bluuebunny/crossref_metadata_2025 huggingface dataset:
A “Wicked Problem” Reconciling Human-Shark Conflict, Shark Bite Mitigation, and Threatened Species
Authors: Niella Yuri , Peddemors Victor M. , Green Marcel , Smoothey Amy F. , Harcourt Robert
Published: October 2021

Conservation measures often result in a “wicked problem,” i.e., a complex problem with conflicting aims and no clear or straightforward resolution without severe adverse effects on one or more parties. Here we discuss a novel approach to an ongoing problem, in which actions to reduce risk to humans, involve lethal control of otherwise protected species. To protect water users, nets are often used to catch potentially dangerous sharks at popular bathing beaches, yet in Australian waters one of the targeted species, the white shark (Carcharodon carcharias) is listed as Vulnerable, while bycatch includes the Critically Endangered grey nurse shark (Carcharias taurus). Recent, highly publicised, shark attacks have triggered demands for improved bather protection, whilst welfare and conservation organisations have called for removal of lethal measures. This leaves management and policy makers with a wicked problem: removing nets to reduce impacts on threatened species may increase risk to humans; or leaving the program as it is on the premise that the benefits provided by bather protection are greater than the impact on threatened and protected species. We used multivariate analysis and generalised additive models to investigate the biological, spatial-temporal, and environmental patterns influencing catch rates of threatened and of potentially dangerous shark species in the New South Wales shark nets over two decades to April 2019. Factors influencing catches were used to develop a matrix of potential changes to reduce catch of threatened species. Our proposed solutions include replacing existing nets with alternative mitigation strategies at key beaches where catch rate of threatened species is high. This approach provides stakeholders with a hierarchy of scenarios that address both social demands and threatened species conservation and is broadly applicable to human-wildlife conflict scenarios elsewhere.
Synthesis of Single-Atom Catalysts Through Top-Down Atomization Approaches
Authors: Zhang Aijing , Zhou Mingzheng , Liu Siyuan , Chai Maorong , Jiang Shengjuan
Published: October 2021

Single-atom catalysts (SACs) have emerged as a hot research topic in recently years, and have been intensively investigated for energy storage and conversion applications. Significant advances in the synthesis of SACs have been achieved through enormous efforts in this area, however, their application is hindered by the low active site loading and poor long-term stability. In contrast with other methods, atomization, in which the SACs are synthesized from transformation of the nanoparticles to atomic sites, is a very attractive and innovative top-down approach to achieve high-density supported active sites with outstanding stability. However, limited attention has been paid to this area, despite the significant advances achieved in the past two years. In this short review, we discuss in detail the latest advances in atomization approaches for the synthesis of SACs and highlight the associated advantages and opportunities.
Oxidative Stress in Takotsubo Syndrome—Is It Essential for an Acute Attack? Indirect Evidences Support Multisite Impact Including the Calcium Overload—Energy Failure Hypothesis
Authors: Manousek Jan , Kala Petr , Lokaj Petr , Ondrus Tomas , Helanova Katerina , Miklikova Marie , Brazdil Vojtech , Tomandlova Marie , Parenica Jiri , Pavkova Goldbergova Monika , Hlasensky Jiri
Published: October 2021

Indirect evidences in reviews and case reports on Takotsubo syndrome (TTS) support the fact that the existence of oxidative stress (OS) might be its common feature in the pre-acute stage. The sources of OS are exogenous (environmental factors including pharmacological and toxic influences) and endogenous, the combination of both may be present, and they are being discussed in detail. OS is associated with several pathological conditions representing TTS comorbidities and triggers. The dominant source of OS electrones are mitochondria. Our analysis of drug therapy related to acute TTS shows many interactions, e.g., cytostatics and glucocorticoids with mitochondrial cytochrome P450 and other enzymes important for OS. One of the most frequently discussed mechanisms in TTS is the effect of catecholamines on myocardium. Yet, their metabolic influence is neglected. OS is associated with the oxidation of catecholamines leading to the synthesis of their oxidized forms – aminochromes. Under pathological conditions, this pathway may dominate. There are evidences of interference between OS, catecholamine/aminochrome effects, their metabolism and antioxidant protection. The OS offensive may cause fast depletion of antioxidant protection including the homocystein-methionine system, whose activity decreases with age. The alteration of effector subcellular structures (mitochondria, sarco/endoplasmic reticulum) and subsequent changes in cellular energetics and calcium turnover may also occur and lead to the disruption of cellular function, including neurons and cardiomyocytes. On the organ level (nervous system and heart), neurocardiogenic stunning may occur. The effects of OS correspond to the effect of high doses of catecholamines in the experiment. Intensive OS might represent “conditio sine qua non”for this acute clinical condition. TTS might be significantly more complex pathology than currently perceived so far.
Cardiopulmonary Support During Catheter Ablation of Ventricular Arrhythmias With Hemodynamic Instability: The Role of Inducibility
Authors: Grimaldi Massimo , Marino Maria Monica , Vitulano Nicola , Quadrini Federico , Troisi Federica , Caporusso Nicola , Perniciaro Vera , Caruso Rosa , Duni Nicola , Cecere Giacomo , Martinelli Alberto , Guida Pietro , Del Monte Vito , Langialonga Tommaso , Di Biase Luigi , Di Monaco Antonio
Published: October 2021

Background: Catheter ablation is a treatment option for sustained ventricular tachycardias (VTs) that are refractory to pharmacological treatment; however, patients with fast VT and electrical storm (ES) are at risk for cardiogenic shock. We report our experience using cardiopulmonary support with extracorporeal membrane oxygenation (ECMO) during catheter ablation of VT.

Methods: Sixty-two patients (mean age 68 ± 9 years; 94% male) were referred to our center for catheter ablation of repeated episodes of hemodynamically unstable ventricular arrhythmias. ES was defined as the occurrence of three or more VT/ventricular fibrillation episodes requiring electrical cardioversion or defibrillation in a 24-h period. All patients had hemodynamically unstable VTs.

Results: Thirty-one patients (group 1) performed catheter ablation without ECMO support and 31 patients (group 2) with ECMO support. At the end of the procedure, ventricular inducibility was not performed in 16 patients of group 1 (52%) due to significant hemodynamic instability. Ventricular inducibility was performed in the other 15 patients (48%); polymorphic VTs were inducible in eight patients. In group 2, VTs were not inducible in 29 patients (93%); polymorphic VTs were inducible in two patients. The median follow-up duration was 24 months. Four patients of group 1 (13%) and five patients of group 2 (16%) died due to refractory heart failure. An implantable cardioverter-defibrillator intervention (shock or antitachycardia pacing) was documented in 13 patients of group 1 (42%) and six patients of group 2 (19%).

Conclusions: Extracorporeal membrane oxygenation support during catheter ablation for hemodynamically unstable VTs is a useful tool to prevent acute procedural heart failure and to reduce arrhythmic burden.
The New Swiss Glacier Inventory SGI2016: From a Topographical to a Glaciological Dataset
Authors: Linsbauer Andreas , Huss Matthias , Hodel Elias , Bauder Andreas , Fischer Mauro , Weidmann Yvo , Bärtschi Hans , Schmassmann Emanuel
Published: October 2021

Glaciers in Switzerland are shrinking rapidly in response to ongoing climate change. Repeated glacier inventories are key to monitor such changes at the regional scale. Here we present the new Swiss Glacier Inventory 2016 (SGI2016) that has been acquired based on sub-meter resolution aerial imagery and digital elevation models, bringing together topographical and glaciological approaches and knowledge. We define the process, workflow and required glaciological adaptations to compile a highly detailed inventory based on the digital Swiss Topographic Landscape model. The SGI2016 provides glacier outlines (areas), supraglacial debris cover and ice divides for all Swiss glaciers referring to the years 2013–2018. The SGI2016 maps 1,400 individual glacier entities with a total surface area of 961 ± 22 km2, whereof 11% (104 km2) are debris-covered. It constitutes the so far most detailed cartographic representation of glacier extent in Switzerland. Interpretation in the context of topographic parameters indicates that glaciers with moderate inclination and low median elevation tend to have highest fractions of supraglacial debris. Glacier-specific area changes since 1973 show the largest relative changes for small and low-elevation glaciers. The analysis further indicates a tendency for glaciers with a high share of supraglacial debris to show larger relative area changes. Between 1973 and 2016, an area change rate of –0.6% a−1 is found. Based on operational data sets and the presented methodology, the Swiss Glacier Inventory will be updated in 6-yr time intervals, leading to a high consistency in future glacier change assessments.
Applications of an Innovative Strength Parameter Estimation Method of the SoilRock Mixture in Evaluating the Deposit Slope Stability Under Rainfall
Authors: Fu Xiaodong , Zhang Zhenping , Sheng Qian , Zhou Yongqiang , Huang Juehao , Wu Zhe , Liu Mingyang
Published: October 2021

Deposit landslides are one of the most representative geological hazards around the world, and the poor understanding of the mechanical characteristics of the soilrock mixture (S-RM) increases the difficulties in evaluating the stability of the deposit slope subjected to rainfall. This study attempted to propose an innovative strength parameter estimation method of the S-RM based on the concept and format of the generalized HoekBrown criterion. The system of “rock blocks–soil–contact surface” was considered the main source providing resistance to the external force, and the effect of the soil matrix, rock blocks, and the contact surface between them was taken into account. The verification of the estimation method was proved based on the abundant test data. A typical deposit slope located in the Taoyuan region of Yunnan Province, China, was selected as a case study, and the estimation method was applied to provide the shear parameters of the S-RM. The slope stability subjected to different types of rainfall was analyzed considering the parameter deteriorations, and the results show that the deposit landslide is more prone to the wave-type rainfall, which shows a deeper response depth of pore water pressure and a smaller safety factor. The present study suggests a simple estimation method for the shear parameters of the S-RM using a few parameters for the engineers and provides an understanding of the deposit slope stability during the rainfall process.
High-Resolution Ensemble Projection of Mean and Extreme Precipitation Over China Based on Multiple Bias-Corrected RCM Simulations
Authors: Xie Ye , Dong Guangtao , Wang Ya , Fan Dongli , Tian Zhan , Tan Jianguo , Wu Wei , Zhang Ming
Published: October 2021

In this study, we used the cumulative distribution function transform to conduct a bias correction for simulations from different regional climate models (RCMs) driven by one global climate model (HadGEM2-ES). We divided the historical period into two time-frames, i.e., the calibration period and the validation period. These two periods are 1986–1998 and 1999–2011, respectively. We then choose the period from 1986 to 2005 as the calibration period. The data for the future 2006–2098 were revised and used to explore future climate change under the RCP8.5 scenario. The difference before and after bias correction were compared. The results show that the cumulative distribution function transform method can improve the simulation accuracy of RCM in terms of the average precipitation and seasonal precipitation can improve in north arid regions. For extreme precipitation and different rainfall levels, the root mean squared errors of most indexes are reduced by about 60–80% in China, and the correlation coefficients are close to 1. For future precipitation, the bias correction method could reduce the overestimation of RCM simulations, but cannot change trends of precipitation variation. Compared with the simulations before bias correction, the predicted future precipitation indicates some differences in different regions. After correction, the spread of the precipitation and the most extreme precipitation indexes was smaller than those before correction. The predicted future daily precipitation intensity was also smaller. The reduction of drought days in the arid areas is more than before the correction, and the increase days of R50 in the southern regions is larger than before the correction.
Decreasing Youth Hyperactivity and Inattention Problems Through Mentoring: Evaluation of the Mentor-UP Program
Authors: Marino Claudia , Cardillo Ramona , Canale Natale , Lenzi Michela , Bergamin Marisa , Bonichini Sabrina , Santinello Massimo
Published: October 2021

Few studies so far have analysed the potential role of mentoring in decreasing hyperactivity and inattention problems. The aim of the current study is to investigate the impact of the Italian Mentor-UP mentoring program on hyperactivity and inattention problems in a non-clinical sample of mentees. “Mentor-UP” is a weekly school- and community-based mentoring program implemented in northern Italy over a period of 8 months. The sample included 468 students, 65 from the experimental group (mentees) and 403 as comparison group. Participants’ age ranged between 8 and 14 years (M = 11.31, SD = 1.40), 46% were females and 20% were non-Italian youths. Students reported their levels of hyperactivity and inattention problems at the beginning and at the end of the program. A significant interaction between time and group revealed a significant effect of the program on hyperactivity and inattention problems (B = −0.10, t (450) = −2.00, p = 0.04), which decreased in mentees (Cohen’s d = −0.21) but not in the comparison group. Results supported the effectiveness of Mentor-UP in decreasing youths’ hyperactivity and inattention. This might be due to the structural characteristics of the mentoring relationships established in the context of Mentor-UP.
Counselor-Perceived Teacher Actions Needed to Carry out Educational and Vocational Guidance in Secondary Schools in Spain
Authors: Falcón-Linares Carolina , Rodríguez-Martínez Ana , Cortés-Pascual Alejandra , Quilez-Robres Alberto
Published: October 2021

After analyzing the scientific literature referring to guiding actions developed in secondary education, there is an appreciable lack of research on process efficiency performed by teachers. This study explores the practice of tutoring, which in Spain is coordinated by counselors but the responsibility of teachers. An ad hoc semistructured questionnaire was designed, validated and applied within the framework of a collaboration agreement between professional institutions of counselors and researchers. The questionnaire was answered by 102 counselors who are heads of guidance departments because the insight of counseling experts was desired. The quantitative and qualitative data analyses indicated correlations between the profile of the counselors and the performance of tutoring, described the content and predominant intervention models and identified needs for improvement. A much more intensive and direct intervention by counselors is necessary in a system in which teachers are not trained enough and time dedicated to tutorial action is deficient. Notably, counselors coordinate and supervise tutoring, but they feel overwhelmed by the lack of concrete norms and their workload.
Application of the Theory of Planned Behavior to Identify Variables Related to Academic Help Seeking in Higher Education
Authors: Bornschlegl Madeleine , Townshend Kishani , Caltabiano Nerina Jane
Published: October 2021

Universities admit and enrol increasingly diverse student cohorts with varying academic entry standards. To increase student success, universities offer academic support to students, however, often students do not engage in or access this academic support. Building on the Theory of Planned Behavior and a comprehensive literature review, this study aims to identify personality variables, background variables and variables related to the Theory of Planned Behavior that can predict academic help seeking in higher education to inform the design of engaging and accessible academic support. Quantitative data were collected via an online survey across a range of different disciplines and undergraduate year levels at an Australian university. Structural Equation Modelling revealed that public stigma, self-stigma, extraversion, agreeableness, neuroticism, gender and the Theory of Planned Behavior variables perceived behavioural control, subjective norm and attitude towards help seeking play a role in predicting intentions to seek academic help, and academic help-seeking behaviour. Findings indicate that 20% of the variance of help-seeking intentions but only 5.7% of the variance of academic help seeking could be explained. Findings are discussed as to how they can inform interventions to increase help-seeking intentions and behaviour. Finally, this study explores how to overcome the present intention-behaviour gap.
GH Deficiency and Replacement Therapy in Hypopituitarism: Insight Into the Relationships With Other Hypothalamic-Pituitary Axes
Authors: Profka Eriselda , Rodari Giulia , Giacchetti Federico , Giavoli Claudia
Published: October 2021

GH deficiency (GHD) in adult patients is a complex condition, mainly due to organic lesion of hypothalamic-pituitary region and often associated with multiple pituitary hormone deficiencies (MPHD). The relationships between the GH/IGF-I system and other hypothalamic-pituitary axes are complicated and not yet fully clarified. Many reports have shown a bidirectional interplay both at a central and at a peripheral level. Signs and symptoms of other pituitary deficiencies often overlap and confuse with those due to GH deficiency. Furthermore, a condition of untreated GHD may mask concomitant pituitary deficiencies, mainly central hypothyroidism and hypoadrenalism. In this setting, the diagnosis could be delayed and possible only after recombinant human Growth Hormone (rhGH) replacement. Since inappropriate replacement of other pituitary hormones may exacerbate many manifestations of GHD, a correct diagnosis is crucial. This paper will focus on the main studies aimed to clarify the effects of GHD and rhGH replacement on other pituitary axes. Elucidating the possible contexts in which GHD may develop and examining the proposed mechanisms at the basis of interactions between the GH/IGF-I system and other axes, we will focus on the importance of a correct diagnosis to avoid possible pitfalls.
Resistance to the Insulin and Elevated Level of Androgen: A Major Cause of Polycystic Ovary Syndrome
Authors: Ding Haigang , Zhang Juan , Zhang Feng , Zhang Songou , Chen Xiaozhen , Liang Wenqing , Xie Qiong
Published: October 2021

PCOS has a wide range of negative impacts on women’s health and is one of the most frequent reproductive systemic endocrine disorders. PCOS has complex characteristics and symptom heterogeneity due to the several pathways that are involved in the infection and the absence of a comm14on cause. A recent study has shown that the main etiology and endocrine aspects of PCOS are the increased level of androgen, which is also known as “hyperandrogenemia (HA)” and secondly the “insulin resistance (IR)”. The major underlying cause of the polycystic ovary is these two IR and HA, by initiating the disease and its severity or duration. As a consequence, study on Pathogenesis is crucial to understand the effect of “HA” and “IR” on the pathophysiology of numerous symptoms linked to PCOS. A deep understanding of the pattern of the growth in PCOS for HA and IR can help ameliorate the condition, along with adjustments in nutrition and life, as well as the discovery of new medicinal products. However, further research is required to clarify the mutual role of IR and HA on PCOS development.
Sex Dimorphic Responses of the Hypothalamus-Pituitary-Thyroid Axis to Energy Demands and Stress
Authors: Parra-Montes de Oca Marco Antonio , Sotelo-Rivera Israim , Gutiérrez-Mata Angélica , Charli Jean-Louis , Joseph-Bravo Patricia
Published: October 2021

The hypothalamus-pituitary-thyroid-axis (HPT) is one of the main neuroendocrine axes that control energy expenditure. The activity of hypophysiotropic thyrotropin releasing hormone (TRH) neurons is modulated by nutritional status, energy demands and stress, all of which are sex dependent. Sex dimorphism has been associated with sex steroids whose concentration vary along the life-span, but also to sex chromosomes that define not only sexual characteristics but the expression of relevant genes. In this review we describe sex differences in basal HPT axis activity and in its response to stress and to metabolic challenges in experimental animals at different stages of development, as well as some of the limited information available on humans. Literature review was accomplished by searching in Pubmed under the following words: “sex dimorphic” or “sex differences” or “female” or “women” and “thyrotropin” or “thyroid hormones” or “deiodinases” and “energy homeostasis” or “stress”. The most representative articles were discussed, and to reduce the number of references, selected reviews were cited.
In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood
Authors: Faure Mélanie C. , Khoueiry Rita , Quanico Jusal , Acloque Hervé , Guerquin Marie-Justine , Bertoldo Michael J. , Chevaleyre Claire , Ramé Christelle , Fournier Isabelle , Salzet Michel , Dupont Joëlle , Froment Pascal
Published: October 2021

Metformin is a drug used for the treatment of type 2 diabetes and disorders associated with insulin resistance. Metformin is also used in the treatment of pregnancy disorders such as gestational diabetes. However, the consequences of foetal exposure to metformin on the fertility of exposed offspring remain poorly documented. In this study, we investigated the effect of in utero metformin exposure on the fertility of female and male offspring. We observed that metformin is detectable in the blood of the mother and in amniotic fluid and blood of the umbilical cord. Metformin was not measurable in any tissues of the embryo, including the gonads. The effect of metformin exposure on offspring was sex specific. The adult females that had been exposed to metformin in utero presented no clear reduction in fertility. However, the adult males that had been exposed to metformin during foetal life exhibited a 30% reduction in litter size compared with controls. The lower fertility was not due to a change in sperm production or the motility of sperm. Rather, the phenotype was due to lower sperm head quality – significantly increased spermatozoa head abnormality with greater DNA damage – and hypermethylation of the genomic DNA in the spermatozoa associated with lower expression of the ten-eleven translocation methylcytosine dioxygenase 1 (TET1) protein. In conclusion, while foetal metformin exposure did not dramatically alter gonad development, these results suggest that metabolic modification by metformin during the foetal period could change the expression of epigenetic regulators such as Tet1 and perturb the genomic DNA in germ cells, changes that might contribute to a reduced fertility.
Local-Regional Recurrence of Pheochromocytoma/Paraganglioma: Characteristics, Risk Factors and Outcomes
Authors: Cui Yunying , Ma Xiaosen , Gao Yinjie , Chang Xiaoyan , Chen Shi , Lu Lin , Tong Anli
Published: October 2021

Objective

To study the characteristics, risk factors, and outcomes of local-regional recurrence of pheochromocytoma and paraganglioma (PPGL).

Methods

Clinical data of 96 PPGL patients with local-regional recurrence and 112 patients without recurrence were retrospectively analyzed.

Results

Recurrent patients exhibited a median recurrence time of 6.0 (4.0, 9.0) years after resection of the primary tumor. SDHB mutation [HR 4.1 (1.7, 9.5), p=0.001), primary tumor size ≥5cm [HR 2.3 (1.1, 4.7), p=0.028], and average Ki-67 count ≥3% in the primary tumor [HR 2.6 (1.4, 4.9), p=0.003] were independent predictors for recurrence of PPGL. Primary tumor sizes ≥5cm [HR 5.1 (1.7, 15.3), p=0.003] and average Ki-67 counts ≥3% of the primary tumor [HR 2.4 (1.1, 5.2), p=0.035] were independent predictors for recurrence of pheochromocytoma, while SDHB mutation [HR 4.6 (1.5, 13.9), p=0.007] was a predictor for paraganglioma recurrence. Among recurrent patients, 47% (45/96) had multiple nodules in recurrent sites, and 58% (56/96) had metastases, with 20% (19/96) being implantation metastases. The risk of metastases (42% vs. 25%, p=0.030) and death (15% vs. 8%, p=0.003) was significantly increased in untreated patients after recurrence compared with treated patients.

Conclusion

Long-term follow-up is necessary for all PPGL patients. Risk factors for recurrence of pheochromocytoma and paraganglioma differ, with primary tumor size and average Ki-67 count representing independent predictors for pheochromocytoma patients and SDHB mutations predicting paraganglioma recurrence. Although the treatment of recurrence can be difficult, patients should be treated once recurrence is detected as it decreases the risk of metastases and death.
The Role of RECK in Hepatobiliary Neoplasia Reveals Its Therapeutic Potential in NASH
Authors: Dashek Ryan J. , Diaz Connor , Chandrasekar Bysani , Rector R. Scott
Published: October 2021

Non-alcoholic fatty liver disease (NAFLD) is a multimorbidity disorder ranging from excess accumulation of fat in the liver (steatosis) to steatohepatitis (NASH) and end-stage cirrhosis, and the development of hepatocellular carcinoma (HCC) in a subset of patients. The defining features of NASH are inflammation and progressive fibrosis. Currently, no pharmaceutical therapies are available for NAFLD, NASH and HCC; therefore, developing novel treatment strategies is desperately needed. Reversion Inducing Cysteine Rich Protein with Kazal motifs (RECK) is a well-known modifier of the extracellular matrix in hepatic remodeling and transition to HCC. More recently, its role in regulating inflammatory and fibrogenic processes has emerged. Here, we summarize the most relevant findings that extend our current understanding of RECK as a regulator of inflammation and fibrosis, and its induction as a potential strategy to blunt the development and progression of NASH and HCC.
Comprehensive Analysis of Transcriptome-wide m6A Methylome Upon Clostridium perfringens Beta2 Toxin Exposure in Porcine Intestinal Epithelial Cells by m6A Sequencing
Authors: Zhang Juanli , Yang Qiaoli , Yang Jiaojiao , Gao Xiaoli , Luo Ruirui , Huang Xiaoyu , Yan Zunqiang , Wang Pengfei , Wang Wei , Xie Kaihui , Zhang Bo , Gun Shuangbao
Published: October 2021

Piglet diarrhea is a swine disease responsible for serious economic impacts in the pig industry. Clostridium perfringens beta2 toxin (CPB2), which is a major toxin of C. perfringens type C, may cause intestinal diseases in many domestic animals. N6-methyladenosine (m6A) RNA methylation plays critical roles in many immune and inflammatory diseases in livestock and other animals. However, the role of m6A methylation in porcine intestinal epithelial (IPEC-J2) cells exposed to CPB2 has not been studied. To address this issue, we treated IPEC-J2 cells with CPB2 toxin and then quantified methylation-related enzyme expression by RT-qPCR and assessed the m6A methylation status of the samples by colorimetric N6-methyladenosine quantification. The results showed that the methylation enzymes changed to varying degrees while the m6A methylation level increased (p < 0.01). On this basis, we performed N6-methyladenosine sequencing (m6A-seq) and RNA sequencing (RNA-seq) to examine the detailed m6A modifications and gene expression of the IPEC-J2 cells following CPB2 toxin exposure. Our results indicated that 1,448 m6A modification sites, including 437 up-regulated and 1,011 down-regulated, differed significantly between CPB2 toxin exposed cells and non-exposed cells (p < 0.05). KEGG pathway analysis results showed that m6A peaks up-regulated genes (n = 394) were mainly enriched in cancer, Cushing syndrome and Wnt signaling pathways, while m6A peaks down-regulated genes (n = 920) were mainly associated with apoptosis, small cell lung cancer, and the herpes simplex virus 1 infection signaling pathway. Furthermore, gene expression (RNA-seq data) analysis identified 1,636 differentially expressed genes (DEGs), of which 1,094 were up-regulated and 542 were down-regulated in the toxin exposed group compared with the control group. In addition, the down-regulated genes were involved in the Hippo and Wnt signaling pathways. Interestingly, the combined results of m6A-seq and RNA-seq identified genes with up-regulated m6A peaks but with down-regulated expression, here referred to as “hyper-down” genes (n = 18), which were mainly enriched in the Wnt signaling pathway. Therefore, we speculate that the genes in the Wnt signaling pathway may be modified by m6A methylation in CPB2-induced IPEC-J2 cells. These findings provide new insights enabling further exploration of the mechanisms underlying piglet diarrhea caused by CPB2 toxin.
Relationships of N6-Methyladenosine-Related Long Non-Coding RNAs With Tumor Immune Microenvironment and Clinical Prognosis in Lung Adenocarcinoma
Authors: Zhao Jianhui , Lin Xi , Zhuang Jinman , He Fei
Published: October 2021

Background: Lung adenocarcinoma (LUAD) is the major subtype of lung cancer and is associated with very high mortality. Emerging studies have shown that N6-methyladenosine (m6A)-related long non-coding (lnc) RNAs play crucial roles in tumor prognosis and the tumor immune microenvironment (TME). We aimed to explore the expression patterns of different m6A-related lncRNAs concerning patient prognosis and construct an m6A-related lncRNA prognostic model for LUAD.

Methods: The prognostic value of m6A-related lncRNAs was investigated in LUAD samples from The Cancer Genome Atlas (TCGA). Potential prognostic m6A-related lncRNAs were selected by Pearson’s correlation and univariate Cox regression analysis. Patients were divided into clusters using principal component analysis and the m6A-related lncRNA prognostic signature was calculated using least absolute shrinkage and selection operator (LASSO) Cox regression analysis.

Results: Based on 91 prognostic m6A-related lncRNAs, we identified two m6A-related-lncRNA pattern clusters with different overall survival (OS) and different TMEs. We subsequently verified our findings multidimensionally by constructing a 13 m6A-related lncRNA prognostic signature (m6A-LPS) to calculate the risk score, which was robust in different subgroups. The receiver operating characteristic (ROC) curves and concordance index demonstrated that m6A-LPS harbored a promising ability to predict OS in TCGA data set and independent GSE11969 cohort. The risk score was also related to OS, TME, and clinical stage, and the risk score calculated by our model was also identified as independent prognostic predictive factors for LUAD patients after adjustment for age, smoking, gender, and stage. Enrichment analysis indicated that malignancy and drug resistance-associated pathways were more common in cluster2 (LUAD-unfavorable m6A-LPS). Furthermore, the results indicated that the signaling pathway enriched by the target gene of 13 m6A-related lncRNAs may be associated with metastasis and progression of cancer according to current studies.

Conclusion: The current results indicated that different m6A-related-lncRNA patterns could affect OS and TME in patients with LUAD, and the prognostic signature based on 13 m6A-related lncRNAs may help to predict the prognosis in LUAD patients.
Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification
Authors: Zeng Yi-Heng , Lin Bi-Wei , Su Hui-Zhen , Guo Xin-Xin , Li Yun-Lu , Lai Lu-Lu , Chen Wan-Jin , Zhao Miao , Yao Xiang-Ping
Published: October 2021

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.
A Novel Three-LncRNA Signature Predicting Tumor Recurrence in Nonfunctioning Pituitary Adenomas
Authors: Cheng Sen , Guo Jing , Wang Dawei , Fang Qiuyue , Liu Yulou , Xie Weiyan , Zhang Yazhuo , Li Chuzhong
Published: October 2021

The nonfunctioning pituitary adenoma (NFPA) recurrence rate is relatively high after surgical resection. Here, we constructed effective long noncoding RNA (lncRNA) signatures to predict NFPA prognosis. LncRNAs expression microarray sequencing profiles were obtained from 66 NFPAs. Sixty-six patients were randomly separated into a training (n = 33) and test group (n = 33). Univariable Cox regression and a machine learning algorithm was used to filter lncRNAs. Time-dependent receiver operating characteristic (ROC) analysis was performed to improve the prediction signature. Three lncRNAs (LOC101927765, RP11-23N2.4 and RP4-533D7.4) were included in a prognostic signature with high prediction accuracy for tumor recurrence, which had the largest area under ROC curve (AUC) value in the training/test group (AUC = 0.87/0.73). The predictive ability of the signature was validated by Kaplan-Meier survival analysis. A signature-based risk score model divied patients into two risk group, and the recurrence-free survival rates of the groups were significantly different (log-rank p < 0.001). In addition, the ROC analysis showed that the lncRNA signature predictive ability was significantly better than that of age in the training/testing/entire group (AUC = 0.87/0.726/0.798 vs. AUC = 0.683/0.676/0.679). We constructed and verified a three-lncRNA signature predictive of recurrence, suggesting potential therapeutic targets for NFPA.
Trends of Anger and Physical Aggression in Russian Women During COVID-19 Lockdown
Authors: Klimovich-Mickael Alexandra , Kubick Norwin , Milanesi Elena , Dobre Maria , Łazarczyk Marzena , Wijas Baraba , Sacharczuk Mariusz , Mickael Michel-Edwar
Published: October 2021

The effect of social lockdown during the COVID-19 outbreak on female aggressiveness is not well known. The strict measures of lockdown have resulted in millions of people, worldwide, confined to their homes during the pandemic. However, the consequence of lockdown strategies on females' psychological status including aggressiveness has not yet been investigated. We conducted a cross-sectional study on 31 Russian females' homemakers who are participants in an online fitness platform to investigate the immediate anxiety, depression, and aggression experienced under strict lockdown measures. The participants were surveyed using the hospital anxiety depression scale (HADS) and the Buss-Perry Aggression Questionnaire. We used descriptive and statistical methods to investigate the prevalence of these emotions among two age groups (20–35 and 36–65 years). We found that moderate anxiety prevalence was 77.4% in the entire group while mild depression was 54.8%. Interestingly, the whole sample showed a high level of angriness (p = 0.0002) and physical aggression (p = 0.019). These two emotions seem to be more prevalent than other negative emotions such as hostility, verbal aggression. This relationship was not dependent on age. Overall, there is a significant worsening in female aggression that could lead to higher chances of female victimization and being subjected to partner violence. Future policies designing lockdown strategies should consider this effect on active female homemakers. Due to the small size of our cohort, our results are only indicative of data trends. Larger studies are still needed to confirm the current findings.
Evaluation of Berberine as an Adjunct to TB Treatment
Authors: Ozturk Mumin , Chia Julius E. , Hazra Rudranil , Saqib Mohd , Maine Rebeng A. , Guler Reto , Suzuki Harukazu , Mishra Bibhuti B. , Brombacher Frank , Parihar Suraj P.
Published: October 2021

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.
Radiogenomics Map Reveals the Landscape of m6A Methylation Modification Pattern in Bladder Cancer
Authors: Ye Fangdie , Hu Yun , Gao Jiahao , Liang Yingchun , Liu Yufei , Ou Yuxi , Cheng Zhang , Jiang Haowen
Published: October 2021

We aimed to develop a noninvasive radiomics approach to reveal the m6A methylation status and predict survival outcomes and therapeutic responses in patients. A total of 25 m6A regulators were selected for further analysis, we confirmed that expression level and genomic mutations rate of m6A regulators were significantly different between cancer and normal tissues. Besides, we constructed methylation modification models and explored the immune infiltration and biological pathway alteration among different models. The m6A subtypes identified in this study can effectively predict the clinical outcome of bladder cancer (including m6AClusters, geneClusters, and m6Ascore models). In addition, we observed that immune response markers such as PD1 and CTLA4 were significantly corelated with the m6Ascore. Subsequently, a total of 98 obtained digital images were processed to capture the image signature and construct image prediction models based on the m6Ascore classification using a radiomics algorithm. We constructed seven signature radiogenomics models to reveal the m6A methylation status, and the model achieved an area under curve (AUC) degree of 0.887 and 0.762 for the training and test datasets, respectively. The presented radiogenomics models, a noninvasive prediction approach that combined the radiomics signatures and genomics characteristics, displayed satisfactory effective performance for predicting survival outcomes and therapeutic responses of patients. In the future, more interdisciplinary fields concerning the combination of medicine and electronics remains to be explored.
Immunometabolic Dysregulation at the Intersection of Obesity and COVID-19
Authors: Khwatenge Collins N. , Pate Marquette , Miller Laura C. , Sang Yongming
Published: October 2021

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.
N6-Methyladenosine Methylomic Landscape of Lung Tissues in Murine Acute Allergic Asthma
Authors: Teng Fangzhou , Tang Weifeng , Wuniqiemu Tulake , Qin Jingjing , Zhou Yaolong , Huang Xi , Wang Shiyuan , Zhu Xueyi , Tang Zhao , Yi La , Wei Ying , Dong Jingcheng
Published: October 2021

Allergic asthma is well known as a common respiratory disorder comprising an allergic inflammatory nature and excessive immune characteristic. N6-methyladenosine (m6A) methylation is an RNA epigenetic modification that post-transcriptionally regulates gene expression and function by affecting the RNA fate. Currently, m6A methylation is gaining attention as a mechanism of immunoregulation. However, whether m6A methylation engages the pathological process of asthma remains uncertain. Here, we present the m6A methylomic landscape in the lung tissues of ovalbumin-induced acute asthma mice using MeRIP-seq and RNA-seq. We identified 353 hypermethylated m6A peaks within 329 messenger RNAs (mRNAs) and 150 hypomethylated m6A peaks within 143 mRNAs in the lung tissues of asthmatic mice. These differentially methylated mRNAs were found to be involved in several immune function-relevant signaling pathways. In addition, we predicted 25 RNA-binding proteins that recognize the differentially methylated peak sites by exploring public databases, and the roles of these proteins are mostly related to mRNA biogenesis and metabolism. To further investigate the expression levels of the differentially methylated genes, we performed combined analysis of the m6A methylome and transcriptome data and identified 127 hypermethylated mRNAs (107 high and 20 low expression) and 43 hypomethylated mRNAs with differential expressions (9 high and 34 low expression). Of these, there are a list of mRNAs involved in immune function and regulation. The present results highlight the essential role of m6A methylation in the pathogenesis of asthma.
GAS6/Axl Signaling Modulates Blood-Brain Barrier Function Following Intravenous Thrombolysis in Acute Ischemic Stroke
Authors: Guo Zhen-Ni , Liu Jie , Chang Junlei , Zhang Peng , Jin Hang , Sun Xin , Yang Yi
Published: October 2021

Background and Purpose

Recent studies have shown that several proteins, including Axl, are related to hemorrhagic transformation (HT) following intravenous thrombolysis by affecting blood-brain barrier (BBB) function. However, the effects of these proteins on BBB function have been studied primarily in animal models. In this study, we aimed to identify serum protein markers that predict HT following intravenous thrombolysis in patients with acute ischemic stroke (AIS) and verify whether these serum proteins regulate BBB function and HT in animal stroke models.

Methods

First, 118 AIS patients were enrolled in this study, including 52 HT patients and 66 non-HT patients. In Step 1, baseline serum levels of Axl, angiopoietin-like 4, C-reactive protein, ferritin, hypoxia-inducible factor-1 alpha, HTRA2, Lipocalin2, matrix metallopeptidase 9, platelet-derived growth factor-BB, and tumor necrosis factor alpha were measured using a quantitative cytokine chip. Next, sequence mutations and variations in genes encoding the differentially expressed proteins identified in Step 1 and subsequent function-related proteins were detected. Finally, we verified whether manipulation of differentially expressed proteins affected BBB function and HT in a hyperglycemia-induced rat stroke model.

Results

Serum Axl levels were significantly lower in the HT group than in the non-HT group; none of the other protein markers differed significantly between the two groups. Genetic testing revealed that sequence variations of GAS6 (the gene encoding the Axl ligand)-derived long non-coding RNA, GAS6-AS1, were significantly correlated with an increased risk of HT after intravenous thrombolysis. In animal studies, administration of recombinant GAS6 significantly reduced brain infarction and neurological deficits and attenuated BBB disruption and HT.

Conclusions

Lower serum Axl levels, which may result from sequence variations in GAS6-AS1, are correlated with an increased risk of HT after intravenous thrombolysis in stroke patients. Activation of the Axl signaling pathway by the GAS6 protein may serve as a therapeutic strategy to reduce HT in AIS patients.