bluuebunny/crossref_metadata_2025 huggingface dataset:
Dengue Underestimation in Guangzhou, China: Evidence of Seroprevalence in Communities With No Reported Cases Before a Large Outbreak in 2014
Authors: Jing Qinlong , Li Yilan , Liu Jianhua , Jiang Liyun , Chen Zongqiu , Su Wenzhe , Birkhead Guthrie S , Lu Jiahai , Yang Zhicong
Published: June 2019

Objective

Dengue has become a serious public health problem in southern China particularly with a record-breaking outbreak in 2014. Serological evidence from areas with no known dengue cases reported prior to 2014 could provide information on possible unrecognized circulation of dengue virus (DENV) before this outbreak.

Method

Between March and May 2015, we performed a cross-sectional serosurvey using a stratified random sampling method among individuals aged 1–84 years-old in 7 communities in Guangzhou with no reported dengue cases before 2014. Sera of subjects were initially screened with the indirect DENV IgG enzyme-linked immunosorbent assay, and positive samples were further tested by the indirect immunofluorescence assay to identify specific serotypes.

Results

A total of 850 subjects had complete information available. The overall seroprevalence against DENV was 6.59% (56 of 850; 95% CI, 4.92%–8.26%). The seroprevalence increased with age in general (3.86%, 4.58%, 8.72%, 7.22%, and 10.69% among participants in ≤14, 15–29, 30–44, 45–59 and ≥60 years age group, respectively). Living in rural or peri-urban communities and longer years of residence therein were risk factors for higher seroprevalence, whereas wearing long sleeves and pants when outdoors was associated with lower seroprevalence. Of the total subjects, 55.36% (31 of 56) sera were successfully identified with specific serotypes, with 12.90% (4 of 31) being coinfected with 2 serotypes.

Conclusions

Dengue transmission in the study communities had occurred prior to the 2014 massive outbreak, possibly for many years, but went undiagnosed and unreported. A proportion of the study population experienced secondary infection as different serotypes of DENV increased the risk for severe diseases. Active surveillance and education of both healthcare providers and the general population should be conducted in areas at risk for dengue emergence in order to better reduce disease burden.
Spectropolarimetry of the superwind filaments of the starburst galaxy M 82 II: Kinematics of the dust surrounding the nuclear starburst
Authors: Yoshida Michitoshi , Kawabata Koji S , Ohyama Youichi , Itoh Ryosuke , Hattori Takashi
Published: June 2019

We performed deep spectropolarimetric observations of the prototypical starburst galaxy M 82 with the Subaru Telescope in order to study the kinematics of the dust outflow. We obtained optical polarized emission-line spectra up to ∼4 kpc away from the nucleus of the galaxy along three position angles, 138°, 150°, and 179° within the conical outflowing wind (superwind). The Hα emission line in the superwind is strongly polarized and the polarization pattern shows dust scattering of central light sources, being consistent with the previous works. The intensity weighted polarization degree of the Hα line reaches ∼30% at maximum. There are at least two light sources at the central region of the galaxy; one is located at the near-infrared nucleus and the other resides at one of the peaks of the 3 mm radio and molecular gas emission. The outer (>1 kpc) dust is illuminated by the former, whereas the inner dust is scattering the light from the latter. We also investigated the dust motion from the velocity field of the polarized Hα emission line. The dust is accelerated outward on the northwest side of the nucleus. A simple bi-conical dust outflow model shows that the outflow velocity of the dust reaches ≳ 300–450 km s−1 at ∼4 kpc from the nucleus, suggesting that some portion of the dust escapes from the gravitational potential of M 82 into the intergalactic space. At some regions on the southeast side, in particular along the position angle of 138°, the dust has a radial velocity that is slower than the systemic velocity of the galaxy, apparently suggesting inflowing motion toward the nucleus. These components are spatially consistent with a part of the molecular gas stream, which is kinematically independent of the outflow gas; thus the apparent inflow motion of the dust reflects the streaming motion associated with the molecular gas stream.
Fluctuation of the background sky in the Hubble Extremely Deep Field (XDF) and its origin
Authors: Matsumoto Toshio , Tsumura Kohji
Published: June 2019

We performed a fluctuation analysis of the Hubble Extremely Deep Field (XDF) at four optical wavelength bands and found large fluctuations that are significantly brighter than those expected for ordinary galaxies. Good cross-correlations with flat spectra are found down to ${0{^{\prime\prime}_{.}}2}$, indicating the existence of a spatial structure even at the ${0{^{\prime\prime}_{.}}2}$ scale. The detected auto- and cross-correlations provide a lower limit of 24 nW m−2 sr−1 for the absolute sky brightness at 700–900 nm, which is consistent with previous observations. We searched for candidate objects to explain the detected large fluctuation using the catalog of the Hubble Ultra Deep Field (UDF), and found that the surface number density of faint compact objects (FCOs) rapidly increases toward the faint end. Radial profiles of FCOs are indistinguishable from the point spread function (PSF), and the effective radius based on de Vaucouleur’s law is estimated to be smaller than ${0{^{\prime\prime}_{.}}02}$. The spectral energy densities (SEDs) of FCOs follow a power law at optical wavelengths, but show greater emission and structure at $\lambda \gt 1\, \mu$m. Assuming that the FCOs are the cause of the excess brightness and fluctuations, the faint magnitude limit is 34.9 mag for the F775W band, and the surface number density reaches 2.6 × 103 arcsec−2. Recent γ-ray observations require that the redshift of FCOs must be less than 0.1, if FCOs are the origin of the excess optical and infrared background. Assuming that FCOs consist of missing baryons, the mass and luminosity of a single FCO range from 102 to 103 solar units, and the mass-to-luminosity ratio is significantly lower than 1.0 solar unit. The maximum effective radius of an FCO is 4.7 pc. These results and the good correlation between the near-infrared and X-ray background indicate that FCOs could be powered by the gravitational energy associated with black holes.
Reflections on Responsibility and the Prospect of a Long Life
Authors: MacKay Kathryn
Published: June 2019

In this commentary on Brown and colleagues’ paper, entitled ‘Against Moral Responsibilisation of Health: Prudential Responsibility and Health Promotion’, I highlight the tension between individual responsibility—even when this is prudential and not moral—and systemic factors that impact people's health. Brown and colleagues and I agree that individuals are frequently held inappropriately responsible for health-related behaviours or diseases that have become associated with the so-called ‘lifestyle’ diseases. We further agree that health is an instrumental value to people, allowing them to achieve their goals or plans. However, while Brown and colleagues argue that health promotion is justified in providing education campaigns that highlight the pragmatic reasons people have for improving their health-related behaviours, I argue that this amounts to the same inaction on systemic issues as holding individuals morally responsible. Further, without action on systemic issues such as the social determinants of health, some people lack the kinds of future-oriented pragmatic reasons that Brown and colleagues place at the centre of their argument. Rather, for some groups, the pragmatic thing is to enjoy current pleasures even if unhealthy, rather than to forego them for the sake of health in a mythical future.
Classism in Pain Care: The Role of Patient Socioeconomic Status on Nurses’ Pain Assessment and Management Practices
Authors: Brandão Tânia , Campos Lúcia , de Ruddere Lies , Goubert Liesbet , Bernardes Sónia F
Published: June 2019

Objective

Research on social disparities in pain care has been mainly focused on the role of race/racism and sex/sexism. Classism in pain assessment and management practices has been much less investigated. We aimed to test the effect of patient socioeconomic status (SES; a proxy of social class) on nurses’ pain assessment and management practices and whether patient SES modulated the effects of patient distress and evidence of pathology on such practices.

Design

Two experimental studies with a two (patient SES: low/high) by two (patient distress or evidence of pathology: absent/present) between-subject design.

Subjects

Female nurses participated in two experimental studies (N = 150/N = 158).

Methods

Nurses were presented with a vignette/picture depicting the clinical case of a female with chronic low back pain, followed by a video of the patient performing a pain-inducing movement. Afterwards, nurses reported their pain assessment and management practices.

Results

The low-SES patient’s pain was assessed as less intense, more attributed to psychological factors, and considered less credible (in the presence of distress cues) than the higher-SES patient’s pain. Higher SES buffered the detrimental impact of the presence of distress cues on pain assessment. No effects were found on management practices.

Conclusions

Our findings point to the potential buffering role of SES against the detrimental effect of certain clinical cues on pain assessments. This study contributes to highlighting the need for further investigation of the role of SES/social class on pain care and its underlying meanings and processes.
Directed evolution of a bacterial WS/DGAT acyltransferase: improving tDGAT from Thermomonospora curvata
Authors: Santín Omar , Galié Serena , Moncalián Gabriel
Published: June 2019

Some bacteria belonging to the actinobacteria and proteobacteria groups can accumulate neutral lipids expressing enzymes of the wax ester synthase/acyl coenzyme A: diacylglycerol acyltransferase (WS/DGAT) family. tDGAT is a WS/DGAT-like enzyme from Thermomonospora curvata able to produce TAGs and WEs when heterologously expressed in Escherichia coli. In this study, a protocol for the directed evolution of bacterial lipid-producing enzymes based on fluorimetry is developed and tested. tDGAT has been successfully evolved towards the improvement of TAG production with an up to 2.5 times increase in TAG accumulation. Mutants with no ability to produce TAGs but able to accumulate waxes were also selected during the screening. The localization of the mutations that enhance TAG production in the outer surface of tDGAT points out possible new mechanisms that contribute to the activity of this family of enzymes. This Nile red-based high throughput screening provides an evolution platform for other WS/DGAT-like enzymes.
Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity During Neurogenesis
Authors: Chen Hao , Seifikar Helia , Larocque Nicholas , Kim Yvonne , Khatib Ibrahim , Fernandez Charles J , Abello Nicomedes , Robinson Joshua F
Published: June 2019

Although the ramifications associated with polybrominated diphenyl ethers (PBDEs) exposures during human pregnancy have yet to be determined, increasing evidence in humans and animal models suggests that these compounds cause neurodevelopmental toxicity. Human embryonic stem cells (hESCs) models can be used to study the effects of environmental chemicals throughout the successive stages of neuronal development. Here, using a hESC differentiation model, we investigated the effects of common PBDE congeners (BDE-47 or -99) on the successive stages of early neuronal development. First, we determined the points of vulnerability to PBDEs across 4 stages of in vitro neural development by using assays to assess for cytotoxicity. Differentiated neural progenitors were identified to be more sensitive to PBDEs than their less differentiated counterparts. In follow-up investigations, we observed BDE-47 to inhibit functional processes critical for neurogenesis (eg, proliferation, expansion) in hESC-derived neural precursor cells (NPCs) at sub-lethal concentrations. Finally, to determine the mechanism(s) underlying PBDE-toxicity, we conducted global transcriptomic and methylomic analyses of BDE-47. We identified 589 genes to be differentially expressed due to BDE-47 exposure, including molecules involved in oxidative stress mediation, cell cycle, hormone signaling, steroid metabolism, and neurodevelopmental pathways. In parallel analyses, we identified a broad significant increase in CpG methylation. In summary our results suggest, on a cellular level, PBDEs induce human neurodevelopmental toxicity in a concentration-dependent manner and sensitivity to these compounds is dependent on the developmental stage of exposure. Proposed mRNA and methylomic perturbations may underlie toxicity in early embryonic neuronal populations.
Evaluation of Selected Nonfumigant Nematicides on Increasing Inoculation Densities of Meloidogyne incognita on Cucumber
Authors: Hajihassani Abolfazl , Davis Richard F. , Timper Patricia
Published: June 2019

The southern root-knot nematode (RKN), Meloidogyne incognita, is particularly difficult to manage because of high susceptibility of all commercial cucumber (Cucumis sativus) cultivars to this nematode. Growers have conventionally relied on nematicide applications to control RKN. Two microplot experiments were conducted in which four nonfumigant nematicides, oxamyl, fluopyram, fluensulfone, and fluazaindolizine, were examined for their efficacy in reducing gall severity and postharvest soil nematode numbers in microplots inoculated with increasing inoculation densities (1,000, 5,000, 10,000, and 20,000 nematodes/microplot), and improving growth and yield of cucumber. Nematicides were applied 1 day prior to transplanting cucumber seedlings, except fluensulfone, which was applied 7 days before transplanting. At harvest, root gall indices differed significantly (P < 0.0001) among nematode inoculation densities and nematicides. All four nematicides were effective in reducing the root gall index when compared with the untreated control on a consistent basis at all M. incognita inoculation densities. At the lowest inoculation density, no significant difference in gall index or final population density was observed among nematicides; however, gall index increased with increasing nematode inoculation densities in nematicide-treated microplots. Correlations between gall index and inoculation density clearly showed that soil treatment with fluensulfone, fluazaindolizine, or fluopyram was more effective in reducing gall severity than treatment with oxamyl. Regression analysis also indicated no significant effect of nematode inoculation densities on yield of cucumber treated with these nematicides. Results of this study will provide guidance for improving nematicide efficiencies in soil with varying inoculation densities of RKN.
Epigenetic regulation of a mouse PPARγ splicing variant, Pparγ1sv, during adipogenesis in 3T3-L1 cells
Authors: Takenaka Yasuhiro , Nakano Takanari , Ikeda Masaaki , Kakinuma Yoshihiko , Inoue Ikuo
Published: June 2019

We have previously reported the abundant and ubiquitous expression of a newly identified splicing variant of mouse peroxisome proliferator-activated receptor-γ (Pparγ), namely Pparγ1sv that encodes PPARγ1 protein, and plays an important role in adipogenesis. Pparγ1sv has a unique 5’UTR sequence, compared to those of mouse Pparγ1 and Pparγ2 mRNAs. This implies the presence of a novel transcriptional initiation site and promoter for Pparγ1sv. We found that DNA methylation of 42 CpG sites in the proximal promoter region (−733 to −76) of Pparγ1sv was largely unchanged five days after adipocyte differentiation, whereas chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac revealed that these modifications significantly elevated at the transcription start sites of Pparγ1sv and Pparγ2 after differentiation.
Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids
Authors: Quinn Robert A. , Vrbanac Alison , Melnik Alexey V. , Patras Kathryn A. , Christy Mitchell , Nelson Andrew T. , Aksenov Alexander , Tripathi Anupriya , Humphrey Greg , da Silva Ricardo , Bussell Robert , Thron Taren , Wang Mingxun , Vargas Fernando , Gauglitz Julia M. , Meehan Michael J. , Poulsen Orit , Boland Brigid S. , Chang John T. , Sandborn William J. , Lim Meerana , Garg Neha , Lumeng Julie , Kazmierczak Barbara I. , Jain Ruchi , Egan Marie , Rhee Kyung E. , Haddad Gabriel G. , Siegel Dionicio , Mazmanian Sarkis , Nizet Victor , Knight Rob , Dorrestein Pieter C.
Published: June 2019

A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia1. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition, but we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes2. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, aromatic amino acid metabolites, complex polysaccharides, and host lipids; such as sphingolipids and bile acids3–11. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units12, a plethora of molecular diversity remains to be discovered. Here, we use unique mass spectrometry informatics approaches and data mapping onto a murine 3D-model13–15to provide an untargeted assessment of the chemical diversity between germ-free (GF) and colonized mice (specific-pathogen free, SPF), and report the finding of novel bile acids produced by the microbiome in both mice and humans that have evaded characterization despite 170 years of research on bile acid chemistry16.
Comparative analyses of 3654 chloroplast genomes unraveled new insights into the evolutionary mechanism of green plants
Authors: Yang Ting , Liao Xuezhu , Yang Lingxiao , Liu Yang , Mu Weixue , Sahu Sunil Kumar , Liu Xin , Strube Mikael Lenz , Zhong Bojian , Liu Huan
Published: June 2019

Background

Chloroplast are believed to arise from a cyanobacterium through endosymbiosis and they played vital roles in photosynthesis, oxygen release and metabolites synthesis for the plant. With the advent of next-generation sequencing technologies, until December 2018, about 3,654 complete chloroplast genome sequences have been made available. It is possible to compare the chloroplast genome structure to elucidate the evolutionary history of the green plants.

Results

We compared the 3654 chloroplast genomes of the green plants and found extreme conservation of gene orders and gene blocks in the green plant such as ATP synthase cluster, Phytosystem, Cytochrome cluster, and Ribosomal cluster. For the chloroplast-based phylogenomics, we used three different data sets to recover the relationships within green plants which accounted for biased GC content and could mitigate the bias in molecular data sets by increasing taxon sampling. The main topology results include: I) Chlorokybales + Mesostigmatales as the earliest-branching lineage and a clade comprising Zygnematales+ Desmidiales formed a grade as the sister group to the land plants, II) Based on matrix AA data, Bryophytes was strongly supported as monophyletic but for matrix nt123 data, hornworts, mosses and liverworts were placed as successive sister lineages of Tracheophytes with strong support, III) Magnoliids were placed in the outside of Monocots using the matrix nt123 data and the matrix AA data, IV) Ceratophyllales + Chloranthales as sister to the Eudicots using matrix nt123 data, but when using matrix nt12 data and AA data, only Ceratophyllales sister to the Eudicots.

Conclusion

We present the first of its kind large scale comparative analyses of the chloroplast coding gene constitution for 3654 green plants. Some important genes likely showed co-occurrence and formed gene cluster and gene blocks in Streptophyta. We found a clear expansion of IRs (Inverted Repeats) among seed plants. The comprehensive taxon sampling and different data sets recovered a strong relationship for green plants.
A single-parasite transcriptional atlas of Toxoplasma gondii reveals novel control of antigen expression
Authors: Xue Yuan , Theisen Terence C. , Rastogi Suchita , Ferrel Abel , Quake Stephen R. , Boothroyd John C.
Published: June 2019

Toxoplasma gondii, a protozoan parasite, undergoes a complex and poorly understood developmental process that is critical for establishing a chronic infection in its intermediate hosts. Here, we applied single-cell RNA-sequencing (scRNA-seq) on >5,400 Toxoplasma in both tachyzoite and bradyzoite stages using three widely studied strains to construct a comprehensive atlas of cell-cycle and asexual development, revealing hidden states and transcriptional factors associated with each developmental stage. Analysis of SAG1-related sequence (SRS) antigenic repertoire reveals a highly heterogeneous, sporadic expression pattern unexplained by measurement noise, cell cycle, or asexual development. Furthermore, we identified AP2IX-1 as a transcription factor that controls the switching from the ubiquitous SAG1 to rare surface antigens not previously observed in tachyzoites. In addition, comparative analysis between Toxoplasma and Plasmodium scRNA-seq results reveals concerted expression of gene sets, despite fundamental differences in cell division. Lastly, we built an interactive data-browser for visualization of our atlas resource.
Enhanced polar auxin transport in tomato polycotyledon mutant seems to be related to glutathione levels
Authors: Nongmaithem Sapana , Ponukumatla Rachana , Sreelakshmi Yellamaraju , Frasse Pierre , Bouzayen Mondher , Sharma Rameshwar
Published: June 2019

Glutathione-dependent root growth in Arabidopsis is linked to polar auxin transport (PAT). Arabidopsis mutants with reduced glutathione (GSH) levels also show reduced PAT. To gain an insight into the relationship between PAT and GSH level, we analysed tomato polycotyledon mutant, pct1-2, which has enhanced PAT. Microarray analysis of gene expression in pct1-2 mutant revealed underexpression of several genes related to glutamate and glutathione metabolism. In consonance with microarray analysis, enzymatic as well as in-vivo assay revealed higher glutathione level in the early phase of pct1-2 seedling growth than WT. The inhibition of auxin transport by 2,3,5-triiodobenzoic acid (TIBA) reduced both GSH level and PIN1 expression in pct1-2 root tips. The reduction of in vivo GSH accumulation in pct1-2 root tips by buthionine sulfoximine (BSO) stimulated elongation of the short root of pct1-2 mutant akin to TIBA. The rescue of short root phenotype of pct1-2 mutant was restricted to TIBA and BSO. The other auxin transport inhibitors 1-N-naphthylphthalamic acid (NPA), 2-[4-(diethylamino)-2-hydroxybenzoyl] benzoic acid (BUM), 3-chloro-4-hydroxyphenylacetic acid (CHPAA), brefeldin and gravacin inhibited root elongation in both WT and pct1-2 mutant. Our results indicate a relationship between PAT and GSH level in tomato akin to Arabidopsis. Our work also highlights that TIBA rescues short root phenotype of the pct1-2 mutant by acting on a PAT component distinct from the site of action of other PAT inhibitors.
Epidermal Growth Factor signaling acts directly and through a sedation neuron to depolarizes a sleep-active neuron following cellular stress
Authors: Konietzka Jan , Fritz Maximilian , Spiri Silvan , McWhirter Rebecca , Leha Andreas , Palumbos Sierra , Costa Wagner Steuer , Oranth Alexandra , Gottschalk Alexander , Miller David M. , Hajnal Alex , Bringmann Henrik
Published: June 2019

Sleep is induced by sleep-active neurons that depolarize at sleep onset to inhibit wake circuits. Sleep-active neurons are under the control of homeostatic and allostatic mechanisms that determine sleep need. However, little is known about the molecular and circuit mechanisms that translate sleep need into the depolarization of sleep-active neurons. During many conditions inC. eleganssleep induction requires a sleep-active neuron called RIS. Here, we defined the transcriptome of RIS to discover that genes of the Epidermal Growth Factor Receptor (EGFR) signaling pathway are expressed in RIS. With cellular stress, EGFR activates RIS, and RIS induces sleep. Activation of EGFR signaling in the ALA neuron has previously been suggested to promote sleep independently of RIS. Unexpectedly, we found that ALA activation promotes RIS depolarization. Our results suggest that ALA is a sedating neuron with two separable functions. (1) It inhibits specific wakefulness behaviors independently of RIS, (2) and it activates RIS to induce sleep. Whereas ALA plays a strong role in surviving cellular stress, surprisingly, RIS does not. In summary, EGFR signaling can induce sleep-active neuron depolarization by an indirect mechanism through activation of the sedating ALA neuron that acts upstream of the sleep-active RIS neuron as well as through a direct mechanism using EGFR signaling in RIS. Sedation rather than sleep appears to be important for increasing survival following cellular stress, suggesting that sedation and sleep play different roles in restoring health.

Highlights

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The transcriptome of the sleep-active RIS neuron reveals the presence of the EGFR signaling machinery

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EGFR activates RIS directly upon cellular stress to induce sleep bouts

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In parallel, EGFR activates RIS indirectly through the sedating ALA neuron

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Sedation rather than sleep bouts support survival following cellular stress
Designing viscoelastic mucin-based hydrogels
Authors: Joyner Katherine , Song Daniel , Hawkins Robert F. , Silcott Richard D. , Duncan Gregg A.
Published: June 2019

We report the design of a mucin hydrogel created using a thiol-based cross-linking strategy. By using a cross-linking reagent capable of forming disulfide linkages between mucins, the mucin-based hydrogels possess viscoelastic properties comparable to native mucus as measured by bulk rheology. We confirmed disulfide cross-links mediate gel formation in our system using chemical treatments to block and reduce cysteines where we found mucin hydrogel network formation was inhibited and disrupted, respectively. Particle tracking microrheology was used to investigate the kinetics and evolution of microstructure and viscoelasticity within the hydrogel as it formed. We found that the rate of gel formation could be tuned by varying the mucin to crosslinker ratio, producing network pore sizes in the range measured previously in human mucus. The results of this work provide a new, simple method for creating mucin hydrogels with physiologically relevant properties using readily available reagents.
Prochlorococcusrely on microbial interactions rather than on chlorotic resting stages to survive long-term nutrient starvation
Authors: Roth-Rosenberg Dalit , Aharonovich Dikla , Luzzatto-Knaan Tal , Vogts Angela , Zoccarato Luca , Eigemann Falk , Nago Noam , Grossart Hans-Peter , Voss Maren , Sher Daniel
Published: June 2019

Many microorganisms produce resting cells with very low metabolic activity that allow them to survive phases of prolonged nutrient or energy stress. In cyanobacteria and some eukaryotic phytoplankton, the production of resting stages is accompanied by a loss of photosynthetic pigments, a process termed chlorosis. Here, we show that a chlorosis-like process occurs under multiple stress conditions in axenic laboratory cultures ofProchlorococcus, the dominant phytoplankton linage in large regions of the oligotrophic ocean and a global key player in ocean biogeochemical cycles. InProchlorococcusstrain MIT9313, chlorotic cells show reduced metabolic activity, measured as C and N uptake by NanoSIMS. However, unlike many other cyanobacteria, chloroticProchlorococcuscells are not viable and do not re-grow under axenic conditions when transferred to new media. Nevertheless, co-cultures with a heterotrophic bacterium,Alteromonas macleodiiHOT1A3, allowedProchlorococcusto survive nutrient starvation for months. We propose that reliance on co-occurring heterotrophic bacteria, rather than the ability to survive extended starvation as resting cells, underlies the ecological success ofProchlorococcus.

Importance

The ability of microorganisms to withstand long periods of nutrient starvation is key to their survival and success under highly fluctuating conditions as is common in nature. Therefore, one would expect this trait to be prevalent among organisms in the nutrient-poor open ocean. Here, we show that this is not the case forProchlorococcus, a globally abundant and ecologically impactful marine cyanobacterium. Instead,Prochlorococcusrely on co-occurring heterotrophic bacteria to survive extended phases of nutrient and light starvation. Our results highlight the power of microbial interactions to drive major biogeochemical cycles in the ocean and elsewhere with consequences at the global scale.
Rapid and site-specific deep phosphoproteome profiling by data-independent acquisition (DIA) without the need for spectral libraries
Authors: Bekker-Jensen Dorte B. , Bernhardt Oliver M. , Hogrebe Alexander , del Val Ana Martinez , Verbeke Lynn , Gandhi Tejas , Kelstrup Christian D. , Reiter Lukas , Olsen Jesper V.
Published: June 2019

Quantitative phosphoproteomics has in recent years revolutionized understanding of cell signaling, but it remains a challenge to scale the technology for high-throughput analyses. Here we present a rapid and reproducible phosphoproteomics approach to systematically analyze hundreds of samples by fast liquid chromatography tandem mass spectrometry using data independent acquisition (DIA). To overcome the inherent issue of positional phosphopeptide isomers in DIA-based phosphoproteomics, we developed and employed an accurate site localization scoring algorithm, which is incorporated into the Spectronaut software tool. Using a library of synthetic phosphopeptides spiked-in to a yeast phosphoproteome in different ratios we show that it is on par with the top site localization score for data-dependent acquisition (DDA) based phosphoproteomics. Single-shot DIA-based phosphoproteomics achieved an order of magnitude broader dynamic range, higher reproducibility of identification and improved sensitivity and accuracy of quantification compared to state-of-the-art DDA-based phosphoproteomics. Importantly, direct DIA without the need of spectral libraries performed almost on par with analyses using specific project-specific libraries. Moreover, we implemented and benchmarked an algorithm for globally determining phosphorylation site stoichiometry in DIA. Finally, we demonstrate the scalability of the DIA approach by systematically analyzing the effects of thirty different kinase inhibitors in context of epidermal growth factor (EGF) signaling showing that a large proportion of EGF-dependent phospho-regulation is mediated by a specific set of protein kinases.
Untargeted Metabolomic Profiling Identifies Disease-specific Profiles in Food Allergy
Authors: Crestani E , Harb Hani , Charbonnier Louis Marie , Leirer J , Motsinger-Reif A , Rachid Rima , Phipatanakul W , Kaddurah-Daouk R , Chatila T.A.
Published: June 2019

Background

Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Identification of pathogenic mechanisms involved in FA using untargeted metabolomic approaches may provide much needed diagnostic and prognostic disease biomarkers and improved treatment options.

Methods

Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone or both FA and asthma as well as healthy pediatric controls.

Results

FA subjects exhibited a disease-specific metabolomic signature as compared to both control subjects and asthmatics. In particular, FA was uniquely associated with a marked decrease in sphingolipids, as well as a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T (NKT) cells. Specific comparison of FA and asthmatic subjects revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, distinct profiles were associated with history of severe reactions and presence of multiple FA.

Conclusions

Children with FA display a disease-specific metabolomic profile that is informative of disease mechanisms and severity, and which dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in FA children may reflect the interplay between an altered microbiota and immune cell subsets in the gut.
Electromagnetic mapping of the effects of deep brain stimulation and dopaminergic medication on movement-related cortical activity and corticomuscular coherence in Parkinson’s disease
Authors: Sridharan Kousik Sarathy , Højlund Andreas , Johnsen Erik Lisbjerg , Sunde Niels Aagaard , Beniczky Sándor , Østergaard Karen
Published: June 2019

Background

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder. PD can be treated with deep brain stimulation (DBS) when dopaminergic medication is no longer a viable option. Both treatments are effective in improving motor symptoms, however, their underlying mechanisms are not fully elucidated yet.

Objectives

To study the effects of DBS and dopaminergic medication treatments on cortical processing and corticomuscular drive during movements.

Methods

Magnetoencephalography (MEG) was recorded in 10 PD patients and 10 healthy controls, performing phasic hand contractions (hand gripping). Measurements were performed in DBS-treated, untreated and dopaminergic-medicated states; healthy controls received no treatment interventions. Participants performed phasic contractions with their right hand, recorded with electromyography (EMG). Our measures of interest were beta (13-30 Hz) corticomuscular coherence (CMC) and low-gamma (31-45 Hz) power. We used Bayesian statistics on summary values from sensor space data, and we localized the sources of the effects of treatments on beta-CMC and low-gamma power using beamforming.

Results

In PD patients, DBS led to reduced CMC values, whereas dopaminergic medication increased beta-CMC values (localized to contralateral M1) to even higher levels than the controls. DBS, on the other hand, increased low-gamma power (localized to M1) compared to controls and to other conditions. Yet both treatments had similar beneficial effects on the patients’ motor symptoms evaluated by UPDRS-III.

Conclusion

Despite comparable improvements from both treatments on motor symptoms, DBS and dopaminergic medication seem to have different effects on motor cortical function. This indicates that the treatments undertake different functional strategies to improve PD symptoms.
Learning Context-aware Structural Representations to Predict Antigen and Antibody Binding Interfaces
Authors: Pittala Srivamshi , Bailey-Kellogg Chris
Published: June 2019

Understanding how antibodies specifically interact with their antigens can enable better drug and vaccine design, as well as provide insights into natural immunity. Experimental structural characterization can detail the “ground truth” of antibody-antigen interactions, but computational methods are required to efficiently scale to large-scale studies. In order to increase prediction accuracy as well as to provide a means to gain new biological insights into these interactions, we have developed a unified deep learning-based framework to predict binding interfaces on both antibodies and antigens. The framework leverages three key aspects of antibody-antigen interactions in order to learn predictive structural representations: (1) since interfaces are formed from multiple residues in spatial proximity, we employ graph convolutions to aggregate properties across local regions in a protein; (2) since interactions are specific between antibody-antigen pairs, we employ an attention layer to explicitly encode the context of the partner; (3) since more data is available for general protein-protein interactions, we employ transfer learning to leverage this data as a prior for the specific case of antibody-antigen interactions. We show that this single framework achieves state-of-the-art performance at predicting binding interfaces on both antibodies and antigens, and that each of its three aspects drives additional improvement in the performance. We further show that the attention layer not only improves performance, but also provides a biologically interpretable perspective into the mode of interaction.
Walking cadence affects the recruitment of the medial-lateral balance mechanisms
Authors: Fettrow Tyler , Reimann Hendrik , Grenet David , Crenshaw Jeremy , Higginson Jill , Jeka John
Published: June 2019

We have previously identified three balance mechanisms that young healthy adults use to maintain balance while walking. The three mechanisms are: 1) The lateral ankle mechanism, an active modulation of ankle inversion/eversion in stance; 2) The foot placement mechanism, an active shift of the swing foot placement; and 3) The push-off mechanism, an active modulation of the ankle plantarflexion angle during double stance. Here we seek to determine whether there are changes in neural control of balance when walking at different cadences and speeds. Twenty-one healthy young adults walked on a self-paced treadmill while immersed in a 3D virtual reality cave, and periodically received balance perturbations (bipolar galvanic vestibular stimulation) eliciting a perceived fall to the side. Subjects were instructed to match two cadences specified by a metronome, 110bpm (High) and 80bpm (Low), which led to faster and slower gait speeds, respectively. The results indicate that subjects altered the use of the balance mechanisms at different cadences. The lateral ankle mechanism was used more in the Low condition, while the foot placement mechanism was used more in the High condition. There was no difference in the use of the push-off mechanism between cadence conditions. These results suggest that neural control of balance is altered when gait characteristics such as cadence change, suggesting a flexible balance response that is sensitive to the constraints of the gait cycle. We speculate that the use of the balance mechanisms may be a factor resulting in well-known characteristics of gait in populations with compromised balance control, such as slower gait speed in older adults or higher cadence in people with Parkinson’s disease.
Localist neural plasticity identified by mutual information
Authors: Scheler Gabriele , Schumann Martin L , Schumann Johann
Published: June 2019

We present a model of pattern memory and retrieval with novel, technically useful and biologically realistic properties. Specifically, we enter n variations of k pattern classes (n*k patterns) onto a cortex-like balanced inhibitory-excitatory network with heterogeneous neurons, and let the pattern spread within the recurrent network. We show that we can identify high mutual-information (MI) neurons as major information-bearing elements within each pattern representation. We employ a simple one-shot adaptive (learning) process focusing on high MI neurons and inhibition. Such ‘localist plasticity’ has high efficiency, because it requires only few adaptations for each pattern. Specifically, we store k=10 patterns of size s=400 in a 1000/1200 neuron network. We stimulate high MI neurons and in this way recall patterns, such that the whole network represents this pattern. We assess the quality of the representation (a) before learning, when entering the pattern into a naive network, (b) after learning, on the adapted network, and (c) after recall by stimulation. The recalled patterns could be easily recognized by a trained classifier. The recalled pattern ‘unfolds’ over the recurrent network with high similarity to the original input pattern. We discuss the distribution of neuron properties in the network, and find that an initial Gaussian distribution changes into a more heavy-tailed, lognormal distribution during the adaptation process. The remarkable result is that we are able to achieve reliable pattern recall by stimulating only high information neurons. This work provides a biologically-inspired model of cortical memory and may have interesting technical applications.
A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space
Authors: Günther Patrick , Cirovic Branko , Baßler Kevin , Händler Kristian , Becker Matthias , Dutertre Charles Antoine , Bigley Venetia , Newell Evan , Collin Matthew , Ginhoux Florent , Schlitzer Andreas , Schultze Joachim L.
Published: June 2019

Single-cell genomic techniques are opening new avenues to understand the basic units of life. Large international efforts, such as those to derive a Human Cell Atlas, are driving progress in this area; here, cellular map generation is key. To expedite the inevitable iterations of these underlying maps, we have developed a rule-based data-informed approach to build next generation cellular consensus maps. Using the human dendritic-cell and monocyte compartment in peripheral blood as an example, we performed computational integration of previous, partially overlapping maps using an approach we termed ‘backmapping’, combined with multi-color flow-cytometry and index sorting-based single-cell RNA-sequencing. Our general strategy can be applied to any atlas generation for humans and other species.

Graphical Abstract

Highlights

Defining a consensus of the human myeloid cell compartment in peripheral blood

3 monocytes subsets, pDC, cDC1, DC2, DC3 and precursor DC make up the compartment

Distinguish myeloid cell compartment from other cell spaces, e.g. the NK cell space

Providing a generalizable method for building consensus maps for the life sciences
A versatile ES cell-based melanoma mouse modeling platform
Authors: Bok Ilah , Vera Olga , Xu Xiaonan , Jasani Neel , Nakamura Koji , Reff Jordan , Nenci Arianna , Gonzalez Jose G. , Karreth Florian A.
Published: June 2019

The cumbersome and time-consuming process of generating new mouse strains and multi-allelic experimental animals often hinders the use of genetically engineered mouse models (GEMM) in cancer research. Here, we describe the development and validation of an embryonic stem cell (ESC)-GEMM platform for rapid modeling of melanoma in mice. Our platform incorporates twelve clinically relevant genotypes composed of combinations of four driver alleles (LSL-BrafV600E, LSL-NrasQ61R, PtenFlox, Cdkn2aFlox) and regulatory alleles to spatiotemporally control the perturbation of genes-of-interest. Our ESCs produce high contribution chimeras, which recapitulate the melanoma phenotypes of conventionally bred mice. Using our ESC-GEMM platform to modulate Pten expression in melanocytes in vivo, we highlight the utility and advantages of gene depletion by CRISPR-Cas9, RNAi, or conditional knockout for melanoma modeling. Moreover, we use complementary genetic methods to demonstrate the impact of Pten restoration on the prevention and maintenance of Pten-deficient melanomas. Finally, we show that chimera-derived melanoma cell lines retain regulatory allele competency and are a powerful resource to complement ESC-GEMM chimera experiments in vitro and in syngeneic grafts in vivo. Thus, when combined with sophisticated genetic tools, our ESC-GEMM platform enables rapid, high-throughput, and versatile studies aimed at addressing outstanding questions in melanoma biology.
The cohesin loader NIPBL interacts with pre-ribosomal RNA and treacle to regulate ribosomal RNA synthesis
Authors: Kong Xiangduo , Chen Yen-Yun , Lin Jianhuang , Flowers Ebony , Van Nostrand Eric , Blue Steven M. , Chau Jonathan , Ma Christopher I-Hsing , Mohr Isaiah , Thai Ryan , Yao Chengguo , Ball Alexander R. , Chien Richard , Kawauchi Shimako , Santos Rosaysela , Calof Anne L. , Lander Arthur D. , Shi Yongsheng , Okuwaki Mitsuru , Yeo Gene W. , Yokomori Kyoko
Published: June 2019

NIPBL is an essential loader of cohesin to mediate sister chromatid cohesion and chromatin loop organization. NIPBL mutations cause Cornelia de Lange Syndrome. How NIPBL’s genomic localization is specified is not fully understood. We found that NIPBL localizes to the nucleolus in an RNA-dependent manner and binds directly to ribosomal RNA (rRNA). We identified two RNA binding domains in NIPBL in vitro, both of which are required for efficient rRNA binding in vivo. NIPBL binds to ribosomal DNA (rDNA) in an RNA-stimulated manner, recruits PAF1 and promotes pre-rRNA transcription. Stress that inhibits rRNA synthesis displaces NIPBL from the nucleolus and rDNA. Interestingly, treacle, mutated in Treacher Collins syndrome, tightly binds to and recruits NIPBL to the nucleolus, nucleolar organizer regions, and the stress-induced nucleolar cap. The results reveal that a subpopulation of NIPBL is recruited to the nucleolus through its interaction with RNA and treacle and regulates pre-rRNA transcription.
Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1
Authors: Yin Qi , Wang Hongye , Xie Zhenfei , Jin Lifang , Ding Yifu , Li Na , Li Yan , Wang Qiong , Liu Xinyi , Xu Liuqing , Wang Kai , Cheng Yanbo , Chang Boran , Zhong Cuiqing , Yu Qian , Tang Wei , Chen Wanjin , Yang Wenjun , Zhang Fan , Ding Chen , Bao Lan , Zhou Bin , Hu Ping , Li Jinsong
Published: June 2019

Multisystem manifestations in myotonic dystrophy type 1 (DM1) may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK, including Dmpk and its neighboring genes (Six5 or Dmwd) and downstream Mbnl1. However, the direct evidences are lack. Here, we develop a new strategy to generate mice carrying multigene mutations in one step by injection of haploid embryonic stem cells with mutant Dmpk, Six5 and Mbnl1 into oocytes. The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes. With the additional mutation in Dmwd, quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1. Moreover, muscle stem cells in both models display reduced stemness. Our results suggest that the complex symptoms of DM1 result from the reduced gene dosage of multiple genes.