bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnoses of Antarctic Inland Water Cycle Regime: Perspectives From Atmospheric Water Vapor Isotope Observations Along the Transect From Zhongshan Station to Dome A
Authors: Liu Jingfeng , Du Zhiheng , Zhang Dongqi , Wang Shimeng
Published: February 2022

Water stable isotopes are crucial for paleoclimate reconstruction and water cycle tracing in Antarctica. Accurate measurement of atmospheric water vapor isotopic composition of hydrogen and oxygen is required urgently for understanding the processes controlling the atmosphere–snow interaction and associated isotope fractionation. This study presents in situ real-time measurements of water vapor isotopes along the transect from Zhongshan Station to Dome Argus (hereafter Dome A) in East Antarctica for the first time. The results reveal that the surface vapor stable isotopes of δ18O and δ D showed a gradual decreasing trend in the interior plateau region with the distance away from the coast, with significant δ18O-temperature correlation gradient of 1.61‰°/C and δ18O-altitude gradient of –2.13‰/100 m. Meanwhile, d-excess gradually arises with elevation rise. Moreover, the spatial variation of vapor isotopic composition displays three different characters implying different atmosphere circulation backgrounds controlling the inland water cycle; it can be divided as the coastal steep area below 2,000 m, a vast inland area with an elevation varied between 2,000 and 3,000 m, and high central plateau. Thirdly, observed high inland Antarctica water vapor d-excess quantitatively confirms stratosphere air intrusion and vapor derived from low latitudes by Brewer–Dobson circulation. Finally, the diurnal cycle signals of interior area water vapor isotopes δ18O, δ D, and air temperature highlighted the substantial domination of the supersaturation sublimation/condensation effect in inland, and this suggests that fractionation occurs during sublimation and vapor–snow exchanges should no longer be considered insignificant for the isotopic composition of near-surface snow in Antarctica.
Object-Oriented Mapping as a Tool for the Assessment of Landslide Hazard in Higly Urbanized Areas
Authors: Dramis Francesco , Guida Domenico , Valiante Mario
Published: February 2022

The assessment and mitigation of landslide risk affecting hillslopes in highly urbanized and infrastructured environments are often problematic due to the inadequacy of the traditional approach based on landslide inventories and the absence of a shared language between the different scientific-technical operators (geologists, engineers, architects, environmentalists, economists, jurists) and recurrent understanding problems with policymakers, stakeholders, and property owners. Therefore, innovative technologies and working procedures are required to address these problems. In this context, the European INSPIRE Directive and the Italian national Catalog of Territorial Data with the related Geo-Topographic DB provide positive responses in terms of data standardization and transdisciplinary interoperability. On the other hand, the application of the object-oriented geomorphological mapping of landslides and, even more, the recently proposed Landslide Object-Oriented Model (LOOM) make it possible to develop a more thorough approach to assess the spatial and temporal relationships between landslides and affected slopes. Following the above perspective, the InterUniversity Research Center for Prevision and Prevention of Great Risks (C.U.G.RI.) produced the LOOM-based “eventory” of landslides over a sector of the Tyrrhenian coastal belt, northwest of Salerno city, in the framework of a multi-disciplinary investigation project launched by the Campania Regional Administration to assess the landslide risk. The quantitative assessment of the geomorphological expert-judgment procedures has been carried out exploiting morphometric indexes: the Topographic Position Index (TPI) for automatic slope features recognition, and the Slope-Area plots for surficial process domains. Furthermore, the application of the INSPIRE, and related Italian National Geo-Topographic DB standards allowed transdisciplinary interaction between scientists, technicians, and managers. Such proposal can support the risk management procedure, adding in the Value Judgement and Risk Tolerance Criteria simplicity and effective interoperability in trans-disciplinary frameworks.
Heparin and Related Substances for Treating Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis
Authors: Su Na , Xu Ting , Li Xiaodan , Zheng Hanrui , Wu Bin , Zhang Shengzhao , Zhou Yiling , Du Liang , Zhao Yinglan
Published: February 2022

Background

Diabetic foot ulcers are a major complication of diabetes mellitus (DM), when heparin and heparin related substances may be potentially used as an adjuvant treatment. We aimed to evaluate the efficacy and safety of heparin and heparin related substances for the treatment of diabetic foot ulcers.

Methods

We searched up to March 2021 in the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; EBSCO CINAHL; VIP Chinese Science and Technique Journals Database; China National Knowledge Infrastructure (CNKI) Database and Wan Fang Database investigating heparin or heparin-related substances in patients with diabetic foot ulcers. The primary outcomes included proportion of ulcers completely healed and time to complete ulcer healing. We assessed each included study with the Cochrane ‘Risk of bias’ tool and used the GRADE approach to assess the overall quality of the evidence.

Results

We included nine randomized studies involving 620 participants in the meta-analysis, involving two different heparin and heparin-related substances, low molecular weight heparin (LMWH) and hyaluronic acid. Our study did not show the benefits from LMWH on increasing chance of the ulcer healing (RR: 1.26; 95% CI: 0.78 to 2.04; P=0.35; very low) or shortening the time to complete ulcer healing (SMD: 0.13 d; 95% CI: -0.29 to 0.56; P=0.54; very low). Hyaluronic acid may improve the complete ulcer healing (RR: 1.57; 95% CI: 1.29 to 1.91; P˂0.00001; very low) and shorten the time to complete ulcer healing (SMD -0.84, 95% CI -1.15 to -0.53; P<0.00001; low). Hyaluronic acid and LMWH were generally well tolerated for treating diabetic foot ulcers in this review.

Conclusion

Hyaluronic acid may improve diabetic foot ulcer with very low quality evidence but not LMWH. However, the benefits and harms need further validation in larger trials with different population.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero/], identifier [PROSPERO, CRD42021269212].
Recent Trends in the Incidence of Clear Cell Adenocarcinoma and Survival Outcomes: A SEER Analysis
Authors: Guo Yadong , Shrestha Anil , Maskey Niraj , Dong Xiaohui , Zheng Zongtai , Yang Fuhan , Wang Ruiliang , Ma Wenchao , Liu Ji , Li Cheng , Zhang Wentao , Mao Shiyu , Zhang Aihong , Liu Shenghua , Yao Xudong
Published: February 2022

Background

Clear cell adenocarcinoma (CCA) is considered a relatively rare tumor with a glycogen-rich phenotype. The prognosis of CCA patients is unclear. In this study, recent trends in the epidemiological and prognostic factors of CCA were comprehensively investigated.

Methods

Patients with CCA from years 2000 to 2016 were identified from the Surveillance, Epidemiological, and End Results (SEER) database. Relevant population data were used to analyze the rates age-adjusted incidence, age-standardized 3-year and 5-year relative survivals, and overall survival (OS).

Results

The age-adjusted incidence of CCA increased 2.7-fold from the year 2000 (3.3/100,000) to 2016 (8.8/100,000). This increase occurred across all ages, races, stages, and grades. Of all these subgroups, the increase was largest in the grade IV group. The age-standardized 3-year and 5-year relative survivals increased during this study period, rising by 9.1% and 9.5% from 2000 to 2011, respectively. Among all the stages and grades, the relative survival increase was greatest in the grade IV group. According to multivariate analysis of all CCA patients, predictors of OS were: age, gender, year of diagnosis, marital status, race, grade, stage, and primary tumor site (P < 0.001). The OS of all CCA patients during the period 2008 to 2016 was significantly higher than that from 2000 to 2007 (P < 0.001).

Conclusions

The incidence of CCA and survival of these patients improved over time. In particular, the highest increases were reported for grade IV CCA, which may be due to an earlier diagnosis and improved treatment.
Progress in the Study of Colorectal Cancer Caused by Altered Gut Microbiota After Cholecystectomy
Authors: Ma Yanpeng , Qu Ruize , Zhang Yi , Jiang Changtao , Zhang Zhipeng , Fu Wei
Published: February 2022

Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy.
Mesenchymal Stem Cells Exposed to Persistently High Glucocorticoid Levels Develop Insulin-Resistance and Altered Lipolysis: A Promising In Vitro Model to Study Cushing’s Syndrome
Authors: Di Vincenzo Mariangela , Martino Marianna , Lariccia Vincenzo , Giancola Giulia , Licini Caterina , Di Benedetto Giovanni , Arnaldi Giorgio , Orciani Monia
Published: February 2022

Background

In Cushing’s syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, thus revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS.

Methods

MSCs isolated from the abdominal skin of healthy subjects were treated thrice daily with GCs according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) versus persistently higher doses (Higher, Constant Exposure, HCE), aimed at mimicking either the physiological condition or CS, respectively. Subsequently, MSCs were stimulated with insulin and glucose thrice daily, resembling food uptake and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints over three days.

Results

LDE to GCs did not impair glucose uptake by MSCs, whereas HCE significantly decreased glucose uptake by MSCs only when prolonged. Persistent signs of IR occurred after 30 hours of HCE to GCs. Compared to LDE, MSCs experiencing HCE to GCs showed a downregulation of lipolysis-related genes in the acute period, followed by overexpression once IR was established.

Conclusions

Preserving circadian GC rhythmicity is crucial to prevent the occurrence of metabolic alterations. Similar to mature adipocytes, MSCs suffer from IR and impaired lipolysis due to chronic GC excess: MSCs could represent a reliable model to track the mechanisms involved in GC-induced IR throughout cellular differentiation.
Characteristics of Intraoperative Hemodynamic Instability in Postoperatively Diagnosed Pheochromocytoma and Sympathetic Paraganglioma Patients
Authors: Kim Jung Hee , Lee Hyung-Chul , Kim Su-jin , Lee Kyu Eun , Jung Kyeong Cheon
Published: February 2022

Background

Despite an improved understanding of pheochromocytoma and extra-adrenal sympathetic parganglioma (PPGL), including diagnosis and management, some PPGLs are postoperatively diagnosed. Clinical characteristics and intraoperative haemodynamic instability (HI) in postoperatively diagnosed PPGL patients have been poorly defined. Thus, we investigated the clinical characteristics and HI in patients with postoperatively diagnosed PPGLs compared to patients with preoperatively diagnosed PPGLs.

Methods

We obtained clinical and haemodynamic data from the electronic medical records of 256 patients with pathologically confirmed PPGLs at our institution from January 2005 to December 2019. We assessed the intraoperative HI (systolic blood pressure [SBP]>160 mmHg (min) or mean blood pressure [MBP]<60 mmHg (min)) over time.

Results

Twenty-nine patients (11.3%) were diagnosed with PPGLs postoperatively. Hypertension (34.5% vs. 63.0%, P=0.006) and pheochromocytoma (17.2% vs. 81.1%, P<0.001) case rates were lower in postoperatively diagnosed patients than in preoperatively diagnosed patients. Preoperative SBP in the ward was similar between groups, but the use of α-blockers and β-blockers was more frequent in preoperatively diagnosed patients (89.0% vs. 3.4%, P<0.001; 36.3% vs. 6.9%, P=0.003). Considering intraoperative HI, postoperatively diagnosed patients demonstrated a similar percentage of time with SBP>160 mmHg (median [IQR]; 7.9% [2.5; 11.9] % vs. 4.6% [0.0; 11.9], P=0.088) but a significantly lower percentage of time with MBP<60 mmHg (0.0% [0.0; 3.0] vs. 5.6% [0.0, 12.6], P=0.002) compared with preoperatively diagnosed patients.

Conclusions

Patients diagnosed with PPGLs postoperatively may have no further higher risk of intraoperative hypertension than those diagnosed preoperatively despite insufficient preoperative management for PPGLs. Further study will be needed to ascertain intrinsic tumour characteristics, and need for universal preoperative use of α- and β-blockers in PPGL patients postoperatively diagnosed or without typical symptoms related PPGLs.
Comparative Analysis of Gene Expression Profiles in the Adipose Tissue of Obese Adult Mice With Rapid Infantile Growth After Undernourishment In Utero
Authors: Suzuki Misako , Kohmura-Kobayashi Yukiko , Ueda Megumi , Furuta-Isomura Naomi , Matsumoto Masako , Oda Tomoaki , Kawai Kenta , Itoh Toshiya , Matsuya Madoka , Narumi Megumi , Tamura Naoaki , Uchida Toshiyuki , Mochizuki Kazuki , Itoh Hiroaki
Published: February 2022

Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the ‘Developmental Origins of Metaflammation’, the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation.
The Association Between FokI Vitamin D Receptor Polymorphisms With Metabolic Syndrome Among Pregnant Arab Women
Authors: Alzaim Maysa , Al-Daghri Nasser M. , Sabico Shaun , Fouda Mona A. , Al-Musharaf Sara , Khattak Malak N. K. , Mohammed Abdul Khader , Al-Ajlan Abdulrahman , Binjawhar Dalal N. , Wood Richard
Published: February 2022

Metabolic syndrome (MetS) is a serious health condition that is becoming extremely threatening in Saudi Arabia. The link between vitamin D receptor (VDR) gene polymorphisms and maternal MetS has been observed in several ethnic groups, but is yet to be clarified in the Arabian population. This study aims to investigate the relationship between the FokI VDR genotype and the risk of MetS and its components in pregnant Saudi women. A cross-sectional study was conducted using 368 pregnant Saudi women on first trimester screened for MetS (44 with MetS and 324 without MetS). Measurements included anthropometrics, glycemic and lipid profile and 25(OH)D. TaqMan genotyping assay was used to determine Fokl VDR genotype of participants. Vitamin D deficiency (25(OH)D <50nmol/l) was seen in 85% of the participants. An estimated 12% of participants had MetS. In the MetS group, the FokI VDR genotyping frequencies for FF, Ff, and ff genotypes were 50%, 36.4% and 13.6%, respectively. In controls, the frequencies were 62.7%, 31.4% and 5.9%, respectively. No significant association between the individual MetS components and FokI VDR genotypes were observed. Nevertheless, carriers of the ff allele had a significant risk for full maternal MetS [Odds Ratio 4.2 (95% Confidence Interval 1.4-12.2; adjusted p=0.009). The study suggests that the ff FokI VDR genotype is a genetic marker of maternal MetS in pregnant Arabian women. Prospective studies that include neonatal outcomes may confirm present findings.
The Association Between Genomic Heterozygosity and Carcass Merit in Cattle
Authors: Kenny David , Carthy Tara R. , Murphy Craig P. , Sleator Roy D. , Evans Ross D. , Berry Donagh P.
Published: February 2022

The objective of the present study was to quantify the association between both pedigree and genome-based measures of global heterozygosity and carcass traits, and to identify single nucleotide polymorphisms (SNPs) exhibiting non-additive associations with these traits. The carcass traits of interest were carcass weight (CW), carcass conformation (CC) and carcass fat (CF). To define the genome-based measures of heterozygosity, and to quantify the non-additive associations between SNPs and the carcass traits, imputed, high-density genotype data, comprising of 619,158 SNPs, from 27,213 cattle were used. The correlations between the pedigree-based heterosis coefficient and the three defined genomic measures of heterozygosity ranged from 0.18 to 0.76. The associations between the different measures of heterozygosity and the carcass traits were biologically small, with positive associations for CW and CC, and negative associations for CF. Furthermore, even after accounting for the pedigree-based heterosis coefficient of an animal, part of the remaining variability in some of the carcass traits could be captured by a genomic heterozygosity measure. This signifies that the inclusion of both a heterosis coefficient based on pedigree information and a genome-based measure of heterozygosity could be beneficial to limiting bias in predicting additive genetic merit. Finally, one SNP located on Bos taurus (BTA) chromosome number 5 demonstrated a non-additive association with CW. Furthermore, 182 SNPs (180 SNPs on BTA 2 and two SNPs on BTA 21) demonstrated a non-additive association with CC, while 231 SNPs located on BTA 2, 5, 11, 13, 14, 18, 19 and 21 demonstrated a non-additive association with CF. Results demonstrate that heterozygosity both at a global level and at the level of individual loci contribute little to the variability in carcass merit.
Establishing a Sickle Cell Disease Registry in Africa: Experience From the Sickle Pan-African Research Consortium, Kumasi-Ghana
Authors: Paintsil Vivian , Amuzu Evans Xorse , Nyanor Isaac , Asafo-Adjei Emmanuel , Mohammed Abdul Razak , Yawnumah Suraj Abubakar , Oppong-Mensah Yaa Gyamfua , Nguah Samuel Blay , Obeng Paul , Dogbe Elliot Eli , Jonas Mario , Nembaware Victoria , Mazandu Gaston , Ohene-Frempong Kwaku , Wonkam Ambroise , Makani Julie , Ansong Daniel , Osei-Akoto Alex ,   the Sickle Cell Disease in Sub-Saharan Africa Consortium
Published: February 2022

Sickle cell disease (SCD) is the most common clinically significant hemoglobinopathy, characterized by painful episodes, anemia, high risk of infection, and other acute and chronic complications. In Africa, where the disease is most prevalent, large longitudinal data on patients and their outcomes are lacking. This article describes the experiences of the Kumasi Center for SCD at the Komfo Anokye Teaching Hospital (KCSCD-KATH), a Sickle Pan-African Research Consortium (SPARCO) site and a SickleInAfrica Consortium member, in establishing a SCD registry for the evaluation of the outcomes of patients. It also provides a report of a preliminary analysis of the data. The process of developing the registry database involved comprehensive review of the center’s SCD patient medical records, incorporating data elements developed by the SickleInAfrica Consortium and obtaining ethical clearance from the local Institutional Review Board. From December 2017 to March 2020, 3,148 SCD patients were enrolled into the SCD registry. Enrollment was during the SCD outpatient clinic visits or through home visits. A significant proportion of the patients was from the newborn screening cohort (50.3%) and was males (52.9%). SCD-SS, SCD-SC, and Sβ +thalassemia were seen in 67.2, 32.5, and 0.3% patients, respectively. The majority of the patients were in a steady state at enrollment; however, some were enrolled after discharge for an acute illness admission. The top two clinical diagnoses for SCD-SS patients were sickle cell painful events and acute anemia secondary to hyperhemolysis with incidence rates of 141.86 per 10,000 person months of observation (PMO) and 32.74 per 10,000 PMO, respectively. In SCD-SC patients, the top two diagnoses were sickle cell painful events and avascular necrosis with incidence rates of 203.09 per 10,000 PMO and 21.19 per 10,000 PMO, respectively. The SPARCO Kumasi site has developed skills and infrastructure to design, manage, and analyze data in the SCD registry. The newborn screening program and alternative recruitment methods such as radio announcement and home visits for defaulting patients were the key steps taken in enrolling patients into the registry. The registry will provide longitudinal data that will help improve knowledge of SCD in Ghana and Africa through research.
Identification and Characterization of Key Genes Responsible for Weedy and Cultivar Growth Types in Soybean
Authors: Basnet Prakash , Um Taeyoung , Roy Neha Samir , Cho Woo Suk , Park Soo Chul , Park Kyong-Cheul , Choi Ik-Young
Published: February 2022

In cultivated plants, shoot morphology is an important factor that influences crop economic value. However, the effects of gene expression patterns on shoot morphology are not clearly understood. In this study, the molecular mechanism behind shoot morphology (including leaf, stem, and node) was analyzed using RNA sequencing to compare weedy (creeper) and cultivar (stand) growth types obtained in F7 derived from a cross of wild and cultivated soybeans. A total of 12,513 (in leaves), 14,255 (in stems), and 11,850 (in nodes) differentially expressed genes were identified among weedy and cultivar soybeans. Comparative transcriptome and expression analyses revealed 22 phytohormone-responsive genes. We found that GIBBERELLIN 2-OXIDASE 8 (GA2ox), SPINDLY (SPY), FERONIA (FER), AUXIN RESPONSE FACTOR 8 (ARF8), CYTOKININ DEHYDROGENASE-1 (CKX1), and ARABIDOPSIS HISTIDINE KINASE-3 (AHK3), which are crucial phytohormone response genes, were mainly regulated in the shoot of weedy and cultivar types. These results indicate that interactions between phytohormone signaling genes regulate shoot morphology in weedy and cultivar growth type plants. Our study provides insights that are useful for breeding and improving crops to generate high-yield soybean varieties.
Network Analysis Reveals Different Cellulose Degradation Strategies Across Trichoderma harzianum Strains Associated With XYR1 and CRE1
Authors: Rosolen Rafaela Rossi , Aono Alexandre Hild , Almeida Déborah Aires , Ferreira Filho Jaire Alves , Horta Maria Augusta Crivelente , De Souza Anete Pereira
Published: February 2022

Trichoderma harzianum, whose gene expression is tightly controlled by the transcription factors (TFs) XYR1 and CRE1, is a potential candidate for hydrolytic enzyme production. Here, we performed a network analysis of T. harzianum IOC-3844 and T. harzianum CBMAI-0179 to explore how the regulation of these TFs varies between these strains. In addition, we explored the evolutionary relationships of XYR1 and CRE1 protein sequences among Trichoderma spp. The results of the T. harzianum strains were compared with those of Trichoderma atroviride CBMAI-0020, a mycoparasitic species. Although transcripts encoding carbohydrate-active enzymes (CAZymes), TFs, transporters, and proteins with unknown functions were coexpressed with cre1 or xyr1, other proteins indirectly related to cellulose degradation were identified. The enriched GO terms describing the transcripts of these groups differed across all strains, and several metabolic pathways with high similarity between both regulators but strain-specific differences were identified. In addition, the CRE1 and XYR1 subnetworks presented different topology profiles in each strain, likely indicating differences in the influences of these regulators according to the fungi. The hubs of the cre1 and xyr1 groups included transcripts not yet characterized or described as being related to cellulose degradation. The first-neighbor analyses confirmed the results of the profile of the coexpressed transcripts in cre1 and xyr1. The analyses of the shortest paths revealed that CAZymes upregulated under cellulose degradation conditions are most closely related to both regulators, and new targets between such signaling pathways were discovered. Although the evaluated T. harzianum strains are phylogenetically close and their amino acid sequences related to XYR1 and CRE1 are very similar, the set of transcripts related to xyr1 and cre1 differed, suggesting that each T. harzianum strain used a specific regulation strategy for cellulose degradation. More interestingly, our findings may suggest that XYR1 and CRE1 indirectly regulate genes encoding proteins related to cellulose degradation in the evaluated T. harzianum strains. An improved understanding of the basic biology of fungi during the cellulose degradation process can contribute to the use of their enzymes in several biotechnological applications and pave the way for further studies on the differences across strains of the same species.
Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis
Authors: Huang Yuancheng , Huang Chaoyuan , Jiang Xiaotao , Yan Yanhua , Zhuang Kunhai , Liu Fengbin , Li Peiwu , Wen Yi
Published: February 2022

Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value.

Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database.

Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified.

Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.
A Novel Ras--Related Signature Improves Prognostic Capacity in Oesophageal Squamous Cell Carcinoma
Authors: Yang Hao-Shuai , Liu Wei , Zheng Shao-Yi , Cai He-Yuan , Luo Hong-He , Feng Yan-Fen , Lei Yi-Yan
Published: February 2022

Oesophageal squamous cell carcinoma (ESCC) remains a clinically challenging disease with high morbidity rates and poor prognosis. ESCC is also the most common pathological type of oesophageal cancer (EC) in China. Ras-related genes are one of the most frequently mutated gene families in cancer and regulate tumour development and progression. Given this, we investigated the Ras-related gene expression profiles and their values in ESCC prognosis, using data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. We found that we could identify three distinct oesophageal cancer clusters based on their unique expression profile for 11 differentially expressed Ras-related genes with each of these demonstrating some prognostic value when, evaluated using univariate Cox analysis. We then used multivariate Cox analysis to identify relevant independent prognostic indicators and used these to build a new prognostic prediction model for oesophageal cancer patients using these three Ras-related genes. These evaluations produced an area under the curve (AUC) of 0.932. We found that our Ras-related signatures could also act as independent factors in ESCC prognosis and that patients with low Ras scores showed a higher overall expression levels of various immune checkpoint genes, including TNFSF4, TNFRSF8, TNFRSF9, NRP1, CD28, CD70, CD200, CD276, METTL16, METTL14, ZC3H13, YTHDF3, VIRMA, FTO, and RBM15, as well as a higher CSMD3, FLG, DNAH5, MUC4, PLCO, EYS, and ZNF804B mutation rates, and better sensitivity to drugs such as erlotinib, paclitaxel, and gefitinib. In conclusion, we were able to use the unique expression profiles of several Ras-related genes to produce a novel disease signature which might facilitate improved prognosis in ESCC, providing new insight into both diagnosis and treatment in these cancers.
Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis
Authors: Myasoedova Veronika A. , Massaiu Ilaria , Moschetta Donato , Chiesa Mattia , Songia Paola , Valerio Vincenza , Alfieri Valentina , Capoulade Romain , Trabattoni Daniela , Andreini Daniele , Mass Elvira , Parisi Valentina , Poggio Paolo
Published: February 2022

Background

Aortic stenosis (AS) is the most common valve disorder characterized by fibro-calcific remodeling of leaflets. Recent evidence indicated that there is a sex-related difference in AS development and progression. Fibrotic remodeling is peculiar in women’s aortic valves, while men’s leaflets are more calcified. Our study aimed to assess aortic valve fibrosis (AVF) in a severe AS cohort using non-invasive diagnostic tools and determine whether sex-specific pathological pathways and cell types are associated with severe AS.

Materials and Methods

We have included 28 men and 28 women matched for age with severe AS who underwent echocardiography and cardiac contrast-enhanced computed tomography (CT) before intervention. The calcium and fibrosis volumes were assessed and quantified using the ImageJ thresholding method, indexed calcium and fibrosis volume were calculated by dividing the volume by the aortic annular area. For a deeper understanding of molecular mechanisms characterizing AS disorder, differentially expressed genes and functional inferences between women and men’s aortic valves were carried out on a publicly available microarray-based gene expression dataset (GSE102249). Cell types enrichment analysis in stenotic aortic valve tissues was used to reconstruct the sex-specific cellular composition of stenotic aortic valves.

Results

In agreement with the literature, our CT quantifications showed that women had significantly lower aortic valve calcium content compared to men, while fibrotic tissue composition was significantly higher in women than men. The expression profiles of human stenotic aortic valves confirm sex-dependent processes. Pro-fibrotic processes were prevalent in women, while pro-inflammatory ones, linked to the immune response system, were enhanced in men. Cell-type enrichment analysis showed that mesenchymal cells were over-represented in AS valves of women, whereas signatures for monocytes, macrophages, T and B cells were enriched men ones.

Conclusions

Our data provide the basis that the fibro-calcific process of the aortic valve is sex-specific, both at gene expression and cell type level. The quantification of aortic valve fibrosis by CT could make it possible to perform population-based studies and non-invasive assessment of novel therapies to reduce or halt sex-related calcific aortic valve stenosis (CAVS) progression, acting in an optimal window of opportunity early in the course of the disease.
Cross-Neutralizing Breadth and Longevity Against SARS-CoV-2 Variants After Infections
Authors: Kurahashi Yukiya , Sutandhio Silvia , Furukawa Koichi , Tjan Lidya Handayani , Iwata Sachiyo , Sano Shigeru , Tohma Yoshiki , Ohkita Hiroyuki , Nakamura Sachiko , Nishimura Mitsuhiro , Arii Jun , Kiriu Tatsunori , Yamamoto Masatsugu , Nagano Tatsuya , Nishimura Yoshihiro , Mori Yasuko
Published: February 2022

Background

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. The emergence of variants of concern (VOCs) has become one of the most pressing issues in public health. To control VOCs, it is important to know which COVID-19 convalescent sera have cross-neutralizing activity against VOCs and how long the sera maintain this protective activity.

Methods

Sera of patients infected with SARS-CoV-2 from March 2020 to January 2021 and admitted to Hyogo Prefectural Kakogawa Medical Center were selected. Blood was drawn from patients at 1-3, 3-6, and 6-8 months post onset. Then, a virus neutralization assay against SARS-CoV-2 variants (D614G mutation as conventional strain; B.1.1.7, P.1, and B.1.351 as VOCs) was performed using authentic viruses.

Results

We assessed 97 sera from 42 patients. Sera from 28 patients showed neutralizing activity that was sustained for 3-8 months post onset. The neutralizing antibody titer against D614G significantly decreased in sera of 6-8 months post onset compared to those of 1-3 months post onset. However, the neutralizing antibody titers against the three VOCs were not significantly different among 1-3, 3-6, and 6-8 months post onset.

Discussion

Our results indicate that neutralizing antibodies that recognize the common epitope for several variants may be maintained for a long time, while neutralizing antibodies having specific epitopes for a variant, produced in large quantities immediately after infection, may decrease quite rapidly.
Low-Dose 5-Aza and DZnep Alleviate Acute Graft-Versus-Host Disease With Less Side Effects Through Altering T-Cell Differentiation
Authors: Wang Qing Ya , Liu Hui Hui , Dong Yu Jun , Liang Ze Yin , Yin Yue , Liu Wei , Wang Qing Yun , Wang Qian , Sun Yu Hua , Xu Wei Lin , Han Na , Li Yuan , Ren Han Yun
Published: February 2022

Objective

Previous studies showed that hypomethylating agents (HMAs) could alleviate acute graft-versus-host disease (aGvHD), but affect engraftment after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The combination of two different HMAs in lower doses might overcome this problem. This study aimed to evaluate the treatment effect of the combination of two HMAs—azacitidine (5-Aza) and histone H3K27 methyltransferase inhibitor 3-deazaneplanocin (DZNep)—for the prophylaxis of aGvHD after allo-HSCT and to explore the possible mechanisms.

Methods

We first optimized the concentrations of individual and combinational 5-Aza and DZNep treatments to ensure no obvious toxicities on activated T cells by evaluating T-cell proliferation, viability, and differentiation. A mouse model of aGvHD was then established to assess the prophylactic efficacy of 5-Aza, DZNep, and their combination on aGvHD. The immunomodulatory effect on T cells and the hematopoietic reconstruction were assessed. Additionally, RNA sequencing (RNA-seq) was performed to identify the underlying molecular mechanisms.

Results

Compared with single treatments, the in vitro application of 5-Aza with DZNep could more powerfully reduce the production of T helper type 1 (Th1)/T cytotoxic type 1 (Tc1) cells and increase the production of regulatory T cells (Tregs). In an allo-HSCT mouse model, in vivo administration of 5-Aza with DZNep could enhance the prophylactic effect for aGvHD compared with single agents. The mechanism study demonstrated that the combination of 5-Aza and DZNep in vivo had an enhanced effect to inhibit the production of Th1/Tc1, increase the proportions of Th2/Tc2, and induce the differentiation of Tregs as in vitro. RNA-seq analysis revealed the cytokine and chemokine pathways as one mechanism for the alleviation of aGvHD with the combination of 5-Aza and DZNep.

Conclusion

The combination of 5-Aza and DZNep could enhance the prophylactic effect for aGvHD by influencing donor T-cell differentiation through affecting cytokine and chemokine pathways. This study shed light on the effectively prophylactic measure for aGvHD using different epigenetic agent combinations.
Functional Characterization of Glycoprotein Nonmetastatic Melanoma Protein B in Scleroderma Fibrosis
Authors: Palisoc Pamela J. , Vaikutis Leah , Gurrea-Rubio Mikel , Model Ellen N. , O’mara Morgan M. , Ory Sarah , Vichaikul Sirapa , Khanna Dinesh , Tsou Pei-Suen , Sawalha Amr H.
Published: February 2022

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is involved in various cell functions such as cell adhesion, migration, proliferation, and differentiation. In this study, we set forth to determine the role of GPNMB in systemic sclerosis (SSc) fibroblasts. Dermal fibroblasts were isolated from skin biopsies from healthy subjects and patients with diffuse cutaneous (dc)SSc. GPNMB was upregulated in dcSSc fibroblasts compared to normal fibroblasts, and correlated negatively with the modified Rodnan skin score. In addition, dcSSc fibroblasts secreted higher levels of soluble (s)GPNMB (147.4 ± 50.2 pg/ml vs. 84.8 ± 14.8 pg/ml, p<0.05), partly due to increased ADAM10. sGPNMB downregulated profibrotic genes in dcSSc fibroblasts and inhibited cell proliferation and gel contraction. The anti-fibrotic effect of sGPNMB was at least in part mediated through CD44, which is regulated by histone acetylation. TGFβ downregulated GPNMB and decreased the release of its soluble form in normal fibroblasts. In dcSSc fibroblasts, GPNMB is upregulated by its own soluble form. Our data demonstrate an anti-fibrotic role of sGPNMB in SSc and established a role for the ADAM10-sGPNMB-CD44 axis in dermal fibroblasts. Upregulating GPNMB expression might provide a novel therapeutic approach in SSc.
Fast Maturation of Splenic Dendritic Cells Upon TBI Is Associated With FLT3/FLT3L Signaling
Authors: Zhang Jin , Li Zhenghui , Chandrasekar Akila , Li Shun , Ludolph Albert , Boeckers Tobias Maria , Huber-Lang Markus , Roselli Francesco , olde Heuvel Florian
Published: February 2022

The consequences of systemic inflammation are a significant burden after traumatic brain injury (TBI), with almost all organs affected. This response consists of inflammation and concurrent immunosuppression after injury. One of the main immune regulatory organs, the spleen, is highly interactive with the brain. Along this brain–spleen axis, both nerve fibers as well as brain-derived circulating mediators have been shown to interact directly with splenic immune cells. One of the most significant comorbidities in TBI is acute ethanol intoxication (EI), with almost 40% of patients showing a positive blood alcohol level (BAL) upon injury. EI by itself has been shown to reduce proinflammatory mediators dose-dependently and enhance anti-inflammatory mediators in the spleen. However, how the splenic immune modulatory effect reacts to EI in TBI remains unclear. Therefore, we investigated early splenic immune responses after TBI with and without EI, using gene expression screening of cytokines and chemokines and fluorescence staining of thin spleen sections to investigate cellular mechanisms in immune cells. We found a strong FLT3/FLT3L induction 3 h after TBI, which was enhanced by EI. The FLT3L induction resulted in phosphorylation of FLT3 in CD11c+ dendritic cells, which enhanced protein synthesis, maturation process, and the immunity of dendritic cells, shown by pS6, peIF2A, MHC-II, LAMP1, and CD68 by immunostaining and TNF-α expression by in-situ hybridization. In conclusion, these data indicate that TBI induces a fast maturation and immunity of dendritic cells which is associated with FLT3/FLT3L signaling and which is enhanced by EI prior to TBI.
Inflammatory Response Against Staphylococcus aureus via Intracellular Sensing of Nucleic Acids in Keratinocytes
Authors: Ngo Quang Vinh , Faass Larissa , Sähr Aline , Hildebrand Dagmar , Eigenbrod Tatjana , Heeg Klaus , Nurjadi Dennis
Published: February 2022

Staphylococcus aureus is one of the clinically most relevant pathogens causing infections. Humans are often exposed to S. aureus. In approximately one-third of the healthy population it can be found on the skin either for long or short periods as colonizing “commensals”, without inducing infections or an inflammatory immune response. While tolerating S. aureus seems to be limited to certain individuals and time periods in most cases, Staphylococcus epidermidis is tolerated permanently on the skin of almost all individuals without activating overwhelming skin inflammation. To investigate this, we co-cultured a keratinocyte cell line (HaCaT) with viable S. aureus or S. epidermidis to study the differences in the immune activation. S. aureus activated keratinocytes depicted by a profound IL-6 and IL-8 response, whereas S. epidermidis did not. Our data indicate that internalization of S. aureus and the subsequent intracellular sensing of bacterial nucleic acid may be essential for initiating inflammatory response in keratinocytes. Internalized dsRNA activates IL-6 and IL-8 release, but not TNF-α or IFNs by human keratinocytes. This is a non-specific effect of dsRNA, which can be induced using Poly(I:C), as well as RNA from S. aureus and S. epidermidis. However, only viable S. aureus were able to induce this response as these bacteria and not S. epidermidis were actively internalized by HaCaT. The stimulatory effect of S. aureus seems to be independent of the TLR3, -7 and -8 pathways.
Mycobacterium tuberculosis Rv0309 Dampens the Inflammatory Response and Enhances Mycobacterial Survival
Authors: Peng Yongchong , Zhu Xiaojie , Gao Lin , Wang Jieru , Liu Han , Zhu Tingting , Zhu Yifan , Tang Xin , Hu Changmin , Chen Xi , Chen Huanchun , Chen Yingyu , Guo Aizhen
Published: February 2022

To reveal functions of novel Mycobacterium tuberculosis (M. tb) proteins responsible for modulating host innate immunity is essential to elucidation of mycobacterial pathogenesis. In this study, we aimed to identify the role of a putative protein Rv0309 encoded within RD8 of M. tb genome in inhibiting the host inflammatory response and the underlying mechanism, using in-vitro and in-vivo experiments. A recombinant M. smegmatis strain Ms_rv0309 expressing Rv0309 and a mutant Bacillus Calmette-Guérin (BCG)ΔRS01790 strain with deletion of BCG_RS01790, 100% homologue of Rv0309 in BCG, were constructed. Rv0309 was found to localize in the cell wall and be able to decrease cell wall permeability. Purified recombinant rRv0309 protein inhibited lipopolysaccharide-induced IL-6 release in RAW264.7 cells. BCG_RS01790 in BCG or Rv0309 in Ms_rv0309 strain greatly inhibited production of IL-6, IL-1β, and TNF-α in RAW264.7 cells. Similarly, BCGΔRS01790 strongly induced expression of these cytokines compared with wild-type BCG and complement strain, cBCGΔRS01790::RS01790. Further BCG_RS01790 or Rv0309 suppressed cytokine production through NF-κB p65/IκBα and MAPK ERK/JNK signaling. Importantly, BCG_RS01790 in BCG and Rv0309 in Ms_rv0309 strain enhanced mycobacterial survival in macrophages. Mice infected with BCGΔRS01790 exhibited high levels of IFN-γ, TNF-α and IL-1β, and large numbers of neutrophils and lymphocytes in the early stage, and minimal lung bacterial load and inflammatory damage in late stage of the experiment. In conclusion, the cell wall protein Rv0309 or BCG_RS01790 enhanced mycobacterial intracellular survival after infection likely through inhibition of the pro-inflammatory response and decrease of bacterial cell wall permeability, thereby contributing to mycobacterial pathogenesis.
Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines
Authors: Hou Jue , Ye Weijian , Chen Jianzhu
Published: February 2022

Dengue is the most common arboviral disease caused by one of four distinct but closely related dengue viruses (DENV) and places significant economic and public health burdens in the endemic areas. A dengue vaccine will be important in advancing disease control. However, the effort has been challenged by the requirement to induce effective protection against all four DENV serotypes and the potential adverse effect due to the phenomenon that partial immunity to DENV may worsen the symptoms upon subsequent heterotypic infection. Currently, the most advanced dengue vaccines are all tetravalent and based on recombinant live attenuated viruses. CYD-TDV, developed by Sanofi Pasteur, has been approved but is limited for use in individuals with prior dengue infection. Two other tetravalent live attenuated vaccine candidates: TAK-003 by Takeda and TV003 by National Institute of Allergy and Infectious Diseases, have completed phase 3 and phase 2 clinical trials, respectively. This review focuses on the designs and evaluation of TAK-003 and TV003 vaccine candidates in humans in comparison to the licensed CYD-TDV vaccine. We highlight specific lessons from existing studies and challenges that must be overcome in order to develop a dengue vaccine that confers effective and balanced protection against all four DENV serotypes but with minimal adverse effects.