bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of tart cherries (Prunus Cerasus) on vascular function and the urinary metabolome: a randomised placebo-controlled pilot study
Authors: Kimble Rachel , Murray Lucy , Keane Karen M. , Haggerty Karen , Howatson Glyn , Lodge John K.
Published: September 2021

Montmorency tart cherries (MC) have been found to modulate indices of vascular function with interventions of varying duration. The objective of this preliminary study was to identify the chronic effects of MC supplementation on vascular function and the potential for urinary metabolomics to provide mechanistic evidence. We performed a placebo-controlled, double-blind, randomised study on 23 healthy individuals (18M, 7F) that consumed 30 ml MC or a placebo twice daily for 28 days. Whole body measures of vascular function and spot urine collections were taken at baseline and after supplementation. There were no significant changes to vascular function including blood pressure and arterial stiffness. Urinary metabolite profiling highlighted significant changes (P < 0⋅001) with putative discriminatory metabolites related to tryptophan and histidine metabolism. Overall, MC supplementation for 28 days does not improve indices of vascular function but changes to the urinary metabolome could be suggestive of potential mechanisms.
School-Based Abuse Prevention Programs for Children With Disabilities: A Qualitative Study of Components and Methods
Authors: Nyberg Amanda , Ferm Ulrika , Bornman Juan
Published: September 2021

Children with communicative and/or intellectual disabilities are disproportionally affected by abuse when compared to their typically developing peers. In this study, we investigate the key components and teaching methods for abuse prevention programs for use in special schools. The views of parents of children with disabilities were obtained via semistructured individual interviews (n = 6), and the views of special education teachers (n = 7) and practitioners who work with child victims with disabilities (n = 5) via focus groups. Results were coded using thematic analysis and are reported using the behavioural ecological model. Results indicate that children’s rights and empowerment were seen as key components. Videos and role-play were reported as effective interactive teaching methods. Using augmentative and alternative communication strategies, such as pictorial support and manual signs, were thought to increase children’s understanding and participation. We conclude that teacher involvement in school-based abuse prevention is essential to meet the needs of children with disabilities.
Holocene regional climate change and formation of southern Ontario's largest swamp inferred from a kettle-lake pollen record
Authors: Byun Eunji , Cowling Sharon A. , Finkelstein Sarah A.
Published: September 2021

Greenock Swamp wetland complex is one of few remaining natural wetlands in the Great Lakes region and, at 89 km2in areal extent, is currently the largest hardwood swamp in southern Ontario, Canada. We present here pollen and sediment records from a kettle hole (Schmidt Lake) and adjacentThuja occidentalisswamp to reconstruct regional paleoclimate and vegetation history, and to assess the timing and development of the swamp ecosystem and associated carbon stocks. Pollen-inferred paleoclimate reconstructions show the expected warming in the Early Holocene, and indicate the Mid-Holocene initiation of lake-effect snow. This enhanced snowfall may have maintained high water tables in the adjacent wetland since ca. 8300 years ago, promoting the establishment of a swamp dominated byThuja occidentalis. Carbon accumulation rates in a >2-m-long peat core collected from aThuja occidentalisstand adjacent to Schmidt Lake are 30–40 g C/m2/yr, which is higher than the average of northern high-latitude peatlands. Using topographic and hydrological parameters, we estimated that mean swamp peat thicknesses could exceed 2 m. Thus, this study encourages future investigations on temperate swamps from the perspective of hitherto underestimated Holocene carbon sinks and shows the importance of regional hydroclimate in supporting swamp ecosystems.
Violence in the American Imaginary: Gender, Race, and the Politics of Superheroes
Authors: PHILIPS MENAKA
Published: September 2021

What does the superhero—an icon of the American imaginary—communicate about the politics of violence? Responding to nationwide protests of police brutality in 2020, law enforcement officers adopted the skull logo of The Punisher, an exceptionally violent fictional vigilante. That adoption signals what I call theprivilege of violence: the force individuals may deploy based on normative expectations concerning gender and race. Comparing Marvel-Netflix productions includingThe Punisherseries, I identify three modes of violence in operation: theunrestrictedrage of a white male vigilante, thevulnerabilityof a feminist heroine, and thesacrificialcontrol of a Black male hero. The article demonstrates the gendered and racialized conditions under which heroic violence is rendered legitimate to American audiences. As I conclude, Punisher’s unrestricted violence valorizes white male grievance, and this is precisely what appeals to armed agents of the American state.
Payments and Penalties for Democracy: Gendered Electoral Financing in Action Worldwide
Authors: MURIAAS RAGNHILD , MAZUR AMY G. , HOARD SEASON
Published: September 2021

This article examines the interplay between gendered electoral financing (GEF) and other crucial factors in democratic elections worldwide to determine whether, how, and why these understudied mechanisms help achieve gender balance in national parliaments. Integrating qualitative comparative analysis and minimalist causal mechanism case studies, the sequential mixed methods study of GEF implementation in 31 elections in 17 countries shows that enhanced gender balance is achieved when GEF is combined with several conditions, providing a much-needed financial incentive—payments and penalties—for party gatekeepers and eligible women to change their behavior. In successful cases of top-down GEF implementation, gender quotas combine with a PR electoral system or a 15% minimum of women MPs, a measure developed for this study. Success in bottom-up GEF implementation is unexpected and complex and occurs without a quota. The article ends with a discussion of the research agenda, policy recommendations, and implications for the pursuit of democratic quality.
Intellectualism, Anti-Intellectualism, and Epistemic Hubris in Red and Blue America
Authors: BARKER DAVID C. , DETAMBLE RYAN , MARIETTA MORGAN
Published: September 2021

Epistemic hubris—the expression of unwarranted factual certitude—is a conspicuous yet understudied democratic hazard. Here, in two nationally representative studies, we examine its features and analyze its variance. We hypothesize, and find, that epistemic hubris is (a) prevalent, (b) bipartisan, and (c) associated with both intellectualism (an identity marked by ruminative habits and learning for its own sake) and anti-intellectualism (negative affect toward intellectuals and the intellectual establishment). Moreover, these correlates of epistemic hubris are distinctly partisan: intellectuals are disproportionately Democratic, whereas anti-intellectuals are disproportionately Republican. By implication, we suggest that both the intellectualism of Blue America and the anti-intellectualism of Red America contribute to the intemperance and intransigence that characterize civil society in the United States.
Overweight and obesity in polycystic ovary syndrome: association with inflammation, oxidative stress and dyslipidaemia
Authors: Perovic Blagojevic Iva M. , Vekic Jelena Z. , Macut Djuro P. , Ignjatovic Svetlana D. , Miljkovic-Trailovic Milica M. , Zeljkovic Aleksandra R. , Spasojevic-Kalimanovska Vesna V. , Bozic-Antic Ivana B. , Bjekic-Macut Jelica D. , Kastratovic-Kotlica Biljana A. , Andric Zoran G. , Ilic Dusan S. , Kotur-Stevuljevic Jelena M.
Published: September 2021

Polycystic ovary syndrome (PCOS) is associated with altered lipid profile and increased small, dense LDL particles (sdLDL). Considering that paraoxonase 1 (PON1) is an antioxidative enzyme located on HDL particles, the aim of this study was to investigate the connection between oxidative stress (OS) and PON1 activity with lipoprotein subclasses in PCOS depending on obesity. In 115 PCOS patients, lipoprotein subclasses distributions were determined by gradient gel electrophoresis. OS status was assessed by total oxidative status (TOS), advanced oxidation protein products, malondialdehyde (MDA), prooxidant-antioxidant balance (PAB), total antioxidative status (TAS) and superoxide dismutase (SOD) and PON1 activity. Overweight/obese PCOS patients (n 55) had increased OS compared with normal weight patients (n 60). In addition, overweight/obese group had lower HDL size and higher proportion of HDL 3a subclasses (P < 0·05). PAB was in negative correlation with HDL 2a (P < 0·001), whereas MDA and SOD correlated positively with HDL 3 subclasses (P < 0·05). Serum PON1 activity was positively associated with proportions of PON1 activity on HDL 2b (P < 0·05) and 2a (P < 0·01), but negatively with the proportion on HDL 3 particles (P < 0·01). LDL B phenotype patients had increased TAS, SOD and PON1 activity on HDL 2b, but decreased PON1 activity on HDL 3 subclasses. OS is associated with altered lipoprotein subclasses distribution in PCOS patients. Obesity in PCOS affects the profile of HDL subclasses, reflected through the reduced proportion of PON1 activity on HDL 3 subclasses in the presence of sdLDL particles.
Food group intake of children and adolescents (6–18 years) on a vegetarian, vegan or omnivore diet: results of the VeChi Youth Study
Authors: Alexy Ute , Fischer Morwenna , Weder Stine , Längler Alfred , Michalsen Andreas , Keller Markus
Published: September 2021

Plant-based, i.e. vegetarian (without meat and fish) or vegan (exclusively plant-based foods) diets are in trend also among children and adolescents, but data on food intake in this group are lacking. Here, we compare the consumption of food groups of vegetarian (n145), vegan (n110) and omnivore (n135) children and adolescents (6–18 years) in Germany using data of the VeChi Youth Study. Each food item reported in 3 d weighed dietary records was assigned to one of eighteen food groups and individual mean intake per day (g/MJ) was calculated. Group differences were assessed using covariance analyses adjusted for age, sex and other covariates. For food groups with a high number of non-consumers, non-parametric Kruskal–Wallis tests were run. Pairwise comparison of vegetarian and vegan groups indicated significantly higher intakes of legumes, nuts, milk alternatives (allP= 0·0003) and meat alternatives (P= 0·0065) among vegan subjects. Intake of these food groups of omnivore participants was low (Q3:0·0 g/MJ for legumes, milk alternatives and meat alternatives, 0·5 g/MJ for nuts). Dairy intake of vegetarians (11·6 g/MJ) was significantly lower than of omnivore subjects (24·7 g/MJ) (P= 0·0003). Intake of fats/oils and sweet foods was lowest in vegan compared with vegetarian and omnivore participants (P< 0·05). Whole grain intake was higher in vegan participants (14·5 g/MJ) than of vegetarian (9·1 g/MJ) and omnivore (6·5 g/MJ) participants (P= 0·0003). Longitudinal studies are necessary to evaluate the long-term health consequences of vegetarian, vegan and omnivore food patterns, especially in childhood and adolescence.
Liver and kidney function markers among gym users: the role of dietary supplement usage
Authors: Schlickmann Diene S. , Molz Patrícia , Brand Caroline , dos Santos Caroline , da Silva Thalia G. , Rieger Alexandre , Benito Pedro J. , Reuter Cézane P. , Renner Jane D. P. , Rech Franke Silvia I.
Published: September 2021

Dietary supplements have been increasingly used by gym users and are often consumed without the guidance of a health professional. Moreover, the indiscriminate supplements use can have adverse health effects, such as changes in liver and kidney function. The aim of this study was to verify the association between dietary supplements intake with alterations in the liver and kidney function among gym users. A cross-sectional study was conducted with 594 gym users (mean age 37 (sd 14) years, 55·2 % women) from a city in southern Brazil. A questionnaire was used to evaluate the use of dietary supplements. The markers of the liver (alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, γ-glutamyltransferase) and renal (creatinine and urea) function were also evaluated on a subsample of the study population. Data were analysed by binary logistic regression, adjusted for sex, age and education. The prevalence of dietary supplement intake was 36·0 %. Individuals who intake dietary supplements showed a higher prevalence to present slight alterations in the AST enzyme and in the urea after adjustments for potential confounders. In conclusion, the use of dietary supplement was associated with slight alterations in AST enzyme and in the urea among gym users. These findings show the importance of using supplements correctly, especially with guidance from professionals trained to avoid possible risks to health.
Comparing Fading of Oral Narrative Features in Three Balochi Dialects
Authors: NOURZAEI MARYAM
Published: September 2021

This paper discusses discourse features such as tail-head linkage and repetition, development devices, associative strategies and subordination in oral narrative texts in the Koroshi (KoB), Sistani (SiB), and Coastal (CoB) dialects of Balochi, all of which belong to the North-West branch of the Iranian language family. The frequency with which these features vary with the dialect, and the variation can be attributed to different stages of orality. Three stages have been identified, with CoB and SiB at the ends of the cline and KoB located in between. CoB is the most conservative dialect, as different aspects of its grammar also show; it demonstrates a pure orality state by its frequent use of tail-head linkage, repetition and juxtaposition, and by the relative infrequency with which it employs associative and subordination strategies. SiB and its close relation Turkmenistan Balochi [TB])1 use associative and subordination strategies more frequently, have fully lexicalised development devices and seldom employs tail-head linkage, repetition and juxtaposition. This loss of oral techniques demonstrates that the state of narration in SiB has switched from oral to written style. Finally, KoB represents a language in a state of transition by using more unmarked tail-head linkage, repetition and juxtaposition and by a strong tendency to employ subordination strategies.
Measuring satisfaction with democracy: how good are different scales across countries and languages?
Authors: Poses Carlos , Revilla Melanie
Published: September 2021

The Satisfaction With Democracy (SWD) indicator is very often used in social sciences’ research. However, while there is debate about which concept it measures, the discussion about the size of its measurement errors (how well it measures the underlying concept ‘satisfaction with the way democracy works’) is scarce. Nonetheless, measurement errors can affect the results and threaten comparisons across studies, countries and languages. Thus, in this paper, we estimated the measurement quality (complement of measurement errors) of the SWD indicator for 7 response scales across 38 country-language groups, using three multitrait-multimethod experiments from the European Social Survey. Results show that measurement errors explain from 16% (11-point scale) to 54% (4-point scale) of the variance in the observed responses. Additionally, we provide insights to improve questionnaire design and evaluate the indicator’s comparability across scales, countries and languages.
Start Small, not Random: Why does Justifying your Time-Lag Matter?
Authors: Griep Yannick , Vranjes Ivana , Kraak Johannes M. , Dudda Leonie , Li Yingjie
Published: September 2021

Repeated measurement designs have been growing in popularity in the fields of Organizational Behavior and Work and Organizational Psychology. This brings up questions regarding the appropriateness of time-lag choices and validity of justification used to make time-lag decisions in the current literature. We start by explaining how time-lag choices are typically made and explain issues associated with these approaches. Next, we provide some insights into how an optimal time-lag decision should be made and the importance of time-sensitive theory building in helping guide these decisions. Finally, we end with some brief suggestions as to how authors can move forward by urging them to explicitly address temporal dynamics in their research, and by advocating for descriptive studies with short time-lags, which are needed to uncover how the changes happen over time.
Agricultural Intensification and Soil Fertility in Atlantic Spain, 1750–1890
Authors: Corbacho González Beatriz , Padró Caminal Roc
Published: September 2021

This article describes the intensification process of agriculture and its environmental limits regarding soil fertility in the rural community of Fonsagrada, in the inner region of Galicia in northwestern Spain. It addresses changes in land use, crops, and agricultural productivity between 1750 and 1890, framed within the theory of social metabolism and based on the method of nutrient balances. That technique measures nitrogen, phosphorus, and potassium flows across the landscape within a given agro-ecosystem to assess its biophysical functioning and to detect environmental constraints related to management. The intensification of cropland resulted in net losses of potassium in outlying rough grazing land and hay meadows that served as the sources of cropland nutrients. Agricultural intensification was possible due to the close stabling of livestock, which allowed for more manure availability. Doing so, however, deprived pastureland of nutrient recover through manure deposition, which created a metabolic rift in the agro-ecosystem.
History of knotweed (Fallopiaspp.) invasiveness
Authors: Drazan Dallas , Smith Alan G. , Anderson Neil O. , Becker Roger , Clark Matthew
Published: September 2021

Knotweed (Fallopiaspp.) is an herbaceous perennial from East Asia that was brought to Europe and North America and, despite control efforts, subsequently spread aggressively on both continents. Data are available on knotweed’s modes of sexual and asexual spread, historical spread, preferred habitat, and ploidy levels. Incomplete information is available on knotweed’s current global geographic distribution and genetic diversity. The chemical composition of knotweed leaves and rhizomes has been partially discovered as related to its ability to inhibit growth and germination of neighboring plant communities via phytochemicals. There is still critical information missing. There are currently no studies detailing knotweed male and female fertility. Specifically, information on pollen viability would be important for further understanding sexual reproduction as a vector of spread in knotweed. This information would help managers determine the potential magnitude of knotweed sexual reproduction and the continued spread of diverse hybrid swarms. The potential range of knotweed and its ability to spread into diverse habitats makes studies on knotweed seed and rhizome cold tolerance of utmost importance, yet to date no such studies have been conducted. There is also a lack of genetic information available on knotweed in the upper Midwest. Detailed genetic information, such as ploidy levels and levels of genetic diversity, would answer many questions about knotweed in Minnesota, including understanding its means of spread, what species are present in what densities, and current levels of hybridization. This literature review summarizes current literature on knotweed to better understand its invasiveness and to highlight necessary future research that would benefit and inform knotweed management in the upper Midwest.
What Can We Know About Recent Past Precipitation Over Africa? Daily Characteristics of African Precipitation From a Large Ensemble of Observational Products for Model Evaluation
Authors: Dosio Alessandro , Pinto Izidine , Lennard Christopher , Sylla Mouhamadou Bamba , Jack Christopher , Nikulin Grigory
Published: September 2021

We assess the daily characteristics of recent past precipitation over Africa by means of a large ensemble of observational products, including reanalysis, gauge‐based, and satellite‐based products. The spatial distribution of seasonal mean precipitation varies considerably amongst products especially over areas where gauge networks are sparse. Large uncertainties in the annual precipitation cycle are visible in particular over the Ethiopian Highlands, the eastern Sahel, the coasts of the Gulf of Guinea, and the Horn of Africa. Interannual variability shows large differences especially amongst reanalysis data sets whereas satellite and gauge‐based products usually show more consistent results.
Controlling Induced Earthquake Magnitude by Cycled Fluid Injection
Authors: Zhu J. B. , Kang J. Q. , Elsworth D. , Xie H. P. , Ju Y. , Zhao J.
Published: September 2021

The possibility of controlling induced earthquake magnitude through managed metering of water injection has yet to be rationalized. Mechanisms of reducing magnitudes of induced events through cycled fluid injection remain unclear. To explore such mechanisms and this possibility, we report experiments with water injection into laboratory faults. Water injection results in early triggering for both single and cycled injection. However, the maximum moment magnitude and total energy of the repeating induced earthquakes during cycled water injection are both lower than those of induced earthquakes induced with continuous injection and for natural earthquakes without water injection. Higher permeability of the host reduces the number of injection‐induced earthquakes but increases their moment. With an increasing number of water injection cycles, both maximum moment and total energy decrease, particularly as permeability decreases, while the number of induced events increases. The moment magnitude of induced events can thereby be controlled through cycled fluid injection.
ENSO‐Based Predictability of a Regional Severe Thunderstorm Index
Authors: Tippett Michael K. , Lepore Chiara
Published: September 2021

Here we use coupled climate model forecasts of Niño 3.4 and a regional (Texas, Oklahoma, Arkansas, and Louisiana) tornado environment index (TEI) to examine the modulation of US severe thunderstorm activity by the El Niño‐Southern Oscillation (ENSO). The large number of forecast initializations, leads, and ensemble members reduces sampling variability and increases detail in the analysis. The strongest negative relations between TEI and concurrent Niño 3.4 are found in February and March. Both the average of TEI and its spread are larger during cool ENSO conditions, which raises the question of how predictability differs between warm and cool conditions. Predictability is measured using perfect‐model skill scores. For a deterministic skill score, which is equivalent to signal‐to‐noise ratio, larger spread during cool conditions means less predictability. On the other hand, perfect‐model probabilistic skill scores are slightly higher (higher predictability) during February and March for cool conditions than for warm conditions due to larger probability shifts.
A New Body‐Wave Amplitude Ratio‐Based Method for Imaging Shallow Crustal Structure and Its Application in the Sichuan Basin, Southwestern China
Authors: Wang Xu , Chen Ling , Yao Huajian
Published: September 2021

Shallow crustal velocity and Poisson's ratio structures are of key importance to understand rock properties and near‐surface tectonic deformation and evolution. We propose a novel imaging method to acquire such information at individual stations by joint inversion of amplitude ratios between the horizontal and vertical components of both teleseismic P and S waves. Our synthetic experiments demonstrate the validity of the method in recovering subsurface structures up to ∼8–10 km depth. We apply this method to construct the velocity and Poisson's ratio images along a NW‐SE‐trending seismic array within the Sichuan Basin, southwestern China. The results reveal well developed stratification and localized high Poisson's ratio anomalies, which reflect a long‐term stable sedimentary environment and fault‐related deformation in response to the Cenozoic Tibet–basin collision, consistent with geological observations. Our new method builds a bridge between fine‐scale near‐surface seismic exploration and large‐scale deep passive‐source imaging, especially for areas of weak seismicity.
Tectonic and Geometric Control on Fault Kinematics of the 2021 Mw7.3 Maduo (China) Earthquake Inferred From Interseismic, Coseismic, and Postseismic InSAR Observations
Authors: Zhao Dezheng , Qu Chunyan , Chen Han , Shan Xinjian , Song Xiaogang , Gong Wenyu
Published: September 2021

The 2021 Mw7.3 Maduo (Qinghai, China) earthquake ruptured ∼160 km along a poorly known secondary fault inside the Bayanhar block on the northern Tibetan plateau, which is generally parallel to the Kunlun fault. Here we integrate the interseismic (2015–2020) and coseismic geodetic observations to quantify the interseismic strain rate, fault geometry and coseismic slip distribution. Our results reveal that the seismogenic fault is featured by the low (<20 nanostrain/yr) and nearly undetectable interseismic strain rate. Three‐dimensional displacement fields and coseismic strain maps demonstrate the spatial variations of rupture kinematics due to the change of fault geometry. Our study reveals the steeply north‐dipping fault geometry of the seismogenic fault. The majority of coseismic slip occurred between 0 and 15 km with slight shallow slip deficit, which not penetrates through the inferred elastic upper crust (∼20–25 km). Our study highlights the tectonic and geometric control on fault kinematics of the Maduo earthquake.
Off‐Equatorial Minima Effects on ULF Wave‐Ion Interaction in the Dayside Outer Magnetosphere
Authors: Li Xing‐Yu , Liu Zhi‐Yang , Zong Qiu‐Gang , Zhou Xu‐Zhi , Hao Yi‐Xin , Pollock Craig J. , Russell Christopher T. , Lindqvist Per‐Arne
Published: September 2021

The ultra‐low frequency wave‐particle drift‐bounce resonance in the inner magnetosphere has been studied in detail, due to its important role in particle energization. However, it remains an open question how drift‐bounce resonance manifests in the dayside outer magnetosphere, where particles' orbits show bifurcations because of off‐equatorial magnetic field minima. In this study, we investigate this question, by analyzing Magnetospheric Multiscale observations of the January 20, 2017 event. A test‐particle simulation is conducted to help us understand the observations. The observed pitch angle‐time spectrograms show “pawtrack‐like” structures. We find there are more than two resonant pitch angles at fixed energy, since off‐equatorial minima change the relationship between the bounce (drift) frequency and pitch angle from unimodal function to trimodal function. These results reveal a new drift‐bounce acceleration mechanism in the dayside outer magnetosphere, which potentially affects the efficiency of particle energization during geomagnetic activities like geomagnetic storms.
MicroRNA-26a/b-5p promotes myocardial infarction-induced cell death by downregulating cytochrome c oxidase 5a
Authors: Jung Seung Eun , Kim Sang Woo , Jeong Seongtae , Moon Hanbyeol , Choi Won Seok , Lim Soyeon , Lee Seahyoung , Hwang Ki-Chul , Choi Jung-Won
Published: September 2021

Myocardial infarction (MI) damage induces various types of cell death, and persistent ischemia causes cardiac contractile decline. An effective therapeutic strategy is needed to reduce myocardial cell death and induce cardiac recovery. Therefore, studies on molecular and genetic biomarkers of MI, such as microRNAs (miRs), have recently been increasing and attracting attention due to the ideal characteristics of miRs. The aim of the present study was to discover novel causative factors of MI using multiomics-based functional experiments. Through proteomic, MALDI-TOF-MS, RNA sequencing, and network analyses of myocardial infarcted rat hearts and in vitro functional analyses of myocardial cells, we found that cytochrome c oxidase subunit 5a (Cox5a) expression is noticeably decreased in myocardial infarcted rat hearts and myocardial cells under hypoxic conditions, regulates other identified proteins and is closely related to hypoxia-induced cell death. Moreover, using in silico and in vitro analyses, we found that miR-26a-5p and miR-26b-5p (miR-26a/b-5p) may directly modulate Cox5a, which regulates hypoxia-related cell death. The results of this study elucidate the direct molecular mechanisms linking miR-26a/b-5p and Cox5a in cell death induced by oxygen tension, which may contribute to the identification of new therapeutic targets to modulate cardiac function under physiological and pathological conditions.
MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3
Authors: Singh Sunil Kumar , Kumar Sandeep , Viswakarma Navin , Principe Daniel R. , Das Subhasis , Sondarva Gautam , Nair Rakesh Sathish , Srivastava Piush , Sinha Subhash C. , Grippo Paul J. , Thatcher Gregory R. J. , Rana Basabi , Rana Ajay
Published: September 2021

MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including in cancer. However, the mechanism by which MAP4K4 promotes pancreatic cancer is not fully understood. It is suggested that MAP4K4 might function as a cancer promoter via specific downstream target(s) in an organ-specific manner. Here we identified MLK3 as a direct downstream target of MAP4K4. The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. The phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. Moreover, MAP4K4 is overexpressed in human pancreatic tumors and directly correlates with the disease progression. The MAP4K4-specific pharmacological inhibitor, GNE-495, impedes pancreatic cancer cell growth, migration, induces cell death, and arrests cell cycle progression. Additionally, the GNE-495 reduced the tumor burden and extended survival of the KPC mice with pancreatic cancer. The MAP4K4 inhibitor also reduced MAP4K4 protein expression, tumor stroma, and induced cell death in murine pancreatic tumors. These findings collectively suggest that MLK3 phosphorylation by MAP4K4 promotes pancreatic cancer, and therefore therapies targeting MAP4K4 might alleviate the pancreatic cancer tumor burden in patients.
Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
Authors: Musiu Chiara , Caligola Simone , Fiore Alessandra , Lamolinara Alessia , Frusteri Cristina , Del Pizzo Francesco Domenico , De Sanctis Francesco , Canè Stefania , Adamo Annalisa , Hofer Francesca , Barouni Roza Maria , Grilli Andrea , Zilio Serena , Serafini Paolo , Tacconelli Evelina , Donadello Katia , Gottin Leonardo , Polati Enrico , Girelli Domenico , Polidoro Ildo , Iezzi Piera Amelia , Angelucci Domenico , Capece Andrea , Chen Ying , Shi Zheng-Li , Murray Peter J. , Chilosi Marco , Amit Ido , Bicciato Silvio , Iezzi Manuela , Bronte Vincenzo , Ugel Stefano
Published: September 2021

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.
Postloading insulinemia is independently associated with arterial stiffness in young Japanese persons
Authors: Murai Norimitsu , Saito Naoko , Nii Sayuri , Nishikawa Yuto , Suzuki Asami , Kodama Eriko , Iida Tatsuya , Mikura Kentaro , Imai Hideyuki , Hashizume Mai , Kigawa Yasuyoshi , Tadokoro Rie , Sugisawa Chiho , Endo Kei , Iizaka Toru , Otsuka Fumiko , Ishibashi Shun , Nagasaka Shoichiro
Published: September 2021

Associations of arterial stiffness with glucose, insulin, and proinsulin dynamics during the oral glucose tolerance test (OGTT) remain under debate. The aim of this study was to investigate whether plasma glucose (PG), insulin, and proinsulin (Pro) contribute to arterial stiffness, measured by pulse wave velocity (PWV), in young Japanese persons. PG, immunoreactive insulin (IRI), and Pro levels were determined in 1193 young Japanese subjects (<40 years of age) with normal glucose tolerance or nondiabetic hyperglycemia before and at 30, 60, and 120 min during a 75-g OGTT. Participants were divided into two groups according to the median PWV. Background factors, PG, IRI, and Pro levels during the OGTT, and insulin sensitivity (SI) indices in each group were compared. Several multiple regression analysis models were used to evaluate factors contributing to PWV. All IRI and Pro levels before and after glucose loading and the area under the curve (AUC) values for IRI and Pro increased with higher PWV. 1/HOMA-IR and ISI-Matsuda as measures of SI decreased with higher PWV. The IRI AUC and Pro level before glucose loading (Pro0) were independently associated with PWV, in addition to male sex, heart rate, and mean blood pressure. The IRI AUC had a stronger relationship with PWV than Pro0. The IRI AUC had an independent relationship with PWV, whereas both SI indices did not. Postloading insulinemia, but not reduced SI, was independently associated with arterial stiffness in young Japanese persons.
The SARS-CoV-2 spike protein is vulnerable to moderate electric fields
Authors: Arbeitman Claudia R. , Rojas Pablo , Ojeda-May Pedro , Garcia Martin E.
Published: September 2021

Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.
DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation
Authors: Batra Rajbir Nath , Lifshitz Aviezer , Vidakovic Ana Tufegdzic , Chin Suet-Feung , Sati-Batra Ankita , Sammut Stephen-John , Provenzano Elena , Ali H. Raza , Dariush Ali , Bruna Alejandra , Murphy Leigh , Purushotham Arnie , Ellis Ian , Green Andrew , Garrett-Bakelman Francine E. , Mason Chris , Melnick Ari , Aparicio Samuel A. J. R. , Rueda Oscar M. , Tanay Amos , Caldas Carlos
Published: September 2021

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.
The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors
Authors: Khateb Ali , Deshpande Anagha , Feng Yongmei , Finlay Darren , Lee Joo Sang , Lazar Ikrame , Fabre Bertrand , Li Yan , Fujita Yu , Zhang Tongwu , Yin Jun , Pass Ian , Livneh Ido , Jeremias Irmela , Burian Carol , Mason James R. , Almog Ronit , Horesh Nurit , Ofran Yishai , Brown Kevin , Vuori Kristiina , Jackson Michael , Ruppin Eytan , Deshpande Aniruddha J. , Ronai Ze’ev A.
Published: September 2021

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors.
Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility
Authors: Wen Wanqing , Chen Zhishan , Bao Jiandong , Long Quan , Shu Xiao-ou , Zheng Wei , Guo Xingyi
Published: September 2021

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.
Relief of excited-state antiaromaticity enables the smallest red emitter
Authors: Kim Heechan , Park Woojin , Kim Younghun , Filatov Michael , Choi Cheol Ho , Lee Dongwhan
Published: September 2021

It is commonly accepted that a large π-conjugated system is necessary to realize low-energy electronic transitions. Contrary to this prevailing notion, we present a new class of light-emitters utilizing a simple benzene core. Among different isomeric forms of diacetylphenylenediamine (DAPA), o- and p-DAPA are fluorescent, whereas m-DAPA is not. Remarkably, p-DAPA is the lightest (FW = 192) molecule displaying red emission. A systematic modification of the DAPA system allows the construction of a library of emitters covering the entire visible color spectrum. Theoretical analysis shows that their large Stokes shifts originate from the relief of excited-state antiaromaticity, rather than the typically assumed intramolecular charge transfer or proton transfer. A delicate interplay of the excited-state antiaromaticity and hydrogen bonding defines the photophysics of this new class of single benzene fluorophores. The formulated molecular design rules suggest that an extended π-conjugation is no longer a prerequisite for a long-wavelength light emission.
Structure and function relationship of OqxB efflux pump from Klebsiella pneumoniae
Authors: Bharatham Nagakumar , Bhowmik Purnendu , Aoki Maho , Okada Ui , Sharma Sreevalli , Yamashita Eiki , Shanbhag Anirudh P. , Rajagopal Sreenath , Thomas Teby , Sarma Maitrayee , Narjari Riya , Nagaraj Savitha , Ramachandran Vasanthi , Katagihallimath Nainesh , Datta Santanu , Murakami Satoshi
Published: September 2021

OqxB is an RND (Resistance-Nodulation-Division) efflux pump that has emerged as a factor contributing to the antibiotic resistance in Klebsiella pneumoniae. OqxB underwent horizontal gene transfer and is now seen in other Gram-negative bacterial pathogens including Escherichia coli, Enterobacter cloacae and Salmonella spp., further disseminating multi-drug resistance. In this study, we describe crystal structure of OqxB with n-dodecyl-β-D-maltoside (DDM) molecules bound in its substrate-binding pocket, at 1.85 Å resolution. We utilize this structure in computational studies to predict the key amino acids contributing to the efflux of fluoroquinolones by OqxB, distinct from analogous residues in related transporters AcrB and MexB. Finally, our complementation assays with mutated OqxB and minimum inhibitory concentration (MIC) experiments with clinical isolates of E. coli provide further evidence that the predicted structural features are indeed involved in ciprofloxacin efflux.
Emergence and expansion of highly infectious spike protein D614G mutant SARS-CoV-2 in central India
Authors: Sharma Shashi , Dash Paban Kumar , Sharma Sushil Kumar , Srivastava Ambuj , Kumar Jyoti S. , Karothia B. S. , Chelvam K. T. , Singh Sandeep , Gupta Abhaydeep , Yadav Ram Govind , Yadav Ruchi , Greeshma T. S. , Kushwaha Pramod Kumar , Kumar Ravi Bhushan , Nagar D. P. , Nandan Manvendra , Kumar Subodh , Thavaselvam Duraipandian , Dubey Devendra Kumar
Published: September 2021

COVID-19 has emerged as global pandemic with largest damage to the public health, economy and human psyche.The genome sequence data obtained during the ongoing pandemic are valuable to understand the virus evolutionary patterns and spread across the globe. Increased availability of genome information of circulating SARS-CoV-2 strains in India will enable the scientific community to understand the emergence of new variants and their impact on human health. The first case of COVID-19 was detected in Chambal region of Madhya Pradesh state in mid of March 2020 followed by multiple introduction events and expansion of cases within next three months. More than 5000 COVID-19 suspected samples referred to Defence Research and Development Establishment, Gwalior, Madhya Pradesh were analyzed during the nation -wide lockdown and unlock period. A total of 136 cases were found positive over a span of three months that included virus introduction to the region and its further spread. Whole genome sequences employing Oxford nanopore technology were generated for 26 SARS-CoV-2 circulating in 10 different districts in Madhya Pradesh state of India. This period witnessed index cases with multiple travel histories responsible for introduction of COVID-19 followed by remarkable expansion of virus. The genome wide substitutions including in important viral proteins were identified. The detailed phylogenetic analysis revealed the circulating SARS-CoV-2 clustered in multiple clades including A2a, A4 and B. The cluster-wise segregation was observed, suggesting multiple introduction links and subsequent evolution of virus in the region. This is the first comprehensive whole genome sequence analysis from central India, which revealed the emergence and evolution of SARS-CoV-2 during thenation-wide lockdown and unlock.