bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Study of Square CFST Stub Columns With a Low Steel Ratio Under Axial Loading
Authors: Lu Deren , Gong Yongzhi , Ding Faxing , Wang Liping , Deng Chao , Yuan Tao , Luo Chen , Ren Enhui
Published: April 2021

This paper presents an experimental and numerical study on large dimension concrete-filled square low steel ratio steel tubular (CFST) stub columns under axial loading. Four specimens were designed to investigate the effects of steel ratio on the confinement effect of square CFST stub columns with a low steel ratio. ABAQUS was used to establish 3D finite element (FE) models for simulation of square CFST stub columns with a low steel ratio under axial loading. Furthermore, based on the experimental verification, the definition of the confinement index (ϕ = fsAs/(fcAc)) was discussed and the effect of the grade of concrete and steel tube was also investigated. With the same cross-sectional dimensions, the confinement effect of the square CFST stub columns with a low steel ratio (less than 0.05) was better than the others. The stub columns with the yield strength of steel tube fs = 235 MPa (345, 420 MPa) and compressive cubic strength of concrete fcu = 40 MPa (60, 80 MPa) can give fully demonstrate the material performance and reflect the better confinement effect. Based on the experimental results and FE modeling, a practical calculation formula for the ultimate load-carrying capacity of square CFST stub columns with a low steel ratio was proposed. The formula calculation results presented in this paper show good agreement with the experimental results. Compared with the existing formulas, the proposed formula has better precision.
Low-Cycle Fatigue Life Prediction of 10CrNi3MoV Steel and Undermatched Welds by Damage Mechanics Approach
Authors: Song W. , Liu X. , Xu Jie , Fan Yu , Shi Duanhu , Yang Feng , Xia Xiaolei , Berto F. , Wan Di
Published: April 2021

Welding of steel is a technique frequently used in practical engineering applications; however, their mechanical performance is strongly dependent on the physical metallurgical status of the weldments. In the present study, fully reversed, strain-controlled low-cycle fatigue (LCF) tests were conducted on 10CrNi3MoV steel and its undermatched weldments with strain amplitudes varying from Δε = ±0.5 to ±1.2%. Both base metal and weldments exhibited softening behavior at the beginning of the cyclic stage. Numerical investigations of cyclic stress–strain evolutions of the materials have been studied by the cyclic plastic model considering nonlinear hardening. The continuous damage mechanics (CDM) theory based on the experimental hysteresis stress–strain energy concept was employed to illustrate LCF failure, including damage initiation and deterioration. The damage mechanics approach calibrates the material parameters from the measured fatigue life for initiation and growth stages. Afterward, the combination of material cyclic plastic parameters and damage parameters was implemented to predict the LCF life. Good agreement can be observed between the experimental results and the FE results based on the CDM approach. Finally, the damage evolution of the materials under different strain amplitudes by this approach was assessed.
A Comprehensive Urine Proteome Database Generated From Patients With Various Renal Conditions and Prostate Cancer
Authors: Swensen Adam C. , He Jingtang , Fang Alexander C. , Ye Yinyin , Nicora Carrie D. , Shi Tujin , Liu Alvin Y. , Sigdel Tara K. , Sarwal Minnie M. , Qian Wei-Jun
Published: April 2021

Urine proteins can serve as viable biomarkers for diagnosing and monitoring various diseases. A comprehensive urine proteome database, generated from a variety of urine samples with different disease conditions, can serve as a reference resource for facilitating discovery of potential urine protein biomarkers. Herein, we present a urine proteome database generated from multiple datasets using 2D LC-MS/MS proteome profiling of urine samples from healthy individuals (HI), renal transplant patients with acute rejection (AR) and stable graft (STA), patients with non-specific proteinuria (NS), and patients with prostate cancer (PC). A total of ~28,000 unique peptides spanning ~2,200 unique proteins were identified with a false discovery rate of <0.5% at the protein level. Over one third of the annotated proteins were plasma membrane proteins and another one third were extracellular proteins according to gene ontology analysis. Ingenuity Pathway Analysis of these proteins revealed 349 potential biomarkers in the literature-curated database. Forty-three percentage of all known cluster of differentiation (CD) proteins were identified in the various human urine samples. Interestingly, following comparisons with five recently published urine proteome profiling studies, which applied similar approaches, there are still ~400 proteins which are unique to this current study. These may represent potential disease-associated proteins. Among them, several proteins such as serpin B3, renin receptor, and periostin have been reported as pathological markers for renal failure and prostate cancer, respectively. Taken together, our data should provide valuable information for future discovery and validation studies of urine protein biomarkers for various diseases.
The Effect of Promoter and RBS Combination on the Growth and Glycogen Productivity of Sodium-Dependent Bicarbonate Transporter (SbtA) Overexpressing Synechococcus sp. PCC 7002 Cells
Authors: Gupta Jai Kumar , Srivastava Shireesh
Published: April 2021

Sodium dependent bicarbonate transporter, SbtA is a high-affinity, inducible bicarbonate transporter in cyanobacterial cells. Our previous work has shown that overexpression of this transporter can significantly increase growth and glycogen accumulation in Synechococcus sp. PCC 7002 cells. In this work, we have tested the effect of two different RBS sequences (RBS1: GGAGGA and RBS2: AGGAGA) and three different promoters (PcpcB, PcpcB560, and PrbcL2) on the growth and glycogen production in SbtA-overexpressing Synechococcus sp. PCC 7002 cells. Our results show that PcpcB or PcpcB560 were more effective than PrbcL2 in increasing the growth and glycogen content. The choice of RBS sequence had relatively minor effect, though RBS2 was more effective than RBS1. The transformant E, with PcpcB560 and RBS2, showed the highest growth. The biomass after 5 days of growth on air or 1% CO2 was increased by about 90% in the strain E compared to PCC 7002 cells. All transformants overexpressing SbtA had higher glycogen content. However, growing the cells with bubbling of 1% CO2 did not increase cellular glycogen content any further. The strain E had about 80% higher glycogen content compared to WT PCC 7002 cells. Therefore, the glycogen productivity of the strain E grown with air-bubbling was about 2.5-fold that of the WT PCC 7002 cells grown similarly. Additionally, some of the transformants had higher chlorophyll content while all the transformants had higher carotenoid content compared to the PCC 7002 cells, suggesting interaction between carbon transport and pigment levels. Thus, this work shows that the choice of photosynthetic promoters and RBSs sequences can impact growth and glycogen accumulation in SbtA-overexpressing cells.
De novo Sequencing of Novel Mycoviruses From Fusarium sambucinum: An Attempt on Direct RNA Sequencing of Viral dsRNAs
Authors: Mizutani Yukiyoshi , Uesaka Kazuma , Ota Ayane , Calassanzio Matteo , Ratti Claudio , Suzuki Takamasa , Fujimori Fumihiro , Chiba Sotaro
Published: April 2021

An increasing number of viruses are continuously being found in a wide range of organisms, including fungi. Recent studies have revealed a wide viral diversity in microbes and a potential importance of these viruses in the natural environment. Although virus exploration has been accelerated by short-read, high-throughput sequencing (HTS), and viral de novo sequencing is still challenging because of several biological/molecular features such as micro-diversity and secondary structure of RNA genomes. This study conducted de novo sequencing of multiple double-stranded (ds) RNA (dsRNA) elements that were obtained from fungal viruses infecting two Fusarium sambucinum strains, FA1837 and FA2242, using conventional HTS and long-read direct RNA sequencing (DRS). De novo assembly of the read data from both technologies generated near-entire genomic sequence of the viruses, and the sequence homology search and phylogenetic analysis suggested that these represented novel species of the Hypoviridae, Totiviridae, and Mitoviridae families. However, the DRS-based consensus sequences contained numerous indel errors that differed from the HTS consensus sequences, and these errors hampered accurate open reading frame (ORF) prediction. Although with its present performance, the use of DRS is premature to determine viral genome sequences, the DRS-mediated sequencing shows great potential as a user-friendly platform for a one-shot, whole-genome sequencing of RNA viruses due to its long-reading ability and relative structure-tolerant nature.
Improved Aflatoxins and Fumonisins Forecasting Models for Maize (PREMA and PREFUM), Using Combined Mechanistic and Bayesian Network Modeling—Serbia as a Case Study
Authors: Liu Ningjing , Liu Cheng , Dudaš Tatjana N. , Loc Marta Č. , Bagi Ferenc F. , van der Fels-Klerx H. J.
Published: April 2021

Contamination of maize with aflatoxins and fumonisins is one of the major food safety concerns worldwide. Knowing the contamination in advance can help to reduce food safety risks and related health issues and economic losses. The current study aimed to develop forecasting models for the contamination of maize grown in Serbia with aflatoxins and fumonisins. An integrated modeling approach was used, linking mechanistic modeling with artificial intelligence, in particular Bayesian network (BN) modeling. Two of such combined models, i.e., the prediction model for aflatoxins (PREMA) and for fumonisins (PREFUM) in maize, were developed. Data used for developing PREMA were from 867 maize samples, collected in Serbia during the period from 2012 to 2018, of which 190 were also used for developing PREFUM. Both datasets were split randomly in a model training set and a model validation set. With corresponding geographical and meteorological data, the so-called risk indices for total aflatoxins and total fumonisins were calculated using existing mechanistic models. Subsequently, these risk indices were used as input variables for developing the BN models, together with the longitudes and latitudes of the sites at which the samples were collected and related weather data. PREMA and PREFUM were internally and externally validated, resulting in a prediction accuracy of PREMA of, respectively, 83 and 70%, and of PREFUM of 76% and 80%. The capability of PREMA and PREFUM for predicting aflatoxins and fumonisins contamination using data from the early maize growth stages only was explored as well, and promising results were obtained. The integrated approach combining two different modeling techniques, as developed in the current study, was able to overcome the obstacles of unbalanced data and deficiency of the datasets, which are often seen in historical observational data from the food safety domain. The models provide predictions for mycotoxin contamination at the field level; this information can assist stakeholders of the maize supply chain, including farmers, buyers/collectors, and food safety authorities, to take timely decisions for improved mycotoxin control. The developed models can be further validated by applying them into practice, and they can be extended to other European maize growing areas.
Fungal Toxins and Host Immune Responses
Authors: Brown Rhys , Priest Emily , Naglik Julian R. , Richardson Jonathan P.
Published: April 2021

Fungi are ubiquitous organisms that thrive in diverse natural environments including soils, plants, animals, and the human body. In response to warmth, humidity, and moisture, certain fungi which grow on crops and harvested foodstuffs can produce mycotoxins; secondary metabolites which when ingested have a deleterious impact on health. Ongoing research indicates that some mycotoxins and, more recently, peptide toxins are also produced during active fungal infection in humans and experimental models. A combination of innate and adaptive immune recognition allows the host to eliminate invading pathogens from the body. However, imbalances in immune homeostasis often facilitate microbial infection. Despite the wide-ranging effects of fungal toxins on health, our understanding of toxin-mediated modulation of immune responses is incomplete. This review will explore the current understanding of fungal toxins and how they contribute to the modulation of host immunity.
Effects of Microbial Inoculation and Storage Length on Fermentation Profile and Nutrient Composition of Whole-Plant Sorghum Silage of Different Varieties
Authors: Diepersloot E. Cole , Pupo Matheus R. , Ghizzi Lucas G. , Gusmão Jessica O. , Heinzen Celso , McCary Cody L. , Wallau Marcelo O. , Ferraretto Luiz F.
Published: April 2021

This study aimed to assess the effects of a heterofermentative microbial inoculant and storage length on fermentation profile, aerobic stability, and nutrient composition in whole-plant sorghum silage (WPSS) from different varieties. Experiment 1, a completely randomized design with a 2 × 3 factorial treatment arrangement, evaluated microbial inoculation [CON (50 mL distilled water) or LBLD (Lactobacillus plantarum DSM 21762, L. buchneri DSM 12856, and L. diolivorans DSM 32074; 300,000 CFU/g of fresh forage)] and storage length (14, 28, or 56 d) in forage WPSS. The LBLD silage had lower pH compared to CON, and greater concentrations of succinic acid, ethanol, 1,2-propanediol (1,2-PD), 1-propanol, 2,3-butanediol and total acids. After 56 d, lactic acid concentration was greater for CON, while acetic acid and aerobic stability were greater in LBLD silage. Experiment 2, a completely randomized design with a 2 × 3 factorial treatment arrangement, evaluated effects of microbial inoculation (same as experiment 1) and storage length (14, 28, or 56 d) in WPSS of three varieties [forage sorghum (Mojo Seed, OPAL, Hereford, TX), sorghum-sudangrass (Dyna-gro Seed, Fullgraze II, Loveland, CO, United States), or sweet sorghum (MAFES Foundation Seed Stocks, Dale, MS State, MS)]. The LBLD forage sorghum had greater acetic acid and 1,2-PD concentrations at 56 d and 28 d, respectively, but lower concentrations of propionic acid at 56 d and butyric acid at 14 and 28 d. Additionally, WSC concentration was greater for CON than LBLD at 28 d. Furthermore, CON sweet sorghum had greater lactic acid, propionic acid, and butyric acid concentrations. However, greater acetic acid and 1,2-PD were observed for LBLD sweet sorghum. The CON sweet sorghum had greater concentration of WSC and yeast counts. The CON sorghum sudangrass had greater lactic and butyric acid concentrations than LBLD at 14 d, but lower acetic acid and 1,2-PD concentrations at 56 d. Yeast counts were greater for CON than LBLD sorghum sudangrass silage. Overall, results indicate inoculation of WPSS with Lactobacillus plantarum DSM 21762, L. buchneri DSM 12856, and L. diolivorans DSM 32074 improves heterofermentative co-fermentation allowing the accumulation of acetic acid concentration and increasing antifungal capacities and aerobic stability of WPSS.
Glycans of SARS-CoV-2 Spike Protein in Virus Infection and Antibody Production
Authors: Zhao Xiaohui , Chen Huan , Wang Hongliang
Published: April 2021

Viral protein glycosylation represents a successful strategy employed by the parasite to take advantage of host–cell machinery for modification of its own proteins. The resulting glycans have unneglectable roles in viral infection and immune response. The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which presents on the surface of matured virion and mediates viral entry into the host, also undergoes extensive glycosylation to shield it from the human defense system. It is believed that the ongoing COVID-19 pandemic with more than 90,000,000 infections and 1,900,000 deaths is partly due to its successful glycosylation strategy. On the other hand, while glycan patches on S protein have been reported to shield the host immune response by masking “nonself” viral peptides with “self-glycans,” the epitopes are also important in eliciting neutralizing antibodies. In this review, we will summarize the roles of S protein glycans in mediating virus–receptor interactions, and in antibody production, as well as indications for vaccine development.
Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development
Authors: Li Xin , Wang Yaxi , Ye Xin , Liang Ping
Published: April 2021

Despite the application of antiviral drugs and improved surveillance tools, the number of patients diagnosed with hepatocellular carcinoma (HCC) at an advanced stage and with a dismal prognosis is still on the rise. Systemic treatment with multiple multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib, has been a widely utilized approach for a decade. In addition, the use of a combination of TKIs with other types of compounds, including immune checkpoint inhibitors (ICIs) and antiangiogenic inhibitors, has shown efficacy in treating advanced HCC. However, the presence of intolerable adverse events, low disease response and control rates, and relative short overall survival of such combinatory therapies makes novel or optimized therapies for advance HCC urgently needed. Locoregional therapy (transarterial chemoembolization, and thermal ablation) can destroy primary tumors and decrease tumor burden and is widely used for HCC management. This type of treatment modality can result in local hypoxia and increased vascular permeability, inducing immunogenic effects by releasing tumor antigens from dying cancer cells and producing damage-associated molecular patterns that facilitate antiangiogenic therapy and antitumor immunity. The combination of systemic and locoregional therapies may further produce synergistic effects without overlapping toxicity that can improve prognoses for advanced HCC. In preliminary studies, several combinations of therapeutic modes exhibited promising levels of safety, feasibility, and antitumor effects in a clinical setting and have, thus, garnered much attention. This review aims to provide a comprehensive, up-to-date overview of the underlying mechanisms of combined systemic and locoregional therapies in the treatment of advanced HCC, commenting on both their current status and future direction.
The Vibrio cholerae SpeG Spermidine/Spermine N-Acetyltransferase Allosteric Loop and β6-β7 Structural Elements Are Critical for Kinetic Activity
Authors: Le Van Thi Bich , Tsimbalyuk Sofiya , Lim Ee Qi , Solis Allan , Gawat Darwin , Boeck Paloma , Lim Ee Qing , Renolo Rosselini , Forwood Jade K. , Kuhn Misty L.
Published: April 2021

Polyamines regulate many important biological processes including gene expression, intracellular signaling, and biofilm formation. Their intracellular concentrations are tightly regulated by polyamine transport systems and biosynthetic and catabolic pathways. Spermidine/spermine N-acetyltransferases (SSATs) are catabolic enzymes that acetylate polyamines and are critical for maintaining intracellular polyamine homeostasis. These enzymes belong to the Gcn5-related N-acetyltransferase (GNAT) superfamily and adopt a highly conserved fold found across all kingdoms of life. SpeG is an SSAT protein found in a variety of bacteria, including the human pathogen Vibrio cholerae. This protein adopts a dodecameric structure and contains an allosteric site, making it unique compared to other SSATs. Currently, we have a limited understanding of the critical structural components of this protein that are required for its allosteric behavior. Therefore, we explored the importance of two key regions of the SpeG protein on its kinetic activity. To achieve this, we created various constructs of the V. cholerae SpeG protein, including point mutations, a deletion, and chimeras with residues from the structurally distinct and non-allosteric human SSAT protein. We measured enzyme kinetic activity toward spermine for ten constructs and crystallized six of them. Ultimately, we identified specific portions of the allosteric loop and the β6-β7 structural elements that were critical for enzyme kinetic activity. These results provide a framework for further study of the structure/function relationship of SpeG enzymes from other organisms and clues toward the structural evolution of members of the GNAT family across domains of life.
Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy
Authors: Chen Xin , Dou Q. Ping , Liu Jinbao , Tang Daolin
Published: April 2021

Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.
D-Tagatose Feeding Reduces the Risk of Sugar-Induced Exacerbation of Myocardial I/R Injury When Compared to Its Isomer Fructose
Authors: Durante Mariaconcetta , Sgambellone Silvia , Lucarini Laura , Failli Paola , Laurino Annunziatina , Collotta Debora , Provensi Gustavo , Masini Emanuela , Collino Massimo
Published: April 2021

It is known that fructose may contribute to myocardial vulnerability to ischemia/reperfusion (I/R) injury. D-tagatose is a fructose isomer with less caloric value and used as low-calorie sweetener. Here we compared the metabolic impact of fructose or D-tagatose enriched diets on potential exacerbation of myocardial I/R injury. Wistar rats were randomizedly allocated in the experimental groups and fed with one of the following diets: control (CTRL), 30% fructose-enriched (FRU 30%) or 30% D-tagatose-enriched (TAG 30%). After 24 weeks of dietary manipulation, rats underwent myocardial injury caused by 30 min ligature of the left anterior descending (LAD) coronary artery followed by 24 h′ reperfusion. Fructose consumption resulted in body weight increase (49%) as well as altered glucose, insulin and lipid profiles. These effects were associated with increased I/R-induced myocardial damage, oxidative stress (36.5%) and inflammation marker expression. TAG 30%-fed rats showed lower oxidative stress (21%) and inflammation in comparison with FRU-fed rats. Besides, TAG diet significantly reduced plasmatic inflammatory cytokines and GDF8 expression (50%), while increased myocardial endothelial nitric oxide synthase (eNOS) expression (59%). Overall, we demonstrated that D-tagatose represents an interesting sugar alternative when compared to its isomer fructose with reduced deleterious impact not only on the metabolic profile but also on the related heart susceptibility to I/R injury.
Choriocapillaris Changes Are Correlated With Disease Duration and MoCA Score in Early-Onset Dementia
Authors: Zhang Shuting , Kwapong William Robert , Yang Tang , Liu Peng , Tuo Qingzhang , Cheng Yajun , Li Xue , Liu Ming , Lei Peng , Wu Bo
Published: April 2021

Purpose: Imaging of the choroid may detect the microvascular changes associated with early-onset dementia (EOD) and may represent an indicator for detection of the disease. We aimed to analyze the in vivo choriocapillaris (CC) flow density in EOD patients using optical coherence tomography angiography (OCTA) and evaluate the association with its clinical measures.

Methods: This cross-sectional study used the OCTA to image and analyze the choriocapillaris (CC) of 25 EOD patients and 20 healthy controls. Choriocapillaris flow density in the 3 mm area and 6 mm area was measured by an inbuilt algorithm in the OCT tool. Brain volume using magnetic resonance imaging and cognitive assessment was done and recorded.

Results: Significantly reduced capillary flow density of the choriocapillaris was seen in EOD patients when compared to healthy controls in the 3.0 mm (P = 0.001) and 6.0 mm (P < 0.001) area respectively. Montreal Cognitive Assessment (MoCA) scores in EOD patients positively correlated with choriocapillaris flow density in the 3 mm area (Rho = 0.466, P = 0.021). Disease duration of EOD patients also negatively correlated with choriocapillaris density in the 3 mm area (Rho = −0.497, P = 0.008).

Discussion: Our report suggests that choriocapillaris damage may be a potential indicator of early-onset dementia. Microvascular impairment may be involved in the early phase of dementia without aging playing a role in its impairment.

Clinical Trial Registration: www.ClinicalTrials.gov, ChiCTR2000041386.
Dynamic Change of Lymphocyte-to-Monocyte Is Associated With the Occurrence of POCD After Cardiovascular Surgery: A Prospective Observational Study
Authors: Zhao Qi , Gao Rui , Liu Changliang , Chen Hai , Zhang Xueying , Guan Jing , Xie Xiaoyu , Qiu Yanhua , Cheng Xu , Lv Peilin , Zhu Tao , Chen Chan
Published: April 2021

Objective: Postoperative cognitive dysfunction (POCD) is a common and severe complication of cardiovascular surgery. Lymphocyte-to-monocyte ratio (LMR) has been reported to be an independent predictor of lots of diseases associated with inflammation, but the association between the LMR and POCD is not clear. The present study aimed to investigate the potential value of LMR level to predict POCD in patients undergoing cardiovascular surgery.

Methods: A prospective observational study was performed on the patients diagnosed with heart diseases undergoing cardiovascular surgeries with cardiopulmonary bypass. The leukocyte counts were measured by blood routine examination preoperatively. Then we calculated the LMR by dividing the lymphocyte count by the monocyte count. Neurocognitive functions were assessed 1 day before and 7 days after surgery. Perioperative factors were recorded to explore the relationship between LMR and POCD.

Results: In total, 75 patients finished the whole study, while 34 patients developed POCD. The preoperative LMR level in the POCD group was higher than that in the non-POCD group. A cutoff value of 4.855 was identified to predict POCD occurrence according to ROC curve. The perioperative dynamic change of LMR level in the POCD group was higher than those in the non-POCD group. A cutoff value of 2.255 was identified to predict POCD occurrence according to ROC curve and the dynamic LMR change had similar varying trend with preoperative LMR level.

Conclusions: The dynamic change of LMR level in the peripheral blood is associated with occurrence of POCD, and preoperative LMR level seems to be a prognostic biomarker of postoperative cognitive dysfunction in patients after cardiovascular surgery.
The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory
Authors: Titulaer Joep , Björkholm Carl , Feltmann Kristin , Malmlöf Torun , Mishra Devesh , Bengtsson Gonzales Carolina , Schilström Björn , Konradsson-Geuken Åsa
Published: April 2021

Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.
Geometrical Consistency Modeling on B-Spline Parameter Domain for 3D Face Reconstruction From Limited Number of Wild Images
Authors: Peng Weilong , Su Yong , Tang Keke , Xu Chao , Feng Zhiyong , Fang Meie
Published: April 2021

A number of methods have been proposed for face reconstruction from single/multiple image(s). However, it is still a challenge to do reconstruction for limited number of wild images, in which there exists complex different imaging conditions, various face appearance, and limited number of high-quality images. And most current mesh model based methods cannot generate high-quality face model because of the local mapping deviation in geometric optics and distortion error brought by discrete differential operation. In this paper, accurate geometrical consistency modeling on B-spline parameter domain is proposed to reconstruct high-quality face surface from the various images. The modeling is completely consistent with the law of geometric optics, and B-spline reduces the distortion during surface deformation. In our method, 0th- and 1st-order consistency of stereo are formulated based on low-rank texture structures and local normals, respectively, to approach the pinpoint geometric modeling for face reconstruction. A practical solution combining the two consistency as well as an iterative algorithm is proposed to optimize high-detailed B-spline face effectively. Extensive empirical evaluations on synthetic data and unconstrained data are conducted, and the experimental results demonstrate the effectiveness of our method on challenging scenario, e.g., limited number of images with different head poses, illuminations, and expressions.
Trigeminal Nerve Control of Cerebral Blood Flow: A Brief Review
Authors: White Timothy G. , Powell Keren , Shah Kevin A. , Woo Henry H. , Narayan Raj K. , Li Chunyan
Published: April 2021

The trigeminal nerve, the fifth cranial nerve, is known to innervate much of the cerebral arterial vasculature and significantly contributes to the control of cerebrovascular tone in both healthy and diseased states. Previous studies have demonstrated that stimulation of the trigeminal nerve (TNS) increases cerebral blood flow (CBF) via antidromic, trigemino-parasympathetic, and other central pathways. Despite some previous reports on the role of the trigeminal nerve and its control of CBF, there are only a few studies that investigate the effects of TNS on disorders of cerebral perfusion (i.e., ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury). In this mini review, we present the current knowledge regarding the mechanisms of trigeminal nerve control of CBF, the anatomic underpinnings for targeted treatment, and potential clinical applications of TNS, with a focus on the treatment of impaired cerebral perfusion.
An Immune-Related Gene Pairs Signature Predicts Prognosis and Immune Heterogeneity in Glioblastoma
Authors: Zhang Nijia , Ge Ming , Jiang Tao , Peng Xiaoxia , Sun Hailang , Qi Xiang , Zou Zhewei , Li Dapeng
Published: April 2021

Purpose

Glioblastoma is one of the most aggressive nervous system neoplasms. Immunotherapy represents a hot spot and has not been included in standard treatments of glioblastoma. So in this study, we aim to filtrate an immune-related gene pairs (IRGPs) signature for predicting survival and immune heterogeneity.

Methods

We used gene expression profiles and clinical information of glioblastoma patients in the TCGA and CGGA datasets, dividing into discovery and validation cohorts. IRGPs significantly correlative with prognosis were selected to conduct an IRGPs signature. Low and high risk groups were separated by this IRGPs signature. Univariate and multivariate cox analysis were adopted to check whether risk can be a independent prognostic factor. Immune heterogeneity between different risk groups was analyzed via immune infiltration and gene set enrichment analysis (GSEA). Some different expressed genes between groups were selected to determine their relationship with immune cells and immune checkpoints.

Results

We found an IRGPs signature consisting of 5 IRGPs. Different risk based on IRGPs signature is a independent prognostic factor both in the discovery and validation cohorts. High risk group has some immune positive cells and more immune repressive cells than low risk group by means of immune infiltration. We discovered some pathways are more active in the high risk group, leading to immune suppression, drug resistance and tumor evasion. In two specific signaling, some genes are over expressed in high risk group and positive related to immune repressive cells and immune checkpoints, which indicate aggression and immunotherapy resistance.

Conclusion

We identified a robust IRGPs signature to predict prognosis and immune heterogeneity in glioblastoma patients. Some potential targets and pathways need to be further researched to make different patients benefit from personalized immunotherapy.
First-Generation EGFR-TKI Plus Chemotherapy Versus EGFR-TKI Alone as First-Line Treatment in Advanced NSCLC With EGFR Activating Mutation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Wu Qiang , Luo Wuxia , Li Wen , Wang Ting , Huang Lin , Xu Feng
Published: April 2021

Objective

The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation.

Methods

A systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7th, 2020. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for progress-free survival (PFS) and overall survival (OS). Risk ratio (RR) and Odds ratio (OR) were calculated as effect values for objective response rate (ORR) and toxicity, respectively.

Results

A total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI = 0.50–0.64; P <0.00001) and 0.70 (95% CI = 0.54–0.90; P = 0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P = 0.02) and concurrent therapy (P = 0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10–1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia.

Conclusions

Compared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC. Although increasing incidence of chemotherapy-induced toxicities occurs in the combination group, it is well tolerated and clinically manageable.
PD-1 Inhibition Enhances Blinatumomab Response in a UCB/PDX Model of Relapsed Pediatric B-Cell Acute Lymphoblastic Leukemia
Authors: Wunderlich Mark , Manning Nicole , Sexton Christina , O’Brien Eric , Byerly Luke , Stillwell Cody , Perentesis John P. , Mulloy James C. , Mizukawa Benjamin
Published: April 2021

Immune therapies such as blinatumomab, CD19-directed bispecific CD3 T-cell Engager (BiTE), have resulted in significant improvements in outcomes for relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, up to half of blinatumomab treated patients do not respond completely or relapse after therapy. As a result, there is a need to identify potential strategies to improve the efficacy of BiTE therapy. The anti-PD-1 antibody pembrolizumab has been shown to successfully activate T cells against a wide range of cancer types. Here, we tested the ability of umbilical cord blood (UCB) reconstituted mice to respond to blinatumomab therapy with or without concurrent pembrolizumab treatment. Humanized mice were engrafted with patient-derived xenograft (PDX) cells derived from pediatric and adolescent/young adult (AYA) B-ALL patients who had either failed to achieve remission with negative minimum residual disease (MRD negative) or experienced a relapse. Mock-treated humanized mice engrafted with PDX cells efficiently developed overt disease within 30 days of engraftment of B-ALL. However, single agent therapy with either blinatumomab or pembrolizumab reduced disease burden in engrafted mice, with some mice observed to be MRD negative after the 28-day treatment course. Combination therapy significantly improved the percentage of MRD negative mice and improved long-term survival and cure rates as compared to mice that were given blinatumomab alone. Importantly, no benefits were observed in treated mice that lacked human immune cell reconstitution. These results indicate that UCB-humanized NRGS mice develop activatable immune function, and UCB-humanized PDX leukemia models can be used in preclinical studies to evaluate specificity, efficacy, and cooperativity of immune therapies in B-ALL.
Dynamic Three-Dimensional ADC Changes of Parotid Glands During Radiotherapy Predict the Salivary Secretary Function in Patients With Head and Neck Squamous Carcinoma
Authors: Feng Mei , Yin Qingping , Ren Jing , Wu Fei , Lan Mei , Wang He , Wang Min , Li Lu , Chen Xiaojian , Lang Jinyi
Published: April 2021

Objective

To investigate the changes of three-dimensional apparent diffusion coefficient (3D-ADC) of bilateral parotid glands during radiotherapy for head and neck squamous cell carcinoma (HNSCC) patients and explore the correlations with the radiation dose, volume reduction of parotid gland and the salivary secretary function.

Materials and Methods

60 HNSCC were retrospectively collected in Sichuan cancer hospital. The patients were all received diffusion-weighted imaging (DWI) scan at pre-radiation, the 15th radiation, the 25th radiation and completion of radiation. Dynamic 3D-ADC were measured in different lobes of parotid glands (P1: deep lobe of ipsilateral; P2: superficial lobe of ipsilateral; P3: deep lobe of contralateral; P4: superficial lobe of contralateral), and the 3D-ADC of spinal cord were also recorded. Chewing stimulates test, radionuclide scan and RTOG criteria were recorded to evaluate the salivary secretary function. Pearson analysis was used to assess the correlation between 3D-ADC value, radiation dose, volume change, and salivary secretary function.

Results

The mean 3D-ADC of parotid glands increased. It began to change at the 15th radiation and the mostly increased in P1. However, there was no change for the maximum and minimum 3D-ADC. The 3D-ADC values of spinal cord changes were almost invisible (ratio ≤ 0.03 ± 0.01). The mean 3D-ADC was negatively correlated with the salivary secretary function (r=-0.72) and volume reduction of different lobes of parotid glands (r1=-0.64; r2=-0.61; r3=-0.57; r4=-0.49), but it was positively correlated with the delivered dose (r1 = 0.73; r2 = 0.69; r3 = 0.65; r4 = 0.78).

Conclusion

Dynamic 3D-ADC changes might be a new and early indicator to predict and evaluate the secretary function of parotid glands during radiotherapy.
New Trends in Injection-Based Therapy for Thumb-Base Osteoarthritis: Where Are We and where Are We Going?
Authors: Tenti Sara , Cheleschi Sara , Mondanelli Nicola , Giannotti Stefano , Fioravanti Antonella
Published: April 2021

Thumb-base osteoarthritis (TBOA) is a common condition, mostly affecting post-menopausal women, often inducing a significant impact on quality of life and hand functionality. Despite its high prevalence and disability, the therapeutic options in TBOA are still limited and few have been investigated. Among the pharmacological strategies for TBOA management, it would be worthwhile to mention the injection-based therapy. Unfortunately, its efficacy is still the subject of debate. Indeed, the 2018 update of the European League Against Rheumatism (EULAR) recommendations for the management of hand osteoarthritis (OA) stated that intra-articular (IA) injections of glucocorticoids should not generally be used, but may be considered in patients with painful interphalangeal joints, without any specific mention to the TBOA localization and to other widely used injections agents, such as hyaluronic acid (HA) and platelet-rich plasma (PRP). Even American College of Rheumatology (ACR) experts conditionally recommended against IA HA injections in patients with TBOA, while they conditionally encouraged IA glucocorticoids. However, the recommendations from international scientific societies don’t often reflect the clinical practice of physicians who routinely take care of TBOA patients; indeed, corticosteroid injections are a mainstay of therapy in OA, especially for patients with pain refractory to oral treatments and HA is considered as a safe and effective treatment. The discrepancy with the literature data is due to the great heterogeneity of the clinical trials published in this field: indeed, the studies differ for methodology and protocol design, outcome measures, treatment (different formulations of HA, steroids, PRP, and schedules) and times of follow-up. For these reasons, the current review will provide deep insight into the injection-based therapy for TBOA, with particular attention to the different employed agents, the variety of the schedule treatments, the most common injection techniques, and the obtained results in terms of efficacy and safety. In depth, we will discuss the available literature on corticosteroids and HA injections for TBOA and the emerging role of PRP and other injection agents for this condition. We will consider in our analysis not only randomized controlled trials (RCTs) but also recent pilot or retrospective studies trying to step forward to identify satisfactory management strategies for TBOA.
Tetramethylpyrazine Ameliorates Peritoneal Angiogenesis by Regulating VEGF/Hippo/YAP Signaling
Authors: Zhu Xiaolin , Shan Yun , Yu Manshu , Shi Jun , Tang Lei , Cao Huimin , Sheng Meixiao
Published: April 2021

Angiogenesis of human peritoneal vascular endothelial cells (HPVECs), linked to vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling, is a complication of peritoneal fibrosis (PF). Hippo/YAP signaling interacts with VEGF/VEGFR2 signaling, but the effect on peritoneal angiogenesis and PF has not been studied. We tested VEGF/Hippo/YAP inhibition by tetramethylpyrazine (TMP) in PF mice and HPVECs. This treatment ameliorated peritoneal dialysis (PD)–induced angiogenesis and PF. In mice, PF was associated with upregulation of VEGF, and TMP ameliorated submesothelial fibrosis, perivascular bleeding, and Collagen I abundance. In HPVECs, angiogenesis occurred due to human peritoneal mesothelial cells (HPMCs)–conditioned medium, and TMP alleviated HPVECs migration, tube formation, and YAP nuclear translocation. YAP knockdown PF mouse and HPVEC models were established to further confirm our finding. YAP deletion attenuated the PD-induced or VEGF-induced increase in angiogenesis and PF. The amount of CYR61 and CTGF was significantly less in the YAP knockdown group. To study the possibility that TMP could benefit angiogenesis, we measured the HPVECs migration and tube formation and found that both were sharply increased in YAP overexpression; TMP treatment partly abolished these increases. As well, the amount of VEGFR localized in the trans-Golgi network was lower by double immunofluorescence; VEGFR and its downstream signaling pathways including p-ERK, p-P38, and p-Akt were more in HPVECs with YAP overexpression. Overall, TMP treatment ameliorated angiogenesis, PF, and peritoneum injury. These changes were accompanied by inhibition of VEGF/Hippo/YAP.
Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration
Authors: Maurya Shashank Kumar , Bhattacharya Neetu , Mishra Suman , Bhattacharya Amit , Banerjee Pratibha , Senapati Sabyasachi , Mishra Rajnikant
Published: April 2021

Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.