bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Research on Material Removal Mechanism and Grinding Force of FeCoNiCrMo0.1 High Entropy Alloy (HEA)
Authors: Xu Ruchu , Wen Xuelong , Gong Yadong , Yu Xingchen
Published: September 2021

High entropy alloy (HEA) is an advanced alloy material, which has a wide application prospect due to its excellent properties. However, the material removal mechanism and change rule of grinding force of HEA in the grinding process have seldom been studied. The main work of this paper is that the material removal mechanism of the FeCoNiCrMo0.1 HEA is obtained by analyzing grinding debris and subsurface microstructure after grinding, the theoretical grinding force model of HEAs in plane grinding process is established on the basis of the force of a single abrasive grain, and the experimental verification is performed. According to the experimental results, the influences of different grinding parameters on grinding force are discussed, the influences of different types of grinding wheels on grinding force are analyzed, and the grinding forces generated by grinding different FeCoNiCr HEAs are compared. The results indicate that the material removal mechanism of FeCoNiCrMo0.1 HEA is the plastic removal. With the increase of grinding speed and the decrease of grinding depth and feed speed, both normal and tangential grinding forces decrease. Under the same grinding parameters, the grinding force produced by electroplated CBN grinding wheel is greater, followed by resin-bonded CBN grinding wheel and vitrified CBN grinding wheel. The grinding force produced by grinding FeCoNiCrAl0.1 HEA is lower than that produced by grinding FeCoNiCrMo0.1 HEA under the same grinding conditions. The calculated value of grinding force model is consistent with the experimental value, which can scientifically reflect the variation law of HEA grinding force.
Risk of Metastatic Disease Using [18F]PSMA-1007 PET/CT for Primary Prostate Cancer Staging
Authors: Chikatamarla Venkata Avinash , Okano Satomi , Jenvey Peter , Ansaldo Alexander , Roberts Matthew J. , Ramsay Stuart C. , Thomas Paul A. , Pattison David A.
Published: September 2021

Purpose: Accurate prostate cancer imaging is critical for patient management. Multiple studies have demonstrated superior diagnostic accuracy of [68Ga]-PSMA-11 PET/CT over conventional imaging for disease detection, with validated clinical and biochemical predictors of disease detection. More recently [18F]PSMA-1007 offers theoretical imaging advantages, but there is limited evidence of clinical and biochemical predictors of scan findings in the staging population. This study investigates the correlation of clinical variables with imaging characteristics among patients who underwent [18F]PSMA-1007 PET/CT for primary staging of men with histopathologically confirmed prostate carcinoma. Methods: A retrospective review of 194 consecutive patients imaged between May 2019 to May 2020 was performed. Imaging performance (presence and distribution of metastatic disease, primary tumour avidity) was assessed considering clinical variables (EAU risk criteria) with logistic regression and ROC curve analysis. Results: ISUP grade was associated with the presence of metastasis overall (p=0.008) as well as regional nodal (p = 0.003), non-regional nodal (p = 0.041) and bone (p = 0.006) metastases. PSA level was associated with metastatic disease overall (p=0.001), regional (p = 0.001) and non-regional nodal metastases (p = 0.004), but not with bone metastases (p = 0.087). There were too few visceral metastases for meaningful analysis. SUVmax of the primary prostatic tumour was associated with ISUP grade (p = 0.004), PSA level (p < 0.001) and AJCC stage (p = 0.034). PSA > 20 ng/mL and ISUP grade > 3 had a specificity of 85% (95% CI 78-91%) and 60% (95% CI 50-68%), and a sensitivity of 36% (95% CI 25-49%) and 62% (95% CI 49-74%) respectively, for detection of metastatic disease.Conclusion: Metastatic disease according to [18F]PSMA-1007 PET/CT was associated with ISUP grade and PSA level. This is the largest study using [18F]PSMA-1007 PET/CT to confirm a positive correlation of PSA level, ISUP grade and stage with primary prostate tumour SUVmax.
The Absorption Characteristics and the Genetic Response of Beauveria Bassiana Z1 under Cd2+ Stress
Authors: Yu Tiantian , Zhang Lijie , Gao Yanhui , Ma Zhengfa , Zhang Mei , Tan Weiqun , Zhang Lei , Zhang Yunru , Zhao Tiantao
Published: September 2021

Cadmium (Cd2+) has carcinogenic and teratogenic toxicity, which can be accumulated in the human body through the food chain, endangering human health and life. In this study, a fungus named Beauveria bassiana Z1 was isolated and identified to absorb Cd2+, and its Cd2+ absorption rate was 85.1 % when the Cd2+ concentration was 1 mM. Furthermore, the absorption rate of activated strain was significantly higher than that of inactivated, especially with a high Cd2+ concentration. The genetic response results show that the expression of Reactive Oxygen Species (ROS) scavenging enzyme gene and the stress resistance genes (p-type ATP transferase, heavy metal tolerance protein, cytochrome P450) was up-regulated, which was conducive to the ROS removal and heavy metal modification, thereby improving the tolerance of strain Z1 to Cd2+. The research results are of great significance for elucidating the mechanism of fungi for heavy metal, and provide theoretical support for bioremediation of heavy metal pollution.
Oral GLP-1 Analogue Ameliorates Obesity-Induced Diabetes In Db/Db Mouse
Authors: Zhang Hanlin , Dong Meng , Jin Wanzhu
Published: September 2021

Type 2 diabetes is currently experiencing an outbreak worldwide. GLP-1 effectively lowers blood glucose level as an emerging target for the treatment of type 2 diabetes. However, the application of GLP-1 is limited by short half-life and too expensive cost in clinic. In this study we employed the food-grade probiotics as delivery system to express human GLP-1 and its analogue. Recombinant lactococcus lactis could express GLP-1 and analogue in vitro and modified GLP-1 analogue was more resistant to DPP-4 degradation. Oral administration of GLP-1 analogue could reduce the fat mass. More importantly, GLP-1 analogue improved hyperglycemia and insulin resistance in Db/Db mouse although the insulin secretion is not observed in vitro. Our study demonstrates that lactococcus lactis genetically modified with single amino acid mutation could prolong half-life of GLP-1 and increase insulin sensitivity in Db/Db mouse model as an oral drug delivery system driving the development and innovation of drug therapy for type 2 diabetes.
Fuel Gas Production From Self-Sustaining Smouldering Combustion of Lignocellulosic Waste
Authors: Wyn Hons K , Konarova Muxina , Perkins Greg , Yermán Luis
Published: September 2021

Smouldering combustion has shown to be an effective application for soil remediation and as a waste treatment method for solids with high moisture content. The experimental set-up of smouldering combustion reactors is similar to autothermal fixed-bed gasification, updraft reactor configuration. In this study, smouldering experiments were conducted using lignocellulosic agricultural waste. The moisture content of lignocellulosic biomass was varied between 10 % to 50 %. Air flux was varied between 1.8 and 7.4 cm/s. Experiments were also conducted with varying oxygen concentration in the airflow (3.6 – 21 %), addition of sand (4 and 8 g/g) and other lignocellulosic material (wood pellets, and residual berry plant). Fuel gas with maximum H2, CO, CH4, CO2 concentrations of 7.7, 32.6, 2.3, and 57.4 % (N2 free) respectively were obtained with 10 % moisture content and 7.4 cm/s air flux. The smouldering yielded 1.24 Nm3/kgfeed_dry of gas with calorific value of 1.82 MJ/Nm3 (HHV).
The Senescence Difference Between the Central and Peripheral Cornea Induced by Sutures
Authors: Li Suxia , Dong Qiaoqiao , Dong Muchen , Qu Mingli , Wang Yao , zhou Qingjun , Shi Weiyun
Published: September 2021

Introduction: Cell senescence plays a regulatory role in tissue fibrosis, and corneal scarring is usually more severe in the central cornea based on clinical observation. We attempted to explore the senescence difference between the central and peripheral cornea in an in vivo mouse model of suture-induced senescence and an in vitro model of senescence with hydrogen peroxide (H2O2)-induced rabbit corneal fibroblasts. Methods: Male Balb/c mice (6-8 weeks) received sutures in the central, superior, inferior, nasal, and temporal cornea, and the sutures were removed on day 14. Corneal neovascularization (CNV) was observed under a slit lamp microscope with a digital camera. Fibroblasts isolated from central and peripheral rabbit corneas were induced with H2O2 to establish an in vitro model of senescence. The senescence was evaluated with SA-β-gal staining and gene expression analysis of p21, p27, and p53. Results: Senescent cells accumulated in the corneal stroma from day 3 to day 14 after the operation and peaked on day 14, later than CNV. More senescent keratocytes were observed in the peripheral cornea in the mouse model. The peripheral corneal fibroblasts were more likely to become senescent related to H2O2 in vitro. The PCR results revealed that the senescence-related genes, p21, p27, and p53, were all highly expressed in the peripheral corneal fibroblasts. Conclusions: As senescent fibroblasts can limit tissue fibrosis, the senescence difference between the central and peripheral cornea may contribute to the difference in scarring.
The Transcriptome-Wide N6-Methyladenosine (m6A) Map Profiling Reveals the Regulatory Role of m6A in the Yak Ovary
Authors: Guo Shaoke , Wang Xingdong , Cao Mengli , Wu Xiaoyun , Xiong Lin , Bao Pengjia , Chu Min , Liang Chunnian , Yan Ping , Pei Jie , Guo Xian
Published: September 2021

Background and aim: Yak estrus is a seasonal phenomenon, probably involving epigenetic regulation of synthesis and secretion of sex hormones as well as growth and development of follicles. N6-methyladenosine (m6A) is the most common internal modification of the eukaryotic mRNA. However, there are no detailed reports on the m6A transcriptome map of yak ovary. Therefore, this study aimed to collected the yak ovarian tissues at three different states of anestrus (YO-A), estrus (YO-F), and pregnancy (YO-P), and obtained the full transcriptome m6A map in yak by MeRIP-seq. Results: The HE staining revealed that the number of growing follicles and mature follicles in the ovary during the estrus period was relatively higher than those in the estrus period and the pregnancy period. The RT-qPCR showed that the expression of METTL3, METTL14, FTO, YTHDC1 were significantly different across different periods in the ovaries, which suggests that m6A may play a regulatory role in ovarian activity. Next, we identified 20174, 19747 and 13523 m6A peaks in the three ovarian samples of YO-A, YO-F and YO-P using the methylated RNA immunoprecipitation sequencing (MeRIP-seq). The m6A peaks are highly enriched in the coding sequence (CDS) region and 3′untranslated region (3′UTR) as well as the conserved sequence of “RRACH.” Functional analysis revealed the involvement of m6A in many physiological activities of the yak’s ovary during reproductive cycle. The association analysis found that some genes such as BNC1, HOMER1, BMP15, BMP6, GPX3, and WNT11 were related to ovarian functions. Conclusions: The comparison of the distribution patterns of methylation peaks in the ovarian tissues across different periods further explored the m6A markers related to the regulation of ovarian ovulation and follicular development in the yak ovary. This comprehensive map provides a solid foundation for revealing the potential function of the mRNA m6A modification in the yak ovary.
Rifaximin-Mediated Gut Microbiota Regulation Modulates the Polarization of Microglia During CUMS in Rat
Authors: Li Haonan , Xiang Yujiao , Zhu Zemeng , Wang Wei , Jiang Zhijun , Zhao Mingyue , Cheng Shuyue , Pan Fang , Liu Dexiang , Ho Roger , Ho Cyrus
Published: September 2021

Background: Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. Activated M1 microglia can cause pro-inflammatory and neurotoxic effects, while M2 microglia serve anti-inflammatory and neuroprotective functions. The balance between the two phenotypes of microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. We hypothesized that rifaximin exerts an antidepressant effect by changing the abundance of fecal SFCA metabolites and transforming the microglial phenotype. Methods: We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, microglial phenotypic profiles and hippocampal neurogenesis. Results: Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae, which were significantly positively correlated with high levels of butyrate in the brain. Rifaximin also increased the transformation of M1 microglia into the M2 type in the hippocampal dentate gyrus (DG) and ameliorated neurogenic abnormalities and functional deficits caused by CUMS.Conclusions: These results suggest that rifaximin can enhance the neuroprotective effect of microglia to some extent by regulating the gut microbiome and one of its metabolites, butyrate.
The Impact of Atmospheric Rossby Waves and Cyclones On The Arctic Sea Ice Variability
Authors: Hofsteenge Marte Gé , Graversen Rune Grand , Rydsaa Johanne Hope , Rey Zoé
Published: September 2021

The Arctic sea-ice extent has strongly declined over recent decades. A large inter-annual variability is superimposed on this negative trend. Previous studies have emphasised a significant warming effect associated with latent energy transport into the Arctic region, in particular due to an enhanced greenhouse effect associated with the convergence of the humidity transport over the Arctic. The atmospheric energy transport into the Arctic is mostly accomplished by waves such as Rossby waves and cyclones. Here we present a systematic study of the effect on Arctic sea ice of these atmospheric wave types. Through a regression analysis we investigate the coupling between transport anomalies of both latent and dry-static energy and sea-ice anomalies. From the state-of-the-art ERA5 reanalysis product the latent and dry-static transport over the Arctic boundary (70 ºN) is calculated. The transport is then split into transport by planetary and synoptic-scale waves using a Fourier decomposition. The results show that latent energy transport as compared to that of dry-static shows a much stronger potential to decrease sea ice concentration. However, taking into account that the variability of dry-static transport is of an order of magnitude larger than latent, the actual impact on the sea ice appears similar for the two components. In addition, the energy transport by planetary waves causes a strong decline of the sea ice concentration whereas the transport by synoptic-scale waves shows only little effect on the sea ice. The study emphasises the importance of the large-scale waves on the sea ice variability.
Electrochemical Degradation of Reactive Dyes in Textile Industrial Wastewater by Modified Electrodes
Authors: Gezahegn Getasew Yehuala
Published: September 2021

This research was formulated to introduce an electrochemical degradation for the degradation of reactive dyes of the textile industrial wastewater applying a full factorial experimental design. Electrochemical degradation is a green process which immensely reduces the chemical consumption of the wastewater leaving no impurities. Three factors with three-levels were used i.e. the NaCl electrolyte concentrations of 2, 4.5, 5.8 g/L, pH 4.2, 5.8, and 6.9, and reaction time 12.4, 15.5, and 20 min. The experiment was expected to generate 27 runs but due to the Design Expert 12, the number of experimental runs became 20. DC power supply of 14.6 V was used for the electrochemical degradation system whereas chemicals such as nitric acid (400 g/L), sulphuric acid (1.5 mg/L), and oxalic acid solution (100 g/L) were used for surface modification of the electrodes. The textile industrial wastewater was characterized based on the standard method of APHA. Dye, COD, BOD5, and pH of the textile industrial effluent were found to be 0.35 ± 1.00 Abs., 1,711.55 ± 2.00 mg/L, 450.00 ± 3.00 mg/L, and pH of 6.63 ± 0.30, respectively. The maximum color removal was 94.89% at the optimum experimental condition after the results validated by design expert 12. These optimum conditions were the electrolyte concentration 5.1 g/L, pH 6.5, and reaction time 17 min, whereas the minimum color removal of 63.0% was recorded. The regression analysis of the color removal (R2 = 0.95) depicts that electrolyte concentration was the dominant factor for the electrochemical degradation.
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Authors: Shah Kathleen , Maradana Muralidhara Rao , Delas M Joaquina , Metidji Amina , Graelmann Frederike , Llorian Miriam , Chakravarty Probir , Li Ying , Tolaini Mauro , Shapiro Michael , Kelly Gavin , Stockinger Brigitta
Published: September 2021

The aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associated Yap/Tead transcriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.*As a note, Kathleen Shah and Muralidhara Rao Maradana are joint first authors.
Multistakeholder Perspectives on the Mistreatment of Indigenous Women During Childbirth in Colombia: Drivers and Points for Intervention
Authors: Gleason Emily Gaffney , Ríos Jennifer Marcela López , Berrío Diana Patricia Molina , Merino Cristina Mejía
Published: September 2021

Background: Abusive and disrespectful treatment of women during childbirth is a critical global issue that threatens women’s sexual rights and reproductive rights and access to quality maternal care. This phenomenon has been documented in Colombia. However, little emphasis has been placed on identifying the drivers of and potential interventions against disrespect and abuse against particularly vulnerable populations in the country, including internally displaced indigenous women. Methods: This report is a sub-analysis of a larger project. Semi-structured interviews were conducted with indigenous (Embera) women with childbirth experience (n=10), maternal healthcare workers (n=6), and community stakeholders (n=5) in Medellín, Colombia. Qualitative analysis techniques, consisting of inductive and deductive approaches, were used to identify and characterize the drivers of disrespect and abuse against indigenous women during childbirth and points for intervention. Existing frameworks were adapted to thematically organize drivers and potential solutions into four interrelated subsystems: individual and community factors, clinician factors, facility factors, and national health system factors.Results: Participants highlighted risk disrespect and abuse as stemming from (within the individual and community level) its normalization, lack of autonomy and empowerment among indigenous women, lacking antenatal care, (within the clinician level) prejudice, linguistic or cultural barriers to communication, lack of understanding of indigenous culture, medical culture and training, burnout and demoralization, (within the facility level) inadequate infrastructure, space, and human resources, and (within the national systems level) lack of clear policies and the devaluing of respectful maternity care. They called for interventions specific to these drivers, grounded in dignity and respect for indigenous culture.Conclusion: This paper expands upon the growing literature on global mistreatment during childbirth by highlighting drivers of mistreatment and identifying points for intervention in a previously unstudied population. Our data show that indigenous women are especially vulnerable to mistreatment due to cultural and linguistic barriers and prejudice. Broad and meaningful action is urgently needed to realize these women’s rights to respectful maternity care. Interventions must be multifaceted and locally specific, taking into account the needs and wants of the women they serve.
Verification of a Cryptic T(Y;15) Translocation in a Male With an Apparent 45,X Karyotype
Authors: Qin Shengfang , Zhang Zhuo , Chen Ximin , Yin Yan , Ye Mengling , Li-Ling Jesse
Published: September 2021

BackgroundA rare disease is that an individual with a non-chimeric karyotype of 45, X develops into a male. We explored the genetic aetiology of an infertility male with an apparent 45, X karyotype, which was subsequently verified as cryptic translocation between chromosomes Y and 15. MethodsPeripheral blood sample was collected from the patient and subjected to a range of genetic testing, including conventional chromosomal karyotyping, short tandem repeat (STR) analysis for azoospermia factor (AZF) region, fluorescence in situ hybridization (FISH) with specific probes for CSP X/CSP Y, CSP Y/D15Z1/PML and SRY/D15Z1/PML, and chromosomal microarray analysis (CMA) for genomic copy number variations (CNVs). ResultsThe patient was found to have an apparent 45,X karyotype. STR analysis showed that he possessed a short arm of the Y chromosome, including the SRY gene but the absence of a long arm of the Y chromosome, including AZFa+b+c and Yqter. A FISH assay using CSP X and CSP Y probes showed a green signal at the centromere of the X chromosome and a red signal for the Y centromeric sequence on a D-group-sized chromosome. By FISH assaying with D15Z1 and CSP Y probes, chromosomes 15 and Y centromeric signals appeared closely on a single chromosome, as ascertained by the PML control probe. A further FISH assay with D15Z1 and SRY probes revealed a signal of the SRY gene at the end of one arm of chromosome 15. The result of the CMA indicated a deletion with an approximate size of 45.31 Mb spanning from Yq11 to Yter. Conclusion﻿Although the 45,X male patient did not harbour an intact Y chromosome, his genome contained the SRY gene derived from the translocation of the Yp, which probably triggered the male differentiation and development. Imbalanced translocations of Yp to other chromosomes can result in short stature and infertility among patients. Delineation of the genetic aetiology can guide early intervention and assisted reproduction in adulthood.
Synthesis and anticancer activity of two highly water-soluble and ionic Pt(IV) complexes as prodrugs for Pt(II) anticancer drugs
Authors: Gao Anli , Wu Yaxi , Jiang Jing , Gong Hongyu , Yu Juan , Yang Caihong , Liu Weiping , Qing Chen
Published: September 2021

Two new Pt(IV) complexes featuring mesylate as outer sphere anions, cis,trans,cis-[PtCl2(OH2)2 (NH3)2](CH3SO3)2 (SPt-1) and cis,trans,cis-[PtCl2(OH2)2((1R,2R-DACH)](CH3SO3)2 (SPt-2) were synthesized, and characterized by elemental analysis, 1H- and 13C-NMR,IR, and ESI-MS. Both complexes have excellent water-solubility and high molar conductivity as well as good water-stability. They exhibit an irreversible two-electron reduction event with the peak potentials (Ep) for the processes being − 0.39 V and − 0.64 V for SPt-1 and 0.09 V and − 0.52 V for SPt-2. The biological tests reveal that SPt-2 possesses high in vitro anticancer activity against three human cancer cell lines and its overall anticancer activity is slightly greater than that of oxaliplatin, whereas SPt-1 is less active than cisplatin. Moreover, the antitumor efficacy of SPt-2 on human colon carcinoma HCT-116 xenografts in nude mice is also greater than that of oxaliplatin, suggesting SPt-2 deserves further evaluation as a prodrug for oxaliplatin.
Entomological Assessment of the Impact of Long-term Mass Administration of Ivermectin in Onchocerciasis – Endemic Communities in Kaduna State, Nigeria.
Authors: Isiyaku Sunday , Adamani William , Louise Hamill , Ndams Iliya Shehu , Ezekiel Kogi , Kal Alphonsus , Gazama James , Nock Ishaya Haruna
Published: September 2021

Background: Onchocerciasis constitutes a major public health burden in endemic communities and areas because of its dermal and ocular manifestations. Nigeria accounts for the highest burden of the disease globally. Long term mass distribution of ivermectin has been recommended by the World Health Organization as a potent strategy in halting the transmission of the disease in endemic communities.Aim: The aim of this study was to evaluate the prevalence of infective blackflies after 17 years of community-based treatment with ivermectin in two onchocerciasis foci in Kaduna State, Nigeria.Method: Blood seeking female flies were collected using human landing capture from two breeding sites (River Galma and Gurara) in Lere and Kagarko LGAs of Kaduna State in 2010 and 2011. The fly heads and bodies, in pools of 100, were analysed using Polymerase Chain Reaction (PCR)-ELISA specific for O. volvulus DNA. Results: A total of 24,937 blackflies were caught during two-year catching period. The prevalence of infective flies reduced from 0.15% to 0% at River Galma and 0.08% to 0.04% at river Gurara in 2010 and 2011 catching period. Some pools containing the bodies of the flies were also positive for Onchocerca volvulus. Conclusion: The presence of O. volvulus in the heads and bodies of the black flies collected confirmed that there was ongoing transmission of onchocerciasis in Kaduna State, Nigeria during the period of survey. There is continued need for mass distribution of ivermectin in Kaduna in order to halt the transmission.
Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases
Authors: Ho Wing-Hong Jonathan , Law Andrew M. K. , Masle-Farquhar Etienne , Castillo Lesley E. , Mawson Amanda , O’Bryan Moira K. , Goodnow Christopher C. , Ortega David Gallego , Oakes Samantha R. , Ormandy Christopher
Published: September 2021

BackgroundThe interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea mutagenesis we found a mouse with an activating mutation in oligoadenylate synthetase 2 ( Oas2 ), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. MethodsTo determine if activation of Oas2 could alter the course of mammary cancer we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry. ResultsOas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 (PD-L1) was more effective when the Oas2 mutation was present. ConclusionsThese data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy in cases of pregnancy-associated breast cancer and outside of pregnancy in cases showing the lactation and involution-mimicry phenotypes.
Salidroside Alleviates Oxidative Stress and Apoptosis via AMPK/Nrf2 Pathway in DHT-induced Human Granulosa Cell Line KGN
Authors: Ji Rui , Jia Fang-yuan , Chen Xin , Wang Ze-hao , Jin Wen-yi , Yang Jing
Published: September 2021

Background: In the past few years, emerging evidence established persistent oxidative stress to be a key player in the pathogenesis of polycystic ovary syndrome (PCOS). Particularly, it damages the function of granulosa cells, and thus hinders the development of follicles. The present study aimed to explore and establish the protective effects of salidroside on dihydrotestosterone (DHT)‐induced Granulosa‐like tumor cell line (KGN), mediated via antioxidant mechanisms.Methods: KGN cells were treated with DHT as a PCOS cell model, and then incubated with salidroside in different concentrations. Apoptosis and reactive oxygen species (ROS) accumulation were assessed by flow cytometry, mitochondrial membrane potential depolarization and the nuclear translocation of Nrf2 were detected by immunofluorescence staining, and the level of apoptosis-related proteins and antioxidant proteins was assessed by western blotting.Results: Salidroside partly reversed DHT mediated effects, via stimulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway and the downstream antioxidant proteins heme oxygenase‐1(HO‐1) and quinine oxidoreductase 1(NQO1). Additionally, knockdown of Nrf2 resulted in a deterioration in DHT‐induced oxidative stress and apoptosis. It partly moderated the protective effects of salidroside as well. Mechanistically, AMPK was identified to be the upstream signaling involved in salidroside‐induced Nrf2 activation, as silencing of AMPK partly prevented the upregulation of Nrf2 and the downstream proteins HO‐1 and NQO1. Conclusion: The present study is the first to effectively demonstrate the inhibitory effect of salidroside on DHT‐stimulated oxidative stress and apoptosis in KGN cells, which was dependent on Nrf2 activation that involved AMPK.
Dysregulated GLUT1 May Be Involved in the Pathogenesis of Preeclampsia by Impairing Decidualization
Authors: Yang Man , Li Hua , Rong Miaomiao , Zhang Hongya , Hou Linlin , Zhang Cong
Published: September 2021

Background: Preeclampsia (PE), a hypertensive complication in pregnancy, is a major contributor to maternal and fetal morbidity and mortality. Thus far, the molecular mechanism underlying PE has not been investigated thoroughly. Glucose transporter 1 (GLUT1) is a central rate-limiting pump for glucose uptake and subsequent utilization. Our previous RNA-seq results demonstrated it was significantly downregulated in deciduas from severe PE patients. Therefore, we aimed to explore the role of GLUT1 in the occurrence of PE.Methods: In this study, GLUT1 levels were evaluated by quantitative PCR, Western blotting and immunohistochemical staining in severe preeclamptic deciduas. The levels of GLUT1 during decidualization were also studied in human endometrial stromal cells (hESCs). Moreover, the role of GLUT1 during decidualization was studied by GLUT1-siRNA treatment. Furthermore, we explored the regulatory role of miRNA in GLUT1 expression.Results: The expression of GLUT1 was significantly downregulated in the deciduas from severe PE patients. Additionally, the level of GLUT1 was substantially induced in hESCs during in vitro decidualization. Moreover, GLUT1 knockdown significantly reduced the mRNA levels of decidualization markers (IGFBP1 and PRL) and aerobic glycolysis-related genes (LDHA and MCT4), and decreased glucose uptake and lactate production. Furthermore, the levels of apoptotic genes P53, P21 and BAX increased whereas the levels of BCL2 decreased after GLUT1 knockdown. Target prediction results and luciferase analysis showed GLUT1 is one of the targets of miR-140-5p, which is partly responsible for the impaired GLUT1 level. Conclusion: These results demonstrate that GLUT1 exerts pivotal role in human decidualization by participating in glycolysis, and its deficiency may trigger aberrant glycolysis and thus leads to destructive decidualization, which may be a pathogenetic mechanism of PE. These data suggest GLUT1 might be a promising target for PE therapy.
Association of ACE I/D Gene Polymorphism and Related Risk Factors in Impaired Fasting Glucose and Type 2 Diabetes: A Study Among Two Tribal Populations of North-East India.
Authors: RAJKUMARI SUNANDA , NINGOMBAM SOMORJIT SINGH , CHHUNGI VARHLUN , NEWMEI MASAN KAMBO , DEVI NAOREM KIRANMALA , MONDAL PRAKASH RANJAN , Saraswathy Kallur Nava
Published: September 2021

AIMType 2 diabetes is a serious public health concern in India, even the indigenous tribal populations are not felt unaffected. The present study aims to understand the association of major risk factors i.e obesity, hypertension, dyslipidemia, ACE I/D polymorphism with impaired (IFG) and type 2 diabetes (T2D) among two different Mendelian populations of North East India. METHODDemographic, somatometric and physiological variables along with fasting blood samples were collected from 609 individuals. ACE I/D polymorphism was screened. RESULTACE I/D polymorphism was found to follow HWE among Liangmai tribe but not among Mizo tribe. Distribution of DD genotype/D allele was found to be significantly higher for T2D among Mizo (OR 2.10; 95% CI 1.10-4.39, OR 2.10;1.16-4.09 respectively ).Significant association between DD genotype/D allele of ACE I/D polymorphism and TC in both IFG (OR 2.22; 95% CI 1.14-4.32) and T2D (OR 2.53;95%CI 1.51-4.23) were observed . LDL was also found to posed significant risk for IFG (OR 2.10;95% CI 1.10-3.91) and T2D (OR 1.04; 95%CI 1.02-1.06). CONCLUSIONThe present study is an example of gene-environment interaction where DD genotype or D allele and dyslipidemia (high TC and high LDL) are posing risk for IFG and T2D both independently and in combination only among Mizo tribe with relatively less physical activity attributed to their residence in less hilly terrain, but Liangmai tribe which resides in high hilly terrain shows no such association.
Synergistic Sorafenib with Jianpi Huayu Decoction Resulted in Tumor Regression and Prevented Adverse Events in Hepatocellular Carcinoma by Remodeling the Gut Microbiota
Authors: Deng Xue , Xie Yingjie , Lu Yantong , Li Xueyan , Guo Xuan , Zhang Yuan , Lin Juze , Tan Wei , Wang Changjun , Huang Xuhui
Published: September 2021

Background: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Sorafenib is first-line treatment for HCC, which has a modest efficacy due to severe adverse effects(AE), acquired resistance and others. Combination therapy may be able to overcome this limitation. Jianpi Huayu Decoction (JHD) is a traditional Chinese medicine formulation, which has been shown to be effective as an alternative and complementary therapy of HCC. We investigated the synergistic effect of JHD with sorafenib by a xenograft model.Methods: Growth of mouse-derived HCC cells and adverse events(AE) of treatment were evaluated in a subcutaneous model with JHD and clinical-dose sorafenib combination treatment. Diarrhea, the most frequently reported AE, was evaluated by diarrhea score. The gut microbiota(GM) composition of the mice was analyzed by Illumina NovaSeq. Results: JHD administration in mice synergistically enhanced the anti-tumor response, thereby suppressing HCC, and prevented occurrence of the most common AEs(diarrhea and body weight loss) of sorafenib. Sorafenib induced increased proinflammatory GM(Helicobacter) which promoted the progression of HCC and against anti-tumor treatment. JHD reduced the abundance of anti-inflammatory microbiota Muribaculum, Fusicatenibacter, and Dorea. Following the modulation of GM, the proinflammatory signaling interleukin 6/signal transducer and activator of transcription-3 pathway was downregulated by JHD.Conclusions: Our finding suggested that differences in the microbial gut flora may modulate resistance to sorafenib through IL-6/STAT3 signaling. JHD with microbiota modulation properties could potentiate sorafenib and provided a promising approach for HCC treatment.
Longitudinal Preclinical Evaluation of the Novel Radioligand [11C]CHDI-626 for PET Imaging of Mutant Huntingtin Aggregates in Huntington’s Disease
Authors: Bertoglio Daniele , Verhaeghe Jeroen , Miranda Alan , Wyffels Leonie , Stroobants Sigrid , Mrzljak Ladislav , Khetarpal Vinod , Skinbjerg Mette , Liu Longbin , Dominguez Celia , Munoz-Sanjuan Ignacio , Bard Jonathan , Staelens Steven
Published: September 2021

PurposeAs several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.MethodsAfter evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography.ResultsDespite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography.Conclusion﻿With clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.
Specific Features of The Structure Formation of Aluminum Alloys During Rapid Crystallization-Deformation
Authors: Sidelnikov Sergey Borisovich , Lopatina Ekaterina Sergeevna , Voroshilov Denis Sergeevich , Dovzhenko Nikolay Nikolaevich , Konstantinov Igor Lazarevich , Mansurov Yulbarskhon Nabievich , Bespalov Vadim Mikhaylovich , Durnopyanov Aleksandr Vasilyevich , Galiev Roman Ilsurovich , Voroshilova Marina Vladimirovna , Bersenev Andrey Sergeevich
Published: September 2021

The results of studies of the structure and properties of semi-finished products from aluminum and its alloys, obtained with the use of cast-free rolling-extruding are presented. It has been found that the rods obtained by the high-speed crystallization-deformation technology by the direct rolling-extrusion method have a stable ultrafine subgrain structure, which makes it possible to use them as modifiers. Experimental studies have been carried out, which confirmed the assumption that the initial structure of the modifying rod affects the melt. It was revealed that the size and density of distribution of additional crystallization centers formed in the volume of the melt based on clusters are inherited from the original subgrain structure of the modifying rod made of aluminum or its alloys. Metallographic studies have also shown that the subsequent severe plastic deformation by equal-channel angular extruding of rods obtained by direct rolling-extruding from an experimental alloy of the composition Al-0.2Zr-0.2Fe-0.4Mg makes it possible to achieve additional strengthening of the metal, since even more refines its structure, while the average grain size is 647 μm.
Compound Dihuang Granule Protects against 6-OHDA Induced Toxicity in Parkinson’s Disease Rats by Suppressing the Phosphorylation of MAPK/ERK1/2
Authors: Wang Li , Zhang Jian-ying , Chen Long , Zhang Lei , He Zhu-qing , Huan Peng-fei , Yang Yu-fang , He Jian-cheng
Published: September 2021

BackgroundParkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein in the substantia nigra pars compacta (SNpc). Compound Dihuang Granule (CDG), a famous traditional Chinese medicine (TCM) has been clinically used in PD therapy with curative effects. However, the specific functions and the mechanism of action remained unclear. This study explored the therapeutic effects and potential mechanisms of CDG in the PD rats induced by 6-OHDA toxicity.MethodsThe PD rat model was induced by unilaterally stereotactic injection of 6-OHDA into the SNpc of midbrain. The behavioral performances of rats were evaluated by rotation test, muscle strength assessment and balance beam walking test. The striatal contents of neurotransmitters were detected by HPLC.The numbers of dopaminergic (DA) neurons were determined with immunohistochemistry (IHC) staining and Western blotting assay. Indicators of oxidative stress were determined with colorimetric method. Apoptotic cells were detected by TUNEL assay. The expression levels of neurotrophic factors were examined with IHC staining and real-time quantitative PCR. The related protein expression levels were determined with Western blotting assay.ResultsCDG significantly attenuated the 6-OHDA induced abnormal rotational behaviors and alleviated the loss of DA neurons in the nigrostriatal axis of PD rats with a 6-week treatment. Consistently, the striatal contents of DA and its metabolites including DOPAC and HVA of PD rats were all significantly increased with CDG treatment. The 6-OHDA induced oxidative stress indicated with decreased superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and increased malondialdehyde (MDA) was also suppressed by CDG treatment. Moreover, CDG treatment increased the expression levels of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in the nigrostriatal axis of PD rats. Consistently, the 6-OHDA induced cell apoptosis was inhibited by the 6-week CDG treatment. Further, the phosphorylation of MAPK/ERK1/2 and CREB proteins in the striatum of PD rats was suppressed by CDG treatment and CDG showed synergistic effects with the MAPK/ERK1/2 phosphorylation inhibitor SL327.Conclusion﻿CDG could ameliorate the 6-OHDA induced brain injuries and motor symptoms, and also inhibit the oxidative stress and cell apoptosis in the nigrostriatal axis, which was mainly mediated by enhancing the expression levels of the neurotrophic factors and suppressing the phosphorylation of MAPK/ERK1/2 pathway in the midbrain of rats.
The Diagnostic Efficacy of Three-Dimensional Reconstruction System-Based Methods for Predicting Axillary Lymph Node Metastasis in Breast Cancer Patients: An Exploratory Study
Authors: Qu Limeng , Yi Wenjun , Luo Na , Zhao Piao , Zou Qiongyan , Chen Qitong , Mei Xilong
Published: September 2021

Background: The status of axillary lymph node metastases determines the treatment and overall survival of breast cancer (BC) patients. Three-dimensional (3D) assessment methods have advantages for spatial localization and are more responsive to morphological changes in lymph nodes than two-dimensional (2D) assessment methods, and we speculate that methods developed using 3D reconstruction systems have high diagnostic efficacy.Methods: This exploratory study included 43 patients with histologically confirmed BC diagnosed at Second Xiangya Hospital of Central South University between July 2017 and August 2020, all of whom underwent preoperative CT scans. Patients were divided into a training cohort to train the model and a validation cohort to validate the model. A 3D axillary lymph node atlas was constructed on a 3D reconstruction system to create various methods of assessing lymph node metastases for a comparison of diagnostic efficacy. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic values of these methods.Results: A total of 43 patients (mean [SD] age, 47 [10] years) met the eligibility criteria and completed 3D reconstruction. An axillary lymph node atlas was established, and a correlation between lymph node sphericity and lymph node metastasis was revealed. By continuously fitting the size and characteristics of axillary lymph nodes on the 3D reconstruction system, formulas and models were established to determine the presence or absence of lymph node metastasis, and the 3D method had better sensitivity for axillary lymph node assessment than the 2D method, with a statistically significant difference in the correct classification rate. The combined diagnostic method was superior to a single diagnostic method, with a 92.3% correct classification rate for the 3D method combined with ultrasound. In addition, in patients who received neoadjuvant chemotherapy (NAC), the correct classification rate of the 3D method (72.7%) was significantly higher than that of ultrasound (45.5%) and CT (54.5%).Conclusion: By establishing an axillary lymph node atlas, the sphericity formula and model developed with the 3D reconstruction system achieve a high correct classification rate when combined with ultrasound or CT and can also be applied to patients receiving NAC.