bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular Vesicles in Reprogramming of the Ewing Sarcoma Tumor Microenvironment
Authors: Pachva Manideep C. , Lai Horton , Jia Andy , Rouleau Melanie , Sorensen Poul H.
Published: September 2021

Ewing sarcoma (EwS) is a highly aggressive cancer and the second most common malignant bone tumor of children and young adults. Although patients with localized disease have a survival rate of approximately 75%, the prognosis for patients with metastatic disease remains dismal (<30%) and has not improved in decades. Standard-of-care treatments include local therapies such as surgery and radiotherapy, in addition to poly-agent adjuvant chemotherapy, and are often associated with long-term disability and reduced quality of life. Novel targeted therapeutic strategies that are more efficacious and less toxic are therefore desperately needed, particularly for metastatic disease, given that the presence of metastasis remains the most powerful predictor of poor outcome in EwS. Intercellular communication within the tumor microenvironment is emerging as a crucial mechanism for cancer cells to establish immunosuppressive and cancer-permissive environments, potentially leading to metastasis. Altering this communication within the tumor microenvironment, thereby preventing the transfer of oncogenic signals and molecules, represents a highly promising therapeutic strategy. To achieve this, extracellular vesicles (EVs) offer a candidate mechanism as they are actively released by tumor cells and enriched with proteins and RNAs. EVs are membrane-bound particles released by normal and tumor cells, that play pivotal roles in intercellular communication, including cross-talk between tumor, stromal fibroblast, and immune cells in the local tumor microenvironment and systemic circulation. EwS EVs, including the smaller exosomes and larger microvesicles, have the potential to reprogram a diversity of cells in the tumor microenvironment, by transferring various biomolecules in a cell-specific manner. Insights into the various biomolecules packed in EwS EVs as cargos and the molecular changes they trigger in recipient cells of the tumor microenvironment will shed light on various potential targets for therapeutic intervention in EwS. This review details EwS EVs composition, their potential role in metastasis and in the reprogramming of various cells of the tumor microenvironment, and the potential for clinical intervention.
The Application of Microfluidic Technologies in Aptamer Selection
Authors: Liu Yang , Wang Nijia , Chan Chiu-Wing , Lu Aiping , Yu Yuanyuan , Zhang Ge , Ren Kangning
Published: September 2021

Aptamers are sequences of single-strand oligonucleotides (DNA or RNA) with potential binding capability to specific target molecules, which are increasingly used as agents for analysis, diagnosis, and medical treatment. Aptamers are generated by a selection method named systematic evolution of ligands by exponential enrichment (SELEX). Numerous SELEX methods have been developed for aptamer selections. However, the conventional SELEX methods still suffer from high labor intensity, low operation efficiency, and low success rate. Thus, the applications of aptamer with desired properties are limited. With their advantages of low cost, high speed, and upgraded extent of automation, microfluidic technologies have become promising tools for rapid and high throughput aptamer selection. This paper reviews current progresses of such microfluidic systems for aptamer selection. Comparisons of selection performances with discussions on principles, structure, operations, as well as advantages and limitations of various microfluidic-based aptamer selection methods are provided.
Toll Like Receptors as Sensors of the Tumor Microbial Dysbiosis: Implications in Cancer Progression
Authors: Le Noci Valentino , Bernardo Giancarla , Bianchi Francesca , Tagliabue Elda , Sommariva Michele , Sfondrini Lucia
Published: September 2021

The microbiota is a complex ecosystem of active microorganisms resident in the body of mammals. Although the majority of these microorganisms resides in the distal gastrointestinal tract, high-throughput DNA sequencing technology has made possible to understand that several other tissues of the human body host their own microbiota, even those once considered sterile, such as lung tissue. These bacterial communities have important functions in maintaining a healthy body state, preserving symbiosis with the host immune system, which generates protective responses against pathogens and regulatory pathways that sustain the tolerance to commensal microbes. Toll-like receptors (TLRs) are critical in sensing the microbiota, maintaining the tolerance or triggering an immune response through the direct recognition of ligands derived from commensal microbiota or pathogenic microbes. Lately, it has been highlighted that the resident microbiota influences the initiation and development of cancer and its response to therapies and that specific changes in the number and distribution of taxa correlate with the existence of cancers in various tissues. However, the knowledge of functional activity and the meaning of microbiome changes remain limited. This review summarizes the current findings on the function of TLRs as sensors of the microbiota and highlighted their modulation as a reflection of tumor-associated changes in commensal microbiota. The data available to date suggest that commensal “onco-microbes” might be able to break the tolerance of TLRs and become complicit in cancer by sustaining its growth.
Complexity and Simplification in Language Shift
Authors: Kantarovich Jessica , Grenoble Lenore A. , Vinokurova Antonina , Nesterova Elena
Published: September 2021

This paper examines the question of linguistic complexity in two shift ecologies in northeastern Russia. It is frequently claimed that language shift results in linguistic simplification across a range of domains in the grammars of shifting speakers (Campbell and Muntzel 1989;Dorian 1989;O’Shannessy 2011). We challenge the breadth of this claim, showing that while there are undoubtedly patterns that can be described as a simplification of some grammatical domain, the overall grammars of these speakers cannot be said to be “simple,” as simplification in one part of the grammar often corresponds to complexification in other parts (“complexity trade-offs”). Furthermore, patterns that are deemed loss or simplification are often presented in such a way because they are being compared to earlier varieties of the shifting languages; however, such patterns are entirely typologically expected, are consistent with other languages of the world, and can be seen as more or less complex depending on one’s locus of measurement. In this paper, we present incipient changes taking place in Chukchi (Chukotko-Kamchatkan, ISO ckt) and Even (Tungusic, ISO eve) stemming from the modern language shift context. We evaluate these changes against different notions of complexity to demonstrate that a more nuanced approach to morphosyntactic change in language obsolescence is warranted. While morphological simplification is expected in these scenarios, other changes in these speakers’ systems (occurring as potential adaptations in light of simplification) provide a more enlightening avenue for research on shifting varieties.
Heterogeneity Characteristics of Lacustrine Shale Oil Reservoir Under the Control of Lithofacies: A Case Study of the Dongyuemiao Member of Jurassic Ziliujing Formation, Sichuan Basin
Authors: Li Peng , Liu Zhongbao , Nie Haikuan , Liang Xinping , Li Qianwen , Wang Pengwei
Published: September 2021

The lacustrine shale in the Dongyuemiao Member of the Fuling area, Sichuan Basin, is widely distributed and has huge shale oil resource potential. It is one of the important replacement areas for shale oil exploration in China. To investigate the key shale oil evaluation well, Well FY10, in the Fuling area, X-ray diffraction (XRD) mineral analysis, Rock-Eval, argon ion polishing-scanning electron microscope (SEM), Mercury injection capillary pressure (MICP), and low pressure nitrogen adsorption were launched to determine the heterogeneity of the pore system in the lacustrine shale of the Dongyuemiao Member. The mineral composition exhibits a high degree of heterogeneity, and the shale can be divided into two main lithofacies: argillaceous shale and mixed shale. The porosity ranges from 2.95 to 8.43%, and the permeability ranges from 0.05 to 1.07 × 10−3 μm2. The physical properties of mixed shale are obviously better than those of argillaceous shale. Inorganic mineral pores, such as linear pores between clay minerals and calcite dissolution pores, are mainly developed, while a small amount of organic pores can be observed. The average total pore volume (Vp) is 0.038 ml/g with an average specific surface area of 5.38 m2/g. Mesopores provide the main Vp (average 61.72%), and micropores provide mostly specific surface area. TOC imposes a strong controlling effect on the development of micropores. Clay minerals are the main contributors to mesopores and macropores. The organic-inorganic interaction during the process of diagenesis and hydrocarbon generation controls the formation of shale pore systems.
Interdecadal Linkage Between the Winter Northern Hemisphere Climate and Arctic Sea Ice of Diverse Location and Seasonality
Authors: He Xulong , Zhang Ruonan , Ding Shuoyi , Zuo Zhiyan
Published: September 2021

During the past few decades, Arctic sea-ice has declined rapidly in both autumn and winter, which is likely to link extreme weather and climate events across the Northern Hemisphere midlatitudes. Here, we use reanalysis data to investigate the possible linkage between mid–high-latitude atmospheric circulation and Arctic sea-ice loss in different geographical locations and seasons and associated impacts on wintertime climate on interdecadal timescales. Four critical sea-ice subregions are analyzed in this study—namely, the Pan-Arctic, Barents–Kara–Laptev Seas (BKL), East Siberia–Chukchi–Beaufort Seas (EsCB), and Bering Sea (Ber). Results suggest that interdecadal reduction of autumn sea-ice, irrespective of geographical location, is dynamically associated with the negative phase of the North Atlantic Oscillation (NAO) in the subsequent winter via stratospheric pathways. Specifically, autumn sea-ice loss appears to cause a weakened stratospheric polar vortex that propagates to the troposphere in the ensuing months, leading to lower surface air temperature and a deficit in precipitation over Siberia and northeastern North America. Meanwhile, an anomalous cyclone over Europe favors excessive precipitation over southern Europe. For wintertime sea-ice loss in the Pan-Arctic and BKL, a weak positive NAO phase, with a dipole pressure pattern over Greenland–northeastern North America and North Atlantic, and a shrunken Siberian high over Eurasia are observed over mid–high-latitudes. The former results in excessive precipitation over northwestern and southeastern North America, whilst the latter leads to less precipitation and mild winter over Siberia. In contrast, Ber sea-ice loss is associated with a circumglobal wave train downstream of the Bering Sea, leading to extensive warming over Eurasia. The anomalous dipole cyclone and anticyclone over the Bering Sea transport more Pacific and Arctic water vapor to North America, and the anomalous cyclone over the Barents Sea results in abundant precipitation in Siberia. Such midlatitude anomaly is dynamically linked to winter sea-ice loss, mainly through tropospheric rather than stratospheric pathways. These results have important implications for future seasonal and interdecadal forecasts in the context of ongoing sea-ice decline.
Effectiveness of Medical Treatment of Cushing’s Disease: A Systematic Review and Meta-Analysis
Authors: Simões Corrêa Galendi Julia , Correa Neto Afonso Nogueira Simões , Demetres Michelle , Boguszewski Cesar Luiz , Nogueira Vania dos Santos Nunes
Published: September 2021

Objective

The objective of this systematic review was to evaluate the effectiveness and safety of pasireotide, cabergoline, ketoconazole, levoketoconazole, metyrapone, osilodrostat, and temozolomide for the treatment of Cushing’s disease (CD).

Methods

The primary outcomes were the proportion of CD control, adverse events (AE), and reduction of urinary free cortisol. Search strategies were applied to Embase, Medline, and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Standardized mean difference was calculated with 95% confidence interval (CI) for continuous data (i.e., pre- and post-intervention). Random meta-analyses for the proportion of CD control and AE were conducted.

Results

Twenty-nine controlled and non-controlled studies were included. No study with temozolomide and levoketoconazole and one study with osilodrostat fulfilled the inclusion criteria. The meta-analyses of proportion of CD control was 35% for cabergoline (95% CI: 27–43%, six studies, 141 participants), 44% for pasireotide (95% CI: 25–35%, eight studies, 522 participants), 41% for ketoconazole (95% CI: 36–46%, six studies, 450 participants), 66% for metyrapone (95% CI: 46–87%, four studies, 66 participants), and of 66.4% for osilodrostat (95% CI: 57.9, 74.3, 97 participants, one study). One study compared two different treatments (cabergoline vs. ketoconazole), and no statistical difference was observed in CD control (RR: 0.53, 95% CI: 0.15 to 1.87, 14 participants, very low certainty of evidence). The most frequent AE associated with pasireotide was hyperglycemia, dizziness and nausea with cabergoline and metyrapone, and elevated transaminases with ketoconazole.

Conclusion

The superiority of one drug over another could not be determined due to lack of controlled studies, but the proportion of disease control identified in our meta-analysis may support clinical decision. New therapeutic options should be investigated due to the limited efficacy and tolerability of the currently available medical treatment for patients with Cushing’s disease.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205567, identifier CRD42020205567.
The Prevalence, Popular Trends, and Associated and Predictive Factors of Non-Obese Fatty Liver Disease
Authors: Deng Jiang , Zhang Yonghong , Bu Limei , Shi Haitao , Tang Hailing , Wang Shenhao , Wang Qian , Dang Shuangsuo , Li Ming , Han Zhiyi , Lu Xiaolan
Published: September 2021

Background and Aims

There are few studies on non-obese fatty liver disease, the aims of this study was to analyze its prevalence, popular trends, and associated and predictive factors, so as to provide reference for its prevention and treatment.

Methods

Individuals with complete data of body mass index, sex, age, and abdominal ultrasound in Karamay Central Hospital from 2009 to 2016 were selected to analyze the prevalence and popular trends of non-obese fatty liver disease (body mass index <24 kg/m2), and associated and predictive factors.

Results

Between 2009 and 2016, a total of 191,555 medical check-ups were included. The prevalence of non-obese fatty liver disease increased from 1.9% to 5.1% among general medical examinants (P<0.001), increased from 4.6% to 11.7% in non-obese individuals (P<0.001). Compared with the non-obese control group, the levels of age, body mass index, blood pressure, fasting blood glucose, triglycerides, total cholesterol and uric acid in the non-obese fatty liver group were higher (P<0. 05). Even among non-obese subjects, elevated body mass index was associated with a 0.63-fold increased risk for non-obese fatty liver disease (P<0.001, odds ratio=1.63, 95% confidence interval 1.54-1.72) for every one-unit increase in body mass index. The most common abnormal indicator of non-obese fatty liver disease was elevated triglycerides (44.2%), which was also the best predictor of non-obese fatty liver disease (area under the curve =0.795) in non-obese physical examinators.

Conclusions

The prevalence of non-obese fatty liver disease was high and increasing rapidly in Karamay. Triglycerides is the best predictor of non-obese fatty liver in non-obese physical examinators.
Distributed Economic Optimal Scheduling Scheme for Ship-Integrated Energy System Based on Load Prediction Algorithm
Authors: Zhang Yuxin , Shan Qihe , Teng Fei , Li Tieshan
Published: September 2021

In order to enhance navigation safety and promote environmental protection, this paper takes the problem of energy management in a ship-integrated energy system into consideration. According to the characteristics of navigation, an intelligent ship energy management model, simultaneously considering the social and economic benefits, has been proposed. Meanwhile, this paper analyzes a distributed optimal scheduling problem which considers renewable generation devices and an energy storage system. Combined with an electricity-power system and thermal-power system, we propose an optimal scheduling scheme to accurately meet the actual load demand based on the pre-results analyzed by the ensemble learning short-term load forecasting algorithm. In addition, the related stability analysis is given. Further, a series of simulation results have been presented, which denote that the proposed load forecasting algorithm can accurately analyze the short-term load demand trend, and the proposed optimization algorithm can effectively coordinate economic and environmental protection.
Regional Non-point Source Pollution Control Method: A Design of Ecological Compensation Standards
Authors: Lu Shibao , Zhong Weijun , Li Wei , Taghizadeh-Hesary Farhad
Published: September 2021

Reasonable ecological compensation standard is the key to solve farmland non-point source pollution. In the design of compensation standards, the current investigation included ecological benefits in selecting the experimental method. The Multinomial Logit model is used to analyze the willingness of farmers to receive compensation for non-point source pollution control of cultivated land. The results are as follows: 1) Financial compensation can effectively stimulate farmers’ willingness to control non-point source pollution. 2) The willingness of farmers to participate in the ecological compensation is greater when there prevails a higher level of risk preferences and higher understanding of farmland non-point source pollution control policy. Also, willingness is higher in younger, highly educated, and highly involved in a part-time family business with higher recognition degree in the ecological function of farmland non-point source pollution control. 3) The difference in treatment measures and compensation methods should be included in the standard compensation design. Therefore, the design of the ecological compensation standard should take into account the economic loss and ecological benefits of farmers at the same time, and environmental protection publicity and education for farmers can also be carried out with the help of modern media.
Necromys lasiurus: Lessons From a 38-Year Study in an Amazonian Savanna
Authors: da Rosa Clarissa Alves , Ganança Pedro Henrique Salomão , Lima Albertina Pimentel , Magnusson William Ernest
Published: September 2021

Amazonian savannas are isolated patches of open habitats within an array of extensive tropical forest. The mammal fauna of the savannas in the Alter do Chão region (Santarém Municipality), is dominated byNecromys lasiurus, whose populations have been studied by researchers of the National Institute of Amazonian Research since 1983. Here, we summarize the studies and advances made so far to better understand aspects related to population dynamics and ecology of savanna rodents and the strategies they use to persist in an environment with frequent fires subject to global climatic influences. In the Amazonian savannas the species acts as a seed disperser and population fluctuations are related to invertebrate availability, but not with fire or vegetation structure. Global climate appears to affectN. lasiuruspopulation dynamics at local scale (i.e., plot scale) but not at the regional scale of the Alter do Chão savannas. The long-term studies in Alter do Chão generated many advances aboutNecromys lasiuruspopulation dynamics and ecology, including aspects relating to feeding, home range, animal-plant interactions, the effects of fire and climate change.
Nutritional Immunity, Zinc Sufficiency, and COVID-19 Mortality in Socially Similar European Populations
Authors: Singh Samer , Diwaker Amita , Singh Brijesh P. , Singh Rakesh K.
Published: September 2021

The impact of zinc (Zn) sufficiency/supplementation on COVID-19-associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of “nutritional immunity” to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8,000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150-fold difference in death rates) and at the matching stage of the pandemic (March 12 to June 26, 2020; first wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations’ Zn-sufficiency status and COVID-19 mortality [r (23): 0.7893–0.6849, p-value < 0.0003] as well as incidence [r (23):0.8084–0.5658; p-value < 0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients’ data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.
Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity
Authors: Hadjadj Jérôme , Frémond Marie-Louise , Neven Bénédicte
Published: September 2021

Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.
TP53 Mutation Status and Biopsy Lesion Type Determine the Immunotherapeutic Stratification in Non-Small-Cell Lung Cancer
Authors: Lu Jun , Zhong Runbo , Lou Yuqing , Hu Minjuan , Yang Zhengyu , Wang Yanan , Chen Ya , Zou Benkun , Zhang Wei , Wang Huimin , Han Baohui
Published: September 2021

Immunotherapy, a chemotherapy-free process, has emerged as a promising therapeutic strategy to prolong the overall survival (OS) of patients with non-small-cell lung cancer (NSCLC). However, effective stratification factors for immunotherapy remain unclear. The purpose of this study was to discuss the potential stratification factors of NSCLC immunotherapy using immune checkpoint inhibitors (ICIs) by integrating genomic profiling and tumor lesion–type information. In this study, 344 patients with NSCLC, whose clinical and tissue (including metastatic and primary lesions) mutation information was available, were included. The potential gene mutation status for predicting the outcomes of immunotherapy was screened by comparing the difference in mutation frequency between responders and non-responders. Our results indicated that the potential predictors of immunotherapy were significantly different, especially between patients with TP53(+) (including metastatic and primary lesions) and TP53(−) (including metastatic and primary lesions). According to this classification, patients with NSCLC who suggested immunotherapy had a higher OS than those who did not (25 months vs. 7 months, P < 0.0001, hazard ratio = 0.39). Collectively, this study provides a new perspective for screening immunotherapy predictors in NSCLC, suggesting that the TP53 mutation status and source of biopsy tissue should be considered during the development of immunotherapy biomarkers.
IL-7 in SARS-CoV-2 Infection and as a Potential Vaccine Adjuvant
Authors: Bekele Yonas , Sui Yongjun , Berzofsky Jay A.
Published: September 2021

IL-7/IL-7R signaling is critical for development, maturation, maintenance and survival of many lymphocytes in the thymus and periphery. IL-7 has been used as immunotherapy in pre-clinical and clinical studies to treat cancer, HIV infection and sepsis. Here, we discuss the critical function of IL-7 in diagnosis, prognosis and treatment of COVID-19 patients. We also summarize a promising role of IL-7 as a vaccine adjuvant. It could potentially enhance the immune responses to vaccines especially against SARS-CoV-2 or other new vaccines.
Peripheral B-Cell Immunophenotyping Identifies Heterogeneity in IgG4-Related Disease
Authors: Li Jieqiong , Liu Zheng , Zhang Panpan , Lin Wei , Lu Hui , Peng Yu , Peng Linyi , Zhou Jiaxin , Wang Mu , Chen Hua , Zhao Lidan , Wang Li , Qin Chenman , Hu Chaojun , Zeng Xiaofeng , Zhao Yan , Fei Yunyun , Zhang Wen
Published: September 2021

Objectives

To elucidate heterogeneity of IgG4-related disease (IgG4-RD) based on B cell immunophenotyping.

Methods

Immunophenotyping of 4 B-cell subsets in peripheral blood from patients with active IgG4-RD (aIgG4-RD, n=105) was performed using flow cytometry to get preliminary B-cell heterogeneity spectrum. Then 10 B-cell subsets were characterized in aIgG4-RD (n = 49), remissive IgG4-RD (rIgG4-RD, n = 49), and healthy controls (HCs, n = 47), followed by principal components analysis (PCA) and cluster analysis to distinguish B-cell immunophenotypes and classify IgG4-RD patients into subgroups.

Results

Cluster analysis identified two endotypes in 105 aIgG4-RD patients based on 4 B-cell subsets: Group1 with higher Breg and naive B cells (n = 48), and Group2 with higher plasmablasts and memory B cells (MBCs) (n = 57). PCA indicated that aIgG4-RD consisted of plasmablast-naive B cell and MBCs-Breg axes abnormalities. There was a negative relationship between naive B cells and disease activity. Both plasmablasts and MBCs were positively associated with serological biomarkers. Cluster analysis stratified aIgG4-RD patients into 3 subgroups based on 10 B-cell subsets: subgroup1 with low MBCs and normal Breg, subgroup2 with high MBCs and low Breg, and subgroup3 with high plasmablasts and low naive B cells. Patients in subroup2 and subgroup3 were more likely to be resistant to treatment.

Conclusion

Patients with aIgG4-RD can be divided into 3 subgroups based on B cell heterogeneity. The B cell immunophenotyping could help elucidate the pathogenesis of IgG4-RD, identify patients with potential refractory IgG4-RD, and provide important information for the development of new therapies.
Where Epigenetics Meets Food Intake: Their Interaction in the Development/Severity of Gout and Therapeutic Perspectives
Authors: Georgel Philippe T. , Georgel Philippe
Published: September 2021

Gout is the most frequent form of inflammatory arthritis in the world. Its prevalence is particularly elevated in specific geographical areas such as in the Oceania/Pacific region and is rising in the US, Europe, and Asia. Gout is a severe and painful disease, in which co-morbidities are responsible for a significant reduction in life expectancy. However, gout patients remain ostracized because the disease is still considered “self-inflicted”, as a result of unhealthy lifestyle and excessive food and alcohol intake. While the etiology of gout flares is clearly associated with the presence of monosodium urate (MSU) crystal deposits, several major questions remain unanswered, such as the relationships between diet, hyperuricemia and gout flares or the mechanisms by which urate induces inflammation. Recent advances have identified gene variants associated with gout incidence. Nevertheless, genetic origins of gout combined to diet-related possible uric acid overproduction account for the symptoms in only a minor portion of patients. Hence, additional factors must be at play. Here, we review the impact of epigenetic mechanisms in which nutrients (such as ω-3 polyunsaturated fatty acids) and/or dietary-derived metabolites (like urate) trigger anti/pro-inflammatory responses that may participate in gout pathogenesis and severity. We propose that simple dietary regimens may be beneficial to complement therapeutic management or contribute to the prevention of flares in gout patients.
A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions
Authors: Watanabe Aruma , Mizoguchi Izuru , Hasegawa Hideaki , Katahira Yasuhiro , Inoue Shinya , Sakamoto Eri , Furusaka Yuma , Sekine Ami , Miyakawa Satomi , Murakami Fumihiro , Xu Mingli , Yoneto Toshihiko , Yoshimoto Takayuki
Published: September 2021

The interleukin-6 (IL-6)/IL-12 family of cytokines plays critical roles in the induction and regulation of innate and adaptive immune responses. Among the various cytokines, only this family has the unique characteristic of being composed of two distinct subunits, α- and β-subunits, which form a heterodimer with subunits that occur in other cytokines as well. Recently, we found a novel intracellular role for one of the α-subunits, Epstein-Barr virus-induced gene 3 (EBI3), in promoting the proper folding of target proteins and augmenting its expression at the protein level by binding to its target protein and a well-characterized lectin chaperone, calnexin, presumably through enhancing chaperone activity. Because calnexin is ubiquitously and constitutively expressed but EBI3 expression is inducible, these results could open an avenue to establish a new paradigm in which EBI3 plays an important role in further increasing the expression of target molecules at the protein level in collaboration with calnexin under inflammatory conditions. This theory well accounts for the heterodimer formation of EBI3 with p28, and probably with p35 and p19 to produce IL-27, IL-35, and IL-39, respectively. In line with this concept, another β-subunit, p40, plays a critical role in the assembly-induced proper folding of p35 and p19 to produce IL-12 and IL-23, respectively. Thus, chaperone-like activities in proper folding and maturation, which allow the secretion of biologically active heterodimeric cytokines, have recently been highlighted. This review summarizes the current understanding of chaperone-like activities of EBI3 to form heterodimers and other associations together with their possible biological implications.
Grounding Ocean Ethics While Sharing Knowledge and Promoting Environmental Responsibility: Empowering Young Ambassadors as Agents of Change
Authors: Cappelletto Margherita , Giuffredi Rita , Kastanidi Erasmia , Vassilopoulou Vassiliki , L'Astorina Alba
Published: September 2021

Actions addressing youths and marine science for “ambassadorship” are increasingly implemented via dedicated programs at the European and global level within the relevant policy frameworks, as a way for fostering the exchange of knowledge and cross-fertilizing practices among the Countries and basins. These programs are conceived to address the future generations of scientists, entrepreneurs, policymakers, and citizens, and to promote the awareness and shared responsibility on the sustainable use of marine resources in an authentic and credible way, through the empowerment of young researchers and professionals, communicators, or activists. Thus, such ambassadors are well-positioned to act as agents of change, improving the dimension of Ocean Ethics related to inclusive governance, especially necessary for an equal, just, and sustainable management of multi-actor and transboundary socio-environmental contexts. Pivoting on the Young Ambassadors' Program developed in the framework of the BlueMed Research and Innovation (R&I) Initiative for blue jobs and growth in the Mediterranean area as case practice, the article aimed to propose some reflections about the long-term perspective of such experiences. Outlining an emerging physiognomy of the “One Ocean Ambassadors,” it discusses their potential to build the next generation of responsible scientists, citizens, and decision-makers and to embed ethical principles in research-based marine governance. In addition, it addresses process-related elements, such as balancing advocacy and ethics and reflecting on the role of science communication. To further consolidate this practice, this article finally seeks to incorporate the intercultural aspects to connect the local to the global dimension toward a sustainable and value-based ocean governance.
Detection of Excess Presence of 99mTc-MDP Near Injection Site—A Case Report
Authors: Crowley James R. , Barvi Iryna , Greulich Debbie , Kiser Jackson W.
Published: September 2021

Nuclear medicine extravasations and prolonged venous stasis may cause poor quality and quantification errors that can affect image interpretation and patient management. Radiopharmaceutical remaining near the administration site means that some portion of the radioactivity is not circulating as required for the prescribed uptake period. This case describes how detection of excess presence of99mTc-MDP near the injection site enabled the technologist to apply mitigation tactics early in the uptake process. It also suggests that detecting an extravasation or stasis early in the injection process can be important for image interpretation and minimizing radiation dose to tissue.
Cerebral Aneurysm Occlusion at 12-Month Follow-Up After Flow-Diverter Treatment: Statistical Modeling for V&V With Real-World Data
Authors: Narata Ana Paula , Obradó Laura , Moyano Raquel Kalé , Macho Juan M. , Blasco Jordi , Rueda Antonio López , Roman Luis San , Remollo Sebastian , Marinelli Claudia , Cepeda Rosana , Fernández Héctor , Larrabide Ignacio
Published: September 2021

Background: Flow-Diverter (FD) porosity has been pointed as a critical factor in the occlusion of cerebral aneurysms after treatment.

Objective: Verification and Validation of computational models in terms of predictive capacity, relating FD porosity and occlusion after cerebral aneurysms treatment.

Methods: Sixty-four aneurysms, with pre-treatment and follow-up images, were considered. Patient demographics and aneurysm morphological information were collected. The computational simulation provided by ANKYRAS provided FD porosity, expansion, and mesh angle. FD occlusion was assessed and recorded from follow-up images. Multiple regression Logit and analysis of covariance (ANCOVA) models were used to model the data with both categorical and continuous models.

Results: Occlusion of the aneurysm after 12 months was affected by aneurysm morphology but not by FD mesh morphology. A Time-To-Occlusion (TTO) of 6.92 months on average was observed with an SE of 0.24 months in the aneurysm population surveyed. TTO was estimated with statistical significance from the resulting model for the data examined and was capable of explaining 92% of the data variation.

Conclusions: Porosity was found to have the most correction power when assessing TTO, proving its importance in the process of aneurysm occlusion. Still, further Verification and Validation (V&V) of treatment simulation in more extensive, multi-center, and randomized databases is required.
Multidrug Resistant Acinetobacter baumannii Biofilms: Evaluation of Phenotypic–Genotypic Association and Susceptibility to Cinnamic and Gallic Acids
Authors: Sherif Mahmoud M. , Elkhatib Walid F. , Khalaf Wafaa S. , Elleboudy Nooran S. , Abdelaziz Neveen A.
Published: September 2021

Acinetobacter baumannii armed with multidrug resistance (MDR) and biofilm-forming ability is increasingly recognized as an alarming pathogen. A deeper comprehension of the correlation between these two armories is required in circumventing its infections. This study examined the biofilm-forming ability of the isolates by crystal violet staining and the antibiotic susceptibility by broth microdilution method. The genetic basis of the MDR and biofilm-forming phenotypes was screened by polymerase chain reaction. The antimicrobial activities of cinnamic and gallic acids against planktonic cells and biofilms of A. baumannii were investigated, and the findings were confirmed with scanning electron microscopy (SEM). Among 90 A. baumannii isolates, 69 (76.6%) were MDR, and all were biofilm formers; they were classified into weak (12.2%), moderate (53.3%), and strong (34.5%) biofilm formers. Our results underlined a significant association between MDR and enhanced biofilm formation. Genotypically, the presence of blaVIM and blaOXA–23 genes along with biofilm-related genes (ompA, bap, and csuE) was statistically associated with the biofilm-forming abilities. Impressively, both gallic and cinnamic acids could significantly reduce the MDR A. baumannii biofilms with variable degrees dependent on the phenotype–genotype characteristics of the tested isolates. The current findings may possess future therapeutic impact through augmenting antimicrobial arsenal against life-threatening infections with MDR A. baumannii biofilms.
Fnr Negatively Regulates Prodigiosin Synthesis in Serratia sp. ATCC 39006 During Aerobic Fermentation
Authors: Sun Di , Zhou Xuge , Liu Cong , Zhu Jingrong , Ru Yunrui , Liu Weijie , Liu Jiawen
Published: September 2021

The well-known Crp/Fnr family regulator Fnr has long been recognized as an oxygen sensor to regulate multiple biological processes, including the switch between aerobic/anaerobic metabolism, nitrogen fixation, bioluminescence, infection, and virulence. In most cases, Fnr was found to be active under anaerobic conditions. However, its role in aerobic antibiotic metabolism has not yet been revealed. In this research, we report that in the model organism, Serratia sp. ATCC 39006, Fnr (Ser39006_013370) negatively regulates prodigiosin production by binding to the spacer between the −10 and −35 region in the promoter of prodigiosin biosynthetic gene cluster under aerobic conditions. Fnr was also shown to modulate the anti-bacterial activity and motility by regulating pathway-specific regulatory genes, indicating that Fnr acts as a global regulator in Serratia sp. ATCC 39006. For the first time, we describe that Fnr regulates antibiotic synthesis in the presence of oxygen, which expands the known physiological functions of Fnr and benefits the further investigation of this important transcriptional regulator.
Alteration and the Function of Intestinal Microbiota in High-Fat-Diet- or Genetics-Induced Lipid Accumulation
Authors: Qiao Fang , Tan Fang , Li Ling-Yu , Lv Hong-Bo , Chen Liqiao , Du Zhen-Yu , Zhang Mei-Ling
Published: September 2021

Diet and host genetics influence the composition of intestinal microbiota, yet few studies have compared the function of intestinal microbiota in the diet- or genotype-induced lipid deposition, which limits our understanding of the role of intestinal bacteria in metabolic disorders. The lipid accumulation in wild-type zebrafish fed with control (CON) or high-fat (HF) diet and two gene-knockout zebrafish lines (cpt1b–/– or pparab–/–) fed with control diet was measured after a 4-week feeding experiment. The intestinal microbiota composition of these groups was investigated using 16S ribosomal RNA (rRNA) gene sequencing (DNA-based) and 16S rRNA sequencing (RNA-based). The HF diet or deficiency of two genes induced more weight gain and higher triglyceride content in the liver compared with their control group. 16S rRNA gene sequencing (DNA-based) indicated the decreased abundance of Proteobacteria in the HF group compared with CON, but there was no significant difference in bacterial α diversity among treatments. 16S rRNA sequencing (RNA-based) confirmed the decreased abundance of Proteobacteria and the bacterial α diversity in the HF group compared with CON. Deficiency of cpt1b or pparab showed less change in microbiota composition compared with their wild-type group. Intestinal microbiota of each group was transferred to germ-free zebrafish, and the quantification of Nile red staining indicated that the intestinal microbiota of the HF group induced more lipid accumulation compared with CON, whereas intestinal microbiota of cpt1b–/– and pparab–/– zebrafish did not. The results showed that RNA-based bacterial sequencing revealed more bacterial alteration than DNA-based bacterial sequencing. HF diet had a more dominant role in shaping gut microbiota composition to induce lipid accumulation compared with the gene-knockout of cpt1b or pparab in zebrafish, and the transplant of intestinal microbiota from HF-fed fish induced more lipid deposition in germ-free zebrafish. Together, these data suggested that a high-fat diet exerted a more dominant role over the deletion of cpt1b or pparab on the intestinal bacterial composition, which corresponded to lipid accumulation.
Combined Transcriptomic and Lipidomic Analysis Reveals Dysregulated Genes Expression and Lipid Metabolism Profiles in the Early Stage of Fatty Liver Disease in Rats
Authors: Zhai Ruina , Feng Lei , Zhang Yu , Liu Wei , Li Shengli , Hu Zhiyong
Published: September 2021

Non-alcoholic fatty liver disease develops from simple steatosis to non-alcoholic steatohepatitis (NASH), which then potentially develops into liver cirrhosis. It is a serious threat to human health. Therefore, investigating the formation and development mechanism of non-alcoholic fatty liver disease (NAFLD) is of great significance. Herein, an early model of NAFLD was successfully established by feeding rats with a high-fat and choline-deficient diet. Liver tissue samples were obtained from rats in the fatty liver model group (NAFL) and normal diet control group (CON). Afterward, transcriptome and lipidomic analysis was performed. Transcriptome results revealed that 178 differentially expressed genes were detected in NAFL and CON groups. Out of which, 105 genes were up-regulated, 73 genes were downregulated, and 8 pathways were significantly enriched. A total of 982 metabolites were detected in lipidomic analysis. Out of which 474 metabolites were significantly different, 273 were up-regulated, 201 were downregulated, and 7 pathways were significantly enriched. Based on the joint analysis, 3 common enrichment pathways were found, including cholesterol metabolism and fat digestion and absorption metabolic pathways. Overall, in the early stage of NAFLD, a small number of genetic changes caused a strong response to lipid components. The strongest reflection was glycerides and glycerophospholipids. A significant increase in fatty acid uptake accompanied by cholesterol metabolism is the most prominent metabolic feature of the liver in the early stage of NAFLD. In the early stage of fatty liver, the liver had shown the characteristics of NASH.
Multi-Task Deep Supervision on Attention R2U-Net for Brain Tumor Segmentation
Authors: Ma Shiqiang , Tang Jijun , Guo Fei
Published: September 2021

Accurate automatic medical image segmentation technology plays an important role for the diagnosis and treatment of brain tumor. However, simple deep learning models are difficult to locate the tumor area and obtain accurate segmentation boundaries. In order to solve the problems above, we propose a 2D end-to-end model of attention R2U-Net with multi-task deep supervision (MTDS). MTDS can extract rich semantic information from images, obtain accurate segmentation boundaries, and prevent overfitting problems in deep learning. Furthermore, we propose the attention pre-activation residual module (APR), which is an attention mechanism based on multi-scale fusion methods. APR is suitable for a deep learning model to help the network locate the tumor area accurately. Finally, we evaluate our proposed model on the public BraTS 2020 validation dataset which consists of 125 cases, and got a competitive brain tumor segmentation result. Compared with the state-of-the-art brain tumor segmentation methods, our method has the characteristics of a small parameter and low computational cost.
High Throughput Transcriptome Data Analysis and Computational Verification Reveal Immunotherapy Biomarkers of Compound Kushen Injection for Treating Triple-Negative Breast Cancer
Authors: Liu Xinkui , Wu Yang , Zhang Yingying , Bu Dechao , Wu Chao , Lu Shan , Huang Zhihong , Song Yurong , Zhao Yi , Guo Fengying , Ye Peizhi , Fu Changgeng , Shen Liangliang , Zhang Jingyuan , Wang Haojia , Duan Xianchun , Wu Jiarui
Published: September 2021

Background

Although notable therapeutic and prognostic benefits of compound kushen injection (CKI) have been found when it was used alone or in combination with chemotherapy or radiotherapy for triple-negative breast cancer (TNBC) treatment, the effects of CKI on TNBC microenvironment remain largely unclear. This study aims to construct and validate a predictive immunotherapy signature of CKI on TNBC.

Methods

The UPLC-Q-TOF-MS technology was firstly used to investigate major constituents of CKI. RNA sequencing data of CKI-perturbed TNBC cells were analyzed to detect differential expression genes (DEGs), and the GSVA algorithm was applied to explore significantly changed pathways regulated by CKI. Additionally, the ssGSEA algorithm was used to quantify immune cell abundance in TNBC patients, and these patients were classified into distinct immune infiltration subgroups by unsupervised clustering. Then, prognosis-related genes were screened from DEGs among these subgroups and were further overlapped with the DEGs regulated by CKI. Finally, a predictive immunotherapy signature of CKI on TNBC was constructed based on the LASSO regression algorithm to predict mortality risks of TNBC patients, and the signature was also validated in another TNBC cohort.

Results

Twenty-three chemical components in CKI were identified by UPLC-Q-TOF-MS analysis. A total of 3692 DEGs were detected in CKI-treated versus control groups, and CKI significantly activated biological processes associated with activation of T, natural killer and natural killer T cells. Three immune cell infiltration subgroups with 1593 DEGs were identified in TNBC patients. Then, two genes that can be down-regulated by CKI with hazard ratio (HR) > 1 and 26 genes that can be up-regulated by CKI with HR < 1 were selected as key immune- and prognosis-related genes regulated by CKI. Lastly, a five-gene prognostic signature comprising two risky genes (MARVELD2 and DYNC2I2) that can be down-regulated by CKI and three protective genes (RASSF2, FERMT3 and RASSF5) that can be up-regulated by CKI was developed, and it showed a good performance in both training and test sets.

Conclusions

This study proposes a predictive immunotherapy signature of CKI on TNBC, which would provide more evidence for survival prediction and treatment guidance in TNBC as well as a paradigm for exploring immunotherapy biomarkers in compound medicines.