bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioprospecting wild South African microalgae as a potential third-generation biofuel feedstock, biological carbon-capture agent and for nutraceutical applications
Authors: Ahiahonu Elvis Kodzo , Anku William Wilson , Roopnarain Ashira , Green Ezekiel , Govender Penny Poomani , Serepa-Dlamini Mahloro Hope
Published: June 2021

Microalgae are among the few biological resources studied that are found to possess vast biotechnological potential. This study isolated, identified and investigated two wild green microalgal species with substantial potential as a bioresource and climate change mitigation importance. Two isolates, Chlorella sorokiniana and Tetradesmus reginae were cultivated in selected artificial media under laboratory conditions. The isolates were analysed for nutrient consumption, biomass productivity, CO2 biosequestration rate, elemental composition and fatty acid methyl profiles/composition. The outcome showed maximum daily biomass productivity of 0.128 ± 0.003 and 0.2 ± 0.004 g L−1 for C. sorokiniana and T. reginae, respectively. CO2 biosequestration rate of T. reginae was the highest among the isolates, indicating that it can act as a biological climate change mitigation agent. Moreover, T. reginae recorded a significantly higher (p < 0.05) total lipid and carbohydrate content than C. sorokiniana. The C/N ratio for T. reginae was significantly higher than the C/N ratio for C. sorokiniana. Tetradesmus reginae also demonstrated the ability to produce a considerable quantity of omega-3 oils; hence, the species is of nutraceutical importance. Furthermore, T. reginae demonstrated maximal carbohydrate content and is therefore considered a potential feedstock for bioethanol production. Chlorella sorokiniana, on the other hand, showed a remarkable (p < 0.05) protein content making it a potential source for human food and animal feed supplement. Finally, the two isolates met both European and American quality biodiesel standards with exceptional cetane (CN) and iodine numbers (IV).
Large Vessel Occlusion Stroke Detection in the Prehospital Environment
Authors: Patrick Lauren , Smith Wade , Keenan Kevin J.
Published: June 2021

Purpose of Review

Endovascular therapy for acute ischemic stroke secondary to large vessel occlusion (LVO) is time-dependent. Prehospital patients with suspected LVO stroke should be triaged directly to specialized stroke centers for endovascular therapy. This review describes advances in LVO detection among prehospital suspected stroke patients.

Recent Findings

Clinical prehospital stroke severity tools have been validated in the prehospital setting. Devices including EEG, SSEPs, TCD, cranial accelerometry, and volumetric impedance phase-shift-spectroscopy have recently published data regarding LVO detection in hospital settings. Mobile stroke units bring thrombolysis and vessel imaging to patients.

The use of a prehospital stroke severity tool for LVO triage is now widely supported. Ease of use should be prioritized as there are no meaningful differences in diagnostic performance amongst tools. LVO diagnostic devices are promising, but none have been validated in the prehospital setting. Mobile stroke units improve patient outcomes and cost-effectiveness analyses are underway.
Editorial, special issue on “Advances in Robust Statistics”
Authors: Riani Marco , Hubert Mia
Published: June 2021

Starting with 2020 volume, the journal Metron has decided to celebrate the centenary since its foundation with three special issues. This volume is dedicated to robust statistics. A striking feature of most applied statistical analyses is the use of methods that are well known to be sensitive to outliers or to other departures from the postulated model. Robust statistical methods provide useful tools for reducing this sensitivity, through the detection of the outliers by first fitting the majority of the data and then by flagging deviant data points. The six papers in this issue cover a wide orientation in all fields of robustness. This editorial first provides some facts about the history and current state of robust statistics and then summarizes the contents of each paper.
$$\pi _1$$ of Miranda moduli spaces of elliptic surfaces
Authors: Lönne Michael
Published: June 2021

We give finite presentations for the fundamental group of moduli spaces due to Miranda of smooth Weierstrass curves over $${\mathbf {P}}^1$$

P

1

which extend the classical result for elliptic curves to the relative situation over the projective line. We thus get natural generalisations of $$SL_2{{\mathbb {Z}}}$$

S

L
2

Z

presented in terms of $$\Bigg (\begin{array}{ll} 1&{}1\\ 0&{}1\end{array} \Bigg )$$

(

1

1

0

1

)

, $$\Bigg (\begin{array}{ll} 1&{}0\\ {-1}&{}1\end{array} \Bigg )$$

(

1

0

-
1

1

)

on one hand and the first examples of fundamental groups of moduli stacks of elliptic surfaces on the other.

Our approach exploits the natural $${\mathbb {Z}}_2$$

Z
2

-action on Weierstrass curves and the identification of $${\mathbb {Z}}_2$$

Z
2

-fixed loci with smooth hypersurfaces in an appropriate linear system on a projective line bundle over $${{\mathbf {P}}}^1$$

P

1

. The fundamental group of the corresponding discriminant complement can be presented in terms of finitely many generators and relations using methods in the Zariski tradition.
On transfer homomorphisms of Krull monoids
Authors: Geroldinger Alfred , Kainrath Florian
Published: June 2021

Every Krull monoid has a transfer homomorphism onto a monoid of zero-sum sequences over a subset of its class group. This transfer homomorphism is a crucial tool for studying the arithmetic of Krull monoids. In the present paper, we strengthen and refine this tool for Krull monoids with finitely generated class group.
Essay mills and other contract cheating services: to buy or not to buy and the consequences of students changing their minds
Authors: Draper Michael , Lancaster Thomas , Dann Sandie , Crockett Robin , Glendinning Irene
Published: June 2021

Very few parts of the world have legislation that prohibits the operation or the promotion of contract cheating services. This means that commercial companies providing such services can formally register and operate in most countries. If a student enters into an agreement with a contract cheating provider, what rights do they have to change their mind and what are the risks if they choose to do so? This paper examines the question through legal, institutional and societal lenses, showing that although a student has the consumer rights to withdraw from a contract with an essay mill, they may also be putting their future at risk by doing so. Contract cheating providers are now embedded within many institutions, using sharp practices to connect with vulnerable customers, but are also perfectly placed to blackmail students or threaten to report them to their institution if they ask to cancel their order. The paper argues that, while not condoning the practice of contract cheating, supportive processes need to be in place to help students at risk as part of standard institutional duty of care. This must be backed up by institutional policy that considers academic integrity as a core value for all.
Detailed Modeling of Cork-Phenolic Ablators in Preparation for the Post-flight Analysis of the QARMAN Re-entry CubeSat
Authors: Miccoli Claudio , Turchi Alessandro , Schrooyen Pierre , D’Ambrosio Domenic , Magin Thierry
Published: June 2021

This work deals with the analysis of the cork P50, an ablative thermal protection material (TPM) used for the heat shield of the qarman Re-entry CubeSat. Developed for the European Space Agency (ESA) at the von Karman Institute (VKI) for Fluid Dynamics, qarman is a scientific demonstrator for Aerothermodynamic Research. The ability to model and predict the atypical behavior of the new cork-based materials is considered a critical research topic. Therefore, this work is motivated by the need to develop a numerical model able to respond to this demand, in preparation to the post-flight analysis of qarman. This study is focused on the main thermal response phenomena of the cork P50: pyrolysis and swelling. Pyrolysis was analyzed by means of the multi-physics Computational Fluid Dynamics (CFD) code argo, developed at Cenaero. Based on a unified flow-material solver, the Volume Averaged Navier–Stokes (VANS) equations were numerically solved to describe the interaction between a multi-species high enthalpy flow and a reactive porous medium, by means of a high-order Discontinuous Galerkin Method (DGM). Specifically, an accurate method to compute the pyrolysis production rate was implemented. The modeling of swelling was the most ambitious task, requiring the development of a physical model accounting for this phenomenon, for the purpose of a future implementation within argo. A 1D model was proposed, mainly based on an a priori assumption on the swelling velocity and the resolution of a nonlinear advection equation, by means of a Finite Difference Method (FDM). Once developed, the model was successfully tested through a matlab code, showing that the approach is promising and thus opening the way to further developments.
Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies
Authors: Moorkoth Sudheer , Prathyusha N. Sai , Manandhar Suman , Xue Yuanxin , Sankhe Runali , Pai K. S. R. , Kumar Nitesh
Published: June 2021

Background

Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo.

Method

The binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry.

Results

DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential.

Conclusion

DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.
Naming the Baga: Problems in the Identity of a Guinean Cultural Amalgamation
Authors: Lamp Frederick John
Published: June 2021

Along the coast of the Republic of Guinea, the term “Baga” has been used to cover a large amalgamation of cultural groups, always previously misinterpreted. There are five dialect groups called Baga within the Temne language group. The question raised here concerns the etymology of the name Baga, as it has evolved in juxtaposition to the name Temne in Sierra Leone. It is an attempt to parse the intricate use of language to describe the historical and hierarchical relationship between these two segments of the same group.
Breakfast patterns and weight status among adolescents: a study on the Brazilian National Dietary Survey 2008–2009
Authors: Hassan Bruna Kulik , Cunha Diana Barbosa , Santos Roberta de Oliveira , Baltar Valéria Troncoso
Published: June 2021

Examining the composition of breakfast concerning weight status is essential for evaluating adolescent health and understanding this gap. This study aimed to identify breakfast patterns and investigate the relationship with weight status among Brazilian adolescents. We used a subsample of 7425 adolescents aged 10–19 years from the 2008–2009 Brazilian Household Budget Survey. Breakfast eaters were those with intake of at least 50 kcal (209·2 kJ) between 05.00 and 10.00 hours. Breakfast dietary patterns were derived by principal component factor analysis with varimax rotation. We performed logistic regression analyses between breakfast patterns and weight status, considering the complexity of the survey sample design. Three breakfast patterns were identified explaining 44·8 % of data variability: (1) the Cereal, protein, fruit beverages and Northern/Northeastern pattern, characterised by high consumption of cookies, meats, dairy products, preparations with maize, eggs, fruit juices/fruit drinks/soya-based drinks, tubers/roots/potatoes and cereals, and negative adherence to cold cut meat and savoury snacks/crackers; (2) the Protein-based pattern, characterised by positive loadings for cold cut meat, milk and cheese, and negative for cookies, fruit juices/fruit drinks/soya-based drinks, tubers/roots/potatoes and cereals; and (3) the Mixed pattern, with positive loadings for cakes, coffee/tea, bread, fruit juices/fruit drinks/soya-based drinks, chocolate/desserts and savoury snacks/crackers. No association was found between skipping and weight status. Overweight adolescents had lower adherence to the Cereal, protein, fruit beverages and Northern/Northeastern pattern (OR = 0·67; 95 % CI 0·47, 0·96). This is the first study to address dietary patterns at the meal level with adolescent population-based data, which requires further investigation.
FROM BEST INTERESTS TO BETTER INTERESTS? VALUES, UNWISDOM AND OBJECTIVITY IN MENTAL CAPACITY LAW
Authors: Coggon John , Kong Camillia
Published: June 2021

The Mental Capacity Act 2005 governs personal decision-making for adults. It incorporates five overarching principles, including that incapacity may not be inferred merely from a person's unwise decisions and that where a person lacks capacity decisions must be made in her best interests. Through analysis of judicial treatment of unwisdom, best interests, subjectivity and objectivity, considered against parliamentary debates on the Mental Capacity Bill and philosophical critique of ideas of (un)wisdom, we argue that these principles are problematically irreconcilable. The Act's radical under-specificity means, paradoxically, that this comes to be resolved through abstracted values, rather than the centricity of the person herself.
Does Voluntary Voting Enhance Partisan Bias? Evidence from Chile
Authors: Argote Pablo
Published: June 2021

Although partisan bias – when an authority transfers discretionary public resources to a politically aligned receiver − has been extensively studied, less is known about how this practice is affected by the voting regime − compulsory or voluntary voting. In this article, I study partisan bias in Chile, using administrative data of transfers from the central authority to local governments, highlighting two relevant scope conditions: the electoral cycle, and electoral uncertainty caused by the adoption of voluntary voting. I found strong evidence of partisan bias, especially in election years and in electorally riskier municipalities. This suggests that the uncertainty introduced by this electoral reform induced politicians to allocate a large share of resources to risky municipalities, because such resources would play a more significant role in the electoral outcome. Overall, these results imply that voluntary voting has a large impact on the way that resources are allocated across subnational units.
Subsidized Household Services and Informal Employment: The Belgian Service Voucher Policy
Authors: ADRIAENSSENS STEF , THEYS TOBIAS , VERHAEST DIETER , DESCHACHT NICK
Published: June 2021

Labour markets for personal and household services (PHS) are rife with informal employment. Some policies aim to combat informality in PHS with subsidized service vouchers, but their effects are poorly documented. This contribution evaluates the Belgian service vouchers (1) documenting their formalization effectiveness, and (2) accounting for the persistence of informal employment. To this end, we exploit several types of data and methods.

A first analysis, based on Eurobarometer data, brings in evidence that informal PHS purchased were approximately halved under the policy introduced in 2001. Second, a discrete choice experiment shows that households prefer formal employment, including those that currently employ informally. Third, a survey in the Brussels metropolitan area shows that the persistence of informal employment lies in the relationship of informal employers with their domestic, from whom they are not willing to part. They nevertheless intend to switch to formal employment in the case of turnover. One thus expects partially delayed effects of formalization policies in general, and of the service voucher system in particular. Overall, these results are in line with Portes’ claim that informality is facilitated by strong social relationships, and by differences in price and transaction costs.
Carbohydrates deteriorate fatty liver by activating the inflammatory response
Authors: Gao Yuqi , Hua Rui , Hu Kaiqiang , Wang Zhao
Published: June 2021

Non-alcoholic fatty liver disease (NAFLD) was defined in 1980 and has the same histological characteristics as alcoholic liver disease except for alcohol consumption. After 40 years, the understanding of this disease is still imperfect. Without specific drugs available for treatment, the number of patients with NAFLD is increasing rapidly, and NAFLD currently affects more than one-quarter of the global population. NAFLD is mostly caused by a sedentary lifestyle and excessive energy intake of fat and sugar. To ameliorate or avoid NAFLD, people commonly replace high-fat foods with high-carbohydrate foods (especially starchy carbohydrates) as a way to reduce caloric intake and reach satiety. However, there are few studies that concentrate on the effect of carbohydrate intake on liver metabolism in patients with NAFLD, much fewer than the studies on fat intake. Besides, most of these studies are not systematic, which has made identification of the mechanism difficult. In this review, we collected and analysed data from studies on human and animal models and, surprisingly, found that carbohydrates and liver steatosis could be linked by inflammation. This review not only describes the effects of carbohydrates on NAFLD and body lipid metabolism but also analyses and predicts possible molecular pathways of carbohydrates in liver lipid synthesis that involve inflammation. Furthermore, the limitations of recent research and possible targets for regulating inflammation and lipogenesis are discussed. This review describes the effects of starchy carbohydrates, a nutrient signal, on NAFLD from the perspective of inflammation.
Marketing of commercial foods for infant and young children in Uruguay: sugary products, health cues on packages and fun social products on Facebook
Authors: Karageuzián Gonzalo , Vidal Leticia , de León Carolina , Girona Alejandra , Ares Gastón
Published: June 2021

Objective:

To analyse the content of the marketing of commercial foods for infants and young children on packages and social media.

Design:

Commercial foods targeted at children, regarded as potential breast-milk substitutes according to the Uruguayan breast-feeding standard, were considered: dairy products; teas, juices and bottled waters; glucose solutions; cereals and mixtures of fruits and vegetables. All the products sold at forty-four retail outlets were purchased. A Facebook search was performed to identify accounts of these products. For each account, all the content posted by the brands between July 2017 and July 2019 was recorded. The visual and textual information included in the packages and Facebook posts was analysed using content analysis. Products were classified using the nutrient profile model of the Pan American Health Organization.

Setting:

Montevideo, Uruguay.

Results:

Seventy-six unique commercial foods targeted at infants and young children were identified, 96 % of which were excessive in sugar. Packages frequently included textual and visual elements to convey health-related associations, including images of fruits and vegetables, nutrient content claims and endorsement logos. Ten Facebook accounts were identified, which generated 302 posts. Parents and caregivers were the main target audience of the posts, which mainly included content related to fun and social aspects of food consumption. Additionally, the posts frequently conveyed the idea that products would contribute to children’s growth and development.

Conclusions:

Results suggest the need to implement comprehensive regulations on the marketing of commercial foods targeted at children, regarded as potential breast-milk substitutes according to the Uruguayan breast-feeding standard.
Diasporic Foreign Policy Interest Groups in the United States: Democracy, Conflict, and Political Entrepreneurship
Authors: Prasad Shubha Kamala , Savatic Filip
Published: June 2021

Why do some immigrant diasporas in the United States (U.S.) establish foreign policy interest groups while others do not? While scholars have demonstrated that diasporic interest groups often successfully influence U.S. foreign policy, we take a step back to ask why only certain diasporas attempt to do so in the first place. We argue that two factors increase the likelihood of diaspora mobilization: a community’s experience with democratic governance and conflict in its country of origin. We posit that these conditions make it more likely that political entrepreneurs emerge to serve as catalysts for top-down mobilization. To test our hypotheses, we collect and analyze novel data on diasporic interest groups as well as the characteristics of their respective countries of origin. In turn, we conduct the first in-depth case studies of the historical and contemporary Indian-American lobbies, using original archival and interview evidence.
A great convergence: The American frontier and the origins of Japanese migration to Brazil
Authors: Lu Sidney Xu
Published: June 2021

This article explains how the US westward expansion influenced and stimulated Japanese migration to Brazil. Emerging in the nineteenth century as expanding powers in East Asia and Latin America, respectively, both Meiji Japan and post-independence Brazil looked to the US westward expansion as a central reference for their own processes of settler colonialism. The convergence of Japan and Brazil in their imitation of US settler colonialism eventually brought the two sides together at the turn of the twentieth century to negotiate for the start of Japanese migration to Brazil. This article challenges the current understanding of Japanese migration to Brazil, conventionally regarded as a topic of Latin American ethnic studies, by placing it in the context of settler colonialism in both Japanese and Brazilian histories. The study also explores the shared experiences of East Asia and Latin America as they felt the global impact of the American westward expansion.
An Integrated Framework to Streamline Resilience in the Context of Urban Climate Risk Assessment
Authors: Urquiza A. , Amigo C. , Billi M. , Calvo R. , Gallardo L. , Neira C. I. , Rojas M.
Published: June 2021

Cities are increasingly acknowledged as crucial when facing climate change—and the environmental crisis more in general—, offering challenges and opportunities in terms of both mitigation and adaptation. Climate change‐sensitive urban governance requires proactive, integrated, and contextualized approaches, making room for the complex, multilayered, multiscalar, and dynamic processes constituting a city. The notion of “resilience” has been acquiring growing recognition as a flexible and powerful concept to respond to these challenges. Resilience itself, however, is also a polysemic notion, often treated as little more than a catchword or a wishful aim or superimposed with other climate‐related terms, such as risk, vulnerability, or adaptation. To promote a stronger integration among different problem‐settings and epistemic communities, this paper advances six analytical distinctions aiming to provide structure and articulation to existing definitions of the concept of “resilience.” Likewise, it offers an integrated analytical framework and methodological pipeline to streamline resilience analysis in the context of urban climate risk assessment. The framework is specially defined to link up with the definition of climate risk provided by the Intergovernmental Panel on Climate Change (IPCC) latest Assessment Reports and is illustrated through examples derived from the recent experience of the Chilean Climate Risk Atlas.
An Early Garnet Redox‐Filter as an Additive Oxidizer in Lower Continental Arc Crust Traced Through Fe Isotopes
Authors: Li Qi‐Wei , Nebel‐Jacobsen Yona , Zhao Jun‐Hong , Nebel Oliver , Richter Marianne , Cawood Peter A. , Wang Qiang
Published: June 2021

The magmatic differentiation of cooling arc lavas on their way to the surface is dominated by fractional crystallization, which predominantly occurs at lower crustal arc levels (25–40 km) at continental margins. The magmatic storage in the deep crust is complex and remote, and rarely studied compared to shallow magma fractionation, but carries key information for the formation and evolution of the lower continental crust. At convergent continental margins, mantle‐derived melts must pass through a complex system of rocks in the lower arc crust. In particular, melts inevitably transition through deep “hot” (melt‐rich) or “cold” (i.e., water‐rich) zones, collectively termed here lower crustal arc zones (LoCAZ) to account for both scenarios. Their role in driving melt modification, including formation and oxidation of calc‐alkaline suites, remains unclear. Here we report stable Fe isotope compositions of 40 well‐characterized Neoproterozoic mafic dikes from the northwestern margin of the Yangtze Block, representing three stages of continental arc evolution. Rocks from the Tongde dikes display strong correlations between δ57Fe values and trace element indices of garnet fractionation (e.g., high La/Yb and depleted heavy REE patterns). An increase in heavy Fe isotopes with garnet fractionation indicates a redox‐filtering of melts through LoCAZ. We thus propose that retention of Fe2+ in deep crustal garnet is one driver for elevated fO2 and the calc‐alkaline trend in continental margin rocks. With continental arc rocks being on average more oxidized than intra‐oceanic arc lavas, garnet redox‐filtering may be an additive oxidizer in thicker arc crust. The Tongde dike swarms may represent a rare, volumetrically small, direct example of melts ejected out of the lower arc crust. The complex mixing and mingling of melts reported for most arcs and their plutons may obscure this redox process contributing to continental crust growth.
Estimation of Macrodispersivity in Bounded Formations by Circulant Embedding and Analysis of Variance
Authors: Liao Qinzhuo , Lei Gang , Zhang Dongxiao , Patil Shirish
Published: June 2021

We present a new method to estimate the displacement covariance and macrodispersivity for solute transport in bounded formations. Here we use circulant embedding, which is based on fast Fourier transform and is much more efficient than eigen‐decomposition, for the factorization of random spatial fields. We compute the displacement covariances by the analysis of variance approach, and introduce an interpolation process to significantly reduce the number of forward simulations. Once the effect of each eigenvector on the displacement covariance is obtained, it is unnecessary to rerun the simulator for different spatial covariance functions or anisotropy ratios, which saves a large amount of computational effort. The proposed method is validated in various tests in two‐dimensional and three‐dimensional examples and accurately matches the results from the Monte Carlo simulation. It is found that the longitudinal dispersivity is less sensitive to the impervious boundaries, while the transverse and vertical dispersivities are greatly affected. The method is applied to the Borden site and provides a better explanation of the observed data after considering the effect of vertical boundaries. These results show that our method could serve as a promising tool for studying and predicting the characteristics of solute transport in heterogeneous media.
Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli
Authors: Wu Hao , Wang Yuqi , Ying Minfeng , Jin Chengmeng , Li Jiangtao , Hu Xun
Published: June 2021

Previous studies demonstrated that superoxide could initiate and amplify LDH-catalyzed hydrogen peroxide production in aqueous phase, but its physiological relevance is unknown. Here we showed that LDHA and LDHB both exhibited hydrogen peroxide-producing activity, which was significantly enhanced by the superoxide generated from the isolated mitochondria from HeLa cells and patients’ cholangiocarcinoma specimen. After LDHA or LDHB were knocked out, hydrogen peroxide produced by Hela or 4T1 cancer cells were significantly reduced. Re-expression of LDHA in LDHA-knockout HeLa cells partially restored hydrogen peroxide production. In HeLa and 4T1 cells, LDHA or LDHB knockout or LDH inhibitor FX11 significantly decreased ROS induction by modulators of the mitochondrial electron transfer chain (antimycin, oligomycin, rotenone), hypoxia, and pharmacological ROS inducers piperlogumine (PL) and phenethyl isothiocyanate (PEITC). Moreover, the tumors formed by LDHA or LDHB knockout HeLa or 4T1 cells exhibited a significantly less oxidative state than those formed by control cells. Collectively, we provide a mechanistic understanding of a link between LDH and cellular hydrogen peroxide production or oxidative stress in cancer cells in vitro and in vivo.
U2AF1 mutation promotes tumorigenicity through facilitating autophagy flux mediated by FOXO3a activation in myelodysplastic syndromes
Authors: Zhu Yuqian , Song Dandan , Guo Juan , Jin Jiacheng , Tao Ying , Zhang Zheng , Xu Feng , He Qi , Li Xiao , Chang Chunkang , Wu Lingyun
Published: June 2021

Mutations in the U2 small nuclear RNA auxiliary factor 1 (U2AF1) gene are the common feature of a major subset in myelodysplastic syndromes (MDS). However, the genetic landscape and molecular pathogenesis of oncogenic U2AF1S34F mutation in MDS are not totally understood. We performed comprehensive analysis for prognostic significance of U2AF1 mutations in acute myeloid leukemia (AML) cohort based on The Cancer Genome Atlas (TCGA) database. Functional analysis of U2AF1S34F mutation was performed in vitro. Differentially expressed genes (DEGs) and significantly enriched pathways were identified by RNA sequencing. The forkhead box protein O3a (FOXO3a) was investigated to mediate the function of U2AF1S34F mutation in cell models using lentivirus. Chromatin immunoprecipitation, immunoblotting analyses, and immunofluorescence assays were also conducted. U2AF1 mutations were associated with poor prognosis in MDS and AML samples, which significantly inhibited cell proliferation and induced cellular apoptosis in cell models. Our data identified that U2AF1-mutant cell lines undergo FOXO3a-dependent apoptosis and NLRP3 inflammasome activation, which induces pyroptotic cell death. Particularly, an increase in the level of FOXO3a promoted the progression of MDS in association with restored autophagy program leading to NLRP3 inflammasome activation in response to U2AF1S34F mutation. Based on the result that U2AF1S34F mutation promoted the transcriptional activity of Bim through upregulating FOXO3a with transactivation of cell cycle regulators p21Cip1 and p27Kip1, FOXO3a, a potentially cancer-associated transcription factor, was identified as the key molecule on which these pathways converge. Overall, our studies provide new insights that U2AF1S34F mutation functions the crucial roles in mediating MDS disease progression via FOXO3a activation, and demonstrate novel targets of U2AF1 mutations to the pathogenesis of MDS.
Endoplasmic reticulum−mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells
Authors: Lopez-Crisosto Camila , Díaz-Vegas Alexis , Castro Pablo F. , Rothermel Beverly A. , Bravo-Sagua Roberto , Lavandero Sergio
Published: June 2021

Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca2+ between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER−mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial−ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBPβ, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca2+ uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial−ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.
Teprotumumab for thyroid eye disease: early response is not required for benefit
Authors: Ugradar Shoaib , Wang Yao , Mester Tunde , Kahaly George J. , Douglas Raymond S.
Published: June 2021

Purpose

In recent trials, 50% of patients treated with teprotumumab for thyroid eye disease had significant improvements in proptosis at 6 weeks. However, a small subgroup of patients did not have a significant response by week 12. We examine the outcomes at week 24 in patients from both trials who had little or no proptosis response at week 12.

Design

In this post hoc analysis, data from teprotumumab-treated patients in the placebo-controlled randomized phases 2 and 3 trials were reviewed.

Methods

Patients treated with teprotumumab or placebo with a ≤2 mm reduction from baseline in proptosis at week 12 and completed assessments at both the weeks 12 and 24 visits were included. The main outcome measures were a change in proptosis, clinical activity score (CAS) and diplopia in response to teprotumumab therapy at baseline and weeks 6, 12, 18, and 24.

Results

From the phases 2 and 3 studies, 24 patients from the treated and placebo groups were included for analysis (48 total). In the teprotumumab group, of the 24 who had no improvement in proptosis (≥2 mm from baseline) at 12 weeks, 15 (63%) demonstrated a clinically significant improvement at week 24. No patients from the 24 placebo patients had a clinically significant improvement in proptosis at 12 weeks, and 24 weeks. At week 12, 22 patients (92%) in the teprotumumab group had a significant reduction in the CAS (≥2 points) and at 24 weeks all patients achieved this reduction. At week 12, 11 (46%) patients from the placebo group had a significant improvement, while 10 (42%) had a significant improvement at 24 weeks. 22 of the 24 patients (92%) in the teprotumumab group had a diplopia grade > 0 at baseline. At week 12, 12 of the 22 (55%) had improvement in diplopia ≥ 1 grade. By week 24, 16 patients (73%) had an improvement in diplopia ≥ 1 grade. In the placebo group, 15 (63%) had significant diplopia. At week 12, 3 (20%) from this group had improvement in diplopia ≥ 1 grade, while at 24 weeks this number rose to 4 (27%).

Conclusions

There is variability in the time taken to manifest a clinically significant response to teprotumumab, some patients my need a longer time to respond.
The Great Oxygenation Event as a consequence of ecological dynamics modulated by planetary change
Authors: Olejarz Jason , Iwasa Yoh , Knoll Andrew H. , Nowak Martin A.
Published: June 2021

The Great Oxygenation Event (GOE), ca. 2.4 billion years ago, transformed life and environments on Earth. Its causes, however, are debated. We mathematically analyze the GOE in terms of ecological dynamics coupled with a changing Earth. Anoxygenic photosynthetic bacteria initially dominate over cyanobacteria, but their success depends on the availability of suitable electron donors that are vulnerable to oxidation. The GOE is triggered when the difference between the influxes of relevant reductants and phosphate falls below a critical value that is an increasing function of the reproductive rate of cyanobacteria. The transition can be either gradual and reversible or sudden and irreversible, depending on sources and sinks of oxygen. Increasing sources and decreasing sinks of oxygen can also trigger the GOE, but this possibility depends strongly on migration of cyanobacteria from privileged sites. Our model links ecological dynamics to planetary change, with geophysical evolution determining the relevant time scales.
Emergence of local and global synaptic organization on cortical dendrites
Authors: Kirchner Jan H. , Gjorgjieva Julijana
Published: June 2021

Synaptic inputs on cortical dendrites are organized with remarkable subcellular precision at the micron level. This organization emerges during early postnatal development through patterned spontaneous activity and manifests both locally where nearby synapses are significantly correlated, and globally with distance to the soma. We propose a biophysically motivated synaptic plasticity model to dissect the mechanistic origins of this organization during development and elucidate synaptic clustering of different stimulus features in the adult. Our model captures local clustering of orientation in ferret and receptive field overlap in mouse visual cortex based on the receptive field diameter and the cortical magnification of visual space. Including action potential back-propagation explains branch clustering heterogeneity in the ferret and produces a global retinotopy gradient from soma to dendrite in the mouse. Therefore, by combining activity-dependent synaptic competition and species-specific receptive fields, our framework explains different aspects of synaptic organization regarding stimulus features and spatial scales.
Type II alveolar cell MHCII improves respiratory viral disease outcomes while exhibiting limited antigen presentation
Authors: Toulmin Sushila A. , Bhadiadra Chaitali , Paris Andrew J. , Lin Jeffrey H. , Katzen Jeremy , Basil Maria C. , Morrisey Edward E. , Worthen G. Scott , Eisenlohr Laurence C.
Published: June 2021

Type II alveolar cells (AT2s) are critical for basic respiratory homeostasis and tissue repair after lung injury. Prior studies indicate that AT2s also express major histocompatibility complex class II (MHCII) molecules, but how MHCII expression by AT2s is regulated and how it contributes to host defense remain unclear. Here we show that AT2s express high levels of MHCII independent of conventional inflammatory stimuli, and that selective loss of MHCII from AT2s in mice results in modest worsening of respiratory virus disease following influenza and Sendai virus infections. We also find that AT2s exhibit MHCII presentation capacity that is substantially limited compared to professional antigen presenting cells. The combination of constitutive MHCII expression and restrained antigen presentation may position AT2s to contribute to lung adaptive immune responses in a measured fashion, without over-amplifying damaging inflammation.
Tuning of lattice oxygen reactivity and scaling relation to construct better oxygen evolution electrocatalyst
Authors: Huang Zhen-Feng , Xi Shibo , Song Jiajia , Dou Shuo , Li Xiaogang , Du Yonghua , Diao Caozheng , Xu Zhichuan J. , Wang Xin
Published: June 2021

Developing efficient and low-cost electrocatalysts for oxygen evolution reaction is crucial in realizing practical energy systems for sustainable fuel production and energy storage from renewable energy sources. However, the inherent linear scaling relation for most catalytic materials imposes a theoretical overpotential ceiling, limiting the development of efficient electrocatalysts. Herein, using modeled NaxMn3O7 materials, we report an effective strategy to construct better oxygen evolution electrocatalyst through tuning both lattice oxygen reactivity and scaling relation via alkali metal ion mediation. Specifically, the number of Na+ is linked with lattice oxygen reactivity, which is determined by the number of oxygen hole in oxygen lone-pair states formed by native Mn vacancies, governing the barrier symmetry between O–H bond cleavage and O–O bond formation. On the other hand, the presence of Na+ could have specific noncovalent interaction with pendant oxygen in *OOH to overcome the limitation from linear scaling relation, reducing the overpotential ceiling. Combining in situ spectroscopy-based characterization with first-principles calculations, we demonstrate that an intermediate level of Na+ mediation (NaMn3O7) exhibits the optimum oxygen evolution activity. This work provides a new rational recipe to develop highly efficient catalyst towards water oxidation or other oxidative reactions through tuning lattice oxygen reactivity and scaling relation.
Restoration of the molecular clock is tumor suppressive in neuroblastoma
Authors: Moreno-Smith Myrthala , Milazzo Giorgio , Tao Ling , Fekry Baharan , Zhu Bokai , Mohammad Mahmoud A. , Di Giacomo Simone , Borkar Roshan , Reddy Karthik Reddy Kami , Capasso Mario , Vasudevan Sanjeev A. , Sumazin Pavel , Hicks John , Putluri Nagireddy , Perini Giovanni , Eckel-Mahan Kristin , Burris Thomas P. , Barbieri Eveline
Published: June 2021

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
A universal Urbach rule for disordered organic semiconductors
Authors: Kaiser Christina , Sandberg Oskar J. , Zarrabi Nasim , Li Wei , Meredith Paul , Armin Ardalan
Published: June 2021

In crystalline semiconductors, absorption onset sharpness is characterized by temperature-dependent Urbach energies. These energies quantify the static, structural disorder causing localized exponential-tail states, and dynamic disorder from electron-phonon scattering. Applicability of this exponential-tail model to disordered solids has been long debated. Nonetheless, exponential fittings are routinely applied to sub-gap absorption analysis of organic semiconductors. Herein, we elucidate the sub-gap spectral line-shapes of organic semiconductors and their blends by temperature-dependent quantum efficiency measurements. We find that sub-gap absorption due to singlet excitons is universally dominated by thermal broadening at low photon energies and the associated Urbach energy equals the thermal energy, regardless of static disorder. This is consistent with absorptions obtained from a convolution of Gaussian density of excitonic states weighted by Boltzmann-like thermally activated optical transitions. A simple model is presented that explains absorption line-shapes of disordered systems, and we also provide a strategy to determine the excitonic disorder energy. Our findings elaborate the meaning of the Urbach energy in molecular solids and relate the photo-physics to static disorder, crucial for optimizing organic solar cells for which we present a revisited radiative open-circuit voltage limit.
Shallow slow earthquakes to decipher future catastrophic earthquakes in the Guerrero seismic gap
Authors: Plata-Martinez R. , Ide S. , Shinohara M. , Garcia E. S. , Mizuno N. , Dominguez L. A. , Taira T. , Yamashita Y. , Toh A. , Yamada T. , Real J. , Husker A. , Cruz-Atienza V. M. , Ito Y.
Published: June 2021

The Guerrero seismic gap is presumed to be a major source of seismic and tsunami hazard along the Mexican subduction zone. Until recently, there were limited observations at the shallow portion of the plate interface offshore Guerrero, so we deployed instruments there to better characterize the extent of the seismogenic zone. Here we report the discovery of episodic shallow tremors and potential slow slip events in Guerrero offshore. Their distribution, together with that of repeating earthquakes, seismicity, residual gravity and bathymetry, suggest that a portion of the shallow plate interface in the gap undergoes stable slip. This mechanical condition may not only explain the long return period of large earthquakes inside the gap, but also reveals why the rupture from past M < 8 earthquakes on adjacent megathrust segments did not propagate into the gap to result in much larger events. However, dynamic rupture effects could drive one of these nearby earthquakes to break through the entire Guerrero seismic gap.
Control of membrane barrier during bacterial type-III protein secretion
Authors: Hüsing Svenja , Halte Manuel , van Look Ulf , Guse Alina , Gálvez Eric J. C. , Charpentier Emmanuelle , Blair David F. , Erhardt Marc , Renault Thibaud T.
Published: June 2021

Type-III secretion systems (T3SSs) of the bacterial flagellum and the evolutionarily related injectisome are capable of translocating proteins with a remarkable speed of several thousand amino acids per second. Here, we investigate how T3SSs are able to transport proteins at such a high rate while preventing the leakage of small molecules. Our mutational and evolutionary analyses demonstrate that an ensemble of conserved methionine residues at the cytoplasmic side of the T3SS channel create a deformable gasket (M-gasket) around fast-moving substrates undergoing export. The unique physicochemical features of the M-gasket are crucial to preserve the membrane barrier, to accommodate local conformational changes during active secretion, and to maintain stability of the secretion pore in cooperation with a plug domain (R-plug) and a network of salt-bridges. The conservation of the M-gasket, R-plug, and salt-bridge network suggests a universal mechanism by which the membrane integrity is maintained during high-speed protein translocation in all T3SSs.