bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual trust and quality of regional government
Authors: Lombardo Rosetta , Ricotta Fernanda
Published: December 2021

The impact of trust on economic performance has been widely explored, but the reasons for its variability across countries are not well understood. We analyse the effect of the quality of government at the regional level on individual generalized trust in a multi-country context across regions in Europe. Social phenomena are often subnational and a number of public services are provided at a subnational level; the trust of individuals living in the same country may, therefore, differ by region depending also on the quality of the local government. As a proxy of the quality of institutions, we use the European Quality of Government Index, calculated at the regional level over 27 European Union (EU) countries. The analysis conducted on data extracted from the European Social Survey 2012 refers to 142 regions from 15 EU member states. Considering the clustered nature of the data, a multilevel approach is used. The findings show that living in a region with high-quality local government positively influences individual trust. This positive association survives the inclusion of several contextual regional variables.
Lost in Translation or Just Too Pragmatic?
Authors: Lorenz Timo , Algner Mona
Published: December 2021

Abstract. The Broader Autism Phenotype Questionnaire (BAPQ) is a measure to assess a set of personality and language characteristics reflecting the phenotypic expression of autistic traits in neurotypically developing individuals. This paper aims to evaluate the newly developed German version of the BAPQ (BAPQ-G) in terms of its factorial validity. We performed confirmatory factor analyses and correlations with other measures of the broader autism phenotype on three German samples ( N1 = 248, N2 = 289, N3 = 255). Associations with other constructs are in line with the assumptions, yet the anticipated factor structure of the BAPQ-G did not meet the cutoff criteria. These results are discussed along with recent findings regarding other cultural versions of the BAPQ.
Tracing Uncertainty Contributors in the Multi‐Hazard Risk Analysis for Compound Extremes
Authors: Fan Y. R. , Yu L. , Shi X. , Duan Q. Y.
Published: December 2021

In this study, an iterative factorial multimodel Bayesian copula (IFMBC) framework was developed for revealing uncertainties in risk inferences of compound extremes under the consideration of diverse model structures and parameter sets. Particularly, an iterative factorial analysis (IFA) method would be advanced in IFMBC to track the dominant contributors to the imprecise predictions of multi‐hazard risks. The developed IFMBC framework was applied for the risk assessment of compound floods at two estuarine systems (i.e., Washington and Philadelphia) in US. The results indicate that the most likely compound events, under predefined return periods, exhibit noticeable uncertainties. Those uncertainties also present multiple hotspots which may be attributed to different impacts from different factors. By applying the IFA method, the results suggest the copula structure would likely be ranked as one of the top 2 impact factors for predictions of failure probabilities (FPs) in the scenarios of AND, and Kendall, with its contributions higher than 30% for FP in Kendall (more than 40% at Washington) and more than 25% for FP in Kendall (larger than 40% at Philadelphia). In comparison, the copula structure may not pose a visible effect on the predictive uncertainty for FP in OR, with its contribution possibly less than 5% under long‐term service time periods. However, the marginal distributions would have higher effects on FP in OR than the effects on the other two FPs. Particularly, the marginal distribution for the extreme variable with high skewness and kurtosis values tends to be ranked as one of the most significant impact factors for FP in OR. Also, the overall impacts from parametric uncertainties in both marginal and dependence models cannot be neglected for the predictions of all three FPs with their contributions probably larger than 20% under a short service time period. Compared with the traditional multilevel factorial analysis, the IFA method can provide more reliable characterization for uncertainty contributors in multi‐hazard risk analyses, since the traditional method seems to significantly overestimate the contributions from parameter uncertainties.
Controlled Abstention Neural Networks for Identifying Skillful Predictions for Classification Problems
Authors: Barnes Elizabeth A. , Barnes Randal J.
Published: December 2021

The earth system is exceedingly complex and often chaotic in nature, making prediction incredibly challenging: we cannot expect to make perfect predictions all of the time. Instead, we look for specific states of the system that lead to more predictable behavior than others, often termed “forecasts of opportunity.” When these opportunities are not present, scientists need prediction systems that are capable of saying “I don't know.” We introduce a novel loss function, termed the “NotWrong loss,” that allows neural networks to identify forecasts of opportunity for classification problems. The NotWrong loss introduces an abstention class that allows the network to identify the more confident samples and abstain (say “I don't know”) on the less confident samples. The abstention loss is designed to abstain on a user‐defined fraction of the samples via a standard adaptive controller. Unlike many machine learning methods used to reject samples post‐training, the NotWrong loss is applied during training to preferentially learn from the more confident samples. We show that the NotWrong loss outperforms other existing loss functions for multiple climate use cases. The implementation of the proposed loss function is straightforward in most network architectures designed for classification as it only requires the addition of an abstention class to the output layer and modification of the loss function.
Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells
Authors: Wilson Elisabeth R. , Helton Nichole M. , Heath Sharon E. , Fulton Robert S. , Payton Jacqueline E. , Welch John S. , Walter Matthew J. , Westervelt Peter , DiPersio John F. , Link Daniel C. , Miller Christopher A. , Ley Timothy J. , Spencer David H.
Published: December 2021

Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4000 focal regions that were uniquely hypermethylated in IDHmut samples vs. normal CD34+ cells and other AMLs. These regions had modest hypermethylation in AMLs with biallelic TET2 mutations, and levels of 5-hydroxymethylation that were diminished in IDH and TET-mutant samples, indicating that this hypermethylation results from inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred at regions with low methylation in CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that IDHmut-associated hypermethylation is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.
Dynamic assessment of measurable residual disease in favorable-risk acute myeloid leukemia in first remission, treatment, and outcomes
Authors: Yu Sijian , Lin Tong , Nie Danian , Zhang Yu , Sun Zhiqiang , Zhang Qing , Wang Caixia , Xiong Mujun , Fan Zhiping , Huang Fen , Xu Na , Liu Hui , Yu Guopan , Zhang Hongyu , Shi Pengcheng , Xu Jun , Xuan Li , Guo Ziwen , Wu Meiqing , Han Lijie , Xiong Yiying , Sun Jing , Wang Yu , Liu Qifa
Published: December 2021

We aimed to investigate outcomes of different post-remission treatment (PRT) choices based on dynamic measurable residual disease (MRD) by multiparameter flow cytometry in favorable-risk AML (FR-AML). Four hundred and three younger patients with FR-AML in first complete remission (CR1) were enrolled in this registry-based cohort study, including 173 who received chemotherapy (CMT), 92 autologous stem cell transplantation (auto-SCT), and 138 allogeneic SCT (allo-SCT). The primary endpoint was the 5-year overall survival (OS). Subgroup analyses were performed based on dynamic MRD after the 1st, 2nd, and 3rd courses of chemotherapy. In subgroups of patients with negative MRD after 1 or 2 course of chemotherapy, comparable OS was observed among the CMT, auto-SCT, and allo-SCT groups (p = 0.340; p = 0.627, respectively). But CMT and auto-SCT had better graft-versus-host-disease-free, relapse-free survival (GRFS) than allo-SCT in both subgroups. For patients with negative MRD after three courses of chemotherapy, allo-SCT had better disease-free-survival than CMT (p = 0.009). However, OS was comparable among the three groups (p = 0.656). For patients with persistently positive MRD after 3 courses of chemotherapy or recurrent MRD, allo-SCT had better OS than CMT and auto-SCT (p = 0.011; p = 0.029, respectively). Dynamic MRD might improve therapy stratification and optimize PRT selection for FR-AML in CR1.
A geometric criterion for the optimal spreading of active polymers in porous media
Authors: Kurzthaler Christina , Mandal Suvendu , Bhattacharjee Tapomoy , Löwen Hartmut , Datta Sujit S. , Stone Howard A.
Published: December 2021

Efficient navigation through disordered, porous environments poses a major challenge for swimming microorganisms and future synthetic cargo-carriers. We perform Brownian dynamics simulations of active stiff polymers undergoing run-reverse dynamics, and so mimic bacterial swimming, in porous media. In accord with experiments ofEscherichia coli, the polymer dynamics are characterized by trapping phases interrupted by directed hopping motion through the pores. Our findings show that the spreading of active agents in porous media can be optimized by tuning their run lengths, which we rationalize using a coarse-grained model. More significantly, we discover a geometric criterion for the optimal spreading, which emerges when their run lengths are comparable to the longest straight path available in the porous medium. Our criterion unifies results for porous media with disparate pore sizes and shapes and for run-and-tumble polymers. It thus provides a fundamental principle for optimal transport of active agents in densely-packed biological and environmental settings.
Single cell atlas for 11 non-model mammals, reptiles and birds
Authors: Chen Dongsheng , Sun Jian , Zhu Jiacheng , Ding Xiangning , Lan Tianming , Wang Xiran , Wu Weiying , Ou Zhihua , Zhu Linnan , Ding Peiwen , Wang Haoyu , Luo Lihua , Xiang Rong , Wang Xiaoling , Qiu Jiaying , Wang Shiyou , Li Haimeng , Chai Chaochao , Liang Langchao , An Fuyu , Zhang Le , Han Lei , Zhu Yixin , Wang Feiyue , Yuan Yuting , Wu Wendi , Sun Chengcheng , Lu Haorong , Wu Jihong , Sun Xinghuai , Zhang Shenghai , Sahu Sunil Kumar , Liu Ping , Xia Jun , Zhang Lijing , Chen Haixia , Fang Dongming , Zeng Yuying , Wu Yiquan , Cui Zehua , He Qian , Jiang Sanjie , Ma Xiaoyan , Feng Weimin , Xu Yan , Li Fang , Liu Zhongmin , Chen Lei , Chen Fang , Jin Xin , Qiu Wei , Wang Tianjiao , Li Yang , Xing Xiumei , Yang Huanming , Xu Yanchun , Hua Yan , Liu Yahong , Liu Huan , Xu Xun
Published: December 2021

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.
Widespread homogenization of plant communities in the Anthropocene
Authors: Daru Barnabas H. , Davies T. Jonathan , Willis Charles G. , Meineke Emily K. , Ronk Argo , Zobel Martin , Pärtel Meelis , Antonelli Alexandre , Davis Charles C.
Published: December 2021

Native biodiversity decline and non-native species spread are major features of the Anthropocene. Both processes can drive biotic homogenization by reducing trait and phylogenetic differences in species assemblages between regions, thus diminishing the regional distinctiveness of biotas and likely have negative impacts on key ecosystem functions. However, a global assessment of this phenomenon is lacking. Here, using a dataset of >200,000 plant species, we demonstrate widespread and temporal decreases in species and phylogenetic turnover across grain sizes and spatial extents. The extent of homogenization within major biomes is pronounced and is overwhelmingly explained by non-native species naturalizations. Asia and North America are major sources of non-native species; however, the species they export tend to be phylogenetically close to recipient floras. Australia, the Pacific and Europe, in contrast, contribute fewer species to the global pool of non-natives, but represent a disproportionate amount of phylogenetic diversity. The timeline of most naturalisations coincides with widespread human migration within the last ~500 years, and demonstrates the profound influence humans exert on regional biotas beyond changes in species richness.
A plant virus satellite RNA directly accelerates wing formation in its insect vector for spread
Authors: Jayasinghe Wikum H. , Kim Hangil , Nakada Yusuke , Masuta Chikara
Published: December 2021

Cucumber mosaic virus (CMV) often accompanies a short RNA molecule called a satellite RNA (satRNA). When infected with CMV in the presence of Y-satellite RNA (Y-sat), tobacco leaves develop a green mosaic, then turn yellow. Y-sat has been identified in the fields in Japan. Here, we show that the yellow leaf colour preferentially attracts aphids, and that the aphids fed on yellow plants, which harbour Y-sat-derived small RNAs (sRNAs), turn red and subsequently develop wings. In addition, we found that leaf yellowing did not necessarily reduce photosynthesis, and that viral transmission was not greatly affected despite the low viral titer in the Y-sat-infected plants. Y-sat-infected plants can therefore support a sufficient number of aphids to allow for efficient virus transmission. Our results demonstrate that Y-sat directly alters aphid physiology via Y-sat sRNAs to promote wing formation, an unprecedented survival strategy that enables outward spread via the winged insect vector.
Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance
Authors: Deng Yalan , Xia Xianghou , Zhao Yang , Zhao Zilong , Martinez Consuelo , Yin Wenjuan , Yao Jun , Hang Qinglei , Wu Weiche , Zhang Jie , Yu Yang , Xia Weiya , Yao Fan , Zhao Di , Sun Yutong , Ying Haoqiang , Hung Mien-Chie , Ma Li
Published: December 2021

Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought to suppress immunity by acting on immune cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR in activating PD-L1 expression and repressing the major histocompatibility complex class I (MHC-I) expression in pancreatic ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models of PDAC, either tumor cell-specific depletion or pharmacologic inhibition of GR leads to PD-L1 downregulation and MHC-I upregulation in tumor cells, which in turn promotes the infiltration and activity of cytotoxic T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. In patients with PDAC, GR expression correlates with high PD-L1 expression, low MHC-I expression, and poor survival. Our results reveal GR signaling in cancer cells as a tumor-intrinsic mechanism of immunosuppression and suggest that therapeutic targeting of GR is a promising way to sensitize pancreatic cancer to immunotherapy.
A tough nitric oxide-eluting hydrogel coating suppresses neointimal hyperplasia on vascular stent
Authors: Chen Yin , Gao Peng , Huang Lu , Tan Xing , Zhou Ningling , Yang Tong , Qiu Hua , Dai Xin , Michael Sean , Tu Qiufen , Huang Nan , Guo Zhihong , Zhou Jianhua , Yang Zhilu , Wu Hongkai
Published: December 2021

Vascular stent is viewed as one of the greatest advancements in interventional cardiology. However, current approved stents suffer from in-stent restenosis associated with neointimal hyperplasia or stent thrombosis. Herein, we develop a nitric oxide-eluting (NOE) hydrogel coating for vascular stents inspired by the biological functions of nitric oxide for cardiovascular system. Our NOE hydrogel is mechanically tough and could selectively facilitate the adhesion of endothelial cells. Besides, it is non-thrombotic and capable of inhibiting smooth muscle cells. Transcriptome analysis unravels the NOE hydrogel could modulate the inflammatory response and induce the relaxation of smooth muscle cells. In vivo study further demonstrates vascular stents coated with it promote rapid restoration of native endothelium, and persistently suppress inflammation and neointimal hyperplasia in both leporine and swine models. We expect such NOE hydrogel will open an avenue to the surface engineering of vascular implants for better clinical outcomes.
Janus acoustic metascreen with nonreciprocal and reconfigurable phase modulations
Authors: Zhu Yifan , Cao Liyun , Merkel Aurélien , Fan Shi-Wang , Vincent Brice , Assouar Badreddine
Published: December 2021

Integrating different reliable functionalities in metastructures and metasurfaces has become of remarkable importance to create innovative multifunctional compact acoustic, optic or mechanical metadevices. In particular, implementing different wave manipulations in one unique material platform opens an appealing route for developing integrated metamaterials. Here, the concept of Janus acoustic metascreen is proposed and demonstrated, producing two-faced and independent wavefront manipulations for two opposite incidences. The feature of two-faced sound modulations requires nonreciprocal phase modulating elements. An acoustic resonant unit cell with rotating inner core, which produces a bias by a circulating fluid, is designed to achieve high nonreciprocity, leading to decoupled phase modulations for both forward and backward directions. In addition, the designed unit cell consisting of tunable phase modulators is reconfigurable. A series of Janus acoustic metascreens including optional combinations of extraordinary refraction, acoustic focusing, sound absorption, acoustic diffusion, and beam splitting are demonstrated through numerical simulations and experiments, showing their great potential for acoustic wavefront manipulation.
High efficiency laser resonance ionization of plutonium
Authors: Galindo-Uribarri Alfredo , Liu Yuan , Romero Romero Elisa , Stracener Daniel W.
Published: December 2021

Three-step resonance photoionization spectra of plutonium have been studied with Ti:Sapphire lasers for the development of efficient laser ionization schemes for ultra-trace analysis of Pu isotopes by resonance ionization mass spectrometry. We observed eighteen intermediate excited states of even parity in the energy range 35568–36701 $${\text {cm}}^{-1}$$

cm

-
1

, thirteen of them have not been previously documented, and a larger number of high-lying excited states and autoionizing states of odd-parity between 48238 and 49510 $${\text {cm}}^{-1}$$

cm

-
1

. Three-color, three-photon ionization schemes via six intermediate states were evaluated under similar ion source operating conditions. This led to a highly efficient three-step scheme with an overall ionization efficiency of $$51.1 \pm 1.3\%$$

51.1
±
1.3
%

, which is an order of magnitude improvement over the previously reported ionization efficiency for Pu.
Systems biology and machine learning approaches identify drug targets in diabetic nephropathy
Authors: Abedi Maryam , Marateb Hamid Reza , Mohebian Mohammad Reza , Aghaee-Bakhtiari Seyed Hamid , Nassiri Seyed Mahdi , Gheisari Yousof
Published: December 2021

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has become a massive global health burden. Despite considerable efforts, the underlying mechanisms have not yet been comprehensively understood. In this study, a systematic approach was utilized to identify the microRNA signature in DN and to introduce novel drug targets (DTs) in DN. Using microarray profiling followed by qPCR confirmation, 13 and 6 differentially expressed (DE) microRNAs were identified in the kidney cortex and medulla, respectively. The microRNA-target interaction networks for each anatomical compartment were constructed and central nodes were identified. Moreover, enrichment analysis was performed to identify key signaling pathways. To develop a strategy for DT prediction, the human proteome was annotated with 65 biochemical characteristics and 23 network topology parameters. Furthermore, all proteins targeted by at least one FDA-approved drug were identified. Next, mGMDH-AFS, a high-performance machine learning algorithm capable of tolerating massive imbalanced size of the classes, was developed to classify DT and non-DT proteins. The sensitivity, specificity, accuracy, and precision of the proposed method were 90%, 86%, 88%, and 89%, respectively. Moreover, it significantly outperformed the state-of-the-art (P-value ≤ 0.05) and showed very good diagnostic accuracy and high agreement between predicted and observed class labels. The cortex and medulla networks were then analyzed with this validated machine to identify potential DTs. Among the high-rank DT candidates are Egfr, Prkce, clic5, Kit, and Agtr1a which is a current well-known target in DN. In conclusion, a combination of experimental and computational approaches was exploited to provide a holistic insight into the disorder for introducing novel therapeutic targets.
A rapid point of care CC16 kit for screening of occupational silica dust exposed workers for early detection of silicosis/silico-tuberculosis
Authors: Nandi Shyam Sundar , Lambe Upendra P. , Sarkar Kamalesh , Sawant Sonali , Deshpande Jagadish
Published: December 2021

Silicosis is an irreversible, incurable and progressive occupational disease caused by prolonged exposure to crystalline-silica dust while working in the relevant industries. Conventionally diagnosis is done by chest radiology, often in an advanced stage as early symptoms often go unnoticed. Early detection and necessary intervention (secondary prevention) could be a realistic possible control strategy for controlling silicosis as no effective treatment is available to stop and/or reverse the pathological process. Additionally, these patients are also vulnerable to pulmonary tuberculosis, which often becomes difficult to treat and with uncertain treatment outcome. Considering India has a huge burden of silicosis and silico-tuberculosis, a rapid and inexpensive screening method was realized to be an urgent need for early detection of silicosis among silica dust exposed workers. Serum club cell protein 16 (CC16) is evidenced to be a useful proxy screening marker for early detection of silicosis as evidenced from the recent research work of ICMR-National Institute of Occupational Health (ICMR-NIOH), India. In this study a lateral-flow assay for semi-quantitative estimation of serum CC16 level was developed. The detection was performed using gold nanoparticles conjugated anti-CC16 monoclonal antibodies. A sum of 106 serum samples was tested to do the performance evaluation of the assay. A concentration of 6 ng/ml or less produced one band, 6.1–9 ng/ml produced two bands, while more than 9 ng/ml produced all the three bands at the test zone. The sensitivity of the assay was 100% while the specificity was 95%. This assay may be used as a sensitive tool for periodic screening of silica dust exposed vulnerable workers for early detection of silicosis in them.
A host-directed macrocyclic peptide therapeutic for MDR gram negative bacterial infections
Authors: Schaal Justin B. , Eriguchi Yoshihiro , Tran Dat Q. , Tran Patti A. , Hawes Chase , Cabebe Anthony E. , Pike Kaitlyn , Trinh Katie , Ouellette André J. , Selsted Michael E.
Published: December 2021

The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis. MTD12813 is a theta-defensin inspired cyclic peptide that is highly effective against CRE pathogens K. pneumoniae and E. coli in vivo. In mouse septicemia models, single dose administration of MTD12813 significantly enhanced survival by promoting rapid host-mediated bacterial clearance and by modulating pathologic cytokine responses, restoring immune homeostasis, and preventing lethal septic shock. The peptide lacks direct antibacterial activity in the presence of mouse serum or in peritoneal fluid, further evidence for its indirect antibacterial mode of action. MTD12813 is highly stable in biological matrices, resistant to bacterial proteases, and nontoxic to mice at dose levels 100 times the therapeutic dose level, properties which support further development of the peptide as a first in class anti-infective therapeutic.
In vitro additive effects of dalbavancin and rifampicin against biofilm of Staphylococcus aureus
Authors: Jacob Benjamin , Makarewicz Oliwia , Hartung Anita , Brodt Steffen , Roehner Eric , Matziolis Georg
Published: December 2021

Dalbavancin is a novel glycopeptide antibiotic approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). It is characterized by a potent activity against numerous Gram-positive pathogens, a long elimination half-life and a favorable safety profile. Most recently, its application for the treatment of periprosthetic joint infections (PJIs) was introduced. The aim of this study was to proof our hypothesis, that dalbavancin shows superior efficacy against staphylococcal biofilms on polyethylene (PE) disk devices compared with vancomycin and additive behavior in combination with rifampicin. Staphylococcus aureus biofilms were formed on PE disk devices for 96 h and subsequently treated with dalbavancin, vancomycin, rifampicin and dalbavancin-rifampicin combination at different concentrations. Quantification of antibacterial activity was determined by counting colony forming units (CFU/ml) after sonification of the PE, serial dilution of the bacterial suspension and plating on agar-plates. Biofilms were additionally life/dead-stained and visualized using fluorescence microscopy. Dalbavancin presented superior anti-biofilm activity compared to vancomycin. Additive effects of the combination dalbavancin and rifampicin were registered. Dalbavancin combined with rifampicin presents promising anti-biofilm activity characteristics in vitro. Further in vivo studies are necessary to establish recommendations for the general use of dalbavancin in the treatment of PJIs.
Comparable genetic alteration profiles between gastric cancers with current and past Helicobacter pylori infection
Authors: Tsuyuki Sho , Takeshima Hideyuki , Sekine Shigeki , Yamagata Yukinori , Ando Takayuki , Yamashita Satoshi , Maeda Shin , Yoshikawa Takaki , Ushijima Toshikazu
Published: December 2021

Gastric cancers can develop even after Helicobacter pylori (H. pylori) eradication in 0.2–2.9% cases per year. Since H. pylori is reported to directly activate or inactivate cancer-related pathways, molecular profiles of gastric cancers with current and past H. pylori infection may be different. Here, we aimed to analyze whether profiles of point mutation and gene amplification are different between the two groups. Current or past infection by H. pylori was determined by positive or negative amplification of H. pylori jhpr3 gene by PCR, and past infection was established by the presence of endoscopic atrophy. Among the 90 gastric cancers analyzed, 55 were with current infection, and 35 were with past infection. Target sequencing of 46 cancer-related genes revealed that 47 gastric cancers had 68 point mutations of 15 different genes, such as TP53 (36%), KRAS (4%), and PIK3CA (4%) and that gene amplification was present for ERBB2, KRAS, PIK3CA, and MET among the 26 genes assessed for copy number alterations. Gastric cancers with current and past infection had similar frequencies of TP53 mutations (38% and 31%, respectively; p = 0.652) and oncogene activation (20% and 29%, respectively; p = 0.444). Gastric cancers with current and past infection had comparable profiles of genetic alterations.
Design and implementation of an illumination system to mimic skyglow at ecosystem level in a large-scale lake enclosure facility
Authors: Jechow Andreas , Schreck Günther , Kyba Christopher C. M. , Berger Stella A. , Bistarelli Lukas Thuile , Bodenlos Matthias , Gessner Mark O. , Grossart Hans-Peter , Kupprat Franziska , Nejstgaard Jens C. , Pansch Andreas , Penske Armin , Sachtleben Michael , Shatwell Tom , Singer Gabriel A. , Stephan Susanne , Walles Tim J. W. , Wollrab Sabine , Zielinska-Dabkowska Karolina M. , Hölker Franz
Published: December 2021

Light pollution is an environmental stressor of global extent that is growing exponentially in area and intensity. Artificial skyglow, a form of light pollution with large range, is hypothesized to have environmental impact at ecosystem level. However, testing the impact of skyglow at large scales and in a controlled fashion under in situ conditions has remained elusive so far. Here we present the first experimental setup to mimic skyglow at ecosystem level outdoors in an aquatic environment. Spatially diffuse and homogeneous surface illumination that is adjustable between 0.01 and 10 lx, resembling rural to urban skyglow levels, was achieved with white light-emitting diodes at a large-scale lake enclosure facility. The illumination system was enabled by optical modeling with Monte-Carlo raytracing and validated by measurements. Our method can be adapted to other outdoor and indoor skyglow experiments, urgently needed to understand the impact of skyglow on ecosystems.
Pyrazoline derivatives as promising novel antischistosomal agents
Authors: Morais Cristiane S. , Mengarda Ana C. , Miguel Fábio B. , Enes Karine B. , Rodrigues Vinícius C. , Espírito-Santo Maria Cristina C. , Siyadatpanah Abolghasem , Wilairatana Polrat , Couri Mara R. C. , de Moraes Josué
Published: December 2021

Praziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15–31) and three pyrazoles (32–34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 μM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 µM. Additionally, compound 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure–activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies’ filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.
Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with abnormal accumulation of specific lipids
Authors: Yamada Tomohiro , Horikawa Makoto , Sato Tomohito , Kahyo Tomoaki , Takanashi Yusuke , Ushirozako Hiroki , Kurosu Kenta , Al Mamun Md. , Mihara Yuki , Oe Shin , Arima Hideyuki , Banno Tomohiro , Yosida Go , Hasegawa Tomohiko , Yamato Yu , Matsuyama Yukihiro , Setou Mitsutoshi
Published: December 2021

Ligamentum flavum hypertrophy (HLF) is the most important component of lumbar spinal canal stenosis (LSCS). Analysis of hypertrophied ligamentum flavum (HLF) samples from patients with LSCS can be an important que. The current study analyzed the surgical samples of HLF samples in patients with LCSC using quantitative and qualitative high performance-liquid chromatography and mass spectrometry. We collected ligamentum flavum (LF) tissue from twelve patients with LSCS and from four patients with lumbar disk herniation (LDH). We defined LF from LSCS patients as HLF and that from LDH patients as non-hypertrophied ligamentum flavum (NHLF). Total lipids were extracted from the LF samples and evaluated for quantity and quality using liquid chromatography and mass spectrometry. The total lipid amount of the HLF group was 3.6 times higher than that of the NHLF group. Phosphatidylcholines (PCs), ceramides (Cers), O-acyl-ω-hydroxy fatty acids (OAHFAs), and triglycerides (TGs) in the HLF group were more than 32 times higher than those of the NHLF group. PC(26:0)+H+, PC(25:0)+H+, and PC(23:0)+H+ increased in all patients in the HLF group compared to the NHLF group. The thickness of the LF correlated significantly with PC(26:0)+H+ in HLF. We identified the enriched specific PCs, Cers, OAHFAs, and TGs in HLF.
Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer
Authors: Gansmo Liv B. , Sofiyeva Nigar , Bjørnslett Merete , Romundstad Pål , Hveem Kristian , Vatten Lars , Dørum Anne , Lønning Per E. , Knappskog Stian
Published: December 2021

A germline 29.5-kb deletion variant removes the 3’ end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61–0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50–0.95; p = 0.018 and OR = 0.77; CI = 0.62–0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59–1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69–1.00).
Graphene oxide and fluorescent aptamer based novel biosensor for detection of 25-hydroxyvitamin D3
Authors: Gupta Ritika , Kaul Sunaina , Singh Vishal , Kumar Sandeep , Singhal Nitin Kumar
Published: December 2021

For maintaining the healthy metabolic status, vitamin D is a beneficial metabolite stored majorly in its pre-activated form, 25-hydroxyvitamin D3 (25(OH)D3). Due to its important role in bone strengthening, the study was planned to quantify 25(OH)D3 levels in our blood. Quantification techniques for 25(OH)D3 are costly thus requiring a need for a low cost, and sensitive detection methods. In this work, an economic, and sensitive sensor for the detection of 25(OH)D3 was developed using aptamer and graphene oxide (GO). Aptamer is an oligonucleotide, sensitive towards its target, whereas, GO with 2D nanosheets provides excellent quenching surface. Aptamer labeled with fluorescein (5’, 6-FAM) is adsorbed by π–π interaction on the GO sheets leading to quenching of the fluorescence due to Förster resonance energy transfer (FRET). However, in the presence of 25(OH)D3, a major portion of aptamer fluorescence remains unaltered, due to its association with 25(OH)D3. However, in the absence, aptamer fluorescence gets fully quenched. Fluorescence intensity quenching was monitored using fluorescence spectrophotometer and agarose gel based system. The limit of detection of 25(OH)D3 by this method was found to be 0.15 µg/mL whereas when GO-COOH was used, limit of detection was improved to 0.075 µg/mL. Therefore, this method could come up as a new sensing method in the field of vitamin D detection.
Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload
Authors: Shao Dan , Zhai Peiyong , Hu Chengchen , Mukai Risa , Sciarretta Sebastiano , Del Re Dominic , Sadoshima Junichi
Published: December 2021

The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.
Thoracic skeletal muscle quantification using computed tomography and prognosis of elderly ICU patients
Authors: Moon Sung Woo , Kim Song Yee , Choi Ji Soo , Leem Ah Young , Lee Su Hwan , Park Moo Suk , Kim Young Sam , Chung Kyung Soo
Published: December 2021

In elderly ICU patients, the prevalence of skeletal muscle loss is high. Longitudinal effect of thoracic muscles, especially in elderly ICU patients, are unclear although skeletal muscle loss is related with the short- and long-term outcomes. This study aimed to evaluate whether pectoralis muscle mass loss could be a predictor of prognosis in elderly ICU patients. We retrospectively evaluated 190 elderly (age > 70 years) patients admitted to the ICU. We measured the cross-sectional area (CSA) of the pectoralis muscle (PMCSA) at the fourth vertebral region. CT scans within two days before ICU admission were used for analysis. Mortality, prolonged mechanical ventilation, and longitudinal changes in Sequential Organ Failure Assessment (SOFA) scores were examined. PMCSA below median was significantly related with prolonged ventilation (odds ratio 2.92) and a higher SOFA scores during the ICU stay (estimated mean = 0.94). PMCSA below median was a significant risk for hospital mortality (hazards ratio 2.06). In elderly ICU patients, a low ICU admission PMCSA was associated with prolonged ventilation, higher SOFA score during the ICU stay, and higher mortality. Adding thoracic skeletal muscle CSA at the time of ICU admission into consideration in deciding the therapeutic intensity in elderly ICU patients may help in making medical decisions.
Plant age at the time of ozone exposure affects flowering patterns, biotic interactions and reproduction of wild mustard
Authors: Duque Laura , Poelman Erik H. , Steffan-Dewenter Ingolf
Published: December 2021

Exposure of plants to environmental stressors can modify their metabolism, interactions with other organisms and reproductive success. Tropospheric ozone is a source of plant stress. We investigated how an acute exposure to ozone at different times of plant development affects reproductive performance, as well as the flowering patterns and the interactions with pollinators and herbivores, of wild mustard plants. The number of open flowers was higher on plants exposed to ozone at earlier ages than on the respective controls, while plants exposed at later ages showed a tendency for decreased number of open flowers. The changes in the number of flowers provided a good explanation for the ozone-induced effects on reproductive performance and on pollinator visitation. Ozone exposure at earlier ages also led to either earlier or extended flowering periods. Moreover, ozone tended to increase herbivore abundance, with responses depending on herbivore taxa and the plant age at the time of ozone exposure. These results suggest that the effects of ozone exposure depend on the developmental stage of the plant, affecting the flowering patterns in different directions, with consequences for pollination and reproduction of annual crops and wild species.
Quantitative modeling of carcinogenesis induced by single beams or mixtures of space radiations using targeted and non-targeted effects
Authors: Shuryak Igor , Sachs Rainer K. , Brenner David J.
Published: December 2021

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Here we used a TE + NTE model to analyze data on APC(1638N/+) mouse tumorigenesis induced by space-relevant doses of protons, 4He, 12C, 16O, 28Si or 56Fe ions, or γ rays. A customized weighted Negative Binomial distribution was used to describe the radiation type- and dose-dependent data variability. This approach allowed detailed quantification of dose–response shapes, NTE- and TE-related model parameters, and radiation quality metrics (relative biological effectiveness, RBE, and radiation effects ratio, RER, relative to γ rays) for each radiation type. Based on the modeled responses for each radiation type, we predicted the tumor yield for a Mars-mission-relevant mixture of these radiations, using the recently-developed incremental effect additivity (IEA) synergy theory. The proposed modeling approach can enhance current knowledge about quantification of space radiation quality effects, dose response shapes, and ultimately the health risks for astronauts.
Fishing intensification as response to Late Holocene socio-ecological instability in southeastern South America
Authors: Toso Alice , Hallingstad Ellen , McGrath Krista , Fossile Thiago , Conlan Christine , Ferreira Jessica , da Rocha Bandeira Dione , Giannini Paulo César Fonseca , Gilson Simon-Pierre , de Melo Reis Bueno Lucas , Bastos Murilo Quintans Ribeiro , Borba Fernanda Mara , do Santos Adriana M. P. , Colonese André Carlo
Published: December 2021

The emergence of plant-based economies have dominated evolutionary models of Middle and Late Holocene pre-Columbian societies in South America. Comparatively, the use of aquatic resources and the circumstances for intensifying their exploitation have received little attention. Here we reviewed the stable carbon and nitrogen isotope composition of 390 human individuals from Middle and Late Holocene coastal sambaquis, a long-lasting shell mound culture that flourished for nearly 7000 years along the Atlantic Forest coast of Brazil. Using a newly generated faunal isotopic baseline and Bayesian Isotope Mixing Models we quantified the relative contribution of marine resources to the diet of some of these groups. Through the analysis of more than 400 radiocarbon dates we show that fishing sustained large and resilient populations during most of the Late Holocene. A sharp decline was observed in the frequency of sambaqui sites and radiocarbon dates from ca. 2200 years ago, possibly reflecting the dissolution of several nucleated groups into smaller social units, coinciding with substantial changes in coastal environments. The spread of ceramics from ca. 1200 years ago is marked by innovation and intensification of fishing practices, in a context of increasing social and ecological instability in the Late Holocene.
Toxicity of internalized polyalanine to cells depends on aggregation
Authors: Iizuka Yutaro , Owada Ryuji , Kawasaki Takayasu , Hayashi Fumio , Sonoyama Masashi , Nakamura Kazuhiro
Published: December 2021

In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.