bluuebunny/crossref_metadata_2025 huggingface dataset:
Timescales of spontaneous fMRI fluctuations relate to structural connectivity in the brain
Authors: Fallon John , Ward Phil , Parkes Linden , Oldham Stuart , Arnatkevic̆iūtė Aurina , Fornito Alex , Fulcher Ben D.
Published: May 2019

Intrinsic timescales of activity fluctuations vary hierarchically across the brain. This variation reflects a broad gradient of functional specialization in information storage and processing, with integrative association areas displaying slower timescales that are thought to reflect longer temporal processing windows. The organization of timescales is associated with cognitive function, distinctive between individuals, and disrupted in disease, but we do not yet understand how the temporal properties of activity dynamics are shaped by the brain’s underlying structural-connectivity network. Using resting-state fMRI and diffusion MRI data from 100 healthy individuals from the Human Connectome Project, here we show that the timescale of resting-state fMRI dynamics increases with structural-connectivity strength, matching recent results in the mouse brain. Our results hold at the level of individuals, are robust to parcellation schemes, and are conserved across a range of different timescale-related statistics. We establish a comprehensive BOLD dynamical signature of structural connectivity strength by comparing over 6000 time-series features, highlighting a range of new temporal features for characterizing BOLD dynamics, including measures of stationarity and symbolic motif frequencies. Our findings indicate a conserved property of mouse and human brain organization in which a brain region’s spontaneous activity fluctuations are closely related to their surrounding structural scaffold.
Enzymatic degradation of biofilm by metalloprotease fromMicrobacteriumsp. SKS10
Authors: Saggu Sandeep Kaur , Jha Gopaljee , Mishra Prakash Chandra
Published: May 2019

Enzymes have replaced or decreased usage of toxic chemicals for industrial and medical applications leading towards sustainable chemistry. In this study, we report purification and characterization of a biofilm degrading protease secreted byMicrobacteriumsp. SKS10. The protease was identified as a metalloprotease, Peptidase M16 using mass spectrometry. It showed optimum activity at 60 °C, pH 12 and retained its activity in the presence of various salts and organic solvents. The enzyme was able to degrade biofilms efficiently at enzyme concentration lower than other known enzymes such as papain, trypsin and □-amylase. The presence of this protease increased the accessibility of antibiotics inside the biofilm, and was found to be non-cytotoxic towards human epidermoid carcinoma cells (A431) at the effective concentration for biofilm degradation. Thus, this protease may serve as an effective tool for management of biofilms.
(p)ppGpp and CodY promoteEnterococcus faecalisvirulence in a murine model of catheter-associated urinary tract infection
Authors: Colomer-Winter C , Flores-Mireles AL , Kundra S , Hultgren SJ , Lemos JA
Published: May 2019

In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp andcodYmutant strains ofEnterococcus faecalisin a catheter-associated urinary tract infections (CAUTI) mouse model and used global transcriptional analysis to investigate the (p)ppGpp and CodY relationship. Absence of (p)ppGpp or single inactivation ofcodYled to lower bacterial loads in catheterized bladders, and diminished biofilm formation on fibrinogen-coated surfaces underin vitroandin vivoconditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolasereldid not affect virulence supporting previous evidence that association of (p)ppGpp with enterococcal virulence is not dependent on activation of the stringent response. Inactivation ofcodYin the (p)ppGpp0strain restoredE. faecalisvirulence in the CAUTI model as well as the ability to form biofilmsin vitro. Transcriptome analysis revealed that inactivation ofcodYrestores, for the most part, the dysregulated metabolism of (p)ppGpp0cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicate that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may plays a role in enterococcal CAUTI. Collectively, this study identifies the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and supports that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism during adverse conditions.

Importance

Catheter-associated urinary tract infections (CAUTI) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently cause complicated CAUTI is the bacteriumEnterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by whichE. faecaliscauses CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability ofE. faecalisto infect the catheterized bladder of mice.
Novel inducers of the expression of multidrug efflux pumps that triggerPseudomonas aeruginosatransient antibiotic resistance
Authors: Laborda Pablo , Alcalde-Rico Manuel , Blanco Paula , Martínez José Luis , Hernando-Amado Sara
Published: May 2019

The study of the acquisition of antibiotic resistance (AR) has mainly focused in inherited processes, namely mutations and acquisition of AR genes. However, inducible, non-inheritable AR has received less attention and most information in this field derives from the study of antibiotics as inducers of their associated resistance mechanisms. Less is known about non-antibiotic compounds or situations that can induce AR during infection. Multidrug resistance efflux pumps are a category of AR determinants characterized by the tightly regulation of their expression. Their contribution to acquired AR relies in their overexpression. Herein we analyzed potential inducers of the expression of the chromosomally-encodedPseudomonas aeruginosaclinically-relevant efflux pumps, MexCD-OprJ and MexAB-OprM. For this purpose, we developed a set ofluxCDABE-basedP. aeruginosabiosensor strains, which allows the high-throughput analysis of compounds able of modifying the expression of these efflux pumps. Using these strains, we analyzed a set of 240 compounds present in Biolog Phenotype Microarrays. Several inducers of the expression of the genes that encode these efflux pumps were found. The study focused in dequalinium chloride, procaine and atropine, compounds that can be found in clinical settings. Using real-time PCR, we confirmed that these compounds indeed induce the expression ofmexCD-oprJ.In addition,P. aeruginosapresents lower susceptibility to ciprofloxacin (a MexCD-OprJ substrate) when dequalinium chloride, procaine or atropine are present. This work emphasizes the need of studying compounds that can trigger transient AR during antibiotic treatment, a phenotype difficult to discover using classical susceptibility tests.
Genome-resolved viral and cellular metagenomes revealed potential key virus-host interactions in a deep freshwater lake
Authors: Okazaki Yusuke , Nishimura Yosuke , Yoshida Takashi , Ogata Hiroyuki , Nakano Shin-ichi
Published: May 2019

Metagenomics has dramatically expanded the known virosphere, but freshwater viral diversity and their ecological interaction with hosts remain poorly understood. Here, we conducted a metagenomic exploration of planktonic dsDNA prokaryotic viruses by sequencing both virion (<0.22 μm) and cellular (0.22–5.0 μm) fractions collected spatiotemporally from a deep freshwater lake (Lake Biwa, Japan). This simultaneously reconstructed 183 complete (i.e., circular) viral genomes and 57 bacterioplankton metagenome-assembled genomes. Analysis of metagenomic read coverage revealed vertical partitioning of the viral community analogous to the vertically stratified bacterioplankton community. The hypolimnetic community was generally stable during stratification, but occasionally shifted abruptly, presumably due to lysogenic induction. Genes involved in assimilatory sulfate reduction were encoded in 20 (10.9%) viral genomes, including those of dominant viruses, and may aid viral propagation in sulfur-limited freshwater systems. Hosts were predicted for 40 (21.9%) viral genomes, encompassing 10 phyla (or classes of Proteobacteria) including ubiquitous freshwater bacterioplankton lineages (e.g., Ca. Fonsibacter and Ca. Nitrosoarchaeum). Comparison with viral genomes derived from published metagenomes revealed viral phylogeographic connectivity in geographically isolated habitats. Notably, analogous to their hosts, actinobacterial viruses were among the most diverse, ubiquitous, and abundant viral groups in freshwater systems, with potential high lytic activity in surface waters.
Taurine promotes axonal regeneration after a complete spinal cord injury in lampreys
Authors: Sobrido-Cameán Daniel , Fernández-López Blanca , Pereiro Natividad , Lafuente Anunciación , Rodicio María Celina , Barreiro-Iglesias Antón
Published: May 2019

Taurine is one of the most abundant free amino acids in the brain. It is well known that taurine protects the brain from further damage after a traumatic event. However, only a few ex vivo studies have looked at the possible role of taurine in the regulation of axon regeneration after injury. Here, we aimed to reveal the possible role for taurine in the modulation of axonal regeneration following a complete spinal cord injury (SCI) using lampreys as an animal model. The brainstem of lampreys contains several individually identifiable descending neurons that differ greatly in their capacity for axonal regeneration after SCI. This offers a convenient model to promote or inhibit axonal regrowth in the same in vivo preparation. First, we carried out high performance liquid chromatography experiments to measure taurine levels in the spinal cord following SCI. Our results revealed a statistically significant increase in taurine levels 4 weeks post lesion, which suggested that taurine might have a positive effect on axonal regrowth. Based on these results, we decided to apply an acute taurine treatment at the site of injury to study its effect on axon regeneration. Results from these experiments show that an acute taurine treatment enhances axonal regeneration following SCI in lampreys. This offers a novel way to try to promote axon regeneration after nervous system injuries in mammalian models.
Development of copy number assays for detection and surveillance of piperaquine resistance associated plasmepsin 2/3 copy number variation in Plasmodium falciparum
Authors: Jacob Christopher G , Ansbro Megan R , Amato Roberto , Kekre Mihir , Vongpromek Ranitha , Dhorda Mehul , Amaratunga Chanaki , Sreng Sokunthea , Suon Seila , Miotto Olivo , Fairhurst Rick M , Wellems Thomas E , Kwiatkowski Dominic P
Published: May 2019

Long regarded as an epicenter of drug-resistant malaria, Southeast Asia continues to provide new challenges to the control of Plasmodium falciparum malaria. Recently, resistance to the artemisinin combination therapy partner drug piperaquine has been observed in multiple locations across Southeast Asia. Genetic studies have identified a single nucleotide polymorphism as well as a copy number variation molecular marker that associate with clinical and in vitro resistance. The copy number polymorphism is a duplication of a region containing members of the plasmepsin multi-gene family of proteases. To accurately and quickly determine the presence of copy number variation in the plasmepsin 2/3 duplication in field isolates, we developed a quantitative PCR assay using TaqMan probes. We validated copy number estimates using a separate SYBR green-based quantitative PCR assay as well as a novel breakpoint assay to detect the hybrid gene product. Field samples from 2012 – 2015 across 3 sites in Cambodia were tested using DNA extracted from dried blood spots and whole blood to monitor the extent of plasmepsin 2/3 gene duplications, as well as pfmdr1. We found high concordance across all methods of copy number detection. For samples derived from dried blood spots we found a greater than 80% success rate in each assay, with more recent samples performing better. We found evidence of extensive plasmepsin 2/3 copy number amplifications in Pursat (94%, 2015) and Preah Vihear (87%, 2014), and lower levels in Ratanakiri (16%, 2014) in eastern Cambodia. We also see evidence of a shift from two copies of plasmepsin 2/3 in Pursat 2013 to three copies in 2014-15 (25% to 64%). Pfmdr1 duplications are absent from all samples in 2014 from Preah Vihear and Ratanakiri and 2015 from Pursat. This study shows increasing levels of plasmepsin 2/3 gene amplifications across Cambodia from 2012 – 2015 and a complete reversion of pfmdr1 mutant parasites in all study locations. The multiplex TaqMan assay is a robust tool for monitoring both plasmepsin and pfmdr1 copy number variations in field isolates, and the SYBR-green and breakpoint assays are useful for monitoring plasmepsin 2/3 duplications.
Regulatory regions in natural transposable element insertions drive interindividual differences in response to immune challenges in Drosophila
Authors: Ullastres Anna , Merenciano Miriam , González Josefa
Published: May 2019

Background

Variation in gene expression underlies interindividual variability in relevant traits including immune response. However, the genetic variation responsible for these gene expression changes remain largely unknown. Among the non-coding variants that could be relevant, transposable element insertions are promising candidates as they have been shown to be a rich and diverse source of cis-regulatory elements.

Results

In this work, we used a population genetics approach to identify transposable element insertions likely to increase the tolerance of Drosophila melanogaster to bacterial infection by affecting the expression of immune-related genes. We identified 12 insertions associated with allele-specific expression changes in immune-related genes. We experimentally validated three of these insertions including one likely to be acting as a silencer, one as an enhancer, and one with a dual role as enhancer and promoter. The direction in the change of gene expression associated with the presence of several of these insertions was consistent with an increased survival to infection. Indeed, for one of the insertions, we showed that this is the case by analyzing both natural populations and CRISPR/Cas9 mutants in which the insertion was deleted from its native genomic context.

Conclusions

We showed that transposable elements contribute to gene expression variation in response to infection in D. melanogaster and that this variation is likely to affect their survival capacity. Because the role of transposable elements as regulatory elements is not restricted to Drosophila, TEs are likely to play a role in immune response in other organisms as well.
Recombination detected in the Heat Shock Protein 90 (HSP90) of theBemisia tabacispecies complex
Authors: Kinene Tonny , De Marchi Bruno Rossito , Alicai Titus , Luboobi Livingstone S. , Omongo Christopher Abu , Savill Anders , Boykin Laura M.
Published: May 2019

Background

Bemisia tabaci(whiteflies) are a global insect pest causing billions of dollars in damage each year, leaving farmers with low yields. In East Africa, whiteflies are superabundant and present on cassava plants throughout the year. Whiteflies do not decrease in number in the hot dry seasons in East Africa, therefore, it has been suggested that the synthesis of Heat Shock Protein (HSP) may protect the whitefly from heat stress and other biotic factors. In this study we used data sequence generated from individual whiteflies to assess variability and recombination of the HSP90 gene in members of theB. tabacispecies complex.

Results

A total of 21 samples were sequenced on Illumina Hiseq 2500 and Hiseq 4000. These included eight genetic groups ofB. tabaci: 7 SSA1, 5 SSA2, 2 Australia I (AUSI), 2 New World Africa (NWAfrica),B. afer, Uganda, Mediterranean (MED), and Middle East Asia Minor 1 (MEAM1). An alignment of 21 HSP90 sequences was generated after mapping andde novoassembly. Recombination analysis was performed on an alignment of 27 HSP90 sequences (we added an additional 6 sequences from GenBank). There were 18 recombination events detected in the HSP90 gene of theB. tabacispecies complex, 7 of which were regarded as events that could be caused by evolutionary mechanisms such as gene duplication other than recombination. The phylogenetic analysis carried out on dataset without recombination events revealed a tree pattern with short terminal branches.

Conclusion

Recombination events were detected for members of theB. tabacispecies complex in the HSP90 gene. This could explain the variability in the HSP90 gene of theB. tabacispecies complex and highlight the phenomenon of the increased chance of survival and reproductive abundance of whiteflies in hot conditions in East Africa, since recombination is a major driving force of evolution.
Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation
Authors: Dilna Aysha , K.V Deepak , Damodaran Nandini , Kielkopf Claudia S. , Kagedal Katarina , Ollinger Karin , Nath Sangeeta
Published: May 2019

Alzheimer’s disease (AD) pathology progresses gradually via anatomically connected brain regions. Earlier studies have shown that amyloid-β1-42 oligomers (oAβ) can be directly transferred between connected neurons. However, the mechanism of transfer is not fully revealed. We observed formation of oAβ induced tunneling nanotubes (TNTs), nanoscaled f-actin containing membrane conduit, in differentially differentiated SH-SY5Y neuronal models. Time-lapse images showed that TNTs propagate oligomers from one cell to another. Preceding the TNT-formation, we detected oAβ induced plasma membrane (PM) damage and calcium-dependent repair through lysosomal-exocytosis and significant membrane surface expansion, followed by massive endocytosis to re-establish the PM. Massive endocytosis was monitored by an influx of the membrane-impermeable dye TMA-DPH and PM damage was quantified by propidium iodide influx in the absence of calcium. The massive endocytosis eventually caused accumulation of internalized oAβ in Lamp1 positive multi vesicular bodies/lysosomes via the actin cytoskeleton remodulating p21-activated kinase1 (PAK1) dependent endocytic pathway. Three dimensional quantitative and qualitative confocal imaging, structured illumination superresolution microscopy (SIM) and flowcytometry data revealed that oAβ induces activated phospho-PAK1, which modulates the formation of long stretched f-actin extensions between cells. Moreover, formation of TNTs can be inhibited by preventing PAK1 dependent internalization of oAβ using small-molecule inhibitor IPA-3, a highly selective cell permeable auto-regulatory inhibitor of PAK1. The present study gives insight that the TNTs are probably instigated as a consequence of oAβ induced PM damage and repair process, followed by PAK1 dependent endocytosis and actin remodeling, probably to maintain cell surface expansion and/or membrane tension in equilibrium.
Glutathione is Required for Efficient Post-Golgi Trafficking of Incoming HPV16 Genome
Authors: Li Shuaizhi , Bronnimann Matthew P. , Williams Spencer J. , Campos Samuel K.
Published: May 2019

Human papillomavirus (HPV) is the most common sexually transmitted pathogen in the United States, causing 99% of cervical cancers and 5% of all human cancers worldwide. HPV infection requires transport of the viral genome (vDNA) into the nucleus of basal keratinocytes. During this process, minor capsid protein L2 facilitates subcellular retrograde trafficking of the vDNA from endosomes to the Golgi, and accumulation at host chromosomes during mitosis for nuclear retention and localization during interphase. Here we investigated the relationship between cytosolic GSH and HPV16 infection. siRNA knockdown of GSH biosynthetic enzymes results in a partial decrease of HPV16 infection. Likewise, infection of HPV16 in GSH depleted keratinocytes is inefficient, an effect that was not seen with adenoviral vectors. Analysis of trafficking revealed no defects in cellular binding, entry, furin cleavage of L2, or retrograde trafficking of HPV16, but GSH depletion hindered post-Golgi trafficking and translocation, decreasing nuclear accumulation of vDNA. Although precise mechanisms have yet to be defined, this work suggests that GSH is required for a specific post-Golgi trafficking step in HPV16 infection.
VGLUT2/ Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain By CFA
Authors: Tang YuWen , Peng ZhiYou , Tao ShouJun , Sun Jianliang , Wang WenYuan , Guo XueJiao , Liu GongLu , Luo XianZhe , Chen Yuan , Shen Yue , Ma HaiXiang , Xu Peng , Li Qing Hua , Zhang HongHai , Feng ZhiYing
Published: May 2019

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating the heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in mediating release of glutamate, contributed to the inflammatory heat. It remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in Inflammatory pain mediated by Cdk5 and the heat hyperalgesia induced by complete Freund’s adjuvant (CFA) can be reversed by roscovitine, a selective inhibitor for Cdk5 through inhibition of VGLUT2 expression. Immunohistochemistry results suggest that when compared with rats in a control group, rats in an experimental group showed significant coexpression of Cdk5/VGLUT2 in small and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA. Moreover, our study revealed that the expression of VGLUT2 protein in DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection. Additionally, p25 but not p35, a activator of Cdk5, protein was significantly increased and reduced by roscovitine. The increased expressions of VGLUT2 protein was significantly reduced by roscovitine as well. Our study showed that VGLUT2/Cdk5 signaling pathway contributed to the inflammatory pain medicated by Cdk5/p25.
A slight decrease in serum albumin level is associated with rapid progression of kidney dysfunction even within the normal range: The Yuport Health Checkup Center Cohort Study
Authors: Amano Hoichi , Yoshimura Kazunobu , Iijima Ryutaro , Waki Kaito , Matsumoto Keisei , Ueda Hitomi , Ito Yasuko , Miyamoto Ken , Akimoto Kimihiko , Yokoo Takashi , Inoue Kazuo , Terawaki Hiroyuki
Published: May 2019

Objective

A low-normal albumin level is associated with a high risk of cardiovascular disease and mortality in the general population. However, the relationship between serum albumin level and future decline of kidney function is unclear. We aimed to clarify the effect of serum albumin level on the decline of kidney function in the general population.

Methods

The data used were from 11,000 participants of a voluntary health checkup program between 1998 and 2006 conducted in Japan. The primary outcome for kidney function was a difference in estimated glomerular filtration rate (ΔeGFR) of ≥3 mL/min/1.73 m2/year. The association of the risk of decreased kidney function with albumin level was determined using a logistic regression analysis. We fit separate multivariable logistic regressions for serum albumin levels (g/dL) as a continuous variable and as categorical data, classified as ≤4.3 (n=2,530), 4.4– 4.6 (n=5,427), and ≥4.7 (n=3,043).

Results

Of 11,000 participants, 346 had a ΔeGFR/year of ≥3. As compared with the participants with albumin levels of ≥4.7 g/dL, the risk of decline in kidney function was higher not only in those with albumin levels of ≤4.3 g/dL (adjusted OR = 2,29, 95% CI: 1.65–3.18) but also in 4.4-4.6 g/dL (adjusted OR = 1.60, 95% CI: 1.20–2.14).

Conclusion

Decreased albumin level is an independent risk factor for rapid decline in kidney function even within the normal range.
Accuracy of somatic variant detection in multiregional tumor sequencing data
Authors: Detering Harald , Tomás Laura , Prieto Tamara , Posada David
Published: May 2019

Multiregional bulk sequencing data is necessary to characterize intratumor genetic heterogeneity. Novel somatic variant calling approaches aim to address the particular characteristics of multiregional data, but it remains unclear to which extent they improve compared to single-sample strategies. Here we compared the performance of 16 single-nucleotide variant calling approaches on multiregional sequencing data under different scenarios with in-silico and real sequencing reads, including varying sequencing coverage and increasing levels of spatial clonal admixture. Under the conditions simulated, methods that use information across multiple samples do not necessarily perform better than some of the standard calling methods that work sample by sample. Nonetheless, our results indicate that under difficult conditions, Mutect2 in multisample mode, in combination with a correction step, seems to perform best. Our analysis provides data-driven guidance for users and developers of somatic variant calling tools.
Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells
Authors: Peereboom David M. , Alban Tyler J. , Grabowski Matthew M. , Alvarado Alvaro G. , Otvos Balint , Bayik Defne , Roversi Gustavo , McGraw Mary , Huang Pengjing , Mohammadi Alireza M. , Kornblum Harley I. , Ahluwalia Manmeet S. , Vogelbaum Michael A. , Lathia Justin D.
Published: May 2019

Background

Myeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.

Methods

A phase 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to surgery with low-dose chemotherapy via capecitabine followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight.

Results

A total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid, with a progression-free survival of 5.8 months (range of 1.8-27.8 months) and an overall survival of 11.5 months (range of 3->28.0 months) from trial enrollment. No serious adverse events related to the drug combination were observed. Compared to pre-treatment baseline, circulating MDSCs were found to be higher after surgery in the 150 mg treatment arm and lower in the 300 mg and 450 mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared to untreated GBM patients in the 300 mg and 450 mg treatment arms.

Conclusions

Low-dose, metronomic capecitabine in combination with bevacizumab is well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.

Trial registration

NCT02669173

Funding

This research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, Musella Foundation, and B*CURED. Capecitabine was provided in kind by Mylan Pharmaceuticals.
IF3 licenses newly made 30S subunits for translation during stress
Authors: Sharma Indra Mani , Woodson Sarah A.
Published: May 2019

Bacterial ribosome biogenesis and translation occur in the same cellular compartment. Therefore, a biochemical gate-keeping step is required to prevent immature ribosomes from engaging in protein synthesis. Here, we show that the abundant ribosome assembly factor, RbfA, creates this checkpoint by suppressing protein synthesis by immatureE. coli30S subunits. After 30S maturation, RbfA is released by initiation factor 3 (IF3), which remains bound to 30S subunits to promote translation initiation. Genetic interactions between RbfA and IF3 show that IF3 is important for RbfA release during logarithmic growth. Moreover, IF3 is the main pathway for RbfA release in stationary phase when the activity of a less abundant RbfA-release factor, RsgA GTPase, is inhibited by the alarmone (p)ppGpp. By gating the transition from 30S biogenesis to translation initiation, RbfA and IF3 maintain the integrity of bacterial protein synthesis under a range of growth conditions and especially under stress.
Modeling pupil responses to rapid sequential events
Authors: Denison Rachel N. , Parker Jacob A. , Carrasco Marisa
Published: May 2019

Pupil size is an easily accessible, noninvasive online indicator of various perceptual and cognitive processes. Pupil measurements have the potential to reveal continuous processing dynamics throughout an experimental trial, including anticipatory responses. However, the relatively sluggish (∼2 s) response dynamics of pupil dilation make it challenging to connect changes in pupil size to events occurring close together in time. Researchers have used models to link changes in pupil size to specific trial events, but such methods have not been systematically evaluated. Here we developed and evaluated a general linear model (GLM) pipeline that estimates pupillary responses to multiple rapid events within an experimental trial. We evaluated the modeling approach using a sample dataset in which multiple sequential stimuli were presented within 2-s trials. We found: (1) Model fits improved when the pupil impulse response function (puRF) was fit for each observer. PuRFs varied substantially across individuals but were consistent for each individual. (2) Model fits also improved when pupil responses were not assumed to occur simultaneously with their associated trial events, but could have non-zero latencies. For example, pupil responses could anticipate predictable trial events. (3) Parameter recovery confirmed the validity of the fitting procedures, and we quantified the reliability of the parameter estimates for our sample dataset. (4) A cognitive task manipulation modulated pupil response amplitude. We provide our pupil analysis pipeline as open-source software (Pupil Response Estimation Toolbox: PRET) to facilitate the estimation of pupil responses and the evaluation of the estimates in other datasets.
The human gut virome database
Authors: Gregory Ann C. , Zablocki Olivier , Howell Allison , Bolduc Benjamin , Sullivan Matthew B.
Published: May 2019

The gut microbiome profoundly impacts human health and disease, but viruses that infect these microbes are likely also important. Problematically, viral sequences are often missed due to insufficient reference viral genomes. Here we (i) built a human gut virome database, GVD, from 648 viral particle metagenomes or microbial metagenomes from 572 individuals previously searched for viruses, (ii) assessed its effectiveness, and (iii) conducted meta-analyses. GVD contains 13,203 unique viral populations (approximately species-level taxa) organized into 702 novel genera, which roughly doubles known phage genera and improves viral detection rates over NCBI viral RefSeq nearly 60-fold. Applying GVD, we assessed and rejected the idea of a ‘core’ gut virome in healthy individuals, and found through meta-analyses that technical artifacts are more impactful than any ‘treatment’ effect across the entire meta-study dataset. Together, this foundational resource and these findings will help human microbiome researchers better identify viral roles in health and disease.
Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain
Authors: Oliva Idaira , Donate Melissa M. , Lefner Merridee J. , Wanat Matthew J.
Published: May 2019

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). For example, acute stress engages CRF signaling in the VTA to suppress the motivation to work for food rewards and promote drug seeking behavior. These diverging behavioral effects in food- and drug-based tasks could indicate that CRF modulates goal-directed actions in a reinforcer-specific manner. Alternatively, prior drug experience could functionally alter how CRF in the VTA regulates dopamine-dependent behavior. To address these possibilities, we examined how intra-VTA injections of CRF influenced cocaine intake and whether prior drug experience alters how CRF modulates the motivation for food rewards. Our results demonstrate that intra-VTA injections of CRF had no effect on drug intake when self-administering cocaine under a progressive ratio reinforcement schedule. We also found that a prior history of either contingent or non-contingent cocaine infusions abolished the capacity for CRF to reduce the motivation for food rewards. Furthermore, voltammetry recordings in the nucleus accumbens illustrate that CRF in the VTA had no effect on cocaine-evoked dopamine release. These results collectively illustrate that exposure to abused substances functionally alters how neuropeptides act within the VTA to influence motivated behavior.
Let-7miRNAs control auditory sensory progenitor behavior in the vertebrate inner ear
Authors: Evsen Lale , Zhang Shuran , Doetzlhofer Angelika
Published: May 2019

The evolutionary conserved lethal-7 (let-7) family of microRNAs (miRNAs) is a well-known activator of terminal mitosis and differentiation. Surprisingly, we previously found that overexpression oflet-7miRNAs in the murine auditory organ accelerated the terminal mitosis of auditory sensory progenitors (pro-sensory cells) but failed to stimulate their differentiation into mechano-sensory hair cells (HCs). To further address the role oflet-7miRNAs in auditory sensory differentiation, we conducted gain and loss of function experiments in the developing chicken auditory organ, the basilar papilla (BP). Using a sponge approach, we show that the disruption oflet-7miRNA function in the developing BP delays pro-sensory cell exit and delays differentiation of auditory HCs, revealing that endogenouslet-7miRNAs limit pro-sensory cell self-renewal in the developing BP. However, consistent with the role oflet-7miRNAs in the murine auditory organ,let-7boverexpression in the developing BP delayed HC differentiation, suggesting that too low or too highlet-7miRNA levels disrupt HC differentiation. Furthermore, we provide evidence that the repressive role oflet-7miRNAs in HC differentiation may be due to its targeting of the chromatin remodeler CHD7. Mutation in the humanCHD7gene causes CHARGE syndrome, which amongst others is characterized by inner ear and hearing deficits. Using target prediction algorithms, we uncovered a highly predictive and evolutionary conservedlet-7binding site within theChd7transcript. Consistent with being a target oflet-7repression, we demonstrate thatlet-7boverexpression significantly reduced CHD7 protein expression in to the developing BP. Furthermore, utilizing an induciblelet-7gtransgenic mouse model, we show thatlet-7miRNAs negatively regulate CHD7 protein expression in developing murine cochlear, retinal and brain tissue. CHD7 is dosage dependent and the here described regulation bylet-7miRNAs may be critical to fine tune CHD7 protein levels during sensory and neuronal development.

SIGNIFICANCE

The evolutionary highly conservedlet-7miRNAs are essential for proper timing of cell state transitions during embryogenesis. Even though abundantly expressed in the vertebrate auditory organ, surprisingly little is known about their function in auditory sensory differentiation. Here, we demonstrate that endogenouslet-7miRNAs are essential for limiting auditory sensory progenitor (pro-sensory) cell self-renewal. Furthermore, we find that precociouslet-7miRNAs expression interferes with auditory hair cell differentiation and identify chromatin remodeler CHD7 as a potential target gene oflet-7repressive function in HC differentiation.
Conservation and Divergence of Related Neuronal Lineages in theDrosophilaCentral Brain
Authors: Lee Ying-Jou , Yang Ching-Po , Huang Yu-Fen , He Yisheng , Ren Qingzhong , Chen Hui-Min , Miyares Rosa Linda , Otsuna Hideo , Aso Yoshi , Ito Kei , Lee Tzumin
Published: May 2019

Wiring a complex brain requires enormous cell specificity. This specificity is laid out via a developmental process where neural stem cells produce countless diverse neurons. To help elucidate this process and resolve the considerable dynamic specificity, we need to observe the development of multiple neuronal lineages.Drosophilacentral brain lineages are predetermined, comprised of a fixed set of neurons born in pairs in a specific order. To reveal specific roles of lineage identity, Notch-dependent sister fate specification, and temporal patterning in morphological diversification, we mapped approximately one quarter of theDrosophilacentral brain lineages. While we found large aggregate differences, we also discovered similar patterns of morphological specification and diversification. Lineage identity plus Notch state govern primary neuronal trajectories, whereas temporal fates diversify terminal elaborations in target-specific manners. In addition, we identified ‘related’ lineages of analogous neuron types produced in similar temporal patterns. Two stem cells even yield identical series of dopaminergic neuron types, but with completely disparate sister neurons. These phenomena suggest that large changes in morphological diversity can be the consequence of relatively small differences in lineage fating. Taken together, this large-scale lineage mapping study reveals that relatively simple rules drive incredible neuronal complexity.
Microbiome data enhances predictive models of lung function in people with cystic fibrosis
Authors: Zhao Conan Y. , Hao Yiqi , Wang Yifei , Varga John J. , Stecenko Arlene A. , Goldberg Joanna B. , Brown Sam P.
Published: May 2019

Background

Microbiome sequencing has brought increasing attention to the polymicrobial context of chronic infections. However, clinical microbiology continues to focus on canonical human pathogens, which may overlook informative, but non-pathogenic, biomarkers. We address this disconnect in lung infections in people with cystic fibrosis (CF).

Methods

We collected health information (lung function, age, BMI) and sputum samples from a cohort of 77 children and adults with CF. Samples were collected during a period of clinical stability and 16S rDNA sequenced for airway microbiome compositions. We use Elastic Net regularization to train linear models predicting lung function and extract the most informative features.

Results

Models trained on whole microbiome quantitation outperform models trained on pathogen quantitation alone, with or without the inclusion of patient metadata. Our most accurate models retain key pathogens as negative predictors (Pseudomonas, Achromobacter) along with established correlates of CF disease state (age, BMI, CF related diabetes). In addition, our models select non-pathogen taxa (Fusobacterium, Rothia) as positive predictors of lung health.

Conclusions

These results support a reconsideration of clinical microbiology pipelines to ensure the provision of informative data to guide clinical practice.
Reconstructing the blood metabolome and genotype using long-range chromatin interactions
Authors: Fadason Tayaza , Schierding William , Kolbenev Nikolai , Liu Jiamou , Ingram John , O’Sullivan Justin M.
Published: May 2019

The mechanisms of metabolism comprise a large number of biochemical pathways with a myriad of poorly characterised genetic influences. In this study, we perform a systematic integration of chromatin interaction (Hi-C), expression quantitative trait loci (eQTL), gene ontology, drug interaction, and literature-supported connections to deconvolute the genetic regulatory influences of 145 blood metabolite-associated single nucleotide polymorphisms (SNPs). We identify 577 genes that are regulated via chromatin looping to 130 distal and proximal SNPs across 48 different human tissues. The affected genes are enriched in categories that include metabolism, enzymes, plasma proteins, disease development, and potential drug targets. These novel SNP-gene-metabolite associations are a valuable resource for understanding the molecular mechanisms guiding pathologic metabolite levels in human tissues, and for further investigation into disease diagnosis and therapy.
Marine Cyanobacteria Tune Energy Transfer Efficiency in their Light-harvesting Antennae by Modifying Pigment Coupling
Authors: Kolodny Yuval , Zer Hagit , Propper Mor , Yochelis Shira , Paltiel Yossi , Keren Nir
Published: May 2019

Photosynthetic organisms regulate energy transfer to fit to changes in environmental conditions. The biophysical principles underlying the flexibility and efficiency of energy transfer in the light-harvesting process are still not fully understood. Here we examine how energy transfer is regulatedin-vivo. We compare different acclimation states of the photosynthetic apparatus in a marine cyanobacterial species that is well adapted to vertical mixing of the ocean water column and identify a novel acclimation strategy for photosynthetic life under low light intensities. Antennae rods extend, as expected, increasing light absorption. Surprisingly, in contrast to what was known for plants and predicted by classic calculations, these longer rods transfer energy fasteri.e.more efficiently. The fluorescence lifetime and emission spectra dependence on temperature, at the range of 4-300K, suggests that energy transfer efficiency is tuned by modifying the energetic coupling strength between antennae pigments.
RintC: fast and accuracy-aware decomposition of distributions of RNA secondary structures with extended logsumexp
Authors: Takizawa Hiroki , Iwakiri Junichi , Asai Kiyoshi
Published: May 2019

The analysis of secondary structures is essential to understanding the function of RNAs. Because RNA molecules thermally fluctuate, it is necessary to analyze the probability distribution of secondary structures. Existing methods, however, are not applicable to long RNAs owing to their high computational complexity. Additionally, previous research has suffered from two numerical difficulties: overflow and significant numerical error. In this research, we reduced the computational complexity in calculating the landscape of the probability distribution of secondary structures by introducing a maximum-span constraint. In addition, we resolved numerical computation problems through two techniques: extended logsumexp and accuracy-guaranteed numerical computation. We analyzed the stability of the secondary structures of 16S ribosomal RNAs at various temperatures without overflow. The results obtained are consistent with in vivo assay results reported in previous research. Furthermore, we quantitatively assessed numerical stability using our method. These results demonstrate that the proposed method is applicable to long RNAs. Source code is available on https://github.com/eukaryo/rintc.
White matter alterations in autism spectrum disorder and attention-deficit/hyperactivity disorder in relation to sensory profile
Authors: Ohta Haruhisa , Aoki Yuta , Itahashi Takashi , Kanai Chieko , Fujino Junya , Nakamura Motoaki , Kato Nobumasa , Hashimoto Ryu-ichiro
Published: May 2019

Background

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) have high rates of co-occurrence and share atypical behavioral characteristics, including sensory problems. The present diffusion tensor imaging (DTI) study was conducted to examine whether and how white matter abnormalities are observed in adult populations with developmental disabilities (DD) and to determine how brain-sensory relationships are either shared between or distinct to ASD and ADHD.

Methods

We collected DTI data from adult developmental disorder (DD) populations (a primary diagnosis of ASD: n=105, ADHD: n=55) as well as age and sex matched typically developed (TD) participants (n=58). Voxel-wise fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD) were analyzed using tract-based spatial statistics. The severities of sensory problems were assessed using the Adolescent/Adult Sensory Profile (AASP).

Results

Categorical analyses identified voxel clusters showing significant effects of DD on FA and RD in the posterior portion of the corpus callosum and its extension in the right hemisphere. Furthermore, regression analyses using the AASP scores revealed that slopes in relationships of FA or RD with the degree of sensory problems were parallel between the two DDs in large parts of the affected corpus callosum regions, although a small but significant cluster did exist showing interaction between the diagnosis of DD and an AASP subscale score on RD.

Conclusions

These results indicate that white matter abnormalities and their relationships to sensory problems are largely shared between ASD and ADHD, with localized abnormalities showing significant between-diagnosis differences within DD. (247 words)
Effects of rocuronium, sugammadex and rocuronium-sugammadex complex on coagulation in rats
Authors: Cavalcanti Ismar L. , Schanaider Alberto , Barrucand Louis , Braga Estêvão L. C. , Verçosa Nubia , de Boer Hans D. , Vane Luiz A.
Published: May 2019

Background

Sugammadex is an alternative pharmacological drug that is capable of reversing neuromuscular blockades without the limitations that are presented by anticholinesterase drugs. Coagulation disorders that are related to treatment with sugammadex were reported. The exact mechanism of the effects on coagulation are not fully understood.

Objective

To evaluate the effects of rocuronium, sugammadex and the rocuronium-sugammadex complex on coagulation in an experimental model in rats.

Design

An experimental randomized animal study.

Setting

An experimental unit at the State University of São Paulo (UNESP), Botucatu, SP, Brazil.

Interventions

Wistar rats were randomly assigned into the following groups: the Control group; the Ssal Group – 0.5 mL of intravenous saline; the Sugammadex group – intravenous sugammadex (100 mg/kg); and the Rocuronium-Sugammadex group – intravenous solution with rocuronium (3.75 mg/kg) and sugammadex (100 mg/kg). Anaesthesia was performed by using isoflurane with controlled ventilation.

Main outcome measures

Coagulation factors were measured 10 minutes after the end of the preoperative preparation and 30 minutes after the administration of the drugs in accordance with the chosen groups.

Results

Platelet counts, prothrombin times and activated partial thromboplastin times were similar between the groups and between the moments within each group. There were reductions in the plasma fibrinogen levels between sample times 1 and 2 in the Rocuronium-Sugammadex group (P = 0,035).

Conclusion

The rocuronium-sugammadex complex promoted reductions in plasma fibrinogen counts, although the levels were still within normal limits.