bluuebunny/crossref_metadata_2025 huggingface dataset:
Rewriting Nature
Authors: Enríquez Paul
Published: June 2021

History will mark the twenty-first century as the dawn of the age of precise genetic manipulation. Breakthroughs in genome editing are poised to enable humankind to fundamentally transform life on Earth. Those familiar with genome editing understand its potential to revolutionize civilization in ways that surpass the impact of the discovery of electricity and the development of gunpowder, the atomic bomb, or the Internet. Significant questions regarding how society should promote or hinder genome editing loom large in the horizon. And it is up to humans to decide the fate of this powerful technology. Rewriting Nature is a compelling, thought-provoking interdisciplinary exploration of the law, science, and policy of genome editing. The book guides readers through complex legal, scientific, ethical, political, economic, and social issues concerning this emerging technology, and challenges the conventional false dichotomy often associated with science and law, which contributes to a growing divide between both fields.
Advanced Optimization for Process Systems Engineering
Authors: Grossmann Ignacio E.
Published: June 2021

Based on the author's forty years of teaching experience, this unique textbook covers both basic and advanced concepts of optimization theory and methods for process systems engineers. Topics covered include continuous, discrete and logic optimization (linear, nonlinear, mixed-integer and generalized disjunctive programming), optimization under uncertainty (stochastic programming and flexibility analysis), and decomposition techniques (Lagrangean and Benders decomposition). Assuming only a basic background in calculus and linear algebra, it enables easy understanding of mathematical reasoning, and numerous examples throughout illustrate key concepts and algorithms. End-of-chapter exercises involving theoretical derivations and small numerical problems, as well as in modeling systems like GAMS, enhance understanding and help put knowledge into practice. Accompanied by two appendices containing web links to modeling systems and models related to applications in PSE, this is an essential text for single-semester, graduate courses in process systems engineering in departments of chemical engineering.
Stylistic Virtue and Victorian Fiction
Authors: Sussman Matthew
Published: June 2021

What is style, and why does it matter? This book answers these questions by recovering the concept of 'stylistic virtue,' once foundational to rhetoric and aesthetics but largely forgotten today. Stylistic virtues like 'ease' and 'grace' are distinguishing properties that help realize a text's essential character. First described by Aristotle, they were integral to the development of formalist methods and modern literary criticism. The first half of the book excavates the theory of stylistic virtue during its period of greatest ascendance, in the late eighteenth and nineteenth centuries, when belletristic rhetoric shaped how the art of literary style and 'the aesthetic' were understood. The second half offers new readings of Thackeray, Trollope, and Meredith to show how stylistic virtue changes our understanding of style in the novel and challenges conventional approaches to interpreting the ethics of art.
Havana Tradition Platform Pipe Production and Disposition: Implications for Interpreting Regional Variation in Midwestern Hopewell Ceremonialism
Authors: Farnsworth Kenneth B. , Emerson Thomas E. , Hughes Randall E.
Published: June 2021

This study documents the contexts of platform pipe creation, distribution, and disposition at Illinois Havana Hopewell Tradition (50 BC to AD 200–250) sites to identify regional variation in Hopewell ceremonialism and exchange. We observe that the large deposits of stone pipes buried during communal rituals in the Scioto Valley and the continued influence of the Hopewell Sphere of Interaction have skewed archaeological interpretation. Aside from the several large deposits, pipes are limited in the Scioto Tradition and seldom found in habitation areas. In Illinois, pipe fabrication debris commonly occurs in habitation areas along with numerous examples of pipe repair and maintenance. Local pipestones—often from northern Illinois Sterling deposits—predominate, and exotic imported pipestones are unusual. Pipes are rare inclusions with individual burials as indicators of status, spiritual prowess, achievement, or group membership. The high value placed on pipes as communal sacra in Ohio and their value in Illinois as items of personal influence parallels their common occurrence in Illinois and their unique context in Ohio Hopewell. This study of the contexts of pipe manufacture and deposition reinforces current discussions of such artifact assemblages as important in documenting local variations in political, social, and religious mortuary ceremonialism across the “Hopewellian sphere.”
Evaluation of Solar-Powered Battery Systems for Individuals Using Electricity-Dependent Medical Devices in Puerto Rico Following Hurricane Maria
Authors: Tosado Gabriella A. , Matos Marvi , Ahumada-Paras Mareldi , Chapko Michael K. , Pozzo Lilo D. ,   the Puerto Rico Solar Health Study Group
Published: June 2021

Objectives:

To determine if solar-powered battery systems could be successfully used for electricity-dependent medical devices by families during a power outage.

Methods:

We assessed the use of and satisfaction with solar-powered battery systems distributed to 15 families following Hurricane Maria in rural Puerto Rico. Interviews were conducted in July 2018, 3 mo following distribution of the systems.

Results:

The solar-powered battery systems powered refrigeration for medications and prescribed diets, asthma therapy, inflatable mattresses to prevent bedsores, and continuous positive airway pressure machines for sleep apnea. Despite some system problems, such as inadequate power, defective cables, and blown fuses, families successfully dealt with these issues with some outside help. Almost all families were pleased with the systems and a majority would recommend solar-powered battery systems to a neighbor.

Conclusions:

Families accepted and successfully used solar-powered battery systems to power medical devices. Solar-powered battery systems should be considered as alternatives to generators for power outages after hurricanes and other disasters. Additional research and analysis are needed to inform policy on increasing access to such systems.
Jeremy Bentham: Pauperism, Colonialism, and Imperialism
Authors: ARNEIL BARBARA
Published: June 2021

Using two recently published folios by Jeremy Bentham, I draw out a fundamental but little-analyzed connection between pauperism and both domestic and settler colonialism in opposition to imperialism in his thought. The core theoretical contribution of this article is to draw a distinction between a colonial, internal, and productive form of power that claims to improve people and land from within, which Bentham defends, and an imperial, external, and repressive form of power that dominates or rules over people from above and afar, that he rejects. Inherent in colonialism and the power unleashed by it are specific and profoundly negative implications in practice for the poor and disabled of Europe in the nineteenth and early twentieth centuries subject to domestic colonialism and indigenous peoples subject to settler colonialism from first contact until today. I conclude Bentham is best understood as a pro-colonialist and anti-imperialist thinker.
Potential displacement of the native Tenuisvalvae notata by the invasive Cryptolaemus montrouzieri in South America suggested by differences in climate suitability
Authors: Ferreira Larissa F. , Silva-Torres Christian S. A. , Torres Jorge B. , Venette Robert C.
Published: June 2021

Tenuisvalvae notata (Mulsant) (Coccinellidae) is a predatory ladybird beetle native to South America. It specializes in mealybugs prey (Pseudococcidae), but relatively little is known about its ecology. In contrast, the ladybird beetle Cryptolaemus montrouzieri Mulsant (Coccinellidae) is indigenous to Australia and has been introduced to many countries worldwide including Brazil for biological control of mealybugs. The potential impacts of these introductions to native coccinellids have rarely been considered. The software CLIMEX estimated the climate suitability for both species as reflected in the Ecoclimatic Index (EI). Much of South America, Africa, and Australia can be considered climatically suitable for both species, but in most cases, the climate is considerably more favorable for C. montrouzieri than T. notata, especially in South America. The CLIMEX model also suggests seasonal differences in growth conditions (e.g. rainfall and temperature) that could affect the phenology of both species. These models suggest that few locations in South America would be expected to provide T. notata climatic refugia from C. montrouzieri. Although other ecological factors will also be important, such as prey availability, this analysis suggests a strong potential for displacement of a native coccinellid throughout most of its range as a consequence of the invasion by an alien competitor.
Bispectral analysis of broadband turbulence and geodesic acoustic modes in the T-10 tokamak
Authors: Riggs Greg A. , Nogami S.H. , Koepke M.E. , Melnikov A.V. , Eliseev L.G. , Lysenko S.E. , Khabanov P.O. , Drabinskij M.A. , Kharchev N.K. , Kozachek A.S. , Ufimtsev M.V. ,   HIBP Team
Published: June 2021

Local fluctuations of electrostatic potential, poloidal electric field, magnetic potential and electron density are simultaneously measured in the T-10 tokamak by a heavy ion beam probe (HIBP) having a five-slit energy analyser, which allows an estimate of the turbulent particle flux and

$\boldsymbol {E}\times \boldsymbol {B}$

rotation velocity in the off-minor-axis gradient zone of the toroidal plasma column. The high spatial and temporal resolution of the modern multichannel HIBP makes it an effective tool to study plasma oscillations. Motivated by previous work that has documented time-resolved interactions between measured plasma parameters using correlation analysis (coherence of

$E_{\textrm {pol}}$

and density

$n_e$

, and cross-phase), a new result from bicorrelation analysis (bicoherence of magnetic potential

$A_\zeta$

and density

$n_e$

, and biphase) is reported for documenting the evidence of wave–wave coupling and energy transfer associated with the interaction between geodesic acoustic modes (GAM) and broadband, quasi-coherent modes.
General dispersion properties of magnetized plasmas with drifting bi-Kappa distributions. DIS-K: Dispersion Solver for Kappa Plasmas
Authors: López R.A. , Shaaban S.M. , Lazar M.
Published: June 2021

Space plasmas are known to be out of (local) thermodynamic equilibrium, as observations show direct or indirect evidences of non-thermal velocity distributions of plasma particles. Prominent are the anisotropies relative to the magnetic field, anisotropic temperatures, field-aligned beams or drifting populations, but also, the suprathermal populations enhancing the high-energy tails of the observed distributions. Drifting bi-Kappa distribution functions can provide a good representation of these features and enable for a kinetic fundamental description of the dispersion and stability of these collision-poor plasmas, where particle–particle collisions are rare but wave–particle interactions appear to play a dominant role in the dynamics. In the present paper we derive the full set of components of the dispersion tensor for magnetized plasma populations modelled by drifting bi-Kappa distributions. A new solver called DIS-K (DIspersion Solver for Kappa plasmas) is proposed to solve numerically the dispersion relations of high complexity. The solver is validated by comparing with the damped and unstable wave solutions obtained with other codes, operating in the limits of drifting Maxwellian and non-drifting Kappa models. These new theoretical tools enable more realistic characterizations, both analytical and numerical, of wave fluctuations and instabilities in complex kinetic configurations measured in-situ in space plasmas.
Injection fears and COVID-19 vaccine hesitancy
Authors: Freeman Daniel , Lambe Sinéad , Yu Ly-Mee , Freeman Jason , Chadwick Andrew , Vaccari Cristian , Waite Felicity , Rosebrock Laina , Petit Ariane , Vanderslott Samantha , Lewandowsky Stephan , Larkin Michael , Innocenti Stefania , McShane Helen , Pollard Andrew J. , Loe Bao Sheng
Published: June 2021

Background

When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears.

Methods

In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January–5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey–injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears.

Results

In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97–2.40, p < 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09–0.14, p < 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale, r = 0.22, p < 0.001, Medical Fear Survey, r = 0.23, p = <0.001 and injection fears, r = 0.25, p < 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups.

Conclusions

Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes.
Microvariation in the division of labor between null- and overt-subject pronouns: the case of Italian and Spanish
Authors: Contemori Carla , Di Domenico Elisa
Published: June 2021

In Italian, null pronouns are typically interpreted toward antecedents in a prominent syntactic position, whereas overt pronouns prefer antecedents in lower positions. Interpretation preferences in Spanish are less clear. While comprehension and production have never been systematically compared in Italian and Spanish, here we look at the preferences for overt- and null-subject pronouns in the two languages using the same production and comprehension materials. Using an offline comprehension task with a group of Spanish and Italian speakers, we tested sentences where the type of pronoun (null vs. explicit) and position of the pronoun (anaphoric vs. cataphoric) are manipulated, to determine how context affects speakers’ interpretations in the two languages. With two production tasks, we measured referential choice in controlled discourse contexts, linking the production patterns to the differences observed in comprehension. Our results indicate microvariation in the two null-subject languages, with Spanish following the Position of Antecedent Hypothesis but to a lesser degree than Italian. More specifically, in Spanish, the weaker object bias for overt pronouns parallels with a higher use of overt pronouns (and with fewer null pronouns) in contexts of topic maintenance.
CLASSROOM LEARNERS’ ACQUISITION OF THE SPANISH COPULA WITH ADJECTIVES
Authors: Long Avizia Yim
Published: June 2021

Research on the second language (L2) acquisition of the Spanish copulas has been central to our understanding of key concepts and issues in the field of SLA such as stages of development and variability in L2s. However, this research has focused nearly exclusively on native English-speaking learners. The present study examined native Korean-speaking learners’ acquisition and use of the Spanish copulas with adjectives in oral production. Analyses of the range and frequency of copula forms produced across four levels of Spanish language study revealed an increase inserandestaruse and a decrease in developmental omission as learner level increased. Predicate type, resultant state, and Spanish grammar score significantly influenced use ofestaroverser.Comparison with native English-speaking learners revealed differences between first language groups in terms of rates of form use, but similar developmental trends and predictors ofestaruse overall.
Writing Novels, Simulating Voices: Euphonia,Trilby, and the Technological Sounding of Identity
Authors: McGuire Riley
Published: June 2021

This article troubles a tendency in literary criticism to equate novelistic speech with sound recording. It recovers the history of Joseph Faber's Euphonia (a speech simulator exhibited from the 1840s to the 1880s) in order to articulate an alternative vocal ontology of the novel—one of simulation rather than recording. The Euphonia has striking parallels to the eponymous heroine of George Du Maurier'sTrilby(1894): their comparably mechanized utterances flatten hierarchies of difference, instead of phonographically using the voice to archive particularity. In dialogue, the Euphonia and Trilby elucidate the relationship between page and voice as always collaborative, though contoured by power.
Factors Influencing Distribution Characteristics of Total Dissolved Gas Supersaturation at Confluences
Authors: Shen X. , Hodges B. R. , Li R. , Li Z. , Fan J. L. , Cui N. B. , Cai H. J.
Published: June 2021

Total dissolved gas supersaturation (TDGS) produced by flood flows over a high dam has negative consequences on downstream fish. Reducing the total dissolved gas (TDG) levels and/or providing adequate low‐TDGS fish shelter areas remains a challenge. The presence of a low‐TDG‐saturation (LTS) zone at river confluences can protect the fish from harmful high TDG levels, but the effects of confluence hydrodynamics on the TDGS distribution are not well understood. In this study, three‐dimensional (3D) hydrodynamic simulations are performed to understand the influence of flow ratio and junction angle on the TDGS distribution downstream of river confluences. The simulation results show that the TDGS distribution is mainly affected by (a) inflow TDGS that determines the supply, (b) secondary flow that leads to rapid renewal of surface water for degassing, and (c) increased turbulence intensity that promotes dissipation of TDGS. Relationship between the LTS area, the flow ratio and the junction angle is constructed via regression analysis. The regression model is validated against a 3D numerical simulation that is compared to field observations at two river confluences along the Jinshajiang River (China). This study provides scientific basis for potential hydraulic modifications at confluences to enlarge an LTS zone and reduce fish fatality.
Geometric Criteria for the Snap‐Off of a Non‐Wetting Droplet in Pore‐Throat Channels With Rectangular Cross‐Sections
Authors: Cha Luming , Xie Chiyu , Feng Qihong , Balhoff Matthew
Published: June 2021

Snap‐off is a phenomenon that occurs when a non‐wetting fluid is displaced by wetting fluid in pore‐throat channels, leading to the breakup of droplets at the throat. Snap‐off plays a key role in many industrial processes involving immiscible multiphase flows, such as aquifer remediation, carbon capture and geological storage, recovery of hydrocarbons. Here we derive geometric criteria for the capillary snap‐off at the pore‐throat junctions in 2D microchannels with rectangular cross‐sections. The criteria are theoretically presented in three categories according to the range of the throat depth, h. We find that if h is smaller than the throat width, snap‐off will be inhibited, if h is larger than the pore width, snap‐off may occur but it is independent of h, and if h is in between the throat width and the pore width, a critical depth exists for the occurrence of snap‐off. These criteria are verified using numerical CFD simulations and validated using microfluidic experiments. These results indicate the conditions for snap‐off in the pore‐throat channel with rectangular cross‐sections, which clarify previous debates in the literature. One application of this work is for micromodels, which are porous microfluidic chips used as tools to observe multiphase flow in porous media at the pore‐scale. Most micromodels are two‐dimensional (2D), which have rectangular cross‐sections with uniform depth. The geometric criteria derived here provide guidelines for the design of micromodels used in the study of multiphase flow processes in porous media.
The Madden‐Julian Oscillation Modulates the Air Quality in the Maritime Continent
Authors: Kuwata Mikinori , Miyakawa Takuma , Yokoi Satoru , Khan Md Firoz , Latif Mohd Talib
Published: June 2021

Air quality in the Maritime Continent, which worsens particularly during peatland fire periods, causes climate and environmental concerns. The occurrence of peatland fire haze has been related to the interannual variations of the El Niño‐Southern Oscillation, Indian Ocean Dipole, and inter‐seasonal monsoon cycle. However, the factors affecting the region's air quality on subseasonal timescales have not been clearly identified. We investigated the role of the Madden‐Julian Oscillation (MJO), which has a 30–90‐day cycle, in air quality using a long‐term observation data set from Malaysia. The results show that in MJO Phase 3, during which the region is covered by convective clouds, only accounted for 4 ± 2% of high PM10 concentration days (daily average PM10 concentration at site X > average + standard deviation of daily average PM10 concentration at site X) among all active MJO periods. In contrast, the corresponding values were considerably higher in MJO Phases 1 and 5–8. The MJO also modulated CO and ozone concentrations. This study shows that the MJO influences air quality during both fire and non‐fire seasons, demonstrating that variations in wildfire activity are not the only cause of air quality changes. Other factors, such as precipitation, also need to be considered to better understand the relationship between the MJO and air quality.
Depth Estimation of Potential Field by Using a New Downward Continuation Based on the Continued Fraction in Space Domain
Authors: Zhou Wenna , Zhang Chong , Zhang Dailei
Published: June 2021

Depth estimation of potential field data is a powerful tool for geologic source interpretation. It can be implemented by using downward continuation method based on a normalized algorithm. However, when several geological bodies with different burial depths exist in the research area, the calculated depth usually tends to be the average depth. To overcome this limitation, we proposed a new downward continuation method based on the relationship between the Taylor series and the continued fraction in space domain. Theoretically, it can obtain the singular (quasi‐singular) source point directly, which indicates the position of source. In practical applications, we only need to calculate downward continuation data from the original level to an expected maximum depth. The absolute value is calculated so that the maximum value indicates the source depth range. We used different synthetic models to test our method and obtained satisfactory results. The advantages of depth estimation using the new method were illustrated by comparing it with the normalized total gradient method. Finally, we applied the new method to field data, and results were in agreement with the previous results. This illustrated that the new method can be used for high resolution, high accuracy depth estimation.
Relative Paleointensity Record of Integrated Ocean Drilling Program Site U1396 in the Caribbean Sea: Geomagnetic and Chronostratigraphic Observations in the Pliocene
Authors: Hatfield R. G. , Stoner J. S. , Fraass A. J.
Published: June 2021

Continuous sedimentary records of paleomagnetic directional variability and relative paleointensity (RPI) provide valuable information on the evolution of the geodynamo while also facilitating stratigraphic correlation and age control. While the Quaternary RPI record has received much attention, Pliocene records are relatively rare. Here, a u‐channel paleomagnetic study from Integrated Ocean Drilling Program (IODP) Site U1396 in the Caribbean Sea refines the shipboard‐derived polarity stratigraphy and generates an RPI and directional record extending back 4.5 Ma. Rock magnetic data reveal changes in magnetic coercivity around 2.1 Ma that influences the quality of the paleomagnetic record; while the older record is well‐resolved and passes RPI quality criteria, much of the younger section does not. To facilitate the development of the RPI record, spike noise associated with discrete intervals of volcanogenic sediments are filtered from the data set. The resulting record passes RPI reliability criteria between 0–0.6 Ma and 2.1–4.5 Ma and represents the highest resolution RPI record extending into the early Pliocene. We use this record to refine the existing benthic δ18O chronology and open the door to high‐resolution RPI chronostratigraphies during the Pliocene. Although we find no evidence for a previously observed increase in magnetic field intensity after ∼4 million years ago, we do observe an asymmetrical form to RPI in the normal polarity intervals of the Gauss chron. We also find a polarity bias in inclination that cannot be simply explained by a drill string overprint, suggesting polarity‐driven field asymmetries that are particularly pronounced during the Pliocene.
Reflection of K1 Internal Tides at the Continental Slope in the Northern South China Sea
Authors: Wang Shuya , Cao Anzhou , Li Qun , Chen Xu
Published: June 2021

Reflection of the K1 internal tides (ITs) in the northern South China Sea (SCS) is investigated using a high‐resolution three‐dimensional numerical model. The simulated results indicate that the westward K1 ITs generated at the Luzon Strait (LS) first impact the continental slope in the northern SCS, and thereafter are reflected. There is a total of 0.31 GW of K1 energy that are reflected, suggesting a weak reflection considering 3.54 GW of westward K1 energy from the LS. Two reflected K1 beams are revealed. The southeast one is the more energetic and can propagate across the deep basin, agreeing with that extracted from satellite altimeter data. The eastward one propagates toward the LS, but it is absent in altimeter results because of its lower intensity. Both the two reflected beams are radiated from the supercritical region in shallow water. Different from the incident waves that are dominated by mode‐1, the reflected waves exhibit a multimodal structure. Contribution of high modes to reflected waves is comparable to that of mode‐1. Moreover, modal content is different for the two reflected beams, with higher proportion of high‐mode energy flux for eastward reflected beam. In contrast to the K1 ITs, no remarkable reflected O1 ITs are detected from either simulated or altimeter results. This is due to the weak generation of O1 ITs at the LS, which leads to less O1 energy reaching the continental slope. The results of this work can provide essential insight on IT dynamics in the SCS.
A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies
Authors: Li Shouyun , Yang Xue , Liu Shuang , Chen Yirui , Xing Haiyan , Tang Kejing , Tian Zheng , Xu Yingxi , Rao Qing , Wang Min , Wang Jianxiang
Published: June 2021

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and its fusion partners. For decades, the advent of all-trans retinoic acid (ATRA) synergized with arsenic trioxide (As2O3) has turned most APL from highly fatal to highly curable. TBLR1-RARα (TR) is the tenth fusion gene of APL identified in our previous study, with its oncogenic role in the pathogenesis of APL not wholly unraveled. In this study, we found the expression of TR in mouse hematopoietic progenitors induces blockade of differentiation with enhanced proliferative capacity in vitro. A novel murine transplantable leukemia model was then established by expressing TR fusion gene in lineage-negative bone marrow mononuclear cells. Characteristics of primary TR mice revealed a rapid onset of aggressive leukemia with bleeding diathesis, which recapitulates human APL more accurately than other models. Despite the in vitro sensitivity to ATRA-induced cell differentiation, neither ATRA monotherapy nor combination with As2O3 confers survival benefit to TR mice, consistent with poor clinical outcome of APL patients with TR fusion gene. Based on histone deacetylation phenotypes implied by bioinformatic analysis, HDAC inhibitors demonstrated significant survival superiority in the survival of TR mice, yielding insights into clinical efficacy against rare types of APL.
Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway
Authors: Sun Shilong , Duan Zehua , Wang Xinyu , Chu Chengnan , Yang Chao , Chen Fang , Wang Daojuan , Wang Chenyang , Li Qiurong , Ding Weiwei
Published: June 2021

Increased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.
Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming
Authors: Dai Yi , Li Fan , Jiao Yuwen , Wang Guoguang , Zhan Tian , Xia Yunwei , Liu Hanyang , Yang Haojun , Zhang Jianping , Tang Liming
Published: June 2021

Platinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CRcells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.
Solid-state nanopore systems: from materials to applications
Authors: He Yuhui , Tsutsui Makusu , Zhou Yue , Miao Xiang-Shui
Published: June 2021

Ion transport and hydrodynamic flow through nanometer-sized channels (nanopores) have been increasingly studied owing to not only the fundamental interest in the abundance of novel phenomena that has been observed but also their promising application in innovative nanodevices, including next-generation sequencers, nanopower generators, and memristive synapses. We first review various kinds of materials and the associated state-of-the-art processes developed for fabricating nanoscale pores, including the emerging structures of DNA origami and 2-dimensional nanopores. Then, the unique transport phenomena are examined wherein the surface properties of wall materials play predominant roles in inducing intriguing characteristics, such as ion selectivity and reverse electrodialysis. Finally, we highlight recent progress in the potential application of nanopores, ranging from their use in biosensors to nanopore-based artificial synapses.
Construction of C-C bonds via photoreductive coupling of ketones and aldehydes in the metal-organic-framework MFM-300(Cr)
Authors: Luo Tian , Li Lili , Chen Yinlin , An Jie , Liu Chengcheng , Yan Zheng , Carter Joseph H. , Han Xue , Sheveleva Alena M. , Tuna Floriana , McInnes Eric J. L. , Tang Chiu C. , Schröder Martin , Yang Sihai
Published: June 2021

Construction of C-C bonds via reductive coupling of aldehydes and ketones is hindered by the highly negative reduction potential of these carbonyl substrates, particularly ketones, and this renders the formation of ketyl radicals extremely endergonic. Here, we report the efficient activation of carbonyl compounds by the formation of specific host-guest interactions in a hydroxyl-decorated porous photocatalyst. MFM-300(Cr) exhibits a band gap of 1.75 eV and shows excellent catalytic activity and stability towards the photoreductive coupling of 30 different aldehydes and ketones to the corresponding 1,2-diols at room temperature. Synchrotron X-ray diffraction and electron paramagnetic resonance spectroscopy confirm the generation of ketyl radicals via confinement within MFM-300(Cr). This protocol removes simultaneously the need for a precious metal-based photocatalyst or for amine-based sacrificial agents for the photochemical synthesis.
Evidence of the interplay of genetics and culture in Ethiopia
Authors: López Saioa , Tarekegn Ayele , Band Gavin , van Dorp Lucy , Bird Nancy , Morris Sam , Oljira Tamiru , Mekonnen Ephrem , Bekele Endashaw , Blench Roger , Thomas Mark G. , Bradman Neil , Hellenthal Garrett
Published: June 2021

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with–and shape–genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals’ birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.
Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
Authors: Crowe-McAuliffe Caillan , Murina Victoriia , Turnbull Kathryn Jane , Kasari Marje , Mohamad Merianne , Polte Christine , Takada Hiraku , Vaitkevicius Karolis , Johansson Jörgen , Ignatova Zoya , Atkinson Gemma C. , O’Neill Alex J. , Hauryliuk Vasili , Wilson Daniel N.
Published: June 2021

Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.
Optoregulated force application to cellular receptors using molecular motors
Authors: Zheng Yijun , Han Mitchell K. L. , Zhao Renping , Blass Johanna , Zhang Jingnan , Zhou Dennis W. , Colard-Itté Jean-Rémy , Dattler Damien , Çolak Arzu , Hoth Markus , García Andrés J. , Qu Bin , Bennewitz Roland , Giuseppone Nicolas , del Campo Aránzazu
Published: June 2021

Progress in our understanding of mechanotransduction events requires noninvasive methods for the manipulation of forces at molecular scale in physiological environments. Inspired by cellular mechanisms for force application (i.e. motor proteins pulling on cytoskeletal fibers), we present a unique molecular machine that can apply forces at cell-matrix and cell-cell junctions using light as an energy source. The key actuator is a light-driven rotatory molecular motor linked to polymer chains, which is intercalated between a membrane receptor and an engineered biointerface. The light-driven actuation of the molecular motor is converted in mechanical twisting of the entangled polymer chains, which will in turn effectively “pull” on engaged cell membrane receptors (e.g., integrins, T cell receptors) within the illuminated area. Applied forces have physiologically-relevant magnitude and occur at time scales within the relevant ranges for mechanotransduction at cell-friendly exposure conditions, as demonstrated in force-dependent focal adhesion maturation and T cell activation experiments. Our results reveal the potential of nanomotors for the manipulation of living cells at the molecular scale and demonstrate a functionality which at the moment cannot be achieved by other technologies for force application.
Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy
Authors: Kimura Kenichi , Ooms Astrid , Graf-Riesen Kathrin , Kuppusamy Maithreyan , Unger Andreas , Schuld Julia , Daerr Jan , Lother Achim , Geisen Caroline , Hein Lutz , Takahashi Satoru , Li Guang , Röll Wilhelm , Bloch Wilhelm , van der Ven Peter F. M. , Linke Wolfgang A. , Wu Sean M. , Huesgen Pitter F. , Höhfeld Jörg , Fürst Dieter O. , Fleischmann Bernd K. , Hesse Michael
Published: June 2021

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.
Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations
Authors: Li Xinjun , Sundquist Kristina , Sundquist Jan , Försti Asta , Hemminki Kari
Published: June 2021

Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.
Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene
Authors: Kohzaki Masaoki , Ootsuyama Akira , Umata Toshiyuki , Okazaki Ryuji
Published: June 2021

Tumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81–0.93 (p = 0.1–0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35–0.68 (p = 0.034–0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.
The potential of adoptive transfer of γ9δ2 T cells to enhance blinatumomab’s antitumor activity against B-cell malignancy
Authors: Chen Yun-Hsiang , Wang Yun , Liao Cheng-Hao , Hsu Shu-Ching
Published: June 2021

Blinatumomab, a bispecific T cell engager (BiTE) antibody targeting CD19 and CD3ε, can redirect T cells toward CD19-positive tumor cells and has been approved to treat relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, chemotherapeutic regimens can severely reduce T cells’ number and cytotoxic function, leading to an inadequate response to blinatumomab treatment in patients. In addition, it was reported that a substantial portion of R/R B-ALL patients failing blinatumomab treatment had the extramedullary disease, indicating the poor ability of blinatumomab in treating extramedullary disease. In this study, we investigated whether the adoptive transfer of ex vivo expanded γ9δ2 T cells could act as the effector of blinatumomab to enhance blinatumomab’s antitumor activity against B-cell malignancies in vivo. Repeated infusion of blinatumomab and human γ9δ2 T cells led to more prolonged survival than that of blinatumomab or human γ9δ2 T cells alone in the mice xenografted with Raji cells. Furthermore, adoptive transfer of γ9δ2 T cells reduced tumor mass outside the bone marrow, indicating the potential of γ9δ2 T cells to eradicate the extramedullary disease. Our results suggest that the addition of γ9δ2 T cells to the blinatumomab treatment regimens could be an effective approach to enhancing blinatumomab’s therapeutic efficacy. The concept of this strategy may also be applied to other antigen-specific BiTE therapies for other malignancies.