bluuebunny/crossref_metadata_2025 huggingface dataset:
Rates of asymptomatic respiratory virus infection across age groups
Authors: Galanti M. , Birger R. , Ud-Dean M. , Filip I. , Morita H. , Comito D. , Anthony S. , Freyer G. A. , Ibrahim S. , Lane B. , Matienzo N. , Ligon C. , Rabadan R. , Shittu A. , Tagne E. , Shaman J.
Published: April 2019

Respiratory viral infections are a leading cause of disease worldwide. A variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. Standard surveillance systems typically only target severe infections (ED outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. Here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. We enrolled 214 individuals at multiple New York City locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. We combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. Asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. Symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. Upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. These findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population.
Decreasing case fatality rate following invasive pneumococcal disease, North East England, 2006–2016
Authors: Houseman C. , Chapman K. E. , Manley P. , Gorton R. , Wilson D. , Hughes G. J.
Published: April 2019

Declining mortality following invasive pneumococcal disease (IPD) has been observed concurrent with a reduced incidence due to effective pneumococcal conjugate vaccines. However, with IPD now increasing due to serotype replacement, we undertook a statistical analysis to estimate the trend in all-cause 30-day case fatality rate (CFR) in the North East of England (NEE) following IPD. Clinical, microbiological and demographic data were obtained for all laboratory-confirmed IPD cases (April 2006–March 2016) and the adjusted association between CFR and epidemiological year estimated using logistic regression. Of the 2510 episodes of IPD included in the analysis, 486 died within 30 days of IPD (CFR 19%). Increasing age, male sex, a diagnosis of septicaemia, being in ⩾1 clinical risk groups, alcohol abuse and individual serotypes were independently associated with increased CFR. A significant decline in CFR over time was observed following adjustment for these significant predictors (adjusted odds ratio 0.93, 95% confidence interval 0.89–0.98; P = 0.003). A small but significant decline in 30-day all-cause CFR following IPD has been observed in the NEE. Nonetheless, certain population groups remain at increased risk of dying following IPD. Despite the introduction of effective vaccines, further strategies to reduce the ongoing burden of mortality from IPD are needed.
The impacts of the Brazilian NDC and their contribution to the Paris agreement on climate change
Authors: Gurgel Angelo C. , Paltsev Sergey , Breviglieri Gustavo Velloso
Published: April 2019

This paper measures the economic impacts of Brazil's climate mitigation strategies contained in its Nationally Determined Contribution (NDC). To do so, we employ the computable general equilibrium MIT Economic Projection and Policy Analysis model and simulate alternative carbon pricing scenarios (sectoral versus economy-wide carbon markets), set to achieve the country's overall emissions targets announced under the Paris Agreement. The results show relatively cheap emissions reductions from land-use changes and agriculture in the short run: the cost of the Brazilian NDC is predicted to be only 0.7 per cent of GDP in 2030. Further efforts to reduce carbon emissions beyond 2030 would require policy changes, since all the potential emissions reductions from deforestation would be finished and the capacity to expand renewable energy sources would be constrained. In this case, an economy-wide carbon pricing system would help substantially to avoid higher compliance costs.
The Language Experience and Proficiency Questionnaire (LEAP-Q): Ten years later
Authors: Kaushanskaya Margarita , Blumenfeld Henrike K. , Marian Viorica
Published: April 2019

The Language Experience and Proficiency Questionnaire (LEAP-Q) is a validated questionnaire tool for collecting self-reported proficiency and experience data from bilingual and multilingual speakers ages 14 to 80. It is available in over 20 languages, and can be administered in a digital, paper-and-pencil, and oral interview format. The LEAP-Q is used by researchers across various disciplines (Psychology, Neuroscience, Linguistics, Education, Communication Sciences & Disorders, etc.) to provide a comprehensive description of their bilingual participants, to substantiate a division of bilinguals into groups (e.g., early vs. late bilinguals), and to screen participants for adequate or threshold levels of language proficiency. Best practices for using the LEAP-Q include administration of the full questionnaire, consideration of acquisition and history of language use together with self-ratings of proficiency, and supplementation of self-reported data with objective language measures whenever possible. The LEAP-Q can be downloaded at no cost at https://bilingualism.northwestern.edu/leapq/.
Quantity Superlatives in Germanic, or “Life on the Fault Line Between Adjective and Determiner”
Authors: Coppock Elizabeth
Published: April 2019

This paper concerns the superlative forms of the wordsmany,much,few, andlittle, and their equivalents in German, Dutch, Swedish, Norwegian, Danish, Dalecarlian, Icelandic, and Faroese. It demon-strates that every possible relationship between definiteness marking and interpretation is attested. It also demonstrates that different kinds of agreement mismatches are found under relative and proportional readings. One consistent pattern is that under a relative interpretation, quantity superlatives with adverbial morphology show neuter singular agreement even if the target noun is plural. In contrast, under a proportional interpretation, quantity superlatives always agree in number. This evidence is taken to show that quantity superlatives are not structurally analogous to quality superlatives such astalleston either a relative or a proportional reading; however, depending on their interpretation, quantity superlatives depart from a plain attributive structure in different ways. On relative readings, they can have a structure akin to that of pseudo-partitives (as intwo liters of milk), while on proportional readings, they tend to have a quantificational structure, sometimes involving a true partitive (as insome of the children). Furthermore, I suggest that the agreement features of a quantity superlative depend on the domain from which the target is drawn (the Target-Domain Hypothesis).
ON THE EXTENSION OF ISOMETRIES BETWEEN THE UNIT SPHERES OF A -TRIPLE AND A BANACH SPACE
Authors: Becerra-Guerrero Julio , Cueto-Avellaneda María , Fernández-Polo Francisco J. , Peralta Antonio M.
Published: April 2019

We prove that if$M$is a$\text{JBW}^{\ast }$-triple and not a Cartan factor of rank two, then$M$satisfies the Mazur–Ulam property, that is, every surjective isometry from the unit sphere of$M$onto the unit sphere of another real Banach space$Y$extends to a surjective real linear isometry from$M$onto$Y$.
The Effect of Vitamin D on Serum Asymmetric Dimethylarginine in Patients with Mild to Moderate Ulcerative Colitis
Authors: Javad Hosseinzadeh-Attar Mohammad , Sharifi Amrollah , Nedjat Saharnaz , Mohamadkhani Ashraf , Vahedi Homayoon
Published: April 2019

Abstract. Purpose: In inflammatory bowel disease increased asymmetric dimethylarginine (ADMA) levels could inhibit nitric oxide (NO) synthase. Vitamin D may increase activity and expression of endothelial NO synthase, which could be done through its possible mechanism of decreasing ADMA levels. The aim of this study is to investigate the possible effect of Vitamin D3 on serum ADMA levels in ulcerative colitis (UC) patients. Methods: Ninety mild to moderate UC patients were randomized. Each patient received one single muscular injection of 300,000 IU (7500 μg) Vitamin D3 (Vitamin D group) or 1 ml normal saline (Placebo group). At baseline and 90 days after the intervention measurements were done. Data were analyzed using independent t-test and analysis of covariance. Baseline correlations were assessed by Pearson and Spearman correlation coefficients. Results: Following data analysis of 86 participants (40 in placebo and 46 in vitamin D group), there was no correlation between baseline ADMA with baseline vitamin D, ESR and hs-CRP at baseline (p = 0.77) and at the end of study (p = 0.82). Serum ADMA levels were not statistically different between two groups. Adjustment for baseline ADMA levels and baseline body mass index (BMI) did not change the results. With subgroup analyses based on gender and vitamin D level no statistical differences in ADMA levels between two groups were found. Conclusions: In this study, we found no significant changes in serum ADMA levels 3 months following a high dose vitamin D administration in mild to moderate UC patients. Further studies in vitamin D deficient patients are needed.
Effects of Astaxanthin Supplementation on Oxidative Stress
Authors: Wu Di , Xu Hao , Chen Jinyao , Zhang Lishi
Published: April 2019

Abstract. A systematic review and meta-analysis was conducted in six databases from 1948 to 2015 to assess the antioxidant activity of astaxanthin in humans. Nine randomized controlled trials were included in the systematic review. Results of meta-analysis revealed a borderline significant antioxidant effect of astaxanthin between the intervention and control groups, with a malondialdehyde-lowering effect for lipid peroxidation ( p = 0.050). However, the data included here are insufficient. When compared with the baseline in intervention groups, the meta-analysis suggested that astaxanthin supplements significantly decreased plasma malondialdehyde {Standard mean difference (SMD) −1.32 μmol/L [95% CI −1.92, −0.72]; p < 0.0001} and isoprostane (SMD −3.10 ng/mL [95% CI −4.69, −1.51]; p < 0.0001). However, they increased superoxide dismutase (SMD 1.57 U/mL [95% CI 0.57, 2.56]; p = 0.002) and total antioxidant capacity (SMD 0.77 mmol 95% CI [0.12, 1.43]; p = 0.018). For dosage subgroup analysis, high dose (≥20 mg/day) of astaxanthin showed significant antioxidant effect (on total antioxidant capacity, isoprostane, and superoxide dismutase, p < 0.05). However, low dose (<20 mg/day) showed no significant effect ( p > 0.05). Further duration subgroup analysis indicated that astaxanthin showed antioxidant effect after a 3-week intervention ( p < 0.001), whereas this effect was not observed after a 12-week or 3-month intervention (on isoprostane and superoxide dismutase, p > 0.05). This review suggested that the antioxidant effect of astaxanthin on humans is unclear.
Characteristics of CME‐ and CIR‐Driven Ion Upflows in the Polar Ionosphere
Authors: Ogawa Y. , Seki K. , Keika K. , Ebihara Y.
Published: April 2019

We investigated how velocity and flux of ionospheric ion upflows vary during magnetic storms driven by corotating interaction regions (CIRs) and coronal mass ejections (CMEs), using data from the European Incoherent Scatter (EISCAT) Tromsø UHF and Svalbard radars between 1996 and 2015. The characteristics of ion upflows were compared with ion and electron temperature variations measured with the EISCAT radars and also joule heating rate, electric field, and field‐aligned current distribution derived from the Weimer model. Upward ion velocity increases in the nighttime at Tromsø (66.2 °N geomagnetic latitude) just after the CIR‐ and CME‐driven storms, corresponding to electron temperature enhancements due to soft particle precipitation and also ion temperature enhancements in the strong westward electric field region. The CME‐driven storms have larger upward ion flux (~1.7 × 1013 m−2s−1) than those under the CIR‐driven storms (~0.3 × 1013 m−2s−1). In the daytime, ion upflows are seen at Longyearbyen, Svalbard (75.2 °N geomagnetic latitude), with an upward flux of typically 1013 m−2s−1 for small CIR and CME storm cases. Substantial ion upflows last for a few days after the storm onsets under small CIR storms, whereas they last for only a day under small CME storms. Under both the cases, the substantial ion upflows are associated with an enhancement of the Region 1 field‐aligned current, eastward electric field and Joule heating rate. For large CME storms, substantial ion upflows are absent in the daytime probably due to equatorward expansion of the auroral oval.
Global Ionospheric Current System Associated With Penetration Electric Field and New Mechanism for the Generation of Dayside Westward Electric Field at Low Latitudes During Northward IMF
Authors: Huang Chao‐Song
Published: April 2019

It is well known that penetration and shielding electric fields are related to the southward and northward turnings of the interplanetary magnetic field (IMF). The shielding electric field is assumed to be caused by the region‐2 field‐aligned currents. We have analyzed observations of equatorial ionospheric plasma drifts measured by the Jicamarca incoherent scatter radar and global ground magnetic perturbations in an event when the IMF fluctuates between southward and northward. The vertical plasma drifts/zonal electric fields in the dayside equatorial ionosphere are well correlated with the IMF reorientations, indicating that the disturbance electric fields in the equatorial ionosphere are caused by the IMF. Magnetometer data are used to reconstruct the global ionospheric currents and convection. The DP 2 current system consists of a large vortex in the afternoon‐evening sector and a much smaller vortex in the dawn sector, and the ionospheric currents associated with the dayside penetration electric field extend into the postmidnight sector. The downward plasma drift and southward magnetic perturbations at equatorial latitudes during northward IMF are correlated with the reverse convection in the polar cap, indicating that the polar electric field associated with the reverse convection is an important source of the westward electric field in the dayside equatorial region. A new mechanism is proposed to explain the generation of westward electric field in the dayside equatorial ionosphere during northward IMF.
On the Nature of the Intraseasonal Variability of Nighttime Ionospheric Irregularities Over Taiwan
Authors: Joshi L. M. , Tsai L. C. , Su S. Y. , Caton Ronald G. , Groves K. M. , Lu C. H.
Published: April 2019

The nature of intraseasonal (within a season) variability of the nighttime ionospheric irregularities has been studied utilizing the observation of the recently installed VHF scintillation receiver from Pingtung, Taiwan. Investigation is based on observations made in 2015 (high‐moderate solar epoch) and 2017 (low solar epoch). Detailed investigation has revealed coexistence of planetary‐scale variability (3–7 days), 10‐ to 16‐day variability, and > 25‐day variability in 2015. Interestingly, the Lomb‐Scargle frequency domain analysis indicated the variability of larger timescales to display somewhat greater amplitudes. The virtual height of the F layer, h'F, over Sanya, also indicated intraseasonal periodicities similar to S4 periodicities observed at Pingtung. Observations have also revealed that, equatorial plasma bubbles (EPBs) over Pingtung tended to occur on contiguous nights as compared to isolated occurrence, and > 60% of the EPB nights were part of two or more (up to 6) nights of contiguous occurrence. Spectral analysis revealed a quasi‐27‐day variability in the ap and AE geomagnetic indices presumably associated with the solar rotation period. The time period of geomagnetic variability corresponded with the period of dominant S4 variability, indicating that the effect of geomagnetic activity on the low‐latitude ionosphere can be periodic in nature. In 2017 (low solar flux), even with a very low occurrence of ionospheric irregularities, planetary‐scale variability was observed. The dominant period of S4 variability in the autumnal equinox was highly correlated with the periodic geomagnetic activity. Results indicate that a deeper understanding of the periodic intraseasonal variability can be imperative for extended range forecast/prediction of ionospheric irregularities.
A Numerical Model Analysis of the Mean and Seasonal Nitrogen Budget on the Northeast U.S. Shelf
Authors: Zhang Shuwen , Stock Charles A. , Curchitser Enrique N. , Dussin Raphael
Published: April 2019

The supply of nitrogen is a primary limiting factor for the productivity of the Northeast United States (NEUS) continental shelf. In this study, a 12‐year (1996–2007) retrospective physical‐biogeochemical simulation over the Northwest Atlantic was used to analyze the mean and seasonal NEUS shelf nitrogen budget, including the connections between shelf subregions: the Gulf of Maine/Georges Bank (GoM/GB), and the Mid‐Atlantic Bight (MAB). The model captures the primary mean and seasonal patterns of shelf circulation, nitrate, and plankton dynamics. Results confirm aspects of previous nitrogen budget analyses, including the dominance of offshore nitrogen influxes into the GoM/GB and the prominent role of riverine influxes and sedimentary denitrification in the MAB. However, detailed spatiotemporal analysis of nitrogen fluxes highlights the importance of dispersed inflows of shallow to intermediate depth waters (0–75 m), which can at times exceed the deep nitrogen influx emphasized in previous studies. A seasonal analysis shows a pronounced shift from the net import of nitrogen to the GoM/GB region during late fall and winter, to the net export of nitrogen from the region in the spring and early summer. The MAB, in contrast, consistently exports nitrogen to offshore waters. The prominence of the 0‐75m nitrogen supply has implications for the roles of Labrador Slope Water and Atlantic Temperate Slope Water on the NEUS ecosystems, as Atlantic Temperate Slope Water has greater nitrate concentrations than Labrador Slope Water at depth but often less at the surface. Results suggest the need for further study of shallow to intermediate depth inflows beyond those from the Scotian Shelf, particularly during the fall/winter of net nitrogen inflow.
Farmer and Farmland Owner Views on Spatial Targeting for Soil Conservation and Water Quality
Authors: Zimmerman E. K. , Tyndall J. C. , Schulte L. A. , Larsen G. L. D.
Published: April 2019

The U.S. Corn Belt is highly productive with respect to grain and livestock commodities but often neglects to deliver other benefits such as soil stability, nutrient retention, and clean water. New precision technologies and conservation planning frameworks offer opportunities to adapt the current agricultural system to meet environmental goals along with production by strategically placing best management practices (BMPs) to target and address specific in‐field resource concerns. To understand farmers' and farmland owners' willingness to participate in such targeting schemes, we conducted in‐depth interviews with 18 farmers and farmland owners whose fields were targeted for soil and nutrient loss in two watersheds in central Iowa. We examined their current application of BMPs and opportunities and constraints to further adoption. We found that farmers and farmland owners often recognized the importance of producing a diverse suite of on‐ and off‐farm environmental benefits but lacked the context, information, certainty, and strong incentives to manage for them. Interviewees were generally receptive to using technologies to target BMPs to areas with resource concerns but expressed concerns about applications on their own land. They specifically perceived challenges related to cost, management complexity, coordination with government programs, and loss of autonomy. For broad acceptance, a spatially targeted conservation approach would need to be paired with expanded partnerships, trusted technical service, and adaptation incentives to reduce farm‐level economic trade‐offs.
S-nitrosylation of the Peroxiredoxin-2 promotes S-nitrosoglutathione-mediated lung cancer cells apoptosis via AMPK-SIRT1 pathway
Authors: Zhang Yihan , Sun Changning , Xiao Guokai , Shan Hui , Tang Luyao , Yi Yujiao , Yu Wengong , Gu Yuchao
Published: April 2019

Protein S-nitrosylation, the redox-based posttranslational modification of a cysteine thiol by the attachment of a nitric oxide (NO) group, is responsible for a variety of signaling effects. Dysregulation of S-nitrosylation may be directly linked to cancer apoptotic resistance and cancer therapy outcomes, emphasizing the importance of S-nitrosylation in cancer. Peroxiredoxin-2 (Prdx2), an antioxidant enzyme, plays an important role in the protection of cancer cells from oxidative radical damage caused by hydrogen dioxide (H2O2), which is a potential target for cancer therapy. Our studies showed that, as an endogenous NO carrier, S-nitrosoglutathione (GSNO) induced apoptosis in lung cancer cells via nitrosylating Prdx2. The nitrosylation of Prdx2 at Cys51 and Cys172 sites disrupted the formation of Prdx2 dimer and repressed the Prdx2 antioxidant activity, causing the accumulation of endogenous H2O2. H2O2 activated AMPK, which then phosphorylated SIRT1 and inhibited its deacetylation activity toward p53 in A549 cells or FOXO1 in NCI-H1299 cells. Taken together, our results elucidate the roles and mechanisms of Prdx2 S-nitrosylation at Cys51 and Cys172 sites in lung cancer cells apoptosis and this finding provides an effective lung cancer treatment strategy for managing aberrant Prdx2 activity in lung cancers.
Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells
Authors: Gao Ji , Gu Jian , Pan Xiongxiong , Gan Xiaojie , Ju Zheng , Zhang Shaopeng , Xia Yongxiang , Lu Ling , Wang Xuehao
Published: April 2019

In vitro induced human regulatory T cells (iTregs) have in vivo therapeutic utility. MicroRNAs (miRNAs) are a family of approximately 22-nucleotide non-coding RNAs that are processed from longer precursors by the RNases Drosha and Dicer. miRNAs regulate post-transcriptional protein expression through messenger RNA destabilization or translational silencing; miR-142-3p regulates natural Treg function through autophagy. We hypothesized that this miRNA may also have an iTreg regulation function. Antagomir-mediated knockdown of miR-142-3p improved Foxp3 (forkhead box P3) expression, regulatory function, cytokine expression, and apoptosis of iTregs in vitro, with or without inflammatory cytokine stimulation. miR-142-3p knockdown increased autophagy-related protein 16-1-mediated autophagy. Target prediction and luciferase assay results indicated that miR-142-3p binds directly to lysine demethylase 6A (KDM6A), which resulted in demethylation of H3K27me3 and in turn upregulated expression of the anti-apoptotic protein Bcl-2. Based on these results, we propose a novel strategy that uses knockdown of miR-142-3p to enhance anti-apoptotic ability and function of iTregs by increasing KDM6A and Bcl-2 expression. This approach might be used as a treatment to control established chronic immune-mediated autoimmune and inflammatory diseases.
Exosomes from adipose-derived mesenchymal stem cells prevent cardiomyocyte apoptosis induced by oxidative stress
Authors: Liu Zhi , Xu Yueqiao , Wan Yungao , Gao Jing , Chu Yanyan , Li Jing
Published: April 2019

Exosomes from bone marrow stem cells or cardiac progenitor cells can reduce apoptosis in myocardial cells after ischemia and reperfusion injury. However, there is little known about the effects of exosomes from adipose-derived stem cells (ADSCs), which are more abundant and have a lower risk of side effects. The aim of this study was to characterize exosomes from ADSCs and evaluate their cardioprotective actions against ischemia reperfusion injury. The exosomes were isolated from ADSCs and analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. The ADSC-exosomes were then used for ex vivo investigation of the cardioprotective effects on cardiomyocytes after exposure to oxidative stress. Exosomes from ADSCs exhibited a diameter of 150 nm and expressed the marker proteins, CD9 and CD29. ADSC-exosomes had no effect on proliferation of untreated cardiomyocytes. In contrast, ADSC-derived exosomes reduced apoptosis in myocardial cells subjected to oxidative stress. This study confirms that exosomes originating from ADSCs can protect cardiomyocytes from oxidative stress.
Staged developmental mapping and X chromosome transcriptional dynamics during mouse spermatogenesis
Authors: Ernst Christina , Eling Nils , Martinez-Jimenez Celia P. , Marioni John C. , Odom Duncan T.
Published: April 2019

Male gametes are generated through a specialised differentiation pathway involving a series of developmental transitions that are poorly characterised at the molecular level. Here, we use droplet-based single-cell RNA-Sequencing to profile spermatogenesis in adult animals and at multiple stages during juvenile development. By exploiting the first wave of spermatogenesis, we both precisely stage germ cell development and enrich for rare somatic cell-types and spermatogonia. To capture the full complexity of spermatogenesis including cells that have low transcriptional activity, we apply a statistical tool that identifies previously uncharacterised populations of leptotene and zygotene spermatocytes. Focusing on post-meiotic events, we characterise the temporal dynamics of X chromosome re-activation and profile the associated chromatin state using CUT&RUN. This identifies a set of genes strongly repressed by H3K9me3 in spermatocytes, which then undergo extensive chromatin remodelling post-meiosis, thus acquiring an active chromatin state and spermatid-specific expression.
Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction
Authors: Carlini Andrea S. , Gaetani Roberto , Braden Rebecca L. , Luo Colin , Christman Karen L. , Gianneschi Nathan C.
Published: April 2019

Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). However, most hydrogels tested in preclinical studies are not candidates for minimally invasive catheter delivery due to excess material viscosity, rapid gelation times, and/or concerns regarding hemocompatibility and potential for embolism. We describe a platform technology for progelator materials formulated as sterically constrained cyclic peptides which flow freely for low resistance injection, and rapidly assemble into hydrogels when linearized by disease-associated enzymes. Their utility in vivo is demonstrated by their ability to flow through a syringe and gel at the site of MI in rat models. Additionally, synthetic functionalization enables these materials to flow through a cardiac injection catheter without clogging, without compromising hemocompatibility or cytotoxicity. These studies set the stage for the development of structurally dynamic biomaterials for therapeutic hydrogel delivery to the MI.
Effect of molecular architecture on ring polymer dynamics in semidilute linear polymer solutions
Authors: Zhou Yuecheng , Hsiao Kai-Wen , Regan Kathryn E. , Kong Dejie , McKenna Gregory B. , Robertson-Anderson Rae M. , Schroeder Charles M.
Published: April 2019

Understanding the dynamics of ring polymers is a particularly challenging yet interesting problem in soft materials. Despite recent progress, a complete understanding of the nonequilibrium behavior of ring polymers has not yet been achieved. In this work, we directly observe the flow dynamics of DNA-based rings in semidilute linear polymer solutions using single molecule techniques. Our results reveal strikingly large conformational fluctuations of rings in extensional flow long after the initial transient stretching process has terminated, which is observed even at extremely low concentrations (0.025 c*) of linear polymers in the background solution. The magnitudes and characteristic timescales of ring conformational fluctuations are determined as functions of flow strength and polymer concentration. Our results suggest that ring conformational fluctuations arise due to transient threading of linear polymers through open ring chains stretching in flow.
Visualizing conformation transitions of the Lipid II flippase MurJ
Authors: Kuk Alvin C. Y. , Hao Aili , Guan Ziqiang , Lee Seok-Yong
Published: April 2019

The biosynthesis of many polysaccharides, including bacterial peptidoglycan and eukaryotic N-linked glycans, requires transport of lipid-linked oligosaccharide (LLO) precursors across the membrane by specialized flippases. MurJ is the flippase for the lipid-linked peptidoglycan precursor Lipid II, a key player in bacterial cell wall synthesis, and a target of recently discovered antibacterials. However, the flipping mechanism of LLOs including Lipid II remains poorly understood due to a dearth of structural information. Here we report crystal structures of MurJ captured in inward-closed, inward-open, inward-occluded and outward-facing conformations. Together with mutagenesis studies, we elucidate the conformational transitions in MurJ that mediate lipid flipping, identify the key ion for function, and provide a framework for the development of inhibitors.
Measuring topology from dynamics by obtaining the Chern number from a linking number
Authors: Tarnowski Matthias , Ünal F. Nur , Fläschner Nick , Rem Benno S. , Eckardt André , Sengstock Klaus , Weitenberg Christof
Published: April 2019

Integer-valued topological indices, characterizing nonlocal properties of quantum states of matter, are known to directly predict robust physical properties of equilibrium systems. The Chern number, e.g., determines the quantized Hall conductivity of an insulator. Using non-interacting fermionic atoms in a periodically driven optical lattice, here we demonstrate experimentally that the Chern number determines also the far-from-equilibrium dynamics of a quantum system. Extending a respective proposal to Floquet systems, we measure the linking number that characterizes the trajectories of momentum-space vortices emerging after a strong quench. We observe that it directly corresponds to the ground-state Chern number. This one-to-one relation between a dynamical and a static topological index allows us to experimentally map out the phase diagram of our system. Furthermore, we measure the instantaneous Chern number and show that it remains zero under the unitary dynamics.
Scalable dissolution-dynamic nuclear polarization with rapid transfer of a polarized solid
Authors: Kouřil Karel , Kouřilová Hana , Bartram Samuel , Levitt Malcolm H. , Meier Benno
Published: April 2019

In dissolution-dynamic nuclear polarization, nuclear spins are hyperpolarized at cryogenic temperatures using radicals and microwave irradiation. The hyperpolarized solid is dissolved with hot solvent and the solution is transferred to a secondary magnet where strongly enhanced magnetic resonance signals are observed. Here we present a method for transferring the hyperpolarized solid. A bullet containing the frozen, hyperpolarized sample is ejected using pressurized helium gas, and shot into a receiving structure in the secondary magnet, where the bullet is retained and the polarized solid is dissolved rapidly. The transfer takes approximately 70 ms. A solenoid, wound along the entire transfer path ensures adiabatic transfer and limits radical-induced low-field relaxation. The method is fast and scalable towards small volumes suitable for high-resolution nuclear magnetic resonance spectroscopy while maintaining high concentrations of the target molecule. Polarization levels of approximately 30% have been observed for 1-13C-labelled pyruvic acid in solution.
Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp
Authors: Cheng Hung-Wei , Onder Lucas , Novkovic Mario , Soneson Charlotte , Lütge Mechthild , Pikor Natalia , Scandella Elke , Robinson Mark D. , Miyazaki Jun-ichi , Tersteegen Anne , Sorg Ursula , Pfeffer Klaus , Rülicke Thomas , Hehlgans Thomas , Ludewig Burkhard
Published: April 2019

The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
Characterising side chains in large proteins by protonless 13C-detected NMR spectroscopy
Authors: Pritchard Ruth B. , Hansen D. Flemming
Published: April 2019

Side chains cover protein surfaces and are fundamental to processes as diverse as substrate recognition, protein folding and enzyme catalysis. However, characterisation of side-chain motions has so far been restricted to small proteins and methyl-bearing side chains. Here we present a class of methods, based on 13C-detected NMR spectroscopy, to more generally quantify motions and interactions of side chains in medium-to-large proteins. A single, uniformly isotopically labelled sample is sufficient to characterise the side chains of six different amino acid types. Side-chain conformational dynamics on the millisecond time-scale can be quantified by incorporating chemical exchange saturation transfer (CEST) into the presented methods, whilst long-range 13C-13C scalar couplings reporting on nanosecond to millisecond motions can be quantified in proteins as large as 80 kDa. The presented class of methods promises characterisation of side-chain behaviour at a level that has so far been reserved for the protein backbone.
PDGFRα+ stromal adipocyte progenitors transition into epithelial cells during lobulo-alveologenesis in the murine mammary gland
Authors: Joshi Purna A. , Waterhouse Paul D. , Kasaian Katayoon , Fang Hui , Gulyaeva Olga , Sul Hei Sook , Boutros Paul C. , Khokha Rama
Published: April 2019

The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contribute to epithelial biology is unknown. Here we identify, in mouse, the transition of a PDGFRα+ mesenchymal cell population into mammary epithelial progenitors. In addition to being adipocyte progenitors, PDGFRα+ cells make a de novo contribution to luminal and basal epithelia during mammary morphogenesis. In the adult, this mesenchymal lineage primarily generates luminal progenitors within lobuloalveoli during sex hormone exposure or pregnancy. We identify cell migration as a key molecular event that is activated in mesenchymal progenitors in response to epithelium-derived chemoattractant. These findings demonstrate a stromal reservoir of epithelial progenitors and provide insight into cell origins and plasticity during mammary tissue growth.
Co-translational assembly of mammalian nuclear multisubunit complexes
Authors: Kamenova Ivanka , Mukherjee Pooja , Conic Sascha , Mueller Florian , El-Saafin Farrah , Bardot Paul , Garnier Jean-Marie , Dembele Doulaye , Capponi Simona , Timmers H. T. Marc , Vincent Stéphane D. , Tora László
Published: April 2019

Cells dedicate significant energy to build proteins often organized in multiprotein assemblies with tightly regulated stoichiometries. As genes encoding subunits assembling in a multisubunit complex are dispersed in the genome of eukaryotes, it is unclear how these protein complexes assemble. Here, we show that mammalian nuclear transcription complexes (TFIID, TREX-2 and SAGA) composed of a large number of subunits, but lacking precise architectural details are built co-translationally. We demonstrate that dimerization domains and their positions in the interacting subunits determine the co-translational assembly pathway (simultaneous or sequential). The lack of co-translational interaction can lead to degradation of the partner protein. Thus, protein synthesis and complex assembly are linked in building mammalian multisubunit complexes, suggesting that co-translational assembly is a general principle in mammalian cells to avoid non-specific interactions and protein aggregation. These findings will also advance structural biology by defining endogenous co-translational building blocks in the architecture of multisubunit complexes.
Structural basis of specific H2A K13/K15 ubiquitination by RNF168
Authors: Horn Velten , Uckelmann Michael , Zhang Heyi , Eerland Jelmer , Aarsman Ivette , le Paige Ulric B. , Davidovich Chen , Sixma Titia K. , van Ingen Hugo
Published: April 2019

Ubiquitination of chromatin by modification of histone H2A is a critical step in both regulation of DNA repair and regulation of cell fate. These very different outcomes depend on the selective modification of distinct lysine residues in H2A, each by a specific E3 ligase. While polycomb PRC1 complexes modify K119, resulting in gene silencing, the E3 ligase RNF168 modifies K13/15, which is a key event in the response to DNA double-strand breaks. The molecular origin of ubiquitination site specificity by these related E3 enzymes is one of the open questions in the field. Using a combination of NMR spectroscopy, crosslinking mass-spectrometry, mutagenesis and data-driven modelling, here we show that RNF168 binds the acidic patch on the nucleosome surface, directing the E2 to the target lysine. The structural model highlights the role of E3 and nucleosome in promoting ubiquitination and provides a basis for understanding and engineering of chromatin ubiquitination specificity.
Single platinum atoms embedded in nanoporous cobalt selenide as electrocatalyst for accelerating hydrogen evolution reaction
Authors: Jiang Kang , Liu Boyang , Luo Min , Ning Shoucong , Peng Ming , Zhao Yang , Lu Ying-Rui , Chan Ting-Shan , de Groot Frank M. F. , Tan Yongwen
Published: April 2019

Designing efficient electrocatalysts for hydrogen evolution reaction is significant for renewable and sustainable energy conversion. Here, we report single-atom platinum decorated nanoporous Co0.85Se (Pt/np-Co0.85Se) as efficient electrocatalysts for hydrogen evolution. The achieved Pt/np-Co0.85Se shows high catalytic performance with a near-zero onset overpotential, a low Tafel slope of 35 mV dec−1, and a high turnover frequency of 3.93 s−1 at −100 mV in neutral media, outperforming commercial Pt/C catalyst and other reported transition-metal-based compounds. Operando X-ray absorption spectroscopy studies combined with density functional theory calculations indicate that single-atom platinum in Pt/np-Co0.85Se not only can optimize surface states of Co0.85Se active centers under realistic working conditions, but also can significantly reduce energy barriers of water dissociation and improve adsorption/desorption behavior of hydrogen, which synergistically promote thermodynamics and kinetics. This work opens up further opportunities for local electronic structures tuning of electrocatalysts to effectively manipulate its catalytic properties by an atomic-level engineering strategy.
Nickel-catalysed selective migratory hydrothiolation of alkenes and alkynes with thiols
Authors: Zhang Yulong , Xu Xianfeng , Zhu Shaolin
Published: April 2019

Direct (utilize easily available and abundant precursors) and selective (both chemo- and regio-) aliphatic C–H functionalization is an attractive mean with which to streamline chemical synthesis. With many possible sites of reaction, traditional methods often need an adjacent polar directing group nearby to achieve high regio- and chemoselectivity and are often restricted to a single site of functionalization. Here we report a remote aliphatic C–H thiolation process with predictable and switchable regioselectivity through NiH-catalysed migratory hydrothiolation of two feedstock chemicals (alkenes/alkynes and thiols). This mild reaction avoids the preparation of electrophilic thiolation reagents and is highly selective to thiols over other nucleophilic groups, such as alcohols, acids, amines, and amides. Mechanistic studies show that the reaction occurs through the formation of an RS-Bpin intermediate, and THF as the solvent plays an important role in the regeneration of NiH species.
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
Authors: Brinkman Arie B. , Nik-Zainal Serena , Simmer Femke , Rodríguez-González F. Germán , Smid Marcel , Alexandrov Ludmil B. , Butler Adam , Martin Sancha , Davies Helen , Glodzik Dominik , Zou Xueqing , Ramakrishna Manasa , Staaf Johan , Ringnér Markus , Sieuwerts Anieta , Ferrari Anthony , Morganella Sandro , Fleischer Thomas , Kristensen Vessela , Gut Marta , van de Vijver Marc J. , Børresen-Dale Anne-Lise , Richardson Andrea L. , Thomas Gilles , Gut Ivo G. , Martens John W. M. , Foekens John A. , Stratton Michael R. , Stunnenberg Hendrik G.
Published: April 2019

Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
Rabies-based vaccine induces potent immune responses against Nipah virus
Authors: Keshwara Rohan , Shiels Thomas , Postnikova Elena , Kurup Drishya , Wirblich Christoph , Johnson Reed F. , Schnell Matthias J.
Published: April 2019

Nipah Virus (NiV) is a re-emerging zoonotic pathogen in the genus Henipavirus of the Paramyxoviridae family of viruses. NiV is endemic to Bangladesh and Malaysia and is highly fatal to both livestock and humans (human case fatality rate = 74.5%). Currently, there is no approved vaccine against NiV on the market. The goal of this study was to use a recombinant RABV vector expressing NiV glycoprotein (NiV G) to develop a bivalent candidate vaccine against NiV disease and rabies virus (RABV) disease, which is also a significant health burden in the regions where NiV is endemic. The rabies vector is a well-established vaccine strain that lacks neurovirulence and can stably expresses foreign antigens that are immunogenic in various animal models. Mice inoculated intranasally with the live recombinant RABV/NiV vaccine (NIPARAB) showed no signs of disease. To test the immunogenicity of the vaccine candidate, groups of C57BL/6 mice were immunized intramuscularly with a single dose of live vaccine particles or two doses of chemically inactivated viral particles. Both vaccination groups showed NiV G-specific seroconversion, and the inactivated (INAC) vaccine group yielded higher titers of NiV G-specific antibodies. Furthermore, cross-reactivity of NiV G-specific immune sera against Hendra virus (HeV), was confirmed by immunofluorescence (IF) and indirect ELISA against soluble recombinant HeV glycoprotein (HeV G). Both live and killed vaccines induced neutralizing antibodies. These results indicate that NIPARAB may be used as a killed virus vaccine to protect humans against NiV and RABV, and possibly as a preventative measure against HeV as well.
Statistically downscaled climate dataset for East Africa
Authors: Gebrechorkos Solomon H. , Hülsmann Stephan , Bernhofer Christian
Published: April 2019

For many regions of the world, current climate change projections are only available at coarser spatial resolution from Global Climate Models (GCMs) that cannot directly be used in impact assessment and adaptation studies at regional and local scale. Impact assessment studies require high-resolution climate data to drive impact assessment models. To overcome this data challenge, we produced a station based climate projection (precipitation and maximum and minimum temperature) for Ethiopia, Kenya, and Tanzania using observed daily data from 211 stations obtained from the National Meteorological Agency of Ethiopia and international databases. Moreover, 26 large-scale climate variables derived from the National Centers for Environmental Prediction reanalysis data (1961–2005) and second generation Canadian Earth System Model (CanESM2, 1961–2100) are used. Statistical Down-Scaling Model (SDSM) is used to produce the required high-resolution climate projection by developing a statistical relationship between the large- and local-scale climate variables. The predictors are analysed more than 16458 times and we provided 20 ensembles for the current (1961–2005) and future (2006–2100, under RCP2.6, RCP4.5, and RCP8.5) climate.
Automated cell-based luminescence assay for profiling antiviral compound activity against enteroviruses
Authors: Zhang Mingyu , Zhang Yong , Wang Yan , Lv Wanyu , Zhang Yanyang
Published: April 2019

We describe the development, optimisation, and validation of an automated, cell-based and high-throughput screening assay using existing luminescence-based ATPlite reagents for identifying antiviral compounds that inhibit enterovirus replication. Antiviral efficacy was determined by measuring the ATP levels in cells that were protected from the viral cytopathic effect (CPE) by the antiviral compounds pleconaril and rupintrivir. CPE-based assay conditions were optimised at a cell density of 5000 cells/well and a viral infection dose of 100 CCID50 in 384-well plates. The assay exhibited excellent robustness, with Z′-factor values between 0.75 and 0.82, coefficients of variation between 0.33% and 1.45%, and signal-to-background ratios ranging from 6.92 to 22.6 when testing three enterovirus A71 isolates circulating in China. The assay was also suitable for screening other picornaviruses, such as poliovirus, coxsackievirus, echovirus, and parechovirus.