bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells
Authors: Geng Hua , Subramanian Saravanan , Wu Longtao , Bu Heng-Fu , Wang Xiao , Du Chao , De Plaen Isabelle G. , Tan Xiao-Di
Published: June 2021

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8SARS-CoV-2) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8SARS-CoV-2 and its role in the regulation of human lung epithelial cell proliferation and antiviral immunity. Using live imaging and immunofluorescent staining analyses, we found that ectopically expressed ORF8SARS-CoV-2 forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8SARS-CoV-2 possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8SARS-CoV-2 expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8SARS-CoV-2 aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8SARS-CoV-2 in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8SARS-CoV-2 attenuated the induction of antiviral molecules by IFNγ but not by IFNβ in lung epithelial cells. Taken together, ORF8SARS-CoV-2 is a unique viral accessory protein that forms aggregates when expressing in lung epithelial cells. It potently inhibits the expression of lung cellular anti-viral proteins at baseline and in response to IFNγ in lung epithelial cells, which may facilitate SARS-CoV-2 escape from the host antiviral innate immune response during early viral infection. In addition, it seems that formation of ORF8SARS-CoV-2 aggregate is independent from the viral infection. Thus, it would be interesting to examine whether any COVID-19 patients exhibit persistent ORF8 SARS-CoV-2 expression after recovering from SARS-CoV-2 infection. If so, the pathogenic effect of prolonged ORF8SARS-CoV-2 expression and its association with post-COVID symptoms warrant investigation in the future.
Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients
Authors: Giron Leila B. , Dweep Harsh , Yin Xiangfan , Wang Han , Damra Mohammad , Goldman Aaron R. , Gorman Nicole , Palmer Clovis S. , Tang Hsin-Yao , Shaikh Maliha W. , Forsyth Christopher B. , Balk Robert A. , Zilberstein Netanel F. , Liu Qin , Kossenkov Andrew , Keshavarzian Ali , Landay Alan , Abdel-Mohsen Mohamed
Published: June 2021

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.
Inflammasomes and Type 1 Diabetes
Authors: Pearson James Alexander , Wong F. Susan , Wen Li
Published: June 2021

Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes.
The Role of CLEC-2 and Its Ligands in Thromboinflammation
Authors: Meng Danyang , Luo Man , Liu Beibei
Published: June 2021

C-type lectin-like receptor 2 (CLEC-2, also known as CLEC-1b) is expressed on platelets, Kupffer cells and other immune cells, and binds to various ligands including the mucin-like protein podoplanin (PDPN). The role of CLEC-2 in infection and immunity has become increasingly evident in recent years. CLEC-2 is involved in platelet activation, tumor cell metastasis, separation of blood/lymphatic vessels, and cerebrovascular patterning during embryonic development. In this review, we have discussed the role of CLEC-2 in thromboinflammation, and focused on the recent research.
Estimating Ocean Surface Currents With Machine Learning
Authors: Sinha Anirban , Abernathey Ryan
Published: June 2021

Global surface currents are usually inferred from directly observed quantities like sea-surface height, wind stress by applying diagnostic balance relations (like geostrophy and Ekman flow), which provide a good approximation of the dynamics of slow, large-scale currents at large scales and low Rossby numbers. However, newer generation satellite altimeters (like the upcoming SWOT mission) will capture more of the high wavenumber variability associated with the unbalanced components, but the low temporal sampling can potentially lead to aliasing. Applying these balances directly may lead to an incorrect un-physical estimate of the surface flow. In this study we explore Machine Learning (ML) algorithms as an alternate route to infer surface currents from satellite observable quantities. We train our ML models with SSH, SST, and wind stress from available primitive equation ocean GCM simulation outputs as the inputs and make predictions of surface currents (u,v), which are then compared against the true GCM output. As a baseline example, we demonstrate that a linear regression model is ineffective at predicting velocities accurately beyond localized regions. In comparison, a relatively simple neural network (NN) can predict surface currents accurately over most of the global ocean, with lower mean squared errors than geostrophy + Ekman. Using a local stencil of neighboring grid points as additional input features, we can train the deep learning models to effectively “learn” spatial gradients and the physics of surface currents. By passing the stenciled variables through convolutional filters we can help the model learn spatial gradients much faster. Various training strategies are explored using systematic feature hold out and multiple combinations of point and stenciled input data fed through convolutional filters (2D/3D), to understand the effect of each input feature on the NN's ability to accurately represent surface flow. A model sensitivity analysis reveals that besides SSH, geographic information in some form is an essential ingredient required for making accurate predictions of surface currents with deep learning models.
Relationship Between Multi-Factors and Short-Term Changes in Fishery Resources
Authors: Sun Mingshuai , Zhao Xianyong , Cai Yancong , Zhang Kui , Chen Zuozhi
Published: June 2021

The objective of this research is to explore the relationships among various multidimensional factor groups and the density of fishery resources of ecosystems in offshore waters and to expand the application of deep machine learning algorithm in this field. Based on XGBoost and random forest algorithms, we first conducted regulatory importance ranking analysis on the time factor, space factor, acoustic technology factor, abiotic factor, and acoustic density of offshore fishery resources in the South China Sea. Based on these analyses, data slicing is carried out for multiple factors and acoustic density, and the relationship between multidimensional factor group and the density of marine living resources in the ecosystem of offshore waters is elaborately compared and analyzed. Importance ranking shows that the concentration of active silicate at 20 m depth, water depth, moon phase perfection, and the number of pulses per unit distance (Ping) are the first-order factors with a cumulative contribution rate of 50%. The comparative analysis shows that there are some complex relationships between the multidimensional factor group and the density of marine biological resources. Within a certain range, one factor strengthens the influence of another factor. When Si20 is in the range of 0–0.1, and the moon-phase perfection is in the range of 0.3–1, both Si20 and moon-phase perfection strengthened the positive influence of water depth on the density of fishery biological resources.
Nonlinear Magneto-Electro-Mechanical Response of Physical Cross-Linked Magneto-Electric Polymer Gel
Authors: Fan Xiwen , Wang Yu , Wang Bochao , Shen Longjiang , Li Jun , Xu Zhenbang , Wang Sheng , Gong Xinglong
Published: June 2021

This work reports on a novel magnetorheological polymer gel with carbon nanotubes and carbonyl iron particles mixed into the physical cross-linked polymer gel matrix. The resulting composites show unusual nonlinear magneto-electro-mechanical responses. Because of the low matrix viscosity, effective conductive paths formed by the CNTs were mobile and high-performance sensing characteristics were observed. In particular, due to the transient and mutable physical cross-linked bonds in the polymer gel, the electromechanical behavior acted in a rate-dependent manner. External stimulus at a high rate significantly enhanced the electrical resistance response during mechanical deformation. Meanwhile, the rheological properties were regulated by the external magnetic field when magnetic particles were added. This dual enhancement mechanism further contributes to the active control of electromechanical performance. These polymer composites could be adopted as electromechanical sensitive sensors to measure impact and vibration under different frequencies. There is great potential for this magnetorheological polymer gel in the application of intelligent vibration controls.
Fatigue Behavior of an Al-12.7Si-0.7Mg Alloy Processed by Extrusion and Heat Treatment
Authors: Liu Fang , Yu Fuxiao , Zhao Dazhi , Gao Li
Published: June 2021

The fatigue life of a hot extruded Al-12.7Si-0.7Mg alloy under T1, T4, and T6 conditions was studied. The microstructure and tensile properties of the alloy were investigated in order to analyze the fatigue behavior. The results of the fatigue test showed that an extruded Al-12.7Si-0.7Mg alloy provided greater fatigue life compared to a cast Al-Si alloy, which was explained by the refined microstructure characterized by fine Si particles uniformly distributed in the Al matrix of fine equiaxed grains promoted by hot extrusion. The fatigue property of the alloy in T6 treatment was higher than that in the T4 and T1 conditions due to strengthening precipitation.
Knowledge and Determinants of Behavioral Responses to the Pandemic of COVID-19
Authors: Lv Gang , Yuan Jing , Hsieh Stephanie , Shao Rongjie , Li Minghui
Published: June 2021

Background: Understanding knowledge and behavioral responses to the pandemic of coronavirus disease 2019 (COVID-19) is important for appropriate public health interventions.

Objectives: To assess knowledge of COVID-19 and to examine determinants associated with the adoption of preventive health behaviors among future health care providers.

Methods: An anonymous online survey was sent out to pharmacy students in high and low-endemic areas of COVID-19 in China. Based on recommendations from the Chinese Center for Disease Control and Prevention, preventive health behaviors examined in this study included washing hands, wearing a face mask, and maintaining social distancing. The Health Belief Model (HBM) was used and measured by a seven-point Likert scale (one as extremely unlikely; seven as extremely likely). Multivariate linear regression models were used to examine predictors of preventive health behaviors.

Results: Among 203 respondents who finished the survey, a medium level of knowledge (4.41 ± 0.95) of COVID-19 was reported. Respondents were extremely likely to wear a face mask (6.85 ± 0.60), but only moderately likely to engage in washing hands (5.95 ± 1.38) and maintaining social distancing (6.19 ± 1.60). Determinants of washing hands were cue to action, self-efficacy, knowledge, and gender; wearing a face mask were cue to action, self-efficacy, knowledge, and ethnicity; and maintaining social distancing were cue to action and self-efficacy.

Conclusions: Public health interventions should consider incorporating cue to action, self-efficacy, and knowledge as factors to potentially improve the adoption of face mask-wearing, hand washing, and social distancing as appropriate individual preventive measures, especially if local and regional authorities are considering reopening schools sometime in future.
The Energetic Potential for Undiscovered Manganese Metabolisms in Nature
Authors: LaRowe Douglas E. , Carlson Harold K. , Amend Jan P.
Published: June 2021

Microorganisms are found in nearly every surface and near-surface environment, where they gain energy by catalyzing reactions among a wide variety of chemical compounds. The discovery of new catabolic strategies and microbial habitats can therefore be guided by determining which redox reactions can supply energy under environmentally-relevant conditions. In this study, we have explored the thermodynamic potential of redox reactions involving manganese, one of the most abundant transition metals in the Earth’s crust. In particular, we have assessed the Gibbs energies of comproportionation and disproportionation reactions involving Mn2+and several Mn-bearing oxide and oxyhydroxide minerals containing Mn in the +II, +III, and +IV oxidation states as a function of temperature (0–100°C) and pH (1–13). In addition, we also calculated the energetic potential of Mn2+oxidation coupled to O2, NO2–, NO3–, and FeOOH. Results show that these reactions—none of which, except O2+ Mn2+, are known catabolisms—can provide energy to microorganisms, particularly at higher pH values and temperatures. Comproportionation between Mn2+and pyrolusite, for example, can yield 10 s of kJ (mol Mn)–1. Disproportionation of Mn3+can yield more than 100 kJ (mol Mn)–1at conditions relevant to natural settings such as sediments, ferromanganese nodules and crusts, bioreactors and suboxic portions of the water column. Of the Mn2+oxidation reactions, the one with nitrite as the electron acceptor is most energy yielding under most combinations of pH and temperature. We posit that several Mn redox reactions represent heretofore unknown microbial metabolisms.
2-Heptylcyclopropane-1-Carboxylic Acid Disperses and Inhibits Bacterial Biofilms
Authors: Harrison Zoe L. , Awais Rukhsana , Harris Michael , Raji Babatunde , Hoffman Brian C. , Baker Daniel L. , Jennings Jessica Amber
Published: June 2021

Fatty-acid signaling molecules can inhibit biofilm formation, signal dispersal events, and revert dormant cells within biofilms to a metabolically active state. We synthesized 2-heptylcyclopropane-1-carboxylic acid (2CP), an analog of cis-2-decenoic acid (C2DA), which contains a cyclopropanated bond that may lock the signaling factor in an active state and prevent isomerization to its least active trans-configuration (T2DA). 2CP was compared to C2DA and T2DA for ability to disperse biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa. 2CP at 125 μg/ml dispersed approximately 100% of S. aureus cells compared to 25% for C2DA; both 2CP and C2DA had significantly less S. aureus biofilm remaining compared to T2DA, which achieved no significant dispersal. 2CP at 125 μg/ml dispersed approximately 60% of P. aeruginosa biofilms, whereas C2DA and T2DA at the same concentration dispersed 40%. When combined with antibiotics tobramycin, tetracycline, or levofloxacin, 2CP decreased the minimum concentration required for biofilm inhibition and eradication, demonstrating synergistic and additive responses for certain combinations. Furthermore, 2CP supported fibroblast viability above 80% for concentrations below 1 mg/ml. This study demonstrates that 2CP shows similar or improved efficacy in biofilm dispersion, inhibition, and eradication compared to C2DA and T2DA and thus may be promising for use in preventing infection for healthcare applications.
Rapid Determination of Antibiotic Resistance in Klebsiella pneumoniae by a Novel Antibiotic Susceptibility Testing Method Using SYBR Green I and Propidium Iodide Double Staining
Authors: Zhang Yabin , Fan Weihua , Shao Chunhong , Wang Jiajia , Jin Yan , Shao Jing , Zhang Ying , Wang Yong
Published: June 2021

Due to the broad-spectrum antibiotic usage and empirical treatments, the pathogenic bacterium, Klebsiella pneumoniae, has shown extremely high detection rates at hospitals with an increasing antibiotic resistance. Therefore, rapid detection of the antibiotic resistance is urgently required and essential for effective treatments. In this study, we evaluated the performance of a newly developed method for ultra-rapid detection of antibiotic resistance in 30–60 min in K. pneumoniae by using the SYBR Green I and propidium iodide (PI) staining. A total of 100 clinical isolates were tested for antibiotic resistance using four different antibiotics (ceftriaxone, cefepime, meropenem, and ciprofloxacin). The results showed that the SYBR Green I/PI rapid antibiotic susceptibility test (AST) could reliably detect antibiotic resistance to the four drugs in 60 min, and the results were highly concordant with the conventional AST (i.e., Kirby-Bauer method and broth microdilution method) for detection of ceftriaxone, cefepime, meropenem, and ciprofloxacin resistance with a high accuracy of 99, 96, 96, and 93%, respectively. Therefore, the rapid AST established in our study helps to enable targeted therapy to save lives and reduce the empirical use of antibiotics and ultimately the health and economic burdens of antibiotic resistance.
A Hyperthermophilic Argonaute From Ferroglobus placidus With Specificity on Guide Binding Pattern
Authors: Guo Xiang , Sun Yingying , Chen Liuqing , Huang Fei , Liu Qian , Feng Yan
Published: June 2021

Argonaute proteins (Agos) from thermophilic archaea are involved in several important processes, such as host defense and DNA replication. The catalytic mechanism of Ago from different microbes with great diversity and genome editing potential is attracting increasing attention. Here, we describe an Argonaute from hyperthermophilic Ferroglobus placidus (FpAgo), with a typical DNA-guided DNA endonuclease activity but adopted with only a short guide 15–20 nt length rather than a broad guide selectivity for reported Agos. FpAgo performed the precise cleavage of phosphodiester bonds between 10 and 11 nt on the target strand (counting from the guide strand) guided strictly by 5′-phosphorylated DNA at temperatures ranging from 75 to 99°C. The cleavage activity was regulated by the divalent cations Mn2+, Mg2+, Co2+, and Ni2+. In addition, FpAgo possesses guide/target mismatch tolerance in the seed region but is sensitive to mismatches in the 3′-guide region. Notably, the EMSA assay revealed that the FpAgo-guide-target ternary complex exhibited a stronger binding affinity for short 15 and 16 nt guide DNAs than longer guides. Moreover, we performed structural modeling analyses that implied the unique PAZ domain of FpAgo for 3′-guide recognition and binding to affect guide length specificity. This study broadens our understanding of thermophilic Agos and paves the way for their use in DNA manipulation.
In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2
Authors: Milanetti Edoardo , Miotto Mattia , Di Rienzo Lorenzo , Nagaraj Madhu , Monti Michele , Golbek Thaddeus W. , Gosti Giorgio , Roeters Steven J. , Weidner Tobias , Otzen Daniel E. , Ruocco Giancarlo
Published: June 2021

We propose a computational investigation on the interaction mechanisms between SARS-CoV-2 spike protein and possible human cell receptors. In particular, we make use of our newly developed numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular isoelectronic density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, which was unfeasible with previous methods. Our results indicate that SARS-CoV-2 uses a dual strategy: in addition to the known interaction with angiotensin-converting enzyme 2, the viral spike protein can also interact with sialic-acid receptors of the cells in the upper airways.
Robotics Dexterous Grasping: The Methods Based on Point Cloud and Deep Learning
Authors: Duan Haonan , Wang Peng , Huang Yayu , Xu Guangyun , Wei Wei , Shen Xiaofei
Published: June 2021

Dexterous manipulation, especially dexterous grasping, is a primitive and crucial ability of robots that allows the implementation of performing human-like behaviors. Deploying the ability on robots enables them to assist and substitute human to accomplish more complex tasks in daily life and industrial production. A comprehensive review of the methods based on point cloud and deep learning for robotics dexterous grasping from three perspectives is given in this paper. As a new category schemes of the mainstream methods, the proposed generation-evaluation framework is the core concept of the classification. The other two classifications based on learning modes and applications are also briefly described afterwards. This review aims to afford a guideline for robotics dexterous grasping researchers and developers.
Prognostic Structural Neural Markers of MRI in Response to Mechanical Thrombectomy for Basilar Artery Occlusion
Authors: Liu Chang , Song Jia-Xin , Guo Zhang-Bao , Chen Lu-Ming , Zhao Chen-Hao , Zi Wen-Jie , Yang Qing-Wu
Published: June 2021

Objective: Mechanical thrombectomy (MT) has been an effective first-line therapeutic strategy for ischemic stroke. With impairment characteristics separating it from anterior circulation stroke, we aimed to explore prognostic structural neural markers for basilar artery occlusion (BAO) after MT.

Methods: Fifty-four BAO patients with multi-modal magnetic resonance imaging at admission from the multicenter real-world designed BASILAR research were enrolled in this study. Features including volumes for cortical structures and subcortical regions, locations and volumes of infarctions, and white matter hyperintensity (WMH) volumes were recorded from all individuals. The impact features were identified using ANCOVA and logistic analysis. Another cohort (n = 21) was further recruited to verify the prognostic roles of screened prognostic structures.

Results: For the primary clinical outcome, decreased brainstem volume and total infarction volumes from mesencephalon and midbrain were significantly related to reduced 90-day modified Rankin score (mRS) after MT treatment. WMH volume, WMH grade, average cortex thickness, white matter volume, and gray matter volume did not exhibit a remarkable relationship with the prognosis of BAO. The increased left caudate volume was obviously associated with early symptomatic recovery after MT. The prognostic role of the ratio of pons and midbrain infarct volume in brainstem was further confirmed in another cohort with area under the curve (AUC) = 0.77.

Conclusions: This study was the first to provide comprehensive structural markers for the prognostic evaluation of BAO. The fully automatic and semiautomatic segmentation approaches in our study supported that the proportion of mesencephalon and midbrain infarct volume in brainstem was a crucial prognostic structural neural marker for BAO.
Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury
Authors: Mayer Andrew R. , Ling Josef M. , Dodd Andrew B. , Rannou-Latella Julie G. , Stephenson David D. , Dodd Rebecca J. , Mehos Carissa J. , Patton Declan A. , Cullen D. Kacy , Johnson Victoria E. , Pabbathi Reddy Sharvani , Robertson-Benta Cidney R. , Gigliotti Andrew P. , Meier Timothy B. , Vermillion Meghan S. , Smith Douglas H. , Kinsler Rachel
Published: June 2021

Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood–brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.
Approximate Number Sense in Students With Severe Hearing Loss: A Modality-Neutral Cognitive Ability
Authors: Ma Hailin , Bu Xiaoou , Sanford Emily M. , Zeng Tongao , Halberda Justin
Published: June 2021

The Approximate Number System (ANS) allows humans and non-human animals to estimate large quantities without counting. It is most commonly studied in visual contexts (i.e., with displays containing different numbers of dots), although the ANS may operate on all approximate quantities regardless of modality (e.g., estimating the number of a series of auditory tones). Previous research has shown that there is a link between ANS and mathematics abilities, and that this link is resilient to differences in visual experience (Kanjlia et al., 2018). However, little is known about the function of the ANS and its relationship to mathematics abilities in the absence of other types of sensory input. Here, we investigated the acuity of the ANS and its relationship with mathematics abilities in a group of students from the Sichuan Province in China, half of whom were deaf. We found, consistent with previous research, that ANS acuity improves with age. We found that mathematics ability was predicted by Non-verbal IQ and Inhibitory Control, but not visual working memory capacity or Attention Network efficiencies. Even above and beyond these predictors, ANS ability still accounted for unique variance in mathematics ability. Notably, there was no interaction with hearing, which indicates that the role played by the ANS in explaining mathematics competence is not modulated by hearing capacity. Finally, we found that age, Non-verbal IQ and Visual Working Memory capacity were predictive of ANS performance when controlling for other factors. In fact, although students with hearing loss performed slightly worse than students with normal hearing on the ANS task, hearing was no longer significantly predictive of ANS performance once other factors were taken into account. These results indicate that the ANS is able to develop at a consistent pace with other cognitive abilities in the absence of auditory experience, and that its relationship with mathematics ability is not contingent on sensory input from hearing.
Regulation of Hippo, TGFβ/SMAD, Wnt/β-Catenin, JAK/STAT, and NOTCH by Long Non-Coding RNAs in Pancreatic Cancer
Authors: Farooqi Ammad Ahmad , Nayyab Sawera , Martinelli Chiara , Berardi Rossana , Katifelis Hector , Gazouli Maria , Cho William C.
Published: June 2021

Rapidly evolving and ever-increasing knowledge of the molecular pathophysiology of pancreatic cancer has leveraged our understanding altogether to a next level. Compared to the exciting ground-breaking discoveries related to underlying mechanisms of pancreatic cancer onset and progression, however, there had been relatively few advances in the therapeutic options available for the treatment. Since the discovery of the DNA structure as a helix which replicates semi-conservatively to pass the genetic material to the progeny, there has been conceptual refinement and continuous addition of missing pieces to complete the landscape of central dogma. Starting from transcription to translation, modern era has witnessed non-coding RNA discovery and central role of these versatile regulators in onset and progression of pancreatic cancer. Long non-coding RNAs (lncRNAs) have been shown to act as competitive endogenous RNAs through sequestration and competitive binding to myriad of microRNAs in different cancers. In this article, we set spotlight on emerging evidence of regulation of different signaling pathways (Hippo, TGFβ/SMAD, Wnt/β-Catenin, JAK/STAT and NOTCH) by lncRNAs. Conceptual refinements have enabled us to understand how lncRNAs play central role in post-translational modifications of various proteins and how lncRNAs work with epigenetic-associated machinery to transcriptionally regulate gene network in pancreatic cancer.
Nrf2 Down-Regulation by Camptothecin Favors Inhibiting Invasion, Metastasis and Angiogenesis in Hepatocellular Carcinoma
Authors: Liu Qian , Zhao Shanshan , Meng Fanguang , Wang Hankang , Sun Liwei , Li Guijie , Gao Feng , Chen Feng
Published: June 2021

Higher oxidant stress capacity could promote invasion and metastasis. A previous study showed hepatocellular carcinoma (HCC) expressed more Nrf2 than para-carcinoma tissue. The chemotherapeutics such as epirubicin (EPI) could increase Nrf2 expression, while Camptothecin (CPT) could inhibit tumor growth by down-regulating the key molecule of antioxidant stress signal—Nrf2. The role of Nrf2 in invasion and metastasis was still unclear. In this study, we use EPI and CPT to determine the invasion and metastasis in Huh7 cells, H22 and Huh7 mouse models. In Huh7 cells, Nrf2 expression and ROS level were found increased after incubation with EPI by western blot and flow cytometry assay. But with the combination of EPI and CPT, inhibition of Nrf2 could decrease proliferation, invasion, and metastasis, which were investigated by CCK8 assay, wound healing, and Transwell assays. In Huh7 and H22 mouse models, EPI promoted Nrf2 up-regulation and nucleus translocation. Tumor growth was obviously inhibited with a single application of EPI or CPT. The combination of EPI and CPT could inhibit Nrf2 expression but demonstrated more suppressing effect of tumor growth than EPI. Western blot and immunohistochemical staining study revealed that Nrf2 inhibition was beneficial in decreasing the expression of N-cadherin, MMP9, Snail as well as Twist, and increasing E-cadherin, which were associated with epithelial–mesenchymal transition (EMT). Nrf2 down-regulation promoted lung metastasis of H22 cells in vivo. In addition, H&E staining and immunofluorescence staining of VEGFR suggested angiogenesis of Huh7 and H22 tumors was reduced. In conclusion, down-regulation of Nrf2 demonstrated inhibition of invasion, metastasis, and angiogenesis of hepatoma, which may provide a potential therapy in HCC.
Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial
Authors: Qi Hui , Wu Yue-E , Liu Ya-Li , Kou Chen , Wang Ze-Ming , Peng Xiao-Xia , Chen Liang , Cui Hong , Wang Ya-Juan , Li Jie-Qiong , Zhao Wei , Shen A-Dong
Published: June 2021

Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18–72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children’s Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.
Evaluation of Potential Complications of Interstitial Lung Disease Associated With Antiandrogens Using Data From Databases Reporting Spontaneous Adverse Effects
Authors: Nawa Hideki , Niimura Takahiro , Hamano Hirofumi , Yagi Kenta , Goda Mitsuhiro , Zamami Yoshito , Ishizawa Keisuke
Published: June 2021

From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide. Total prostatectomy (including robot-assisted prostatectomy), radiation therapy, and pharmacological treatment are commonly used to treat prostate cancer. The Chief of the Pharmaceutical Safety Division, that is, the Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ), recently called for the revision of package inserts for ethical drugs. However, the pathogenesis of interstitial lung disease (ILD), a serious drug-induced adverse effect, remains unclear. Moreover, there have been no large-scale evaluations of potential complications associated with currently used antiandrogens, which are commonly employed to treat prostate cancer. Hence, ILD, as an adverse event, remains poorly understood. Therefore, we conducted a survey of reports in the Japanese Adverse Drug Event Report (JADER) database to investigate the potential association between the reporting of ILD and antiandrogen drug use in clinical practice. The occurrence of ILD was investigated by evaluating the relationship between antiandrogen drug use and ILD. Adverse event signals were detected with reporting odds ratios (RORs), using data from the JADER and FDA Adverse Event Reporting System (FAERS) databases, for the analysis of post-marketing adverse event reports. The JADER was used to examine the time profile of adverse event occurrence for each drug, whereas the FAERS was used to screen cases of unknown adverse events and analyze their trends of occurrence. The analysis of data from both databases revealed the 95% confidence interval lower limits of ROR for bicalutamide and flutamide to be > 1, and adverse event signals were detected following the use of either drug. While caution should be exercised for drugs that are new to the market, we conclude that drugs with similar therapeutic effects that have been in use for a long period should also be re-examined for potential adverse events.
Modulation of TRIB3 and Macrophage Phenotype to Attenuate Insulin Resistance After Downhill Running in Mice
Authors: Luo Wei , Zhou Yue , Tang Qiang , Ai Lei , Zhang Yuan
Published: June 2021

Eccentric exercise training accompanied by a low-fat diet can prevent insulin resistance (IR) and is currently an effective method for the treatment of IR induced by high-fat diet (HFD)-associated obesity. However, the molecular mechanisms underlying this improvement of IR in adipose tissue are still not completely clear. In this study, 5–6-week-old male mice were randomly divided into a standard control diet (SCD) group (SC, n = 12) and a HFD group (HF, n = 72). After 12 weeks, 12 mice in each group were randomly sacrificed. The remaining mice in the HF group were randomly submitted to one of the following experimental protocols for 8 weeks: obesity-HFD-sedentary (OHF-Sed, n = 14), obesity-HFD-exercise (OHF-Ex, n = 16), obesity-SCD-sedentary (OSC-Sed, n = 14), and obesity-SCD-exercise (OSC-Ex, n = 16). All obese mice in the exercise group were subjected to downhill running. Half of the mice in each group received an insulin injection (0.75 U/kg) before sample collection. Epididymal fat was removed and weighed. Adipocyte size and inflammatory cell infiltration were observed by H&E staining. Both basal and insulin-stimulated GLUT4 fluorescence and protein contents were detected by immunofluorescence and Western blot. Levels of IL-1β and IL-10 were detected by ELISA. Protein contents of iNOS, Arg-1, TRIB3, p-AKT, and AKT were determined by Western blot. CD86 and CD206 fluorescence were determined by immunofluorescence. The results showed that a HFD for 12 weeks induced IR accompanied by adipose tissue macrophages M1 polarization (increased iNOS protein content and CD86 fluorescence) and TRIB3-AKT activation. Downhill running accompanied by a low-fat diet attenuated IR (p < 0.01), reduced inflammation levels (increased IL-10 protein content and decreased IL-1β protein content), inhibited adipose tissue macrophages M1 polarization (decreased iNOS protein content and CD86 fluorescence) and promoted M2 polarization (increased Arg-1 protein content and CD206 fluorescence), and suppressed TRIB3-AKT signaling. We concluded that downhill running accompanied by dietary fat regulation attenuates HFD-related IR in mice, which may be associated with reduced TRIB3-AKT signaling and activated M2 macrophages in adipose tissue.
Relationship Between Critical Power and Different Lactate Threshold Markers in Recreational Cyclists
Authors: Valenzuela Pedro L. , Alejo Lidia B. , Montalvo-Pérez Almudena , Gil-Cabrera Jaime , Talavera Eduardo , Lucia Alejandro , Barranco-Gil David
Published: June 2021

Purpose: To analyze the relationship between critical power (CP) and different lactate threshold (LT2) markers in cyclists.

Methods: Seventeen male recreational cyclists [33 ± 5 years, peak power output (PO) = 4.5 ± 0.7 W/kg] were included in the study. The PO associated with four different fixed (onset of blood lactate accumulation) and individualized (Dmaxexp, Dmaxpol, and LTΔ1) LT2 markers was determined during a maximal incremental cycling test, and CP was calculated from three trials of 1-, 5-, and 20-min duration. The relationship and agreement between each LT2 marker and CP were then analyzed.

Results: Strong correlations (r = 0.81–0.98 for all markers) and trivial-to-small non-significant differences (Hedges’ g = 0.01–0.17, bias = 1–9 W, and p > 0.05) were found between all LT2 markers and CP with the exception of Dmaxexp, which showed the strongest correlation but was slightly higher than the CP (Hedges’ g = 0.43, bias = 20 W, and p < 0.001). Wide limits of agreement (LoA) were, however, found for all LT2 markers compared with CP (from ±22 W for Dmaxexp to ±52 W for Dmaxpol), and unclear to most likely practically meaningful differences (PO differences between markers >1%, albeit <5%) were found between markers attending to magnitude-based inferences.

Conclusion: LT2 markers show a strong association and overall trivial-to-small differences with CP. Nevertheless, given the wide LoA and the likelihood of potentially meaningful differences between these endurance-related markers, caution should be employed when using them interchangeably.
Baseline Sensitivity of Echinochloa crus-gall and E. oryzicola to Florpyrauxifen-Benzyl, a New Synthetic Auxin Herbicide, in Korea
Authors: Lim Soo-Hyun , Kim Harim , Noh Tae-Kyeong , Lim Ji-Soo , Yook Min-Jung , Kim Jin-Won , Yi Jee-Hwan , Kim Do-Soon
Published: June 2021

Echinochloa species is one of the most problematic weed species due to its high competitiveness and increasing herbicide resistance. Florpyrauxifen-benzyl, a new auxin herbicide, was recently introduced for Echinochloa management; however, the potential risk for the development of herbicide resistance in Echinochloa species has not been well-investigated. Thus, this study was conducted to evaluate the baseline sensitivity of Echinochloa species to florpyrauxifen-benzyl to estimate the risk of future resistance development. A total of 70 and 71 accessions of Echinochloa crus-galli and Echinochloa oryzicola were collected from paddy fields in Korea, respectively. These two Echinochloa species were grown in plastic pots up to the 5-leaf stage, and treated with florpyrauxifen-benzyl at a range of doses from 2.2 g to 70.0 g a.i. ha–1. Nonlinear regression analyses revealed that GR50 values for E. oryzicola ranged from 4.54 g to 29.66 g a.i. ha–1, giving a baseline sensitivity index (BSI) of 6.53, while those for E. crus-galli ranged from 6.15 g to 16.06 g a.i. ha–1, giving a BSI of 2.61. Our findings suggest that E. oryzicola has a greater potential risk than E. crus-galli for the development of metabolism-based resistance to florpyrauxifen-benzyl.
Mutual Promotion of LAP2 and CAT2 Synergistically Regulates Plant Salt and Osmotic Stress Tolerance
Authors: Zhang Yu , Wang Lin-Feng , Li Ting-Ting , Liu Wen-Cheng
Published: June 2021

Almost all abiotic stresses induce reactive oxygen species (ROS) overaccumulation, causing oxidative damages to plant cells. Catalase (CAT) plays a vital role in plant oxidative stress tolerance by scavenging stress-induced excess H2O2; thus, the identification of factors regulating catalase function will shed light on the underlying regulatory mechanisms. Here, we identified leucine aminopeptidase 2 (LAP2) as a novel CAT2-interacting protein and showed a mutual promotion effect of the two proteins in plant stress responses. LAP2 has a physical interaction with CAT2 in plant cells. The loss-of-function mutant of LAP2, lap2-3, is hypersensitive to salt or osmotic stress with increased ROS accumulation and malondialdehyde content and decreased catalase activity. The lap2-3 mutant has less CAT2 protein levels as CAT2 protein stability is impaired in the mutant. Scavenging excess ROS by glutathione or overexpressing CAT2 in the lap2-3 mutant recovers its hypersensitive phenotype to salt or osmotic stress. Further study showed that CAT2 promotes LAP2 hydrolysis activity with leucine-4-methylcoumaryl-7-amides as a substrate in vivo and in vitro, and thus, similar to the lap2-3 mutant, the cat2-1 mutant also has lower γ-aminobutyric acid content than the wild type. Together, our study reveals mutual promotion effects of CAT2 and LAP2 in conferring plant salt and osmotic stress tolerance.
Engineering Betalain Biosynthesis in Tomato for High Level Betanin Production in Fruits
Authors: Grützner Ramona , Schubert Ramona , Horn Claudia , Yang Changqing , Vogt Thomas , Marillonnet Sylvestre
Published: June 2021

Betalains are pigments found in plants of the Caryophyllales order, and include the red-purple betacyanins and the yellow-orange betaxanthins. The red pigment from red beets, betanin, is made from tyrosine by a biosynthetic pathway that consists of a cytochrome P450, a L-DOPA dioxygenase, and a glucosyltransferase. The entire pathway was recently reconstituted in plants that do not make betalains naturally including potato and tomato plants. The amount of betanin produced in these plants was however not as high as in red beets. It was recently shown that a plastidic arogenate dehydrogenase gene involved in biosynthesis of tyrosine in plants is duplicated inBeta vulgarisand other betalain-producing plants, and that one of the two encoded enzymes, BvADHα, has relaxed feedback inhibition by tyrosine, contributing to the high amount of betanin found in red beets. We have reconstituted the complete betanin biosynthetic pathway in tomato plants with or without aBvADHαgene, and with all genes expressed under control of a fruit-specific promoter. The plants obtained with a construct containingBvADHαproduced betanin at a higher level than plants obtained with a construct lacking this gene. These results show that use of BvADHα can be useful for high level production of betalains in heterologous hosts. Unlike red beets that produce both betacyanins and betaxanthins, the transformed tomatoes produced betacyanins only, conferring a bright purple-fuschia color to the tomato juice.