bluuebunny/crossref_metadata_2025 huggingface dataset:
The Human Posterior Superior Temporal Sulcus Samples Visual Space Differently From Other Face-Selective Regions
Authors: Pitcher David , Pilkington Amy , Rauth Lionel , Baker Chris , Kravitz Dwight J , Ungerleider Leslie G
Published: May 2019

Neuroimaging studies show that ventral face-selective regions, including the fusiform face area (FFA) and occipital face area (OFA), preferentially respond to faces presented in the contralateral visual field (VF). In the current study we measured the VF response of the face-selective posterior superior temporal sulcus (pSTS). Across 3 functional magnetic resonance imaging experiments, participants viewed face videos presented in different parts of the VF. Consistent with prior results, we observed a contralateral VF bias in bilateral FFA, right OFA (rOFA), and bilateral human motion-selective area MT+. Intriguingly, this contralateral VF bias was absent in the bilateral pSTS. We then delivered transcranial magnetic stimulation (TMS) over right pSTS (rpSTS) and rOFA, while participants matched facial expressions in both hemifields. TMS delivered over the rpSTS disrupted performance in both hemifields, but TMS delivered over the rOFA disrupted performance in the contralateral hemifield only. These converging results demonstrate that the contralateral bias for faces observed in ventral face-selective areas is absent in the pSTS. This difference in VF response is consistent with face processing models proposing 2 functionally distinct pathways. It further suggests that these models should account for differences in interhemispheric connections between the face-selective areas across these 2 pathways.
Estienne Roger and his agent Adam Christoph Sellius: new light on Italian and French music in Bach’s world
Authors: Górny Tomasz
Published: May 2019

The article opens with a discussion of the Italian and Italianate concertos that Johann Sebastian Bach transcribed for the organ and harpsichord (bwv592–96, bwv972–87). Hans-Joachim Schulze has suggested that Bach encountered these Italian instrumental works as a result of a trip by Prince Johann Ernst of Saxe-Weimar to the Netherlands. This article suggests an alternative route for Bach to have gained copies of Italian concertos, namely via the Halle and Leipzig bookseller Adam Christoph Sellius. He traded in sheet music published by Estienne Roger in Amsterdam and also in French printed music, probably imported through his contacts in the Netherlands.
Combing Transcriptomes for Secrets of Deep-Sea Survival: Environmental Diversity Drives Patterns of Protein Evolution
Authors: Winnikoff J R , Francis W R , Thuesen E V , Haddock S H D
Published: May 2019

Ctenophores, also known as comb jellies, live across extremely broad ranges of temperature and hydrostatic pressure in the ocean. Because various ctenophore lineages adapted independently to similar environmental conditions, Phylum Ctenophora is an ideal system for the study of protein adaptation to extreme environments in a comparative framework. We present such a study here, using a phylogenetically-informed method to compare sequences of four essential metabolic enzymes across gradients of habitat depth and temperature. This method predicts convergent adaptation to these environmental parameters at the amino acid level, providing a novel view of protein adaptation to extreme environments and demonstrating the power and relevance of phylogenetic comparison applied to multi-species transcriptomic datasets from early-diverging metazoa. Across all four enzymes analyzed, 46 amino acid sites were associated with depth-adaptation, 59 with temperature-adaptation, and 56 with both. Sites predicted to be depth- and temperature-adaptive occurred consistently near Rossmann fold cofactor binding motifs and disproportionately in solvent-exposed regions of the protein. These results suggest that the hydrophobic effect and ligand binding may mediate efficient enzyme function at different hydrostatic pressures and temperatures. Using predicted adaptive site maps, such mechanistic hypotheses can now be tested via mutagenesis.
Expressions of melanoma-associated antigen A1 as a prognostic factor in Chinese patients with resectable oesophageal squamous cell carcinoma
Authors: Yu Yue , Huang Chenjun , Li Zhihua , Zhao Fei , Zhou Yue , Li Jun , Zhu Chenxiang , Li Qifan , Zhuang Yu , Xu Jing , Luo Jinhua , Chen Liang , Wang Wei
Published: May 2019

OBJECTIVES

Melanoma-associated antigen A1 (MAGEA1) is a potential target for immunotherapy and has been associated with poor survival rate in several cancers. However, little is known about the prognostic predictive value of MAGEA1 in oesophageal squamous cell carcinoma (OSCC). This study aims to determine whether the expression of MAGEA1 is an independent predictor of survival in patients with resectable OSCC.

METHODS

A retrospective analysis was performed on a large cohort of 197 patients with OSCC who underwent radical surgical treatment in the Department of Thoracic Surgery between January 2006 and December 2012. The expression of MAGEA1 in OSCC and matched normal oesophageal mucosa specimens from these patients was detected by immunohistochemistry with tissue microarray technology.

RESULTS

The MAGEA1 protein was expressed in the cytoplasm and nucleus of tumour cells. The positive expression rate of MAGEA1 was significantly higher in OSCC tissue than in normal oesophageal mucosa (73.6% vs 5.6%, P < 0.001). MAGEA1 expression had no correlations with sex, age, history of smoking, alcohol consumption, family history of upper gastrointestinal cancer, T stage, lymph node metastasis, grade/location of the tumour or TNM stage (all at P > 0.05). Compared with those with negative MAGEA1 expression, patients with positive MAGEA1 expression were associated with a reduced overall survival rate (5-year survival rate: 53.8% vs 37.2%; P = 0.018). The multivariable analysis revealed that MAGEA1 expression is an independent predictor of prognosis (P = 0.007, hazard ratio 1.85, 95% confidence interval 1.19–2.89).

CONCLUSIONS

The expression of MAGEA1 is abundant in Chinese patients with OSCC and is related to a worse clinical outcome. MAGEA1 may be a useful prognostic factor in patients with resectable OSCC.
Cognitive Impairment That Is Induced by (R)-Ketamine Is Abolished in NMDA GluN2D Receptor Subunit Knockout Mice
Authors: Ide Soichiro , Ikekubo Yuiko , Mishina Masayoshi , Hashimoto Kenji , Ikeda Kazutaka
Published: May 2019

Although the N-methyl-D-aspartate receptor antagonist ketamine has attracted attention because of its rapid and sustained antidepressant effects in depressed patients, its side effects have raised some concerns. Ketamine is a racemic mixture of equal amounts of the enantiomers (R)-ketamine and (S)-ketamine. The neural mechanisms that underlie the differential effects of these enantiomers remain unclear. We investigated cognitive impairment that was induced by ketamine and its enantiomers in N-methyl-D-aspartate GluN2D receptor subunit knockout (GluN2D-KO) mice. In the novel object recognition test, (RS)-ketamine and (S)-ketamine caused cognitive impairment in both wild-type and GluN2D-KO mice, whereas (R)-ketamine induced such cognitive impairment only in wild-type mice. The present results suggest that the GluN2D subunit plays an important role in cognitive impairment that is induced by (R)-ketamine, whereas this subunit does not appear to be involved in cognitive impairment that is induced by (RS)-ketamine or (S)-ketamine.
Modeling and Predicting Developmental Trajectories of Neuropsychiatric Dimensions Associated With Copy Number Variations
Authors: Hiroi Noboru , Yamauchi Takahira
Published: May 2019

Copy number variants, such as duplications and hemizygous deletions at chromosomal loci of up to a few million base pairs, are highly associated with psychiatric disorders. Hemizygous deletions at human chromosome 22q11.2 were found to be associated with elevated instances of schizophrenia and autism spectrum disorder in 1992 and 2002, respectively. Following these discoveries, many mouse models have been developed and tested to analyze the effects of gene dose alterations in small chromosomal segments and single genes of 22q11.2. Despite several limitations to modeling mental illness in mice, mouse models have identified several genes on 22q11.2—Tbx1, Dgcr8, Comt, Sept5, and Prodh—that contribute to dimensions of autism spectrum disorder and schizophrenia, including working memory, social communication and interaction, and sensorimotor gating. Mouse studies have identified that heterozygous deletion of Tbx1 results in defective social communication during the neonatal period and social interaction deficits during adolescence/adulthood. Overexpression of Tbx1 or Comt in adult neural progenitor cells in the hippocampus delays the developmental maturation of working memory capacity. Collectively, mouse models of variants of these 4 genes have revealed several potential neuronal mechanisms underlying various aspects of psychiatric disorders, including adult neurogenesis, microRNA processing, catecholamine metabolism, and synaptic transmission. The validity of the mouse data would be ultimately tested when therapies or drugs based on such potential mechanisms are applied to humans.
Microbubble dynamics in a viscous compressible liquid near a rigid boundary
Authors: Wang Qianxi , Liu WenKe , Leppinen David M , Walmsley A D
Published: May 2019

This paper is concerned with microbubble dynamics in a viscous compressible liquid near a rigid boundary. The compressible effects are modelled using the weakly compressible theory of Wang & Blake (2010, Non-spherical bubble dynamics in a compressible liquid. Part 1. Travelling acoustic wave. J. Fluid Mech., 730, 245–272), since the Mach number associated is small. The viscous effects are approximated using the viscous potential flow theory of Joseph & Wang (2004, The dissipation approximation and viscous potential flow. J. Fluid Mech., 505, 365–377), because the flow field is characterized as being an irrotational flow in the bulk volume but with a thin viscous boundary layer at the bubble surface. Consequently, the phenomenon is modelled using the boundary integral method, in which the compressible and viscous effects are incorporated into the model through including corresponding additional terms in the far field condition and the dynamic boundary condition at the bubble surface, respectively. The numerical results are shown in good agreement with the Keller–Miksis equation, experiments and computations based on the Navier–Stokes equations. The bubble oscillation, topological transform, jet development and penetration through the bubble and the energy of the bubble system are simulated and analysed in terms of the compressible and viscous effects.
Newborn screening for sickle cell disease: an innovative pilot program to improve child survival in Dar es Salaam, Tanzania
Authors: Nkya Siana , Mtei Lillian , Soka Deogratias , Mdai Vera , Mwakale Promise B , Mrosso Paul , Mchoropa Issa , Rwezaula Stella , Azayo Mary , Ulenga Nzovu , Ngido Melkiory , Cox Sharon E , D’Mello Brenda S , Masanja Honorati , Kabadi Gregory S , Mbuya Frederick , Mmbando Bruno , Daniel Yvonne , Streetly Allison , Killewo Japhet , Tluway Furahini , Lyimo Magdalena , Makani Julie
Published: May 2019

Background

Sickle cell disease (SCD) is a recognized cause of childhood mortality. Tanzania has the fifth highest incidence of SCD (with an estimated 11 000 SCD annual births) worldwide. Although newborn screening (NBS) for SCD and comprehensive healthcare have been shown to reduce under-5 mortality by up to 94% in high-income countries such as the USA, no country in Africa has maintained NBS for SCD as a national health program. The aims of this program were to establish and evaluate NBS-SCD as a health intervention in Tanzania and to determine the birth prevalence of SCD.

Methods

Muhimbili University of Health and Allied Sciences conducted NBS for SCD from January 2015 to November 2016. Dried blood spot samples were collected and tested for SCD using isoelectric focusing.

Results

Screening was conducted on 3981 newborns. Thirty-one (0.8%) babies had SCD, 505 (12.6%) had sickle cell trait and 26 (0.7%) had other hemoglobinopathies. Twenty-eight (90.3%) of the 31 newborns with SCD were enrolled for comprehensive healthcare.

Conclusions

This is the first report on NBS as a health program for SCD in Tanzania. The SCD birth prevalence of 8 per 1000 births is of public health significance. It is therefore important to conduct NBS for SCD with enrollment into a comprehensive care program.
Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L)
Authors: Kimura Tatsuo , Kawaguchi Tomoya , Chiba Yasutaka , Yoshioka Hiroshige , Watanabe Katsuya , Kijima Takashi , Kogure Yoshihito , Oguri Tetsuya , Yoshimura Naruo , Niwa Takashi , Kasai Takashi , Hayashi Hidetoshi , Ono Akira , Asai Kazuhisa , Tanaka Hiroshi , Yano Seiji , Yamamoto Nobuyuki , Nakanishi Yoichi , Nakagawa Kazuhiko
Published: May 2019

Background

Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy.

Methods

This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2–16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients.

Results

In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2–32.1%) and 53.7% (95%CI: 37.4–69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1–4.5) and 11.3 (95%CI: 8.6–16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3–4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection.

Conclusions

Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.
Early positive effects of tree species richness on soil organic carbon accumulation in a large-scale forest biodiversity experiment
Authors: Li Yin , Bruelheide Helge , Scholten Thomas , Schmid Bernhard , Sun Zhenkai , Zhang Naili , Bu Wensheng , Liu Xiaojuan , Ma Keping
Published: May 2019

Aims

Tree species richness has been reported to have positive effects on aboveground biomass and productivity, but little is known about its effects on soil organic carbon (SOC) accumulation.

Methods

To close this gap, we made use of a large biodiversity–ecosystem functioning experiment in subtropical China (BEF-China) and tested whether tree species richness enhanced SOC accumulation. In 2010 and 2015, vertically layered soil samples were taken to a depth of 30 cm from 57 plots ranging in tree species richness from one to eight species. Least squares-based linear models and analysis of variance were used to investigate tree diversity effects. Structural equation modeling was used to explore hypothesized indirect relationships between tree species richness, leaf-litter biomass, leaf-litter carbon content, fine-root biomass and SOC accumulation.

Important Findings

Overall, SOC content decreased by 5.7 and 1.1 g C kg−1 in the top 0–5 and 5–10 cm soil depth, respectively, but increased by 1.0 and 1.5 g C kg−1 in the deeper 10–20 and 20–30 cm soil depth, respectively. Converting SOC content to SOC stocks using measures of soil bulk density showed that tree species richness did enhance SOC accumulation in the different soil depths. These effects could only to some extent be explained by leaf-litter biomass and not by fine-root biomass. Our findings suggest that carbon storage in new forests in China could be increased by planting more diverse stands, with the potential to contribute to mitigation of climate warming.
Evaluating VITEK MS for the identification of clinically relevant Aspergillus species
Authors: M Américo Fernanda , P Machado Siqueira Lumena , B Del Negro Gilda Maria , M Favero Gimenes Viviane , S Trindade Mario Roberto , L Motta Adriana , Santos de Freitas Roseli , Rossi Flavia , L Colombo Arnaldo , Benard Gil , N de Almeida Júnior João
Published: May 2019

Aspergillus spp. identification has become more relevant in clinical practice since azole-resistant cryptic species have been related to invasive fungal infections. Conventional morphologic identification is not able to discriminate Aspergillus species, and DNA sequencing is not feasible for clinical laboratories. MALDI-TOF mass spectrometry is an emergent technology that has been explored to provide fast and accurate identification of microorganisms, including clinically relevant moulds. However, only a few studies have explored the platform VITEK MS for the identification of Aspergillus species. Hence, we provided additional data regarding the performance of the VITEK MS system for the identification of Aspergillus species, including azole-resistant ones. We also improved the RUO system by adding additional spectral profiles from well-identified Aspergillus strains belonging to different noncryptic and cryptic species. The IVD library correctly identified 91.6% of the organisms at genus and section level, and 84.7% at species level, including the azole-resistant Aspergillus lentulus and Aspergillus calidoustus. The organisms belonging to Aspergillus cryptic species had only 31.2% of correct species identification. The RUO library plus our in-house SuperSpectra correctly identified 100% of the organisms at genus and section level and 91.6% at species level. Among organisms belonging to Aspergillus cryptic species, 68.7% had correct species identification. Some closely related Aspergillus cryptic species showed similar spectral profiles and were difficult to be differentiated.
Stochastic modelling of star-formation histories I: the scatter of the star-forming main sequence
Authors: Caplar Neven , Tacchella Sandro
Published: May 2019

We present a framework for modelling the star-formation histories of galaxies as a stochastic process. We define this stochastic process through a power spectrum density with a functional form of a broken power law. Star-formation histories are correlated on short time-scales, the strength of this correlation described by a power-law slope, α, and they decorrelate to resemble white noise over a time-scale that is proportional to the time-scale of the break in the power spectrum density, τbreak. We use this framework to explore the properties of the stochastic process that, we assume, gives rise to the log-normal scatter about the relationship between star-formation rate and stellar mass, the so-called galaxy star-forming main sequence. Specifically, we show how the measurements of the normalization and width (σMS) of the main sequence, measured in several passbands that probe different time-scales, give a constraint on the parameters of the underlying power spectrum density. We first derive these results analytically for a simplified case where we model observations by averaging over the recent star-formation history. We then run numerical simulations to find results for more realistic observational cases. As a proof of concept, we use observational estimates of the main sequence scatter at z ∼ 0 and M⋆ ≈ 1010 M⊙ measured in H α, UV+IR, and the u-band. The result is degenerate in the τbreak-α space, but if we assume α = 2, we measure $\tau _{\rm break}=170^{+169}_{-85}~\mathrm{Myr}$. This implies that star-formation histories of galaxies lose ‘memory’ of their previous activity on a time-scale of ∼200 Myr.
Massively parallel profiling and predictive modeling of the outcomes of CRISPR/Cas9-mediated double-strand break repair
Authors: Chen Wei , McKenna Aaron , Schreiber Jacob , Haeussler Maximilian , Yin Yi , Agarwal Vikram , Noble William Stafford , Shendure Jay
Published: May 2019

Non-homologous end-joining (NHEJ) plays an important role in double-strand break (DSB) repair of DNA. Recent studies have shown that the error patterns of NHEJ are strongly biased by sequence context, but these studies were based on relatively few templates. To investigate this more thoroughly, we systematically profiled ∼1.16 million independent mutational events resulting from CRISPR/Cas9-mediated cleavage and NHEJ-mediated DSB repair of 6872 synthetic target sequences, introduced into a human cell line via lentiviral infection. We find that: (i) insertions are dominated by 1 bp events templated by sequence immediately upstream of the cleavage site, (ii) deletions are predominantly associated with microhomology and (iii) targets exhibit variable but reproducible diversity with respect to the number and relative frequency of the mutational outcomes to which they give rise. From these data, we trained a model that uses local sequence context to predict the distribution of mutational outcomes. Exploiting the bias of NHEJ outcomes towards microhomology mediated events, we demonstrate the programming of deletion patterns by introducing microhomology to specific locations in the vicinity of the DSB site. We anticipate that our results will inform investigations of DSB repair mechanisms as well as the design of CRISPR/Cas9 experiments for diverse applications including genome-wide screens, gene therapy, lineage tracing and molecular recording.
Effect of Mass Artesunate-Amodiaquine Distribution on Mortality of Patients With Ebola Virus Disease During West African Outbreak
Authors: Garbern Stephanie C , Yam Derrick , Aluisio Adam R , Cho Daniel K , Kennedy Stephen B , Massaquoi Moses , Sahr Foday , Perera Shiromi M , Levine Adam C , Liu Tao
Published: May 2019

Background

Experiments in vitro have shown that the drug amodiaquine may inhibit Ebola virus activity. During the Ebola virus disease (EVD) epidemic in West Africa in 2014–2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. The objective of this study was to assess the effect of the ASAQ MDAs on the mortality of patients with EVD.

Methods

A retrospective cohort design was used to analyze mortality data for patients with EVD admitted to 5 Ebola treatment units in Liberia and Sierra Leone. Patients admitted to the ETUs during the time period of ASAQ’s therapeutic effect from areas where the MDA was implemented were matched to controls not exposed to ASAQ, using a range of covariates, including malaria co-infection status, and a logistic regression analysis was performed. The primary outcome was Ebola treatment unit mortality.

Results

A total of 424 patients with EVD had sufficient data for analysis. Overall, the mortality of EVD patients was 57.5%. A total of 22 EVD patients were exposed to ASAQ during the MDAs and were found to have decreased risk of death compared with those not exposed in a matched analysis, but this did not reach statistical significance (relative risk, 0.63; 95% confidence interval, 0.37–1.07; P = .086).

Conclusions

There was a non–statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Further prospective trials are needed to determine the direct effect of ASAQ on EVD mortality.
Conclusion: Natural Resource Justice and Climate Change
Authors: Blomfield Megan
Published: May 2019

This chapter summarizes the argument of the work. It situates the conception of natural resource justice that has been defended between the (egalitarian) principle of equal division and the (statist) principle of resource sovereignty. As an interpretation of relational egalitarianism concerning natural resources, the view is shown to avoid three of the most common objections to global egalitarianism. This is because the view is compatible with collective self-determination, protects cultural diversity, and avoids the metric problem. The chapter concludes that the method of partial integrationism adopted in the work, considering questions of climate justice by reference to a conception of justice for natural resources alone, has been productive. A remaining task is to integrate this conception of natural resource justice with a more general theory of global justice, encompassing other important goods, institutions, practices, and relations.
Why should a non-profit organization be attractive for an investor?
Authors: Specht Keno
Published: May 2019

Should an investor invest in a non-profit organization? The question seems odd. Discussing that topic, the author shows how SOS Children’s Villages International started to measure the impact of their work and what they learned from it—for their programmes and for the society of the future—and why this question is—in the end—a sustainable base for an investment decision.
Soil moisture regime and palm height influence embolism resistance in oil palm
Authors: Waite Pierre-André , Schuldt Bernhard , Mathias Link Roman , Breidenbach Natalie , Triadiati Triadiati , Hennings Nina , Saad Asmadi , Leuschner Christoph
Published: May 2019

With the prospect of climate change and more frequent El Niño-related dry spells, the drought tolerance of oil palm (Elaeis guineensis Jacq.), one of the most important tropical crop species, is of major concern. We studied the influence of soil water availability and palm height on the plasticity of xylem anatomy of oil palm fronds and their embolism resistance at well-drained and seasonally flooded riparian sites in lowland Sumatra, Indonesia. We found overall mean P12 and P50 values, i.e., the xylem pressures at 12% or 50% loss of hydraulic conductance, of −1.05 and − 1.86 MPa, respectively, indicating a rather vulnerable frond xylem of oil palm. This matches diurnal courses of stomatal conductance, which in combination with the observed low xylem safety evidence a sensitive water loss regulation. While the xylem anatomical traits vessel diameter (Dh), vessel density and potential hydraulic conductivity (Kp) were not different between the sites, palms in the moister riparian plots had on average by 0.4 MPa higher P50 values than plants in the well-drained plots. This could largely be attributed to differences in palm height between systems. As a consequence, palms of equal height had 1.3 MPa less negative P50 values in the moister riparian plots than in the well-drained plots. While palm height was positively related to P50, Dh and Kp decreased with height. The high plasticity in embolism resistance may be an element of the drought response strategy of oil palm, which, as a monocot, has a relatively deterministic hydraulic architecture. We conclude that oil palm fronds develop a vulnerable water transport system, which may expose the palms to increasing drought stress in a warmer and drier climate. However, the risk of hydraulic failure may be reduced by considerable plasticity in the hydraulic system and the environmental control of embolism resistance, and a presumably large stem capacitance.
Expected and observed genotype complexity in prokaryotes: correlation between 16S-rRNA phylogeny and protein domain content
Authors: Koehorst Jasper J. , Saccenti Edoardo , dos Santos Vitor Martins , Suarez-Diez Maria , Schaap Peter J.
Published: May 2019

Background

The omnipresent 16S ribosomal RNA gene (16S-rRNA) is commonly used to identify and classify bacteria though it does not take into account the distinctive functional characteristics of taxa. We explored functional domain landscapes of over 5700 complete bacterial genomes, representing a wide coverage of the bacterial tree of life, and investigated to what extent the observed protein domain diversity correlates with the expected evolutionary diversity, using 16S-rRNA as metric for evolutionary distance.

Results

Analysis of protein domains showed that 83% of the bacterial genes code for at least one of the 9722 domain classes identified. By comparing clade specific and global persistence scores, candidate horizontal gene transfer and signifying domains could be identified. 16S-rRNA and functional domain content distances were used to evaluate and compare species divergence and overall a sigmoid curve is observed. Already at close 16S-rRNA evolutionary distances, high levels of functional diversity can be observed. At a larger 16S-rRNA distance, functional differences accumulate at a relatively lower pace.

Conclusions

Analysis of 16S-rRNA sequences in the same taxa suggests that, in many cases, additional means of classification are required to obtain reliable phylogenetic relationships. Whole genome protein domain class phylogenies correlate with, and complement 16S-rRNA sequence-based phylogenies. Moreover, domain-based phylogenies can be constructed over large evolutionary distances and provide an in-depth insight of the functional diversity within and among species and enables large scale functional comparisons. The increased granularity obtained paves way for new applications to better predict the relationships between genotype, physiology and ecology.
The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix
Authors: Lin Ku-Feng , Fry Michelle Y. , Saladi Shyam M. , Clemons William M.
Published: May 2019

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins.
Seasonal microbial dynamics on grapevine leaves under biocontrol and copper fungicide treatments
Authors: Alex Gobbi , Ifigeneia Kyrkou , Elisa Filippi , Lea Ellegaard-Jensen , Hestbjerg Hansen Lars
Published: May 2019

Winemakers have long used copper as a fungicide on grapevine. However, the potential of copper to accumulate on soil and affect the biota poses a challenge to achieving sustainable agriculture. One recently developed option is the use of biocontrol agents to replace or complement traditional methods. In the present study, a field experiment was conducted in South Africa in which the leaves in two blocks of a vineyard were periodically treated with either copper sulphate or sprayed withLactobacillus plantarumMW-1 as a biocontrol agent. This study evaluated the impact of the two treatments on the bacterial and fungal communities as they changed during the growing season. To do this, NGS was combined with quantitative strain-specific and community qPCRs. The results revealed the progression of the microbial communities throughout the season and how the different treatments affected the microbiota. Bacteria appeared to be relatively stable at the different time points, with the only taxa that systematically changed between treatments beingLactobacillaceae, which included reads from the biocontrol agent. Cells ofLactobacillus plantarumMW-1 were only detected on treated leaves using strain-specific qPCR, with its amount spanning from 103to 105cells/leaves. Conversely the fungal community was largely shaped by a succession of different dominant taxa over the months. Between treatments, only a few fungal taxa appeared to change significantly and the number of ITS copies was also comparable. In this regards, the two treatments seemed to affect the microbial community similarly, revealing the potential of this biocontrol strain as a promising alternative among sustainable fungicide treatments, although further investigation is required.
Analysis of the expression of PIWI-interacting RNAs during cardiac differentiation of human pluripotent stem cells
Authors: La Greca Alejandro , Scarafía María Agustina , Cañás María Clara Hernández , Pérez Nelba , Castañeda Sheila , Colli Carolina , Möbbs Alan Miqueas , Velazque Natalia Lucía Santín , Neiman Gabriel , Garate Ximena , Aban Cyntia , Waisman Ariel , Moro Lucía , Sevlever Gustavo , Luzzani Carlos , Miriuka Santiago
Published: May 2019

PIWI-interacting RNAs (piRNAs) are a class of non-coding RNAs initially thought to be restricted almost exclusively to germ line cells. In recent years, accumulating evidence has demonstrated that piRNAs are actually expressed in somatic cells like pluripotent, neural, cardiac and even cancer cells. However, controversy still remains around the existence and function of somatic piRNAs. Using small RNA-seq samples from H9 pluripotent stem cells differentiated to mesoderm progenitors and cardiomyocytes we identified the expression of 447 piRNAs, of which 241 were detected in pluripotency, 218 in mesoderm and 171 in cardiac cells. The majority of them originated from the sense strand of protein coding and lncRNAs genes in all stages of differentiation, though no evidences for secondary piRNAs (ping-pong loop) were found. Genes hosting piRNAs in cardiac samples were related to critical biological processes in the heart, like contraction and cardiac muscle development. Our results indicate that somatic piRNAs might have a role in fine-tuning the expression of genes involved in the differentiation of pluripotent cells to cardiomyocytes.
The first functional characterization of ancient interleukin-15-like (IL-15L) reveals shared and distinct functions of the IL-2, -15 and -15L family cytokines
Authors: Yamaguchi Takuya , Karger Axel , Keller Markus , Wangkahart Eakapol , Wang Tiehui , Secombes Christopher J. , Kimoto Azusa , Furihata Mitsuru , Hashimoto Keiichiro , Fischer Uwe , Dijkstra Johannes M.
Published: May 2019

The ancient cytokine interleukin 15-like (IL-15L) was lost in humans and mice but not throughout mammals. This is the first study to describe IL-15L functions, namely in the fish rainbow trout. Fish have only one α-chain receptor geneIL-15Rα, whereas in mammalian evolution this gene duplicated and evolved intoIL-15RαplusIL-2Rα. Trout IL-2, IL-15 and IL-15L all could bind IL-15Rα and were able to induce phosphorylation of transcription factor STAT5. Reminiscent of the mammalian situation, trout IL-15 was more dependent on “intrans” presentation by IL-15Rα than IL-2. However, whereas trout IL-15 could also function as a free cytokine as known for mammalian IL-15, trout IL-15L function showed a total dependency on intranspresentation by IL-15Rα. Trout lymphocytes from the mucosal tissues gill and intestine were sensitive to IL-15, but refractory to IL-2 and IL-15L, which is reminiscent of sensitivities to IL-15 in mammals. Distinguishing engagement of the IL-2Rα/IL-15Rα receptor chain may explain why IL-2 and IL-15 were selected in evolution as major growth factors for regulatory T cells and lymphocytes in mucosal tissues, respectively. Trout IL-15L efficiently induced expression ofIL-4andIL-13homologues in CD4-CD8-IgM-splenocytes, and we speculate that the responsive cells within that population were type 2 innate lymphoid cells (ILC2). In contrast, trout IL-15 efficiently induced expression ofinterferon γandperforinin CD4-CD8-IgM-splenocytes, and we speculate that in this case the responsive cells were natural killer (NK) cells. In fish, in apparent absence of IL-25, IL-33 and TSLP, primitive IL-15L may have an important role early in the type 2 immunity cytokine cascade. Among trout thymocytes, only CD4-CD8-thymocytes were sensitive to IL-15L, and different than in mammals the CD4+CD8+thymocytes were quite sensitive to IL-2. In addition, the present study provides (i) the first molecular evidence for inter-species cytokine with receptor chain interaction across fish-mammal borders, and (ii) suggestive evidence for a tendency of IL-2/15/15L cytokines to form homodimers as an ancient family trait. This is the first comprehensive study on IL-2/15/15L functions in fish and it provides important insights into the evolution of this cytokine family.
A universal method for gene expression engineering
Authors: Lale Rahmi , Tietze Lisa , Nesje Jenny , Onsager Ingerid , Engelhardt Kerstin , Wong Che Fai Alex , Akan Madina , Hummel Niklas , Kalinowski Jörn , Rückert Christian , Hohmann-Marriott Martin Frank
Published: May 2019

The precise expression of genes is one of the foundations of biotechnology. Here we present GeneEE, a straightforward method for generating artificial gene expression systems. We demonstrate that GeneEE segments, containing a 200 nucleotide DNA with random nucleotide composition, can facilitate constitutive and inducible gene expression. To highlight the universal character of our method, we demonstrate GeneEE-mediated gene and protein expression in six bacterial species and Baker’s yeast.
Can education be personalised using pupils’ genetic data?
Authors: Morris Tim T , Davies Neil M , Smith George Davey
Published: May 2019

The increasing predictive power of polygenic scores for education has led to their promotion by some as a potential tool for genetically informed policy. How well polygenic scores predict educational performance conditional on other phenotypic data is however not well understood. Using data from a UK cohort study, we investigated how well polygenic scores for education predicted pupils’ realised achievement over and above phenotypic data that are available to schools. Across our sample, prediction of educational outcomes from polygenic scores were inferior to those from parental socioeconomic factors. There was high overlap between the polygenic score and achievement distributions, leading to weak predictive accuracy at the individual level. Furthermore, conditional on prior achievement polygenic scores were not predictive of later achievement. Our results suggest that while polygenic scores can be informative for identifying group level differences, they currently have limited use for predicting individual educational performance or for personalised education.
The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy
Authors: Wilson Parker C. , Wu Haojia , Kirita Yuhei , Uchimura Kohei , Rennke Helmut G. , Welling Paul A. , Waikar Sushrut S. , Humphreys Benjamin D.
Published: May 2019

Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-type-specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K+-ATPase,WNK1, mineralocorticoid receptor andNEDD4Lexpression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy.

Significance Statement

Single nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.
“The flavor enhancer maltol increases pigment aggregation in dermal and neural melanophores in Xenopus laevis tadpoles”
Authors: Dahora Lara I. , Fitzgerald Ashley , Emanuel Matthew , Baiges Alexa F. , Husain Zahabiya , Thompson Christopher K.
Published: May 2019

Melanophores are pigmented cells that change the distribution of pigmented melanosomes, enabling animals to appear lighter or darker for camouflage, thermoregulation, and UV-protection. A complex series of hormonal and neural mechanisms regulates melanophore pigment distribution, making these cells a valuable tool to screen toxicants as a dynamic cell type that responds rapidly to the environment. We found that maltol, a naturally occurring flavor enhancer and fragrance agent, induces melanophore pigment aggregation in a dose-dependent manner in Xenopus laevis tadpoles. To determine if maltol affects camouflage adaptation, we placed tadpoles into maltol baths situated over either white or black background. Maltol induced pigment aggregation in a similar dose-dependent pattern regardless of background color. We also tested how maltol treatment compares to melatonin treatment and found that the degree of pigment aggregation induced by maltol is similar to treatment with melatonin, but the time course differs significantly. Last, maltol had no effect on mRNA expression of pro-opiomelanocortin or melanin concentrating hormone receptor in the brain, both of which regulate camouflage-related pigment aggregation. Our results suggest that maltol does not exert its effects via the camouflage adaptation mechanism nor via melatonin-based mechanisms. These results are the first to identify a specific toxicological effect of maltol exposure and rules out several mechanisms by which maltol may exert its effects on pigment aggregation.
Strain-aware assembly of genomes from mixed samples using flow variation graphs
Authors: Baaijens Jasmijn A. , Stougie Leen , Schönhuth Alexander
Published: May 2019

The goal of strain-aware genome assembly is to reconstruct all individual haplotypes from a mixed sample at the strain level and to provide abundance estimates for the strains. Given that the use of a reference genome can introduce significant biases, de novo approaches are most suitable for this task. So far, reference-genome-independent assemblers have been shown to reconstruct haplotypes for mixed samples of limited complexity and genomes not exceeding 10000 bp in length.

Here, we present VG-Flow, a de novo approach that enables full-length haplotype reconstruction from pre-assembled contigs of complex mixed samples. Our method increases contiguity of the input assembly and, at the same time, it performs haplotype abundance estimation. VG-Flow is the first approach to require polynomial, and not exponential runtime in terms of the underlying graphs. Since runtime increases only linearly in the length of the genomes in practice, it enables the reconstruction also of genomes that are longer by orders of magnitude, thereby establishing the first de novo solution to strain-aware full-length genome assembly applicable to bacterial sized genomes.

VG-Flow is based on the flow variation graph as a novel concept that both captures all diversity present in the sample and enables to cast the central contig abundance estimation problem as a flow-like, polynomial time solvable optimization problem. As a consequence, we are in position to compute maximal-length haplotypes in terms of decomposing the resulting flow efficiently using a greedy algorithm, and obtain accurate frequency estimates for the reconstructed haplotypes through linear programming techniques.

Benchmarking experiments show that our method outperforms state-of-the-art approaches on mixed samples from short genomes in terms of assembly accuracy as well as abundance estimation. Experiments on longer, bacterial sized genomes demonstrate that VG-Flow is the only current approach that can reconstruct full-length haplotypes from mixed samples at the strain level in human-affordable runtime.
Gut microbial dysbiosis in individuals with Sjögren’s disease
Authors: Mendez Roberto , Watane Arjun , Farhangi Monika , Cavuoto Kara M. , Leith Tom , Budree Shrish , Galor Anat , Banerjee Santanu
Published: May 2019

Purpose

To evaluate the gut microbiome in individuals with Sjögrens and correlate bacterial profiles to dry eye (DE) measures.

Methods

Prospective case series of individuals with confirmed (n=13) and unconfirmed (n=8) Sjögrens (n=21; total cases) as compared to healthy controls (n=10). Stool was analyzed by 16S pyrosequencing and associations between bacterial classes and DE symptoms and signs were examined.

Results

Firmicutes was the dominant phylum in the gut, comprising 40-60% of all phyla. On a phyla level, subjects with Sjögrens (confirmed and unconfirmed) had depletion of Firmicutes (1.1- fold) and an expansion of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold), and Bacteroidetes (1.3-fold) compared to controls. Shannon’s diversity index showed no differences between groups with respect to the numbers of different operational taxonomic units (OTUs) encountered (diversity) and the instances these unique OTUs were sampled (evenness). On the other hand, Faith’s phylogenetic diversity showed increased diversity in cases vs controls, which reached significance when comparing confirmed Sjögrens and controls (13.57 ± 0.89 and 10.96 ± 0.76, p=0.02). Using Principle Co-ordinate Analysis, qualitative differences in microbial composition were noted with differential clustering of cases and controls. Dimensionality reduction and clustering of complex microbial data further showed differences between the three groups, with regard to microbial composition, association and clustering. Finally, differences in certain classes of bacteria correlated with DE symptoms and signs.

Conclusions

Individuals with Sjögrens have gut microbiome alterations as compared to healthy controls. Certain classes of bacteria were associated with DE measures.