bluuebunny/crossref_metadata_2025 huggingface dataset:
SPINT1-AS1 Drives Cervical Cancer Progression via Repressing miR-214 Biogenesis
Authors: Song Hongjuan , Liu Yuan , Liang Hui , Jin Xin , Liu Liping
Published: July 2021

Accumulating evidences have revealed the dysregulated expressions and critical roles of non-coding RNAs in various malignancies, including cervical cancer. Nevertheless, our knowledge about the vast majority of non-coding RNAs is still lacking. Here we identified long non-coding RNA (lncRNA) SPINT1-AS1 as a novel cervical cancer-associated lncRNA. SPINT1-AS1 was increased in cervical cancer and correlated with advanced stage and poor prognosis. SPINT1-AS1 was a direct downstream target of miR-214, a well-known tumor suppressive microRNA (miRNA) in cervical cancer. Intriguingly, SPINT1-AS1 was also found to repress miR-214 biogenesis via binding DNM3OS, the primary transcript of miR-214. The interaction between SPINT1-AS1 and DNM3OS repressed the binding of DROSHA and DGCR8 to DNM3OS, blocked DNM3OS cleavage, and therefore repressed mature miR-214 biogenesis. The expression of SPINT1-AS1 was significantly negatively correlated with miR-214 in cervical cancer tissues, supporting the reciprocal repression between SPINT1-AS1 and miR-214 in vivo. Through downregulating mature miR-214 level, SPINT1-AS1 upregulated the expression of β-catenin, a target of miR-214. Thus, SPINT1-AS1 further activated Wnt/β-catenin signaling in cervical cancer. Functionally, SPINT1-AS1 drove cervical cancer cellular proliferation, migration, and invasion in vitro, and also tumorigenesis in vivo. Deletion of the region mediating the interaction between SPINT1-AS1 and DNM3OS, overexpression of miR-214, and inhibition of Wnt/β-catenin signaling all reversed the roles of SPINT1-AS1 in cervical cancer. Collectively, these findings identified SPINT1-AS1 as a novel cervical cancer-associated oncogenic lncRNA which represses miR-214 biogenesis and activates Wnt/β-catenin signaling, highlighting its potential as prognostic biomarker and therapeutic target for cervical cancer.
Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents
Authors: Wu Chung-Pu , Murakami Megumi , Wu Yu-Shan , Chi Ya-Chen , Hsiao Sung-Han , Huang Yang-Hui , Hung Tai-Ho , Ambudkar Suresh V.
Published: July 2021

The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.
Inhibition of Calcineurin/NFAT Signaling Blocks Oncogenic H-Ras Induced Autophagy in Primary Human Keratinocytes
Authors: Wang Shuangshuang , Qian Hua , Zhang Liwei , Liu Panpan , Zhuang Dexuan , Zhang Qun , Bai Fuxiang , Wang Zhihong , Yan Yonggan , Guo Jing , Huang Jun , Wu Xunwei
Published: July 2021

Mutations of H-Ras, a member of the RAS family, are preferentially found in cutaneous squamous cell carcinomas (SCCs). H-Ras has been reported to induce autophagy, which plays an essential role in tissue homeostasis in multiple types of cancer cells and in fibroblasts, however, the potential role of H-Ras in regulating autophagy in human keratinocytes has not been reported. In this study, we found that the stable expression of the G12V mutant of H-RAS (H-RasG12V) induced autophagy in human keratinocytes, and interestingly, the induction of autophagy was strongly blocked by inhibiting the calcineurin/nuclear factor of activated T cells (NFAT) pathway with either a calcineurin inhibitor (Cyclosporin A) or a NFAT inhibitor (VIVIT), or by the small interfering RNA (siRNA) mediated knockdown of calcineurin B1 or NFATc1 in vitro, as well as in vivo. To characterize the role of the calcineurin/NFAT pathway in H-Ras induced autophagy, we found that H-RasG12V promoted the nuclear translocation of NFATc1, an indication of the activation of the calcineurin/NFAT pathway, in human keratinocytes. However, activation of NFATc1 either by the forced expression of NFATc1 or by treatment with phenformin, an AMPK activator, did not increase the formation of autophagy in human keratinocytes. Further study revealed that inhibiting the calcineurin/NFAT pathway actually suppressed H-Ras expression in H-RasG12V overexpressing cells. Finally, chromatin immunoprecipitation (ChIP) assays showed that NFATc1 potentially binds the promoter region of H-Ras and the binding efficiency was significantly enhanced by the overexpression of H-RasG12V, which was abolished by treatment with the calcineurin/NFAT pathway inhibitors cyclosporine A (CsA) or VIVIT. Taking these data together, the present study demonstrates that the calcineurin/NFAT signaling pathway controls H-Ras expression and interacts with the H-Ras pathway, involving the regulation of H-Ras induced autophagy in human keratinocytes.
Recent Developments in the Use of Glyconanoparticles and Related Quantum Dots for the Detection of Lectins, Viruses, Bacteria and Cancer Cells
Authors: Hernando Pedro J. , Dedola Simone , Marín María J. , Field Robert A.
Published: July 2021

Carbohydrate-coated nanoparticles—glyconanoparticles—are finding increased interest as tools in biomedicine. This compilation, mainly covering the past five years, comprises the use of gold, silver and ferrite (magnetic) nanoparticles, silicon-based and cadmium-based quantum dots. Applications in the detection of lectins/protein toxins, viruses and bacteria are covered, as well as advances in detection of cancer cells. The role of the carbohydrate moieties in stabilising nanoparticles and providing selectivity in bioassays is discussed, the issue of cytotoxicity encountered in some systems, especially semiconductor quantum dots, is also considered. Efforts to overcome the latter problem by using other types of nanoparticles, based on gold or silicon, are also presented.
Radical SAM Enzymes and Ribosomally‐Synthesized and Post‐translationally Modified Peptides: A Growing Importance in the Microbiomes
Authors: Benjdia Alhosna , Berteau Olivier
Published: July 2021

To face the current antibiotic resistance crisis, novel strategies are urgently required. Indeed, in the last 30 years, despite considerable efforts involving notably high-throughput screening and combinatorial libraries, only few antibiotics have been launched to the market. Natural products have markedly contributed to the discovery of novel antibiotics, chemistry and drug leads, with more than half anti-infective and anticancer drugs approved by the FDA being of natural origin or inspired by natural products. Among them, thanks to their modular structure and simple biosynthetic logic, ribosomally synthesized and posttranslationally modified peptides (RiPPs) are promising scaffolds. In addition, recent studies have highlighted the pivotal role of RiPPs in the human microbiota which remains an untapped source of natural products. In this review, we report on recent developments in radical SAM enzymology and how these unique biocatalysts have been shown to install complex and sometimes unprecedented posttranslational modifications in RiPPs with a special focus on microbiome derived enzymes.
Label-free Electrochemical Impedance Spectroscopy Aptasensor for Ultrasensitive Detection of Lung Cancer Biomarker Carcinoembryonic Antigen
Authors: Wang Yawei , Chen Lei , Xuan Tiantian , Wang Jian , Wang Xiuwen
Published: July 2021

In this work, an integrated electrode system consisting of a graphene working electrode, a carbon counter electrode and an Ag/AgCl reference electrode was fabricated on an FR-4 glass fiber plate by a polyethylene self-adhesive mask stencil method combined with a manual screen printing technique. The integrated graphene electrode was used as the base electrode, and AuNPs were deposited on the working electrode surface by cyclic voltammetry. Then, the carcinoembryonic antigen aptamer was immobilized using the sulfhydryl self-assembly technique. The sensor uses [Fe(CN)6]3−/4− as a redox probe for label free detection of carcinoembryonic antigen based on the impedance change caused by the difference in electron transfer rate before and after the binding of carcinoembryonic antigen aptamer and the target carcinoembryonic antigen. The results showed a good linear relationship when the CEA concentration is in the range of 0.2–15.0 ng/ml. The detection limit was calculated to be 0.085 ng/ml (S/N = 3).
Contamination of Stream Sediment With Heavy Metals in the Awetu Watershed of Southwestern Ethiopia
Authors: Astatkie Higemengist , Ambelu Argaw , Mengistie Embialle
Published: July 2021

Surface sediment samples were collected from different streams of Awetu Watershed in southwestern Ethiopia. Sediment samples were analyzed for As, Cd, Cr, Pb, and Hg levels using inductively coupled plasma optical emission spectrometry. The heavy metal concentration ranged from 183.60 to 1,102.80 mg/kg for As (mean 623.32 ± 291.65 mg/kg), 4.40–303.20 mg/kg for Cd (151.09 ± 111.5 mg/kg), 149.20–807.20 mg/kg for Cr (375 ± 212.03 mg/kg), 485.60–3,748.80 mg/kg for Pb (2005.94 ± 954.99 mg/kg) and 3.6–5.6 mg/kg for Hg (4.64 ± 0.59 mg/kg). The mean heavy metal concentration in the streams followed the decreasing order of Pb > As > Cr > Cd > Hg. As, Cr and Pb are detected at high concentrations with values of 623.32, 375.00, and 2,005.94 mg/kg respectively. A low level of heavy concentration (3.6 mg/kg) was recorded for Hg. The contamination factor (CF) of all the studied heavy metals ranged from a low degree (CF < 1) to a very high degree (CF ≤ 6). Mainly, Dololo and Kito streams show a very high degree of contamination (CF ≤ 6) than Awetu and Boye streams. Specifically, As, Cd and Cr in the Dololo and Kito streams have significantly elevated concentrations than others. Geo-accumulation index (Igeo) shows low to moderate contamination level with As, Pb, and Hg; uncontaminated to heavily contaminated by Cr; and moderate to extreme contamination by Cd. Untreated solid waste, garages and farmlands were sources of contamination. Streams receiving wastewater effluents from teaching institutions had higher heavy metal concentrations. Dumping of electronic wastes and car washing discharges also identified as another source of pollution.
A Field Guide for Monitoring Riverine Macroplastic Entrapment in Water Hyacinths
Authors: Schreyers Louise , van Emmerik Tim , Nguyen Thanh Luan , Phung Ngoc-Anh , Kieu-Le Thuy-Chung , Castrop Evelien , Bui Thanh-Khiet L. , Strady Emilie , Kosten Sarian , Biermann Lauren , van den Berg Sanne J.P. , van der Ploeg Martine
Published: July 2021

River plastic pollution is an environmental challenge of growing concern. However, there are still many unknowns related to the principal drivers of river plastic transport. Floating aquatic vegetation, such as water hyacinths, have been found to aggregate and carry large amounts of plastic debris in tropical river systems. Monitoring the entrapment of plastics in hyacinths is therefore crucial to answer the relevant scientific and societal questions. Long-term monitoring efforts are yet to be designed and implemented at large scale and various field measuring techniques can be applied. Here, we present a field guide on available methods that can be upscaled in space and time, to characterize macroplastic entrapment within floating vegetation. Five measurement techniques commonly used in plastic and vegetation monitoring were applied to the Saigon river, Vietnam. These included physical sampling, Unmanned Aerial Vehicle imagery, bridge imagery, visual counting, and satellite imagery. We compare these techniques based on their suitability to derive metrics of interest, their relevancy at different spatiotemporal scales and their benefits and drawbacks. This field guide can be used by practitioners and researchers to design future monitoring campaigns and to assess the suitability of each method to investigate specific aspects of macroplastic and floating vegetation interactions.
Bark Effects on Stemflow Chemistry in a Japanese Temperate Forest II. The Role of Bark Anatomical Features
Authors: Oka Ayano , Takahashi Junko , Endoh Yoshikazu , Seino Tatsuyuki
Published: July 2021

A fraction of rainfall drains to the soil surface down tree stems (as “stemflow”), and the resulting stemflow waters can be highly enriched with dissolved nutrients due to prolonged bark contact. To date, stemflow chemistry has been examined mostly in regards to the external morphology of the bark, while its relationship with bark anatomy has received little attention. Arguably, this represents a major knowledge gap, because bark anatomical traits are linked to the storage and transport of soluble (and insoluble) organic materials, and control the proximity of these materials to passing stemflow waters. To initiate this line of investigation, here, we examine bark-water leaching rates for common leachable macronutrient ions (Mg2+, Ca2+, and K+) across six different tree species with varying bark anatomical traits (four deciduous broadleaved and two evergreen coniferous species). These different bark types were subjected to laboratory experiments, including observations of bark anatomy and soaking experiments. Laboratory-derived estimates of leaching rates for Mg2+, Ca2+, and K+ were then analyzed alongside bark anatomical traits. Leaching rates of Mg2+ and Ca2+ appear to be controlled by the thickness of the rhytidome and periderm; while K+ leaching rates appeared to be driven by the presence of cellular structures associated with resource storage (parenchyma) and transfer (sieve cells). Other species-specific results are also identified and discussed. These results suggest that the anatomical features of bark and the concentration of leachable macronutrient ions in stemflow are related, and that these relationships may be important to understand nutrient cycle through the bark. We also conclude that future work on the mechanisms underlying stemflow solute enrichment should consider bark anatomy.
scGPS: Determining Cell States and Global Fate Potential of Subpopulations
Authors: Thompson Michael , Matsumoto Maika , Ma Tianqi , Senabouth Anne , Palpant Nathan J. , Powell Joseph E. , Nguyen Quan
Published: July 2021

Finding cell states and their transcriptional relatedness is a main outcome from analysing single-cell data. In developmental biology, determining whether cells are related in a differentiation lineage remains a major challenge. A seamless analysis pipeline from cell clustering to estimating the probability of transitions between cell clusters is lacking. Here, we present Single Cell Global fate Potential of Subpopulations (scGPS) to characterise transcriptional relationship between cell states. scGPS decomposes mixed cell populations in one or more samples into clusters (SCORE algorithm) and estimates pairwise transitioning potential (scGPS algorithm) of any pair of clusters. SCORE allows for the assessment and selection of stable clustering results, a major challenge in clustering analysis. scGPS implements a novel approach, with machine learning classification, to flexibly construct trajectory connections between clusters. scGPS also has a feature selection functionality by network and modelling approaches to find biological processes and driver genes that connect cell populations. We applied scGPS in diverse developmental contexts and show superior results compared to a range of clustering and trajectory analysis methods. scGPS is able to identify the dynamics of cellular plasticity in a user-friendly workflow, that is fast and memory efficient. scGPS is implemented in R with optimised functions using C++ and is publicly available in Bioconductor.
Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis
Authors: Kristan Aleša , Pajič Tadej , Maver Aleš , Režen Tadeja , Kunej Tanja , Količ Rok , Vuga Andrej , Fink Martina , Žula Špela , Podgornik Helena , Anžej Doma Saša , Preložnik Zupan Irena , Rozman Damjana , Debeljak Nataša
Published: July 2021

An erythrocytosis is present when the red blood cell mass is increased, demonstrated as elevated hemoglobin and hematocrit in the laboratory evaluation. Congenital predispositions for erythrocytosis are rare, with germline variants in several genes involved in oxygen sensing (VHL, EGLN1, and EPAS1), signaling for hematopoietic cell maturation (EPOR and EPO), and oxygen transfer (HBB, HBA1, HBA2, and BPGM) that were already associated with the eight congenital types (ECYT1–8). Screening for variants in known congenital erythrocytosis genes with classical sequencing approach gives a correct diagnosis for only up to one-third of the patients. The genetic background of erythrocytosis is more heterogeneous, and additional genes involved in erythropoiesis and iron metabolism could have a putative effect on the development of erythrocytosis. This study aimed to detect variants in patients with yet unexplained erythrocytosis using the next-generation sequencing (NGS) approach, targeting genes associated with erythrocytosis and increased iron uptake and implementing the diagnostics of congenital erythrocytosis in Slovenia. Selected 25 patients with high hemoglobin, high hematocrit, and no acquired causes were screened for variants in the 39 candidate genes. We identified one pathogenic variant in EPAS1 gene and three novel variants with yet unknown significance in genes EPAS1, JAK2, and SH2B3. Interestingly, a high proportion of patients were heterozygous carriers for two variants in HFE gene, otherwise pathogenic for the condition of iron overload. The association between the HFE variants and the development of erythrocytosis is not clearly understood. With a targeted NGS approach, we determined an actual genetic cause for the erythrocytosis in one patient and contributed to better management of the disease for the patient and his family. The effect of variants of unknown significance on the enhanced production of red blood cells needs to be further explored with functional analysis. This study is of great significance for the improvement of diagnosis of Slovenian patients with unexplained erythrocytosis and future research on the etiology of this rare hematological disorder.
Combination of a Novel Genetic Variant in CFB Gene and a Pathogenic Variant in COL4A5 Gene in a Sibling Renal Disease: A Case Report
Authors: Wang Feng-mei , Yang Yan , Zhang Xiao-liang , Wang Yan-li , Tu Yan , Liu Bi-Cheng , Wang Bin
Published: July 2021

Complement factor B (CFB) variants have been described to play a causative role in auto-immune associated C3 glomerulopathy (C3G) and/or atypical hemolytic uremic syndrome (aHUS) by affecting the dysregulations of alternative pathway activation. However, CFB variant concomitant with COL4A5 variant is scarce. Here, we depict two intriguing cases with concurrent novel heterozygosity for CFB c.2054_2057del (p.Ser687Profs∗16) variant and a previous reported COL4A5 c.2999G > T (p.Gly1000Val) variant in a pair of siblings. The clinical feature of either paternal CFB variant or maternal COL4A5 variant is just mild microscopic hematuria. Interestingly, their two children with paternal CFB c.2054_2057del (p.Ser687Profs∗16) variant and maternal COL4A5 c.2999G > T (p.Gly1000Val) variant presented with massive proteinuria, hematuria, and progressive renal failure with poor treatment response. Moreover, complement pathway activation in renal tissue further supports and strengthens the pathogenic role of CFB variant in the development of renal injury in the presence of COL4A5 variant. In conclusion, the rare sibling cases highlight that the extension of genetic analyses in the proband is helpful for the diagnosis and understanding of some family cluster renal diseases.
Alpha-Enolase Protects Hepatocyte Against Heat Stress Through Focal Adhesion Kinase-Mediated Phosphatidylinositol 3-Kinase/Akt Pathway
Authors: Zeng Tao , Cao Yongqing , Gu Tiantian , Chen Li , Tian Yong , Li Guoqin , Shen Junda , Tao Zhenrong , Lu Lizhi
Published: July 2021

Accumulating pieces of evidence showed that α-enolase (ENO1) is a multifunctional protein that plays a crucial role in a variety of pathophysiological processes. In our previous study, differential expression of ENO1 was observed in different heat-tolerance duck breeds. Here, we examined in vitro expression level of ENO1 in hepatocytes against heat stress. The mechanisms of ENO1 on cell glycolysis, growth, and its potential regulatory pathways were also analyzed. The results showed that ENO1 expression in messenger RNA and protein levels were both greatly increased in heat-treated cells compared with non-treated cells. ENO1-overexpressed cells significantly elevated cell viability and glycolysis levels. It was further shown that stably upregulated ENO1 activated focal adhesion kinase-phosphatidylinositol 3-kinase/Akt and its downstream signals. In addition, the interaction between ENO1 and 70-kDa heat shock protein was detected using co-immunoprecipitation. Our research suggests that ENO1 may interact with 70-kDa heat shock protein to protect hepatocyte against heat stress through focal adhesion kinase-mediated phosphatidylinositol 3-kinase/Akt pathway.
IntSplice2: Prediction of the Splicing Effects of Intronic Single-Nucleotide Variants Using LightGBM Modeling
Authors: Takeda Jun-ichi , Fukami Sae , Tamura Akira , Shibata Akihide , Ohno Kinji
Published: July 2021

Prediction of the effect of a single-nucleotide variant (SNV) in an intronic region on aberrant pre-mRNA splicing is challenging except for an SNV affecting the canonical GU/AG splice sites (ss). To predict pathogenicity of SNVs at intronic positions −50 (Int-50) to −3 (Int-3) close to the 3’ ss, we developed light gradient boosting machine (LightGBM)-based IntSplice2 models using pathogenic SNVs in the human gene mutation database (HGMD) and ClinVar and common SNVs in dbSNP with 0.01 ≤ minor allelic frequency (MAF) < 0.50. The LightGBM models were generated using features representing splicing cis-elements. The average recall/sensitivity and specificity of IntSplice2 by fivefold cross-validation (CV) of the training dataset were 0.764 and 0.884, respectively. The recall/sensitivity of IntSplice2 was lower than the average recall/sensitivity of 0.800 of IntSplice that we previously made with support vector machine (SVM) modeling for the same intronic positions. In contrast, the specificity of IntSplice2 was higher than the average specificity of 0.849 of IntSplice. For benchmarking (BM) of IntSplice2 with IntSplice, we made a test dataset that was not used to train IntSplice. After excluding the test dataset from the training dataset, we generated IntSplice2-BM and compared it with IntSplice using the test dataset. IntSplice2-BM was superior to IntSplice in all of the seven statistical measures of accuracy, precision, recall/sensitivity, specificity, F1 score, negative predictive value (NPV), and matthews correlation coefficient (MCC). We made the IntSplice2 web service at https://www.med.nagoya-u.ac.jp/neurogenetics/IntSplice2.
Community-Engaged Approaches to Cervical Cancer Prevention and Control in Sub-Saharan Africa: A Scoping Review
Authors: Habila Magdiel A. , Kimaru Linda Jepkoech , Mantina Namoonga , Valencia Dora Yesenia , McClelland D. Jean , Musa Jonah , Madhivanan Purnima , Sagay Atiene , Jacobs Elizabeth T.
Published: July 2021

Background:Cervical cancer remains one of the top causes of cancer mortality among African women. Cervical cancer screening and early detection and treatment of precancer is one of the evidence-based interventions to reduce incidence and mortality. The application of community-based participatory research (CBPR) has been used in the United States to improve participation in screening and reduce cervical cancer disparities. However, it is unclear whether these engaged approaches have been used in sub-Saharan African to address disparities related to cervical cancer mortality.

Objectives:Highlight community engagement in cervical cancer prevention and control in Sub-Saharan Africa (SSA), describe the community engagement efforts that are currently being used, and to describe the best practices for community engagement toward the end-goal of cervical cancer prevention and control.

Methods:We searched PubMed, Embase, CINHAL, African Journals Online (AJOL), and African Index Medicus-WHO from inception until June 8, 2020. After screening 620 titles and abstracts, and reviewing 56 full-text articles according to inclusion and exclusion criteria, 9 articles met the selection criteria and were included. Relevant data variables were extracted from the included articles and a narrative synthesis was performed.

Results:Between 2005 and 2019, 9 articles describing research in Ghana, Kenya, Zambia, Senegal, South Africa, and Nigeria were included. These articles described work that largely took place in rural settings predominantly among women age 15–65 years. Leveraging community networks such as community health workers, religious organizations, traditional leaders, and educational institutions increased awareness of cervical cancer. Working within existing social structures and training community members through the research effort were promising methods for addressing the disparities in cervical cancer incidence and mortality among communities.

Discussion:The findings of this scoping review have contributed to the understanding of which novel approaches to community-based practices can be used to address cervical cancer disparities among SSA communities that carry a disproportionate disease burden. Community engagement in the research process, while effortful, has shown to be beneficial to researchers and to the communities that they serve, and provides valuable next steps in the effort to address cervical cancer disparities in SSA.
Influence of HLA Class II Polymorphism on Predicted Cellular Immunity Against SARS-CoV-2 at the Population and Individual Level
Authors: Copley Hannah C. , Gragert Loren , Leach Andrew R. , Kosmoliaptsis Vasilis
Published: July 2021

Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty five human race/ethnic populations to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and individual level. Within populations, we identify wide inter-individual variability in predicted peptide presentation from structural, non-structural and accessory SARS-CoV-2 proteins, according to individual HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race/ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.
Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis
Authors: Jin Shuqing , Ding Xibing , Yang Chenxuan , Li Wenbo , Deng Meihong , Liao Hong , Lv Xin , Pitt Bruce R. , Billiar Timothy R. , Zhang Li-Ming , Li Quan
Published: July 2021

Background

The mechanisms by which moderate tidal volume ventilation (MTV) exacerbates preexisting lung injury are unclear. We hypothesized that systemic endotoxemia via the gut-lung axis would lead to non-canonical and canonical inflammasome activation and pyroptosis in a two-hit model involving polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV and that this would associate with acute lung injury (ALI).

Methods

Anesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype (WT), whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD)-/-, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3)-/- and advanced glycosylation end product-specific receptor (RAGE) -/- mice.

Results

Non-injurious MTV exacerbated the mild lung injury associated with Poly(I:C) administration. This included the disruption of alveolar-capillary barrier and increased levels of interleukin (IL)-6, high mobility group proteins 1 (HMGB-1), IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in caspase-1 and caspase-11. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and release of cytokines in combined injury model.

Conclusions

The previously noted exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two-hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies aimed at disrupting communication between gut and lung, inhibition of inflammasomes or GSDMD in pyroptosis may be useful in ALI.
A Comprehensive Analysis of Immune Constituents in Blood and Bronchoalveolar Lavage Allows Identification of an Immune Signature of Severe Asthma in Children
Authors: Adel-Patient Karine , Grauso Marta , Abou-Taam Rola , Guillon Blanche , Dietrich Céline , Machavoine François , Briard Mélanie , Garcelon Nicolas , Faour Hassan , Neuraz Antoine , Delacourt Christophe , Molina Thierry Jo , Leite-de-Moraes Maria , Lezmi Guillaume
Published: July 2021

Background

Targeted approaches may not account for the complexity of inflammation involved in children with severe asthma (SA), highlighting the need to consider more global analyses. We aimed to identify sets of immune constituents that distinguish children with SA from disease-control subjects through a comprehensive analysis of cells and immune constituents measured in bronchoalveolar lavage (BAL) and blood.

Methods

Twenty children with SA and 10 age-matched control subjects with chronic respiratory disorders other than asthma were included. Paired blood and BAL samples were collected and analyzed for a large set of cellular (eosinophils, neutrophils, and subsets of lymphocytes and innate lymphoid cells) and soluble (chemokines, cytokines, and total antibodies) immune constituents. First, correlations of all immune constituents between BAL and blood and with demographic and clinical data were assessed (Spearman correlations). Then, all data were modelled using supervised multivariate analyses (partial least squares discriminant analysis, PLS-DA) to identify immune constituents that significantly discriminate between SA and control subjects. Univariate analyses were performed (Mann-Whitney tests) and then PLS-DA and univariate analyses were combined to identify the most discriminative and significant constituents.

Results

Concentrations of soluble immune constituents poorly correlated between BAL and blood. Certain constituents correlated with age or body mass index and, in asthmatics, with clinical symptoms, such as the number of exacerbations in the previous year, asthma control test score, or forced expiratory volume. Multivariate supervised analysis allowed construction of a model capable of distinguishing children with SA from control subjects with 80% specificity and 100% sensitivity. All immune constituents contributed to the model but some, identified by variable-important-in-projection values > 1 and p < 0.1, contributed more strongly, including BAL Th1 and Th2 cells and eosinophilia, CCL26 (Eotaxin 3), IgA and IL-19 concentrations in blood. Blood concentrations of IL-26, CCL13, APRIL, and Pentraxin-3 may also help in the characterization of SA.

Conclusions

The analysis of a large set of immune constituents may allow the identification of a biological immune signature of SA. Such an approach may provide new leads for delineating the pathogenesis of SA in children and identifying new targets for its diagnosis, prediction, and personalized treatment.
Antibody Repertoire Analysis of Tumor-Infiltrating B Cells Reveals Distinct Signatures and Distributions Across Tissues
Authors: Aizik Ligal , Dror Yael , Taussig David , Barzel Adi , Carmi Yaron , Wine Yariv
Published: July 2021

The role of B cells in the tumor microenvironment (TME) has largely been under investigated, and data regarding the antibody repertoire encoded by B cells in the TME and the adjacent lymphoid organs are scarce. Here, we utilized B cell receptor high-throughput sequencing (BCR-Seq) to profile the antibody repertoire signature of tumor-infiltrating lymphocyte B cells (TIL−Bs) in comparison to B cells from three anatomic compartments in a mouse model of triple-negative breast cancer. We found that TIL-Bs exhibit distinct antibody repertoire measures, including high clonal polarization and elevated somatic hypermutation rates, suggesting a local antigen-driven B-cell response. Importantly, TIL-Bs were highly mutated but non-class switched, suggesting that class-switch recombination may be inhibited in the TME. Tracing the distribution of TIL-B clones across various compartments indicated that they migrate to and from the TME. The data thus suggests that antibody repertoire signatures can serve as indicators for identifying tumor-reactive B cells.
Assessment of Expression of SOCS Genes in Acquired Immune-Mediated Polyneuropathies
Authors: Taheri Mohammad , Sangseifid Somayeh , Shahani Pariya , Eftekharian Mohammad Mahdi , Arsang-Jang Shahram , Ghafouri-Fard Soudeh
Published: July 2021

Acquired immune-mediated polyneuropathies are classified to some subtypes among them are acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP). These two conditions share some common signs and underlying mechanisms. Based on the roles of Suppressor of cytokine signaling (SOCS) genes in the modulation of immune system reactions, these genes might be involved in the pathogenesis of these conditions. We evaluated expression of SOCS1-3 and SOCS5 genes in the leukocytes of 32 cases of CIDP, 19 cases of AIDP and 40 age- and sex-matched controls using real time PCR method. The Bayesian regression model was used to estimate differences in mean values of genes expressions between cases and control group. Expression levels of SOCS1 and SOCS2 were significantly lower in male patients compared with controls. This sex-specific pattern was also observed for SOCS3 down-regulation. Based on the area under curve values in Receiver Operating Characteristics (ROC) curve, diagnostic powers of SOCS1, SOCS2, SOCS3 and SOCS5 genes in the mentioned disorder were 0.61, 0.73, 0.68 and 0.58, respectively. Expression of none of genes was correlated with age of enrolled cases. The current study shows evidences for participation of SOCS genes in the pathophysiology of acquired immune-mediated polyneuropathies.
Dynamic Alterations of the Distal Intestinal Microbiota, Transcriptome, and Metabolome of Hybrid Grouper by β -Conglycinin With Reconciliations by Sodium Butyrate in Feed
Authors: Yin Bin , Liu Hongyu , Tan Beiping , Dong Xiaohui , Chi Shuyan , Yang Qihui , Zhang Shuang
Published: July 2021

Different doses of β-conglycinin produce different regulations on the intestinal health of aquatic animals, affecting the absorption of nutrients, indirectly changing water quality. Sodium butyrate (NaB) can effectively alleviate the negative effects caused by high-dose β-conglycinin. We investigated the positive response to low-dose (1.5%, bL) and negative response to high-dose (6.0%, bH) β-conglycinin and supplementation with NaB (6.0% β-conglycinin + 0.13% NaB, bHNaB) in terms of water pollutants, microbiota, transcriptome, and metabolome in hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂). The ammonia nitrogen, nitrite, total nitrogen, and total phosphorus contents were significantly higher in the water from bH than from FMb, bL, and bHNaB. Supplementing with NaB significantly reduced the ammonia nitrogen, nitrite, total nitrogen, and total phosphorus contents. Low-dose β-conglycinin increased the relative abundance of Pelagibacterium, Pediococcus, Staphylococcus, and Lactobacillus and promoted the “ribosome,” “peroxisome proliferator-activated receptor (PPAR) signaling” and “histidine metabolism.” High-dose β-conglycinin increased the relative abundance of pathogenic bacteria Ralstonia and Photobacterium and inhibited the “cell cycle” “PPAR signaling” and “starch and proline metabolism.” NaB supplementation at high-dose β-conglycinin reduced the Ralstonia and Photobacterium abundance and promoted the “cell cycle,” “linoleic acid metabolism,” and “ABC transporters.” Overall, these results reveal differences in the effects of high- and low-dose β-conglycinin, as well as NaB supplementation, on the utilization of proteins, carbohydrates, and lipids and on substance transport and signaling among distal intestinal cells of hybrid grouper. A total of 15 differential metabolite biomarkers were identified: FMb vs. bL contained 10-methylimidazole acetic acid, N-acetyl histamine, urocanic acid, creatinine, glutathione, taurine, nervonic acid, stearic acid, docosanoic acid, and D-serine; FMb vs. bH contained 4-L-fucose, sucrose, α,α-trehalose, and quercetin; and bH vs. bHNaB contained 4-N-acetyl histamine, urocanic acid, creatinine, and S-adenosylhomocysteine, respectively. Our study provides new insights into the regulation of intestinal health by β-conglycinin in aquatic animals and the protective mechanism of NaB.
Brain Shape Changes Associated With Cerebral Atrophy in Healthy Aging and Alzheimer’s Disease
Authors: Blinkouskaya Yana , Weickenmeier Johannes
Published: July 2021

Both healthy and pathological brain aging are characterized by various degrees of cognitive decline that strongly correlate with morphological changes referred to as cerebral atrophy. These hallmark morphological changes include cortical thinning, white and gray matter volume loss, ventricular enlargement, and loss of gyrification all caused by a myriad of subcellular and cellular aging processes. While the biology of brain aging has been investigated extensively, the mechanics of brain aging remains vastly understudied. Here, we propose a multiphysics model that couples tissue atrophy and Alzheimer’s disease biomarker progression. We adopt the multiplicative split of the deformation gradient into a shrinking and an elastic part. We model atrophy as region-specific isotropic shrinking and differentiate between a constant, tissue-dependent atrophy rate in healthy aging, and an atrophy rate in Alzheimer’s disease that is proportional to the local biomarker concentration. Our finite element modeling approach delivers a computational framework to systematically study the spatiotemporal progression of cerebral atrophy and its regional effect on brain shape. We verify our results via comparison with cross-sectional medical imaging studies that reveal persistent age-related atrophy patterns. Our long-term goal is to develop a diagnostic tool able to differentiate between healthy and accelerated aging, typically observed in Alzheimer’s disease and related dementias, in order to allow for earlier and more effective interventions.
Production of Sm-153 With Very High Specific Activity for Targeted Radionuclide Therapy
Authors: Van de Voorde Michiel , Duchemin Charlotte , Heinke Reinhard , Lambert Laura , Chevallay Eric , Schneider Thomas , Van Stenis Miranda , Cocolios Thomas Elias , Cardinaels Thomas , Ponsard Bernard , Ooms Maarten , Stora Thierry , Burgoyne Andrew R.
Published: July 2021

Samarium-153 (153Sm) is a highly interesting radionuclide within the field of targeted radionuclide therapy because of its favorable decay characteristics. 153Sm has a half-life of 1.93 d and decays into a stable daughter nuclide (153Eu) whereupon β− particles [E = 705 keV (30%), 635 keV (50%)] are emitted which are suitable for therapy. 153Sm also emits γ photons [103 keV (28%)] allowing for SPECT imaging, which is of value in theranostics. However, the full potential of 153Sm in nuclear medicine is currently not being exploited because of the radionuclide's limited specific activity due to its carrier added production route. In this work a new production method was developed to produce 153Sm with higher specific activity, allowing for its potential use in targeted radionuclide therapy. 153Sm was efficiently produced via neutron irradiation of a highly enriched 152Sm target (98.7% enriched, σth = 206 b) in the BR2 reactor at SCK CEN. Irradiated target materials were shipped to CERN-MEDICIS, where 153Sm was isolated from the 152Sm target via mass separation (MS) in combination with laser resonance enhanced ionization to drastically increase the specific activity. The specific activity obtained was 1.87 TBq/mg (≈ 265 times higher after the end of irradiation in BR2 + cooling). An overall mass separation efficiency of 4.5% was reached on average for all mass separations. Further radiochemical purification steps were developed at SCK CEN to recover the 153Sm from the MS target to yield a solution ready for radiolabeling. Each step of the radiochemical process was fully analyzed and characterized for further optimization resulting in a high efficiency (overall recovery: 84%). The obtained high specific activity (HSA) 153Sm was then used in radiolabeling experiments with different concentrations of 4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA). Even at low concentrations of p-SCN-Bn-DOTA, radiolabeling of 0.5 MBq of HSA 153Sm was found to be efficient. In this proof-of-concept study, we demonstrated the potential to combine neutron irradiation with mass separation to supply high specific activity 153Sm. Using this process, 153SmCl3 suitable for radiolabeling, was produced with a very high specific activity allowing application of 153Sm in targeted radionuclide therapy. Further studies to incorporate 153Sm in radiopharmaceuticals for targeted radionuclide therapy are ongoing.
Lung Ultrasound in the Diagnosis of COVID-19 Pneumonia: Not Always and Not Only What Is COVID-19 “Glitters”
Authors: Quarato Carla Maria Irene , Mirijello Antonio , Maggi Michele Maria , Borelli Cristina , Russo Raffaele , Lacedonia Donato , Foschino Barbaro Maria Pia , Scioscia Giulia , Tondo Pasquale , Rea Gaetano , Simeone Annalisa , Feragalli Beatrice , Massa Valentina , Greco Antonio , De Cosmo Salvatore , Sperandeo Marco
Published: July 2021

Background: In the current coronavirus disease-2019 (COVID-19) pandemic, lung ultrasound (LUS) has been extensively employed to evaluate lung involvement and proposed as a useful screening tool for early diagnosis in the emergency department (ED), prehospitalization triage, and treatment monitoring of COVID-19 pneumonia. However, the actual effectiveness of LUS in characterizing lung involvement in COVID-19 is still unclear. Our aim was to evaluate LUS diagnostic performance in assessing or ruling out COVID-19 pneumonia when compared with chest CT (gold standard) in a population of SARS-CoV-2-infected patients.

Methods: A total of 260 consecutive RT-PCR confirmed SARS-CoV-2-infected patients were included in the study. All the patients underwent both chest CT scan and concurrent LUS at admission, within the first 6–12 h of hospital stay.

Results: Chest CT scan was considered positive when showing a “typical” or “indeterminate” pattern for COVID-19, according to the RSNA classification system. Disease prevalence for COVID-19 pneumonia was 90.77%. LUS demonstrated a sensitivity of 56.78% in detecting lung alteration. The concordance rate for the assessment of abnormalities by both methods increased in the case of peripheral distribution and middle-lower lung location of lesions and in cases of more severe lung involvement. A total of nine patients had a “false-positive” LUS examination. Alternative diagnosis included chronic heart disease (six cases), bronchiectasis (two cases), and subpleural emphysema (one case). LUS specificity was 62.50%. Collateral findings indicative of overlapping conditions at chest CT were recorded also in patients with COVID-19 pneumonia and appeared distributed with increasing frequency passing from the group with mild disease (17 cases) to that with severe disease (40 cases).

Conclusions: LUS does not seem to be an adequate tool for screening purposes in the ED, due to the risk of missing some lesions and/or to underestimate the actual extent of the disease. Furthermore, the not specificity of LUS implies the possibility to erroneously classify pre-existing or overlapping conditions as COVID-19 pneumonia. It seems more safe to integrate a positive LUS examination with clinical, epidemiological, laboratory, and radiologic findings to suggest a “virosis.” Viral testing confirmation is always required.