bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Autophagy in Thyroid Cancer: EMT, Apoptosis, and Cancer Stem Cells
Authors: Holm Tammy M. , Yeo Syn , Turner Kevin M. , Guan Jun-Lin
Published: June 2022

Autophagy is a highly conserved recycling process through which cellular homeostasis is achieved and maintained. With respect to cancer biology, autophagy acts as a double-edged sword supporting tumor cells during times of metabolic and therapeutic stress, while also inhibiting tumor development by promoting genomic stability. Accumulating evidence suggests that autophagy plays a role in thyroid cancer, acting to promote tumor cell viability and metastatic disease through maintenance of cancer stem cells (CSCs), supporting epithelial-to-mesenchymal transition (EMT), and preventing tumor cell death. Intriguingly, well-differentiated thyroid cancer is more prevalent in women as compared to men, though the underlying molecular biology driving this disparity has not yet been elucidated. Several studies have demonstrated that autophagy inhibitors may augment the anti-cancer effects of known thyroid cancer therapies. Autophagy modulation has become an attractive target for improving outcomes in thyroid cancer. This review aims to provide a comprehensive picture of the current knowledge regarding the role of autophagy in thyroid cancer, focusing on the potential mechanism(s) through which inhibition of autophagy may enhance cancer therapy and outcomes.
Design and Initial Characterization of a Small Near-Infrared Fluorescent Calcium Indicator
Authors: Matlashov Mikhail E. , Vera Jorge , Kasatkina Ludmila A. , Khodakhah Kamran , Verkhusha Vladislav V.
Published: June 2022

Near-infrared (NIR) genetically encoded calcium indicators (GECIs) are becoming powerful tools for neuroscience. Because of their spectral characteristics, the use of NIR GECIs helps to avoid signal loss from the absorption by body pigments, light-scattering, and autofluorescence in mammalian tissues. In addition, NIR GECIs do not suffer from cross-excitation artifacts when used with common fluorescent indicators and optogenetics actuators. Although several NIR GECIs have been developed, there is no NIR GECI currently available that would combine the high brightness in cells and photostability with small size and fast response kinetics. Here, we report a small FRET-based NIR fluorescent calcium indicator iGECInano. We characterize iGECInano in vitro, in non-neuronal mammalian cells, and primary mouse neurons. iGECInano demonstrates the improvement in the signal-to-noise ratio and response kinetics compared to other NIR GECIs.
Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase
Authors: Cilenti Lucia , Mahar Rohit , Di Gregorio Jacopo , Ambivero Camilla T. , Merritt Matthew E. , Zervos Antonis S.
Published: June 2022

MUL1 is a multifunctional E3 ubiquitin ligase that is involved in various pathophysiological processes including apoptosis, mitophagy, mitochondrial dynamics, and innate immune response. We uncovered a new function for MUL1 in the regulation of mitochondrial metabolism. We characterized the metabolic phenotype of MUL1(−/−) cells using metabolomic, lipidomic, gene expression profiling, metabolic flux, and mitochondrial respiration analyses. In addition, the mechanism by which MUL1 regulates metabolism was investigated, and the transcription factor HIF-1α, as well as the serine/threonine kinase Akt2, were identified as the mediators of the MUL1 function. MUL1 ligase, through K48-specific polyubiquitination, regulates both Akt2 and HIF-1α protein level, and the absence of MUL1 leads to the accumulation and activation of both substrates. We used specific chemical inhibitors and activators of HIF-1α and Akt2 proteins, as well as Akt2(−/−) cells, to investigate the individual contribution of HIF-1α and Akt2 proteins to the MUL1-specific phenotype. This study describes a new function of MUL1 in the regulation of mitochondrial metabolism and reveals how its downregulation/inactivation can affect mitochondrial respiration and cause a shift to a new metabolic and lipidomic state.
Oral-Gut Microbiome Analysis in Patients With Metabolic-Associated Fatty Liver Disease Having Different Tongue Image Feature
Authors: Lu Chenxia , Zhu Hui , Zhao Dan , Zhang Jia , Yang Kai , Lv Yi , Peng Miao , Xu Xi , Huang Jingjing , Shao Zuoyu , Xiao Mingzhong , Li Xiaodong
Published: June 2022

Objective

The objective of this study was to identify the biological correlation between the tongue coating color and oral and gut micro-characteristics in metabolic-associated fatty liver disease (MAFLD) patients.

Method

The characteristics of the tongue coating were examined using an automatic tongue diagnosis system. Tongue coating and stool samples were collected from 38 MAFLD patients, and 16S rDNA full-length assembly sequencing technology (16S-FAST) was used for bioinformatic analysis.

Results

Twenty-two and 16 subjects were included in two distinct clusters according to the white/yellow color of the tongue coating, which was assessed by the L*a*b* values of the image. Upon analyzing the microorganisms in the tongue coating, 66 and 62 pathognomonic bacterial genera were found in the White and Yellow Coating Groups, respectively. The abundance of Stomatobaculumis positively correlated with the a* values of the tongue coating in the White Coating Group, while Fusobacterium, Leptotrichia, and Tannerella abundance was significantly correlated with the b* values in the Yellow Coating Group. Function prediction mainly showed the involvement of protein families related to BRITE hierarchies and metabolism. The MHR (MONO%/high-density lipoprotein cholesterol) of the Yellow Coating Group was higher than that of the White Coating Group.

Conclusion

In MAFLD patients, lower a* values and higher b* values are indicators of a yellow tongue coating. There were also significant differences in the flora of different tongue coatings, with corresponding changes in the intestinal flora, indicating a correlation between carbohydrate metabolism disorders and inflammation in the oral microbiome.
Multiple Novel Mosquito-Borne Zoonotic Viruses Revealed in Pangolin Virome
Authors: Zhang Duo , Zheng Min , Zhang Ying , Feng Guanrong , Peng Chengcheng , Li Chenghui , Li Yiquan , Zhang He , Li Nan , Xiao Pengpeng
Published: June 2022

Swab samples were collected from 34 pangolins in Guangxi Province, China. Metavirome sequencing and bioinformatics approaches were undertaken to determine the abundant viral sequences in the viromes. The results showed that the viral sequences belong to 24 virus taxonomic families. To verify the results, PCR combined with phylogenetic analysis was conducted. Some viral sequences including Japanese encephalitis virus (JEV), Getah virus (GETV), and chikungunya virus (CHIKV) were detected. On the basis of the metavirome analysis, seven segments belonging to JEV were further identified through PCR amplification. Sequence comparison showed that, among seven sequences, JEV-China/P2020E-1 displayed the highest nucleotide (80.6%), with the JEV isolated in South Korea, 1988, and all of which belonging to genotype III. Seven CHIKV sequences were detected, with the highest homology (80.6%) to the Aedes africanus in Côte d’Ivoire, 1993. Moreover, passage from BHK-21 to Vero cells makes the newly isolated CHIKV-China/P2020-1 more contagious. In addition, the newly verified GETV sequences shared 86.4% identity with the 1955 GETV isolated from Malaysia. Some sudden and recurrent viruses have also been observed from the virome of pangolin in Guangxi Province, China; hence, dissemination tests will be implemented in the future.
Re-burying Artificially Exposed Surface of Viral Subunit Vaccines Through Oligomerization Enhances Vaccine Efficacy
Authors: Han Xuelian , Cai Zhuming , Dai Yulong , Huang He , Cao Xiangwen , Wang Yuan , Fang Yingying , Liu Gang , Zhang Min , Zhang Yuhang , Yang Binhui , Xue Wei , Zhao Guangyu , Tai Wanbo , Li Min
Published: June 2022

Viral subunit vaccines often suffer low efficacy. We recently showed that when taken out of the context of whole virus particles, recombinant subunit vaccines contain artificially exposed surface regions that are non-neutralizing and reduce their efficacy, and thus these regions need to be re-buried in vaccine design. Here we used the envelope protein domain III (EDIII) of Japanese encephalitis virus (JEV), a subunit vaccine candidate, to further validate this important concept for subunit vaccine designs. We constructed monomeric EDIII, dimeric EDIII via a linear space, dimeric EDIII via an Fc tag, and trimeric EDIII via a foldon tag. Compared to monomeric EDIII or linearly linked dimeric EDIII, tightly packed EDIII oligomers via the Fc or foldon tag induce higher neutralizing antibody titers in mice and also protect mice more effectively from lethal JEV challenge. Structural analyses demonstrate that part of the artificially exposed surface areas on recombinant EDIII becomes re-buried in Fc or foldon-mediated oligomers. This study further establishes the artificially exposed surfaces as an intrinsic limitation of subunit vaccines, and suggests that re-burying these surfaces through tightly packed oligomerization is a convenient and effective approach to overcome this limitation.
Water AND Heat: Intervening in Adaptation Hazard Bias
Authors: Barnes Janice , Dow Kirstin
Published: June 2022

After centuries of adapting to coastal living, increases in stormwater and tidal flooding events, along with projected sea level rise, led Charleston, South Carolina, USA to define flooding as an existential threat to the city. With billions of planned flood management projects underway, and additional billions of federal disaster flood recovery funds allocated to the State of South Carolina, the Governor's office established a South Carolina Office of Resilience in September 2020, with a focus on water management. The City of Charleston developed its own Flooding and Sea Level Rise Strategy. Simultaneously, the fourth National Climate Assessment pointed to heat health risks and projected costs of lost labor productivity concentrated in the Southeast, yet local recognition of heat as an equivalent threat to flooding was not apparent. Although Charleston's All Hazards Vulnerability Assessment included extreme heat as a significant hazard, without a group focused on heat, ongoing work in the city continued to prioritize water management as annual flood events rapidly escalated. This narrow adaptation framing was further solidified as funding focused on flood recovery and adaptation and technical experts worked within water-related boundaries. These interacting forces led to Hazard Bias, an inherent organizational process of reinforcing focus on a single hazard in the context of compound, complex hazard risks. To adapt to increasing heat, Charleston will need to raise compound risk awareness and adjust its capital investments in resilience to be inclusive of heat mitigation and adaptation as well as water. Yet in 2020 Charleston lacked basic urban heat data, technical expertise, and a strong source of motivation to develop a prioritization approach for recognizing multiple risks and complementary adaptation opportunities in those investments. Recognizing the inherent bias, a new coalition of heat researchers, practitioners, and health experts launched a tripartite heat-health research program and spurred the development of a new heat network in Charleston. The network reduced hazard bias by raising heat-health risk awareness and by intervening in adaptation planning to broaden water-only considerations to be inclusive of water AND heat. This paper provides a detailed case study how the intersections of multiple networks, messengers, and messages contributed to broadening the local resilience agenda from a “hazard bias” and how the lessons learned during this transformative process further reveal health inequities.
ANGPTL3 Is Involved in the Post-prandial Response in Triglyceride-Rich Lipoproteins and HDL Components in Patients With Coronary Artery Disease
Authors: Guo Xin , Huang Zhijie , Chen Jin , Hu Jiarui , Hu Die , Peng Daoquan , Yu Bilian
Published: June 2022

It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.
Increasing Adiposity Is Associated With QTc Interval Prolongation and Increased Ventricular Arrhythmic Risk in the Context of Metabolic Dysfunction: Results From the UK Biobank
Authors: Patel Kiran Haresh Kumar , Li Xinyang , Xu Xiao , Sun Lin , Ardissino Maddalena , Punjabi Prakash P. , Purkayastha Sanjay , Peters Nicholas S. , Ware James S. , Ng Fu Siong
Published: June 2022

Background

Small-scale studies have linked obesity (Ob) and metabolic ill-health with proarrhythmic repolarisation abnormalities. Whether these are observed at a population scale, modulated by individuals’ genetics, and confer higher risks of ventricular arrhythmias (VA) are not known.

Methods and Results

Firstly, using the UK Biobank, the association between adiposity and QTc interval was assessed in participants with a resting 12-lead ECG (n = 23,683), and a polygenic risk score (PRS) was developed to investigate any modulatory effect of genetics. Participants were also categorised into four phenotypes according to the presence (+) or absence (–) of Ob, and if they were metabolically unhealthy (MU+) or not (MU-). QTc was positively associated with body mass index (BMI), body fat (BF), waist:hip ratio (WHR), and hip and waist girths. Individuals’ genetics had no significant modulatory effect on QTc-prolonging effects of increasing adiposity. QTc interval was comparably longer in those with metabolic perturbation without obesity (Ob-MU+) and obesity alone (Ob+MU-) compared with individuals with neither (Ob-MU-), and their co-existence (Ob+MU+) had an additive effect on QTc interval. Secondly, for 502,536 participants in the UK Biobank, odds ratios (ORs) for VA were computed for the four clinical phenotypes above using their past medical records. Referenced to Ob-MU-, ORs for VA in Ob-MU+ men and women were 5.96 (95% CI: 4.70–7.55) and 5.10 (95% CI: 3.34–7.80), respectively. ORs for Ob+MU+ were 6.99 (95% CI: 5.72–8.54) and 3.56 (95% CI: 2.66–4.77) in men and women, respectively.

Conclusion

Adiposity and metabolic perturbation increase QTc to a similar degree, and their co-existence exerts an additive effect. These effects are not modulated by individuals’ genetics. Metabolic ill-health is associated with a higher OR for VA than obesity.
How Technologies Can Support Self-Injury Self-Management: Perspectives of Young Adults With Lived Experience of Nonsuicidal Self-Injury
Authors: Kruzan Kaylee Payne , Mohr David C. , Reddy Madhu
Published: June 2022

Background

There is growing interest in the design of digital interventions to improve conditions for young people who engage in high-risk behaviors, like nonsuicidal self-injury (NSSI). However, few studies have focused on how young people self-manage NSSI, or their existing, and historic, use of technologies to support their goals related to NSSI behavior change. Such an understanding has the potential to inform the design of digital interventions that meet this population's unique needs.

Objectives

This study aims to (a) understand the self-management practices of young adults who engage in NSSI, (b) explore how they currently use technologies for self-injury self-management, and (c) identify the ways they can envision an app-based technology supporting their self-management.

Methods and Materials

Twenty young adults (aged 18–24) with lived experience of NSSI, and who were not currently enrolled in therapy, were recruited from online venues. Participants completed baseline measures to assess mental health and NSSI characteristics, followed by a virtual 1-h semi-structured interview where they were invited to share their experience of self-management, their goals, and their thoughts on supportive technology. Interview scripts were transcribed and analyzed via thematic analysis.

Results

Themes and sub-themes are organized under two broad domain areas: (1) How young adults self-manage NSSI thoughts and behaviors and (2) Opportunities and challenges for digital interventions to assist young adults in their recovery process. We found that young adults had varied experiences with, and goals related to, NSSI. Participants reported a lack of effective strategies to reduce NSSI urges and a desire for an app-based technology to track patterns and deliver personalized suggestions for self-management. Participants reported existing use of technologies as part of self-management, as well as early information and support seeking for NSSI online.

Conclusions

This study contributes a greater understanding of young people's experiences with self-injury, their self-management practices, and their desire to engage with technology. Our findings highlight the need for design flexibility in developing digital interventions that support individual goals, unique presentations of NSSI, and needs at different phases of recovery. Implications for the design of highly personalized and relevant digital interventions to address NSSI are discussed.
Academic Writing Challenges and Supports: Perspectives of International Doctoral Students and Their Supervisors
Authors: Gupta Shikha , Jaiswal Atul , Paramasivam Abinethaa , Kotecha Jyoti
Published: June 2022

Introduction

Academic writing is a core element of a successful graduate program, especially at the doctoral level. Graduate students are expected to write in a scholarly manner for their thesis and scholarly publications. However, in some cases, limited or no specific training on academic writing is provided to them to do this effectively. As a result, many graduate students, especially those having English as an Additional Language (EAL), face significant challenges in scholarly writing. Further, faculty supervisors often feel burdened by reviewing and editing multiple drafts and find it difficult to help and support EAL students in the process of scientific writing. In this study, we explored academic writing challenges faced by EAL doctoral students and faculty supervisors at a research intensive post-secondary university in Canada.

Methods and Analysis

We conducted a sequential explanatory mixed-method study using an online survey and subsequent focus group discussions with EAL doctoral students (n = 114) and faculty supervisors (n = 31). A cross-sectional online survey was designed and disseminated to the potential study participants using internal communications systems of the university. The survey was designed using a digital software called Qualtrics™. Following the survey, four focus group discussions (FGDs) were held, two each with two groups of our participants with an aim to achieve data saturation. The FGD guide was informed by the preliminary findings of the survey data. Quantitative data was analyzed using Statistical Package of Social Sciences (SPSS) and qualitative data was managed and analyzed using NVivo.

Discussion

The study findings suggest that academic writing should be integrated into the formal training of doctoral graduate students from the beginning of the program. Both students and faculty members shared that discipline-specific training is required to ensure success in academic writing, which can be provided in the form of a formal course specifically designed for doctoral students wherein discipline-specific support is provided from faculty supervisors and editing support is provided from English language experts.

Ethics and Dissemination

The general research ethics board of the university approved the study (#6024751). The findings are disseminated with relevant stakeholders at the university and beyond using scientific presentations and publications.
Signature Pedagogies in Collaborative Creative Learning in Advanced Music Training, Education and Professional Development: A Meta-Synthesis
Authors: Creech Andrea , Zhukov Katie , Barrett Margaret S.
Published: June 2022

Recent debates concerned with Western music performance training have grappled with the question of what kind of education and training will best equip music students to navigate an increasingly dynamic and complex professional environment. Increasingly, attention has turned to the role of collaborative creativity and how collaborative, creative skills can be nurtured. Therefore, this paper interrogates the signature pedagogies of collaborative creative learning in advanced music training, education and professional development. Two research questions were addressed: 1) how can creative collaboration in advanced music training, education and professional development be understood through the lens of signature pedagogies; and 2) what are the core values that underpin signature pedagogies of collaborative creativity in advanced music training, education and professional development. A meta-synthesis of relevant qualitative research published since 2000 was carried out. Ten studies were retained. At the implicit level of signature pedagogies of collaborative creativity, three third-order constructs included a commitment to learning as participation in a community of collaborative practice, valuing collaboration in a creative artistic identity, and the capacity to embrace ambiguity. A further three third-order constructs – relational, experiential and creative exploration - comprised the deep level of pedagogical principles. At the surface level, signature pedagogical practices were structured as social and situated, while reflection in, on and for action was at the core of collaborative, creative pedagogical practices.
Greater Body Fatness Is Associated With Higher Protein Expression of LEPR in Breast Tumor Tissues: A Cross-Sectional Analysis in the Women’s Circle of Health Study
Authors: Llanos Adana A.M. , Aremu John B. , Cheng Ting-Yuan David , Chen Wenjin , Chekmareva Marina A. , Cespedes Feliciano Elizabeth M. , Qin Bo , Lin Yong , Omene Coral , Khoury Thaer , Hong Chi-Chen , Yao Song , Ambrosone Christine B. , Bandera Elisa V. , Demissie Kitaw
Published: June 2022

Background

The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role.

Methods

In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons.

Results

In multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found.

Conclusions

These findings support an association of increased body fatness – beyond overall body size measured using BMI – with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.
Associaton of Retinol Binding Protein 4 (RBP4) Levels With Hyperuricemia: A Cross-Sectional Study in a Chinese Population
Authors: Hong Guo-bao , Shao Xiao-fei , Li Jia-min , Zhou Qin , Ke Xiao-Su , Gao Pei-Chun , Li Xiao-Lin , Ning Jing , Chen Hai-Shan , Xiao Hua , Xiong Chong-Xiang , Zou Hequn
Published: June 2022

Background

There are few studies on predictive biomarkers for hyperuricemia, and the predictive value of these biomarkers tends to be poor. Additionally, no reports have described the predictive value of retinol binding protein 4 (RBP4) for hyperuricemia.

Purpose

This study was performed to evaluate the value of RBP4 for predicting the risk of hyperuricemia in a general population, determine whether RBP4 could be used alone or in combination with other factors to predict the risk of hyperuricemia in the general population, and establish an optimum predictive model.

Methods

We conducted a population-based cross-sectional survey in 2018, involving a questionnaire, physical examination, and laboratory testing. We enrolled 2303 individuals by stratified random sampling, and 2075 were included in the data analysis after applying the eligibility criteria.

Results

Serum RBP4 level had a highly significant association with hyperuricemia (P<0.001). After adjusting for potential confounders, logistic regression indicated that the risk of hyperuricemia was highest in the highest RBP4 quartile (odds ratio: 7.9, 95% confidence interval [CI]: 4.18–14.84, compared to the lowest quartile). The area under the receiver operating characteristic (ROC) curve (AUC) for RBP4 was 0.749 (95% CI: 0.725–0.774, P<0.001), which was higher than that for all the other predictors assessed. The optimum model for predicting hyperuricemia in the general population consisted of RBP4, sex (male), body mass index, serum creatinine, high-sensitivity C-reactive protein, fasting blood glucose, insulin, and alcohol consumption. The AUC was 0.804 (95% CI: 0.782–0.826, P<0.001).

Conclusions

RBP4 is strongly associated with hyperuricemia, and its predictive value was higher than that of traditional predictors.
Postprandial Dynamics of Proglucagon Cleavage Products and Their Relation to Metabolic Health
Authors: Wagner Robert , Eckstein Sabine S. , Fritsche Louise , Prystupa Katsiaryna , Hörber Sebastian , Häring Hans-Ulrich , Birkenfeld Andreas L. , Peter Andreas , Fritsche Andreas , Heni Martin
Published: June 2022

Introduction

While oral glucose ingestion typically leads to a decrease in circulating glucagon levels, a substantial number of persons display stable or rising glucagon concentrations when assessed by radioimmunoassay (RIA). However, these assays show cross-reactivity to other proglucagon cleavage products. Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to metabolic health.

Research Design and Methods

We used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from persons with different categories of glucose tolerance in an extensively phenotyped study cohort.

Results

Glucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36% of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=0.011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p<0.001). Glucagon 1-61 as well as glicentin and GLP-1 kinetics were significantly different between suppressors and non-suppressors (p=0.004, p=0.002, p=0.008 respectively) with higher concentrations of all three hormones in non-suppressors. Levels of insulin, C-peptide, and free fatty acids were comparable between groups. Non-suppressors were leaner and had lower plasma glucose concentrations (p=0.03 and p=0.047, respectively). Despite comparable liver fat content and insulin sensitivity (p≥0.3), they had lower 2-hour post-challenge glucose (p=0.01).

Conclusions

Glucagon 1-61, glicentin and GLP-1 partially account for RIA-derived glucagon measurements due to cross-reactivity of the assay. However, this contribution is small, since the investigated proglucagon cleavage products contribute less than 10% to the variation in RIA measured glucagon. Altered glucagon levels and higher post-challenge incretins are associated with a healthier metabolic phenotype.
Selecting an Individualized Treatment Approach: The Predictive Value of Erotic Stimulation and Nocturnal Erections for Efficacy of Tadalafil and Cure in Patients With Erectile Dysfunction
Authors: Liu Zhiwei , Wu Tao , Ma Shanjin , Xue Wei , Jiang Xiaoye , Tang Qisheng , Ma Jianjun
Published: June 2022

Purpose

This study aimed to evaluate two modes of Rigiscan for predicting tadalafil response, and to identify which Rigiscan variables are the most efficient at making these predictions.

Methods

All patients received at least two rounds of nocturnal penile tumescence and rigidity (NPTR) testing and/or audiovisual sexual stimulation (AVSS), then completed the International Index of Erectile Function-5 (IIEF-5) questionnaire, followed by oral 5 mg tadalafil daily for 4 weeks. After a 4-week washout period, all respondents underwent an the IIEF-5 questionnaire again. ED patients were then categorized into tadalafil responders and tadalafil non-responders, who were then further divided into cured patients and uncured patients.

Results

When predicting tadalafil responders, the area under the curve (AUC) of NPTR was superior to that of AVSS (0.68~0.84 VS 0.69~0.73), and the predicted optimal cut-off values were DOEE60≥17.75 min in NPTR, compared to other parameters regardless of AVSS or NPTR (P<0.05). When predicting which patients would be cured, the AUC of AVSS was superior to NPTR parameters (0.77~0.81 vs 0.61~0.76), and the determined best diagnostic cut-off values were DOEE≥4.125min in AVSS, compared to other parameters regardless of AVSS or NPTR (P < 0.05).

Conclusion

Rigiscan was able to predict the efficacy of daily tadalafil accurately and efficiently. Its diagnostic value was at maximum when DOEE60 ≥17.75 min of NPTR in tadalafil responders and DOEE ≥ 4.125 min of AVSS in cured patients.
A Novel Composite Indicator of Predicting Mortality Risk for Heart Failure Patients With Diabetes Admitted to Intensive Care Unit Based on Machine Learning
Authors: Yang Boshen , Zhu Yuankang , Lu Xia , Shen Chengxing
Published: June 2022

Background

Patients with heart failure (HF) with diabetes may face a poorer prognosis and higher mortality than patients with either disease alone, especially for those in intensive care unit. So far, there is no precise mortality risk prediction indicator for this kind of patient.

Method

Two high-quality critically ill databases, the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and the Telehealth Intensive Care Unit (eICU) Collaborative Research Database (eICU-CRD) Collaborative Research Database, were used for study participants’ screening as well as internal and external validation. Nine machine learning models were compared, and the best one was selected to define indicators associated with hospital mortality for patients with HF with diabetes. Existing attributes most related to hospital mortality were identified using a visualization method developed for machine learning, namely, Shapley Additive Explanations (SHAP) method. A new composite indicator ASL was established using logistics regression for patients with HF with diabetes based on major existing indicators. Then, the new index was compared with existing indicators to confirm its discrimination ability and clinical value using the receiver operating characteristic (ROC) curve, decision curve, and calibration curve.

Results

The random forest model outperformed among nine models with the area under the ROC curve (AUC) = 0.92 after hyper-parameter optimization. By using this model, the top 20 attributes associated with hospital mortality in these patients were identified among all the attributes based on SHAP method. Acute Physiology Score (APS) III, Sepsis-related Organ Failure Assessment (SOFA), and Max lactate were selected as major attributes related to mortality risk, and a new composite indicator was developed by combining these three indicators, which was named as ASL. Both in the initial and external cohort, the new indicator, ASL, had greater risk discrimination ability with AUC higher than 0.80 in both low- and high-risk groups compared with existing attributes. The decision curve and calibration curve indicated that this indicator also had a respectable clinical value compared with APS III and SOFA. In addition, this indicator had a good risk stratification ability when the patients were divided into three risk levels.

Conclusion

A new composite indicator for predicting mortality risk in patients with HF with diabetes admitted to intensive care unit was developed on the basis of attributes identified by the random forest model. Compared with existing attributes such as APS III and SOFA, the new indicator had better discrimination ability and clinical value, which had potential value in reducing the mortality risk of these patients.
Analysis of Fertility Preservation by Ovarian Tissue Cryopreservation in Pediatric Children in China
Authors: Ruan Xiangyan , Cheng Jiaojiao , Du Juan , Jin Fengyu , Gu Muqing , Li Yanglu , Ju Rui , Wu Yurui , Wang Huanmin , Yang Wei , Cheng Haiyan , Li Long , Bai Wenpei , Kong Weimin , Yang Xin , Lv Shulan , Wang Yuejiao , Yang Yu , Xu Xin , Jiang Lingling , Li Yanqiu , Mueck Alfred O.
Published: June 2022

Background

Ovarian tissue cryopreservation (OTC) is the only method of fertility preservation (FP) in prepubertal girls, but the experience remains limited. This study investigates the effectiveness and feasibility of FP of OTC in children facing gonadotoxicity treatment in Chinese first ovarian tissue cryobank.

Procedure

OTC and evaluation of 49 children ≤14 years old in the cryobank of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, from July 2017 to May 19, 2022, were analyzed retrospectively. We compared children’s general characteristics, follicle numbers, and hormone levels with and without chemotherapy before OTC.

Results

The age of 49 children at the time of OTC was 7.55 (1–14) years old. There were 23 cases of hematological non-malignant diseases, eight cases of hematological malignant diseases, four cases of gynecological malignant tumors, one case of neurological malignant tumors, one case of bladder cancer, five cases of sarcoma, three cases of mucopolysaccharidosis, one case of metachromatic leukodystrophy, two cases of dermatomyositis, one case of Turner’s syndrome. The median follicular count per 2-mm biopsy was 705. Age and AMH were not correlated (r = 0.084, P = 0.585). Age and follicle count per 2-mm biopsy was not correlated (r = −0.128, P = 0.403). Log10 (follicle count per 2-mm biopsy) and Log10 (AMH) were not correlated (r = −0.118, P = 0.456). Chemotherapy before OTC decreased AMH levels but had no significant effect on the number of follicles per 2-mm biopsy.

Conclusions

OTC is the only method to preserve the fertility of prepubertal girls, and it is safe and effective. Chemotherapy before OTC is not a contraindication to OTC.
A Real-Time Assessment of Aquatic Ecological Health Using a Process-Based Model: An Example From Lake Poyang, China
Authors: Qi Lingyan , Xiong Ailing , Wu Fengwen , Gao Junfeng , Jia Cai , Zhi Junjun , Liu Wangbing , Wang Jian , Hou Changli , Zhang Lin , Xu Bing
Published: June 2022

Aquatic ecological health is a global challenge due to its significant impacts, and a real-time method to accurately assess the ecological health is therefore particularly useful. Based on the hydrological, water quality, meteorological, and topographic data collected from field observations and organizations, this study developed a process-based hydrodynamic and water quality model using an environmental fluid dynamics code (EFDC) model of Lake Poyang to simulate the spatiotemporal variations in water levels and the total nitrogen (TN), total phosphorus (TP), and chlorophyll a (Chl a) contents. Compared with the measured values, the models were confirmed to be reliable and acceptable. Then, to achieve a real-time assessment, the simulated results were calculated and transformed into five ordinal rating categories by using a lake ecosystem health assessment framework. Our research revealed the following results: (1) the highest and lowest 10-day water level statuses indicated that the hydrological conditions of this lake were at “good” or “excellent” levels. (2) The health levels of TN were mostly at the “fair” level or below, and most of the real-time assessment health curves of lake zones were close to the single peak type. (3) The TP contents were often at “good” levels, and the health assessment curves of the lake zones exhibited downward trends during the periods of rapid rise or retreat. (4) A fluctuating characteristic was found in the health assessment of Chl a with at least two declining peaks in all lake zones. This study demonstrated the high value of physics-based models for assessing the ecological health of aquatic ecosystems in a robust and accurate manner.
Analysis of Ambient Air PM10-Bound Pollutants Surrounding an Industrial Site and Their Prediction Using Artificial Neural Network
Authors: Bonelli M.G. , Cerasa M. , Guerriero E. , Manni A. , Mosca S. , Perilli M. , Rossetti G.
Published: June 2022

The 2030 Agenda dictated the Sustainable Development Goals. It states the waste reduction needs through their reuse, i.e., considering them as secondary raw materials (Objective 12.5). Bottom ashes from municipal or industrial incinerators can be reused as partial cement replacement in concrete after preventive physical processes such as ferrous metals removal (magnetic separation) and nonferrous metals removal (Eddy current separation). Net of the principal pollutant containment systems, diffusive emissions of fine particles from these processes, coupled with several screening steps and a final long-time open-air residues stabilization, could impact the surrounding environment due to the chemical composition of the particulate matter itself (inorganic and organic pollutants). Moreover, the particulate may also arise from transporting the raw bottom ashes to the pre-treatment plant (point source). The present work aims to predict the concentration of the PM10-bound organic contaminants that are usually sampled weekly (PCDD/Fs, PCBs, PAHs) from the concentration of the daily analyzed inorganic pollutants in the surrounding area of an municipal solid waste slag treatment plant, using Artificial Neural Networks (ANNs) as a forecasting tool. Moreover, ANNs have also been used as a clustering tool to evaluate the plant’s environmental impact on the surrounding area with respect to other additional emission sources.
Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure
Authors: Tseng Min-Hua , Yang Sung-Sen , Sung Chih-Chien , Ding Jhao-Jhuang , Hsu Yu-Juei , Chu Shih-Ming , Lin Shih-Hua
Published: June 2022

CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine β-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia.
Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers
Authors: Ni Yanhong , Low Jun T. , Silke John , O’Reilly Lorraine A.
Published: June 2022

When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.
IL-17RA receptor signaling contributes to lung inflammation and parasite burden during Toxocara canis infection in mice
Authors: Leal-Silva Thaís , Lopes Camila de Almeida , Vieira-Santos Flaviane , Oliveira Fabrício Marcus Silva , Kraemer Lucas , Padrão Luiza de Lima Silva , Amorim Chiara Cássia Oliveira , Souza Jorge Lucas Nascimento , Russo Remo Castro , Fujiwara Ricardo Toshio , Magalhães Luisa Mourão Dias , Bueno Lilian Lacerda
Published: June 2022

IL-17 is a cytokine produced by innate and acquired immunity cells that have an action against fungi and bacteria. However, its action in helminth infections is unclear, including in Toxocara canis infection. Toxocariasis is a neglected zoonosis representing a significant public health problem with an estimated seroprevalence of 19% worldwide. In the present study, we describe the immunopathological action of IL-17RA in acute T. canis infection. C57BL/6j (WT) and IL-17RA receptor knockout (IL-17RA-/-) mice were infected with 1000 T. canis eggs. Mice were evaluated 3 days post-infection for parasite load and white blood cell count. Lung tissue was harvested for histopathology and cytokine expression. In addition, we performed multiparametric flow cytometry in the BAL and peripheral blood, evaluating phenotypic and functional changes in myeloid and lymphoid populations. We showed that IL-17RA is essential to control larvae load in the lung; however, IL-17RA contributed to pulmonary inflammation, inducing inflammatory nodular aggregates formation and presented higher pulmonary IL-6 levels. The absence of IL-17RA was associated with a higher frequency of neutrophils as a source of IL-4 in BAL, while in the presence of IL-17RA, mice display a higher frequency of alveolar macrophages expressing the same cytokine. Taken together, this study indicates that neutrophils may be an important source of IL-4 in the lungs during T. canis infection. Furthermore, IL-17/IL-17RA axis is important to control parasite load, however, its presence triggers lung inflammation that can lead to tissue damage.
Immune System Modulation by the Adjuvants Poly (I:C) and Montanide ISA 720
Authors: Marques Rodolfo F. , de Melo Filipe Menegatti , Novais Janaina Tenório , Soares Irene S. , Bargieri Daniel Youssef , Gimenez Alba Marina
Published: June 2022

Adjuvants are essential for vaccine development, especially subunit-based vaccines such as those containing recombinant proteins. Increasing the knowledge of the immune response mechanisms generated by adjuvants should facilitate the formulation of vaccines in the future. The present work describes the immune phenotypes induced by Poly (I:C) and Montanide ISA 720 in the context of mice immunization with a recombinant protein based on the Plasmodium vivax circumsporozoite protein (PvCSP) sequence. Mice immunized with the recombinant protein plus Montanide ISA 720 showed an overall more robust humoral response, inducing antibodies with greater avidity to the antigen. A general trend for mixed Th1/Th2 inflammatory cytokine profile was increased in Montanide-adjuvanted mice, while a balanced profile was observed in Poly (I:C)-adjuvanted mice. Montanide ISA 720 induced a gene signature in B lymphocytes characteristic of heme biosynthesis, suggesting increased differentiation to Plasma Cells. On the other hand, Poly (I:C) provoked more perturbations in T cell transcriptome. These results extend the understanding of the modulation of specific immune responses induced by different classes of adjuvants, and could support the optimization of subunit-based vaccines.