bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrochemical Evolution and Nitrogen Behaviors in Coastal Groundwater Suffered From Seawater Intrusion and Anthropogenic Inputs
Authors: Dun Yu , Ling Junhong , Wang Rui , Wei Jun , Zhou Qianyi , Cao Yingjie , Zhang Yizhang , Xuan Yingxue
Published: July 2022

Coastal aquifers play key roles in providing freshwater resources to maintain the social and economic development in coastal areas. However, climate change and human activities have dramatically affected the quantities and qualities of groundwater in coastal aquifers. In this study, stoichiometric analysis of hydrogeochemistry, multivariate analysis, and isotopic trancing techniques were used to reveal the local hydrochemistry characteristics, the natural and anthropogenic origins, and the major hydrochemical evolution in a typical coastal aquifer located in the Pearl River estuary. According to hydrogeological conditions and groundwater burial conditions, the aquifer was divided into three zones, namely, semiconfined fissure groundwater (SFGW), recharged fissure groundwater (RFGW), and porous medium groundwater (PGW). Seawater intrusion, ion exchange, water–rock reaction, and human activities were the main controlling factors affecting the characteristics of groundwater, but there were significant differences in the main controlling effects of different zones. Among them, the samples from the SFGW was severely affected by seawater intrusion, and the contributions of seawater ranged from 6% to 97%. Obvious cation exchange process occurred during the seawater intrusion. The hydrochemical characteristics of the PGW and the RFGW were mainly controlled by water–rock interaction. In addition, human activities had further influence on the hydrochemical characteristics of groundwater, which resulted in elevated nitrate–nitrogen (NO3−–N). The mean NO3–N concentrations in the PGW and the SFGW were 6.58 and 3.07 mg/L, respectively. Furthermore, the δ15N–NO3− and δ18O–NO3− values in these two regions ranged from +2.35‰ to +27.54‰ and from +0.39‰ to +18.95‰, respectively, indicating that the anthropogenic input contributed to the increased nitrate. Redox analysis and dual nitrogen isotopic evidence indicated that denitrification was the predominant biogeochemical process in the PGW and the RFGW. This study highlights the impacts of seawater intrusion and anthropogenic inputs on hydrochemical evolution and nitrogen behaviors in coastal groundwater, which provides a scientific basis for the management of groundwater resources in coastal aquifers.
Platelet Count/Spleen Thickness Ratio and the Risk of Variceal Bleeding in Cirrhosis With Esophagogastric Varices
Authors: Liu Huimin , Zhang Qun , Gao Fangyuan , Yu Hao , Jiang Yuyong , Wang Xianbo
Published: July 2022

Introduction

The platelet count/spleen thickness ratio (PC/ST ratio) is associated with the grade of esophagogastric varices (EGV) in cirrhotic patients, but little is known about its relationship with esophagogastric variceal bleeding (EGVB). The aim of this study was to investigate the association between the PC/ST ratio and the risk of EGVB within 1 year in cirrhotic patients.

Methods

A total of 1,354 patients with cirrhosis who had EGV were enrolled in this cohort study. A logistic regression model was used to determine the association between the PC/ST ratio and the risk of EGVB within 1 year in patients with cirrhosis by adjusting the PC/ST ratio with all the important clinical variables and confounders.

Results

The quartile values of the PC/ST ratio were 1.01, 1.36, and 1.98, respectively. The PC/ST ratio was an independent risk factor for variceal bleeding in cirrhotic patients with moderate or severe EGV. After adjusting for multiple variables, the relationship was still unchanged. The odds ratios of the first EGVB in these patients were 5.07-fold at non-adjustment and 3.28-fold after multivariate adjustment. The odds ratios of rebleeding in these patients from the lowest to the highest quartile were 2.34-fold at non-adjustment and 2.01-fold after multivariable adjustment. The PC/ST ratio ≤ 1.36 elevated the 1-year risk of first-time variceal bleeding or rebleeding in cirrhotic patients with moderate or severe EGV (All P < 0.05).

Conclusion

The PC/ST ratio ≤ 1.36 is an independent risk factor for the onset of first bleeding or rebleeding in cirrhotic patients with moderate or severe EGV.
Time-Optimal Adaptation in Metabolic Network Models
Authors: Köbis Markus A. , Bockmayr Alexander , Steuer Ralf
Published: July 2022

Analysis of metabolic models using constraint-based optimization has emerged as an important computational technique to elucidate and eventually predict cellular metabolism and growth. In this work, we introduce time-optimal adaptation (TOA), a new constraint-based modeling approach that allows us to evaluate the fastest possible adaptation to a pre-defined cellular state while fulfilling a given set of dynamic and static constraints. TOA falls into the mathematical problem class of time-optimal control problems, and, in its general form, can be broadly applied and thereby extends most existing constraint-based modeling frameworks. Specifically, we introduce a general mathematical framework that captures many existing constraint-based methods and define TOA within this framework. We then exemplify TOA using a coarse-grained self-replicator model and demonstrate that TOA allows us to explain several well-known experimental phenomena that are difficult to explore using existing constraint-based analysis methods. We show that TOA predicts accumulation of storage compounds in constant environments, as well as overshoot uptake metabolism after periods of nutrient scarcity. TOA shows that organisms with internal temporal degrees of freedom, such as storage, can in most environments outperform organisms with a static intracellular composition. Furthermore, TOA reveals that organisms adapted to better growth conditions than present in the environment (“optimists”) typically outperform organisms adapted to poorer growth conditions (“pessimists”).
Generalized Property-Based Encoders and Digital Signal Processing Facilitate Predictive Tasks in Protein Engineering
Authors: Medina-Ortiz David , Contreras Sebastian , Amado-Hinojosa Juan , Torres-Almonacid Jorge , Asenjo Juan A. , Navarrete Marcelo , Olivera-Nappa Álvaro
Published: July 2022

Computational methods in protein engineering often require encoding amino acid sequences, i.e., converting them into numeric arrays. Physicochemical properties are a typical choice to define encoders, where we replace each amino acid by its value for a given property. However, what property (or group thereof) is best for a given predictive task remains an open problem. In this work, we generalize property-based encoding strategies to maximize the performance of predictive models in protein engineering. First, combining text mining and unsupervised learning, we partitioned the AAIndex database into eight semantically-consistent groups of properties. We then applied a non-linear PCA within each group to define a single encoder to represent it. Then, in several case studies, we assess the performance of predictive models for protein and peptide function, folding, and biological activity, trained using the proposed encoders and classical methods (One Hot Encoder and TAPE embeddings). Models trained on datasets encoded with our encoders and converted to signals through the Fast Fourier Transform (FFT) increased their precision and reduced their overfitting substantially, outperforming classical approaches in most cases. Finally, we propose a preliminary methodology to create de novo sequences with desired properties. All these results offer simple ways to increase the performance of general and complex predictive tasks in protein engineering without increasing their complexity.
The Role of Extracellular Loops in the Folding of Outer Membrane Protein X (OmpX) of Escherichia coli
Authors: Hermansen Simen , Ryoo David , Orwick-Rydmark Marcella , Saragliadis Athanasios , Gumbart James C. , Linke Dirk
Published: July 2022

The outer membrane of Gram-negative bacteria acts as an additional diffusion barrier for solutes and nutrients. It is perforated by outer membrane proteins (OMPs) that function most often as diffusion pores, but sometimes also as parts of larger cellular transport complexes, structural components of the cell wall, or even as enzymes. These OMPs often have large loops that protrude into the extracellular environment, which have promise for biotechnological applications and as therapeutic targets. Thus, understanding how modifications to these loops affect OMP stability and folding is critical for their efficient application. In this work, the small outer membrane protein OmpX was used as a model system to quantify the effects of loop insertions on OMP folding and stability. The insertions were varied according to both hydrophobicity and size, and their effects were determined by assaying folding into detergent micelles in vitro by SDS-PAGE and in vivo by isolating the outer membrane of cells expressing the constructs. The different insertions were also examined in molecular dynamics simulations to resolve how they affect OmpX dynamics in its native outer membrane. The results indicate that folding of OMPs is affected by both the insert length and by its hydrophobic character. Small insertions sometimes even improved the folding efficiency of OmpX, while large hydrophilic inserts reduced it. All the constructs that were found to fold in vitro could also do so in their native environment. One construct that could not fold in vitro was transported to the OM in vivo, but remained unfolded. Our results will help to improve the design and efficiency of recombinant OMPs used for surface display.
Quantity as a Fish Views It: Behavior and Neurobiology
Authors: Messina Andrea , Potrich Davide , Perrino Matilde , Sheardown Eva , Miletto Petrazzini Maria Elena , Luu Peter , Nadtochiy Anna , Truong Thai V. , Sovrano Valeria Anna , Fraser Scott E. , Brennan Caroline H. , Vallortigara Giorgio
Published: July 2022

An ability to estimate quantities, such as the number of conspecifics or the size of a predator, has been reported in vertebrates. Fish, in particular zebrafish, may be instrumental in advancing the understanding of magnitude cognition. We review here the behavioral studies that have described the ecological relevance of quantity estimation in fish and the current status of the research aimed at investigating the neurobiological bases of these abilities. By combining behavioral methods with molecular genetics and calcium imaging, the involvement of the retina and the optic tectum has been documented for the estimation of continuous quantities in the larval and adult zebrafish brain, and the contributions of the thalamus and the dorsal-central pallium for discrete magnitude estimation in the adult zebrafish brain. Evidence for basic circuitry can now be complemented and extended to research that make use of transgenic lines to deepen our understanding of quantity cognition at genetic and molecular levels.
The serotonergic system dysfunction in diabetes mellitus
Authors: Cai Yan , Li Xiaolong , Zhou Hongli , Zhou Jiyin
Published: July 2022

Most peripheral serotonin (5-HT) is synthesized in enterochromaffin cells, and most circulating 5-HT is stored in platelets. As a monoamine, 5-HT has several functions in various non-neuronal and neuronal systems. In the central nervous system, it functions as a neurotransmitter to modulate feeding behavior and mood. Numerous clinical trials have focused on increasing 5-HT activation in the central nervous system, including those involving anti-obesity drugs currently in the market, although severe side effects on peripheral system can lead to the withdrawal of certain drugs. Recent studies have revealed that both the peripheral and central serotonergic systems play a vital role in diabetes and its complications. This review summarizes the roles of the serotonergic system in blood glucose regulation, diabetic macroangiopathy, diabetic peripheral neuropathy, and diabetic encephalopathy, indicating its potential clinical significance as a therapeutic target for the treatment of diabetes and its complications.
Developing an Asymmetry Method for Detecting Postictal Hyperperfusion in Poststroke Epilepsy
Authors: Fukuma Kazuki , Tanaka Tomotaka , Takaya Shigetoshi , Tojima Maya , Kobayashi Katsuya , Shimotake Akihiro , Morita Yoshiaki , Nishimura Kunihiro , Koga Masatoshi , Toyoda Kazunori , Matsumoto Riki , Takahashi Ryosuke , Ikeda Akio , Ihara Masafumi
Published: July 2022

Using dual single-photon emission computed tomography (SPECT) scanning, we recently found the postictal-interictal (P-I) subtraction method frequently detects prolonged postictal hyperperfusion in poststroke epilepsy (PSE) and thus may be valuable for auxiliary diagnosis. This study aimed to determine if the asymmetry method can localize hyperperfusion to reflect epileptic activity in PSE using a single postictal SPECT scan. Sixty-four patients with PSE who had undergone perfusion SPECT two times (postictal and interictal) were enrolled. We formulated a novel asymmetry method (subtraction analysis of reversed postictal SPECT from postictal SPECT, co-registered to magnetic resonance imaging) to identify paradoxical asymmetric increase, defined as a higher perfusion area adjacent to stroke lesions compared to the contralateral side. The postictal hyperperfusion area and detection rates were determined by the asymmetry and P-I subtraction methods independently. We subsequently calculated the sensitivity and specificity of the asymmetry method, compared to the gold standard P-I subtraction method. We also evaluated lateralization concordance between the asymmetry method and other clinical findings. Among 64 patients (median age, 75 years), prolonged postictal hyperperfusion was detected in 43 (67%) by the asymmetry, and 54 (84%) the P-I, method. The asymmetry method had high sensitivity (80%) and specificity (100%) in detecting postictal hyperperfusion, showing high lateralization concordance with seizure semiology (97%) and epileptiform electroencephalography findings (interictal/ictal epileptiform discharges or periodic discharges) (100%). The present study demonstrated the advantages of the objective asymmetry method for detecting prolonged hyperperfusion through using one postictal SPECT scan in PSE.
A Brief Overview on BDNF-Trk Pathway in the Nervous System: A Potential Biomarker or Possible Target in Treatment of Multiple Sclerosis?
Authors: Schirò Giuseppe , Iacono Salvatore , Ragonese Paolo , Aridon Paolo , Salemi Giuseppe , Balistreri Carmela Rita
Published: July 2022

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)–tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target.
Nimodipine vs. Milrinone – Equal or Complementary Use? A Retrospective Analysis
Authors: Jentzsch Jennifer , Ziganshyna Svitlana , Lindner Dirk , Merkel Helena , Mucha Simone , Schob Stefan , Quäschling Ulf , Hoffmann Karl-Titus , Werdehausen Robert , Halama Dirk , Gaber Khaled , Richter Cindy
Published: July 2022

Background

Cerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy.

Methods

We searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months.

Results

Between 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia.

Conclusions

The monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.
Do emotions influence safe browsing? Toward an electroencephalography marker of affective responses to cybersecurity notifications
Authors: Conrad Colin D. , Aziz Jasmine R. , Henneberry Jonathon M. , Newman Aaron J.
Published: July 2022

Cybersecurity notifications play an important role in encouraging users to use computers safely. Emotional reactions to such notifications are known to positively influence users’ adherence to these notifications, though it is challenging for researchers to identify and quantify users’ emotional reactions. In this study, we explored electroencephalography (EEG) signals that were elicited by the presentation of various emotionally charged image stimuli provided by the International Affective Picture System (IAPS) and compared signals to those elicited by images of cybersecurity notifications and other computer-related stimuli. Participants provided behavioral assessments of valence and arousal elicited by the images which were used to cross-reference the results. We found that EEG amplitudes corresponding to the late positive potential (LPP) were elevated in reaction to images of cybersecurity notifications as well as IAPS images known to elicit strong positive and negative valence, when compared to neutral valence or other computer-related stimuli. These findings suggest that the LPP may account for emotional deliberation about cybersecurity notifications, which could be a useful measure when conducting future studies into the role such emotional reactions play in encouraging safe computer behavior.
Homocysteine Levels Are Associated With the Rupture of Intracranial Aneurysms
Authors: Wei Sen , Yuan Xin , Li Dongdong , Guo Xinbin , Guan Sheng , Xu Yuming
Published: July 2022

Background

Homocysteine (Hcy) levels may be associated with the development of intracranial aneurysms (IAs). However, whether it increases the risk of rupture of IAs is unknown. This study aimed to determine the association between homocysteine levels and IA rupture.

Methods

We retrospectively reviewed patients with IAs and subarachnoid hemorrhage (SAH) at our hospital between January 2019 and May 2021. Clinical data, including Hcy levels and IA images, were assessed. The association between Hcy level and IA rupture was investigated using multivariate logistic regression analyses in patients with IAs and SAH.

Results

A total of 589 patients were included. 546 patients with IAs, including 331 UIA (Unruptured IA) and 215 RIA (Ruptured IA). The average age was 57.43 ± 10.86 years old, and 67.03% were women. Among them, all 215 RIAs lead to SAH. In addition, we also enrolled 43 non-aneurysmal subarachnoid hemorrhage (Na-SAH) patients. The average age was 54.12 ± 10.55 years old, and 53.48% were female. After adjusting for confounders in the multivariate model, Hcy levels were correlated with the rupture of IA (odds ratio [OR] 1.069; 95% confidence interval [CI] 1.025–1.114, p = 0.002) and a-SAH (OR 1.083; 95% CI 1.002–1.170, p = 0.046).

Conclusion

Hcy levels were associated with IA rupture. These findings provide novel insights into IAs rupture, and future studies are needed to confirm this relationship.
New Alternatives to Milk From Pulses: Chickpea and Lupin Beverages With Improved Digestibility and Potential Bioactivities for Human Health
Authors: Duarte Carla Margarida , Mota Joana , Assunção Ricardo , Martins Carla , Ribeiro Ana Cristina , Lima Ana , Raymundo Anabela , Nunes Maria Cristiana , Ferreira Ricardo Boavida , Sousa Isabel
Published: July 2022

There is a strong demand for plant-based milk substitutes, often low in protein content (<1.5% w/v). Protein-rich pulse seeds and the right processing technologies make it possible to make relevant choices. The major objective of this study was to assess the impact of processing on the nutritional characteristics of beverages with a high impact on health, in particular on digestibility and specific bioactivities. The results suggest that pulse beverages are as high in protein content (3.24% w/v for chickpea and 4.05% w/v for lupin) as cow’s milk. The anti-nutrient level characteristics of pulses have been considerably reduced by strategic processing. However, when present in small quantities, some of these anti-nutritional factors may have health benefits. Controlling processing conditions play a crucial role in this fine balance as a tool to take advantage of their health benefits. There is evidence of protein hydrolysis by in vitro digestion and limited bioaccessibility of minerals. In addition to being highly digestible, lupin and chickpea beverages have anti-inflammatory and anti-carcinogenic potential evaluated through the inhibition of metalloproteinase MMP-9.
Dynamic Changes in the Human Milk Metabolome Over 25 Weeks of Lactation
Authors: Poulsen Katrine Overgaard , Meng Fanyu , Lanfranchi Elisa , Young Jette Feveile , Stanton Catherine , Ryan C. Anthony , Kelly Alan L. , Sundekilde Ulrik Kraemer
Published: July 2022

Human milk (HM) provides essential nutrition for ensuring optimal infant growth and development postpartum. Metabolomics offers insight into the dynamic composition of HM. Studies have reported the impact of lactation stage, maternal genotype, and gestational age on HM metabolome. However, the majority of the studies have considered changes within the first month of lactation or sampled with large intervals. This leaves a gap in the knowledge of progressing variation in HM composition beyond the first month of lactation. The objective of this study was to investigate whether the HM metabolome from mothers with term deliveries varies beyond 1 month of lactation, during the period in which HM is considered fully mature. Human milk samples (n = 101) from 59 mothers were collected at weeks 1–2, 3–5, 7–9, and 20–25 postpartum and analyzed using 1H nuclear magnetic resonance spectroscopy. Several metabolites varied over lactation and exhibited dynamic changes between multiple time points. Higher levels of HM oligosaccharides, cis-aconitate, O-phosphocholine, O-acetylcarnitine, gluconate, and citric acid were observed in early lactation, whereas later in lactation, levels of lactose, 3-fucosyllactose, glutamine, glutamate, and short- and medium-chain fatty acids were increased. Notably, we demonstrate that the HM metabolome is dynamic during the period of maturity.
Dietary Concentrate-to-Forage Ratio Affects Rumen Bacterial Community Composition and Metabolome of Yaks
Authors: Yi Simeng , Dai Dongwen , Wu Hao , Chai Shatuo , Liu Shujie , Meng Qingxiang , Zhou Zhenming
Published: July 2022

Changes in dietary composition affect the rumen microbiota in ruminants. However, information on the effects of dietary concentrate-to-forage ratio changes on yak rumen bacteria and metabolites is limited. This study characterized the effect of three different dietary concentrate-to-forage ratios (50:50, C50 group; 65:35, C65 group; 80:20, C80 group) on yak rumen fluid microbiota and metabolites using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analyses. Rumen fermentation parameters and the abundance of rumen bacteria were affected by changes in the dietary concentrate-to-forage ratio, and there was a strong correlation between them. At the genus level, higher relative abundances of norank_f__F082, NK4A214_group, Lachnospiraceae_NK3A20_group, Acetitomaculum, and norank_f__norank_o__Clostridia_UCG-014 were observed with a high dietary concentrate-to-forage ratio (P < 0.05). Combined metabolomic and enrichment analyses showed that changes in the dietary concentrate-to-forage ratio significantly affected rumen metabolites related to amino acid metabolism, protein digestion and absorption, carbohydrate metabolism, lipid metabolism, and purine metabolism. Compared with the C50 group, 3-methylindole, pantothenic acid, D-pantothenic acid, and 20-hydroxy-leukotriene E4 were downregulated in the C65 group, while spermine and ribose 1-phosphate were upregulated. Compared to the C50 group, Xanthurenic acid, tyramine, ascorbic acid, D-glucuronic acid, 6-keto-prostaglandin F1a, lipoxin B4, and deoxyadenosine monophosphate were upregulated in the C80 group, while 3-methylindole and 20-hydroxy-leukotriene E4 were downregulated. All metabolites (Xanthurenic acid, L-Valine, N-Acetyl-L-glutamate 5-semialdehyde, N-Acetyl-L-glutamic acid, Tyramine, 6-Keto-prostaglandin F1a, Lipoxin B4, Xanthosine, Thymine, Deoxyinosine, and Uric acid) were upregulated in the C80 group compared with the C65 group. Correlation analysis of microorganisms and metabolites provided new insights into the function of rumen bacteria, as well as a theoretical basis for formulating more scientifically appropriate feeding strategies for yak.
Vacuolating Cytotoxin A Triggers Mitophagy in Helicobacter pylori-Infected Human Gastric Epithelium Cells
Authors: Wang Li , Yi Juan , Yin Xiao-Yang , Hou Jin-Xia , Chen Jing , Xie Bei , Chen Gang , Wang Qun-Feng , Wang Li-Na , Wang Xiao-Yuan , Sun Jing , Huo Lei-Ming , Che Tuan-Jie , Wei Hu-Lai
Published: July 2022

Helicobacter pylori (H. pylori)-derived vacuolating cytotoxin A (VacA) causes damage to various organelles, including mitochondria, and induces autophagy and cell death. However, it is unknown whether VacA-induced mitochondrial damage can develop into mitophagy. In this study, we found that H. pylori, H. pylori culture filtrate (HPCF), and VacA could activate autophagy in a gastric epithelial cell line (GES-1). VacA-caused mitochondrial depolarization retards the import of PINK1 into the damaged mitochondria and evokes mitophagy. And, among mass spectrometry (LC-MS/MS) identified 25 mitochondrial proteins bound with VacA, Tom20, Tom40, and Tom70, TOM complexes responsible for PINK1 import, were further identified as having the ability to bind VacA in vitro using pull-down assay, co-immunoprecipitation, and protein–protein docking. Additionally, we found that the cell membrane protein STOM and the mitochondrial inner membrane protein PGAM5 also interacted with VacA. These findings suggest that VacA captured by STOM forms endosomes to enter cells and target mitochondria. Then, VacA is transported into the mitochondrial membrane space through the TOM complexes, and PGAM5 aids in inserting VacA into the inner mitochondrial membrane to destroy the membrane potential, which promotes PINK1 accumulation and Parkin recruitment to induce mitophagy. This study helps us understand VacA entering mitochondria to induce the mitophagy process.
SETD3 Methyltransferase Regulates PLK1 Expression to Promote In Situ Hepatic Carcinogenesis
Authors: Cheng Meng , Yang Qingmiao , Liu Yafei , Zhao Meng-Jie , Du Xinyuan , Sun Jiaqi , Shu Wen-Jie , Huang Zan , Bi Jianping , Xu Ximing , Du Hai-Ning
Published: July 2022

Background

The development of a new strategy to overcome chemoresistance to hepatocellular carcinoma (HCC) treatment is a long-standing issue. We have previously found that upregulated SETD3 levels are closely correlated with HCC. This study aims to explore the mechanism underlying how upregulation of SETD3 promotes liver carcinogenesis.

Methods

RNA-Sequencing analysis was used to explore the correlation of SETD3 with regulatory targets. In vitro assays including cell proliferation and migration were performed to study the oncogenic roles of SETD3 and PLK1. Western blotting, immunohistochemical staining, and blood biochemical assays were performed to examine protein expression or pathological index in tumor tissues and mice liver tissues. Luciferase reporter system and chromatin immunoprecipitation assays were used to explore the mechanism.

Results

We revealed that SETD3 regulates gene expression in subgroups, including cell division, cell proliferation, and cell cycle, in hepatocellular tumor cells. We found that SETD3 upregulation is associated with elevated PLK1 level in both hepatic tumor cells and clinical liver tissues. We further showed that overexpression of SETD3 promoted tumor cell proliferation and migration, whereas inhibition of PLK1 activity attenuated these phenotypes caused by SETD3. By taking advantage of the Sleep Beauty transposase system, we confirmed that upregulated mouse Setd3 promoted hepatic carcinogenesis in situ, but knockdown of mouse Plk1 mitigated Setd3-promoted tumorigenesis in mice. Mechanistically, we showed that SETD3 could be recruited to the promoter of PLK1 gene to facilitate PLK1 transcription.

Conclusions

Our data demonstrate that elevated SETD3 may promote HCC by enhancing PLK1 expression, which suggests that SETD3 may act as a potential drug target combined with PLK1 inhibition to treat HCC.
Recurrent Novel P2RY8/IGH Translocations in B-Lymphoblastic Leukemia/Lymphoma
Authors: Fang Yanglan , Wang Man , Hu Shuhong , Wang Tanzhen , Liu Yujie , Xiao Jinyan , Cai Yiming , Wang Ying , Qiu Huiying , Tang Xiaowen , Chen Suning , Wu Depei , Xu Yang , Liu Tianhui
Published: July 2022

Translocations involving the immunoglobulin heavy chain (IGH) locus are common abnormalities in B-lymphoblastic leukemia/lymphoma (B-ALL) and multiple myeloma. These rearrangements result in a juxtaposition of IGH enhancers to the vicinity of oncogenes, such as MYC and CRLF2, leading to the upregulation of oncogenes. Here, we identified recurrent novel P2RY8/IGH translocations in three B-ALL patients by transcriptome sequencing. Noncoding exon 1 of P2RY8 was translocated to different sites of the IGH gene, resulting in transcripts of P2RY8/IGHM, P2RY8/IGHV, and P2RY8/IGHD. However, a high expression level of truncated P2RY8 was observed in the patients compared with healthy donors, which might be related to the aggressive clinical course and inferior outcome. In summary, we described recurrent novel P2RY8/IGH translocations with high expression levels of P2RY8, which may contribute to the guidelines for clinical diagnosis and treatment.
Predicting Grade of Esophageal Squamous Carcinoma: Can Stretched Exponential Model-Based DWI Perform Better Than Bi-Exponential and Mono-Exponential Model?
Authors: Yang Hui , Ge Xubo , Zheng Xiuzhu , Li Xiaoqian , Li Jiang , Liu Min , Zhu Jianzhong , Qin Jian
Published: July 2022

Background

To evaluate and compare the potential performance of various diffusion parameters obtained from mono-exponential model (MEM)-, bi-exponential model (BEM)-, and stretched exponential model (SEM)-based diffusion-weighted imaging (DWI) in grading of esophageal squamous carcinoma (ESC).

Methods

Eighty-two patients with pathologically confirmed ESC without treatment underwent multi-b-value DWI scan with 13 b values (0~12,00 s/mm2). The apparent diffusion coefficient (ADC) deriving from the MEM; the pure molecular diffusion (ADCslow), pseudo-diffusion coefficient (ADCfast), perfusion, and fraction (f) deriving from the BEM; and the distributed diffusion coefficient (DDC) and water molecular diffusion heterogeneity index (α) deriving from the SEM were calculated and compared between poorly differentiated and well/moderately differentiated ESC, respectively. The prediction parameters and diagnostic efficiency were compared by drawing receiver operating characteristic (ROC) curves.

Results

The ADC, ADCslow, ADCfast, and DDC in poorly ESC were significantly lower than those in well/moderately differentiated ones. By using only one parameter, ADCslow, DDC had the moderate diagnostic efficiency and the areas under the curve (AUC) were 0.758 and 0.813 in differentiating ESC. The DDC had the maximum AUC with sensitivity (88.00%) and specificity (68.42%). Combining ADC with ADCfast, ADCslow, and DDC and combining ADCslow with ADCfast can provide a higher diagnostic accuracy with AUC ranging from 0.756, 0.771, 0.816, and 0.793, respectively.

Conclusion

Various parameters derived from different DWI models including MEM, BEM, and SEM were potentially helpful in grading ESC. DDC obtained from SEM was the most promising diffusion parameter for predicting the grade of ESC.
Improving the Therapeutic Efficacy of Sorafenib for Hepatocellular Carcinoma by Repurposing Disulfiram
Authors: Zhang Gong , Wang Yufeng , Fuchs Bryan C. , Guo Wei , Drum David L. , Erstad Derek J. , Shi Baomin , DeLeo Albert B. , Zheng Hui , Cai Lei , Zhang Liyuan , Tanabe Kenneth K. , Wang Xinhui
Published: July 2022

Background

Sorafenib, a kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC) but provides only a limited survival benefit. Disulfiram (DSF), a drug for treating alcoholism and a chelator of copper (Cu), forms a complex with Cu (DSF/Cu). DSF/Cu is a potent inducer of autophagic apoptosis of cancer stem cells, which can demonstrate drug resistance. Thus, we hypothesized that DSF/Cu could increase the sensitivity of HCC cells to sorafenib by targeting hepatic cancer stem cells.

Methods

The synergistic effect of DSF/Cu and sorafenib on human HCC cell lines was assessed by cell viability MTT assay. Changes in stemness gene expression in HCC cells were investigated by assessing the presence of hepatic cancer stem cells (HCSCs) (defined as ALDH+ cells) using flow cytometry, sphere formation ability as an index of in vitro tumorigenicity, and expression of stemness gene-encoded proteins by western blot. Autophagic apoptosis and the ERK signaling pathway were also assessed by western blot. Most importantly, the in vivo anti-tumor efficacy of DSF/Cu and sorafenib was tested using orthotopic HCC xenografts in mice.

Results

Compared with sorafenib alone, DSF/Cu + sorafenib synergistically inhibited proliferation of all HCC cell lines, decreased the stemness of HCC cells, and increased the autophagy and apoptosis of HCC cells. The mechanism by which DSF/Cu mediated these phenomena with sorafenib was sustained activation of the ERK pathway. The combination of DSF/Cu (formed with endogenous Cu2+) and sorafenib was significantly more effective than sorafenib alone in inhibiting the growth of orthotopic HCC xenografts in mice. This in vivo anti-tumor efficacy was associated with decreased stemness in treated HCC tumors.

Conclusions

DSF/Cu and sorafenib can synergistically and effectively treat HCC by targeting HCSCs in vitro and in vivo. Our data provide a foundation for clinical translation.
Increased MPO in Colorectal Cancer Is Associated With High Peripheral Neutrophil Counts and a Poor Prognosis: A TCGA With Propensity Score-Matched Analysis
Authors: Weng Meilin , Yue Ying , Wu Dan , Zhou Changming , Guo Miaomiao , Sun Caihong , Liao Qingwu , Sun Minli , Zhou Di , Miao Changhong
Published: July 2022

Background

Myeloperoxidase (MPO) has been demonstrated to be a local mediator of inflammation in tissue damage in various inflammatory diseases. Given its controversial effect on colorectal cancer (CRC), there has been growing interest in investigating the role of this enzyme in CRC. The mechanism underlying MPO activity and CRC progression requires further clarification.

Methods

The expression and function of MPO in CRC were evaluated using TCGA analysis. TCGA, TIMER, and Human Cell Landscape analyses were used to analyze the correlation between MPO expression and neutrophil infiltration in CRC. Spearman’s bivariate correlation analysis was used to verify the correlation between MPO levels in CRC and the peripheral neutrophil count. In the clinical analysis, 8,121 patients who underwent elective surgery for CRC were enrolled in this retrospective cohort study from January 2008 to December 2014. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan–Meier method and Cox regression analysis were used to identify independent prognostic factors in patients with CRC.

Results

MPO was upregulated in CRC tissues, which is related to malignant progression and worse survival in CRC patients from TCGA analysis. MPO was significantly correlated with the infiltration level of neutrophils in CRC in TCGA, TIMER, and Human Cell Landscape analyses. MPO was positively correlated with the peripheral neutrophil count. Data of the 8,121 patients who underwent CRC surgery were available for analysis. After propensity score matching, 3,358 patients were included in each group. Kaplan–Meier survival curves showed that high preoperative neutrophil levels were associated with decreased overall survival (OS; P < 0.001) and disease-free survival (DFS; P = 0.015). The preoperative neutrophil count was an independent risk factor for OS (hazard ratio [HR], 1.157; 95% confidence interval [CI], 1.055–1.268; P = 0.002) and DFS (HR, 1.118; 95% CI, 1.009–1.238; P = 0.033).

Conclusions

Our research indicates that increased MPO levels in CRC are significantly correlated with high preoperative neutrophil counts, and both serve as prognostic indicators for worse survival in CRC patients. Our study suggests that neutrophils may be key players in the mechanism linking MPO levels with poor CRC outcomes.
Multidisciplinary Treatment Strategies for Wilms Tumor: Recent Advances, Technical Innovations and Future Directions
Authors: Theilen Till-Martin , Braun Yannick , Bochennek Konrad , Rolle Udo , Fiegel Henning C. , Friedmacher Florian
Published: July 2022

Significant progress has been made in the management of Wilms tumor (WT) in recent years, mostly as a result of collaborative efforts and the implementation of protocol-driven, multimodal therapy. This article offers a comprehensive overview of current multidisciplinary treatment strategies for WT, whilst also addressing recent technical innovations including nephron-sparing surgery (NSS) and minimally invasive approaches. In addition, surgical concepts for the treatment of metastatic disease, advances in tumor imaging technology and potentially prognostic biomarkers will be discussed. Current evidence suggests that, in experienced hands and selected cases, laparoscopic radical nephrectomy and laparoscopic-assisted partial nephrectomy for WT may offer the same outcome as the traditional open approach. While NSS is the standard procedure for bilateral WT, NSS has evolved as an alternative technique in patients with smaller unilateral WT and in cases with imminent renal failure. Metastatic disease of the lung or liver that is associated with WT is preferably treated with a three-drug chemotherapy and local radiation therapy. However, surgical sampling of lung nodules may be advisable in persistent nodules before whole lung irradiation is commenced. Several tumor markers such as loss of heterozygosity of chromosomes 1p/16q, 11p15 and gain of function at 1q are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with WT. In summary, complete resection with tumor-free margins remains the primary surgical aim in WT, while NSS and minimally invasive approaches are only suitable in a subset of patients with smaller WT and low-risk disease. In the future, advances in tumor imaging technology may assist the surgeon in defining surgical resection margins and additional biomarkers may emerge as targets for development of new diagnostic tests and potential therapies.
Determination of the Relative Potency of Norepinephrine and Phenylephrine Given as Infusions for Preventing Hypotension During Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Up-And-Down Sequential Allocation Study
Authors: Qian Jing , Zhao Yan-Ping , Deng Jia-Li , Wang Li-Zhong , Xiao Fei , Shen Bei , Yao Han-Qing
Published: July 2022

Purpose: The relative potency of norepinephrine and phenylephrine given as boluses to treat hypotension during spinal anesthesia for cesarean delivery has been reported but few data are available for infusions. This study aimed to determine the relative potency of norepinephrine and phenylephrine when given by infusion for preventing hypotension during combined spinal-epidural anesthesia for cesarean delivery.

Methods: This was a prospective, randomized, double-blind, up-and-down sequential allocation study. Patients were randomly allocated to receive a prophylactic infusion of norepinephrine or phenylephrine started immediately after induction of anesthesia. The first patients received either norepinephrine 0.1 μg/kg/min or phenylephrine 0.5 μg/kg/min. An effective infusion rate was defined when no hypotension occurred before delivery. For each subsequent patient, the norepinephrine infusion rate was decreased or increased by 0.01 μg/kg/min or the phenylephrine infusion rate was decreased or increased by 0.05 μg/kg/min according to whether the infusion was effective or ineffective respectively in the previous patient. Values for the infusion rate that was effective in preventing hypotension in 50% of patients (ED50) for norepinephrine and phenylephrine were estimated using up-and-down sequential analysis and relative potency was estimated. Probit regression was used as a backup and sensitivity analysis.

Results: The ED50 values for norepinephrine and phenylephrine calculated by the up-and-down method were 0.061 (95% CI 0.054–0.068) μg/kg/min and 0.368 (95% CI 0.343–0.393) μg/kg/min respectively. The estimated relative potency ratio for ED50 for norepinephrine to phenylephrine was 6.03:1 (95% CI 5.26:1 to 6.98:1).

Conclusion: Under the conditions of this study, norepinephrine given by infusion was about 6 times more potent than phenylephrine. This information is useful for clinical practice and further comparative studies of norepinephrine versus phenylephrine.

Clinical Trial Registration:http://www.chictr.org.cn/showproj.aspx, identifier [ChiCTR2200056237]
Numerical Simulation Study of Hydraulic Fracturing Nozzle Erosion in Deep Well
Authors: Xu Yuqiang , Li Qiandeng , Li Bingshuo , Guan Zhichuan
Published: July 2022

Hydraulic jet fracturing technology is one of the main means to develop low permeability and deep reservoirs. However, due to the large displacement and high sand ratio in the construction process, the erosion wear of high-speed sand particles on the hydraulic jet fracturing nozzle is more serious, which reduces the erosion cutting ability of the nozzle. Therefore, based on Finnie principle, a three-dimensional model of nozzle is established to analyze the influence of internal multiphase flow field distribution, flow rate, sand diameter and etc. on nozzle erosion. The results show that the erosion velocity increases nonlinearly with the increase of inlet pressure. With the increase of erosion time, the erosion rate gradually tends to be stable; with the increase of fluid viscosity, the erosion rate decreases; with the increase of the diameter and mass flow rate of the erosion particles, the erosion speed also increases, indicating that the size and mass flow rate of the erosion particles are the main factors affecting the erosion effect of the nozzle. The research results have important guiding significance for the rational use of the tool and the extension of the service life of the tool.
Transient Localized Rotating Structures in a Suspension of Highly Thermophilic Nanoparticles
Authors: Carpineti Marina , Castellini Stefano , Pogliani Andrea , Vailati Alberto
Published: July 2022

A thermophilic suspension of nanoparticles heated from below exhibits a complex stability diagram determined by the competition between the stabilizing flux of nanoparticles induced by thermophoresis and the destabilizing flux determined by thermal convection. We investigate Rayleigh-Bénard convection in a suspension of highly thermophilic nanoparticles with large negative separation ratio ψ = −3.5 heated from below. We show that transient localized states appear in the range of Rayleigh numbers 2200<Ra<3000. These states rotate rapidly around their axis and gradually shrink in size until the system returns in a purely conductive state. We discuss how these states are originated by the travelling waves arising from the competition between Rayleigh-Bénard convection and the solutal stabilisation of the sample.
Qingchang Wenzhong Decoction Prevents the Occurrence of Intestinal Tumors by Regulating Intestinal Microbiota and Gasdermin E
Authors: Ren Lingli , Zhang Zhengwei , Zhao Wenjing , Zhao Bing , Chen Xi , Wang Yongxiang , Chen Zhong , Ye Juan , Yang Yang , Cao Peng
Published: July 2022

Background: Intestinal tumors are the third most common malignant tumors worldwide, accounting for approximately 10% of all new cancer cases worldwide. Cancer prevention is a promising way to limit the intestinal tumor incidence rate; however, challenges remain. Qingchang Wenzhong decoction (QCWZD) can clinically treat mild to moderate ulcerative colitis symptoms. Moreover, the mechanism by which it prevents intestinal tumors has not been clarified. In this study, we explored the mechanism by which QCWZD prevents the occurrence of intestinal tumors.

Methods: To study the preventive mechanism of QCWZD on intestinal tumors, we used two model mice with azoxymethane/dextran sodium sulfate (AOM/DSS)- and Apcmin/+-induced intestinal tumor formation. The two models exhibited colitis-associated cancer and familial adenomatous polyposis, respectively. Colon and small intestine tissues were collected and analyzed based on histopathology and immunohistochemistry analyses. Fecal samples were collected, and 16S rRNA sequencing was used to analyze the correlation between intestinal microbiota and the prevention of intestinal tumors.

Results: In the AOM/DSS mice, the QCWZD reduced the number and size of tumors, as well as tumor load. Similarly, in the Apcmin/+ mice, QCWZD can also reduce the number of tumors and the tumor load. The results of 16S rRNA sequencing confirmed that QCWZD altered the composition of intestinal microbiota in mice, a phenomenon that may prevent the occurrence of intestinal tumors by aiding the increase in the abundance of beneficial bacteria, such as Ralstonia and Butyricicoccus, and reducing that of pathogenic bacteria, such as Desulfobacterota and Bacteroides, in the intestine. Further, immunohistochemistry reveald that QCWZD can improve the expression of intestinal barrier-related proteins and inhibit pyroptosis-related proteins.

Conclusions: QCWZD has the potential to prevent the occurrence of intestinal tumors. The anti-tumor activity may be achieved by regulating the intestinal microbiota, improving the function of the intestinal barrier, and inhibiting GSDME mediated pyroptosis.