bluuebunny/crossref_metadata_2025 huggingface dataset:
A System Integration Analysis of a Molten Carbonate Electrolysis Cell as an Off-Gas Recovery System in a Steam-Reforming Process of an Oil Refinery
Authors: Monforti Ferrario Andrea , Santoni Francesca , Della Pietra Massimiliano , Rossi Mosè , Piacente Nicola , Comodi Gabriele , Simonetti Luca
Published: April 2021

Technologies capable of efficiently exploiting unavoidable CO2 streams, have to be deeply investigated and deployed during the transition phase to achieve long-term climate neutrality targets. Among the technologies, Molten Carbonate Cells (MCC) Operating in Electrolysis Mode (MCEC) represents a promising facility to valorize CO2-rich waste streams, which are typically available in industrial plants, by their conversion into a high-value H2/CO syngas. These gaseous products can be reintegrated in a plant or reused in different applications. This study analyzes the integration of a system of the MCEC unit under different operating conditions in terms of composition, current density, and the utilization of fuels in a steam-reforming process of an Italian oil refinery via a mixed experimental-simulative approach. The aim of the current study is to assess the improvement in the overall product yield and further impacts of the MCEC unit on the plant efficiency. The results have shown that it is possible to obtain an electrochemical Specific Energy Consumption for the production of H2 of 3.24 kWh/NmH23 using the MCEC, whereby the possible integration of a 1-MWe module with a reformer of the proposed plant not only increases the hydrogen yield but also decreases the amount of fuel needed to assist the reforming reaction and separates a CO2 stream after additional purification via an oxy-fuel combustor, consequently determining lower greenhouse gases emissions.
Effects of Harvest and Fertilization Frequency on Protein Yield and Extractability From Flood-Tolerant Perennial Grasses Cultivated on a fen Peatland
Authors: Nielsen Claudia Kalla , Stødkilde Lene , Jørgensen Uffe , Lærke Poul Erik
Published: April 2021

Paludiculture, and in particular the cultivation of perennial grasses as biomass feedstock for green biorefineries, may be an economic and environmentally sustainable option for agricultural peatlands in temperate regions. However, the optimal biomass quality for protein extraction from flood-tolerant grasses is largely unknown. The aim of this study was to define the combined effect of harvest and fertilization frequency, with one to five annual cuts, on protein yield and extractability for the grasses tall fescue (TF) and reed canary grass (RCG), cultivated on an agricultural fen peatland in Denmark.The content of protein fractions was determined according to the Cornell Net Carbohydrate and Protein System (CNCPS). We assessed protein extractability by lab-scale biorefinery techniques using a screw-press followed by acid precipitation of true protein. The two methods were compared to correlate potential extractable protein yields with actual biorefinery outputs. We found the highest annual biomass and crude protein (CP) yields in the two cut treatments, with 13.4 and 15.6 t dry matter (DM) ha−1 year−1, containing 2.9–3.4 t CP ha−1 year−1for TF and RCG, respectively. The highest neutral-extractable (fractions B1and B2) true protein yields of 1.1 and 1.5 t ha−1 year−1were found in the two cut treatments, representing 39% (TF) - 45% (RCG) of total CP. Using biorefining techniques, we were able to precipitate up to 2.2 t DM ha−1 year−1of protein concentrate, containing up to 39% CP. Significant correlations between methods were found, with a distinct relationship between CNCPS fractions B1+ B2and CP yield of the protein concentrate, indicating the suitability of the CNCPS as an indicator for extractable protein yields. Biomass and CP yields were not significantly improved beyond two annual cuts. However, timing and harvest frequencies significantly affected plant maturity and consequently extractable CP contents and protein concentrate yields. We conclude that TF and RCG are promising feedstocks for green biorefineries due to high biomass, extractable CP, and protein concentrate yields, and highlight the potential of flood-tolerant grasses, cultivated on wet agricultural peatlands, for an enhanced valorisation beyond the common utilisation for bioenergy.
Drought Deteriorates the N Stoichiometry of Biomass Production in European Beech Saplings Under Global Change
Authors: Köhler Julia , Yang Nan , Pena Rodica , Polle Andrea , Meier Ina C.
Published: April 2021

Continuous nitrogen (N) deposition has raised concerns that temperate forest ecosystems shift from N limitation to progressing phosphorus (P) limitation under global change. According to the multiple resource limitation theory, this will not only influence P economy, but also reduce N uptake and use efficiencies of trees such that growth is equally limited by N and P. We used different global change scenarios including summer drought to test the prediction of this hypothesis for the N economy of European beech (Fagus sylvatica L.) saplings. Our study demonstrates that the N uptake efficiency (NUptakeE) of beech adjusts to soil N availability and stabilizes leaf and fine root N concentrations. By contrast, both efficiencies of N use were curtailed by increasing P limitation under elevated soil N. The photosynthetic N use efficiency (PNUE) was serially reduced with decreasing soil P availability and increasing foliar N:P ratios, while the N use efficiency (NUE) decreased with increasing fine root N:P ratios. Soil drought induced relative P deficiency alike and reduced NUptakeE, PNUE, and NUE independent from the soil N:P ratios. We conclude that not only N deposition but also increasing summer droughts might affect N:P ratios, thereby inducing P imbalances and affecting the N economy of European beech saplings under global change.
Community Detection in Large-Scale Bipartite Biological Networks
Authors: Calderer Genís , Kuijjer Marieke L.
Published: April 2021

Networks are useful tools to represent and analyze interactions on a large, or genome-wide scale and have therefore been widely used in biology. Many biological networks—such as those that represent regulatory interactions, drug-gene, or gene-disease associations—are of a bipartite nature, meaning they consist of two different types of nodes, with connections only forming between the different node sets. Analysis of such networks requires methodologies that are specifically designed to handle their bipartite nature. Community structure detection is a method used to identify clusters of nodes in a network. This approach is especially helpful in large-scale biological network analysis, as it can find structure in networks that often resemble a “hairball” of interactions in visualizations. Often, the communities identified in biological networks are enriched for specific biological processes and thus allow one to assign drugs, regulatory molecules, or diseases to such processes. In addition, comparison of community structures between different biological conditions can help to identify how network rewiring may lead to tissue development or disease, for example. In this mini review, we give a theoretical basis of different methods that can be applied to detect communities in bipartite biological networks. We introduce and discuss different scores that can be used to assess the quality of these community structures. We then apply a wide range of methods to a drug-gene interaction network to highlight the strengths and weaknesses of these methods in their application to large-scale, bipartite biological networks.
Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
Authors: Xu Lanman , Wang Xiaofang , Chen Yan , Soong Lynn , Chen Yongping , Cai Jiyang , Liang Yuejin , Sun Jiaren
Published: April 2021

Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.
Immune Checkpoints, a Novel Class of Therapeutic Targets for Autoimmune Diseases
Authors: Zhai Yujia , Moosavi Reza , Chen Mingnan
Published: April 2021

Autoimmune diseases, such as multiple sclerosis and type-1 diabetes, are the outcomes of a failure of immune tolerance. Immune tolerance is sustained through interplays between two inter-dependent clusters of immune activities: immune stimulation and immune regulation. The mechanisms of immune regulation are exploited as therapeutic targets for the treatment of autoimmune diseases. One of these mechanisms is immune checkpoints (ICPs). The roles of ICPs in maintaining immune tolerance and hence suppressing autoimmunity were revealed in animal models and validated by the clinical successes of ICP-targeted therapeutics for autoimmune diseases. Recently, these roles were highlighted by the clinical discovery that the blockade of ICPs causes autoimmune disorders. Given the crucial roles of ICPs in immune tolerance, it is plausible to leverage ICPs as a group of therapeutic targets to restore immune tolerance and treat autoimmune diseases. In this review, we first summarize working mechanisms of ICPs, particularly those that have been utilized for therapeutic development. Then, we recount the agents and approaches that were developed to target ICPs and treat autoimmune disorders. These agents take forms of fusion proteins, antibodies, nucleic acids, and cells. We also review and discuss safety information for these therapeutics. We wrap up this review by providing prospects for the development of ICP-targeting therapeutics. In summary, the ever-increasing studies and results of ICP-targeting of therapeutics underscore their tremendous potential to become a powerful class of medicine for autoimmune diseases.
BK Channels Are Activated by Functional Coupling With L-Type Ca2+ Channels in Cricket Myocytes
Authors: Numata Tomohiro , Sato-Numata Kaori , Yoshino Masami
Published: April 2021

Large-conductance calcium (Ca2+)-activated potassium (K+) (BK) channel activation is important for feedback control of Ca2+influx and cell excitability during spontaneous muscle contraction. To characterize endogenously expressed BK channels and evaluate the functional relevance of Ca2+sources leading to BK activity, patch-clamp electrophysiology was performed on cricket oviduct myocytes to obtain single-channel recordings. The single-channel conductance of BK channels was 120 pS, with increased activity resulting from membrane depolarization or increased intracellular Ca2+concentration. Extracellular application of tetraethylammonium (TEA) and iberiotoxin (IbTX) suppressed single-channel current amplitude. These results indicate that BK channels are endogenously expressed in cricket oviduct myocytes. Ca2+release from internal Ca2+stores and Ca2+influx via the plasma membrane, which affect BK activity, were investigated. Extracellular Ca2+removal nullified BK activity. Administration of ryanodine and caffeine reduced BK activity. Administration of L-type Ca2+channel activity regulators (Bay K 8644 and nifedipine) increased and decreased BK activity, respectively. Finally, the proximity between the L-type Ca2+channel and BK was investigated. Administration of Bay K 8644 to the microscopic area within the pipette increased BK activity. However, this increase was not observed at a sustained depolarizing potential. These results show that BK channels are endogenously expressed in cricket oviduct myocytes and that BK activity is regulated by L-type Ca2+channel activity and Ca2+release from Ca2+stores. Together, these results show that functional coupling between L-type Ca2+and BK channels may underlie the molecular basis of spontaneous rhythmic contraction.
Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis
Authors: Nozaki Yuji , Hidaka Toshihiko , Ri Jinhai , Itami Tetsu , Tomita Daisuke , Okada Akinori , Ashida Chisato , Ikeda Fusayo , Yamamoto Atsuhiro , Funahashi Keiko , Kinoshita Koji , Matsubara Tsukasa , Funauchi Masanori , Matsumura Itaru
Published: April 2021

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated–conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF.

Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25–83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1– <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate.

Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage.

Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.
Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2
Authors: Kumar Vikas , Parate Shraddha , Yoon Sanghwa , Lee Gihwan , Lee Keun Woo
Published: April 2021

The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, a very small number of remedies have been to be found effective against SARS-CoV-2 infection. Therefore, further research is required to achieve a lasting solution against this deadly disease. Repurposing available drugs and evaluating natural product inhibitors against target proteins of SARS-CoV-2 could be an effective approach to accelerate drug discovery and development. With this strategy in mind, we derived Marine Natural Products (MNP)-based drug-like small molecules and evaluated them against three major target proteins of the SARS-CoV-2 virus replication cycle. A drug-like database from MNP library was generated using Lipinski’s rule of five and ADMET descriptors. A total of 2,033 compounds were obtained and were subsequently subjected to molecular docking with 3CLpro, PLpro, and RdRp. The docking analyses revealed that a total of 14 compounds displayed better docking scores than the reference compounds and have significant molecular interactions with the active site residues of SARS-CoV-2 virus targeted proteins. Furthermore, the stability of docking-derived complexes was analyzed using molecular dynamics simulations and binding free energy calculations. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, binding affinity, and molecular interactions. Our investigation identified two hit compounds against each targeted proteins displaying stable behavior, higher binding affinity and key residual molecular interactions, with good in silico pharmacokinetic properties, therefore can be considered for further in vitro studies.
The Packaging Regions of G1-Like PB2 Gene Contribute to Improving the Survival Advantage of Genotype S H9N2 Virus in China
Authors: Li Xiuli , Zhao Ying , Qiao Shumiao , Gu Min , Gao Ruyi , Ge Zhichuang , Xu Xiulong , Wang Xiaoquan , Ma Jing , Hu Jiao , Hu Shunlin , Liu Xiaowen , Chen Sujuan , Peng Daxin , Jiao Xinan , Liu Xiufan
Published: April 2021

The genotype S (G57) H9N2 virus, which first emerged in 2007 with the substitution of the G1-like PB2 gene for F98-like ones, has become the predominant genotype in the past 10 years. However, whether this substitution plays a role in the fitness of genotype S H9N2 viruses remains unknown. Comparison of the PB2 genes of F98-like and G1-like viruses revealed a close homology in amino acid sequences but great variations at nucleotide levels. We then determined if the packaging region, a unique sequence in each segment utilized for the assembly of the vRNA into virions, played a role in the fitness of the S genotype. The chimeric H9N2 virus with PB2 segments of the G1-like packaging regions significantly increased viral protein levels and polymerase activity. Substituting the packaging regions in the two terminals of F98-like PB2 with the sequence of G1-like further improved its competitive advantage. Substitution of the packaging regions of F98-like PB2 with those of G1-like sequences increased the infectivity of the chimeric virus in the lungs and brains of chicken at 3 days post infection (dpi) and extended the lengths of virus shedding time. Our study suggests that the packaging regions of the G1-like PB2 gene contribute to improve the survival advantage of the genotype S H9N2 virus in China.
Insects Provide Unique Systems to Investigate How Early-Life Experience Alters the Brain and Behavior
Authors: Westwick Rebecca R. , Rittschof Clare C.
Published: April 2021

Early-life experiences have strong and long-lasting consequences for behavior in a surprising diversity of animals. Determining which environmental inputs cause behavioral change, how this information becomes neurobiologically encoded, and the functional consequences of these changes remain fundamental puzzles relevant to diverse fields from evolutionary biology to the health sciences. Here we explore how insects provide unique opportunities for comparative study of developmental behavioral plasticity. Insects have sophisticated behavior and cognitive abilities, and they are frequently studied in their natural environments, which provides an ecological and adaptive perspective that is often more limited in lab-based vertebrate models. A range of cues, from relatively simple cues like temperature to complex social information, influence insect behavior. This variety provides experimentally tractable opportunities to study diverse neural plasticity mechanisms. Insects also have a wide range of neurodevelopmental trajectories while sharing many developmental plasticity mechanisms with vertebrates. In addition, some insects retain only subsets of their juvenile neuronal population in adulthood, narrowing the targets for detailed study of cellular plasticity mechanisms. Insects and vertebrates share many of the same knowledge gaps pertaining to developmental behavioral plasticity. Combined with the extensive study of insect behavior under natural conditions and their experimental tractability, insect systems may be uniquely qualified to address some of the biggest unanswered questions in this field.
A Hypothesis for Theta Rhythm Frequency Control in CA1 Microcircuits
Authors: Skinner Frances K. , Rich Scott , Lunyov Anton R. , Lefebvre Jeremie , Chatzikalymniou Alexandra P.
Published: April 2021

Computational models of neural circuits with varying levels of biophysical detail have been generated in pursuit of an underlying mechanism explaining the ubiquitous hippocampal theta rhythm. However, within the theta rhythm are at least two types with distinct frequencies associated with different behavioral states, an aspect that must be considered in pursuit of these mechanistic explanations. Here, using our previously developed excitatory-inhibitory network models that generate theta rhythms, we investigate the robustness of theta generation to intrinsic neuronal variability by building a database of heterogeneous excitatory cells and implementing them in our microcircuit model. We specifically investigate the impact of three key “building block” features of the excitatory cell model that underlie our model design: these cells' rheobase, their capacity for post-inhibitory rebound, and their spike-frequency adaptation. We show that theta rhythms at various frequencies can arise dependent upon the combination of these building block features, and we find that the speed of these oscillations are dependent upon the excitatory cells' response to inhibitory drive, as encapsulated by their phase response curves. Taken together, these findings support a hypothesis for theta frequency control that includes two aspects: (i) an internal mechanism that stems from the building block features of excitatory cell dynamics; (ii) an external mechanism that we describe as “inhibition-based tuning” of excitatory cell firing. We propose that these mechanisms control theta rhythm frequencies and underlie their robustness.
A Computational Model of Working Memory Based on Spike-Timing-Dependent Plasticity
Authors: Huang Qiu-Sheng , Wei Hui
Published: April 2021

Working memory is closely involved in various cognitive activities, but its neural mechanism is still under exploration. The mainstream view has long been that persistent activity is the neural basis of working memory, but recent experiments have observed that activity-silent memory can also be correctly recalled. The underlying mechanism of activity-silent memory is considered to be an alternative scheme that rejects the theory of persistent activity. We propose a working memory model based on spike-timing-dependent plasticity (STDP). Different from models based on spike-rate coding, our model adopts temporal patterns of action potentials to represent information, so it can flexibly encode new memory representation. The model can work in both persistent and silent states, i.e., it is compatible with both of these seemingly conflicting neural mechanisms. We conducted a simulation experiment, and the results are similar to the real experimental results, which suggests that our model is plausible in biology.
Computer Vision for Brain Disorders Based Primarily on Ocular Responses
Authors: Li Xiaotao , Fan Fangfang , Chen Xuejing , Li Juan , Ning Li , Lin Kangguang , Chen Zan , Qin Zhenyun , Yeung Albert S. , Li Xiaojian , Wang Liping , So Kwok-Fai
Published: April 2021

Real-time ocular responses are tightly associated with emotional and cognitive processing within the central nervous system. Patterns seen in saccades, pupillary responses, and spontaneous blinking, as well as retinal microvasculature and morphology visualized via office-based ophthalmic imaging, are potential biomarkers for the screening and evaluation of cognitive and psychiatric disorders. In this review, we outline multiple techniques in which ocular assessments may serve as a non-invasive approach for the early detections of various brain disorders, such as autism spectrum disorder (ASD), Alzheimer's disease (AD), schizophrenia (SZ), and major depressive disorder (MDD). In addition, rapid advances in artificial intelligence (AI) present a growing opportunity to use machine learning-based AI, especially computer vision (CV) with deep-learning neural networks, to shed new light on the field of cognitive neuroscience, which is most likely to lead to novel evaluations and interventions for brain disorders. Hence, we highlight the potential of using AI to evaluate brain disorders based primarily on ocular features.
Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury
Authors: Huang Huan , Xia Anqi , Sun Li , Lu Chun , Liu Ying , Zhu Zhenjie , Wang Siye , Cai Junyan , Zhou Xiaoyun , Liu Su
Published: April 2021

Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. This study investigated the pathogenic functions of TRAF6 signaling following TBI in vivo and in vitro. A rat TBI model was established by air pressure contusion while lipopolysaccharide (LPS) exposure was used to induce inflammatory-like responses in cultured astrocytes. Model rats were examined for cell-specific expression of TRAF6, NF-κB, phosphorylated (p)-NF-κB, MAPKs (ERK, JNK, and p38), p-MAPKs, chemokines (CCL2 and CXCL1), and chemokine receptors (CCR2 and CXCR2) by immunofluorescence, RT-qPCR, western blotting, and ELISA, for apoptosis by TUNEL staining, and spatial cognition by Morris water maze testing. These measurements were compared between TBI model rats receiving intracerebral injections of TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-κB inhibitors, or vehicle. Primary astrocytes were stimulated with LPS following TRAF6 siRNA or control transfection, and NF-κB, MAPKs, chemokine, and chemokine receptor expression levels evaluated by western blotting and ELISA. TRAF6 was expressed mainly in astrocytes and neurons of injured cortex, peaking 3 days post-TBI. Knockdown by AAV9-TRAF6-RNAi improved spatial learning and memory, decreased TUNEL-positive cell number in injured cortex, and downregulated expression levels of p-NF-κB, p-ERK, p-JNK, p-p38, CCL2, CCR2, CXCL1, and CXCR2 post-TBI. Inhibitors of NF-κB, ERK, JNK, and p38 significantly suppressed CCL2, CCR2, CXCL1, and CXCR2 expression following TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced NF-κB, ERK, JNK, p38, CCL2, and CXCL1 upregulation in cultured astrocytes. Targeting TRAF6-MAPKs/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.
Wilms Tumor 1 Mutations Are Independent Poor Prognostic Factors in Pediatric Acute Myeloid Leukemia
Authors: Wang Yin , Weng Wen-Jun , Zhou Dun-Hua , Fang Jian-Pei , Mishra Srishti , Chai Li , Xu Lu-Hong
Published: April 2021

The prognostic impact of Wilms tumor 1 (WT1) mutations remains controversial for patients with acute myeloid leukemia (AML). Here, we aimed to determine the clinical implication of WT1 mutations in a large cohort of pediatric AML. The clinical data of 870 pediatric patients with AML were downloaded from the therapeutically applicable research to generate effective treatment (TARGET) dataset. We analyzed the prevalence, clinical profile, and prognosis of AML patients with WT1 mutations in this cohort. Our results showed that 6.7% of total patients harbored WT1 mutations. These WT1 mutations were closely associated with normal cytogenetics (P<0.001), FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutations (P<0.001), and low complete remission induction rates (P<0.01). Compared to the patients without WT1 mutations, patients with WT1 mutations had a worse 5-year event-free survival (21.7 ± 5.5% vs 48.9 ± 1.8%, P<0.001) and a worse overall survival (41.4 ± 6.6% vs 64.3 ± 1.7%, P<0.001). Moreover, patients with both WT1 and FLT3/ITD mutations had a dismal prognosis. Compared to chemotherapy alone, hematopoietic stem cell transplantation tended to improve the prognoses of WT1-mutated patients. Multivariate analysis demonstrated that WT1 mutations conferred an independent adverse impact on event-free survival (hazard ratio 1.910, P = 0.001) and overall survival (hazard ratio 1.709, P = 0.020). In conclusion, our findings have demonstrated that WT1 mutations are independent poor prognostic factors in pediatric AML.
SUMOylation Wrestles With the Occurrence and Development of Breast Cancer
Authors: Qin Yuanyuan , Yuan Hong , Chen Xu , Yang Xinyi , Xing Zhengcao , Shen Yajie , Dong Wanying , An Siming , Qi Yitao , Wu Hongmei
Published: April 2021

Breast cancer has the highest incidence among cancers and is the most frequent cause of death in women worldwide. The detailed mechanism of the pathogenesis of breast cancer has not been fully elucidated, and there remains a lack of effective treatment methods for the disease. SUMOylation covalently conjugates a large amount of cellular proteins, and affects their cellular localization and biological activity to participate in numerous cellular processes. SUMOylation is an important process and imbalance of SUMOylation results in the progression of human diseases. Increasing evidence shows that numerous SUMOylated proteins are involved in the occurrence and development of breast cancer. This review summarizes a series of studies on protein SUMOylation in breast cancer in recent years. The study of SUMOylated proteins provides a comprehensive understanding of the pathophysiology of breast cancer and provides evolving therapeutic strategies for the treatment of breast cancer.
Pediatric Fibrinogen PART II—Overview of Indications for Fibrinogen Use in Critically Ill Children
Authors: Crighton Gemma Louise , Huisman Elise J.
Published: April 2021

Bleeding is frequently seen in critically ill children and is associated with increased morbidity and mortality. Fibrinogen is an essential coagulation factor for hemostasis and hypofibrinogenemia is an important risk factor for bleeding in pediatric and adult settings. Cryoprecipitate and fibrinogen concentrate are often given to critically ill children to prevent bleeding and improve fibrinogen levels, especially in the setting of surgery, trauma, leukemia, disseminated intravascular coagulopathy, and liver failure. The theoretical benefit of fibrinogen supplementation to treat hypofibrinogenemia appears obvious, yet the evidence to support fibrinogen supplementation in children is sparce and clinical indications are poorly defined. In addition, it is unknown what the optimal fibrinogen replacement product is in children and neonates or what the targets of treatment should be. As a result, there is considerable variability in practice. In this article we will review the current pediatric and applicable adult literature with regard to the use of fibrinogen replacement in different pediatric critical care contexts. We will discuss the clinical indications for fibrinogen supplementation in critically ill children and the evidence to support their use. We summarize by highlighting current knowledge gaps and areas for future research.
Methodological Quality Assessment of Budget Impact Analyses for Orphan Drugs: A Systematic Review
Authors: Abdallah Khadidja , Huys Isabelle , Claes Kathleen , Simoens Steven
Published: April 2021

Objectives: This research aims to evaluate the methodological quality of budget impact analyses for orphan drugs and to provide suggestions for future analyses.

Methods: Conference abstracts and peer-reviewed literature on budget impact analyses were collected through searches of Pubmed and Embase. ISPOR good practice guidelines were used as a methodological standard for budget impact analyses. Examined parameters encompassed: perspective, target population, data sources, intervention and comparator(s), time horizon, scope of costs, discounting, validation, assumptions and sensitivity analysis.

Results: Seventy studies on individual orphan drugs and 21 studies on a combination of orphan drugs analyzing budget impact were identified. Overall, analyses considered a third-party payer perspective, reported periodic budget impacts over a one-to-five-year time horizon, and did not apply discounting. A dynamically fluctuating population and costs beyond drug costs were accounted for in 18.7% and 51.7% of studies, respectively. Input data were retrieved from published literature, clinical trials, registries, claims databases, expert opinions, historical data and market research. Assumptions were mostly made about population size and intervention/comparator(s) market uptake, but these assumptions were rarely justified and their impact was insufficiently explored through sensitivity analyses. Budget impact results were rarely validated.

Conclusion: Existing budget impact analyses for orphan drugs are concise, vary greatly and are of substandard methodological quality. To eliminate possible bias in future budget impact analyses, future studies should adhere to national or ISPOR good practice guidelines on budget impact analysis.
Advances in the Application of Natural Products and the Novel Drug Delivery Systems for Psoriasis
Authors: Xie Jin , Huang Shengjie , Huang Haozhou , Deng Xuan , Yue Pengfei , Lin Junzhi , Yang Ming , Han Li , Zhang Ding-kun
Published: April 2021

Psoriasis, an incurable autoimmune skin disease, is one of the most common immune-mediated disorders. Presently, numerous clinical research studies are underway, and treatment options are available. However, these treatments focus on improving symptoms of the disease and fail to achieve a radical cure; they also have certain toxic side effects. In recent years, natural products have increasingly gained attention because of their high efficiency and low toxicity. Despite their obvious therapeutic effects, natural products’ biological activity was limited by their instability, poor solubility, and low bioavailability. Novel drug delivery systems, including liposomes, lipospheres, nanostructured lipid carriers, niosomes, nanoemulsions, nanospheres, microneedles, ethosomes, nanocrystals, and foams could potentially overcome the limitations of poor water solubility and permeability in traditional drug delivery systems. Thus, to achieve a therapeutic effect, the drug can reach the epidermis and dermis in psoriatic lesions to interact with the immune cells and cytokines.
Evaluating the Therapeutic Mechanisms of Selected Active Compounds in Cornus Officinalis and Paeonia Lactiflora in Rheumatoid Arthritis via Network Pharmacology Analysis
Authors: Li Qinglin , Hu Shaoqi , Huang Lichuang , Zhang Jida , Cao Gang
Published: April 2021

Cornus officinalis Sieb et. Zucc and Paeonia lactiflora Pall. have exhibited favorable therapeutic effects against rheumatoid arthritis (RA), but the specific mechanisms of their active compounds remain unclear. The aim of this study was to comprehensively analyze the therapeutic mechanisms of selected active compounds in Cornus officinalis (loganin, ursolic acid, and morroniside) and Paeonia lactiflora (paeoniflorin and albiflorin) via network pharmacology. The pharmacological properties of the five active compounds were evaluated and their potential target genes were identified by database screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analysis were performed to determine the enriched molecular pathways associated with the active compounds. Using network pharmacology tools, eight genes (IL1β, VEGFA, STAT3, TP53, IL6, TNF, FOS, and LGALS3) were identified as common targets between RA and the five active compounds. Molecular docking simulation revealed the compound-target relationship between the five active compounds and three selected targets from the eight common ones (LGALS3, STAT3, and VEGFA). The compound-target relationships were subsequently validated via preliminary in vivo experiments in a rat model of collagen-induced arthritis. Rats subjected to collagen-induced arthritis showed increased protein expression of LGALS3, STAT3, and VEGFA in synovial tissues. However, treatment using Cornus officinalis or/and Paeonia lactiflora, as well as their most drug-like active compounds (ursolic acid or/and paeoniflorin, respectively, identified based on pharmacological properties), attenuated the expression of these three targets, as previously predicted. Collectively, network pharmacology allowed the pharmacological and molecular roles of Cornus officinalis and Paeonia lactiflora to be systematically revealed, further establishing them as important candidate drugs in the treatment and management of RA.
Innate Immunity in Diabetic Wound Healing: Focus on the Mastermind Hidden in Chronic Inflammatory
Authors: Geng Kang , Ma Xiumei , Jiang Zongzhe , Huang Wei , Gao Chenlin , Pu Yueli , Luo Lifang , Xu Youhua , Xu Yong
Published: April 2021

A growing body of evidence suggests that the interaction between immune and metabolic responses is essential for maintaining tissue and organ homeostasis. These interacting disorders contribute to the development of chronic diseases associated with immune-aging such as diabetes, obesity, atherosclerosis, and nonalcoholic fatty liver disease. In Diabetic wound (DW), innate immune cells respond to the Pathogen-associated molecular patterns (PAMAs) and/or Damage-associated molecular patterns (DAMPs), changes from resting to an active phenotype, and play an important role in the triggering and maintenance of inflammation. Furthermore, the abnormal activation of innate immune pathways secondary to immune-aging also plays a key role in DW healing. Here, we review studies of innate immune cellular molecular events that identify metabolic disorders in the local microenvironment of DW and provide a historical perspective. At the same time, we describe some of the recent progress, such as TLR receptor-mediated intracellular signaling pathways that lead to the activation of NF-κB and the production of various pro-inflammatory mediators, NLRP3 inflammatory via pyroptosis, induction of IL-1β and IL-18, cGAS-STING responds to mitochondrial injury and endoplasmic reticulum stress, links sensing of metabolic stress to activation of pro-inflammatory cascades. Besides, JAK-STAT is also involved in DW healing by mediating the action of various innate immune effectors. Finally, we discuss the great potential of targeting these innate immune pathways and reprogramming innate immune cell phenotypes in DW therapy.
Self-Organized Criticality in Economic Fluctuations: The Age of Maturity
Authors: Tebaldi Claudio
Published: April 2021

Self-Organized Criticality (SOC) has been proposed as a paradigm that may rationalize the emergence of macrofinancial fluctuations. The wave of innovative thinking sparked by this proposal continues to produce interesting contributions in many areas of economics, ranging from macroeconomics to finance. In this review, we propose a guided tour to these achievements, highlighting that analysis of SOC equilibria is a promising avenue to establish a nexus between i) a statistical equilibrium characterized by the spontaneous emergence of dynamic critical fluctuations and ii) a strategic equilibrium concept modeling a large number of interacting players. The critical state is the stable outcome arising from a trade-off between cooperation and competition.
Superoscillations in Finite-Energy Airy Beams
Authors: He Yingjun , Chen Xingyuan , Niu Liting
Published: April 2021

Superoscillations naturally arise in optical fields with dense packing of nodal points of amplitude. Airy wave packets are highly oscillatory and rich of phase singularities. We study to the best of our knowledge, for the first time, the superoscillatory behavior in a band-limited Airy beam whose spectrum is sharply truncated. Our results show that not as expected, the superoscillations occur outside of the Airy-like region, but in regions above a defining line where the beam stops being Airy-like. The degree of superoscillation can be very high there.
High Order Coherence Functions and Spectral Distributions as Given by the Scully-Lamb Quantum Theory of the Laser
Authors: Peng Tao , Zhao Xingchen , Shih Yanhua , Scully Marlan O.
Published: April 2021

We propose and demonstrate a method for measuring the time evolution of the off-diagonal elements ρn,n+k(t) of the reduced density matrix obtained from the quantum theory of the laser. The decay rates of the off-diagonal matrix element ρn,n+k(t) (k = 2,3) are measured for the first time and compared with that of ρn,n+1(t), which corresponds to the linewidth of the laser. The experimental results agree with the Scully-Lamb quantum theory of the laser.
Substitution Mapping of a Locus Responsible for Hybrid Breakdown in Populations Derived From Interspecific Introgression Line
Authors: Munguambe Nilsa Emilia , Inoue Shouta , Demeter Zita , Yamagata Yoshiyuki , Yasui Hideshi , Zheng Shao-Hui , Fujita Daisuke
Published: April 2021

Hybrid breakdown, a form of postzygotic reproductive barrier, has been reported to hinder gene flow in many crosses between wild and cultivated rice. Here, the phenomenon of hybrid breakdown was observed as low-tillering (i.e., low tiller number) in some progeny of an interspecific cross produced in an attempt to introduce Oryza meridionalis Ng (W1625) chromosomal segments into Oryza sativa L. ssp. japonica “Taichung 65” (T65). Low-tillering lines were obtained in BC4-derived progeny from a cross between W1625 and “Taichung 65,” but the locus for low-tillering could not be mapped in segregating populations. As a second approach to map the locus for low-tillering, we analyzed an F2 population derived from a cross between the low-tillering lines and a high-yielding indica cultivar, “Takanari.” A major QTL for low-tillering, qLTN4, was detected between PCR-based markers MS10 and RM307 on the long arm of chromosome 4, with a LOD score of 15.6. The low-tillering phenotype was associated with weak growth and pale yellow phenotype; however, low-tillering plant had less reduction of grain fertility. In an F4 population (4896 plants), 563 recombinant plants were identified and the low-tillering locus was delimited to a 4.6-Mbp region between markers W1 and C5-indel3729. This region could not be further delimited because recombination is restricted in this region of qLTN4, which is near the centromere. Understanding the genetic basis of hybrid breakdown, including the low-tillering habit, will be important for improving varieties in rice breeding.
AaPKAc Regulates Differentiation of Infection Structures Induced by Physicochemical Signals From Pear Fruit Cuticular Wax, Secondary Metabolism, and Pathogenicity of Alternaria alternata
Authors: Zhang Miao , Li Yongcai , Wang Tiaolan , Bi Yang , Li Rong , Huang Yi , Mao Renyan , Jiang Qianqian , Liu Yongxiang , Prusky Dov B.
Published: April 2021

Alternaria alternata, the casual agent of black rot of pear fruit, can sense and respond to the physicochemical cues from the host surface and form infection structures during infection. To evaluate the role of cyclic AMP-dependent protein kinase (cAMP-PKA) signaling in surface sensing of A. alternata, we isolated and functionally characterized the cyclic adenosine monophosphate-dependent protein kinase A catalytic subunit gene (AaPKAc). Gene expression results showed that AaPKAc was strongly expressed during the early stages of appressorium formation on hydrophobic surfaces. Knockout mutants ΔAaPKAc were generated by replacing the target genes via homologous recombination events. We found that intracellular cAMP content increased but PKA content decreased in ΔAaPKAc mutant strain. Appressorium formation and infection hyphae were reduced in the ΔAaPKAc mutant strain, and the ability of the ΔAaPKAc mutant strain to recognize and respond to high hydrophobicity surfaces and different surface waxes was lower than in the wild type (WT) strain. In comparison with the WT strain, the appressorium formation rate of the ΔAaPKAc mutant strain on high hydrophobicity and fruit wax extract surface was reduced by 31.6 and 49.3% 4 h after incubation, respectively. In addition, AaPKAc is required for the hypha growth, biomass, pathogenicity, and toxin production of A. alternata. However, AaPKAc negatively regulated conidia formation, melanin production, and osmotic stress resistance. Collectively, AaPKAc is required for pre-penetration, developmental, physiological, and pathological processes in A. alternata.
Characterization of a High Hierarchical Regulator, PtrGATA12, Functioning in Differentially Regulating Secondary Wall Component Biosynthesis in Populus trichocarpa
Authors: Ren Mengxuan , Zhang Yang , Liu Cong , Liu Yingying , Tian Shuanghui , Cheng He , Zhang Huaxin , Wei Hairong , Wei Zhigang
Published: April 2021

In plants, GATA transcription factors (TFs) have been reported to play vital roles in to a wide range of biological processes. To date, there is still no report about the involvement and functions of woody plant GATA TFs in wood formation. In this study, we described the functional characterization of a Populus trichocarpa GATA TF, PtrGATA12, which encodes a nuclear-localized transcriptional activator predominantly expressing in developing xylem tissues. Overexpression of PtrGATA12 not only inhibited growths of most phenotypic traits and biomass accumulation, but also altered the expressions of some master TFs and pathway genes involved in secondary cell wall (SCW) and programmed cell death, leading to alternated SCW components and breaking forces of stems of transgenic lines. The significant changes occurred in the contents of hemicellulose and lignin and SCW thicknesses of fiber and vessel that increased by 13.5 and 10.8%, and 20.83 and 11.83%, respectively. Furthermore, PtrGATA12 bound directly to the promoters of a battery of TFs and pathway genes and activated them; the binding sites include two cis-acting elements that were specifically enriched in their promoter regions. Taken together, our results suggest PtrGATA12, as a higher hierarchical TF on the top of PtrWND6A, PtrWND6B, PtrMYB152, and PtrMYB21, exert a coordinated regulation of SCW components biosynthesis pathways through directly and indirectly controlling master TFs, middle-level TFs, and further downstream pathway genes of the currently known hierarchical transcription network that governs SCW formation.