bluuebunny/crossref_metadata_2025 huggingface dataset:
Fixed-time corrective dose fertilizer nitrogen management in wheat using atLeaf meter and leaf colour chart
Authors: Ali Ali M. , Ibrahim Sherif M. , Hassany Wahby M. , El-Sadek Ashraf N. , Bijay-Singh
Published: September 2021

Fertilizer nitrogen (N) management in any region following standard general recommendations discount the fact that crop response to N varies between sites and seasons. To devise field-specific N management in wheat at jointing stage (Feekes 6 growth stage) using atLeaf meter and leaf colour chart (LCC), eight field experiments were conducted in three wheat seasons during 2017–2020 in the West Delta of Egypt. In the first two seasons, four experiments consisted of treatments with a range of fertilizer N application levels from 0 to 320 kg N ha−1. Monitoring atLeaf and LCC measurements at Feekes 6 growth stage in plots with different yield potentials allowed formulation of different criteria to apply field-specific and crop need-based fertilizer N doses. In the four experiments conducted in the third season in 2019/20, different field-specific N management strategies formulated in 2017/18 and 2018/19 wheat seasons were evaluated. In the atLeaf-based fertilizer N management experiment, prescriptive application of 40 kg N ha−1at 10 days after seeding (DAS) and 60 kg N ha−1at 30 DAS followed by application of an adjustable dose at Feekes 6 stage computed by multiplying the difference of atLeaf measurements of the test plot and the N-sufficient plot with 42.25 (as derived from the functional model developed in this study), resulted in grain yield similar or higher to that obtained by following the standard treatment. The LCC-based strategy to apply field-specific fertilizer N at Feekes 6 stage consisted of applying 150, 100 or 0 kg N ha−1based on LCC shade equal to or less than 4, between 4 and 5 or equal to or more than 5, respectively. Both atLeaf- and LCC-based fertilizer N management strategies not only recorded the highest grain yield levels but also resulted in higher use efficiency with 57–60 kg N ha−1in average less fertilizer use than the standard treatment.
Developmental milestones in early childhood and genetic liability to neurodevelopmental disorders
Authors: Hannigan Laurie J. , Askeland Ragna Bugge , Ask Helga , Tesli Martin , Corfield Elizabeth , Ayorech Ziada , Magnus Per , Njølstad Pål Rasmus , Øyen Anne-Siri , Stoltenberg Camilla , Andreassen Ole A. , Ronald Angelica , Smith George Davey , Reichborn-Kjennerud Ted , Havdahl Alexandra
Published: September 2021

Background

Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia.

Methods

We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences.

Results

We found that ADHD PGS were associated with earlier walking age (β = −0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (β = 0.039, padj = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment.

Conclusions

Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.
Older people's lived experience and the World Health Organization age-friendly policy framework: a critical examination of an age-friendly county programme in Ireland
Authors: McDonald Bernard , Scharf Thomas , Walsh Kieran
Published: September 2021

Developing age-friendly communities is a significant global policy issue. The World Health Organization's (WHO) age-friendly cities and communities initiative significantly influenced the development of Ireland's Age-friendly Programme. This article critically examines the utilisation of the WHO age-friendly planning framework in the context of Ireland. It explores older adults’ experience of living in a county which is currently implementing an age-friendly programme, and uses this analysis to assess how the age-friendly programme addresses older residents’ needs, and to illustrate how the WHO conceptual and planning framework has worked in Ireland. The article reports on a qualitative case study which used constructivist grounded theory to explore the lived experience of older adults. The research identifies salient social and cultural dimensions of the day-to-day lived experience of older people which, although they impact on the age-friendliness of the places in which they live, are downplayed or neglected in the WHO framework. In critically analysing the transfer and relevance of the WHO age-friendly model in light of broader issues such as diversity of place, the dynamic nature of person–place relations, and the interplay between age-friendly policy and other age-related public policy, the article suggests ways in which the use of the WHO framework can be modified to accommodate better the diverse experience of older adults in Ireland, but also in other geographic and cultural contexts.
Design and development of a novel autonomous scaled multiwheeled vehicle
Authors: Tan Aaron Hao , Peiris Michael , El-Gindy Moustafa , Lang Haoxiang
Published: September 2021

This article proposes the design and development of a novel custom-built, autonomous scaled multiwheeled vehicle that features an eight-wheel drive and eight-wheel steer system. In addition to the mechanical and electrical design, high-level path planning and low-level vehicle control algorithms are developed and implemented including a two-stage autonomous parking algorithm is developed. A modified position-based visual servoing algorithm is proposed and developed to achieve precise pose correction. The results show significant gains in accuracy and efficiency comparing with an open-source path planner. It is the aim of this work to expand the research of autonomous platforms taking the form of commercial and off-road vehicles using actuated steering and other mechanisms attributed to passenger vehicles. The outcome of this work is a unique autonomous research platform that features independently driven wheels, steering, autonomous navigation, and parking.
Symptomatic atrial bigeminy masquerading as congenital complete heart block
Authors: Mejia Ernesto , Hoyt Walter J. , Snyder Christopher S.
Published: September 2021

Newborn male with symptomatic bradycardia initially diagnosed with complete atrioventricular block. Isoproterenol drip was initiated, and the patient was scheduled for pacemaker implantation. During the hospital course, repeat electrocardiogram and Holter monitor revealed evidence of near continuous blocked atrial bigeminy with occasional aberrantly conducted premature atrial contractions. Flecainide was started, resulting in normal sinus rhythm, and the pacemaker implantation was cancelled.
Penetrating Heart Injury Repaired with Peripheral Cannulation: Case Report
Authors: Ovali Cengiz , Kocaoglu Alper Selim , Demirdizen Gürkan , Aydar Yuksel
Published: September 2021

Heart injuries usually occur due to penetrating or blunt traumas. High mortality rates are seen in heart injuries, owing to firearms and cutting/piercing tools. Factors such as the degree of injury, its localization, and the length of time to reach the hospital influence mortality rates. Despite the increase in imaging facilities and improvements in hospital transportation in today’s conditions, high mortality rates are still observed, owing to causes such as sudden blood loss, cardiac arrest, or cardiac tamponade. The present study aimed to present the successful treatment of a 46-year-old male patient with injuries to the left atrium and posterior wall of the left ventricle due to a gunshot wound using the approach of median sternotomy and peripheral cannulation.
Costing recommended (healthy) and current (unhealthy) diets in urban and inner regional areas of Australia using remote price collection methods
Authors: Zorbas Christina , Brooks Ruby , Bennett Rebecca , Lee Amanda , Marshall Josephine , Naughton Shaan , Lewis Meron , Peeters Anna , Backholer Kathryn
Published: September 2021

Objective:

To compare the cost and affordability of two fortnightly diets (representing the national guidelines and current consumption) across areas containing Australia’s major supermarkets.

Design:

The Healthy Diets Australian Standardised Affordability and Pricing protocol was used.

Setting:

Price data were collected online and via phone calls in fifty-one urban and inner regional locations across Australia.

Participants:

Not applicable.

Results:

Healthy diets were consistently less expensive than current (unhealthy) diets. Nonetheless, healthy diets would cost 25–26 % of the disposable income for low-income households and 30–31 % of the poverty line. Differences in gross incomes (the most available income metric which overrepresents disposable income) drove national variations in diet affordability (from 14 % of the median gross household incomes in the Australian Capital Territory and Northern Territory to 25 % of the median gross household income in Tasmania).

Conclusions:

In Australian cities and regional areas with major supermarkets, access to affordable diets remains problematic for families receiving low incomes. These findings are likely to be exacerbated in outer regional and remote areas (not included in this study). To make healthy diets economically appealing, policies that reduce the (absolute and relative) costs of healthy diets and increase the incomes of Australians living in poverty are required.
Versatile and non-versatile occupational back-support exoskeletons: A comparison in laboratory and field studies
Authors: Poliero Tommaso , Sposito Matteo , Toxiri Stefano , Di Natali Christian , Iurato Matteo , Sanguineti Vittorio , Caldwell Darwin G. , Ortiz Jesús
Published: September 2021

Assistive strategies for occupational back-support exoskeletons have focused, mostly, on lifting tasks. However, in occupational scenarios, it is important to account not only for lifting but also for other activities. This can be done exploiting human activity recognition algorithms that can identify which task the user is performing and trigger the appropriate assistive strategy. We refer to this ability as exoskeleton versatility. To evaluate versatility, we propose to focus both on the ability of the device to reduce muscle activation (efficacy) and on its interaction with the user (dynamic fit). To this end, we performed an experimental study involving

$ 10 $

healthy subjects replicating the working activities of a manufacturing plant. To compare versatile and non-versatile exoskeletons, our device, XoTrunk, was controlled with two different strategies. Correspondingly, we collected muscle activity, kinematic variables and users’ subjective feedbacks. Also, we evaluated the task recognition performance of the device. The results show that XoTrunk is capable of reducing muscle activation by up to

$ 40\% $

in lifting and

$ 30\% $

in carrying. However, the non-versatile control strategy hindered the users’ natural gait (e.g.,

$ -24\% $

reduction of hip flexion), which could potentially lower the exoskeleton acceptance. Detecting carrying activities and adapting the control strategy, resulted in a more natural gait (e.g.,

$ +9\% $

increase of hip flexion). The classifier analyzed in this work, showed promising performance (online accuracy > 91%). Finally, we conducted 9 hours of field testing, involving four users. Initial subjective feedbacks on the exoskeleton versatility, are presented at the end of this work.
Ranking Forest Effects on Snow Storage: A Decision Tool for Forest Management
Authors: Dickerson‐Lange Susan E. , Vano Julie A. , Gersonde Rolf , Lundquist Jessica D.
Published: September 2021

Forests modify snow accumulation and ablation rates as well as overall snow storage amounts and durations, with multiple processes acting simultaneously and often in different directions. To synthesize complex forest–snow relations and help guide near‐term management decisions, we present a decision tree. The framework is based on a hypothesized hierarchy of processes and associated variables that predict forest effects on snow storage. In locations with high wind speeds, forests enhance snow storage magnitude and duration relative to open areas. Where wind speeds are low, and winter and spring air temperatures are colder, forests diminish snow storage magnitude but enhance duration. Where air temperatures are warmer, forests diminish both snow magnitude and duration. Forest structure and aspect are secondary influences. We apply the decision tree framework to map the influence of forests on snow storage under historic climate conditions across the western United States, but this decision tree is applicable in any region with forests and snow. This framework provides practitioners a first‐step evaluation to guide management decisions that consider where and how forests can be managed to optimize in situ water storage alongside other objectives, such as reducing wildfire hazard. This framework also articulates geospatial hypotheses, in order of anticipated importance, to be tested in future investigations of forest–snow–climate relations.
Data‐Driven Worldwide Quantification of Large‐Scale Hydroclimatic Covariation Patterns and Comparison With Reanalysis and Earth System Modeling
Authors: Ghajarnia Navid , Kalantari Zahra , Destouni Georgia
Published: September 2021

Large‐scale covariations of freshwater fluxes and storages on land can critically regulate the balance of green (evapotranspiration) and blue (runoff) water fluxes, and related land‐atmosphere interactions and hydroclimatic hazards. Such large‐scale covariation patterns are not evident from smaller‐scale hydrological studies that have been most common so far, and remain largely unknown for various regions and climates around the world. To contribute to bridging the large‐scale knowledge gaps, we synthesize and decipher hydroclimatic data time series over the period 1980–2010 for 6,405 catchments around the world. From observation‐based data, we identify dominant large‐scale linear covariation patterns between monthly freshwater fluxes and soil moisture (SM) for different world parts and climates. These covariation patterns are also compared with those obtained from reanalysis products and Earth System Models (ESMs). The observation‐based data sets robustly show the strongest large‐scale hydrological relationship to be that between SM and runoff (R), consistently across the study catchments and their different climate characteristics. This predominantly strongest covariation between monthly SM and R is also the most misrepresented by ESMs and reanalysis products, followed by that between monthly precipitation and R. Comparison of observation‐based and ESM results also shows that an ESM may perform well for individual monthly variables, but fail in representing the patterns of large‐scale linear covariations between them. Observation‐based quantification of these patterns, and ESM and reanalysis improvements for their representation are essential for fundamental understanding, and more accurate and reliable modeling and projection of large‐scale hydrological conditions and changes under ongoing global and regional change.
Climate Change Will Alter Cooling Effects of Volcanic Eruptions
Authors: Allen Michael
Published: September 2021

New research indicates the cooling effect of rare, large eruptions will increase, whereas the effects of more frequent, smaller eruptions will be reduced.
A Joint Soil‐Vegetation‐Atmospheric Modeling Procedure of Water Isotopologues: Implementation and Application to Different Climate Zones With WRF‐Hydro‐Iso
Authors: Arnault Joël , Jung Gerlinde , Haese Barbara , Fersch Benjamin , Rummler Thomas , Wei Jianhui , Zhang Zhenyu , Kunstmann Harald
Published: September 2021

Water isotopologues, as natural tracers of the hydrological cycle on Earth, provide a unique way to assess the skill of climate models in representing realistic atmospheric‐terrestrial water pathways. This study presents the newly developed WRF‐Hydro‐iso, which is a version of the coupled atmospheric‐hydrological WRF‐Hydro model enhanced with a joint soil‐vegetation‐atmospheric description of water isotopologue motions. It allows the consideration of isotopic fractionation processes during water phase changes in the atmosphere, the land surface, and the subsurface. For validation, WRF‐Hydro‐iso is applied to two different climate zones, namely Europe and Southern Africa under the present climate conditions. Each case is modeled with a domain employing a 5 km grid‐spacing coupled with a terrestrial subgrid employing a 500 m grid‐spacing in order to represent lateral terrestrial water flow. A 10‐year slice is simulated for 2003–2012, using ERA5 reanalyses as driving data. The boundary condition of isotopic variables is prescribed with mean values from a 10‐year simulation with the Community Earth System Model Version 1. WRF‐Hydro‐iso realistically reproduces the climatological variations of the isotopic concentrations and from the Global Network of Isotopes in Precipitation. In a sensitivity analysis, it is found that land surface evaporation fractionation increases the isotopic concentrations in the rootzone soil moisture and slightly decreases the isotopic concentrations in precipitation. Lateral terrestrial water flow minorly affects these isotopic concentrations through changes in evaporation‐transpiration partitioning.
The relationship between dose and serotonin transporter occupancy of antidepressants—a systematic review
Authors: Sørensen Anders , Ruhé Henricus G. , Munkholm Klaus
Published: September 2021

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.
ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine
Authors: Rahmani Nora E. , Ramachandra Nandini , Sahu Srabani , Gitego Nadege , Lopez Andrea , Pradhan Kith , Bhagat Tushar D. , Gordon-Mitchell Shanisha , Pena Bianca Rivera , Kazemi Mohammad , Rao Keshav , Giricz Orsi , Maqbool Shahina Bano , Olea Raul , Zhao Yongmei , Zhang Jinghang , Dolatshad Hamid , Tittrea Vickram , Tatwavedi Dharamveer , Singh Shalini , Lee Juseong , Sun Tianyu , Steidl Ulrich , Shastri Aditi , Inoue Daichi , Abdel-Wahab Omar , Pellagatti Andrea , Gavathiotis Evripidis , Boultwood Jacqueline , Verma Amit
Published: September 2021

The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
Selective degradation of AR-V7 to overcome castration resistance of prostate cancer
Authors: Liu Yuan , Yu Cuifu , Shao Zhenlong , Xia Xiaohong , Hu Tumei , Kong Weiyao , He Xiaoyue , Sun Wenshuang , Deng Yuanfei , Liao Yuning , Huang Hongbiao
Published: September 2021

Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.
Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity
Authors: Malkmus Jonas , Ramos Martins Laurène , Jhanwar Shalu , Kircher Bonnie , Palacio Victorio , Sheth Rushikesh , Leal Francisca , Duchesne Amandine , Lopez-Rios Javier , Peterson Kevin A. , Reinhardt Robert , Onimaru Koh , Cohn Martin J. , Zuniga Aimée , Zeller Rolf
Published: September 2021

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs.
Episodic transport of discrete magma batches beneath Aso volcano
Authors: Niu Jieming , Song Teh-Ru Alex
Published: September 2021

Magma ascent, storage, and discharge in the trans-crustal magmatic system are keys to long-term volcanic output and short-term eruption dynamics. How a distinct magma batch transports from a deep reservoir(s) to a pre-eruptive storage pool with eruptible magma remains elusive. Here we show that repetitive very-long-period signals (VLPs) beneath the Aso volcano are preceded by a short-lived (~50–100 s), synchronous deformation event ~3 km apart from the VLP source. Source mechanism of a major volumetric component (~50–440 m3per event) and a minor low-angle normal-fault component, together with petrological evidence, suggests episodic transport of discrete magma batches from an over-pressured chamber roof to a pre-eruptive storage pool near the brittle-ductile transition regime. Magma ascent velocity, decompression rate, and cumulative magma output deduced from recurrent deformation events before recent 2014 and 2016 eruptions reconcile retrospective observations of the eruption style, tephra fallouts, and plume heights, promising real-time evaluation of upcoming eruptions.
Predicting scalar coupling constants by graph angle-attention neural network
Authors: Fang Jia , Hu Linyuan , Dong Jianfeng , Li Haowei , Wang Hui , Zhao Huafen , Zhang Yao , Liu Min
Published: September 2021

Scalar coupling constant (SCC), directly measured by nuclear magnetic resonance (NMR) spectroscopy, is a key parameter for molecular structure analysis, and widely used to predict unknown molecular structure. Restricted by the high cost of NMR experiments, it is impossible to measure the SCC of unknown molecules on a large scale. Using density functional theory (DFT) to theoretically calculate the SCC of molecules is incredibly challenging, due to the cost of substantial computational time and space. Graph neural networks (GNN) of artificial intelligence (AI) have great potential in constructing molecul
ar-like topology models, which endows them the ability to rapidly predict SCC through data-driven machine learning methods, and avoiding time-consuming quantum chemical calculations. With a priori knowledge of angles, we propose a graph angle-attention neural network (GAANN) model to predict SCC by means of some easily accessible related information. GAANN, with a multilayer message-passing network and a self-attention mechanism, can accurately simulate the molecular-like topological structure and predict molecular properties. Our simulations show that the prediction accuracy by GAANN, with the log(MAE) = −2.52, is close to that by DFT calculations. Different from conventional AI methods, GAANN combining the AI method with quantum chemistry theory (Karplus equation) has a strong physicochemical interpretability about angles. From an AI perspective, we find that bond angle has the highest correlation with the SCC among all angle features (dihedral angle, bond angle, geometric angles) about multiple coupling types in the small molecule datasets.
Comparison of dimension reduction methods on fatty acids food source study
Authors: Chen Yifan , Miura Yusuke , Sakurai Toshihiro , Chen Zhen , Shrestha Rojeet , Kato Sota , Okada Emiko , Ukawa Shigekazu , Nakagawa Takafumi , Nakamura Koshi , Tamakoshi Akiko , Chiba Hitoshi , Imai Hideyuki , Minami Hiroyuki , Mizuta Masahiro , Hui Shu-Ping
Published: September 2021

Serum fatty acids (FAs) exist in the four lipid fractions of triglycerides (TGs), phospholipids (PLs), cholesteryl esters (CEs) and free fatty acids (FFAs). Total fatty acids (TFAs) indicate the sum of FAs in them. In this study, four statistical analysis methods, which are independent component analysis (ICA), factor analysis, common principal component analysis (CPCA) and principal component analysis (PCA), were conducted to uncover food sources of FAs among the four lipid fractions (CE, FFA, and TG + PL). Among the methods, ICA provided the most suggestive results. To distinguish the animal fat intake from endogenous fatty acids, FFA variables in ICA and factor analysis were studied. ICA provided more distinct suggestions of FA food sources (endogenous, plant oil intake, animal fat intake, and fish oil intake) than factor analysis. Moreover, ICA was discovered as a new approach to distinguish animal FAs from endogenous FAs, which will have an impact on epidemiological studies. In addition, the correlation coefficients between a published dataset of food FA compositions and the loading values obtained in the present ICA study suggested specific foods as serum FA sources. In conclusion, we found that ICA is a useful tool to uncover food sources of serum FAs.
Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach
Authors: Ashraf Sajda , Ranaghan Kara E. , Woods Christopher J. , Mulholland Adrian J. , Ul-Haq Zaheer
Published: September 2021

Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets.
Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
Authors: Postler Thomas S. , Peng Vincent , Bhatt Dev M. , Ghosh Sankar
Published: September 2021

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.
Stability analysis of reference genes for RT-qPCR assays involving compatible and incompatible Ralstonia solanacearum-tomato ‘Hawaii 7996’ interactions
Authors: Albuquerque Greecy M. R. , Fonseca Fernando C. A. , Boiteux Leonardo S. , Borges Rafaela C. F. , Miller Robert N. G. , Lopes Carlos A. , Souza Elineide B. , Fonseca Maria Esther N.
Published: September 2021

Reverse transcription-quantitative PCR (RT-qPCR) is an analytical tool for gene expression quantification. Reference genes are not yet available for gene expression analysis during interactions of Ralstonia solanacearum with ‘Hawaii 7996’ (the most stable source of resistance in tomato). Here, we carried out a multi-algorithm stability analysis of eight candidate reference genes during interactions of ‘Hawaii 7996’ with one incompatible/avirulent and two compatible/virulent (= resistance-breaking) bacterial isolates. Samples were taken at 24- and 96-h post-inoculation (HPI). Analyses were performed using the ∆∆Ct method and expression stability was estimated using BestKeeper, NormFinder, and geNorm algorithms. TIP41 and EF1α (with geNorm), TIP41 and ACT (with NormFinder), and UBI3 and TIP41 (with BestKeeper), were the best combinations for mRNA normalization in incompatible interactions at 24 HPI and 96 HPI. The most stable genes in global compatible and incompatible interactions at 24 HPI and 96 HPI were PDS and TIP41 (with geNorm), TIP41 and ACT (with NormFinder), and UBI3 and PDS/EXP (with BestKeeper). Global analyses on the basis of the three algorithms across 20 R. solanacearum-tomato experimental conditions identified UBI3, TIP41 and ACT as the best choices as reference tomato genes in this important pathosystem.
Sex-dependent gene co-expression in the human body
Authors: Hartman Robin J. G. , Mokry Michal , Pasterkamp Gerard , den Ruijter Hester M.
Published: September 2021

Many pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene co-expression map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 29.5% of the gene co-expression is influenced by sex. For example, skeletal muscle was predominantly enriched with genes co-expressed stronger in males, whereas thyroid primarily contained genes co-expressed stronger in females. This was accompanied by consistent sex differences in pathway enrichment, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene co-expression over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are associated with sex-biased diseases, such as autoimmunity and cancer, and more often the target of FDA-approved drugs than non-sexbiased genes. Our study suggests that sex affects biological gene networks by differences in gene co-expression and that attention to the effect of sex on biological responses to medical drugs is warranted.
Association of smoking and cancer with the risk of venous thromboembolism: the Scandinavian Thrombosis and Cancer cohort
Authors: Paulsen Benedikte , Gran Olga V. , Severinsen Marianne T. , Hammerstrøm Jens , Kristensen Søren R. , Cannegieter Suzanne C. , Skille Hanne , Tjønneland Anne , Rosendaal Frits R. , Overvad Kim , Næss Inger Anne , Hansen John-Bjarne , Brækkan Sigrid K.
Published: September 2021

Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993–1997 to 2008–2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12–1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96–1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.
Precision delivery of liquid therapy into the arterial wall for the treatment of peripheral arterial disease
Authors: Atigh Marzieh K. , Goel Emily , Erwin Megan , Greer Ricky , Ohayon Jacques , Pettigrew Roderic I. , Yazdani Saami K.
Published: September 2021

Perfusion catheters have recently emerged as a novel approach to deliver liquid anti-proliferative agents into flow obstructed arterial segments. The purpose of this study was to determine the impact of luminal delivery pressure on liquid drug penetration into the vessel wall. An ex vivo model using harvested porcine carotid arteries and a two-dimensional computational model were utilized to determine the impact of delivery pressure of liquid therapy into the arterial wall. A pig peripheral injury model determined the impact of intra-luminal delivery pressure on drug retention. Ex vivo results demonstrated that depth of fluid penetration varies from 6.93 ± 1.90% at 0 atm to 27.75 ± 6.61% penetration of the medial layer at 0.4 atm. Computational results had similar outcomes, as penetration varied between 4.4% and 22.84%. The in vivo results demonstrated significant increase in drug delivery to the arterial tissue at 0.4 atm versus 0.1 atm at 1 h (23.43 ± 13.59 ng/mg vs. 2.49 ± 1.81 ng/mg, p = 0.026) and 7 days (0.50 ± 0.39 ng/mg vs. 0.018 ± 0.023 ng/mg, p = 0.0496). The result of this study provides an innovative strategic and technical approach to enable targeted liquid therapy.
Hibernating brown bears are protected against atherogenic dyslipidemia
Authors: Giroud Sylvain , Chery Isabelle , Arrivé Mathilde , Prost Michel , Zumsteg Julie , Heintz Dimitri , Evans Alina L. , Gauquelin-Koch Guillemette , Arnemo Jon M. , Swenson Jon E. , Lefai Etienne , Bertile Fabrice , Simon Chantal , Blanc Stéphane
Published: September 2021

To investigate mechanisms by which hibernators avoid atherogenic hyperlipidemia during hibernation, we assessed lipoprotein and cholesterol metabolisms of free-ranging Scandinavian brown bears (Ursus arctos). In winter- and summer-captured bears, we measured lipoprotein sizes and sub-classes, triglyceride-related plasma-enzyme activities, and muscle lipid composition along with plasma-levels of antioxidant capacities and inflammatory markers. Although hibernating bears increased nearly all lipid levels, a 36%-higher cholesteryl-ester transfer-protein activity allowed to stabilize lipid composition of high-density lipoproteins (HDL). Levels of inflammatory metabolites, i.e., 7-ketocholesterol and 11ß-prostaglandin F2α, declined in winter and correlated inversely with cardioprotective HDL2b-proportions and HDL-sizes that increased during hibernation. Lower muscle-cholesterol concentrations and lecithin-cholesterol acyltransferase activity in winter suggest that hibernating bears tightly controlled peripheral-cholesterol synthesis and/or release. Finally, greater plasma-antioxidant capacities prevented excessive lipid-specific oxidative damages in plasma and muscles of hibernating bears. Hence, the brown bear manages large lipid fluxes during hibernation, without developing adverse atherogenic effects that occur in humans and non-hibernators.
Vanillin modulates activities linked to dysmetabolism in psoas muscle of diabetic rats
Authors: Salau Veronica F. , Erukainure Ochuko L. , Olofinsan Kolawole A. , Ijomone Omamuyovwi M. , Msomi Nontokozo Z. , Islam Md.Shahidul
Published: September 2021

Skeletal muscles are important in glucose metabolism and are affected in type 2 diabetes (T2D) and its complications. This study investigated the effect of vanillin on redox imbalance, cholinergic and purinergic dysfunction, and glucose-lipid dysmetabolism in muscles of rats with T2D. Male albino rats (Sprague–Dawley strain) were fed 10% fructose ad libitum for 2 weeks before intraperitoneally injecting them with 40 mg/kg streptozotocin to induce T2D. Low (150 mg/kg bodyweight (BW)) and high (300 mg/kg BW) doses of vanillin were orally administered to diabetic rats. Untreated diabetic rats and normal rats made up the diabetic control (DC) and normal control (NC) groups, respectively. The standard antidiabetic drug was metformin. The rats were humanely put to sleep after 5 weeks of treatment and their psoas muscles were harvested. There was suppression in the levels of glutathione, activities of SOD, catalase, ENTPDase, 5′Nucleotidase and glycogen levels on T2D induction. This was accompanied by concomitantly elevated levels of malondialdehyde, serum creatine kinase-MB, nitric oxide, acetylcholinesterase, ATPase, amylase, lipase, glucose-6-phosphatase (G6Pase), fructose-1,6-biphophastase (FBPase) and glycogen phosphorylase activities. T2D induction further resulted in the inactivation of fatty acid biosynthesis, glycerolipid metabolism, fatty acid elongation in mitochondria and fatty acid metabolism pathways. There were close to normal and significant reversals in these activities and levels, with concomitant reactivation of the deactivated pathways following treatment with vanillin, which compared favorably with the standard drug (metformin). Vanillin also significantly increased muscle glucose uptake ex vivo. The results suggest the therapeutic effect of vanillin against muscle dysmetabolism in T2D as portrayed by its ability to mitigate redox imbalance, inflammation, cholinergic and purinergic dysfunctions, while modulating glucose-lipid metabolic switch and maintaining muscle histology.
Use of an endoscopic flexible grasper as a traction tool for excision of polyps: preclinical trial
Authors: Urakawa Shinya , Hirashita Teijiro , Hirashita Yuka , Lowenfeld Lea , Gurram Krishna C. , Nishimura Makoto , Milsom Jeffrey W.
Published: September 2021

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP + Ig), and ESD using IgE (DESP + IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig’s reach. Compared with the STD, both DESP + Ig and DESP + IgE showed significantly shorter procedure time (STD vs. DESP + Ig vs. DESP + IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP + IgE had a shorter procedure time than the DESP + Ig (p = 0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.