bluuebunny/crossref_metadata_2025 huggingface dataset:
A CENTENNIAL AMBIGUITY: THE CHALLENGE OF RESOLVING THE DATE OF THE JEAN-BAPTISTE LAINÉ (MANTLE), ONTARIO, SITE—AROUND AD 1500 OR AD 1600?—AND THE CASE FOR WOOD-CHARCOAL AS A TERMINUS POST QUEM
Authors: Manning Sturt W , Birch Jennifer
Published: April 2022

Considered in isolation, the radiocarbon (14C) dates on short-lived plant remains from the Jean-Baptiste Lainé (formerly Mantle) site, Ontario, yield an ambiguous result: more or less similar probability around AD 1500 or alternatively around AD 1600. This village site, likely of no more than ca. 20–30 years total duration, illustrates the challenges of high-resolution dating across periods with a reversal/plateau in the 14C calibration curve. Another problem we identify is the tendency for dating probability for short-duration sites to sometimes be overly compressed as dating intensity increases under analysis with OxCal, and for probability to shift away from the real age range especially during reversal/plateau episodes. To address both issues additional constraints are necessary. While a tree-ring sequenced 14C “wiggle-match” is the best option where available, we investigate how, in the absence of such an option, use of the in-built age in wood-charcoal samples can be used to distinguish the likely correct date range. This approach can resolve ambiguities in dating, e.g., for shorter-duration Late Woodland village sites in northeastern North America, but also other short-duration cases corresponding with reversal/plateau episodes on the 14C calibration curve. We place the Jean-Baptiste Lainé site most likely in a range between ca. AD 1595–1626 (95.4% probability).
The Irish Land Question, the International Monetary Problem, and Archbishop William Walsh, 1881–1896
Authors: Doyle Patrick
Published: April 2022

This article explores the significance to the Irish land question of a controversial issue in late nineteenth-century international political economy – bimetallism. Bimetallists advocated a monetary system that used gold and silver to define currency value rather than gold alone. Archbishop William Walsh's support for bimetallism is analysed to highlight how Ireland provided a case-study that framed this debate. Walsh believed the gold standard deepened an agrarian crisis that drove the Irish land question. He argued that careful and internationally orchestrated reform of the monetary system offered the means for its resolution. Walsh's bimetallist views marked him out as an original thinker within Irish nationalism, and his views were debated and adopted by monetary reformers across Britain, Europe, and the United States where they featured during the 1896 Presidential Election. Walsh's engagement in monetary politics must also be understood within a tradition of Catholic social teaching in which he positioned himself as a critic of financial capitalism. This article contextualizes the Irish land question within wider debates on the role of silver in the global economy and argues that Walsh's monetary thought reveals him to be a more significant international intellectual than his involvement in Irish politics tends to allow.
How chronic ear disease affects quality of life: a qualitative research study in Nepal
Authors: de Cates C , Jashek-Ahmed F , Bohara RB , Salter C , Youngs R
Published: April 2022

Objective

Hearing loss is the third leading cause globally for ‘years lived with disability’. The majority of those affected live in low and middle-income countries.

Method

This study used qualitative research methods to explore the impact of chronic ear disease on quality of life in Nepal. Twenty face-to-face semi-structured interviews were conducted during a visiting ear camp at the Britain Nepal Otology Service Ear Care Centre in Nepal. Interviews were recorded, transcribed and translated with thematic content analysis performed manually by two researchers.

Results

Chronic ear disease has a significant impact on social interactions, emotional well-being and functionality. Barriers to surgery are cost, accessibility, reputation, gender and fear of complications.

Conclusion

This study provided valuable new insight into patient perspectives on living with chronic ear disease in Nepal. Patients with chronic ear disease experience discrimination and stigmatisation across all levels of personal, family and social life, with their function across all domains being directly limited by symptoms.
Valuing time: Tourism transitions in Svalbard
Authors: Saville Samantha M.
Published: April 2022

As indications of ‘overtourism’ appear in the Arctic, tourism presents both management challenges and ethical dilemmas, applicable to broader discussions about sustainability within Polar tourism. I argue that mapping value relations can contribute to ongoing discussions for positive ways forwards and that the concept of degrowth holds promise in redirecting tourism to better serve the local community. Tourism has become the largest employer and most rapidly growing sector in Svalbard, taking over from coal mining. Longyearbyen is a small urban centre but nevertheless is the central hub where almost all tourism passes through. Indeed, tourism is how the majority of human relations with its lands, seas, human and non-human inhabitants will be enabled. This paper is centred on charting the transition of Longyearbyen to a ‘tourist town’. Drawing on local voices from 2013 to 2016 and 2019, I use a value-based analysis to assess the changes experienced in the context of wider systems of value at work in Svalbard.
Antipsychotic polypharmacy and adverse drug reactions among adults in a London mental health service, 2008–2018
Authors: Yang Justin C. , Thygesen Johan H. , Werbeloff Nomi , Hayes Joseph F. , Osborn David P. J.
Published: April 2022

Background

Antipsychotic polypharmacy (APP) occurs commonly but it is unclear whether it is associated with an increased risk of adverse drug reactions (ADRs). Electronic health records (EHRs) offer an opportunity to examine APP using real-world data. In this study, we use EHR data to identify periods when patients were prescribed 2 + antipsychotics and compare these with periods of antipsychotic monotherapy. To determine the relationship between APP and subsequent instances of ADRs: QT interval prolongation, hyperprolactinaemia, and increased body weight [body mass index (BMI) ⩾ 25].

Methods

We extracted anonymised EHR data. Patients aged 16 + receiving antipsychotic medication at Camden & Islington NHS Foundation Trust between 1 January 2008 and 31 December 2018 were included. Multilevel mixed-effects logistic regression models were used to elucidate the relationship between APP and the subsequent presence of QT interval prolongation, hyperprolactinaemia, and/or increased BMI following a period of APP within 7, 30, or 180 days respectively.

Results

We identified 35 409 observations of antipsychotic prescribing among 13 391 patients. Compared with antipsychotic monotherapy, APP was associated with a subsequent increased risk of hyperprolactinaemia (adjusted odds ratio 2.46; 95% CI 1.87–3.24) and of registering a BMI > 25 (adjusted odds ratio 1.75; 95% CI 1.33–2.31) in the period following the APP prescribing.

Conclusions

Our observations suggest that APP should be carefully managed with attention to hyperprolactinaemia and obesity.
Multimorbidity clusters among people with serious mental illness: a representative primary and secondary data linkage cohort study
Authors: Ma Ruimin , Romano Eugenia , Ashworth Mark , Yadegarfar Mohammad E. , Dregan Alexandru , Ronaldson Amy , de Oliveira Claire , Jacobs Rowena , Stewart Robert , Stubbs Brendon
Published: April 2022

Background

People with serious mental illness (SMI) experience higher mortality partially attributable to higher long-term condition (LTC) prevalence. However, little is known about multiple LTCs (MLTCs) clustering in this population.

Methods

People from South London with SMI and two or more existing LTCs aged 18+ at diagnosis were included using linked primary and mental healthcare records, 2012–2020. Latent class analysis (LCA) determined MLTC classes and multinominal logistic regression examined associations between demographic/clinical characteristics and latent class membership.

Results

The sample included 1924 patients (mean (s.d.) age 48.2 (17.3) years). Five latent classes were identified: ‘substance related’ (24.9%), ‘atopic’ (24.2%), ‘pure affective’ (30.4%), ‘cardiovascular’ (14.1%), and ‘complex multimorbidity’ (6.4%). Patients had on average 7–9 LTCs in each cluster. Males were at increased odds of MLTCs in all four clusters, compared to the ‘pure affective’. Compared to the largest cluster (‘pure affective’), the ‘substance related’ and the ‘atopic’ clusters were younger [odds ratios (OR) per year increase 0.99 (95% CI 0.98–1.00) and 0.96 (0.95–0.97) respectively], and the ‘cardiovascular’ and ‘complex multimorbidity’ clusters were older (ORs 1.09 (1.07–1.10) and 1.16 (1.14–1.18) respectively). The ‘substance related’ cluster was more likely to be White, the ‘cardiovascular’ cluster more likely to be Black (compared to White; OR 1.75, 95% CI 1.10–2.79), and both more likely to have schizophrenia, compared to other clusters.

Conclusion

The current study identified five latent class MLTC clusters among patients with SMI. An integrated care model for treating MLTCs in this population is recommended to improve multimorbidity care.
Design and implementation of a swimming robot with pectoral fins only
Authors: Naser Farah Abbas , Rashid Mofeed Turky
Published: April 2022

The use of swimming robots has increased widely in recent years due to the need of using them in situations where human intervention is difficult or not allowed. Exploring depths of seas, military interventions, or entering areas where the amount of water pollution is high that may threaten the lives of divers. In such cases, the best alternative for humans is to use swimming robots. This paper presents a swimming robot based on Labriform swimming mode. First, it starts with an analytical study of the effect of the fins shape on the performance of a robotic fish. The suggested design of the pectoral fins is concave. The effect of such a design would help largely in achieving the highest thrust in comparison to flat designs provided in the literature. Secondly, a variation in the velocity between the power and recovery strokes is accomplished and a maximum thrust can be obtained when the velocity of the power stroke is three times the velocity of recovery stroke. Thirdly, the kinematics and dynamics of the swimming robot are derived and an evaluation of the total hydrodynamic forces that are exerted on the robot’s body is studied via the computational fluid dynamics method from SOLIDWORKS® platform. Finally, the obtained results are compared to other designs in the literature in terms of some dimensionless numbers of biological fish to examine the efficiency. The proposed design has been validated theoretically and examined experimentally. The results of the simulation and practical experiments confirmed the validity of the design.
A Method for High-Resolution Three-Dimensional Reconstruction with Ewald Sphere Curvature Correction from Transmission Electron Images
Authors: Gureyev Timur E , Paganin David M , Brown Hamish G , Quiney Harry M , Allen Leslie J
Published: April 2022

A method for three-dimensional reconstruction of objects from defocused images collected at multiple illumination directions in high-resolution transmission electron microscopy is presented. The method effectively corrects for the Ewald sphere curvature by taking into account the in-particle propagation of the electron beam. Numerical simulations demonstrate that the proposed method is capable of accurately reconstructing biological molecules or nanoparticles from high-resolution defocused images under conditions achievable in single-particle electron cryo-microscopy or electron tomography with realistic radiation doses, non-trivial aberrations, multiple scattering, and other experimentally relevant factors. The physics of the method is based on the well-known Diffraction Tomography formalism, but with the phase-retrieval step modified to include a conjugation of the phase (i.e., multiplication of the phase by a negative constant). At each illumination direction, numerically backpropagating the beam with the conjugated phase produces maximum contrast at the location of individual atoms in the molecule or nanoparticle. The resultant algorithm, Conjugated Holographic Reconstruction, can potentially be incorporated into established software tools for single-particle analysis, such as, for example, RELION or FREALIGN, in place of the conventional contrast transfer function correction procedure, in order to account for the Ewald sphere curvature and improve the spatial resolution of the three-dimensional reconstruction.
Delving into the divide: how ideological differences fuel out-party hostility in a multi-party context
Authors: van Erkel Patrick F. A. , Turkenburg Emma
Published: April 2022

This study investigates to what extent affective polarization, and more specifically hostility towards opposing party supporters, finds its roots in ideological differences. We look into the way out-groups are constructed when there are more than two political parties, and at the role of ideology in this process. Hereby we position ourselves in the discussion between those who argue that affective polarization finds its root more strongly in group attachments vs. those who argue that it is mostly rooted in ideological differences. We conduct our study in the context of the highly fragmented multi-party system of Belgium which enables us to analytically disentangle party label cues from ideological distance. Our findings demonstrate that affective polarization is largely rooted in ideological differences between party electorates in Belgium. Additionally, we find that this particularly holds for citizens who are more ideologically invested, namely those with higher political interest and more extreme ideological views.
Maternal high-fat diet consumption during pregnancy and lactation predisposes offspring to renal and metabolic injury later in life: comparative study of diets with different lipid contents
Authors: Busnardo de Oliveira Fernanda , Fortunato Silva Jéssica , Prado Helena Severino do , Ferreira-Neto Marcos Luiz , Balbi Ana Paula Coelho
Published: April 2022

Accumulating evidence suggests that maternal overnutrition can result in a higher development risk of obesity and renal disease in the offspring’s adulthood. The present study tested different lipid levels in the maternal diet during pregnancy and lactation and its repercussions on the offspring of Wistar rats. Offspring of 1, 7, 30 and 90-d-old were divided into the following groups: Control (CNT) – offspring of dams that consumed a standard chow diet (3.5% of lipids); Experimental 1 (EXP1) – offspring of dams exposed to a high-fat diet (HFD) (28% of lipids); and Experimental 2 (EXP2) – offspring of dams exposed to a HFD (40% of lipids). Regarding maternal data, there was a decrease in the amount of diet ingested by EXP2. Daily caloric intake was higher in EXP1, while protein and carbohydrate intakes were lower in EXP2. While lipid intake was higher in the experimental groups, EXP1 consumed more lipids than EXP2, despite the body weight gain being higher in EXP2. Adult offspring from EXP1 presented higher blood glucose. Regarding morphometric analysis, in both experimental groups, there was an increase in the glomerular tuft and renal corpuscle areas, but an increase in the capsular space area only in EXP1. There was a decrease in the glomerular filtration rate (GFR) in EXP1, in contrast to an increase in GFR of EXP2, along with an increase in urinary protein excretion. In conclusion, the maternal HFDs caused significant kidney damage in offspring, but had different repercussions on the type and magnitude of recorded change.
Geochemistry of Syntectonic Carbonate Veins Within Late Cretaceous Turbidites, Hikurangi Margin (New Zealand): Implications for a Mid‐Oligocene Age of Subduction Initiation
Authors: van de Lagemaat Suzanna H. A. , Mering John A. , Kamp Peter J. J.
Published: April 2022

We document the geochemistry of calcite veins in the Late Cretaceous Tikihore Formation (Raukumara Peninsula, New Zealand) to characterize their fluid composition and source and to help establish the age of subduction initiation at the Hikurangi margin of the Australia‐Pacific plate boundary. The calcite veins occur within normal faults offsetting turbidites that accumulated in a lower slope basin. Vein calcite trace metal content and rare earth element patterns are consistent with a seawater‐derived brine composition. Oxygen isotope (δ18O) values range from −6.1 to +8.4‰ and are −0.2‰ VPDB on average; positive δ13C values of up to +28‰ VDPB reflect methanogenesis. Oxygen isotope temperature data indicate that calcite vein mineralization occurred at temperatures in the range of 29°C–48°C. This is markedly less than the maximum burial temperature experienced by the host rocks, which we estimate to be 104 ± 10°C at 30–27 Ma from the inverse modeling of apatite fission track data. The vein calcite has a 28.5 ± 4.9 Ma U‐Pb age. From these data, we infer that the succession above Tikihore Formation was removed by slumping, thereby resulting in fluid overpressure in the reservoir, followed by hydraulic fracturing and the precipitation of the vein calcite. Ultimately, the data presented here from the Tikihore veins are consistent with subduction initiation at 30–27 Ma, based on the U‐Pb age of the vein calcite and modeling of apatite fission track data for the host sandstone, corroborated by the 30–27 Ma timing of back thrusting on the Taranaki Fault and related foredeep development in eastern Taranaki Basin.
Study of Slow‐Mode Shock Formation and Particle Acceleration in the Symmetric Magnetic Reconnection Based on Hybrid Simulations
Authors: Walia N. K. , Seki K. , Amano T.
Published: April 2022

The structure of the magnetic reconnection region and the acceleration mechanism of particles as they traverse from upstream into the reconnection exhaust are explored using 2.5D hybrid simulations. The reconnection boundary was analyzed using the Rankine‐Hugoniot conditions and the six specific conditions for slow‐mode shocks. We observe that the reconnection boundary can be interpreted as a slow‐mode shock from as close as ∼9 ( = ion inertial length) from the X‐point. The detection of slow‐mode shocks increases with the increasing distance from the X‐point and with the increasing ion plasma beta. Additionally, it is observed that if the slow‐mode shocks are analyzed by taking artificial satellite cuts at various angles, the detection percentage of slow‐mode shocks can decrease to ∼10% for very oblique crossings. The detection percentage of slow‐mode shocks is the percentage of points out of the total points studied, where the slow‐mode shocks were observed. At the point of incidence into the slow‐mode shocks, cold particles get accelerated and they gain energy. However, as we move further from the X‐point, a nonclassical picture of slow‐mode shocks emerges, where accelerated particles are present in the downstream of the slow‐mode shocks, but they are not accelerated in the immediate vicinity of the shock. This crescent‐shaped beam population is first accelerated at the slow‐mode shock much closer to the X‐point, and then it travels to the slow‐mode shock downstream region further away from the X‐point, gaining energy on the way by reflecting between the two slow‐mode shocks.
How Does CO2 Adsorption Alter Coal Wettability? Implications for CO2 Geo‐Sequestration
Authors: Sun X. , Yao Y. , Liu D. , Elsworth D.
Published: April 2022

Successful sequestration of CO2 into coalbeds relies on sufficient capacity and rates of uptake. Storage volumes are controlled by CO2 adsorption which in turn is affected in a complex manner by the evolving wettability of the sorption surface. However, mechanisms and interrelations between CO2 adsorption and coal wettability remain poorly constrained – especially under recreated in situ reservoir conditions where measurements are difficult. We circumvent this difficulty by combining direct measurements of adsorbed water and inferred wettability through Nuclear Magnetic Resonance spectroscopy with mechanisms recovered from molecular dynamic (MD) simulations. The MD simulations confirm that CO2 gas molecules adsorb to the coal pore surface, partially displace the adsorbed water, and transform the coal surface into a heterogeneous surface comprising solid interspersed with gas pockets. We then use the Cassie‐Baxter equation as a basis to characterize the wettability of this heterogeneous H2O‐solid‐CO2 surface to clarify the relationship between CO2 adsorption and coal wettability – using measurements of adsorbed H2O, alone. This enables the first direct evaluation of coal wettability at in situ pressures of CO2. Constrained observations suggest that water wettability weakens significantly with increasing CO2 pressure. Under low CO2 pressure, changes in wettability are contributed directly by CO2 adsorption and increases in CO2 density ‐ when CO2 adsorption reaches saturation at high gas pressure, then changes are determined primarily by changes in CO2 density. We document a robust method and results for the accurate prediction of CO2 storage capacity in coalbeds and concomitant enhanced methane recovery.
Modeling Performance of SCALE‐AMPS: Simulations of Arctic Mixed‐Phase Clouds Observed During SHEBA
Authors: Ong Chia Rui , Koike Makoto , Hashino Tempei , Miura Hiroaki
Published: April 2022

The Advanced Microphysics Prediction System (AMPS), which adopts a two‐moment hybrid‐bin habit‐predicting scheme, was previously developed to study cloud microphysical processes that depend on ice habit; however, only one particular atmospheric model, the University of Wisconsin‐Nonhydrostatic Modeling System, has been used to test the AMPS. In this study, AMPS is implemented into the Scalable Computing for Advanced Library and Environment (SCALE) large‐eddy simulation model. The AMPS Eulerian advection scheme for non‐mass characteristic variables of ice particles, such as axis lengths, is refined to minimize numerical artifacts. The resulting SCALE‐AMPS model successfully reproduces features of mixed‐phase clouds observed during the Surface Heat Budget of the Arctic campaign, including liquid water path (LWP), ice particle size distributions, and ice habits, when ice particle number concentrations (Nice) are reproduced. Sensitivity studies show that increases in Nice result in reductions of LWP that are generally consistent with previous results. Interestingly, LWP reductions lead to changes in ice habits through increases in cloud temperature due to weaker cloud top radiative cooling. Furthermore, aspect ratios of precipitating particles also change following LWP reductions, because in Bigg's immersion freezing scheme, adopted in this study, the aspect ratios depend on the initial size of the ice particles and freezing rates depend on both temperature and droplet size. Because habits of ice particles affect their growth rates, fall speeds, and collision rates, the results obtained in this study reveal possible feedback processes of Arctic mixed‐phase clouds operating through ice habits.
Material-specific high-resolution table-top extreme ultraviolet microscopy
Authors: Eschen Wilhelm , Loetgering Lars , Schuster Vittoria , Klas Robert , Kirsche Alexander , Berthold Lutz , Steinert Michael , Pertsch Thomas , Gross Herbert , Krause Michael , Limpert Jens , Rothhardt Jan
Published: April 2022

Microscopy with extreme ultraviolet (EUV) radiation holds promise for high-resolution imaging with excellent material contrast, due to the short wavelength and numerous element-specific absorption edges available in this spectral range. At the same time, EUV radiation has significantly larger penetration depths than electrons. It thus enables a nano-scale view into complex three-dimensional structures that are important for material science, semiconductor metrology, and next-generation nano-devices. Here, we present high-resolution and material-specific microscopy at 13.5 nm wavelength. We combine a highly stable, high photon-flux, table-top EUV source with an interferometrically stabilized ptychography setup. By utilizing structured EUV illumination, we overcome the limitations of conventional EUV focusing optics and demonstrate high-resolution microscopy at a half-pitch lateral resolution of 16 nm. Moreover, we propose mixed-state orthogonal probe relaxation ptychography, enabling robust phase-contrast imaging over wide fields of view and long acquisition times. In this way, the complex transmission of an integrated circuit is precisely reconstructed, allowing for the classification of the material composition of mesoscopic semiconductor systems.
Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway
Authors: Lu Lin , Zha Zhiqiang , Zhang Peiling , Wang Peipei , Liu Xia , Fang Xisheng , Weng Chengyin , Li Baoxiu , Mao Haibo , Wang Lina , Guan Mingmei , Wu Yong , Xu Zhixiang , Liu Zhongqiu , Liu Guolong
Published: April 2022

Little is known about the biological functions of neuron-specific enolase (NSE) as a specific biomarker for small-cell lung cancer (SCLC). Herein, we elucidate the effect and mechanism of NSE on SCLC stem cell-like characteristics. Upregulated NSE expression was observed in spheroid cells. The gain-of-function and loss-of-function approaches demonstrated that modulation of NSE positively regulated cell proliferation, drug resistance, spherical clone formation, tumor growth, and stem cell-like characteristics of SCLC cells. Mechanistic studies revealed that NSE might downregulate the expression of neuroblastoma suppressor of tumorigenicity 1 (NBL1) by interacting with NBL1, thereby attenuating the competitive inhibitory effect of NBL1 on BMP2 and enhancing the interaction between BMP2 and BMPR1A; this, in turn, may activate the BMP2/Smad/ID1 pathway and promote SCLC stem cell-like characteristics. Moreover, overexpression of NBL1or knockdown of BMP2 rescued the NSE-induced stem cell-like characteristics. In clinical specimens, NSE expression was positively associated with ALDH1A1 expression and negatively correlated with NBL1 expression. High NSE and ALDH1A1 expressions and low NBL1 expression were correlated with poor prognosis in patients with SCLC. In summary, our study demonstrated that NSE promoted stem cell-like characteristics of SCLC via NBL1 and the activation of the BMP2/Smad/ID1 pathway.
ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer
Authors: Lim Eun-Ji , Kang Jae-Hyeok , Kim Yeon-Ju , Kim Seungmo , Lee Su-Jae
Published: April 2022

Colorectal cancer (CRC) has a 5-year survival rate of <10%, as it can metastasize to the lungs and liver. Anticancer drugs and targeted therapies used to treat metastatic colorectal cancer have insufficient therapeutic efficacy and are associated with complications. Therefore, research to develop new targeted therapeutics is necessary. Here, we present a novel discovery that intracellular adhesion molecule-1 (ICAM-1) is a potential therapeutic target to enhance therapeutic effectiveness for CRC. ICAM-1 is an important regulator of cell–cell interactions and recent studies have shown that it promotes malignancy in several carcinomas. However, little is known about its effect on CRC. Therefore, we conducted a study to define the mechanism by which ICAM-1 acts. ICAM-1 is phosphorylated by tyrosine-protein kinase Met (c-MET), and phosphorylated ICAM-1 can interact with SRC to increase SRC activity. Consequently, ICAM-1 may further accelerate SRC signaling, promoting the malignant potential of cancer. In addition, treatment with antibodies targeting ICAM-1 showed excellent therapeutic effects in reducing metastasis and angiogenesis. These findings suggest for the first time that ICAM-1 is an important adapter protein capable of mediating the c-MET-SRC signaling axis. Therefore, ICAM-1 can be used as a novel therapeutic target and a metastatic marker for CRC.
Molecular basis of antibiotic self-resistance in a bee larvae pathogen
Authors: Dang Tam , Loll Bernhard , Müller Sebastian , Skobalj Ranko , Ebeling Julia , Bulatov Timur , Gensel Sebastian , Göbel Josefine , Wahl Markus C. , Genersch Elke , Mainz Andi , Süssmuth Roderich D.
Published: April 2022

Paenibacillus larvae, the causative agent of the devastating honey-bee disease American Foulbrood, produces the cationic polyketide-peptide hybrid paenilamicin that displays antibacterial and antifungal activity. Its biosynthetic gene cluster contains a gene coding for theN-acetyltransferase PamZ. We show that PamZ acts as self-resistance factor inPaenibacillus larvaeby deactivation of paenilamicin. Using tandem mass spectrometry, nuclear magnetic resonance spectroscopy and synthetic diastereomers, we identified the N-terminal amino group of the agmatinamic acid as theN-acetylation site. These findings highlight the pharmacophore region of paenilamicin, which we very recently identified as a ribosome inhibitor. Here, we further determined the crystal structure of PamZ:acetyl-CoA complex at 1.34 Å resolution. An unusual tandem-domain architecture provides a well-defined substrate-binding groove decorated with negatively-charged residues to specifically attract the cationic paenilamicin. Our results will help to understand the mode of action of paenilamicin and its role in pathogenicity ofPaenibacillus larvaeto fight American Foulbrood.
CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Authors: Sanderlin Edward J. , Keenan Melissa M. , Mense Martin , Revenko Alexey S. , Monia Brett P. , Guo Shuling , Huang Lulu
Published: April 2022

Approximately 10% of cystic fibrosis patients harbor nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which can generate nonsense codons in the CFTR mRNA and subsequently activate the nonsense-mediated decay (NMD) pathway resulting in rapid mRNA degradation. However, it is not known which NMD branches govern the decay of CFTR mRNAs containing nonsense codons. Here we utilize antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. We observe that CFTR mRNAs with nonsense codons G542X, R1162X, and W1282X, but not Y122X, require UPF2 and UPF3 for NMD. Furthermore, we demonstrate that all evaluated CFTR mRNAs harboring nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway. Finally, we show that upregulation of all evaluated CFTR mRNAs with nonsense codons by NMD pathway inhibition improves outcomes of translational readthrough therapy.
Photoinduced ynamide structural reshuffling and functionalization
Authors: Mutra Mohana Reddy , Wang Jeh‐Jeng
Published: April 2022

The radical chemistry of ynamides has recently drawn the attention of synthetic organic chemists to the construction of various N-heterocyclic compounds. Nevertheless, the ynamide-radical chemistry remains a long-standing challenge for chemists due to its high reactivity, undesirable byproducts, severe inherent regio- and chemoselective problems. Importantly, the ynamide C(sp)-N bond fission remains an unsolved challenge. In this paper, we observe Photoinduced radical trigger regio- and chemoselective ynamide bond fission, structural reshuffling and functionalization of 2-alkynyl-ynamides to prepare synthetically inaccessible/challenging chalcogen-substituted indole derivatives with excellent step/atom economy. The key breakthroughs of this work includes, ynamide bond cleavage, divergent radical precursors, broad scope, easy to handle, larger-scale reactions, generation of multiple bonds (N-C(sp2), C(sp2)-C(sp2), C(sp2)-SO2R/C-SR, and C-I/C-Se/C-H) in a few minutes without photocatalysts, metals, oxidants, additives. Control experiments and 13C-labeling experiments supporting the conclusion that sulfone radicals contribute to ynamide structural reshuffling processes via a radical pathway.
In crystallo observation of three metal ion promoted DNA polymerase misincorporation
Authors: Chang Caleb , Lee Luo Christie , Gao Yang
Published: April 2022

Error-free replication of DNA is essential for life. Despite the proofreading capability of several polymerases, intrinsic polymerase fidelity is in general much higher than what base-pairing energies can provide. Although researchers have investigated this long-standing question with kinetics, structural determination, and computational simulations, the structural factors that dictate polymerase fidelity are not fully resolved. Time-resolved crystallography has elucidated correct nucleotide incorporation and established a three-metal-ion-dependent catalytic mechanism for polymerases. Using X-ray time-resolved crystallography, we visualize the complete DNA misincorporation process catalyzed by DNA polymerase η. The resulting molecular snapshots suggest primer 3´-OH alignment mediated by A-site metal ion binding is the key step in substrate discrimination. Moreover, we observe that C-site metal ion binding preceded the nucleotidyl transfer reaction and demonstrate that the C-site metal ion is strictly required for misincorporation. Our results highlight the essential but separate roles of the three metal ions in DNA synthesis.
Comprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer
Authors: Zhao Qi , Wang Feng , Chen Yan-Xing , Chen Shifu , Yao Yi-Chen , Zeng Zhao-Lei , Jiang Teng-Jia , Wang Ying-Nan , Wu Chen-Yi , Jing Ying , Huang You-Sheng , Zhang Jing , Wang Zi-Xian , He Ming-Ming , Pu Heng-Ying , Mai Zong-Jiong , Wu Qi-Nian , Long Renwen , Zhang Xiaoni , Huang Tanxiao , Xu Mingyan , Qiu Miao-Zheng , Luo Hui-Yan , Li Yu-Hong , Zhang Dong-Shen , Jia Wei-Hua , Chen Gong , Ding Pei-Rong , Li Li-Ren , Lu Zheng-Hai , Pan Zhi-Zhong , Xu Rui-Hua
Published: April 2022

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.
Radical SAM-dependent ether crosslink in daropeptide biosynthesis
Authors: Guo Sijia , Wang Shu , Ma Suze , Deng Zixin , Ding Wei , Zhang Qi
Published: April 2022

Darobactin is a ribosomally synthesized and post-translationally modified peptide (RiPP), which possesses potent activity against various Gram-negative bacteria. Darobactin features a highly unique bicyclic scaffold, consisting of an ether crosslink between two Trp residues and a C–C crosslink between a Lys and a Trp. Here we report in vivo and in vitro activity of darobactin synthase DarE. We show DarE is a radical S-adenosylmethionine (rSAM) enzyme and is solely responsible for forming the bicyclic scaffold of darobactin. DarE mainly produced the ether-crosslinked product in vitro, and when the assay was performed in H218O, apparent 18O incorporation was observed into the ether-crosslinked product. These observations suggested an rSAM-dependent process in darobactin biosynthesis, involving a highly unusual oxygen insertion step from a water molecule and subsequent O–H and C–H activations. Genome mining analysis demonstrates the diversity of darobactin-like biosynthetic gene clusters, a subclade of which likely encode monocyclic products with only an ether linkage. We propose the name daropeptide for this growing family of ether-containing RiPPs produced by DarE enzymes.
The critical role of magma degassing in sulphide melt mobility and metal enrichment
Authors: Iacono-Marziano Giada , Le Vaillant Margaux , Godel Belinda M. , Barnes Stephen J. , Arbaret Laurent
Published: April 2022

Much of the world’s supply of battery metals and platinum group elements (PGE) comes from sulphide ore bodies formed in ancient sub-volcanic magma plumbing systems. Research on magmatic sulphide ore genesis mainly focuses on sulphide melt-silicate melt equilibria. However, over the past few years, increasing evidence of the role of volatiles in magmatic sulphide ore systems has come to light. High temperature-high pressure experiments presented here reveal how the association between sulphide melt and a fluid phase may facilitate the coalescence of sulphide droplets and upgrade the metal content of the sulphide melt. We propose that the occurrence of a fluid phase in the magma can favour both accumulation and metal enrichment of a sulphide melt segregated from this magma, independent of the process producing the fluid phase. Here we show how sulphide-fluid associations preserved in the world-class Noril’sk-Talnakh ore deposits, in Polar Siberia, record the processes demonstrated experimentally.
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation
Authors: Billingham Leah K. , Stoolman Joshua S. , Vasan Karthik , Rodriguez Arianne E. , Poor Taylor A. , Szibor Marten , Jacobs Howard T. , Reczek Colleen R. , Rashidi Aida , Zhang Peng , Miska Jason , Chandel Navdeep S.
Published: April 2022

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
Genome-wide association study identifies loci and candidate genes for grain micronutrients and quality traits in wheat (Triticum aestivum L.)
Authors: Rathan Nagenahalli Dharmegowda , Krishna Hari , Ellur Ranjith Kumar , Sehgal Deepmala , Govindan Velu , Ahlawat Arvind Kumar , Krishnappa Gopalareddy , Jaiswal Jai Prakash , Singh Jang Bahadur , SV Saiprasad , Ambati Divya , Singh Sumit Kumar , Bajpai Kriti , Mahendru-Singh Anju
Published: April 2022

Malnutrition due to micronutrients and protein deficiency is recognized among the major global health issues. Genetic biofortification of wheat is a cost-effective and sustainable strategy to mitigate the global micronutrient and protein malnutrition. Genomic regions governing grain zinc concentration (GZnC), grain iron concentration (GFeC), grain protein content (GPC), test weight (TW), and thousand kernel weight (TKW) were investigated in a set of 184 diverse bread wheat genotypes through genome-wide association study (GWAS). The GWAS panel was genotyped using Breeders' 35 K Axiom Array and phenotyped in three different environments during 2019–2020. A total of 55 marker-trait associations (MTAs) were identified representing all three sub-genomes of wheat. The highest number of MTAs were identified for GPC (23), followed by TKW (15), TW (11), GFeC (4), and GZnC (2). Further, a stable SNP was identified for TKW, and also pleiotropic regions were identified for GPC and TKW. In silico analysis revealed important putative candidate genes underlying the identified genomic regions such as F-box-like domain superfamily, Zinc finger CCCH-type proteins, Serine-threonine/tyrosine-protein kinase, Histone deacetylase domain superfamily, and SANT/Myb domain superfamily proteins, etc. The identified novel MTAs will be validated to estimate their effects in different genetic backgrounds for subsequent use in marker-assisted selection.
Maximum reduction of energy losses in multicore MgB2 wires by metastructured soft-ferromagnetic coatings
Authors: Kapolka M. , Ruiz H. S.
Published: April 2022

When compared with rare-earth coated conductors, magnesium diboride superconducting cables are known to show significant advantages by cost and easy production. However, the inherent difficulty for achieving a significant reduction of their magnetization losses in multifilamentary wires, without degrading the high critical current density that is so characteristic of the monowire, is considered as one of the major drawbacks for their practical use in high power density applications. Being this one of the major markets for superconducting cables, from fundamental principles and computational optimization techniques, in this paper we demonstrate how the embedding of the superconducting filaments into soft-ferromagnetic metastructures can render to their full magnetic decoupling, and therefore, to the maximum reduction of the energy losses that can be achieved without deteriorate the critical current density of the cable. The designed multifilamentary metastructure is made of NbTi coated MgB2 superconducting filaments in a Cu-matrix, serving as a reference for validating our model with actual experimental measurements in monowires and multifilamentary wires. The novelty in our computationally aided multifilamentary wires, is that each one of the filaments is embedded within a thin metastructure made of a soft-ferromagnetic layer and a resistive layer. We have found that for soft-ferromagnetic layers with magnetic permeabilities in the range of $$\mu _{r}=$$

μ
r

=

20–100, nearly a full magnetic decoupling between the superconducting filaments can be achieved, leading to efficiencies higher than $$92\%$$

92
%

, and an overall reduction of the AC-losses (including eddy currents at the Cu-matrix) higher than $$50\%$$

50
%

.
Isotopic composition of the eastern gray whale epidermis indicates contribution of prey outside Arctic feeding grounds
Authors: Gelippi Michelle , Caraveo-Patiño Javier , Gauger Marco F. W. , Popp Brian N. , Panigada Simone , Marcín-Medina Rocío
Published: April 2022

Eastern gray whales’ distribution range and plasticity in feeding behavior complicates the understanding of critical life-history such as pregnancy and lactation. Our goal was to determine if females who experienced gestation, gave birth, and lactated their calves, assimilated a high proportion of benthic amphipods from the Bering Sea, which are considered the species’ main prey. We used Bayesian stable isotope mixing models to estimate the probability of contribution of food items sampled along the species’ distributional range, using isotopic data on amphipods from the Bering Sea, mysids from Vancouver Island, and amphipods and polychaetes from Ojo de Liebre Lagoon. We sampled epidermal tissue from lactating females (n = 25) and calves (n = 34) and analyzed their carbon and nitrogen isotopic composition. Model outcome indicated that benthic amphipods from the Bering Sea were not the primary food for the eastern gray whale. Each mother performed a different feeding strategy, and prey from Vancouver Island were generally as important as that from the Bering Sea. Moreover, model results indicate a constant use of Ojo de Liebre Lagoon as a feeding ground. Our results appear to agree with previous studies that report continuous feeding by females to satisfy certain physiological requirements (e.g., fatty acids omega-6) during migration and breeding time. Future investigations of the isotopic composition of all those prey items that could be assimilated by the eastern gray whale emerge as critical. Both historical and recent information, that would provide insights in the species feeding ecology under past and present environmental conditions, should be considered as equally important to establish conservation and management plans.
Strain induced anisotropy in liquid phase epitaxy grown nickel ferrite on magnesium gallate substrates
Authors: Liu Ying , Zhou Peng , Regmi Sudhir , Bidthanapally Rao , Popov Maksym , Zhang Jitao , Zhang Wei , Page Michael R. , Zhang Tianjin , Gupta Arunava , Srinivasan Gopalan
Published: April 2022

This work focuses on the nature of magnetic anisotropy in 2.5–16 micron thick films of nickel ferrite (NFO) grown by liquid phase epitaxy (LPE). The technique, ideal for rapid growth of epitaxial oxide films, was utilized for films on (100) and (110) substrates of magnesium gallate (MGO). The motivation was to investigate the dependence of the growth induced anisotropy field on film thickness since submicron films of NFO were reported to show a very high anisotropy. The films grown at 850–875 C and subsequently annealed at 1000 C were found to be epitaxial, with the out-of-plane lattice constant showing unanticipated decrease with increasing film thickness and the estimated in-plane lattice constant increasing with the film thickness. The uniaxial anisotropy field Hσ, estimated from X-ray diffraction data, ranged from 2.8–7.7 kOe with the films on (100) MGO having a higher Hσ value than for the films on (110) MGO. Ferromagnetic resonance (FMR) measurements for in-plane and out-of-plane static magnetic field were utilized to determine both the magnetocrystalline the anisotropy field H4 and the uniaxial anisotropy field Ha. Values of H4 range from −0.24 to −0.86 kOe. The uniaxial anisotropy field Ha was an order of magnitude smaller than Hσ and it decreased with increasing film thickness for NFO films on (100) MGO, but Ha increased with film thickness for films on (110) MGO substrates. These observations indicate that the origin of the induced anisotropy could be attributed to several factors including (i) strain due to mismatch in the film-substrate lattice constants, (ii) possible variations in the bond lengths and bond angles in NFO during the growth process, and (iii) the strain arising from mismatch in the thermal expansion coefficients of the film and the substrate due to the high growth and annealing temperatures involved in the LPE technique. The LPE films of NFO on MGO substrates studied in this work are of interest for use in high frequency devices.