bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNAs 363 and 149 are differentially expressed in the maternal circulation preceding a diagnosis of preeclampsia
Authors: Whigham Carole-Anne , MacDonald Teresa M. , Walker Susan P. , Hiscock Richard , Hannan Natalie J. , Pritchard Natasha , Cannon Ping , Nguyen Tuong Vi , Miranda Manisha , Tong Stephen , Kaitu’u-Lino Tu’uhevaha J.
Published: October 2020

Preeclampsia is a pregnancy complication associated with angiogenic dysbalance, maternal endothelial dysfunction and end-organ injury. A predictive test to identify those who will develop preeclampsia could substantially decrease morbidity and mortality. MicroRNAs (miRs) are small RNA molecules involved in post-transcriptional gene regulation. We screened for circulating miRs differentially expressed at 36 weeks’ gestation in pregnancies before the development of preeclampsia. We used a case–control group (198 controls, 34 pre-preeclampsia diagnosis) selected from a prospective cohort (n = 2015) and performed a PCR-based microarray to measure the expression of 41 miRs. We found six circulating miRs (miRs 363, 149, 18a, 1283, 16, 424) at 36 weeks' had significantly reduced expression (p < 0.0001–0.04). miR363 was significantly downregulated at 28 weeks’ gestation, 10–12 weeks before the onset of clinical disease. In the circulation of another cohort of 34 participants with established preterm preeclampsia (vs 23 controls), we found miRs363, 18a, 149 and 16 were significantly down regulated (p < 0.0001–0.04). Combined expression of miRs149 and 363 in the circulation at 36 weeks’ gestation provides a test with 45% sensitivity (at a specificity of 90%) which suggests measuring both miRs may have promise as part of a multi-marker test to predict preeclampsia.
The influence of anthropogenic habitat fragmentation on the genetic structure and diversity of the malaria vector Anopheles cruzii (Diptera: Culicidae)
Authors: Multini Laura Cristina , de Souza Ana Letícia da Silva , Marrelli Mauro Toledo , Wilke André Barretto Bruno
Published: October 2020

Fragmentation of natural environments as a result of human interference has been associated with a decrease in species richness and increase in abundance of a few species that have adapted to these environments. The Brazilian Atlantic Forest, which has been undergoing an intense process of fragmentation and deforestation caused by human-made changes to the environment, is an important hotspot for malaria transmission. The main vector of simian and human malaria in this biome is the mosquitoAnopheles cruzii. Anthropogenic processes reduce the availability of natural resources at the tree canopies,An. cruziiprimary habitat. As a consequence,An. cruziimoves to the border of the Atlantic Forest nearing urban areas seeking resources, increasing their contact with humans in the process. We hypothesized that different levels of anthropogenic changes to the environment can be an important factor in driving the genetic structure and diversity inAn. cruziipopulations. Five different hypotheses using a cross-sectional and a longitudinal design were tested to assess genetic structure in sympatricAn. cruziipopulations and microevolutionary processes driving these populations. Single nucleotide polymorphisms were used to assess microgeographic genetic structure inAn. cruziipopulations in a low-endemicity area in the city of São Paulo, Brazil. Our results show an overall weak genetic structure among the populations, indicating a high gene flow system. However, our results also pointed to the presence of significant genetic structure between sympatricAn. cruziipopulations collected at ground and tree-canopy habitats in the urban environment and higher genetic variation in the ground-level population. This indicates that anthropogenic modifications leading to habitat fragmentation and a higher genetic diversity and structure in ground-level populations could be driving the behavior ofAn. cruzii,ultimately increasing its contact with humans. Understanding how anthropogenic changes in natural areas affectAn. cruziiis essential for the development of more effective mosquito control strategies and, on a broader scale, for malaria-elimination efforts in the Brazilian Atlantic Forest.
Brain structure correlates of expected social threat and reward
Authors: Crawford Bonni , Muhlert Nils , MacDonald Geoff , Lawrence Andrew D.
Published: October 2020

Prospection (mentally simulating future events) generates emotionally-charged mental images that guide social decision-making. Positive and negative social expectancies—imagining new social interactions to be rewarding versus threatening—are core components of social approach and avoidance motivation, respectively. Interindividual differences in such positive and negative future-related cognitions may be underpinned by distinct neuroanatomical substrates. Here, we asked 100 healthy adults to vividly imagine themselves in a novel self-relevant event that was ambiguous with regards to possible social acceptance or rejection. During this task we measured participants’ expectancies for social reward (anticipated feelings of social connection) or threat (anticipated feelings of rejection). On a separate day they underwent structural MRI; voxel-based morphometry was used to explore the relation between social reward and threat expectancies and regional grey matter volumes (rGMV). Increased rGMV in key default-network regions involved in prospection, socio-emotional cognition, and subjective valuation, including ventromedial prefrontal cortex, correlated with both higher social reward and lower social threat expectancies. In contrast, social threat expectancies uniquely correlated with rGMV of regions involved in social attention (posterior superior temporal sulcus, pSTS) and interoception (somatosensory cortex). These findings provide novel insight into the neurobiology of future-oriented cognitive-affective processes critical to adaptive social functioning.
Meta-gene markers predict meningioma recurrence with high accuracy
Authors: Zador Zsolt , Landry Alexander P. , Haibe-Kains Benjamin , Cusimano Michael D.
Published: October 2020

Meningiomas, the most common adult brain tumors, recur in up to half of cases. This requires timely intervention and therefore accurate risk assessment of recurrence is essential. Our current practice relies heavily on histological grade and extent of surgical excision to predict meningioma recurrence. However, prediction accuracy can be as poor as 50% for low or intermediate grade tumors which constitute the majority of cases. Moreover, attempts to find molecular markers to predict their recurrence have been impeded by low or heterogenous genetic signal. We therefore sought to apply systems-biology approaches to transcriptomic data to better predict meningioma recurrence. We apply gene co-expression networks to a cohort of 252 adult patients from the publicly available genetic repository Gene Expression Omnibus. Resultant gene clusters (“modules”) were represented by the first principle component of their expression, and their ability to predict recurrence assessed with a logistic regression model. External validation was done using two independent samples: one merged microarray-based cohort with a total of 108 patients and one RNA-seq-based cohort with 145 patients, using the same modules. We used the bioinformatics database Enrichr to examine the gene ontology associations and driver transcription factors of each module. Using gene co-expression analysis, we were able predict tumor recurrence with high accuracy using a single module which mapped to cell cycle-related processes (AUC of 0.81 ± 0.09 and 0.77 ± 0.10 in external validation using microarray and RNA-seq data, respectively). This module remained predictive when controlling for WHO grade in all cohorts, and was associated with several cancer-associated transcription factors which may serve as novel therapeutic targets for patients with this disease. With the easy accessibility of gene panels in healthcare diagnostics, our results offer a basis for routine molecular testing in meningioma management and propose potential therapeutic targets for future research.
Observations of lightning in relation to transitions in volcanic activity during the 3 June 2018 Fuego Eruption
Authors: Schultz Christopher J. , Andrews Virginia P. , Genareau Kimberly D. , Naeger Aaron R.
Published: October 2020

Satellite and ground-based remote sensing are combined to characterize lightning occurrence during the 3 June 2018 Volcán de Fuego eruption in Guatemala. The combination of the space-based Geostationary Lightning Mapper (GLM) and ground-based Earth Networks Total Lightning Network observed two distinct periods of lightning during this eruption totaling 75 unique lightning flash occurrences over five hours (57 in cloud, 18 cloud-to-ground). The first period of lightning coincided with the rapid growth of the ash cloud, while the second maxima occurred near the time of a deadly pyroclastic density current (PDC) and thunderstorm. Ninety-one percent of the lightning during the event was observed by only one of the lightning sensors, thus showing the importance of combining lightning datasets across multiple frequencies to characterize electrical activity in volcanic eruptions. GLM flashes during the event had a median total optical energy and flash length of 16 fJ, and 12 km, respectively. These median GLM flash energies and lengths observed in the volcanic plume are on the lower end of the flash spectrum because flashes observed in surrounding thunderstorms on 3 June had larger median total optical energy values (130 fJ) and longer median flash lengths (20 km). All 18 cloud-to-ground flashes were negative polarity, supportive of net negative charge within the plume. Mechanisms for the generation of the secondary lightning maxima are discussed based on the presence and potential interaction between ash plume, thunderstorm, and PDC transport during this secondary period of observed lightning.
Prediction of rifampicin resistance beyond the RRDR using structure-based machine learning approaches
Authors: Portelli Stephanie , Myung Yoochan , Furnham Nicholas , Vedithi Sundeep Chaitanya , Pires Douglas E. V. , Ascher David B.
Published: October 2020

Rifampicin resistance is a major therapeutic challenge, particularly in tuberculosis, leprosy, P. aeruginosa and S. aureus infections, where it develops via missense mutations in gene rpoB. Previously we have highlighted that these mutations reduce protein affinities within the RNA polymerase complex, subsequently reducing nucleic acid affinity. Here, we have used these insights to develop a computational rifampicin resistance predictor capable of identifying resistant mutations even outside the well-defined rifampicin resistance determining region (RRDR), using clinical M. tuberculosis sequencing information. Our tool successfully identified up to 90.9% of M. tuberculosis rpoB variants correctly, with sensitivity of 92.2%, specificity of 83.6% and MCC of 0.69, outperforming the current gold-standard GeneXpert-MTB/RIF. We show our model can be translated to other clinically relevant organisms: M. leprae, P. aeruginosa and S. aureus, despite weak sequence identity. Our method was implemented as an interactive tool, SUSPECT-RIF (StrUctural Susceptibility PrEdiCTion for RIFampicin), freely available at https://biosig.unimelb.edu.au/suspect_rif/.
Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties
Authors: Martin Brice , Seguin Johanne , Annereau Maxime , Fleury Thomas , Lai-Kuen René , Neri Giovanni , Lam Anita , Bally Marcel , Mignet Nathalie , Corvis Yohann
Published: October 2020

Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions.
Influence of surfactant-tailored Mn-doped ZnO nanoparticles on ROS production and DNA damage induced in murine fibroblast cells
Authors: Popescu Traian , Matei Christien Oktaviani , Vlaicu Ioana Dorina , Tivig Ioan , Kuncser Andrei Cristian , Stefan Mariana , Ghica Daniela , Miclea Luminita Claudia , Savopol Tudor , Culita Daniela Cristina , Moisescu Mihaela Georgeta
Published: October 2020

The present study concerns the in vitro oxidative stress responses of non-malignant murine cells exposed to surfactant-tailored ZnO nanoparticles (NPs) with distinct morphologies and different levels of manganese doping. Two series of Mn-doped ZnO NPs were obtained by coprecipitation synthesis method, in the presence of either polyvinylpyrrolidone (PVP) or sodium hexametaphosphate (SHMTP). The samples were investigated by powder X-ray Diffraction, Transmission Electron Microscopy, Fourier-Transform Infrared and Electron Paramagnetic Resonance spectroscopic methods, and N2 adsorption–desorption analysis. The observed surfactant-dependent effects concerned: i) particle size and morphology; ii) Mn-doping level; iii) specific surface area and porosity. The relationship between the surfactant dependent characteristics of the Mn-doped ZnO NPs and their in vitro toxicity was assessed by studying the cell viability, intracellular reactive oxygen species (ROS) generation, and DNA fragmentation in NIH3T3 fibroblast cells. The results indicated a positive correlation between the specific surface area and the magnitude of the induced toxicological effects and suggested that Mn-doping exerted a protective effect on cells by diminishing the pro-oxidative action associated with the increase in the specific BET area. The obtained results support the possibility to modulate the in vitro toxicity of ZnO nanomaterials by surfactant-controlled Mn-doping.
Improving image quality in fast, time-resolved micro-CT by weighted back projection
Authors: Heyndrickx Marjolein , Bultreys Tom , Goethals Wannes , Van Hoorebeke Luc , Boone Matthieu N.
Published: October 2020

Time-resolved micro-CT is an increasingly powerful technique for studying dynamic processes in materials and structures. However, it is still difficult to study very fast processes with this technique, since fast scanning is typically associated with high image noise levels. We present weighted back projection, a technique applicable in iterative reconstruction methods using two types of prior knowledge: (1) a virtual starting volume resembling the sample, for example obtained from a scan before the dynamic process was initiated, and (2) knowledge on which regions in the sample are more likely to undergo the dynamic process. Therefore, processes on which this technique is applicable are preferably occurring within a static grid. Weighted back projection has the ability to handle small errors in the prior knowledge, while similar 4D micro-CT techniques require the prior knowledge to be exactly correct. It incorporates the prior knowledge within the reconstruction by using a weight volume, representing for each voxel its probability of undergoing the dynamic process. Qualitative analysis on a sparse subset of projection data from a real micro-CT experiment indicates that this method requires significantly fewer projection angles to converge to a correct volume. This can lead to an improved temporal resolution.
Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain
Authors: Gruget Clémence , Bello Oscar , Coleman Jeff , Krishnakumar Shyam S. , Perez Eric , Rothman James E. , Pincet Frederic , Donaldson Stephen H.
Published: October 2020

Synaptotagmin interaction with anionic lipid (phosphatidylserine/phosphatidylinositol) containing membranes, both in the absence and presence of calcium ions (Ca2+), is critical to its central role in orchestrating neurotransmitter release. The molecular surfaces involved, namely the conserved polylysine motif in the C2B domain and Ca2+-binding aliphatic loops on both C2A and C2B domains, are known. Here we use surface force apparatus combined with systematic mutational analysis of the functional surfaces to directly measure Syt1-membrane interaction and fully map the site-binding energetics of Syt1 both in the absence and presence of Ca2+. By correlating energetics data with the molecular rearrangements measured during confinement, we find that both C2 domains cooperate in membrane binding, with the C2B domain functioning as the main energetic driver, and the C2A domain acting as a facilitator.
Maximized quantitative phosphoproteomics allows high confidence dissection of the DNA damage signaling network
Authors: Faca Vitor Marcel , Sanford Ethan J. , Tieu Jennifer , Comstock William , Gupta Shagun , Marshall Shannon , Yu Haiyuan , Smolka Marcus B.
Published: October 2020

The maintenance of genomic stability relies on DNA damage sensor kinases that detect DNA lesions and phosphorylate an extensive network of substrates. The Mec1/ATR kinase is one of the primary sensor kinases responsible for orchestrating DNA damage responses. Despite the importance of Mec1/ATR, the current network of its identified substrates remains incomplete due, in part, to limitations in mass spectrometry-based quantitative phosphoproteomics. Phosphoproteomics suffers from lack of redundancy and statistical power for generating high confidence datasets, since information about phosphopeptide identity, site-localization, and quantitation must often be gleaned from a single peptide-spectrum match (PSM). Here we carefully analyzed the isotope label swapping strategy for phosphoproteomics, using data consistency among reciprocal labeling experiments as a central filtering rule for maximizing phosphopeptide identification and quantitation. We demonstrate that the approach allows drastic reduction of false positive quantitations and identifications even from phosphopeptides with a low number of spectral matches. Application of this approach identifies new Mec1/ATR-dependent signaling events, expanding our understanding of the DNA damage signaling network. Overall, the proposed quantitative phosphoproteomic approach should be generally applicable for investigating kinase signaling networks with high confidence and depth.
Causes of Variations in Sediment Yield in the Jinghe River Basin, China
Authors: Zhang Jinliang , Shang Yizi , Liu Jinyong , Fu Jian , Wei Shitao , Tong Liang
Published: October 2020

The Jinghe River remains the major sediment source of the Yellow River in China; however, sediment discharge in the Jinghe River has reduced significantly since the 1950s. The objective of this study is to identify the causes of sediment yield variations in the Jinghe River Basin based on soil and water conservation methods and rainfall analyses. The results revealed that soil and water conservation projects were responsible for half of the total sediment reduction; sediment retention due to reservoirs and water diversion projects was responsible for 1.3% of the total reduction. Moreover, the Jinghe River Basin has negligible opportunity to improve its vegetation cover (currently 55% of the basin is covered with lawns and trees), and silt-arrester dams play a smaller role in reducing sediment significantly before they are entirely full. Therefore, new large-scale sediment trapping projects must be implemented across the Jinghe River Basin, where heavy rainfall events are likely to substantially increase in the future, leading to higher sediment discharge.
Room temperature deformation of single crystals of Ti5Si3 with the hexagonal D88 structure investigated by micropillar compression tests
Authors: Kishida Kyosuke , Fukuyama Takayoshi , Maruyama Takuto , Inui Haruyuki
Published: October 2020

Micropillar compression tests of Ti5Si3 single crystals were conducted at room temperature as a function of loading axis orientation and specimen size in order to investigate their room temperature plastic deformation behavior. Plastic flow by the operation of three deformation modes, {1$${\overline{1}}$$

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0]-oriented micropillar specimens deformed at room temperature, respectively. The CRSS values were evaluated to be very high above 2.7 GPa and were confirmed to increase up to about 6 GPa with the decrease in the specimen size. The fracture toughness values are evaluated to be 0.45 MPa m1/2 (notch plane // (0001)) and 0.73 MPa m1/2 (notch plane //(1$${\overline{1}}$$

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00)) based on the results of micro-cantilever bend tests of chevron-notched specimens. The fracture toughness values are considerably lower than those for D8l-Mo5SiB2 and D8l-Nb5Si3 evaluated by the same method, indicating the inherent brittleness of binary Ti5Si3 compared to the other transition-metal silicides of the TM5Si3 type (TM: transition-metal).
Characterization of bacterial communities associated with the exotic and heavy metal tolerant wetland plant Spartina alterniflora
Authors: Yang Ying , Ding Jian , Chi Yulang , Yuan Jianjun
Published: October 2020

Heavy metal pollution has seriously disrupted eco-balance and transformed estuaries into sewage depots. Quanzhou bay is a typical heavy metal-contaminated estuary, in which Spartina alterniflora has widely invaded. Plant-associated microbial communities are crucial for biogeochemical cycles, studies of which would be helpful to demonstrate the invasion mechanisms of plants. Meanwhile, they are indispensable to phytoremediation by enhancing the heavy metal tolerance of plants, facilitating heavy metal absorption rate and promoting growth of plants. In the present study, S. alterniflora-associated rhizo- and endobacterial communities from 3 experimental sites were investigated by 454-pyrosequencing. Heavy metal screening generated 16 culturable isolates, further biochemical assays suggested these clones possess various abilities such as phosphate solubilization, indole-3-acetic acid (IAA) production and 1-aminocyclopropane-1-carboxylate (ACC) deaminase production to accelerate heavy metal uptake and growth of the host. This study revealed the bacterial community structures and characterized the predominant resident bacterial strains of S. alterniflora-associated rhizo- and endobacteria under heavy metal stress, and isolated several bacterial species with potential ecological function.
Evidence of wet-dry cycles and mega-droughts in the Eemian climate of southeast Australia
Authors: McGowan Hamish , Campbell Micheline , Callow John Nikolaus , Lowry Andrew , Wong Henri
Published: October 2020

Understanding past climate variability is critical to informing debate of likely impacts of global warming on weather and climate, and water resources. Here we present a near annual resolution reconstruction of climate developed from a speleothem that spans the Eemian [Marine Isotope Stage 5e (MIS 5e)] from 117,500 to 123,500 years BP—the most recent period in the Earth’s history when temperatures were similar to those of today. Using 25 Mg, 88Sr, and 137Ba as proxies, we show the first indication of solar and teleconnection cyclic forcing of Eemian climate in southeast Australia, a region at present often affected by severe drought and bushfires. We find evidence for multi-centennial dry periods interpreted as mega-droughts, and highlight the importance of understanding the causes of these in the context of a rapidly warming world, where temperatures are now, or projected to exceed those of the Eemian.
Multiband linear and circular polarization rotating metasurface based on multiple plasmonic resonances for C, X and K band applications
Authors: Khan M. Ismail , Chen Yixiao , Hu Bin , Ullah Naeem , Bukhari Syed Hashim Raza , Iqbal Shahid
Published: October 2020

In this work, a multiband polarization converting metasurface is presented which achieves cross-polarization conversion in five frequency bands while linear-to-circular and circular-to-linear polarization transformation in eight frequency bands. The polarization transforming functionality of the structure is spread over an ultra-wide frequency range (5–37 GHz) covering most of X, C, Ku, K and Ka bands. Such an extraordinary ultra-wideband operation originates from multiple plasmonic resonances occurring in the structure based on two coupled rectangular split-ring resonators. Moreover, the polarization transforming capability is stable within the frequency range 5–19 GHz for wide oblique incidence angles, which is up to 60°, both for transverse-electric and transverse-magnetic polarizations. Furthermore, the proposed structure acts as a meta-mirror which preserves handedness of the circular polarization upon reflection. Measurements performed on the fabricated metasurface are found to be consistent with numerical simulation results. The ability to perform three functionalities through a single compact structure with extraordinary wideband, qualifies the proposed design to be a promising candidate for integration with important microwave applications such as satellite, radar, and 5G communication.
Loss of RBMS1 as a regulatory target of miR-106b influences cell growth, gap closing and colony forming in prostate carcinoma
Authors: Dankert Jaroslaw Thomas , Wiesehöfer Marc , Wach Sven , Czyrnik Elena Dilâra , Wennemuth Gunther
Published: October 2020

Prostate carcinoma (PCa) is the second most commonly diagnosed cancer in males worldwide. Among hereditary genetic mutations and nutrient factors, a link between the deregulation of microRNA (miRNA) expression and the development of prostate carcinoma is assumed. MiRNAs are small non-coding RNAs which post-transcriptionally regulate gene expression and which are involved in tumour development and progression as oncogenes or tumour suppressors. Although many genes could be confirmed as targets for deregulated miRNAs, the impact of differentially expressed miRNA and their regulatory target genes on prostate tumour development and progression are not fully understood yet. We could validate RBMS1, a barely described RNA-binding protein, as a new target gene for oncogenic miR-106b, which was identified as an induced miRNA in PCa. Further analysis revealed a loss of RBMS1 expression in prostate tumours compared to corresponding normal tissue. Overexpression of RBMS1 in DU145 and LNCaP prostate cancer cells resulted in diminished cell proliferation, colony forming ability as well as in retarded gap closing. Our results demonstrate for the first time a miR-106b dependent downregulation of RBMS1 in prostate carcinoma. Additionally, we show new tumour suppressive properties of RBMS1 whose observed loss may further elucidate the development of PCa.
Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages
Authors: Taguchi Ayumi , Nagasaka Kazunori , Plessy Charles , Nakamura Hiroe , Kawata Yoshiko , Kato Sachi , Hashimoto Kosuke , Nagamatsu Takeshi , Oda Katsutoshi , Kukimoto Iwao , Kawana Kei , Carninci Piero , Osuga Yutaka , Fujii Tomoyuki
Published: October 2020

Transcription of human papillomavirus (HPV) genes proceeds unidirectionally from multiple promoters. Direct profiling of transcription start sites (TSSs) by Cap Analysis Gene Expression (CAGE) is a powerful strategy for examining individual HPV promoter activity. The objective of this study was to evaluate alterations of viral promoter activity during infection using CAGE technology. We used CAGE-based sequencing of 46 primary cervical samples, and quantitatively evaluated TSS patterns in the HPV transcriptome at a single-nucleotide resolution. TSS patterns were classified into two types: early promoter-dominant type (Type A) and late promoter-dominant type (Type B). The Type B pattern was more frequently found in CIN1 and CIN2 lesions than in CIN3 and cancer samples. We detected transcriptomes from multiple HPV types in five samples. Interestingly, in each sample, the TSS patterns of both HPV types were the same. The viral gene expression pattern was determined by the differentiation status of the epithelial cells, regardless of HPV type. We performed unbiased analyses of TSSs across the HPV genome in clinical samples. Visualising TSS pattern dynamics, including TSS shifts, provides new insights into how HPV infection status relates to disease state.
Intracellular accumulation capacity of gadoxetate: initial results for a novel biomarker of liver function
Authors: Fahlenkamp Ute Lina , Ziegeler Katharina , Adams Lisa Christine , Böker Sarah Maria , Engel Günther , Makowski Marcus Richard
Published: October 2020

Previous studies have shown gadoxetate disodium’s potential to represent liver function by its retention in the hepatobiliary phase. Additionally, in cardiac imaging, quantitative characterization of altered parenchyma is established by extracellular volume (ECV) calculation with extracellular contrast agents. Therefore, the purpose of our study was to evaluate whether intracellular accumulation capacity (IAC) of gadoxetate disodium derived from ECV calculation provides added scientific value in terms of liver function compared to the established parameter reduction rate (RR). After local review board approval, 105 patients undergoing standard MR examination with gadoxetate disodium were included. Modified Look-Locker sequences were obtained before and 20 min after contrast agent administration. RR and IAC were calculated and correlated with serum albumin, as a marker of synthetic liver function. Correlation was higher between IAC and albumin, than between RR and albumin. Additionally, capacity of both RR and IAC to distinguish between patients with or without liver cirrhosis was investigated, and differed significantly in their respective means between patients with cirrhosis and those without. We concluded, that the formula to calculate ECV can be transferred to calculate IAC of gadoxetate disodium in hepatocytes, and, thereby, IAC may possibly qualify as an imaging-based parameter to estimate synthetic liver function.
Retinal vascular development in an immature retina at 33–34 weeks postmenstrual age predicts retinopathy of prematurity
Authors: Jang Ji Hye , Kim Yu Cheol
Published: October 2020

In preterm birth, the immature retina can develop a potentially blinding disorder of the eye known as retinopathy of prematurity (ROP). The vaso-proliferative phase of ROP begins at an approximate postmenstrual age (PMA) of 32 weeks. There is little or no evidence of an association between ROP development and retinal status in the early vaso-proliferative phase. We aimed to evaluate the retinal vascular findings of infants at 33–34 weeks PMA to determine their risk of ROP. We reviewed 130 serial wide-field retinal images from 65 preterm infants born before the gestational age of 31 weeks. ROP occurred more frequently in infants having a leading vascular edge within posterior Zone II. This was in contrast to normal infants, who are characterized by complete retinal vascularization up to Zone II at 34 weeks PMA. The probability of ROP development in preterm infants with retinal edge hemorrhage was 24.58 times higher than in preterm infants without retinal edge hemorrhage. Eyes with ROP that required treatment showed significantly delayed retinal vascularization accompanied by pre-plus disease. In conclusion, retinal status in the early vaso-proliferation phase might determine the risk of ROP.
Systems analysis of avascular necrosis of femoral head using integrative data analysis and literature mining delineates pathways associated with disease
Authors: Naik Ashwin Ashok , Narayanan Aswath , Khanchandani Prakash , Sridharan Divya , Sukumar Piruthivi , Srimadh Bhagavatam Sai Krishna , Seshagiri Polani B. , Sivaramakrishnan Venketesh
Published: October 2020

Avascular necrosis of femoral head (AVNFH) is a debilitating disease, which affects the middle aged population. Though the disease is managed using bisphosphonate, it eventually leads to total hip replacement due to collapse of femoral head. Studies regarding the association of single nucleotide polymorphisms with AVNFH, transcriptomics, proteomics, metabolomics, biophysical, ultrastructural and histopathology have been carried out. Functional validation of SNPs was carried out using literature. An integrated systems analysis using the available datasets might help to gain further insights into the disease process. We have carried out an analysis of transcriptomic data from GEO-database, SNPs associated with AVNFH, proteomic and metabolomic data collected from literature. Based on deficiency of vitamins in AVNFH, an enzyme-cofactor network was generated. The datasets are analyzed using ClueGO and the genes are binned into pathways. Metabolomic datasets are analyzed using MetaboAnalyst. Centrality analysis using CytoNCA on the data sets showed cystathionine beta synthase and methylmalonyl-CoA-mutase to be common to 3 out of 4 datasets. Further, the genes common to at least two data sets were analyzed using DisGeNET, which showed their involvement with various diseases, most of which were risk factors associated with AVNFH. Our analysis shows elevated homocysteine, hypoxia, coagulation, Osteoclast differentiation and endochondral ossification as the major pathways associated with disease which correlated with histopathology, IHC, MRI, Micro-Raman spectroscopy etc. The analysis shows AVNFH to be a multi-systemic disease and provides molecular signatures that are characteristic to the disease process.
CUX2, BRAP and ALDH2 are associated with metabolic traits in people with excessive alcohol consumption
Authors: Chen I-Chun , Kuo Po-Hsiu , Yang Albert C. , Tsai Shih-Jen , Liu Tung-Hsia , Liu Hung-Jen , Lan Tsuo-Hung , Chen Hong-Ming , Huang Huang-Nan , Chung Ren-Hua , Liu Yu-Li
Published: October 2020

Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts. This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. We analysed the Taiwan Biobank data of 18,363 Taiwanese people, including 1945 with excessive alcohol use. We found that one or two copies of the G allele in rs671 (ALDH2) increased the risk of excessive alcohol consumption, while one or two copies of the C allele in rs3782886 (BRAP) reduced the risk of excessive alcohol consumption. To minimize the influence of extensive regional linkage disequilibrium, we used the ridge regression. The ridge coefficients of rs7398833, rs671 and rs3782886 were unchanged across different values of the shrinkage parameter. The three variants corresponded to posttranscriptional activity, including cut-like homeobox 2 (a protein coded by CUX2), Glu504Lys of acetaldehyde dehydrogenase 2 (a protein encoded by ALDH2) and Glu4Gly of BRCA1-associated protein (a protein encoded by BRAP). We found that Glu504Lys of ALDH2 and Glu4Gly of BRAP are involved in the negative regulation of excessive alcohol consumption. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver–brain endocrine axis connecting metabolic shifts with excessive alcohol consumption.
Audio-visual combination of syllables involves time-sensitive dynamics following from fusion failure
Authors: Bouton Sophie , Delgado-Saa Jaime , Olasagasti Itsaso , Giraud Anne-Lise
Published: October 2020

In face-to-face communication, audio-visual (AV) stimuli can be fused, combined or perceived as mismatching. While the left superior temporal sulcus (STS) is presumably the locus of AV integration, the process leading to combination is unknown. Based on previous modelling work, we hypothesize that combination results from a complex dynamic originating in a failure to integrate AV inputs, followed by a reconstruction of the most plausible AV sequence. In two different behavioural tasks and one MEG experiment, we observed that combination is more time demanding than fusion. Using time-/source-resolved human MEG analyses with linear and dynamic causal models, we show that both fusion and combination involve early detection of AV incongruence in the STS, whereas combination is further associated with enhanced activity of AV asynchrony-sensitive regions (auditory and inferior frontal cortices). Based on neural signal decoding, we finally show that only combination can be decoded from the IFG activity and that combination is decoded later than fusion in the STS. These results indicate that the AV speech integration outcome primarily depends on whether the STS converges or not onto an existing multimodal syllable representation, and that combination results from subsequent temporal processing, presumably the off-line re-ordering of incongruent AV stimuli.
Overexpression of the third H-NS paralogue H-NS2 compensates fitness loss in hns mutants of the enteroaggregative Escherichia coli strain 042
Authors: Prieto A. , Bernabeu M. , Falgenhauer L. , Chakraborty T. , Hüttener M. , Juárez A.
Published: October 2020

Members of the H-NS protein family play a role both in the chromosome architecture and in the regulation of gene expression in bacteria. The genomes of the enterobacteria encode an H-NS paralogue, the StpA protein. StpA displays specific regulatory properties and provides a molecular backup for H-NS. Some enterobacteria also encode third H-NS paralogues. This is the case of the enteroaggregative E. coli (EAEC) strain 042, which encodes the hns, stpA and hns2 genes. We provide in this paper novel information about the role of the H-NS2 protein in strain 042. A C > T transition in the hns2 promoter leading to increased H-NS2 expression is readily selected in hns mutants. Increased H-NS2 expression partially compensates for H-NS loss. H-NS2 levels are critical for the strain 042 fitness. Under some circumstances, high H-NS2 expression levels dictated by the mutant hns2 promoter can be deleterious. The selection of T > C revertants or of clones harboring insertional inactivations of the hns2 gene can then occur. Temperature also plays a relevant role in the H-NS2 regulatory activity. At 37 °C, H-NS2 targets a subset of the H-NS repressed genes contributing to their silencing. When temperature drops to 25 °C, the repressory ability of H-NS2 is significantly reduced. At low temperature, H-NS plays the main repressory role.
A short peptide of the C-terminal class Y helices of apolipoprotein A-I has preserved functions in cholesterol efflux and in vivo metabolic control
Authors: Edmunds Shelley J. , Liébana-García Rebeca , Stenkula Karin G. , Lagerstedt Jens O.
Published: October 2020

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) induces glucose uptake by muscle tissues and stimulates pancreatic insulin secretion, and also facilitates cholesterol transport in circulation, and is explored for anti-diabetic and anti-atherosclerotic treatments. As the better alternative to complex protein–lipid formulations it was recently established that the C-terminal region of the ApoA-I protein singly improves the metabolic control and prevents formation of atherosclerotic plaques. Additional investigations of peptides based on the ApoA-I structure may lead to novel anti-diabetic drugs. We here investigate a short peptide (33mer, RG33) that corresponds to the two last helical segments (aa 209–241) of the ApoA-I structure (so-called class Y-helices which forms amphipathic helices) for stability and solubility in serum, for in vitro cholesterol efflux capability, and for providing in vivo glucose control in an insulin resistant mouse model. The RG33 peptide efficiently solubilizes lipid-vesicles, and promotes the efflux of cholesterol from cultured macrophages. The efflux capacity is significantly increased in the presence of lipids compared to non-lipidated RG33. Finally, acute treatment with the RG33 peptide significantly improves the glucose clearance capacity of insulin resistant mice. The impact of the RG33 peptide on glucose control and cholesterol transport, as well as the physicochemical properties, makes it a good candidate for translational exploration of its therapeutic potential in diabetes treatment.
Dynamics of cerebrospinal fluid levels of matrix metalloproteinases in human traumatic brain injury
Authors: Minta Karolina , Brinkmalm Gunnar , Al Nimer Faiez , Thelin Eric P. , Piehl Fredrik , Tullberg Mats , Jeppsson Anna , Portelius Erik , Zetterberg Henrik , Blennow Kaj , Andreasson Ulf
Published: October 2020

Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional tissue injury and blood–brain barrier damage. The objectives of this study were to determine longitudinal changes in cerebrospinal fluid (CSF) concentrations of MMPs after acute TBI and in relation to clinical outcomes, with patients with idiopathic normal pressure hydrocephalus (iNPH) serving as a contrast group. The study included 33 TBI patients with ventricular CSF serially sampled, and 38 iNPH patients in the contrast group. Magnetic bead-based immunoassays were utilized to measure the concentrations of eight MMPs in ventricular human CSF. CSF concentrations of MMP-1, MMP-3 and MMP-10 were increased in TBI patients (at baseline) compared with the iNPH group (p < 0.001), while MMP-2, MMP-9 and MMP-12 did not differ between the groups. MMP-1, MMP-3 and MMP-10 concentrations decreased with time after trauma (p = 0.001–0.04). Increased concentrations of MMP-2 and MMP-10 in CSF at baseline were associated with an unfavourable TBI outcome (p = 0.002–0.02). Observed variable pattern of changes in MMP concentrations indicates that specific MMPs serve different roles in the pathophysiology following TBI, and are in turn associated with clinical outcomes.
Analysis of changes in sodium and chloride ion transport in the skin
Authors: Hołyńska-Iwan Iga , Szewczyk-Golec Karolina
Published: October 2020

The measurement of electric potential and resistance reflect the transport of sodium and chloride ions which take place in keratinocytes and is associated with skin response to stimuli arising from external and internal environment. The aim of the study was to assess changes in electrical resistance and the transport of chloride and sodium ions, under iso-osmotic conditions and following the use of inhibitors affecting these ions’ transport, namely amiloride (A) and bumetanide (B). The experiment was performed on 104 fragments of rabbit skin, divided into three groups: control (n = 35), A—inhibited sodium transport (n = 33) and B—inhibited chloride transport (n = 36). Measurement of electrical resistance (R) and electrical potential (PD) confirmed tissue viability during the experiment, no statistically significant differences in relation to control conditions were noted. The minimal and maximal PD measured during stimulation confirmed the repeatability of the recorded reactions to the mechanical and mechanical–chemical stimulus for all examined groups. Measurement of PD during stimulation showed differences in the transport of sodium and chloride ions in each of the analyzed groups relative to the control. The statistical analysis of the PD measured in stationary conditions and during mechanical and/or mechanical–chemical stimulation proved that changes in sodium and chloride ion transport constitute the physiological response of keratinocytes to changes in environmental conditions for all applied experimental conditions. Assessment of transdermal ion transport changes may be a useful tool for assessing the skin condition with tendency to pain hyperactivity and hypersensitivity to xenobiotics.
Making sense of human interaction benefits from communicative cues
Authors: Kourtis Dimitrios , Jacob Pierre , Sebanz Natalie , Sperber Dan , Knoblich Günther
Published: October 2020

We investigated whether communicative cues help observers to make sense of human interaction. We recorded EEG from an observer monitoring two individuals who were occasionally communicating with each other via either mutual eye contact and/or pointing gestures, and then jointly attending to the same object or attending to different objects that were placed on a table in front of them. The analyses were focussed on the processing of the interaction outcome (i.e. presence or absence of joint attention) and showed that its interpretation is a two-stage process, as reflected in the N300 and the N400 potentials. The N300 amplitude was reduced when the two individuals shared their focus of attention, which indicates the operation of a cognitive process that involves the relatively fast identification and evaluation of actor–object relationships. On the other hand, the N400 was insensitive to the sharing or distribution of the two individuals’ attentional focus. Interestingly, the N400 was reduced when the interaction outcome was preceded either by mutual eye contact or by a perceived pointing gesture. This shows that observation of communication “opens up” the mind to a wider range of action possibilities and thereby helps to interpret unusual outcomes of social interactions.
Author Correction: Arbuscular mycorrhizal fungi promote the growth of plants in the mining associated clay
Authors: Song Ziheng , Bi Yinli , Zhang Jian , Gong Yunli , Yang Huihui
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Sea ice and atmospheric circulation shape the high-latitude lapse rate feedback
Authors: Feldl Nicole , Po-Chedley Stephen , Singh Hansi K. A. , Hay Stephanie , Kushner Paul J.
Published: October 2020

Arctic amplification of anthropogenic climate change is widely attributed to the sea-ice albedo feedback, with its attendant increase in absorbed solar radiation, and to the effect of the vertical structure of atmospheric warming on Earth’s outgoing longwave radiation. The latter lapse rate feedback is subject, at high latitudes, to a myriad of local and remote influences whose relative contributions remain unquantified. The distinct controls on the high-latitude lapse rate feedback are here partitioned into “upper” and “lower” contributions originating above and below a characteristic climatological isentropic surface that separates the high-latitude lower troposphere from the rest of the atmosphere. This decomposition clarifies how the positive high-latitude lapse rate feedback over polar oceans arises primarily as an atmospheric response to local sea ice loss and is reduced in subpolar latitudes by an increase in poleward atmospheric energy transport. The separation of the locally driven component of the high-latitude lapse rate feedback further reveals how it and the sea-ice albedo feedback together dominate Arctic amplification as a coupled mechanism operating across the seasonal cycle.