)) we refer to the family of algorithms presented here as ReciPSIICOS.

We asses the performance of the novel approach using realistically simulated MEG data and show its superior performance in comparison to the well established MNE and classical BF approaches. We have also applied our approach to the MEG datasets from the two experiments involving two different auditory tasks.

The analysis of experimental MEG datasets showed that beamformers from ReciPSIICOS family, but not MNE and the classical BF, discovered the expected bilateral focal sources in the primary auditory cortex and detected motor cortex activity associated with the audio-motor task. Moreover, ReciPSIICOS beamformers yielded cortical activity estimates with amplitude an order of magnitude higher than that obtained with the classical BF, which indicates the severeness of the signal cancellation problem when applying classical beamformers to MEG signals generated by synchronous sources.
SMCHD1 Promotes ATM-dependent DNA Damage Signaling and Repair of Uncapped Telomeres
Authors: Vančevska Aleksandra , Pfeiffer Verena , Feretzaki Marianna , Ahmed Wareed , Lingner Joachim
Published: June 2019

SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing protein 1) has been implicated in X-chromosome inactivation, imprinting and DNA damage repair. Mutations inSMCHD1can also cause facioscapulohumoral muscular dystrophy. More recently, SMCHD1 has also been detected as component of telomeric chromatin. Here, we identify requirements of SMCHD1 for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 with TRF2 reduced the rate of 3’ overhang removal in time course experiments and the number of telomere end fusions. In SMCHD1 deficient cells, the formation of ATM pS1981, γH2AX and 53BP1 containing telomere dysfunction induced foci (TIFs) were diminished indicating defects in checkpoint signaling. Strikingly, removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depletedSMCHD1knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent DNA checkpoint signaling. SMCHD1 mediates DNA damage signaling activation upstream of ATM phosphorylation at uncapped telomeres.
TRIM69 inhibits Vesicular Stomatitis Indiana Virus (VSIV)
Authors: Rihn Suzannah J. , Aziz Muhamad Afiq , Stewart Douglas G. , Hughes Joseph , Turnbull Matthew L. , Varela Mariana , Sugrue Elena , Herd Christie S. , Stanifer Megan , Sinkins Steven P. , Palmarini Massimo , Wilson Sam J.
Published: June 2019

Vesicular Stomatitis Indiana Virus (VSIV) is a model virus that is exceptionally sensitive to the inhibitory action of interferons. Interferons induce an antiviral state by stimulating the expression of hundreds of interferon stimulated genes (ISGs). These ISGs constrain viral replication, limit tissue tropism, reduce pathogenicity and inhibit viral transmission. Because VSIV is used as a backbone for multiple oncolytic and vaccine strategies, understanding how ISGs restrict VSIV, not only helps in understanding VSIV-pathogenesis, but helps evaluate and understand the safety and efficacy of VSIV-based therapies. Thus there is a need to identify and characterize the ISGs that possess anti-VSIV activity. Using arrayed ISG expression screening, we identified TRIM69 as an ISG that potently inhibits VSIV. This inhibition was highly specific as multiple viruses (including influenza A virus, HIV-1, Rift Valley Fever Virus and dengue virus) were not affected by TRIM69. Indeed, just one amino acid substitution in VSIV can govern sensitivity/resistance to TRIM69. TRIM69 is highly divergent in human populations and exhibits signatures of positive selection that are consistent with this gene playing a key role in antiviral immunity. We propose that TRIM69 is an IFN-induced inhibitor of VSIV and speculate that TRIM69 could be important in limiting VSIV pathogenesis and might influence the specificity and/or efficacy of vesiculovirus-based therapies.

IMPORTANCE

Vesicular Stomatitis Indiana Virus (VSIV) is a veterinary pathogen that is also used as a backbone for many oncolytic and vaccine strategies. In natural and therapeutic settings, VSIV infection is sensed by the host and host-cells make proteins that protect them from viruses. In the case of VSIV, these antiviral proteins constrain viral replication and protect most healthy tissues from virus infection. In order to understand how VSIV causes disease and how healthy tissues are protected from VSIV-based therapies, it is crucial that we identify the proteins that inhibit VSIV. Here we show that TRIM69 is an antiviral defence that can potently and specifically block VSIV infection.
Approximate Bayesian Inference for a Mechanistic Model of Vesicle Release at a Ribbon Synapse
Authors: Schröder Cornelius , James Ben , Lagnado Leon , Berens Philipp
Published: June 2019

The inherent noise of neural systems makes it difficult to construct models which accurately capture experimental measurements of their activity. While much research has been done on how to efficiently model neural activity with descriptive models such as linear-nonlinear-models (LN), Bayesian inference for mechanistic models has received considerably less attention. One reason for this is that these models typically lead to intractable likelihoods and thus make parameter inference difficult. Here, we develop an approximate Bayesian inference scheme for a fully stochastic, biophysically inspired model of glutamate release at the ribbon synapse, a highly specialized synapse found in different sensory systems. The model translates known structural features of the ribbon synapse into a set of stochastically coupled equations. We approximate the posterior distributions by updating a parametric prior distribution via Bayesian updating rules and show that model parameters can be efficiently estimated for synthetic and experimental data from in vivo two-photon experiments in the zebrafish retina. Also, we find that the model captures complex properties of the synaptic release such as the temporal precision and outperforms a standard GLM. Our framework provides a viable path forward for linking mechanistic models of neural activity to measured data.
Neural correlates of perceptual switching while listening to bistable auditory streaming stimuli
Authors: Higgins NC , Little DF , Yerkes BD , Nave KM , Kuruvilla-Mathew A , Elhilali M , Snyder JS
Published: June 2019

Understanding the neural underpinning of conscious perception remains one of the primary challenges of cognitive neuroscience. Theories based mostly on studies of the visual system differ according to whether the neural activity giving rise to conscious perception occurs in modality-specific sensory cortex or in associative areas, such as the frontal and parietal cortices. Here, we search for modality-specific conscious processing in the auditory cortex using a bistable stream segregation paradigm that presents a constant stimulus without the confounding influence of physical changes to sound properties. ABA_ triplets (i.e., alternating low, A, and high, B, tones, and _ gap) with a 700 ms silent response period after every third triplet were presented repeatedly, and human participants reported nearly equivalent proportions of 1- and 2-stream percepts. The pattern of behavioral responses was consistent with previous studies of visual and auditory bistable perception. The intermittent response paradigm has the benefit of evoking spontaneous perceptual switches that can be attributed to a well-defined stimulus event, enabling precise identification of the timing of perception-related neural events with event-related potentials (ERPs). Significantly more negative ERPs were observed for 2-streams compared to 1-stream, and for switches compared to non-switches during the sustained potential (500-1000 ms post-stimulus onset). Further analyses revealed that the negativity associated with switching was independent of switch direction, suggesting that spontaneous changes in perception have a unique neural signature separate from the observation that 2-streams has more negative ERPs than 1-stream. Source analysis of the sustained potential showed activity associated with these differences originating in anterior superior temporal gyrus, indicating involvement of the ventral auditory pathway that is important for processing auditory objects.

Significance Statement

When presented with ambiguous stimuli, the auditory system takes the available information and attempts to construct a useful percept. When multiple percepts are possible from the same stimuli, however, perception fluctuates back and forth between alternating percepts in a bistable manner. Here, we examine spontaneous switches in perception using a bistable auditory streaming paradigm with a novel intermittent stimulus paradigm, and measure sustained electrical activity in anterior portions of auditory cortex using event-related potentials. Analyses revealed enhanced sustained cortical activity when perceiving 2-streams compared to 1-stream, and when a switch occurred regardless of switch direction. These results indicate that neural responses in auditory cortex reflect both the content of perception and neural dynamics related to switches in perception.
Evolution of satellite plasmids can stabilize the maintenance of newly acquired accessory genes in bacteria
Authors: Zhang Xue , Deatherage Daniel E. , Zheng Hao , Georgoulis Stratton J. , Barrick Jeffrey E.
Published: June 2019

Plasmids play a principal role in the spread of antibiotic resistance and other traits by horizontal gene transfer in bacteria. However, newly acquired plasmids generally impose a fitness burden on a cell, and they are lost from a population rapidly if there is not selection to maintain a unique function encoded on the plasmid. Mutations that ameliorate this fitness cost can sometimes eventually stabilize a plasmid in a new host, but they typically do so by inactivating some of its novel accessory genes. In this study, we identified an additional evolutionary pathway that can prolong the maintenance of newly acquired genes encoded on a plasmid. We discovered that propagation of an RSF1010-based IncQ plasmid inEscherichia colioften generated ‘satellite plasmids’ with spontaneous deletions of accessory genes and genes required for plasmid replication. These smaller plasmid variants are nonautonomous genetic parasites. Their presence in a cell drives down the copy number of full-length plasmids, which reduces the burden from the accessory genes without eliminating them entirely. The evolution of satellite plasmids may be favored relative to other plasmid fates because they give a more immediate fitness advantage to a cell’s progeny and because the organization of IncQ plasmids makes them particularly prone to certain deletions during replication. Satellite plasmids also evolved inSnodgrassella alvicolonizing the honey bee gut, suggesting that this mechanism may broadly contribute to the importance of IncQ plasmids as agents of bacterial gene transfer in nature.

Significance Statement

Plasmids are multicopy DNA elements found in bacteria that replicate independently of a cell’s chromosome. The spread of plasmids carrying antibiotic-resistance genes to new bacterial pathogens is a challenge for treating life-threatening infections. Often plasmids or their accessory genes encoding unique functions are lost soon after transfer into a new cell because they impose a fitness burden. We report that a family of transmissible plasmids can rapidly evolve ‘satellite plasmids’ that replicate as genetic parasites of the original plasmid. Satellite plasmid formation reduces the burden from the newly acquired genes, which may enable them to survive intact for longer after transfer into a new cell and thereby contribute to the spread of antibiotic resistance and other traits within bacterial populations.
Experimental evolution for niche breadth in bacteriophage T4 highlights the importance of structural genes
Authors: Pham Jenny Y. , Ogbunugafor C. Brandon , Nguyen Ba Alex N. , Hartl Daniel L.
Published: June 2019

Ecologists have long studied the evolution of niche breadth, including how variability in environments can drive the evolution of specialism and generalism. This concept is of particular interest in viruses, where niche-breadth evolution may explain viral disease emergence, or underlie the potential for therapeutic measures like phage therapy. Despite the significance and potential applications of virus-host interactions, the genetic determinants of niche-breadth evolution remain unexplored in many bacteriophage. In this study, we present the results of an evolution experiment with a model bacteriophage system,Escherichia virus T4, in several host environments: exposure toE. coliC, exposure toE. coliK-12, and exposure to bothE. coliC andE. coliK-12. This experimental framework allowed us to investigate the phenotypic and molecular manifestations of niche-breadth evolution. First, we show that selection on different hosts led to measurable changes in phage productivity in all experimental populations. Second, whole—genome sequencing of experimental populations revealed signatures of selection. Finally, clear and consistent patterns emerged across the host environments, especially the presence of new mutations in phage structural genes. A comparison of mutations found across functional gene categories revealed that structural genes acquired significantly more mutations than other categories. Our findings suggest that structural genes—those that provide morphological and biophysical integrity to a virus—are central determinants in bacteriophage niche breadth.
Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein
Authors: Lu Daniel R. , Wu Hao , Driver Ian , Ingersoll Sarah , Sohn Sue , Wang Songli , Li Chi-Ming , Phee Hyewon
Published: June 2019

The therapeutic expansion of Foxp3+ regulatory T cells (Tregs) shows promise for treating autoimmune and inflammatory disorders. Yet, how this treatment affects the heterogeneity and function of Tregs is not clear. Using single-cell RNA-seq analysis, we characterized 31,908 Tregs from the mice treated with a half-life extended mutant form of murine IL-2 (IL-2 mutein, IL-2M) that preferentially expanded Tregs, or mouse IgG Fc as a control. Cell clustering analysis revealed that IL-2M specifically expands multiple sub-states of Tregs with distinct expression profiles. TCR-profiling with single-cell analysis uncovered Treg migration across tissues and transcriptional changes between clonally related Tregs following IL-2M treatment. Finally, we identified IL-2M-expanded Tnfrsf9+Il1rl1+ Tregs with superior suppressive function, highlighting the potential of IL-2M to expand highly suppressive Foxp3+ Tregs.

One Sentence Summary

Single-cell analysis revealed that IL-2 mutein treatment expanded multiple sub-states of Tregs with a highly suppressive function in mice.
lncRNAKB: A comprehensive knowledgebase of long non-coding RNAs
Authors: Seifuddin Fayaz , Singh Komudi , Suresh Abhilash , Chen Yun-Ching , Chaitankar Vijender , Tunc Ilker , Ruan Xiangbo , Li Ping , Chen Yi , Cao Haiming , Lee Richard S. , Goes Fernando , Zandi Peter P. , Jafri M. Saleet , Pirooznia Mehdi
Published: June 2019

We have assembled a comprehensivelongnon-codingRNAknowledgebase (lncRNAKB) of 77,199 annotated human lncRNAs (224,286 transcripts) by methodically integrating widely used lncRNAs resources. To facilitate functional characterization of lncRNAs, we employed Genotype-Tissue Expression (GTEx) project to provide tissue-specific gene expression profiles of lncRNAs in 31 solid organ tissues. Additional information includes network analysis to identify co-expressed gene modules to potentially delineate lncRNA function. Tissue-specificity, phylogenetic conservation scores and coding potential for lncRNAs are included. Finally, using whole genome sequencing data from GTEx, expression quantitative trait loci (cis-eQTL) regulated lncRNAs were calculated in all tissues. lncRNAKB is available athttp://www.lncrnakb.org.
Pseudomonas aeruginosaethanol oxidation by AdhA in low oxygen environments
Authors: Crocker Alex W. , Harty Colleen E. , Hammond John H. , Willger Sven D. , Salazar Pedro , Jacobs Nicholas J. , Hogan Deborah A.
Published: June 2019

Pseudomonas aeruginosahas a broad metabolic repertoire that facilitates its co-existence with different microbes. Many microbes secrete products thatP. aeruginosacan then catabolize, including ethanol, a common fermentation product. Here, we show that under oxygen limiting conditionsP. aeruginosautilizes AdhA, an NAD-linked alcohol dehydrogenase, as a previously undescribed means for ethanol catabolism. In a rich medium containing ethanol, AdhA, but not the previously described PQQ-linked alcohol dehydrogenase, ExaA, oxidizes ethanol and leads to the accumulation of acetate in culture supernatants. AdhA-dependent acetate accumulation, and the accompanying decrease in pH, promotesP. aeruginosasurvival in LB-grown stationary phase cultures. The transcription ofadhAis elevated by hypoxia and in anoxic conditions, and we show that it is regulated by the Anr transcription factor. We have shown thatlasRmutants have higher levels of Anr-regulated transcripts in low oxygen conditions compared to their wild type counterparts. Here, we show that alasRmutant, when grown with ethanol, has an even larger decrease in pH than WT that is dependent on bothanrandadhA. The large increase in AdhA activity similar to that of a strain expressing a hyperactive Anr-D149A variant. Ethanol catabolism inP. aeruginosaby AdhA supports growth on ethanol as a sole carbon source and electron donor in oxygen-limited settings and in cells growing by denitrification in anoxic conditions. This is the first demonstration of a physiological role for AdhA in ethanol oxidation inP. aeruginosa.

Importance

Ethanol is a common product of microbial fermentation, and thePseudomonas aeruginosaresponse to and utilization of ethanol is relevant to our understanding of its role in microbial communities. Here, we report that the putative alcohol dehydrogenase, AdhA, is responsible for ethanol catabolism and acetate accumulation in low oxygen conditions and that it is regulated by Anr.
Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014
Authors: Sommer Grit , Schindler Matthias , Redmond Shelagh , Pfeiffer Verena , Konstantinoudis Garyfallos , Ammann Roland A. , Ansari Marc , Hengartner Heinz , Michel Gisela , Kuehni Claudia E. ,   for the Swiss Paediatric Oncology Group (SPOG)
Published: June 2019

STRUCTURED ABSTRACT

Background

Incidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.

Methods

We extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends in annual age-standardised incidence using JoinPoint regression models.

Results

Over the study period from 1985-2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p<0.001). Using the 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.

Conclusion

Trends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and at least partly due to changes in risk factors.

Highlights

In Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.

Increase in incidence was mainly caused by brain tumours and leukaemias.

Improved registration and diagnostics may have increased brain tumour incidence.

Increasing trend for leukaemias may be real, but reasons remain elusive.
Limited thermal plasticity and geographic divergence in the ovipositor of Drosophila suzukii
Authors: Varón-González Ceferino , Fraimout Antoine , Delapré Arnaud , Debat Vincent , Cornette Raphaël
Published: June 2019

Phenotypic plasticity has been repeatedly suggested to facilitate adaptation to new environmental conditions, as in invasions. Here we investigate this possibility by focusing on the worldwide invasion of Drosophila suzukii: an invasive species that has rapidly colonized all continents over the last decade. This species is characterized by a highly developed ovipositor, allowing females to lay eggs through the skin of ripe fruits. Using a novel approach based on the combined use of SEM and photogrammetry, we quantified the ovipositor size and 3D shape, contrasting invasive and native populations raised at three different developmental temperatures. We found a small but significant effect of temperature and geographic origin on the ovipositor shape, showing the occurrence of both geographic differentiation and plasticity to temperature. The shape reaction norms are in turn strikingly similar among populations, suggesting very little difference in shape plasticity among invasive and native populations, and therefore rejecting the hypothesis of a particular role for plasticity of the ovipositor in the invasion success. Overall, the ovipositor shape seems to be a fairly robust trait, indicative of stabilizing selection. The large performance spectrum rather than the flexibility of the ovipositor would thus contribute to the success of D. suzukii worldwide invasion.
Metabolic pathway rerouting inParaburkholderia rhizoxinicaevolved long-overlooked derivatives of coenzyme F420
Authors: Braga Daniel , Last Daniel , Hasan Mahmudul , Guo Huijuan , Leichnitz Daniel , Uzum Zerrin , Richter Ingrid , Schalk Felix , Beemelmanns Christine , Hertweck Christian , Lackner Gerald
Published: June 2019

Coenzyme F420is a specialized redox cofactor with a highly negative redox potential. It supports biochemical processes like methanogenesis, degradation of xenobiotics or the biosynthesis of antibiotics. Although well-studied in methanogenic archaea and actinobacteria, not much is known about F420in Gram-negative bacteria. Genome sequencing revealed F420biosynthetic genes in the Gram-negative, endofungal bacteriumParaburkholderia rhizoxinica, a symbiont of phytopathogenic fungi. Fluorescence microscopy, high-resolution LC-MS, and structure elucidation by NMR demonstrated that the encoded pathway is active and yields unexpected derivatives of F420(3PG-F420). Further analyses of a biogas-producing microbial community showed that these derivatives are more widespread in nature. Genetic and biochemical studies of their biosynthesis established that a specificity switch in the guanylyltransferase CofC re-programmed the pathway to start from 3-phospho-D-glycerate, suggesting a rerouting event during the evolution of F420biosynthesis. Furthermore, the cofactor activity of 3PG-F420was validated, thus opening up perspectives for its use in biocatalysis. The 3PG-F420biosynthetic gene cluster is fully functional inEscherichia coli, enabling convenient production of the cofactor by fermentation.
Reprogramming of 24nt siRNAs in rice gametes
Authors: Li Chenxin , Xu Hengping , Fu Fang-Fang , Russell Scott D. , Sundaresan Venkatesan , Gent Jonathan I.
Published: June 2019

Gametes constitute a critical stage of the plant life cycle, during which the genome undergoes reprogramming in preparation for embryogenesis. Here we characterized the small RNA transcriptomes of egg cells and sperm cells from rice to elucidate genome-wide distributions of 24nt siRNAs, which are a hallmark of RNA-directed DNA methylation (RdDM) in plants and are typically concentrated at boundaries of heterochromatin. We found that 24nt siRNAs were depleted from heterochromatin boundaries in both gametes, reminiscent of siRNA patterns in DDM1-type nucleosome remodeler mutants. In sperm, 24nt siRNAs were spread across broad heterochromatic regions, while in eggs, 24nt siRNAs were concentrated at a smaller number of heterochromatic loci throughout the genome, which were shared with vegetative tissues and sperm. In both gametes, patterns of CHH methylation, typically a strong indicator of RdDM, were similar to vegetative tissues, although lower in magnitude. These findings indicate that the small RNA transcriptome undergoes large-scale re-programming in both male and female gametes, which is not correlated with recruitment of DNA methyltransferases in gametes and suggestive of unexplored regulatory activities of gamete small RNAs in seeds after fertilization.
The Endless Frontier? The Recent Upsurge of R&D Productivity in Pharmaceuticals
Authors: Pammolli Fabio , Righetto Lorenzo , Abrignani Sergio , Pani Luca , Pelicci Pier Giuseppe , Rabosio Emanuele
Published: June 2019

Analyses of pharmaceutical pipelines of drug development in the 1990-2010 documented progressively increasing attrition rates and duration of clinical trials, leading to a diffuse perception of a “productivity crisis”. We produced a new set of analyses for the last decade, using an extensive data of more than 45,000 projects between 1990 and 2017, and report a recent upsurge of R&D productivity within the industry. First, we investigated how R&D projects are allocated across therapeutic areas and found a polarization towards high-risk/high-reward indications, with a strong focus on oncology. Importantly, attrition rates have been decreasing at all clinical stages in recent years. In parallel, we observed an increase of early failures in preclinical research, and a significant reduction of time required to identify projects to be discontinued. Notably, more recent projects are increasingly based on novel mechanisms of action and target indications with small patient populations. Finally, by analyses of the relative contribution of different institutional types and development companies, we show that the observed increased performance in clinical trials is mostly due to the contribution of biotech-nological companies, while pharmaceutical companies have significantly improved their performances in identifying false positives in preclinical research.
Chloris distichophyllaLag. (Poaceae) as stink bug (Pentatomidae) shelter in soybean and corn off-season in southern Brazil
Authors: Engel Eduardo , Pasini Mauricio P. B. , Hörz Daniele C. , Bortolotto Rafael P.
Published: June 2019

The objective of this study was to evaluate the composition and abundance of dormant bedbugs inChloris distichophyllaLag (Poales: Poaceae) over the soybean and corn off-season. The work was carried out in the municipality of Cruz Alta, over the soybean and corn off-season between 2014 and 2018. Plants ofC. distichophyllawith different clump diameter were sampled, and the bugs contained in them were counted and submitted to data analysis for the evaluation of the composition, structure, and diversity of occurring species. At the end of the experiment, 3543 hibernating adults were counted and divided into six species:Euschistus heros(F.),Dichelops furcatus(F.),Dichelops melacanthusDallas,Edessa meditabunda(F.),Edessa ruformaginata(De Geer) (Hemiptera: Pentatomidae). The speciesE. heroswas the most abundant, followed byD. furcatus. The diameter of the clumps directly affects the population density of the stink bugs. Finally,C. distichophyllais shown as a hibernate favorable to the maintenance of the stink bug populations over the soybean and corn off-season.
Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants
Authors: Donovan Margaret K. R. , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A.
Published: June 2019

The Genotype-Tissue Expression (GTEx) resource has contributed a wealth of novel insights into the regulatory impact of genetic variation on gene expression across human tissues, however thus far has not been utilized to study how variation acts at the resolution of the different cell types composing the tissues. To address this gap, using liver and skin as a proof-of-concept tissues, we show that readily available signature genes based on expression profiles of mouse cell types can be used to deconvolute the cellular composition of human GTEx tissues. We then deconvoluted 6,829 bulk RNA-seq samples corresponding to 28 GTEx tissues and show that we are able to quantify cellular heterogeneity, determining both the different cell types present in each of the tissues and how their proportions vary between samples of the same tissue type. Conducting eQTL analyses for GTEx liver and skin samples using cell type composition estimates as interaction terms, we identified thousands of novel genetic associations that had lower effect sizes and were cell-type-associated. We further show that cell-type-associated eQTLs in skin colocalize with melanoma, malignant neoplasm, and infection signatures, indicating variants that influence gene expression in distinct skin cell types play important roles in skin traits and disease. Overall, our study provides a framework to estimate the relative fractions of different cell types in GTEx tissues using signature genes from mouse cell types and functionally characterize human genetic variation that impacts gene expression in a cell-type-specific manner.
Oncoprotein CoAA repeats interact with RNA polymerase II CTD repeats
Authors: Xiong Shiqin , Brooks Yang S. , Yang Zheqiong , Wu Jiacai , Zhang Liyong , Dynan William S. , Xu Wei , O’Malley Bert W. , Ko Lan
Published: June 2019

The heptad repeating sequence of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II is highly conserved in eukaryotes. In yeast, a CTD code consisting of pairs of heptad repeats is essential for viability. However, the strict requirement of diheptad repeats for the CTD function in transcription and splicing is unexplained. Here we show that CoAA (gene symbol RBM14), an oncoprotein and mammalian transcriptional coactivator, possesses diheptad repeats and directly interacts with the CTD. CoAA comprises 27 copies of tyrosine-rich repeats and regulates pre-mRNA synthesis and alternative splicing. Tyrosine substitutions in either the CoAA repeats or the CTD repeats diminish their interactions. Ser2- or Ser5-phosphorylated CTD peptides exhibit higher binding affinity to CoAA than the corresponding non-phosphorylated CTD peptide. CoAA dynamically interacts with both the CTD and hnRNP M, which is an alternative splicing regulator also comprising diheptad repeats. Arginine methylation of CoAA switches its interaction from the hnRNP M repeats to the CTD repeats. This study provides a mechanism for CoAA at the interface of transcription and alternative splicing, and explains the functional requirement of diheptad repeats in the CTD. In the human genome, tyrosine-rich repeats similar to the CoAA repeats were only found in six oncoproteins including EWS and SYT. We suggest that the diheptad sequence is one of the signature features for the CTD interaction among oncoproteins involved in transcription and alternative splicing. We anticipate that direct RNA Pol II interaction is a mechanism in oncogenesis.
Entorhinal velocity signals reflect environmental geometry
Authors: Munn Robert G K , Mallory Caitlin S , Hardcastle Kiah , Chetkovich Dane M , Giocomo Lisa M
Published: June 2019

The entorhinal cortex contains neural signals for representing self-location, including grid cells that fire in periodic locations and velocity signals that encode an animal’s speed and head direction. Recent work revealed that the size and shape of the environment influences grid patterns. Whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here, we report that changes to the size and shape of the environment result in re-scaling in entorhinal speed codes. Moreover, head direction cells re-organize in an experience-dependent manner to align with the axis of environmental change. A knockout mouse model allows a dissociation of the coordination between cell types, with grid and speed, but not head direction, cells responding in concert to environmental change. These results align with predictions of grid cell attractor models and point to inherent flexibility in the coding features of multiple functionally-defined entorhinal cell types.
Neocortical inhibitory interneuron subtypes display distinct responses to synchrony and rate of inputs
Authors: Tran Matthew M. , Prince Luke Y. , Gray Dorian , Saad Lydia , Chasiotis Helen , Kwag Jeehyun , Kohl Michael M. , Richards Blake A.
Published: June 2019

Populations of neurons in the neocortex can carry information with both the synchrony and the rate of their spikes. However, it is unknown whether distinct subtypes of neurons in the cortical microcircuit are more sensitive to information carried by synchrony versus rate. Here, we address this question using patterned optical stimulation in slices of barrel cortex from transgenic mouse lines labelling distinct interneuron populations: fast-spiking parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. We use optical stimulation of channelrhodopsin-2 (ChR2) expressing excitatory neurons in layer 2/3 in order to encode a random 1-bit signal in either the synchrony or rate of activity in presynaptic cells. We then examine the mutual information between this 1-bit signal and the voltage and spiking responses in PV+ and SST+ interneurons. Generally, we find that both interneuron types carry more information than GFP negative (GFP-) control cells. More specifically, we find that for a synchrony encoding, PV+ interneurons carry more information in the first 5 milliseconds, while both interneuron subtypes carry more information than negative controls in their later response. We also find that for a rate encoding, SST+ interneurons carry more information than either PV+ or negative controls after several milliseconds. These data demonstrate that inhibitory interneuron subtypes in the neocortex have distinct responses to information carried by synchrony versus rates of spiking.
Prostaglandin EP3 Receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance
Authors: Wisinski Jaclyn A. , Reuter Austin , Peter Darby C. , Schaid Michael D. , Fenske Rachel J. , Kimple Michelle E.
Published: June 2019

When homozygous for theLeptinObmutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 weeks of age, frankly diabetic. Previous work has shown Prostaglandin EP3 Receptor (EP3) expression and activity is up-regulated in islets from BTBR-Ob mice as compared to lean controls, actively contributing to their beta-cell dysfunction. In this work, we aimed to test the impact of beta-cell-specific EP3 loss on the BTBR-Ob phenotype by crossingPtger3floxed mice with the Rat insulin promoter (RIP)-CreHerrdriver strain. Instead, germline recombination of the floxed allele in the founder mouse – an event whose prevalence we identified as directly associated with underlying insulin resistance of the background strain – generated a full-body knockout. Full-body EP3 loss provided no diabetes protection to BTBR-Ob mice, but, unexpectedly, significantly worsened BTBR-lean insulin resistance and glucose tolerance. Thisin vivophenotype was not associated with changes in beta-cell fractional area or markers of beta-cell replicationex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective up-regulation of constitutively-active EP3 splice variants in islets from young, lean BTBR mice as compared to C57BL/6J, where no phenotype of EP3 loss has been observed, provides a potential explanation for the hypersecretion phenotype. In support of this, high islet EP3 expression in Balb/c females vs. Balb/c males was fully consistent with their sexually-dimorphic metabolic phenotype after loss of EP3-coupled Gαzprotein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion.

New and Noteworthy

Islet Prostaglandin EP3 receptor (EP3) signaling is well-known as up-regulated in the pathophysiological conditions of type 2 diabetes, contributing to beta-cell dysfunction. Unexpected findings in mouse models of non-obese insulin sensitivity and resistance provide a new dimension to our understanding of EP3 as a key modulator of insulin secretion. A previously-unknown relationship between mouse insulin resistance and the penetrance of Rat insulin promoter-driven germline floxed allele recombination is critical to consider when creating beta-cell-specific knockouts.

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Novel Quinazoline derivatives inhibited HCV Serine protease and viral replication in Huh-7 cells
Authors: Rothan Hussin A. , Faraj Fadhil Lafta , Teoh Teow Chong , Yusof Rohana
Published: June 2019

Drugs against HCV infection are facing several drawbacks such as undesirable side effects, emerging of HCV resistant strains, and high cost of the entire course of treatment. Thus, new active and cost-effective compounds are required to develop effective drugs to combat HCV infection. This study was designed to test the antiviral activity of quinazoline derivatives against HCV infection using HCV protease assay (HCV NS3-4Apro) and cell-based HCV replicon assay. The results showed that some of quinazoline derivatives inhibited HCV NS3-4Apro with IC50 ranged from 42 µM of compound 4 to 150 µM of compound 2. In this study, compound 4 was considered as the best compound lead to developing potent anti-HCV NS3-4Apro inhibitors. The toxic dose of compound 4 was more than 80 µM for 24, 48, and 72 h. Compound 4 showed dose-dependent inhibition against HCV replication with a considerable reduction in Rluc activity at 40 µM. This finding was further investigated by immunostaining that showed the inhibitory effect of compound 4 against HCV NS3-4Apro was dose-dependent. This study identified a unique small molecule compound that could lead to the development of HCV NS3-A4pro inhibitors and would be useful to develop highly effective drugs for HCV infection based on HCV NS3-4A protease inhibition.
Foot strike pattern during running alters muscle-tendon dynamics of the gastrocnemius and the soleus
Authors: Yong Jennifer R. , Dembia Christopher L. , Silder Amy , Jackson Rachel W. , Fredericson Michael , Delp Scott L.
Published: June 2019

Running is thought to be an efficient gait due, in part, to the behavior of the plantar flexor muscles and the elastic energy storage in the Achilles tendon. Although plantar flexor muscle mechanics and Achilles tendon energy storage have been explored during rearfoot striking, they have not been fully characterized during forefoot striking. This study examines how plantar flexor muscle-tendon mechanics during running differ between rearfoot and forefoot striking. We used musculoskeletal simulations, driven by joint angles and electromyography recorded from runners using both rearfoot and forefoot striking running patterns, to characterize plantar flexor muscle-tendon mechanics. The simulations revealed that foot strike pattern affected the soleus and gastrocnemius differently. For the soleus, forefoot striking resulted in decreased tendon energy storage and decreased positive fiber work compared to rearfoot striking. For the gastrocnemius, forefoot striking resulted in greater activation and increased negative fiber work compared to rearfoot striking. The increased activation and negative fiber work in the gastrocnemius during forefoot striking suggest that runners planning to convert to forefoot striking would benefit from a progressive eccentric gastrocnemius strengthening program to avoid injury.