bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlorine Heterogeneity in Volcanic Glass as a Faithful Record of Silicic Magma Degassing
Authors: Yoshimura Shumpei , Nakagawa Mitsuhiro
Published: April 2021

Degassing processes occurring within silicic magma, such as bubble growth, bubble resorption, the welding of magma fragments, and open‐system gas loss are crucial in the control of volcanic eruption and lava emplacement, yet their details are still debated. To examine the possibility that these degassing processes are recorded in volcanic glass as heterogeneous Cl distribution patterns, we experimentally simulated these processes by heating rhyolitic obsidian and analyzed the distribution of Cl content in the recovered sample. The results showed that, for bubble growth, Cl diffused toward the bubble interface, leading to Cl depletion around the bubble. For bubble resorption, Cl was discharged from the bubble to the melt, leading to Cl enrichment in the ambient melt. For welding of magma fragments, Cl was depleted near the welded interface because each fragment had degassed Cl at the surface before the welding took place. For open‐system gas loss, Cl exsolved at the bubble interface while the bubble itself was being collapsed into a chain of small bubbles and a Cl‐depleted tail. These results indicate that Cl distribution is a reliable record of the experienced degassing processes. We then analyzed the Cl distribution in silicic lava from Naruko volcano, Japan, to study the gas flow mechanism. We observed that the glassy matrix was progressively corroded into porous crystalline material. The interface of the glass was highly enriched in Cl. We conclude that a Cl‐rich gas fluxed through hot lava and corroded the glass, developing a porous, gas‐permeable region.
Growth and Decay of Northwestern Tropical Atlantic Barrier Layers
Authors: Saha Aurpita , Serra Nuno , Stammer Detlef
Published: April 2021

The growth and decay mechanisms of barrier layers in the northwestern tropical Atlantic are studied by investigating small‐scale processes embedded in the regional circulation of the tropical Atlantic using output from an eddy‐resolving numerical simulation at 4 km resolution forced by an atmospheric reanalysis. The simulation reproduces well the temporal and spatial patterns of barrier layer thickness (BLT) estimated with Argo and CTD in situ profiles. As seen from an analysis of the salinity and temperature vertical gradient balances, localized large barrier layers form inside North Brazil Current rings during late‐June to July because of a thickening of the isothermal layer in the rings due to horizontal temperature advection, stretching of isotherms and tilting of temperature fronts. These barrier layers decay when the isothermal layer reduces again due to the above mechanisms. Further to the north, along the North Equatorial Current, the seasonal variability of BLT is highly pronounced. Thick winter (January to early March) barrier layers locally grow as the base of the mixed layer shoals mainly due to a tilting of the salinity fronts and partly due to stretching of the isohalines, horizontal salt advection and vertical turbulent mixing. The short‐term barrier layers in this case decay due to a deepening of the mixed layer, whereas they get completely eroded in spring by a shoaling of the isothermal layer due to surface temperature stratification. This work highlights that barrier layers are localized phenomena at times growing solely due to ocean dynamics, without a surface freshwater influx.
Transition Between Forced and Oscillatory ENSO Behavior Over the Last Century
Authors: Pivotti Valentina , Anderson Bruce T.
Published: April 2021

As the largest mode of coupled climate variability, the El Niño Southern Oscillation (ENSO) carries consequences for weather patterns worldwide. Because of its impacts, and the subsequent importance of predicting when ENSO might occur, there has been lengthy research into precursor mechanisms that initiate ENSO events. In this paper, thanks to the length of the SODAsi.3 data set, we study the relation between ENSO and a subset of known precursors over 140 years (1871–2011). We uncover that the influence of North Pacific Oscillation (NPO)‐related precursors—namely the Trade Wind Charging and North Pacific Meridional Mode (TWC/NPMM)—upon ENSO is nonstationary. The TWC/NPMM‐ENSO coupling is strong from 1871 to 1920, then weakens before regaining significance from 1960 onward. Importantly, in the intervening period between 1920 and 1960, not only does the TWC/NPMM‐ENSO connection disappear, there are also no other wind‐related drivers preceding ENSO events during this period. We find that in the absence of wind‐driven precursors during this intervening period the temporal characteristics of ENSO variability itself change, as the signal oscillates within a relatively narrow 6–7‐year periodicity band. These features set this intervening period apart from what we see during the first and last periods when the ENSO signal is noisier, and its power is distributed over a wider range of periodicities spanning from 2 to 6 years. These results lead us to hypothesize that, during the last 140 years, ENSO shifted between a stochastically forced interannual mode of variability, to a multiannual, quasi‐regular one with a self‐sustained oscillation.
Quantifying the Dimensionalities and Drivers of Ecosystem Stability at Global Scale
Authors: Chen Jijing , Chi Yonggang , Zhou Wen , Wang Yonglin , Zhuang Jie , Zhao Ning , Ding Jianxi , Song Jun , Zhou Lei
Published: April 2021

Ecosystem stability is the key to maintain the normal service function of the earth, but the dimensionalities and drivers of stability are highly controversial. A global study on the components of stability, including temporal stability, resistance, and resilience, was analyzed by gross productive production of 130 flux sites, species richness, and climate variables such as precipitation, air temperature, and shortwave radiation over a 24‐year period from 1991 to 2014. Our results provided global‐scale evidence that ecosystem stability must be analyzed as a multidimensional construct, and biome‐specific dimensionality should be considered in exploring ecosystem stability. The effective dimensionalities of ecosystem stability were significantly different among biomes, showing the least in savannas and the most in wetlands. In addition, the climate was predicted to be more important than biodiversity in regulating ecosystem stability on a global scale. The result showed that climates explained up to 70%, 49%, and 39% of the variation in temporal stability, resistance, and resilience of ecosystem function, respectively, while species richness only explained up to 5%, 20%, −11%. These findings give a comprehensive assessment for stability at the global scale and highlight the key role of climate in regulating ecosystem stability.
High-fidelity structured illumination microscopy by point-spread-function engineering
Authors: Wen Gang , Li Simin , Wang Linbo , Chen Xiaohu , Sun Zhenglong , Liang Yong , Jin Xin , Xing Yifan , Jiu Yaming , Tang Yuguo , Li Hui
Published: April 2021

Structured illumination microscopy (SIM) has become a widely used tool for insight into biomedical challenges due to its rapid, long-term, and super-resolution (SR) imaging. However, artifacts that often appear in SIM images have long brought into question its fidelity, and might cause misinterpretation of biological structures. We present HiFi-SIM, a high-fidelity SIM reconstruction algorithm, by engineering the effective point spread function (PSF) into an ideal form. HiFi-SIM can effectively reduce commonly seen artifacts without loss of fine structures and improve the axial sectioning for samples with strong background. In particular, HiFi-SIM is not sensitive to the commonly used PSF and reconstruction parameters; hence, it lowers the requirements for dedicated PSF calibration and complicated parameter adjustment, thus promoting SIM as a daily imaging tool.
Phenotypically independent profiles relevant to mental health are genetically correlated
Authors: Roelfs Daniel , Alnæs Dag , Frei Oleksandr , van der Meer Dennis , Smeland Olav B. , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: April 2021

Genome-wide association studies (GWAS) and family-based studies have revealed partly overlapping genetic architectures between various psychiatric disorders. Given clinical overlap between disorders, our knowledge of the genetic architectures underlying specific symptom profiles and risk factors is limited. Here, we aimed to derive distinct profiles relevant to mental health in healthy individuals and to study how these genetically relate to each other and to common psychiatric disorders. Using independent component analysis, we decomposed self-report mental health questionnaires from 136,678 healthy individuals of the UK Biobank, excluding data from individuals with a diagnosed neurological or psychiatric disorder, into 13 distinct profiles relevant to mental health, capturing different symptoms as well as social and risk factors underlying reduced mental health. Utilizing genotypes from 117,611 of those individuals with White British ancestry, we performed GWAS for each mental health profile and assessed genetic correlations between these profiles, and between the profiles and common psychiatric disorders and cognitive traits. We found that mental health profiles were genetically correlated with a wide range of psychiatric disorders and cognitive traits, with strongest effects typically observed between a given mental health profile and a disorder for which the profile is common (e.g. depression symptoms and major depressive disorder, or psychosis and schizophrenia). Strikingly, although the profiles were phenotypically uncorrelated, many of them were genetically correlated with each other. This study provides evidence that statistically independent mental health profiles partly share genetic underpinnings and show genetic overlap with psychiatric disorders, suggesting that shared genetics across psychiatric disorders cannot be exclusively attributed to the known overlapping symptomatology between the disorders.
Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway
Authors: Li Fuli , Huang Tinglei , Tang Yao , Li Qingli , Wang Jianzheng , Cheng Xiaojiao , Zhang Wenhui , Zhang Baiwen , Zhou Cong , Tu Shuiping
Published: April 2021

Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.
The role of γ-aminobutyric acid in aluminum stress tolerance in a woody plant, Liriodendron chinense × tulipifera
Authors: Wang Pengkai , Dong Yini , Zhu Liming , Hao Zhaodong , Hu LingFeng , Hu Xiangyang , Wang Guibin , Cheng Tielong , Shi Jisen , Chen Jinhui
Published: April 2021

The aluminum (Al) cation Al3+ in acidic soil shows severe rhizotoxicity that inhibits plant growth and development. Most woody plants adapted to acidic soils have evolved specific strategies against Al3+ toxicity, but the underlying mechanism remains elusive. The four-carbon amino acid gamma-aminobutyric acid (GABA) has been well studied in mammals as an inhibitory neurotransmitter; GABA also controls many physiological responses during environmental or biotic stress. The woody plant hybrid Liriodendron (L. chinense × tulipifera) is widely cultivated in China as a horticultural tree and provides high-quality timber; studying its adaptation to high Al stress is important for harnessing its ecological and economic potential. Here, we performed quantitative iTRAQ (isobaric tags for relative and absolute quantification) to study how protein expression is altered in hybrid Liriodendron leaves subjected to Al stress. Hybrid Liriodendron shows differential accumulation of several proteins related to cell wall biosynthesis, sugar and proline metabolism, antioxidant activity, cell autophagy, protein ubiquitination degradation, and anion transport in response to Al damage. We observed that Al stress upregulated glutamate decarboxylase (GAD) and its activity, leading to increased GABA biosynthesis. Additional GABA synergistically increased Al-induced antioxidant enzyme activity to efficiently scavenge ROS, enhanced proline biosynthesis, and upregulated the expression of MATE1/2, which subsequently promoted the efflux of citrate for chelation of Al3+. We also showed similar effects of GABA on enhanced Al3+ tolerance in Arabidopsis. Thus, our findings suggest a function of GABA signaling in enhancing hybrid Liriodendron tolerance to Al stress through promoting organic acid transport and sustaining the cellular redox and osmotic balance.
A gene that underwent adaptive evolution, LAC2 (LACCASE), in Populus euphratica improves drought tolerance by improving water transport capacity
Authors: Niu Zhimin , Li Guiting , Hu Hongyin , Lv Jiaojiao , Zheng Qiwei , Liu Jianquan , Wan Dongshi
Published: April 2021

Drought severely limits plant development and growth; accordingly, plants have evolved strategies to prevent water loss and adapt to water deficit conditions. However, experimental cases that corroborate these evolutionary processes are limited. The LACCASEs (LACs) family is involved in various plant development and growth processes. Here, we performed an evolutionary analysis ofLACsfromPopulus euphraticaand characterized the functions ofLACsinArabidopsisand poplar. The results showed that inPeuLACs, multiple gene duplications led to apparent functional redundancy as the result of various selective pressures. Among them,PeuLAC2underwent strong positive selection. Heterologous expression analyses showed that the overexpression ofPeuLAC2alters the xylem structure of plants, including thickening the secondary cell wall (SCW) and increasing the fiber cell length and stem tensile strength. Altogether, these changes improve the water transport capacity of plants. The analysis of the physiological experimental results showed thatPeuLAC2-OE lines exhibited a stronger antioxidant response and greater drought tolerance than WT. Three genes screened by transcriptome analysis,NAC025,BG1, andUGT, that are associated with SCW synthesis and drought stress were all upregulated in thePeuLAC2-OE lines, implying that the overexpression ofPeuLAC2thickened the SCW, improved the water transport capacity of the plant, and further enhanced its drought tolerance. Our study highlights that genes that have undergone adaptive evolution may participate in the development of adaptive traits inP. euphraticaand thatPeuLAC2could be a candidate gene for molecular genetic breeding in trees.
The transcription factor SlHY5 regulates the ripening of tomato fruit at both the transcriptional and translational levels
Authors: Wang Weihao , Wang Peiwen , Li Xiaojing , Wang Yuying , Tian Shiping , Qin Guozheng
Published: April 2021

Light plays a critical role in plant growth and development, but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown. Here, we found that ELONGATED HYPOCOTYL 5 (HY5), a master regulator in the light signaling pathway, is required for normal fruit ripening in tomato (Solanum lycopersicum). Loss of function of tomato HY5 (SlHY5) impairs pigment accumulation and ethylene biosynthesis. Transcriptome profiling identified 2948 differentially expressed genes, which included 1424 downregulated and 1524 upregulated genes, in the Slhy5 mutants. In addition, genes involved in carotenoid and anthocyanin biosynthesis and ethylene signaling were revealed as direct targets of SlHY5 by chromatin immunoprecipitation. Surprisingly, the expression of a large proportion of genes encoding ribosomal proteins was downregulated in the Slhy5 mutants, and this downregulation pattern was accompanied by a decrease in the abundance of ribosomal proteins. Further analysis demonstrated that SlHY5 affected the translation efficiency of numerous ripening-related genes. These data indicate that SlHY5 regulates fruit ripening both at the transcriptional level by targeting specific molecular pathways and at the translational level by affecting the protein translation machinery. Our findings unravel the regulatory mechanisms of SlHY5 in controlling fruit ripening and nutritional quality and uncover the multifaceted regulation of gene expression by transcription factors.
A reconciled solution of Meltwater Pulse 1A sources using sea-level fingerprinting
Authors: Lin Yucheng , Hibbert Fiona D. , Whitehouse Pippa L. , Woodroffe Sarah A. , Purcell Anthony , Shennan Ian , Bradley Sarah L.
Published: April 2021

The most rapid global sea-level rise event of the last deglaciation, Meltwater Pulse 1A (MWP-1A), occurred ∼14,650 years ago. Considerable uncertainty regarding the sources of meltwater limits understanding of the relationship between MWP-1A and the concurrent fast-changing climate. Here we present a data-driven inversion approach, using a glacio-isostatic adjustment model to invert for the sources of MWP-1A via sea-level constraints from six geographically distributed sites. The results suggest contributions from Antarctica, 1.3 m (0–5.9 m; 95% probability), Scandinavia, 4.6 m (3.2–6.4 m) and North America, 12.0 m (5.6–15.4 m), giving a global mean sea-level rise of 17.9 m (15.7–20.2 m) in 500 years. Only a North American dominant scenario successfully predicts the observed sea-level change across our six sites and an Antarctic dominant scenario is firmly refuted by Scottish isolation basin records. Our sea-level based results therefore reconcile with field-based ice-sheet reconstructions.
Nickel isotopes link Siberian Traps aerosol particles to the end-Permian mass extinction
Authors: Li Menghan , Grasby Stephen E. , Wang Shui-Jiong , Zhang Xiaolin , Wasylenki Laura E. , Xu Yilun , Sun Mingzhao , Beauchamp Benoit , Hu Dongping , Shen Yanan
Published: April 2021

The end-Permian mass extinction (EPME) was the most severe extinction event in the past 540 million years, and the Siberian Traps large igneous province (STLIP) is widely hypothesized to have been the primary trigger for the environmental catastrophe. The killing mechanisms depend critically on the nature of volatiles ejected during STLIP eruptions, initiating about 300 kyr before the extinction event, because the atmosphere is the primary interface between magmatism and extinction. Here we report Ni isotopes for Permian-Triassic sedimentary rocks from Arctic Canada. The δ60Ni data range from −1.09‰ to 0.35‰, and exhibit the lightest δ60Ni compositions ever reported for sedimentary rocks. Our results provide strong evidence for global dispersion and loading of Ni-rich aerosol particles into the Panthalassic Ocean. Our data demonstrate that environmental degradation had begun well before the extinction event and provide a link between global dispersion of Ni-rich aerosols, ocean chemistry changes, and the EPME.
Low-temperature nucleation anomaly in silicate glasses shown to be artifact in a 5BaO·8SiO2 glass
Authors: Xia Xinsheng , Van Hoesen D. C. , McKenzie Matthew E. , Youngman Randall E. , Kelton K. F.
Published: April 2021

For over 40 years, measurements of the nucleation rates in a large number of silicate glasses have indicated a breakdown in the Classical Nucleation Theory at temperatures below that of the peak nucleation rate. The data show that instead of steadily decreasing with decreasing temperature, the work of critical cluster formation enters a plateau and even starts to increase. Many explanations have been offered to explain this anomaly, but none have provided a satisfactory answer. We present an experimental approach to demonstrate explicitly for the example of a 5BaO ∙ 8SiO2 glass that the anomaly is not a real phenomenon, but instead an artifact arising from an insufficient heating time at low temperatures. Heating times much longer than previously used at a temperature 50 K below the peak nucleation rate temperature give results that are consistent with the predictions of the Classical Nucleation Theory. These results raise the question of whether the claimed anomaly is also an artifact in other glasses.
Spin-orbit coupling induced splitting of Yu-Shiba-Rusinov states in antiferromagnetic dimers
Authors: Beck Philip , Schneider Lucas , Rózsa Levente , Palotás Krisztián , Lászlóffy András , Szunyogh László , Wiebe Jens , Wiesendanger Roland
Published: April 2021

Magnetic atoms coupled to the Cooper pairs of a superconductor induce Yu-Shiba-Rusinov states (in short Shiba states). In the presence of sufficiently strong spin-orbit coupling, the bands formed by hybridization of the Shiba states in ensembles of such atoms can support low-dimensional topological superconductivity with Majorana bound states localized on the ensembles’ edges. Yet, the role of spin-orbit coupling for the hybridization of Shiba states in dimers of magnetic atoms, the building blocks for such systems, is largely unexplored. Here, we reveal the evolution of hybridized multi-orbital Shiba states from a single Mn adatom to artificially constructed ferromagnetically and antiferromagnetically coupled Mn dimers placed on a Nb(110) surface. Upon dimer formation, the atomic Shiba orbitals split for both types of magnetic alignment. Our theoretical calculations attribute the unexpected splitting in antiferromagnetic dimers to spin-orbit coupling and broken inversion symmetry at the surface. Our observations point out the relevance of previously unconsidered factors on the formation of Shiba bands and their topological classification.
Ontology-driven weak supervision for clinical entity classification in electronic health records
Authors: Fries Jason A. , Steinberg Ethan , Khattar Saelig , Fleming Scott L. , Posada Jose , Callahan Alison , Shah Nigam H.
Published: April 2021

In the electronic health record, using clinical notes to identify entities such as disorders and their temporality (e.g. the order of an event relative to a time index) can inform many important analyses. However, creating training data for clinical entity tasks is time consuming and sharing labeled data is challenging due to privacy concerns. The information needs of the COVID-19 pandemic highlight the need for agile methods of training machine learning models for clinical notes. We present Trove, a framework for weakly supervised entity classification using medical ontologies and expert-generated rules. Our approach, unlike hand-labeled notes, is easy to share and modify, while offering performance comparable to learning from manually labeled training data. In this work, we validate our framework on six benchmark tasks and demonstrate Trove’s ability to analyze the records of patients visiting the emergency department at Stanford Health Care for COVID-19 presenting symptoms and risk factors.
Analysis of SARS-CoV-2 genomic epidemiology reveals disease transmission coupled to variant emergence and allelic variation
Authors: Bandoy D J Darwin R. , Weimer Bart C.
Published: April 2021

The spread of SARS-CoV-2 created a pandemic crisis with > 150,000 cumulative cases in > 65 countries within a few months. The reproductive number (R) is a metric to estimate the transmission of a pathogen during an outbreak. Preliminary published estimates were based on the initial outbreak in China. Whole genome sequences (WGS) analysis found mutational variations in the viral genome; however, previous comparisons failed to show a direct relationship between viral genome diversity, transmission, and the epidemic severity. COVID-19 incidences from different countries were modeled over the epidemic curve. Estimates of the instantaneous R (Wallinga and Teunis method) with a short and standard serial interval were done. WGS were used to determine the populations genomic variation and that underpinned creation of the pathogen genome identity (GENI) score, which was merged with the outbreak curve in four distinct phases. Inference of transmission time was based on a mutation rate of 2 mutations/month. R estimates revealed differences in the transmission and variable infection dynamics between and within outbreak progression for each country examined. Outside China, our R estimates observed propagating dynamics indicating that other countries were poised to move to the takeoff and exponential stages. Population density and local temperatures had no clear relationship to the outbreak progression. Integration of incidence data with the GENI score directly predicted increases in cases as the genome variation increased that led to new variants. Integrating the outbreak curve, dynamic R, and SNP variation found a direct association between increasing cases and transmission genome evolution. By defining the epidemic curve into four stages and integrating the instantaneous country-specific R with the GENI score, we directly connected changes in individual outbreaks based on changes in the virus genome via SNPs. This resulted in the ability to forecast potential increases in cases as well as mutations that may defeat PCR screening and the infection process. By using instantaneous R estimations and WGS, outbreak dynamics were defined to be linked to viral mutations, indicating that WGS, as a surveillance tool, is required to predict shifts in each outbreak that will provide actionable decision making information. Integrating epidemiology with genome sequencing and modeling allows for evidence-based disease outbreak tracking with predictive therapeutically valuable insights in near real time.
Differential characterization of stress sensitivity and its main control mechanism in deep pore-fracture clastic reservoirs
Authors: Han Denglin , Wang Huachao , Wang Chenchen , Yuan Wenfang , Zhang Juan , Lin Wei , Hu Rongrong
Published: April 2021

Stress sensitivity in reservoirs is critical during the exploitation of oil and gas fields. As a deep clastic reservoir under strong tectonic compression, the Ahe Formation in the northern tectonic zone of the Kuqa depression exhibited strong stress sensitivity effect. However, the conventional evaluation method by using permeability damage rate as a constraint restricts the mechanistic understanding of the strong stress sensitivity effect. In this study, morphology of stress sensitivity test curve, coupled with rate change of permeability and extent of irreversible damage in actual sample measurement through micro-CT in-situ scanning, is used to characterize differentially. The strong stress sensitivity effects of the studied intervals can be divided into three types: (1) rapid change in permeability–weak irreversible damage, (2) moderate change in permeability–strong irreversible damage and (3) moderate change in permeability–moderate irreversible damage. The strong stress sensitivity is caused by the micro-pores and micro-fractures, which are widely developed in the studied reservoir. The mechanisms caused by the two types of pore are different. The stress sensitivity effects in micro-fracture-rich reservoirs are characterized by rapid change in permeability and weak irreversible damage. Meanwhile, the stress sensitivity effects in micro-pore-rich reservoirs are manifested as moderate change in permeability and strong irreversible damage. The study shows that the differences in the content of micro-pores and micro-fractures and their reverse mechanisms of stress sensitivity co-create different types of stress sensitivity within the samples. Accordingly, the differences of the stress sensitivity type in macroscopic samples are caused by the competition between the microscopic differences of pore types.
Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity
Authors: Weng Ying Li , Naik Shiv Rakesh , Dingelstad Nadia , Lugo Miguel R. , Kalyaanamoorthy Subha , Ganesan Aravindhan
Published: April 2021

The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand-bound Mpro complexes in the Protein Data Bank (PDB) describing the interactions of different fragment chemotypes within different sites of the Mpro. In this work, we performed rigorous molecular dynamics (MD) simulation of 62 reversible ligand–Mpro complexes in the PDB to gain mechanistic insights about their interactions at the atomic level. Using a total of over 3 µs long MD trajectories, we characterized different pockets in the apo Mpro structure, and analyzed the dynamic interactions and binding affinity of ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets of Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in the lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular-level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
Complexed trace mineral supplementation alters antioxidant activities and expression in response to trailer stress in yearling horses in training
Authors: Latham Christine M. , Dickson Emily C. , Owen Randi N. , Larson Connie K. , White-Springer Sarah H.
Published: April 2021

To test the hypothesis that complexed trace mineral supplementation would increase antioxidant capacity and decrease muscle oxidative stress and damage in young horses entering an exercise training program, Quarter Horses (mean $$\pm$$
±
SD; 9.7 ± 0.7 mo) balanced by age, sex, and BW were assigned to receive complexed (CTM; n = 8) or inorganic (INORG; n = 8) trace minerals at -12 week relative to this study. Blood and muscle samples were collected before (week 0) and after 12 week of light exercise training surrounding a 1.5-h trailer stressor. Muscle glutathione peroxidase (GPx) activity was higher for CTM than INORG horses (P ≤ 0.0003) throughout the study. Following both trailer stressors, serum creatine kinase increased (P < 0.0001) and remained elevated through 24 h post-trailering (P < 0.0001). At week 0, muscle malondialdehyde, expression of superoxide dismutase 2, and whole blood GPx activity increased (P$$\le$$
≤
0.003) following trailering but trailering did not affect these measures at week 12. Young horses supplemented with CTM had higher muscle GPx activity than horses receiving INORG, but CTM did not affect damage markers following a stressor. Dietary CTM may be useful for improving antioxidant capacity during exercise training in young equine athletes.
Speciation of organosulfur compounds in carbonaceous chondrites
Authors: Zherebker Alexander , Kostyukevich Yury , Volkov Dmitry S. , Chumakov Ratibor G. , Friederici Lukas , Rüger Christopher P. , Kononikhin Alexey , Kharybin Oleg , Korochantsev Alexander , Zimmermann Ralf , Perminova Irina V. , Nikolaev Eugene
Published: April 2021

Despite broad application of different analytical techniques for studies on organic matter of chondrite meteorites, information about composition and structure of individual compounds is still very limited due to extreme molecular diversity of extraterrestrial organic matter. Here we present the first application of isotopic exchange assisted Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) for analysis of alkali extractable fraction of insoluble organic matter (IOM) of the Murchison and Allende meteorites. This allowed us to determine the individual S-containing ions with different types of sulfur atoms in IOM. Thiols, thiophenes, sulfoxides, sulfonyls and sulfonates were identified in both samples but with different proportions, which contribution corroborated with the hydrothermal and thermal history of the meteorites. The results were supported by XPS and thermogravimetric analysis coupled to FTICR MS. The latter was applied for the first time for analysis of chondritic IOM. To emphasize the peculiar extraterrestrial origin of IOM we have compared it with coal kerogen, which is characterized by the comparable complexity of molecular composition but its aromatic nature and low oxygen content can be ascribed almost exclusively to degradation of biomacromolecules.
Reorganization of nurse scheduling reduces the risk of healthcare associated infections
Authors: Valdano Eugenio , Poletto Chiara , Boëlle Pierre-Yves , Colizza Vittoria
Published: April 2021

Efficient prevention and control of healthcare associated infections (HAIs) is still an open problem. Using contact data from wearable sensors at a short-stay geriatric ward, we propose a proof-of-concept modeling study that reorganizes nurse schedules for efficient infection control. This strategy switches and reassigns nurses’ tasks through the optimization of shift timelines, while respecting feasibility constraints and satisfying patient-care requirements. Through a Susceptible-Colonized-Susceptible transmission model, we found that schedules reorganization reduced HAI risk by 27% (95% confidence interval [24, 29]%) while preserving timeliness, number, and duration of contacts. More than 30% nurse-nurse contacts should be avoided to achieve an equivalent reduction through simple contact removal. Nurse scheduling can be reorganized to break potential chains of transmission and substantially limit HAI risk, while ensuring the timeliness and quality of healthcare services. This calls for including optimization of nurse scheduling practices in programs for infection control in hospitals.
Photochemical efficiency correlated with candidate gene expression promote coffee drought tolerance
Authors: de Oliveira Santos Meline , Coelho Larissa Sousa , Carvalho Gladyston Rodrigues , Botelho Cesar Elias , Torres Luana Ferreira , Vilela Diego Júnior Martins , Andrade Alan Carvalho , Silva Vânia Aparecida
Published: April 2021

The aim of this study was to identify the correlation between photochemical efficiency and candidate genes expression to elucidate the drought tolerance mechanisms in coffee progenies (Icatu Vermelho IAC 3851-2 × Catimor UFV 1602-215) previously identified as tolerant in field conditions. Four progenies (2, 5, 12 and 15) were evaluated under water-deficit conditions (water deficit imposed 8 months after transplanting seedlings to the pots) and under irrigated system. Evaluations of physiological parameters and expression of candidate genes for drought tolerance were performed. Progeny 5 showed capacity to maintain water potential, which contributed to lower qP variation between irrigated and deficit conditions. However, the increases of qN and NPQ in response to stress indicate that this progeny is photochemically responsive to small variations of Ψam protecting the photosystem and maintaining qP. Data obtained for progeny 12 indicated a lower water status maintenance capacity, but with increased qN and NPQ providing maintenance of the ɸPSII and ETR parameters. A PCA analysis revealed that the genes coding regulatory proteins, ABA-synthesis, cellular protectors, isoforms of ascorbate peroxidase clearly displayed a major response to drought stress and discriminated the progenies 5 and 12 which showed a better photochemical response. The genes CaMYB1, CaERF017, CaEDR2, CaNCED, CaAPX1, CaAPX5, CaGolS3, CaDHN1 and CaPYL8a were up-regulated in the arabica coffee progenies with greater photochemical efficiency under deficit and therefore contributing to efficiency of the photosynthesis in drought tolerant progenies.
Signal quality as Achilles’ heel of graph theory in functional magnetic resonance imaging in multiple sclerosis
Authors: Baijot Johan , Denissen Stijn , Costers Lars , Gielen Jeroen , Cambron Melissa , D’Haeseleer Miguel , D’hooghe Marie B. , Vanbinst Anne-Marie , De Mey Johan , Nagels Guy , Van Schependom Jeroen
Published: April 2021

Graph-theoretical analysis is a novel tool to understand the organisation of the brain.

We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.
Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: a GWAS meta-analysis
Authors: Powell Victoria , Martin Joanna , Thapar Anita , Rice Frances , Anney Richard J. L.
Published: April 2021

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10–8) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10–4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10–4) and in the cross-disorder meta-analysis (p < 5 × 10–8). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.
Association of pre- and early-pregnancy factors with the risk for gestational diabetes mellitus in a large Chinese population
Authors: Zhao Min , Yang Shuyu , Hung Tzu Chieh , Zheng Wenjie , Su Xiaojie
Published: April 2021

Gestational diabetes mellitus (GDM) has aroused wide public concern, as it affects approximately 1.8–25.1% of pregnancies worldwide. This study aimed to examine the association of pre-pregnancy demographic parameters and early-pregnancy laboratory biomarkers with later GDM risk, and further to establish a nomogram prediction model. This study is based on the big obstetric data from 10 “AAA” hospitals in Xiamen. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria. Data are analyzed using Stata (v14.1) and R (v3.5.2). Total 187,432 gestational women free of pre-pregnancy diabetes mellitus were eligible for analysis, including 49,611 women with GDM and 137,821 women without GDM. Irrespective of confounding adjustment, eight independent factors were consistently and significantly associated with GDM, including pre-pregnancy body mass index (BMI), pre-pregnancy intake of folic acid, white cell count, platelet count, alanine transaminase, albumin, direct bilirubin, and creatinine (p < 0.001). Notably, per 3 kg/m2 increment in pre-pregnancy BMI was associated with 22% increased risk [adjusted odds ratio (OR) 1.22, 95% confidence interval (CI) 1.21–1.24, p < 0.001], and pre-pregnancy intake of folic acid can reduce GDM risk by 27% (adjusted OR 0.73, 95% CI 0.69–0.79, p < 0.001). The eight significant factors exhibited decent prediction performance as reflected by calibration and discrimination statistics and decision curve analysis. To enhance clinical application, a nomogram model was established by incorporating age and above eight factors, and importantly this model had a prediction accuracy of 87%. Taken together, eight independent pre-/early-pregnancy predictors were identified in significant association with later GDM risk, and importantly a nomogram modeling these predictors has over 85% accuracy in early detecting pregnant women who will progress to GDM later.
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression
Authors: Busacca Sara , Zhang Qi , Sharkey Annabel , Dawson Alan G. , Moore David A. , Waller David A. , Nakas Apostolos , Jones Carolyn , Cain Kelvin , Luo Jin-li , Salcedo Adriana , Salaroglio Iris Chiara , Riganti Chiara , Le Quesne John , John Tom , Boutros Paul C. , Zhang Shu-Dong , Fennell Dean A.
Published: April 2021

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.
Identification of potential therapeutic antimicrobial peptides against Acinetobacter baumannii in a mouse model of pneumonia
Authors: Jung Chiau-Jing , Liao You-Di , Hsu Chih-Chieh , Huang Ting-Yu , Chuang Yu-Chung , Chen Jeng-Wei , Kuo Yu-Min , Chia Jean-San
Published: April 2021

Acinetobacter baumannii-induced nosocomial pneumonia has become a serious clinical problem because of high antibiotic resistance rates. Antimicrobial peptides (AMP) are an ideal alternative strategy due to their broad-spectrum of antimicrobial activity and low incidence of bacterial resistance. However, their application is limited by toxicity and stability in vivo. The present study used a mouse model to directly identify potential AMPs effective for treatment of A. baumannii-induced pneumonia. Fifty-eight AMPs were screened and two identified (SMAP-29 and TP4) to have prophylactic effects which prevented the death of mice with pneumonia. Furthermore, two TP4 derivatives (dN4 and dC4) were found to have therapeutic activity in pneumonia mouse models by peritoneal or intravenous administration. Both dN4 and dC4 also inhibited and/or eliminated A. baumannii biofilms at higher doses. Taken together, these data suggest the AMP derivatives dN4 and dC4 represent a potential treatment strategy for A. baumannii-induced pneumonia.
Nationwide Glaucoma incidence in end stage renal disease patients and kidney transplant recipients
Authors: Moon Jong Joo , Kim Yong Woo , Oh Baek-Lok , Han Kyungdo , Kim Dong Ki , Joo Kwon Wook , Kim Yon Su , Park Ki Ho , Lee Hajeong , Kim Yong Chul , Jeoung Jin Wook
Published: April 2021

Glaucoma shares common risk factors with chronic kidney disease (CKD) but previous cross-sectional studies have demonstrated discrepancies in the risk of glaucoma in CKD patients. This study enrolled kidney transplantation recipients (KTRs) (n = 10,955), end stage renal disease (ESRD) patients (n = 10,955) and healthy controls (n = 10,955) from National Health Insurance Service database of the Republic of Korea. A Cox proportional hazard regression model was used to calculate the hazard ratios (HR) for primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) incidences. The incidence of POAG was higher in ESRD patients (3.36/1,000 person-years,P < 0.0001) and KTRs (3.22 /1,000 person-years,P < 0.0001), than in healthy controls (1.20/1,000 person-years). However, POAG risk showed no significant increase in either ESRD patients (P = 0.07) or KTRs (P = 0.08) when adjusted for the confounding factors. The incidence of PACG was significantly higher in ESRD patients (0.41/1,000 person-years) than in healthy controls (0.14/1,000 person-years,P = 0.008). The PACG incidence was significantly lower in KTRs than in ESRD patients (HR = 0.35,P = 0.015). In conclusion, this nationwide cohort study demonstrated that kidney transplantation can reduce the risk of PACG but not POAG in ESRD patients.