bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+T cell antitumor immunity
Authors: Li Anqi , Chang Yuzhou , Song No-Joon , Wu Xingjun , Chung Dongjun , Riesenberg Brian P , Velegraki Maria , Giuliani Giuseppe D , Das Komal , Okimoto Tamio , Kwon Hyunwoo , Chakravarthy Karthik B , Bolyard Chelsea , Wang Yi , He Kai , Gatti-Mays Margaret , Das Jayajit , Yang Yiping , Gewirth Daniel T , Ma Qin , Carbone David , Li Zihai
Published: September 2022

Background

Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets.

Methods

We investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer.

Results

We demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using humanLRRC32(encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP+and GARP-cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.

Conclusion

GARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ activation, enhance CD8+T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.
Velocity map imaging and cross sections of Fe(CO)5 for FEBIP applications
Authors: Pintea Maria , Mason Nigel , Tudorovskaya Maria
Published: September 2022

The present paper intends to be a new study of a widely used precursor in nanostructure deposition and FEBID processes with focus on its fragmentation at collisions with low energy electrons. Newer developments in nanotechnology with applications to focused electron beam-induced deposition (FEBID) and extreme ultraviolet lithography (EUVL) based on irradiation-induced chemistry come with advances in the size of the nanostructures at the surface and their flexibility in creating highly complex 3D structures. The deformation in the main structures of the FEBID process characterized by elongation, reduction in diameter of the main structure and the deposition of additional thin layers around the structure, on the substrate, are results of the secondary electrons effect, colliding with energies lower than 20 eV. Fe(CO)5 is one of the most used compounds in FEBID processes as it has a high vaporization pressure and has been shown to provide high-purity deposits (over 90%). This paper combines experiment and simulations to study electron scattering from Fe(CO)5, using Quantemol-N simulations with mass spectroscopy techniques to present the fragmentation pathways and channel distributions for each of the resulting negative ions at low electron energies, while experimental data on dissociative electron attachment make use of the velocity-sliced map imaging (VMI) technique to determine the anions at the incident electron energies. The Quantemol-N simulation package as a standalone is used to study collision processes of low-energy electrons with Fe(CO)5 molecules including elastic, electronic excitation, and dissociative electron attachment (DEA) cross sections for a wide range of process in nuclear industry, medical research and quantum chemistry.

Graphical abstract
WKB approximation with conformable operator
Authors: Al-Masaeed Mohamed , Rabei Eqab M. , Al-Jamel Ahmed
Published: September 2022

In this paper, the Wentzel–Kramers–Brillouin (WKB) method is extended to be applicable for conformable Hamiltonian systems, where the concept of conformable operator with fractional order [Formula: see text] is involved. The WKB approximation for the [Formula: see text]-wave function is derived for potentials which slowly vary in space. Some illustrative examples to demonstrate the method are presented. The quantities of the conformable form are found to be in exact agreement with the corresponding traditional quantities when [Formula: see text].
CONVERGENCE OF DIRICHLET FORMS AND BESOV NORMS ON SCALE IRREGULAR SIERPIŃSKI GASKETS
Authors: GAO JIN , YU ZHENYU , ZHANG JUNDA
Published: September 2022

In this paper, we construct equivalent semi-norms of local and non-local Dirichlet forms on scale irregular Sierpiński gaskets. These fractals are not necessarily self-similar, and have volume doubling Hausdorff measures which are not necessarily Ahlfors regular. We obtain that a sequence of non-local Dirichlet forms converges to a local Dirichlet form, which extends a convergence theorem of Bourgain, Brezis and Mironescu to the scale irregular Sierpiński gaskets for [Formula: see text].
Building a New-Type Power System to Promote Carbon Peaking and Carbon Neutrality in the Power Industry in China
Authors: LIU Changyi , TAN Xin , LIU Yifang
Published: September 2022

Power industry is the largest carbon emission sector in China. Therefore, this industry will play an important role in achieving the carbon peaking and carbon neutrality goals (“dual carbon” goals) for the whole society. For this purpose, it is critical to balance four relationships, i.e. relationship between carbon mitigation and energy security, carbon peaking in the short term and carbon neutrality in the long term, the coordinated carbon mitigation in power industry and other industries, and technical feasibility and economic efficiency. This paper proposes the China’s Energy Interconnection scenario to promote carbon peaking and carbon neutrality of the society, which can be divided into three stages, i.e. peaking carbon emissions before 2030, rapid emission reduction during 2030–2050, and comprehensive carbon neutrality before 2060. It is expected that the power system will achieve zero emissions before other industries and contribute negative emissions afterwards, providing emission space for carbon neutrality in other industries across the society. Looking into the future, China’s electricity demand will continue to grow. Clean energy will become the main power source, the use of coal-fired power will be gradually reduced, and gas-fired power will undertake the function of peak-load regulation. Faster progress will be made in forming an overall grid pattern with ultra-high voltage (UHV) grid as the backbone and featuring “west-to-east and north-to-south power transmission, a balanced energy mix, and transnational power interconnection.” Finally, this paper discusses a new-type of power system characterized by a high proportion of electricity generated from clean energy, high ratio of electric and electronic equipment, and a high proportion of power transmission and reception, together with summer and winter high load periods, and points out the challenges faced by the new-type power system with a high proportion of renewable energy sources in terms of flexibility, safety, and economic efficiency, and proposes corresponding policy recommendations.
Effect of Interconnector Rib on Optimization of SOFC Structural Parameters
Authors: Wang Chen , Li Zheng , He Qijiao , Zhu Meng , Ni Meng
Published: September 2022

Interconnector (IC) is a key component for current collection in solid oxide fuel cell (SOFC) stacks, but leads to uneven distribution of gas (especially O2) and significantly reduces the power density. In this paper, a 3D numerical model is developed to study the effect of interconnector on the optimization of cathode structures of a planar SOFC. After model validation, parametric analyses are conducted to investigate the effects of cathode structural properties on the SOFC performance and temperature distribution, considering the interconnect dimensions and parameter variations along the flow channel. It is found that the interconnector causes more non-uniform distribution of oxygen in the downstream cathode than in the upstream. Increasing porosity or cathode thickness can improve the oxygen uniformity and the cell electrochemical performance especially in the downstream. However, too high porosity (ε > 0.4) or too thick cathode (t
c > 250 μm) can cause significant ohmic or concentration losses, respectively. Besides, gradient porosity can increase the oxygen uniformity (up to 6.5%) and reduce the concentration loss (up to 10.6%) especially under the rib. In addition, a higher temperature region is observed in the cathode area under the channel, while increasing the porosity, the cathode thickness or using gradient porosity all cause a more uniform temperature distribution.
Pathophysiological levels of GDF11 activate Smad2/Smad3 signaling and induce muscle atrophy in human iPSC-derived myocytes
Authors: Honda Mikako , Makino Takumi , Zhao Xiaolin , Matsuto Mariko , Sakurai Hidetoshi , Takahashi Yu , Shimizu Makoto , Sato Ryuichiro , Yamauchi Yoshio
Published: September 2022

Skeletal muscle mass is negatively regulated by several TGF-β superfamily members. Myostatin (MSTN) is the most prominent negative regulator of muscle mass. Recent studies show that in addition to MSTN, GDF11, which shares a high sequence identity with MSTN, induces muscle atrophy in vitro and in vivo at supraphysiological levels, whereas controversy regarding its roles exists. Furthermore, higher circulating GDF11 levels associate with frailty in humans. On the other hand, little is known about the effect of pathophysiological levels of GDF11 on muscle atrophy. Here we seek to determine whether pathophysiological levels of GDF11 are sufficient to activate Smad2/Smad3 signaling and induce muscle atrophy using human iPSC-derived myocytes (hiPSC myocytes). We first show that incubating hiPSC myocytes with pathophysiological concentrations of GDF11 significantly reduces myocyte diameters. We next demonstrate that pathophysiological levels of GDF11 are sufficient to activate Smad2/3 signaling. Finally, we show that pathophysiological levels of GDF11 are capable of inducing the expression of Atrogin-1, an atrophy-promoting E3 ubiquitin ligase and that FOXO1 blockage reverses the GDF11-induced Atrogin-1 expression and atrophic phenotype. Collectively, our results suggest that GDF11 induces skeletal muscle atrophy at the pathophysiological levels through the GDF11-FOXO1 axis.
Development of skeletal muscle atrophy and intermuscular adipose tissue in patients with early breast cancer treated with chemotherapy
Authors: Mallard Joris , Hucteau Elyse , Bender Laura , Charlot Anouk , Debrut Léa , Pflumio Carole , Trensz Philippe , Schott Roland , Favret Fabrice , Pivot Xavier , Hureau Thomas J. , Pagano Allan F.
Published: September 2022

Chemotherapy is a common therapy to treat patients with breast cancer but also leads to skeletal muscle deconditioning. Skeletal muscle deconditioning is multifactorial and intermuscular adipose tissue (IMAT) accumulation is closely linked to muscle dysfunction. To date, there is no clinical study available investigating IMAT development through a longitudinal protocol and the underlying mechanisms remain unknown. Our study was dedicated to investigating IMAT content in patients with early breast cancer who were treated with chemotherapy and exploring the subsequent cellular mechanisms involved in its development. We included 13 women undergoing chemotherapy. Muscle biopsies and ultrasonography assessment were performed before and after chemotherapy completion. Histological and Western blotting analyses were conducted. We found a substantial increase in protein levels of three mature adipocyte markers (perilipin, +901%; adiponectin, +135%; FABP4, +321%; P < 0.05). These results were supported by an increase in oil red O-positive staining (+358%; P < 0.05). A substantial increase in PDGFRα protein levels was observed (+476%; P < 0.05) highlighting an increase in fibro-adipogenic progenitors (FAPs) content. The cross-sectional area of the vastus lateralis muscle fibers substantially decreased (−21%; P < 0.01), and muscle architecture was altered, as shown by a decrease in fascicle length (−15%; P < 0.05) and a decreasing trend in muscle thickness (−8%; P = 0.08). We demonstrated both IMAT development and muscle atrophy in patients with breast cancer who were treated with chemotherapy. FAPs, critical stem cells inducing both IMAT development and skeletal muscle atrophy, also increased, suggesting that FAPs likely play a critical role in the skeletal muscle deconditioning observed in patients with breast cancer who were treated with chemotherapy.
Metalloproteinases in dermal homeostasis
Authors: Kümper Maike , Steinkamp Joy , Zigrino Paola
Published: September 2022

Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including metalloproteinases. The expression and activity of all metalloproteinases are under strict control, and their deregulation is often associated with diseases or chronic conditions, thereby being considered popular targets for developing new therapeutics. This review will highlight metalloproteinases of the MMP and ADAM families with functions in dermal homeostasis and give some insights into the mechanisms regulating their activity and expression. Furthermore, we discuss how the dysregulation of the most prominent family members affects dermal homeostasis by triggering disease development and influencing progression, focusing on cancer and aging. Here, recent discoveries and new approaches that target or exploit metalloproteinase activity in therapy are emphasized. The potential of naturally derived components in regulating metalloproteinase expression and activity in disease is discussed.
Altered cardiac β1 responsiveness in hyperthermic older adults
Authors: Fischer Mads , Moralez Gilbert , Sarma Satyam , MacNamara James P. , Cramer Matthew N. , Huang Mu , Romero Steven A. , Hieda Michinari , Shibasaki Manabu , Ogoh Shigehiko , Crandall Craig G.
Published: September 2022

Compared with younger adults, passive heating induced increases in cardiac output are attenuated by ∼50% in older adults. This attenuated response may be associated with older individuals’ inability to maintain stroke volume through ionotropic mechanisms and/or through altered chronotropic mechanisms. The purpose of this study was to identify the interactive effect of age and hyperthermia on cardiac responsiveness to dobutamine-induced cardiac stimulation. Eleven young (26 ± 4 yr) and 8 older (68 ± 5 yr) participants underwent a normothermic and a hyperthermic (baseline core temperature +1.2°C) trial on the same day. In both thermal conditions, after baseline measurements, intravenous dobutamine was administered for 12 min at 5 µg/kg/min, followed by 12 min at 15 µg/kg/min. Primary measurements included echocardiography-based assessments of cardiac function, gastrointestinal and skin temperatures, heart rate, and mean arterial pressure. Heart rate responses to dobutamine were similar between groups in both thermal conditions ( P > 0.05). The peak systolic mitral annular velocity (S′), i.e., an index of left ventricular longitudinal systolic function, was similar between groups for both thermal conditions at baseline. While normothermic, the increase in S′ between groups was similar with dobutamine administration. However, while hyperthermic, the increase in S′ was attenuated in the older participants with dobutamine ( P < 0.001). Healthy, older individuals show attenuated inotropic, but maintained chronotropic responsiveness to dobutamine administration during hyperthermia. These data suggest that older individuals have a reduced capacity to increase cardiomyocyte contractility, estimated by changes in S′, via β1-adrenergic mechanisms while hyperthermic.
KV4 channels in isolectin B4 muscle dorsal root ganglion neurons of rats with experimental peripheral artery disease: effects of bradykinin B1 and B2 receptors
Authors: Li Qin , Qin Lu , Li Jianhua
Published: September 2022

Muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses are exaggerated during exercise in peripheral artery diseases (PAD). However, the precise signaling pathways and molecular mediators responsible for these abnormal autonomic responses in PAD are poorly understood. Our previous study suggests that A-type voltage-gated K+(KV4) channels regulate the excitability in muscle dorsal root ganglion (DRG) neurons of PAD rats; however, it is still lacking regarding the effects of PAD on characteristics of KV4 currents and engagement of bradykinin (BK) subtype receptors. Thus, we examined KV4 currents in two distinct muscle DRG neurons, namely isolectin B4-positive and B4-negative (IB4+ and IB4−) DRG neurons. IB4+ neurons express receptors for glial cell line-derived neurotrophic factor (GDNF), whereas IB4− DRG neurons are depending on nerve growth factors for survival. Our data showed that current density in muscle DRG neurons of PAD rats was decreased and this particularly appeared in IB4+ DRG neurons as compared with IB4− DRG neurons. We also showed that stimulation of BK B1 and B2 receptors led to a greater inhibitory effect on KV4 currents in IB4+ muscle DRG neurons and siRNA knockdown of KV4 subunit KV4.3 decreased the activity of KV4 currents in IB4+ DRG neurons. In conclusion, our data suggest that limb ischemia and/or ischemia-induced BK inhibit activity of KV4 channels in a subpopulation of the thin fiber muscle afferent neurons depending on GDNF, which is likely a part of signaling pathways involved in the exaggerated blood pressure response during activation of muscle afferent nerves in PAD.
Why is human uterine artery blood flow during pregnancy so high?
Authors: Moore Lorna G. , Wesolowski Stephanie R. , Lorca Ramón A. , Murray Andrew J. , Julian Colleen G.
Published: September 2022

In healthy near-term women, blood flow to the uteroplacental circulation is estimated as 841 mL/min, which is greater than in other mammalian species. We argue that as uterine venous Po2 sets the upper limit for O2 diffusion to the fetus, high uterine artery blood flow serves to narrow the maternal arterial-to-uterine venous Po2 gradient and thereby raise uterine vein Po2. In support, we show that the reported levels for uterine artery blood flow agree with what is required to maintain normal fetal growth. Although residence at high altitudes (>2,500 m) depresses fetal growth, not all populations are equally affected; Tibetans and Andeans have higher levels of uterine artery blood flow than newcomers and exhibit normal fetal growth. Estimates of uterine venous Po2 from the umbilical blood-gas data available from healthy Andean pregnancies indicate that their high levels of uterine artery blood flow are consistent with their reported, normal birth weights. Unknown, however, are the effects on placental gas exchange of the lower levels of uterine artery blood flow seen in high-altitude newcomers or hypoxia-associated pregnancy complications. We speculate that, by widening the maternal artery to uterine vein Po2 gradient, lower levels of uterine artery blood flow prompt metabolic changes that slow fetal growth to match O2 supply.
Identification of Novel Hypoxia Subtypes for Prognosis Based on Machine Learning Algorithms
Authors: Wang Jiawei , Li Tuo , Wei Songquan , Zhao Gengye , Ye Cong , Ma Qiuping , Ma Jinchun , Cheng Xiaoyan
Published: September 2022

Objective. A reduced level or tension or the deprivation of oxygen is termed hypoxia. It is common for tumours to outgrow their natural source of nutrients, which causes hypoxia in some tumour regions. Hypoxia affects ovarian cancer (OC) in several ways. Methods. In this study, the expression patterns of prognostic hypoxia-related genes were curated, and consensus clustering analyses were performed to determine hypoxia subtypes in OC included in The Cancer Genome Atlas cohort. Two hypoxia-related subtypes were observed and considered for further investigation. The analyses of differentially expressed genes (DEGs), gene ontology, mutation, and immune cell infraction were performed to explore the underlying molecular mechanisms. Results. In total, 377 patients with OC were classified into two subgroups based on the subtype of hypoxia. The clinical outcome was considerably poor for patients with hypoxia subtype 2. DEG and protein-protein interaction analyses revealed that the expression levels of CLIP2 and SH3PXD2A were low in OC tissues. Immune cell infarction analysis revealed that the subtypes were associated with the tumour microenvironment (TME). Conclusion. Our findings established the existence of two distinctive, complex, and varied hypoxia subtypes in OC. Findings from the quantitative analysis of hypoxia subtypes in patients improved our understanding of the characteristics of the TME and may facilitate the development of more efficient treatment regimens.
Knockdown MTDH Inhibits Glioma Proliferation and Migration and Promotes Apoptosis by Downregulating MYBL2
Authors: Fu Junqi , Peng Jun , Tu Guolong
Published: September 2022

Glioma is a malignant tumor that often occurs in the adult central nervous system. Metadherin/astrocyte-elevated gene-1 (MTDH) is involved in the development of cancer, but its relationship with glioma remains unclear. This study is aimed at clarifying the role of MTDH in glioma. GEPIA was employed to find the difference of the expression level of MTDH and MYB protooncogene-like 2 (MYBL2) in glioma tissues and normal tissues, and real-time quantitative reverse transcription PCR (qRT-PCR) and western blot (WB) were applied to verify the differential gene expression of MTDH and MYBL2 cells. After knocking down of MTDH, the expressions of forkhead box M1 (FoxM1), MTDH, and MYBL2 were detected by WB cells. Cell counting kit 8 (CCK-8) was used to detect cell proliferation, and flow cytometry was applied to measure cell apoptosis. The transwell assay was utilized to investigate the ability of cell migration and invasion. The results showed that MTDH and MYBL2 were overexpressed in glioma cells compared with normal cells. The knockdown of MTDH would inhibit the expression of MYBL2 through decreasing the expression of FoxM1 and further reduce glioma cell proliferation and cell migration and invasion. The present study showed that knockdown of MTDH inhibits glioma proliferation and migration and promotes apoptosis by downregulating MYBL2, which suggests that MTDH is a potential gene in clinical treatment of glioma.
Mechanism of Salvia miltiorrhiza Bge. for the Treatment of Ischemic Stroke Based on Bioinformatics and Network Pharmacology
Authors: Wu Jiaqi , Li Ming , Li Ang , Ji Xunming
Published: September 2022

Background and Purpose. A large number of pharmacological experiments have proved that many components of Salvia miltiorrhiza Bge. have neuroprotective, anti-inflammatory, and antioxidant effects. Middle cerebral artery occlusion (MCAO) models treated with Salvia miltiorrhiza Bge. can significantly reduce the infarct size and change the pathological morphology of brain tissue. However, not only the internal mechanism but also the material basis is unclear to researchers. Our research aims to elucidate the potential effective material basis and molecular internal mechanism between Salvia miltiorrhiza Bge. and stroke. Methods. In this study, SymMap was used to screen the 50 bioactive scored components and 65 putative targets of Salvia miltiorrhiza Bge., and their targets were standardized using the UniProt platform. The disease targets related to stroke were collected by comparative toxicogenomics database (CTD), GeneCards, and quantitative structure-activity relationships-TargetNet (QSAR-TargetNet). Thereafter, the protein-protein interaction (PPI) network was constructed using the STRING platform and visualized by Cytoscape (3.8.2) software. Then, the Metascape platform was used to analyze the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Cytoscape (3.7.2) software was also used to construct the network of the “herb-component-target-pathway.” We found that Tanshinol B, Tanshinol A, Przewaquinone C, Tanshinone II, and other main components of Salvia miltiorrhiza Bge. may regulate neurotransmitters and neurological function. Therefore, we speculate Salvia miltiorrhiza Bge. has a neuroprotective effect. For further verification, potential core targets (STAT3, MMP2, ESR1, TERT, and MMP9 proteins) for ischemic stroke and core active ingredients (Tanshinol A, Tanshinol B, Tanshinone II A, and Przewaquinone C) for Salvia miltiorrhiza Bge. were further verified by molecular docking. Results. Our findings revealed that Tanshinol A, Tanshinol B, Tanshinone II A, and Przewaquinone C as the main component of Salvia miltiorrhiza Bge. may have a neuroprotective effect against ischemic stroke, which provides a new understanding for the development of therapies for the prevention and treatment of ischemic stroke.
Exploring the Mechanism of Realgar against Esophageal Cancer Based on Ferroptosis Induced by ROS-ASK1-p38 MAPK Signaling Pathway
Authors: Yang Ruyi , Chen Fazhang , Xu Haizhen , Guo Zhanfang , Cao Changxia , Zhang Hongyan , Zhang Changrong
Published: September 2022

Background. Realgar (REA), a Chinese herbal decoction, has been used to treat various tumors and has produced positive outcomes; however, there is a lack of convincing evidence for the treatment of esophageal cancer. The present study aimed to investigate the effects of REA on esophageal cancer (EC) and explore its mechanism. Methods. EC cells Eca109 and KYSE150 were selected for this study, and different groups of treated cells were set up. We studied the inhibition rate and half inhibition concentration (IC50) by CCK-8 method, the clone formation assay was used to detect the clone formation ability, the scratch assay is used to determine the cell migration ability, the Transwell assay was used to detect the cell invasion ability, the protein expressions of E-cadherin, Slug, N-cadherin, ASK1, p38 MAPK, p-p38 MAPK, and GPX4 were determined using Western blot, the mRNA expressions of ASK1 and p38 MAPK were assessed using qRT-PCR, transmission electron microscopy was used to observe the cellular ultrastructure, Prussian blue staining was used to observe the intracellular iron particle distribution, and biochemical analysis of cellular MDA, SOD, GSH, and GPXS activities, flow cytometric analysis of cellular ROS levels, immunofluorescence staining to detect cellular GPX4 expression, and JC-1 method to detect mitochondrial membrane potential were used. Results. REA inhibited the proliferation of Eca109 and KYSE150 cells in a time- and concentration-dependent manner, and REA significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and activated the cellular ferroptosis and ROS-ASK1-p38 MAPK signaling pathways (

P
<
0.05

). Inhibition of activation of the ROS-ASK1-p38 MAPK signaling pathway promoted the inhibition of proliferation, migration, and invasion of Eca109 and KYSE150 cells and the induction of ferroptosis by REA. Conclusion. REA induced ferroptosis and inhibited the migration of EC cells by activating the ROS-ASK1-p38 MAPK signaling pathway.
Evaluation of the Practical Effects of Environmental Measures in the Conservation of Architectural Heritage in Yan’an Based on Recurrent Neural Networks
Authors: Wang Li
Published: September 2022

Yan’an is one of the “two holy places” of the Chinese nation and the Chinese revolution and is one of the first cities of historical and cultural significance and an outstanding tourist city in China, as announced by the state council. The evaluation of the effectiveness of environmental conservation is one of the very important elements of the conservation of Yan’an’s architectural heritage. However, the existing evaluation methods cannot provide new solutions for decision‐making, the meaning of the comprehensive evaluation function is unclear, the naming clarity is low, there is less quantitative data and more qualitative components, and the results are not easily convincing. This paper proposes a method for evaluating the practical effects of environmental class measures in the conservation of Yan’an’s architectural heritage based on recurrent neural networks. The recurrent neural network makes full use of the memory function in the network, considers the causal relationship of the actual effect, and efficiently evaluates the existing measures. In comparison with factor analysis and hierarchical analysis, this paper has greater applicability in evaluating the practical effects of environmental measures in the conservation of Yan’an’s architectural heritage and is basically consistent with the results of the theoretical analysis. It provides a scientific basis for the construction and implementation of environmental measures for the architectural heritage of Yan’an.
Colostomy Delays Cell Loss in the Brain and Improves Juvenile Survival in a Neonatal Rat Model of Hirschsprung’s Disease
Authors: Xie Dan , Du Yitong , Wang Yutao , Croaker Geoffrey David Hain , Wei Zheng Zachory , Song Zan-Min
Published: September 2022

Hirschsprung’s disease is a congenital malformation characterized by the absence of enteric ganglia in the distal intestine and gut obstruction. Our previous study indicates the brain pathology during the disease progression. A subpopulation of Hirschsprung’s disease patients is also associated with anomalies of the central nervous system. In the investigation, we studied a rat model of Hirschsprung’s disease, known as spotting lethal (sl/sl) ETB-/- rats, which carries a spontaneous deletion in endothelin receptor B (human gene name: EDNRB) and manifests a similar phenotype as humans with Hirschsprung’s disease. Homozygous mutant sl/sl rats were successfully rescued from premature death by performing colostomy and dramatically survived to their juvenile age. By the body weight measured, their body growth was not revealed to be significantly different between ETB-/- and wildtype ETB+/+ or heterozygous (+/sl) ETB+/- groups while all underwent the same colostomy. Cell loss was investigated in several brain regions by using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay (TUNEL) in ETB+/+, ETB-/-, and ETB+/- rats. Number of TUNEL-positive cells in the cerebellum and the hippocampus of ETB-/- rats was significantly increased compared with that of the ETB+/+ and ETB+/- rats. TUNEL-positive cells were observed in the molecular layer and granular cell layers of the cerebellum. In contrast, no significant difference in the density of TUNEL-positive cells was revealed in the cerebral cortex. These results suggest that either endothelin receptor B sl mutation or colostomy has predominant lasting effects on the cell survival/loss in the cerebellum and hippocampus of adult ETB-/- rats. Our findings provide the information on cellular changes in the brains of patients with Hirschsprung’s disease due to congenital EDNRB mutation as well as clinically relevant interventions.
Outcomes of Patients with Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil beyond the Second Line: A Multicenter Retrospective Study from Saudi Arabia
Authors: Alghamdi Mohammed , Bazarbashi Shouki , Mahrous Mervat , Alshaer Omar , Mostafa Gad Ahmed , Aseafan Mohamed , Abdelgelil Mai , Alshabi Redhwan Mohammed , Alghanmi Hosam Ali , Naser Nasser Ahmed , Al Hariri Husam , ALHamad Abdulaziz , Al-Saleh Khalid , Abdel-Aziz Nashwa , Elsamany Sherif
Published: September 2022

Background. The outcome of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) beyond the second-line has not been studied in Saudi Arabia. Therefore, this multicenter retrospective analysis was conducted to evaluate the efficacy of FTD/TPI. Methods. This multicenter retrospective analysis included five centers in Saudi Arabia. FTD/TPI was administered to all the patients beyond the oxaliplatin- and irinotecan-based chemotherapy regimens. The electronic medical records were reviewed, and progression-free survival (PFS) and overall survival (OS) were determined. Results. The study included 100 patients with a mean age of

55.4
±
11.8

years. The overall response to FTD/TPI was 4%. The median PFS was 4 months (95% confidence interval (CI) 3.487–4.513), and the median OS was 11 months (95% CI, 9.226–12.771). In a Cox regression analysis of the independent predictors for PFS, advanced stage of the disease (

P
=
0.037

; HR, 2.614; and CI, 1.102–7.524), presence of lymph node metastasis (

P
=
0.018

; HR, 3.664; and 95% CI, 1.187–8.650), and >2 metastatic sites (

P
=
0.020

; HR, 1.723; and 95% CI, 1.089–2.727) were independent factors predicting disease progression. The Cox regression analysis confirmed that

age
≥
55

years (

P
=
0.046

; HR, 1.667; and 95%, 1.097–3.100), advanced disease stage (

P
=
0.044

; HR, 1.283; and 95% CI, 1.035–2.940), prior use of adjuvant chemotherapy (

P
=
0.037

; HR, 0.892; and 95% CI, 0.481–0.994), liver metastasis (

P
=
0.025

; HR, 2.015; and 95% CI, 1.091–3.720), >2 metastatic sites (

P
=
0.038

; HR, 1.248; and 95% CI, 1.036–1.846), development of neutropenia after receiving first cycle of FTD/TPI (

P
=
0.042

; HR, 1.505; and 95% CI, 1.064–2.167), and increased number of FTD/TPI cycles (

P
=
0.002

; HR, 0.769; and 95% CI, 0.664–0.891) were independent variables for OS. Conclusion. Treatment with FTD/TPI is feasible and effective in daily clinical practice in Saudi Arabian patients. The risk of progression increased with advanced disease stage, lymph node metastasis, bone metastasis, and metastasis to >2 sites.

Age
≥
55

years, advanced disease stage, liver metastasis, metastasis to >2 sites, neutropenia after the first cycle of FTD/TPI, and increased number of FTD/TPI cycles were independent factors predicting mortality.
Successful Removal of a Posterior Cardiac Lipoma by Transection of the Ascending Aorta and Main Pulmonary Artery
Authors: Watanabe Saeki , Ichihara Yuki , Morita Kozo , Saito Satoshi , Niinami Hiroshi
Published: September 2022

Primary cardiac tumors are unusual, whereas lipomas are particularly rare. We successfully removed a very large posterior cardiac lipoma by transecting the ascending aorta and main pulmonary artery. Transecting both the ascending aorta and the main pulmonary artery facilitated surgical exposure and complete removal of the posterior cardiac lipoma.
Improvement of K-Means Algorithm and Its Application in Air Passenger Grouping
Authors: Yu Donghua , Dong Shuhua , Yao Shuang
Published: September 2022

The k-means is one of the most popular clustering analysis algorithm and widely used in various fields. Nevertheless, it continues to have some shortcomings, for example, extremely sensitive to the initial center points selection and the special points such as noise or outliers. Therefore, this paper proposed initial center points’ selection optimization and phased assignment optimization to improve the k-means algorithm. The experimental results on 15 real-world and 10 synthetic datasets show that the improved k-means outperforms its main competitor k-means

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and under the same setting conditions, namely, using the default parameters,its clustering performance is better than Affinity Propagation, Mean Shift, and DBSCAN. The proposed algorithm was applied to analyze the airline seat selection data to air passengers grouping. The clustering results, as well as absolute deviation rate analysis, realized customer grouping and found out suitable audience group for the recommendation of seat selection services.
Application of miRNA Biomarkers in Predicting Overall Survival Outcomes for Lung Adenocarcinoma
Authors: Li Tingting , Liu Huanqing , Dong Chunsheng , Lyu Jun
Published: September 2022

Background. With the development of research, the importance of microRNAs (miRNAs) in the occurrence, metastasis, and prognosis of lung adenocarcinoma (LUAD) has attracted extensive attention. This study is aimed at predicting overall survival (OS) results through bioinformatics to identify novel miRNA biomarkers and hub genes. Materials and Methods. The data of LUAD‐related miRNA and mRNA samples was downloaded from The Cancer Genome Atlas (TCGA) database. Upon screening and pretreatment of initial data, TCGA data were analyzed using R platform and a series of analytical tools to identify biomarkers with high specificity and sensitivity. Results. 7 miRNAs and 13 hub genes that had strong relation to the overall surviving status were identified in patients with LUAD. The expression of seven miRNAs (hsa‐miR‐19a‐3p, hsa‐miR‐126‐5p, hsa‐miR‐556‐3p, hsa‐miR‐671‐5p, hsa‐miR‐937‐3p, hsa‐miR‐4664‐3p, and hsa‐miR‐4746‐5p) could apparently improve the OS rate of patient with LUAD. The 13 hub genes, namely, CCT6A, CDK5R1, CEP55, DNAJB4, EGLN3, HDGF, HOXC8, LIMD1, MKI67, PCP4L1, PPIL1, SCAI, and STK32A, showed a correlation with the OS status. Conclusion. 7 miRNAs were identified as novel biomarkers for the prognosis of patients with LUAD. This study offered a deeper comprehension of LUAD treatment and prognosis from the molecular level and helped enhance the understanding of the pathogenesis and potential molecular events of LUAD.
The Influence of Probiotics Consumption on Management of Prediabetic State: A Systematic Review of Clinical Trials
Authors: Zeighamy Alamdary Shabnam , Afifirad Roghayeh , Asgharzadeh Sajjad , Asadollahi Parisa , Mahdizade Ari Marzie , Dashtibin Shirin , Sabaghan Mohamad , Shokouhamiri Mohammad Reza , Ghanavati Roya , Darbandi Atieh
Published: September 2022

Prediabetes consists of the intermediary stage between normal glucose regulation and overt diabetes mellitus and develops when blood glucose levels are higher than normal but not high enough to confirm a type 2 diabetes mellitus diagnosis (T2DM). Recent evidence suggests that probiotics could be promising approaches to improve this state. In this study, we performed a systematic review to compile the results of clinical trials investigating the effects of pro-/pre-/synbiotics on prediabetes subjects from 2010 to 2020. The article search was carried out in Medline, Embase, Scopus, Web of Science, The Cochrane Library, Clinical trials.gov, ProQuest, Open Grey, and Google Scholar. Search filters were developed using 2 parameters: “prestate diabetes” and “probiotics.” Of the 418 studies that were screened, 15 original articles reached the inclusion criteria. Pooling data from these trials showed positive and significant effects of probiotics in the reduction of hyperglycemia, insulin concentration levels, lipid profile, and BMI (Body mass index). Administration of probiotics may provide beneficial and healthful effects in the clinical management of patients with prediabetes and metabolic syndrome. Different probiotics compositions have shown beneficial and noticeable effects on glucose homeostasis, lipid profiles, BMI, and inflammatory markers in subjects with prediabetes, metabolic syndrome, and healthy individuals and could be advantageous in recomposing the gut microbiota back into the normal state during the prediabetic state.
Partial Reconstruction of Uterus Cervix in Rat by Decellularized Human Uterine Cervical Scaffold Combined with Adipose-Derived Stem Cells (ADSCs)
Authors: Li Yuqi , Li Chunbo , Guo Luopei , Liu Xiaotong , Hua Keqin , Zhang Xuyin
Published: September 2022

Surgical management for cervical malformation remains as the main therapeutic challenge for gynecologists. A theoretical alternative is to generate a bioengineered uterus cervix, which requires scaffold structure and appropriate cellular constituents. Here, human uterine cervical tissue was decellularized with detergents to produce an acellular scaffold that retained extracellular matrix (ECM), characterized through histochemical studies and DNA assessments. Recellularized scaffold was then established by decellularized scaffold reseeding with adipose-derived stem cells (ADSCs) isolated from rats. We tested these bioengineering samples in a rat model of partial cervical defect and found that recellularized scaffold improved regeneration abilities of the uterine cervix, promoted better vascularization, and achieved positive pregnancy outcomes. These results suggest that decellularized human uterine cervical scaffold combined with ADSCs could be used for uterine cervical regeneration and provide insights into treatments for cervical malformation.
Microstructure and Properties of Super-Ferritic Stainless Steels Used for Marine Construction after Fire Exposure
Authors: Shen Ke-Yu
Published: September 2022

In this paper, the super-ferritic stainless steels (SFSSs) were simulating treated in a fire accident, and their mechanical properties and corrosion performance before/after fire exposure were studied. The experimental results demonstrated that SFSSs have a good combination property with the tensile strength, total elongation, and corrosion rate in FeCl3 solution of ∼600 MPa, ∼22.5%, and 0.03 mm/a. After fire exposure, the mechanical properties and corrosion performance were affected based on the exposure temperature due to the precipitation of intermetallic compounds. When the fire exposure temperature was 700–800°C, the plasticity was exasperated and the value decreased to only 1.5% at the condition of 800°C × 4 h due to the bulk σ-phase precipitation at grain boundaries. Meanwhile, the brittle fracture patterns emerged, and the corrosion rate in FeCl3 solution increased to 0.4 mm/a. When fire exposure takes place at 600°C for less than 4 h, the mechanical properties and the corrosion performance were little affected. Thus, it was possible to use SFSSs in marine environments.
Study on the Contact Stress Distribution Model of Asphalt Mixture Particles
Authors: Wang Lei , Yang Xiucheng
Published: September 2022

The distribution of contact stress of particles in asphalt mixture could be used to reflect the relationship between the macroscopic mechanical properties and the mesostructure of the material. However, there is no mature method to obtain the internal stress characteristics of asphalt mixture. In this study, the accurate stress distribution and stress transfer state information of particles in asphalt mixture were obtained by using pressure film technology, which provided a good theoretical basis for material gradation design. The pressure film was sandwiched between two Marshall specimens, and the compression part will appear red. After digital processing by software, the total contact area and stress distribution of the two specimens can be obtained. Three kinds of asphalt, three kinds of asphalt pavement gradation, and five kinds of asphalt aggregate ratio were selected to prepare asphalt mixture specimens. The effects of different asphalt, skeleton structure, and asphalt film thickness on the contact characteristics of aggregates were studied. The test results showed that, when the pressure between the two specimens is 0.23 MPa, the contact area of the particles reaches the maximum. The relationship between the contact point distribution probability and the pressure was fitted into a nonlinear curve. The gradation of the mixture, the type of asphalt and the thickness of the asphalt film were used as parameters A, B, and C. The prediction model had a good correlation with the test results. The prediction model proposed in this study could be used to improve the experimental efficiency, save test material and financial resources, as well as get complete contact stress information of the internal particle interface of asphalt mixture.
Modeling the Sustainable Supply Chain Network Design for Food-Agricultural Industries considering Social and Environmental Impacts
Authors: Fesharaki Maryamsadat Hashemi , Safarzadeh Hossein
Published: September 2022

The food supply chain is one of the most sensitive supply chains as it is directly related to the health of humans and society. Therefore, this study aims to evaluate the components of the sustainable supply chain in the food industry. For this purpose, in the first step, several studies and research backgrounds have been conducted by researchers to identify the effective index on sustainability in the food and agricultural supply chain. After reviewing the literature, general indicators of sustainability that affect the agricultural supply chain are specified. Next, by using the fuzzy DEMATEL method, the effectiveness and efficiency of these criteria in three economic, environmental, and social dimensions have been assessed. The results show that in the economic dimension, the use of high technology in the production and the presentation of various citrus forms by using intermediate and conversion industries is the most effective. Criteria for purchasing and using livestock manure instead of using chemical fertilizers have a very high level of effectiveness. In the environmental dimension, reducing or eliminating waste production using recyclable and environmentally friendly materials has the most significant impact. In the social dimension, the positive mental image of customers has a more positive approach to manufacturers who use a sustainable supply chain and has the most impact. The main achievement of this study is that the most important factor in sustainability is the citrus quality control of the agricultural supply chain.
ℒ
-Fuzzy Cosets of
ℒ
-Fuzzy Filters of Residuated Multilattices
Authors: Kengne Pierre Carole , Koguep Njionou Blaise Bleriot , Awouafack Daquin Cèdric , Diékouam Fotso Luc Eméry
Published: September 2022

This paper mainly focuses on building the

ℒ

-fuzzy filter theory of residuated multilattices. Firstly, we introduce the concepts of

ℒ

-fuzzy filter and

ℒ

-fuzzy deductive system of residuated multilattices. Then, we highlight their properties and show how they are linked. Secondly, we introduce the concept of prime

ℒ

-fuzzy filter and propose some illustrative examples. Then, we bring out their properties and show how they are related to the concept of

ℒ

-fuzzy prime filter. Thirdly, we characterize

ℒ

-fuzzy maximal filter and maximal

ℒ

-fuzzy filter by atoms and coatoms. In the case where

ℒ

is a distributive lattice, we prove that maximal

ℒ

-fuzzy filters are prime. Finally, we are interested in

ℒ

-fuzzy cosets of an

ℒ

-fuzzy filter, and we prove that the set of all

ℒ

-fuzzy cosets of any

ℒ

-fuzzy filter of a residuated multilattice is a residuated multilattice.