bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions
Authors: Britz Hannah , Hanke Nina , Taub Mitchell E. , Wang Ting , Prasad Bhagwat , Fernandez Éric , Stopfer Peter , Nock Valerie , Lehr Thorsten
Published: November 2020

Purpose

To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling.

Methods

PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies.

Results

The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmaxratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmaxratios within 2.0-fold.

Conclusions

Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.
Higher-order metaphysics and the tropes versus universals dispute
Authors: Skiba Lukas
Published: November 2020

Higher-order realists about properties express their view thatthere areproperties with the help of higher-order rather than first-order quantifiers. They claim two types of advantages for this way of formulating property realism. First, certain gridlocked debates about the nature of properties, such as the immanentism versus transcendentalism dispute, are taken to bedissolved(roughly: avoided). Second, a further such debate, the tropes versus universals dispute, is taken to beresolved(roughly: decided). In this paper I first argue that higher-order realism does not in fact resolve the tropes versus universals dispute. In a constructive spirit, I then develop higher-order realism in a way that leads to a dissolution, rather than a resolution, of this dispute too.
Von der „Blobology“ zur atomaren Auflösung der Kryo-Elektronenmikroskopie
Authors: Stark Holger
Published: November 2020

It took almost a century to develop electron microscopy into a powerful method for high-resolution structure determination of proteins. Technical improvements in microscopy, detector technology, and image processing software contributed to the exponential growth of high-resolution structures of protein complexes determined by cryo-electron microscopy in recent years. We now succeeded in breaking another resolution barrier in cryo-electron microscopy and for the first time in achieving true atomic resolution, where single atoms in the protein can indeed be visualized individually. These improvements in cryo-EM indicate that the method will continue to gain importance, not only as a method for structure determination but also in the development of new drugs in pharmaceutical research.
Warum Mikroorganismen Naturstoffe produzieren
Authors: Krespach Mario K. C. , Stroe Maria C. , Brakhage Axel A.
Published: November 2020

A key role in the communication between fungi and bacteria is played by natural products. Many of their encoding gene clusters are silent under standard laboratory conditions. Interspecies “talk” between microorganisms represents an ecological trigger to activate such silent gene clusters and leads to the formation of novel natural products by the involved species. The understanding of both the activation of silent gene clusters and the ecological function of the produced compounds is of importance to reveal functional microbial interactions required to shape microbiomes.
Bioplastikproduktion mithilfe eines extremophilen kathodischen Biofilms
Authors: Jung Tobias , Hackbarth Max , Horn Harald , Gescher Johannes
Published: November 2020

As the atmospheric CO2 concentrations are increasing, its usage as biotechnological substrate becomes a focus area of applied scientists. As a rather new technique to energize the process of CO2 fixation, microbial electrosynthesis offers the advantage to establish continuous processes based on a cathodic biofilm that is supplied with electrical energy provided by renewable resources. Here we present the cathodic biofilm growth of Kyrpidia spormannii, a recently isolated thermophilic organism that is naturally capable of producing the biodegradable biopolymer polyhydroxybutyrate (PHB).
Dependent Arising and Interdependence
Authors: Anālayo Bhikkhu
Published: November 2020

The Buddhist teaching on dependent arising (or dependent origination) concerns specific conditions whose presence is indispensable for something to come into existence. In the early stages of Buddhist history, the overarching concern of this doctrine was to identify the specific causes responsible for the human predicament, with a view to bringing about their cessation so as to become liberated. In later times, Buddhist exegesis developed various perspectives on causality, where in Huayan philosophy in particular the notion of interconnectedness or interdependence arose, according to which all phenomena relate to each other in one way or another. Despite its traction in the contemporary setting, this notion needs to be recognized as a later development that is by no means identical with the basic Buddhist teaching on dependent arising.
Health and welfare in organic livestock production systems—a systematic mapping of current knowledge
Authors: Åkerfeldt Magdalena Presto , Gunnarsson Stefan , Bernes Gun , Blanco-Penedo Isabel
Published: November 2020

This review aimed to systematically map and summarize the status of animal health and welfare in organic production. The prevalence of diseases and behavioural effects in organic dairy cow, beef cattle, sheep, pig, laying hen and broiler chicken were discussed in the context of the organic values and current knowledge on animal health and welfare. In total 166 peer-reviewed scientific publications between 2008 and 2020 were included. No strong evidence for neither inferior nor distinctly higher animal welfare in organic compared with conventional production could be supported. The welfare status of organic livestock is in general good in relation to the OIE definition of animal health and welfare. However, organic systems are still facing several challenges related to animal health and the arising of goal conflicts due to management and practical implications. Greater possibilities to perform species-specific behaviours in organic production systems, however, indicate that the organic standards offer a good framework for high animal welfare management. For organic dairy farmers, the main health problems are similar to those of non-organic farms; especially mastitis and lameness need improvement. Parasites, together with mastitis and lamb mortality, are important welfare issues in organic sheep production. Piglet mortality, leg problems, parasite load and increasing respiratory problems are of major relevance in organic pig production. For organic laying hens, major health challenges relate to feather pecking and cannibalism, parasites and possibilities to express species-specific behaviours. For organic broilers, dermatitis of footpads, hocks and breast are reported as main health issues.
Addressing contract cheating in Kosovo and international practices
Authors: Shala Sabiha , Hyseni-Spahiu Mimoza , Selimaj Afrim
Published: November 2020

Although there is much research on the contract cheating phenomenon, there is very little research on the legal solutions available to address such problems and almost zero research on the contract cheating phenomenon specifically in Kosovo in the Western Balkan region. This article presents the current situation with regard to contract cheating in Kosovo and compares it to western countries, with the aim of identifying the best international practices for combating contract cheating. We also present the results of a study we conducted which suggest that the term “contract cheating” is not well defined in university legal documents, nor is there a consistent understanding of what constitutes contract cheating. Consequently, the perpetrators are not being punished. Results from our online survey also show that 5% to 20% of students use contract cheating services, and they are paying an estimated fee of between 100 and 200 euros and in some cases, more than 250 euros.
On models of blast overpressure effects to the thorax
Authors: Stottmeister Alexander , von Ramin Malte , Schneider Johannes M.
Published: November 2020

Shock waves from explosions can cause lethal injuries to humans. Current state-of the-art models for pressure induced lung injuries were typically empirically derived and are only valid for detonations in free-field conditions. In built-up environments, though, pressure–time histories differ significantly from this idealization and not all explosions exhibit detonation characteristics. Hence, those approaches cannot be deployed. However, the actual correlation between dynamic shock wave characteristics and gradual degree of injury have yet to be fully described. In an attempt to characterize the physical response of the human body to complex shock-wave effects, viscoelastic models were developed in the past (Axelsson and Yelverton, in J Trauma Acute Care Surg 40, 31S–37S, 1996; Stuhmiller et al., in J Biomech. 10.1016/0021-9290(95)00039-9, 1996). We discuss those existing modeling approaches especially in view of their viscoelastic behavior and point out drawbacks regarding their response to standard stimuli. Further, we suggest to fully acknowledge the experimentally anticipated viscoelastic behavior of the effective thorax models by using a newly formulated standard model for viscoelastic solids instead of damped harmonic oscillators. Concerning injury assessment, we discuss the individual injury criteria proposed along with existing models pointing out desirable improvements with respect to complex blast situations, e.g. the necessity to account for repeated exposure (criteria with time-memory), and further adaption with respect to nonlinear gas dynamics inside the lung. Finally, we present an improved modeling approach for complex blast overpressure effects to the thorax with few parameters that is more suitable for the characteristics of complex blast wave propagation than other current models.
Emotion regulation and support from others: Buffering of body dysmorphic symptoms in adolescent and young adult men but not women
Authors: Gardner Alex A. , Hawes Tanya , Zimmer‐Gembeck Melanie J. , Webb Haley J. , Waters Allison M. , Nesdale Drew
Published: November 2020

Introduction

Adolescents and young adults who overemphasize the social values placed on an attractive appearance may develop body dysmorphic symptoms (BDS), defined as over‐preoccupation with perceived appearance flaws and repetitive behaviors to conceal the flaws. Further, research has found that a heightened expectation of judgement and rejection by others because of appearance (i.e., appearance‐based rejection sensitivity [appearance‐RS]) is both a maintaining and an aggravating factor in BDS. This study focused on emotion regulation (ER), appearance‐related support from others and self‐acceptance, expecting they would buffer the negative impact of appearance‐RS on BDS.

Methods

Participants included 782 Australian high school and young university students, aged 14–28 years (M = 17.94 years, 40% male) who completed a survey to report their BDS, appearance‐RS, ER, appearance‐related support from others and self‐acceptance.

Results

Multiple regression analyses revealed that youth reported more BDS when they were higher in appearance‐RS but reported less self‐acceptance, ER, and support from others. Further, the association between appearance‐RS and BDS was weaker when young people reported higher (relative to lower) ER and support from others. However, when three‐way interactions with gender were tested, these buffering effects were only significant for young men.

Conclusion

Findings suggest that ER and appearance‐related support from important others are promising targets for intervention, given they could mitigate the risk of appearance‐RS in young men. However, further research is needed to consider additional factors that buffer against the negative effects of appearance‐RS on BDS for young women.
Music and Metamorphosis in Graeco-Roman Thought
Authors: LeVen Pauline A.
Published: November 2020

Where does music come from? What kind of agency does a song have? What is at the root of musical pleasure? Can music die? These are some of the questions the Greeks and the Romans asked about music, song, and the soundscape within which they lived, and that this book examines. Focusing on mythical narratives of metamorphosis, it investigates the aesthetic and ontological questions raised by fantastic stories of musical origins. Each chapter opens with an ancient text devoted to a musical metamorphosis (of a girl into a bird, a nymph into an echo, men into cicadas, etc.) and reads that text as a meditation on an aesthetic and ontological question, in dialogue with 'contemporary' debates – contemporary with debates in the Greco-Roman culture that gave rise to the story, and with modern debates in the posthumanities about what it means to be a human animal enmeshed in a musicking environment.
An analysis of three distinct approaches to using defamation to protect corporate reputation from Australia, England and Wales, and Canada
Authors: Coe Peter
Published: November 2020

The use of defamation law to protect corporate reputation is controversial. Australia, Canada and England and Wales have been at the centre of this debate, as although their defamation laws share many common characteristics, they adopt distinct approaches to allowing companies to sue in defamation. Consequently, in all three jurisdictions defamation law remains a cause of action that is relied upon by companies to protect their reputations. The primary concern of this paper is the efficacy of these approaches,1 particularly in light of the reforms made to Australia's defamation laws, adopted in 2020, that further restrict the right of corporations to sue in defamation. Ultimately, it argues that the Australian and English and Welsh approaches disproportionately disadvantage companies, particularly small ones, whereas the Canadian approach overprotects corporate reputation. It concludes by offering an alternative way forward that, although not perfect, provides a better balance between the interests.
Investing in the New Republic: Multinational Banks, Political Risk, and the Chinese Revolution of 1911
Authors: Moazzin Ghassan
Published: November 2020

This article examines the strategies employed by multinational banks to mitigate political risk following the onset of revolution in their host countries during the early twentieth century. It does so by exploring the activities of multinational banks in China during the Revolution of 1911 and its aftermath. This article first describes the measures that multinational banks took to maintain China's credit on foreign bond markets after the outbreak of revolution. It then examines how these bankers curtailed political instability by first withdrawing financial support from both the Qing government and the revolutionaries and then providing financial assistance to the new Chinese Republican government.
The True Revolution of 1968: Mineral Water Trade and the Early Proliferation of Plastic, 1960s–1970s
Authors: Marty Nicolas
Published: November 2020

This article examines the 1968 decision by the French mineral water company Vittel to use PVC packaging for its main product. This was the first time this type of packaging had been used for a mainstream consumer product. By examining the causes, manifestations, and consequences of this business decision, it aims to show how this model has spread and contributed to the creation of an environmentally damaging waste regime by abandoning deposit systems. The article also seeks to show, through this case, the importance of identifying social and institutional contexts to understand the trajectory of consumer products.
British Fire Insurers in Australia, 1860–1920: A Story of Enterprise, Luck, and Resilience
Authors: Keneley Monica
Published: November 2020

The global expansion of British insurers in the nineteenth century has been a feature of insurance history that has highlighted the strategic nature of the multinational enterprise (MNE). The growth of the Australian colonies from the mid-nineteenth century attracted the interest of these overseas insurers. This article considers the challenges these firms faced and the way in which these trials were overcome. Effective networks were important in establishing a market presence in the Australian colonies. A combination of enterprise, luck, and resilience assisted in building these links. The experience of British insurers in the colonies sheds light on the processes of MNE expansion into markets beyond their range of tacit knowledge and expertise.
Dreams of Iberia
Authors: Rindom Ditlev
Published: November 2020

‘Spain is different’, the Spanish tourist board famously declared in the 1960s as part of its strategy to attract mass tourism to the country. The campaign played a key role in opening up Spain's economy during the later years of Franco's regime – the so-called apertura – following two decades of autarchic rule that had left the country geopolitically isolated. As the slogan suggested, however, exoticism was a key part of Spain's nation-branding. Ideas of Spanish difference were now marketed for their tourist appeal, with images of gypsies and flamenco joined by sizzling beaches and ice-cold sangria.
Educational intervention to improve palliative care knowledge among informal caregivers of cognitively impaired older adults
Authors: Noh Hyunjin , Lee Lewis H. , Won Chorong
Published: November 2020

Objective

Lack of palliative care knowledge among caregivers may pose an access barrier for cognitively impaired older adults, who may benefit from the specialized care. Therefore, this study aims to examine the effectiveness of an educational intervention in improving palliative care knowledge among informal caregivers of cognitively impaired older adults.

Method

Using a one-group, pre- and post-test intervention design, this study implemented an individual, face-to-face educational intervention with an informational brochure for 43 informal caregivers of chronically or seriously ill older adults (50+) with cognitive impairment, recruited from communities in West Alabama. Their level of knowledge about palliative care was assessed by the Palliative Care Knowledge Scale (PaCKS). The pre- and post-test scores were compared by the Wilcoxon signed-ranks test, and the racial subgroup (Whites vs. Blacks) comparison was made by the Mann–Whitney U test.

Results

There was a statistically significant difference between the pre- and post-test scores (z = 5.38, p < 0.001), indicating a statistically significant effect of the educational intervention in improving palliative care knowledge among participants. There was a significant difference (U = 143, p < 0.05) between Whites and Blacks in the pre-test, which, however, disappeared in the post-test (U = 173.50, p > 0.05), suggesting that the amount of increased PaCKS scores were significantly greater for Blacks (Mdn = 9.50) than for Whites (Mdn = 4.00, U = 130.50, p < 0.05).

Significance of results

This study demonstrated that a one-time educational intervention can improve the level of palliative care knowledge among informal caregivers of chronically or seriously ill older adults with cognitive impairment, particularly among Black caregivers. Therefore, further educational efforts can be made to promote palliative care knowledge and reduce racial disparities in palliative care knowledge and its use.
Controls on the 14C Content of Dissolved and Particulate Organic Carbon Mobilized Across the Mackenzie River Basin, Canada
Authors: Campeau A. , Soerensen A. L. , Martma T. , Åkerblom S. , Zdanowicz C.
Published: November 2020

The Mackenzie River Basin (MRB) delivers large quantities of organic carbon (OC) into the Arctic Ocean, with significant implications for the global C budgets and ocean biogeochemistry. The amount and properties of OC in the Mackenzie River's delta have been well monitored in the last decade, but the spatial variability in OC sources transported by its different tributaries is still unclear. Here we present new data on the radiocarbon (14C) content of dissolved and particulate OC (Δ14C‐DOC and Δ14C‐POC) across the mainstem and major tributaries of the MRB, comprising 19 different locations, to identify factors controlling spatial patterns in riverine OC sources. The Δ14C‐DOC and Δ14C‐POC varied across a large range, from −179.9‰ to 62.9‰, and −728.8‰ to −9.0‰, respectively. Our data reveal a positive spatial coupling between the Δ14C of DOC and POC across the MRB, whereby the most 14C‐depleted waters were issued from the mountainous west bank of the MRB. This 14C‐depleted DOC and POC likely originates from a combination of petrogenic sources, connected with the presence of kerogens in the bedrock, and biogenic sources, mobilized by thawing permafrost. Our analysis also reveals intriguing relationships between Δ14C of DOC and POC with turbidity, water stable isotope ratio and catchment elevation, indicating that hydrology and geomorphology are key to understanding riverine OC sources in this landscape. A closer examination of the specific mechanisms giving rise to these relationships is recommended. For now, this study provides a road map of the key OC sources in this rapidly changing river basin.
Provenance and Weathering of Clays Delivered to the Bay of Bengal During the Middle Miocene: Linkages to Tectonics and Monsoonal Climate
Authors: Bretschneider Lisa , Hathorne Ed C. , Huang Huang , Lübbers Julia , Kochhann Karlos G. D. , Holbourn Ann , Kuhnt Wolfgang , Thiede Rasmus , Gebregiorgis Daniel , Giosan Liviu , Frank Martin
Published: November 2020

Tectonics and regional monsoon strength control weathering and erosion regimes of the watersheds feeding into the Bay of Bengal, which are important contributors to global climate evolution via carbon cycle feedbacks. The detailed mechanisms controlling the input of terrigenous clay to the Bay of Bengal on tectonic to orbital timescales are, however, not yet well understood. We produced orbital‐scale resolution geochemical records for International Ocean Discovery Program Site U1443 (southern Bay of Bengal) across five key climatic intervals of the middle to late Miocene (15.8–9.5 Ma). Our new radiogenic Sr, Nd, and Pb isotope time series of clays transported to the Ninetyeast Ridge suggest that the individual contributions from different erosional sources overall remained remarkably consistent during the Miocene despite major tectonic reorganizations in the Himalayas. On orbital timescales, however, high‐resolution data from the five investigated intervals show marked fluctuations of all three isotope systems. Interestingly, the variability was much higher within the Miocene Climatic Optimum (around 16–15 Ma) and across the major global cooling (~13.9–13.8 Ma) until ~13.5 Ma, than during younger time intervals. This change is attributed to a major restriction on the supply of High Himalayan erosion products due to migration of the peak precipitation area toward the frontal domains of the Himalayas and the Indo‐Burman Ranges. The transient excursions of the radiogenic isotope signals on orbital timescales most likely reflect climatically driven shifts in monsoon strength.
Contributions of Triassic Tectonism to Build the Northern Tibetan Plateau: Insights From Tectonic Evolution of the Jinhongshan Range, Central Altyn Tagh Fault System
Authors: Li Jianhua , Zhao Guochun , Johnston Stephen T. , Dong Shuwen , Zhang Yueqiao , Liu Qian , Wu Yu , Yang Hang
Published: November 2020

Clarifying the contributions of pre‐Cenozoic and especially the Mesozoic tectonism to build crustal architecture of the Tibetan plateau is important, especially for evaluating the role of Cenozoic Indo‐Asian collision in creating the present‐day plateau. However, how the Mesozoic tectonism evolved and its influence on the Cenozoic strain distribution remain enigmatic. We provide constraints on these issues by reporting evidence of Triassic (232–223 Ma) and Eocene crustal shortening in the Jinhongshan range of North Tibet, based on coupled structural, zircon U‐Pb, and40Ar/39Ar studies. Triassic shortening was accomplished by two stages manifested as top‐SSE thrust shear (D1) followed by sinistral oblique shear along the ENE trending Jinhongshan shear zone and tight folding (D2), related to ~NNE‐SSW transpression under greenschist‐ to amphibolite‐facies conditions. Such shortening occurred coevally with regional‐scale magmatism, cooling, and exhumation, indicating significant Mesozoic tectonism capable of generating thickened crust and high elevation of North Tibet. We attributed the shortening to far‐field stress effects of terrane collisions between Kunlun and Qiangtang, in which the comparable Jinhongshan and Dangjin shear zones might have formed a continuous, high‐strain zone accommodating relative motion between Tarim and Kunlun‐Qaidam. Eocene shortening (D3) is documented by ENE trending open folds and thrusts, kinematically compatible with left‐lateral activity along the Cenozoic Altyn Tagh fault system. The Triassic Jinhongshan‐Dangjin zone shows a spatial consistency with the Cenozoic Altyn Tagh fault system, implying that at least some segments of this Cenozoic fault system follow more ancient structures. Such evidence reinforces a decisive role of the Triassic tectonic discontinuity in localizing Cenozoic deformation.
Transplant characteristics and self-reported pulmonary outcomes in Swiss childhood cancer survivors after hematopoietic stem cell transplantation—a cohort study
Authors:   for the Swiss Pediatric Oncology Group (SPOG), Otth Maria , Schindera Christina , Güngör Tayfun , Ansari Marc , Scheinemann Katrin , Belle Fabiën N. , Latzin Philipp , von der Weid Nicolas , Kuehni Claudia E.
Published: November 2020

Childhood cancer survivors treated with hematopoietic stem cell transplantation are at high risk for pulmonary morbidity and mortality. In this retrospective study we described transplant characteristics of pediatric patients who underwent hematopoietic stem cell transplantation in Switzerland and how these characteristics changed over time, compared self-reported pulmonary outcomes between transplanted and non-transplanted survivors, and investigated risk factors for the reported pulmonary outcomes. As part of the population-based Swiss Childhood Cancer Survivor Study, we sent questionnaires to all ≥5-year childhood cancer survivors diagnosed 1976–2010 at age ≤20 years. We included 132 transplanted survivors and 368 matched non-transplanted survivors. During the study period transplant characteristics changed, with decreasing use of total body irradiation and increased use of peripheral blood stem cells and mismatched and unrelated donors as transplant source. One-fifth of transplanted survivors (20%, 95%CI 13–27%) and 18% of non-transplanted survivors (95%CI 13–21%) reported at least one pulmonary outcome. None of the analyzed factors was significantly associated with an increased risk of pulmonary outcomes in multivariable analysis. We found that pulmonary outcomes were frequently reported in transplanted and non-transplanted childhood cancer survivors, indicating a strong need for long-term pulmonary follow-up care.
Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma
Authors: Li Wenbin , Yan Yue , Zheng Zongheng , Zhu Qiaohua , Long Qian , Sui Silei , Luo Meihua , Chen Miao , Li Yizhuo , Hua Yijun , Deng Wuguo , Lai Renchun , Li Liren
Published: November 2020

Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.
SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement?
Authors: Yang Ming , Lai Ching Lung
Published: November 2020

Since the outbreak of the new coronavirus in 2019 (SARS-CoV-2), many studies have been performed to better understand the basic mechanisms and clinical features of the disease. However, uncertainties of the underlying mechanisms of multiple organ involvement remain. A substantial proportion of severe coronavirus disease 2019 (COVID-19) patients have lymphopenia, low serum iron levels, and multiple organ involvement. Several therapeutic agents have been used for different stages of the disease, but the treatment for severe disease is still suboptimal. Understanding the mechanism of programmed cell death in COVID-19 may lead to better therapeutic strategies for these patients. On the basis of observations of basic science studies and clinical researches on COVID-19, we hypothesize that ferroptosis, a novel programmed cell death, may be an important cause of multiple organ involvement in COVID-19 and it might serve as a new treatment target. In spite of the existing findings on the involvement of ferroptosis in SARS-CoV-2 infection, there is no reported study to uncover how does ferroptosis acts in SARS-CoV-2 infection yet. Uncovering the role of ferroptosis in SARS-CoV-2 infection is essential to develop new treatment strategies for COVID-19. Intracellular cell iron depletion or new generation of ferroptosis inhibitors might be potential drug candidates for COVID-19. We hope this hypothesis may launch a new wave of studies to uncover the association of ferroptosis and SARS-CoV-2 infection in vitro and in vivo.
Efficacy and safety of once-monthly Risperidone ISM® in schizophrenic patients with an acute exacerbation
Authors: Correll Christoph U. , Litman Robert E. , Filts Yuriy , Llaudó Jordi , Naber Dieter , Torres Ferran , Martínez Javier
Published: November 2020

To evaluate the efficacy and safety of Risperidone ISM® against placebo in patients with acute exacerbation of schizophrenia. A multicenter, randomized, double-blind, placebo-controlled study was conducted between June 2017 and December 2018 (NCT03160521). Eligible patients received once-monthly intramuscular injections of Risperidone ISM® (75 or 100 mg) or placebo for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 12. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Altogether, 438 patients were randomized (1:1:1) and 390 included in the modified ITT efficacy set. The PANSS total score (mean difference, 95% CI) improved significantly from baseline to day 85 with Risperidone ISM® 75 and 100 mg, with placebo-adjusted differences of −13.0 (95% CI, −17.3 to −8.8); (p < 0.0001), and −13.3 (−17.6 to −8.9); (p < 0.0001), respectively. Significantly improved mean changes were also obtained for CGI-S score from baseline to day 85 for both doses of Risperidone ISM® compared with placebo −0.7 (−1.0 to −0.5); p < 0.0001, for both doses. The statistically significant improvement for both efficacy outcomes were observed as early as 8 days after first injection. The most frequently reported treatment-emergent adverse events were increased blood prolactin (7.8%), headache (7.3%), hyperprolactinemia (5%), and weight increase (4.8%). Neither new nor unexpected relevant safety information was recorded. Risperidone ISM® provided rapid and progressive reduction of symptoms in patients with acutely exacerbated schizophrenia without need of oral risperidone supplementation or loading doses. Both doses were safe and well tolerated.
VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots
Authors: Goedhart Joachim , Luijsterburg Martijn S.
Published: November 2020

Comparative genome- and proteome-wide screens yield large amounts of data. To efficiently present such datasets and to simplify the identification of hits, the results are often presented in a type of scatterplot known as a volcano plot, which shows a measure of effect size versus a measure of significance. The data points with the largest effect size and a statistical significance beyond a user-defined threshold are considered as hits. Such hits are usually annotated in the plot by a label with their name. Volcano plots can represent ten thousands of data points, of which typically only a handful is annotated. The information of data that is not annotated is hardly or not accessible. To simplify access to the data and enable its re-use, we have developed an open source and online web tool with R/Shiny. The web app is named VolcaNoseR and it can be used to create, explore, label and share volcano plots (https://huygens.science.uva.nl/VolcaNoseR). When the data is stored in an online data repository, the web app can retrieve that data together with user-defined settings to generate a customized, interactive volcano plot. Users can interact with the data, adjust the plot and share their modified plot together with the underlying data. Therefore, VolcaNoseR increases the transparency and re-use of large comparative genome- and proteome-wide datasets.
Expression profiling of MADS-box gene family revealed its role in vegetative development and stem ripening in S. spontaneum
Authors: Fatima Mahpara , Zhang Xiaodan , Lin Jishan , Zhou Ping , Zhou Dong , Ming Ray
Published: November 2020

Sugarcane is the most important sugar and biofuel crop. MADS-box genes encode transcription factors that are involved in developmental control and signal transduction in plants. Systematic analyses of MADS-box genes have been reported in many plant species, but its identification and characterization were not possible until a reference genome of autotetraploid wild type sugarcane specie, Saccharum spontaneum is available recently. We identified 182 MADS-box sequences in the S. spontaneum genome, which were annotated into 63 genes, including 6 (9.5%) genes with four alleles, 21 (33.3%) with three, 29 (46%) with two, 7 (11.1%) with one allele. Paralogs (tandem duplication and disperse duplicated) were also identified and characterized. These MADS-box genes were divided into two groups; Type-I (21 Mα, 4 Mβ, 4 Mγ) and Type-II (32 MIKCc, 2 MIKC*) through phylogenetic analysis with orthologs in Arabidopsis and sorghum. Structural diversity and distribution of motifs were studied in detail. Chromosomal localizations revealed that S. spontaneum MADS-box genes were randomly distributed across eight homologous chromosome groups. The expression profiles of these MADS-box genes were analyzed in leaves, roots, stem sections and after hormones treatment. Important alleles based on promoter analysis and expression variations were dissected. qRT-PCR analysis was performed to verify the expression pattern of pivotal S. spontaneum MADS-box genes and suggested that flower timing genes (SOC1 and SVP) may regulate vegetative development.
The relationship between maternal dietary patterns during pregnancy in women with gestational diabetes mellitus and infant appetitive feeding behaviour at 6 months
Authors: Amissah Emma , Gamble Gregory D. , Wall Clare R. , Crowther Caroline A. , Harding Jane E.
Published: November 2020

Early dietary exposure may influence infant appetitive feeding behaviour, and therefore their later health. Maternal diabetes in pregnancy is associated with an increased risk of obesity in the offspring. We, therefore, examined third-trimester dietary patterns of women with gestational diabetes, their offspring’s appetitive feeding behaviour at 6 months of age, and relationships between these. We used data from a prospective cohort of women with gestational diabetes and assessed maternal dietary patterns at 36 weeks’ gestation using principal component analysis; infant appetitive feeding behaviour at 6 months of age using the Baby Eating Behaviour Questionnaire; and relationships between these using general linear modelling and chi-square tests. In 325 mother-infant dyads, we identified three distinct maternal dietary patterns: ‘Junk,’ ‘Mixed,’ and ‘Health-conscious.’ The maternal ‘Health-conscious’ pattern was inversely associated with ‘enjoyment of food’ in their sons (β − 0.24, 95% CI − 0.36 to − 0.11, p = 0.0003), but not daughters (β − 0.02, 95% CI − 0.12 to 0.08, p = 0.70), and was positively associated with ‘slowness in eating,’ (β 0.13, 95% CI 0.02 to 0.24, p = 0.01). Third-trimester dietary patterns in women with gestational diabetes may have sex-specific effects on infant appetitive feeding behaviour at 6 months of age.
Molecular-scale origins of wettability at petroleum–brine–carbonate interfaces
Authors: Fenter Paul , Qin Tianzhu , Lee Sang Soo , AlOtaibi Mohammed B. , Ayirala Subhash , Yousef Ali A.
Published: November 2020

Wettability control of carbonates is a central concept for enhanced petroleum recovery, but a mechanistic understanding of the associated molecular-scale chemical processes remains unclear. We directly probe the interface of calcium carbonate (calcite) with natural petroleum oil, synthetic petroleum analogues, and aqueous brines to understand the molecular scale behavior at this interface. The calcite–petroleum interface structure is similar whether or not calcite was previously exposed to an aqueous brine, and is characterized by an adsorbed interfacial layer, significant structural changes within the calcite surface, and increased surface roughness. No evidence for an often-assumed thin-brine wetting layer at the calcite–petroleum interface is observed. These features differ from those observed at the calcite–brine interface, and for parallel measurements using model synthetic petroleum mixtures (consisting of representative components, including dodecane, toluene, and asphaltene). Changes to the interface after petroleum displacement by aqueous brines are also discussed.
Transcriptome divergence between developmental senescence and premature senescence in Nicotiana tabacum L.
Authors: Zhao Zhe , Zhang Jia-Wen , Lu Shao-Hao , Zhang Hong , Liu Fang , Fu Bo , Zhao Ming-Qin , Liu Hui
Published: November 2020

Senescence is a degenerative process triggered by intricate and coordinated regulatory networks, and the mechanisms of age-dependent senescence and stress-induced premature senescence still remain largely elusive. Thus we selected leaf samples of developmental senescence (DS) and premature senescence (PS) to reveal the regulatory divergence. Senescent leaves were confirmed by yellowing symptom and physiological measurement. A total of 1171 and 309 genes (DEGs) were significantly expressed respectively in the whole process of DS and PS. Up-regulated DEGs in PS were mostly related to ion transport, while the down-regulated DEGs were mainly associated with oxidoreductase activity and sesquiterpenoid and triterpenoid biosynthesis. In DS, photosynthesis, precursor metabolites and energy, protein processing in endoplasmic reticulum, flavonoid biosynthesis were notable. Moreover, we found the vital pathways shared by DS and PS, of which the DEGs were analyzed further via protein–protein interaction (PPI) network analysis to explore the alteration responding to two types of senescence. In addition, plant hormone transduction pathway was mapped by related DEGs, suggesting that ABA and ethylene signaling played pivotal roles in formulating the distinction of DS and PS. Finally, we conducted a model containing oxidative stress and ABA signaling as two hub points, which highlighted the major difference and predicted the possible mechanism under DS and PS. This work gained new insight into molecular divergence of developmental senescence and premature senescence and would provide reference on potential mechanism initiating and motivating senescence for further study.
Long-term outcomes following vehicle trauma related acute kidney injury requiring renal replacement therapy: a nationwide population study
Authors: Chan Chieh-Kai , Chi Chun-Yi , Lai Tai-Shuan , Huang Tao-Min , Chou Nai-Kuan , Huang Yi-Ping , Prowle John R. , Wu Vin-Cent , Chen Yung-Ming
Published: November 2020

Acute kidney injury (AKI) is a frequent complication of traumatic injury; however, long-term outcomes such as mortality and end-stage kidney disease (ESKD) have been rarely reported in this important patient population. We compared the long-term outcome of vehicle-traumatic and non-traumatic AKI requiring renal replacement therapy (AKI-RRT). This nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Vehicle-trauma patients who were suffered from vehicle accidents developing AKI-RRT during hospitalization were identified, and matching non-traumatic AKI-RRT patients were identified between 2000 and 2010. The incidences of ESKD, 30-day, and long-term mortality were evaluated, and clinical and demographic associations with these outcomes were identified using Cox proportional hazards regression models. 546 vehicle-traumatic AKI-RRT patients, median age 47.6 years (interquartile range: 29.0–64.3) and 76.4% male, were identified. Compared to non-traumatic AKI-RRT, vehicle-traumatic AKI-RRT patients had longer length of stay in hospital [median (IQR):15 (5–34) days vs. 6 (3–11) days; p < 0.001). After propensity matching with non-traumatic AKI-RRT cases with similar demographic and clinical characteristics. Vehicle-traumatic AKI-RRT patients had lower rates of long-term mortality (adjusted hazard ratio (HR), 0.473; 95% CI, 0.392–0.571; p < 0.001), but similar rates of ESKD (HR, 1.166; 95% CI, 0.829–1.638; p = 0.377) and short-term risk of death (HR, 1.134; 95% CI, 0.894–1.438; p = 0.301) as non-traumatic AKI-RRT patients. In competing risk models that focused on ESKD, vehicle-traumatic AKI-RRT patients were associated with lower ESKD rates (HR, 0.552; 95% CI, 0.325–0.937; p = 0.028) than non-traumatic AKI-RRT patients. Despite severe injuries, vehicle-traumatic AKI-RRT patients had better long-term survival than non-traumatic AKI-RRT patients, but a similar risk of ESKD. Our results provide a better understanding of long-term outcomes after vehicle-traumatic AKI-RRT.
Copper nanoparticles on controlled pore glass (CPG) as highly efficient heterogeneous catalysts for “click reactions”
Authors: Rafi Abdolrahim A. , Ibrahem Ismail , Córdova Armando
Published: November 2020

We herein report that supported copper nanoparticles (CuNPs) on commercially available controlled pore glass (CPG), which exhibit high mechanical, thermal and chemical stability as compared to other silica-based materials, serve as a useful heterogeneous catalyst system for 1,3-dipolar cycloadditions (“click” reactions) between terminal alkynes and organic azides under green chemistry conditions. The supported CuNPs-CPG catalyst exhibited a broad substrate scope and gave the corresponding triazole products in high yields. The CuNPs-CPG catalyst exhibit recyclability and could be reuced multiple times without contaminating the products with Cu.
Photosensitive tyrosine analogues unravel site-dependent phosphorylation in TrkA initiated MAPK/ERK signaling
Authors: Zhao Shu , Shi Jia , Yu Guohua , Li Dali , Wang Meng , Yuan Chonggang , Zhou Huihui , Parizadeh Amirabbas , Li Zhenlin , Guan Min-Xin , Ye Shixin
Published: November 2020

Tyrosine kinase A (TrkA) is a membrane receptor which, upon ligand binding, activates several pathways including MAPK/ERK signaling, implicated in a spectrum of human pathologies; thus, TrkA is an emerging therapeutic target in treatment of neuronal diseases and cancer. However, mechanistic insights into TrKA signaling are lacking due to lack of site-dependent phosphorylation control. Here we engineer two light-sensitive tyrosine analogues, namely p-azido-L-phenylalanine (AzF) and the caged-tyrosine (ONB), through amber codon suppression to optically manipulate the phosphorylation state of individual intracellular tyrosines in TrkA. We identify TrkA-AzF and ONB mutants, which can activate the ERK pathway in the absence of NGF ligand binding through light control. Our results not only reveal how TrkA site-dependent phosphorylation controls the defined signaling process, but also extend the genetic code expansion technology to enable regulation of receptor-type kinase activation by optical control at the precision of a single phosphorylation site. It paves the way for comprehensive analysis of kinase-associated pathways as well as screening of compounds intervening in a site-directed phosphorylation pathway for targeted therapy.
Large genome-wide association study identifies three novel risk variants for restless legs syndrome
Authors: Didriksen Maria , Nawaz Muhammad Sulaman , Dowsett Joseph , Bell Steven , Erikstrup Christian , Pedersen Ole B. , Sørensen Erik , Jennum Poul J. , Burgdorf Kristoffer S. , Burchell Brendan , Butterworth Adam S. , Soranzo Nicole , Rye David B. , Trotti Lynn Marie , Saini Prabhjyot , Stefansdottir Lilja , Magnusson Sigurdur H. , Thorleifsson Gudmar , Sigmundsson Thordur , Sigurdsson Albert P. , Van Den Hurk Katja , Quee Franke , Tanck Michael W. T. , Ouwehand Willem H. , Roberts David J. , Earley Eric J. , Busch Michael P. , Mast Alan E. , Page Grier P. , Danesh John , Di Angelantonio Emanuele , Stefansson Hreinn , Ullum Henrik , Stefansson Kari
Published: November 2020

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.