bluuebunny/crossref_metadata_2025 huggingface dataset:
Glacial Lake Area Change and Potential Outburst Flood Hazard Assessment in the Bhutan Himalaya
Authors: Rinzin Sonam , Zhang Guoqing , Wangchuk Sonam
Published: December 2021

Against the background of climate change-induced glacier melting, numerous glacial lakes are formed across high mountain areas worldwide. Existing glacial lake inventories, chiefly created using Landsat satellite imagery, mainly relate to 1990 onwards and relatively long (decadal) temporal scales. Moreover, there is a lack of robust information on the expansion and the GLOF hazard status of glacial lakes in the Bhutan Himalaya. We mapped Bhutanese glacial lakes from the 1960s to 2020, and used these data to determine their distribution patterns, expansion behavior, and GLOF hazard status. 2,187 glacial lakes (corresponding to 130.19 ± 2.09 km2) were mapped from high spatial resolution (1.82–7.62 m), Corona KH-4 images from the 1960s. Using the Sentinel-2 (10 m) and Sentinel-1 (20 m × 22 m), we mapped 2,553 (151.81 ± 7.76 km2), 2,566 (152.64 ± 7.83 km2), 2,572 (153.94 ± 7.83 km2), 2,569 (153.97 ± 7.79 km2) and 2,574 (156.63 ± 7.95 km2) glacial lakes in 2016, 2017, 2018, 2019 and 2020, respectively. The glacier-fed lakes were mainly present in the Phochu (22.63%) and the Kurichu (20.66%) basins. A total of 157 glacier-fed lakes have changed into non-glacier-fed lakes over the 60 years of lake evolution. Glacier-connected lakes (which constitutes 42.25% of the total glacier-fed lake) area growth accounted for 75.4% of the total expansion, reaffirming the dominant role of glacier-melt water in expanding glacial lakes. Between 2016 and 2020, 19 (4.82 km2) new glacial lakes were formed with an average annual expansion rate of 0.96 km2 per year. We identified 31 lakes with a very-high and 34 with high GLOF hazard levels. These very-high to high GLOF hazard lakes were primarily located in the Phochu, Kurichu, Drangmechu, and Mochu basins. We concluded that the increasing glacier melt is the main driver of glacial lake expansion. Our results imply that extending glacial lakes studies back to the 1960s provides new insights on glacial lake evolution from glacier-fed lakes to non-glacier-fed lakes. Additionally, we reaffirmed the capacity of Sentinel-1 and Sentinel-2 data to determine annual glacial lake changes. The results from this study can be a valuable basis for future glacial lake monitoring and prioritizing limited resources for GLOF mitigation programs.
Exploring the Effectiveness of STEAM-Based Courses on Junior High School Students’ Scientific Creativity
Authors: Tran Ngoc-Huy , Huang Chin-Fei , Hung Jeng-Fung
Published: December 2021

The purpose of this study is to explore the effectiveness of a STEAM (Science, Technology, Engineering, Arts, Mathematics) -based curriculum on junior high school students’ scientific creativity. The main topic of the STEAM-based curriculum in this study is an ancient mechanical clock that was designed and produced by the authors’ team. Further, the main concept of the ancient mechanical clock is about a gear wheel. Hence, this study designed two stages of courses which were gear wheel science courses (2 weeks) and STEAM-based courses (2 weeks). A total of 62 junior high school students from two different courses participated in this study and were divided into a control group and an experimental group. This study adopted a counterbalance design. The control group joined gear wheel science courses first and joined STEAM-based courses second. In contrast, the experimental group joined STEAM-based courses first. Both groups were asked to complete a pre-test, a middle-test, and a post-test by completing the “Scientific Creativity Test (Cronbach’s α 0.87)”. The results from paired t-test analyses showed that control group students did not show significant differences in scientific creativity before and after joining the gear wheel science courses, but they got significantly higher scores after joining STEAM-based courses than before. On the other hand, the experimental group students got higher scores in scientific creativity after joining STEAM-based courses than before, and persisted in getting higher scores after joining the gear wheel courses than before. Furthermore, the results implied that the STEAM-based courses might help students maintain or continue their scientific creativity. Further discussion is provided.
First and Second Graders’ Reading Motivation and Reading Comprehension Were Not Adversely Affected by Distance Learning During COVID-19
Authors: Thomas Almut E.
Published: December 2021

Many assume that school shutdowns in the wake of the COVID-19 pandemic have significantly impaired students’ achievement and self-determined motivation. Of greatest concern given the sudden shift to distance learning are students with inadequate access to digital media and insufficient experience organizing learning processes independently—for example, first and second graders. This study used a quasi-experiment with 206 elementary students to investigate differences in reading comprehension and self-determined reading motivation of students who attended grades one and two during or before the pandemic. Surprisingly, the results revealed no differences in reading comprehension and reading motivation between the groups, contradicting the assumption that the pandemic-driven shift to distance learning would inevitably impair young students’ achievements and self-determined motivation.
Emerging Antioxidant Paradigm of Mesenchymal Stem Cell-Derived Exosome Therapy
Authors: Xia Chen , Dai Zhanqiu , Jin Yongming , Chen Pengfei
Published: December 2021

Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms. The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance. Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.
Pathogenesis Based Diagnosis and Treatment of Endometriosis
Authors: Koninckx Philippe R. , Fernandes Rodrigo , Ussia Anastasia , Schindler Larissa , Wattiez Arnaud , Al-Suwaidi Shaima , Amro Bedayah , Al-Maamari Basma , Hakim Zeinab , Tahlak Muna
Published: December 2021

Understanding the pathophysiology of endometriosis is changing our diagnosis and treatment. Endometriosis lesions are clones of specific cells, with variable characteristics as aromatase activity and progesterone resistance. Therefore the GE theory postulates GE incidents to start endometriosis, which thus is different from implanted endometrium. The subsequent growth in the specific environment of the peritoneal cavity is associated with angiogenesis, inflammation, immunologic changes and bleeding in the lesions causing fibrosis. Fibrosis will stop the growth and lesions look burnt out. The pain caused by endometriosis lesions is variable: some lesions are not painful while other lesions cause neuroinflammation at distance up to 28 mm. Diagnosis of endometriosis is made by laparoscopy, following an experience guided clinical decision, based on history, symptoms, clinical exam and imaging. Biochemical markers are not useful. For deep endometriosis, imaging is important before surgery, notwithstanding rather poor predictive values when confidence limits, the prevalence of the disease and the absence of stratification of lesions by size, localization and depth of infiltration, are considered. Surgery of endometriosis is based on recognition and excision. Since the surrounding fibrosis belongs to the body with limited infiltration by endometriosis, a rim of fibrosis can be left without safety margins. For deep endometriosis, this results in a conservative excision eventually with discoid excision or short bowel resections. For cystic ovarian endometriosis superficial destruction, if complete, should be sufficient. Understanding pathophysiology is important for the discussion of early intervention during adolescence. Considering neuroinflammation at distance, the indication to explore large somatic nerves should be reconsidered. Also, medical therapy of endometriosis has to be reconsidered since the variability of lesions results in a variable response, some lesions not requiring estrogens for growth and some being progesterone resistant. If the onset of endometriosis is driven by oxidative stress from retrograde menstruation and the peritoneal microbiome, medical therapy could prevent new lesions and becomes indicated after surgery.
Postpartum Thyroid Dysfunction in Women With Known and Newly Diagnosed Hypothyroidism in Early Pregnancy
Authors: Gao Xiaotong , Wang Xichang , Han Yutong , Wang Haoyu , Li Jiashu , Hou Yuanyuan , Yang Yang , Wang Huiru , Teng Weiping , Shan Zhongyan
Published: December 2021

Background

Hypothyroidism in the first trimester of pregnancy (T1) has great adverse effects on mothers and foetuses. However, few studies have investigated the influence on postpartum thyroid dysfunction. This study aimed to evaluate their long-term effect on postpartum thyroid function within one year after delivery.

Methods

In total, 151 women were recruited from 1496 participants and were classified as newly diagnosed subclinical hypothyroidism (SCH) in T1 (ND-SCH, n=50), previously known SCH before pregnancy (PK-SCH, n=51) and previously known overt hypothyroidism (PK-OH, n=50). Their thyroid functions were dynamically monitored from pre-conception to one-year postpartum.

Results

During pregnancy, the first thyroid functions’ test time in T1 were 5-8 gestational weeks. After delivery, the prevalence of postpartum thyroiditis (PPT) was comparable in women with previously known and newly diagnosed hypothyroidism [ND-SCH 62.0% vs PK-SCH 64.7% vs PK-OH 64.0%, P=0.96]. For the ND-SCH group, PPT was significantly related with thyroid-stimulating hormone (TSH) >4.0 mU/L occurring at <8 gestational weeks [OR=8.06, 95% CI, 2.08-31.29] and TSH levels outside 1.0-2.5 mU/L near childbirth [OR=3.73, 95% CI, 1.04-13.41]. For patients with known hypothyroidism before pregnancy (PK-SCH and PK-OH), TSH>2.5 mU/L in T1 [OR=3.55, 95% CI, 1.43-8.81] and TPOAb≥300 μIU/mL [OR=6.58, 95% CI, 2.05-21.12] were associated with PPT. Regardless of whether SCH was diagnosed before pregnancy or in T1, the levothyroxine (LT4) treatment was discontinued at delivery. More than 50% of the patients had to face the hypothyroidism phase of postpartum and restarted LT4 treatment in the first-year follow-up. The logistic regression analysis revealed that TSH elevation occurring at <8 gestational weeks [OR=2.48, 95% CI, 1.09-5.6], TSH levels outside 1.0-2.5 mU/L near childbirth [OR=3.42, 95% CI, 1.45-8.05], and TPOAb≥300 μIU/mL [OR=6.59, 95% CI, 1.79-24.30] were the risk factors.

Conclusion

TSH elevation at <8 gestational weeks was associated with PPT after delivery in women with known and newly diagnosed hypothyroidism. Especially for SCH patients who stopped LT4 treatment at delivery, unsatisfactory TSH level at <8 gestational weeks and near childbirth, TPOAb≥300 μIU/mL were the risk factors for LT4 retreatment in one-year postpartum.
Evaluating Glycemic Control During Basalin or Lantus Administration in Adults With Controlled Type 2 Diabetes Mellitus Using Continuous Glucose Monitoring
Authors: Wang Huiying , Zhou Yunting , Zhai Xiaofang , Ding Bo , Jing Ting , Su Xiaofei , Li Huiqin , Ma Jianhua
Published: December 2021

Aim

This study aims at evaluating glycemic control during Basalin or Lantus administration in adults with controlled type 2 diabetes mellitus using continuous glucose monitoring system (CGM).

Methods

47 patients with well-controlled T2DM using both Basalin and oral hypoglycemic drugs were recruited. CGM were applied from day 1 to day 3 with the unchanged dose of Basalin and then removed from day 4. A washout was performed with Lantus at the same dose as Basalin from day 4 to day 10. Then patients were continued to install the CGM under Lantus administration from day 11 to day 13. Variables of CGM, such as the area under the curve (AUC) for both hyperglycemia and hypoglycemia, 24h mean blood glucose (24h MBG), 24h standard deviation of blood glucose (24h SDBG), 24h mean amplitude of glycemic excursion (24h MAGE), PT (percentage of time), and time in range (TIR), were calculated and compared between Basalin group and Lantus group.

Results

The group of Lantus showed lower 24h MBG (p<0.01), 24h MAGE (p<0.05), and lower 24h SDBG (p<0.01) than the Basalin group. Lantus−treated patients had a lower PT and AUC when the cut-off point for blood glucose was 10 mmol/L (p<0.05) and 13.9 mmol/L (p<0.05), respectively. In this study, no patient developed symptomatic hypoglycemia, few hypoglycemia was observed and there was no difference of hypoglycemia between the two groups.

Conclusion

In patients with well-controlled T2DM who were treated with insulin glargine, Lantus group showed lower MBG, GV, and lower PT (BG > 10.0 mmol/L, BG > 13.9 mmol/L) than Basalin group. In summary, for T2DM population with HbA1c ≤ 7%, Lantus may be a better choice compared with Basalin.
Prognostic Indicators of Non-Transection Nerve Injury and Vocal Fold Motion Impairment After Thyroid Surgery – Correlation Between Intraoperative Neuromonitoring Findings and Perioperative Voice Parameters
Authors: Huang Tzu-Yen , Yu Wing-Hei Viola , Chiang Feng-Yu , Wu Che-Wei , Fu Shih-Chen , Tai An-Shun , Lin Yi-Chu , Tseng Hsin-Yi , Lee Ka-Wo , Lin Sheng-Hsuan
Published: December 2021

Objectives

In patients with recurrent laryngeal nerve (RLN) injury after thyroid surgery, unrecovered vocal fold motion (VFM) and subjective voice impairment cause extreme distress. For surgeons, treating these poor outcomes is extremely challenging. To enable early treatment of VFM impairment, this study evaluated prognostic indicators of non-transection RLN injury and VFM impairment after thyroid surgery and evaluated correlations between intraoperative neuromonitoring (IONM) findings and perioperative voice parameters.

Methods

82 adult patients had postoperative VFM impairment after thyroidectomy were enrolled. Demographic characteristics, RLN electromyography (EMG), and RLN injury mechanism were compared. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were administered during I-preoperative; II-immediate, III-short-term and IV-long-term postoperative periods. The patients were divided into R/U Group according to the VFM was recovered/unrecovered 3 months after surgery. The patients in U Group were divided into U1/U2 Group according to total IVST score change was <4 and ≥4 during period-IV.

Results

Compared to R Group (42 patients), U Group (38 patients) had significantly more patients with EMG >90% decrease in the injured RLN (p<0.001) and thermal injury as the RLN injury mechanism (p=0.002). Voice parameter impairments were more severe in U Group compared to R Group. Compared to U1 group (19 patients), U2 Group (19 patients) had a significantly larger proportion of patients with EMG decrease >90% in the injured RLN (p=0.022) and thermal injury as the RLN injury mechanism (p=0.017). A large pitch range decrease in period-II was a prognostic indicator of a moderate/severe long-term postoperative subjective voice impairment.

Conclusion

This study is the first to evaluate correlations between IONM findings and voice outcomes in patients with VFM impairment after thyroid surgery. Thyroid surgeons should make every effort to avoid severe type RLN injury (e.g., thermal injury or injury causing EMG decrease >90%), which raises the risk of unrecovered VFM and moderate/severe long-term postoperative subjective voice impairment. Using objective voice parameters (e.g., pitch range) as prognostic indicators not only enables surgeons to earlier identify patients with low voice satisfaction after surgery, and also enable implementation of interventions sufficiently early to maintain quality of life.
Comprehensive Genomic Characterization of A Case of Granular Cell Tumor of the Posterior Pituitary Gland: A Case Report
Authors: Hong Christopher S. , Elsamadicy Aladine A. , Fisayo Adeniyi , Inzucchi Silvio E. , Gopal Pallavi P. , Vining Eugenia M. , Erson-Omay E. Zeynep , Bulent Omay Sacit
Published: December 2021

Granular cell tumors of the pituitary belong to a rare family of neoplasms, arising from the posterior pituitary gland. Although considered benign, they may cause significant morbidity and residual disease after resection can lead to poor clinical outcomes. Currently, there is no known medical therapy for any posterior pituitary gland tumor, in part due to sparse molecular characterization of these lesions. We report data from whole exome sequencing of a case of granular cell tumor of the pituitary, performed under an institutional review board approved protocol. A 77 year-old female underwent resection of an incidentally diagnosed pituitary mass that was causing radiographic compression of the optic nerves with a subclinical temporal field defect and central hypothyroidism. The pathology of the resected specimen demonstrated a granular cell tumor of the posterior pituitary gland. Whole-exome sequencing revealed mutations predicted to be deleterious in key oncogenes, SETD2 and PAX8, both of which have been described in other cancers and could potentially be amenable to targeted therapies with existing approved drugs, including immune checkpoint inhibitors and histone deacetylase inhibitors, respectively. To our knowledge, this is the first comprehensive genomic characterization of granular cell tumor of the posterior pituitary gland. We report mutations in oncogenes predicted to be deleterious and reported in other cancers with potential for therapeutic targeting with existing pharmacologic agents. These data provide new insights into the molecular pathogenesis of GCT of the pituitary and may warrant further investigation.
Prevalence of Overweight and Obesity in People With Severe Mental Illness: Systematic Review and Meta-Analysis
Authors: Afzal Medhia , Siddiqi Najma , Ahmad Bilal , Afsheen Nida , Aslam Faiza , Ali Ayaz , Ayesha Rubab , Bryant Maria , Holt Richard , Khalid Humaira , Ishaq Kousar , Koly Kamrun Nahar , Rajan Sukanya , Saba Jobaida , Tirbhowan Nilesh , Zavala Gerardo A.
Published: December 2021

Aims

1) To determine the pooled prevalence of overweight and obesity in people with severe mental illness (SMI), overall and by type of SMI, geographical region, and year of data collection; and 2) to assess the likelihood of overweight and obesity, in people with SMI compared with the general population.

Methods

PubMed, Medline, EMBASE, and PsycINFO databases were searched to identify observational studies assessing the prevalence of obesity in adults with SMI. Screening, data extraction and risk of bias assessments were performed independently by two co-authors. Random effect estimates for the pooled prevalence of overweight and obesity and the pooled odds of obesity in people with SMI compared with the general population were calculated. Subgroup analyses were conducted for types of SMI, setting, antipsychotic medication, region of the world, country income classification, date of data collection and sex. We assessed publication bias and performed a series of sensitivity analyses, excluding studies with high risk of bias, with low sample size and those not reporting obesity according to WHO classification.

Result

120 studies from 43 countries were included, the majority were from high income countries. The pooled prevalence of obesity in people with SMI was 25.9% (95% C.I. = 23.3-29.1) and the combined pooled prevalence of overweight and obesity was 60.1% (95% C.I. = 55.8-63.1). Sub-Saharan Africa (13.0%, 95%C.I. = 6.7-25.1) and South Asia (17.7%, 95%C.I. = 10.5-28.5) had the lowest prevalence of obesity whilst North Africa and the Middle East (35.8%, 95%C.I. = 23.8-44.8) reported the highest prevalence. People with SMI were 3.04 more likely (95% C.I. = 2.42-3.82) to have obesity than the general population, but there was no difference in the prevalence of overweight. Women with schizophrenia were 1.44 (95% C.I. = 1.25-1.67) times more likely than men with schizophrenia to live with obesity; however, no gender differences were found among those with bipolar disorder.

Conclusion

People with SMI have a markedly high prevalence and higher odds of obesity than the general population. This may contribute to the very high prevalence of physical health conditions and mortality in this group. People with SMI around the world would likely benefit from interventions to reduce and prevent obesity.
Appetite Regulation of TLR4-Induced Inflammatory Signaling
Authors: Li Yongxiang , Jiang Qingyan , Wang Lina
Published: December 2021

Appetite is the basis for obtaining food and maintaining normal metabolism. Toll-like receptor 4 (TLR4) is an important receptor expressed in the brain that induces inflammatory signaling after activation. Inflammation is considered to affect the homeostatic and non-homeostatic systems of appetite, which are dominated by hypothalamic and mesolimbic dopamine signaling. Although the pathological features of many types of inflammation are known, their physiological functions in appetite are largely unknown. This review mainly addresses several key issues, including the structures of the homeostatic and non-homeostatic systems. In addition, the mechanism by which TLR4-induced inflammatory signaling contributes to these two systems to regulate appetite is also discussed. This review will provide potential opportunities to develop new therapeutic interventions that control appetite under inflammatory conditions.
Endocrine Disorders and Genital Infections Impair Gynecological Health in APECED (APS-1)
Authors: Saari Viivi , Laakso Saila , Tiitinen Aila , Mäkitie Outi , Holopainen Elina
Published: December 2021

Objective

In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) defects in the autoimmune regulator gene lead to impaired immunotolerance. We explored the effects of immunodeficiency and endocrinopathies on gynecologic health in patients with APECED.

Design

Cross-sectional cohort study combined with longitudinal follow-up data.

Methods

We carried out a gynecologic evaluation, pelvic ultrasound, and laboratory and microbiologic assessment in 19 women with APECED. Retrospective data were collected from previous study visits and hospital records.

Results

The study subjects’ median age was 42.6 years (range, 16.7-65.5). Sixteen patients (84%) had premature ovarian insufficiency, diagnosed at the median age of 16.5 years; 75% of them used currently either combined contraception or hormonal replacement therapy. In 76% of women, the morphology and size of the uterus were determined normal for age, menopausal status, and current hormonal therapy. Fifteen patients (79%) had primary adrenal insufficiency; three of them used dehydroepiandrosterone substitution. All androgen concentrations were under the detection limit in 11 patients (58%). Genital infections were detected in nine patients (47%); most of them were asymptomatic. Gynecologic C. albicans infection was detected in four patients (21%); one of the strains was resistant to azoles. Five patients (26%) had human papillomavirus infection, three of which were high-risk subtypes. Cervical cell atypia was detected in one patient. No correlation between genital infections and anti-cytokine autoantibodies was found.

Conclusions

Ovarian and adrenal insufficiencies manifested with very low androgen levels in over half of the patients. Asymptomatic genital infections, but not cervical cell atypia, were common in female patients with APECED.
Responses of Microbial Nutrient Acquisition to Depth of Tillage and Incorporation of Straw in a Chinese Mollisol
Authors: Zhang Naiwen , Chen Xu , Han Xiaozeng , Lu Xinchun , Yan Jun , Zou Wenxiu , Yan Lei
Published: December 2021

Tillage and straw incorporation are important agricultural practices that can break the plow layer and improve Mollisol fertility. The effect of these practices on the limitation of resources for soil microorganisms, however, is unclear. We established a field experiment in 2018 and collection of soil samples in 2020 to study the acquisition of resources by microbes in a Mollisol region in northeastern China. Four treatments were studied: conventional tillage (CT), straw incorporation with conventional tillage (SCT), subsoil tillage (ST) and straw incorporation with subsoil tillage (SST). The limitation of resources for soil microorganisms was assessed using models of extracellular enzymatic stoichiometry. The soil microbes were generally colimited by C and P but not N. The degree of limitation, however, varied among the treatments. SCT and SST alleviated microbial P limitation in the 0–15 and 15–35 cm layers, respectively, but ST did not significantly affect P limitation relative to CT. Interestingly, N-resource contents were strongly correlated with indicators of C and P limitation. A random forest analysis found that the contents of available N and total dissolved N were the most important factors for microbial C and P limitation, respectively. Straw incorporation alleviated microbial P limitation but did not eliminate P limitation and deep tillage aggravate microbial C limitation. We suggest that N fertilization may be reduced due to the N-rich characteristics of the Mollisols in northeastern China.
Pathway Association Studies Reveal Gene Loci and Pathway Networks that Associated With Plasma Cystatin C Levels
Authors: Jiao Hongxiao , Zhang Miaomiao , Zhang Yuan , Wang Yaogang , Li Wei-Dong
Published: December 2021

As a marker for glomerular filtration, plasma cystatin C level is used to evaluate kidney function. To decipher genetic factors that control the plasma cystatin C level, we performed genome-wide association and pathway association studies using United Kingdom Biobank data. One hundred fifteen loci yielded p values less than 1 × 10−100, three genes (clusters) showed the most significant associations, including the CST8-CST9 cluster on chromosome 20, the SH2B3-ATXN2 gene region on chromosome 12, and the SHROOM3-CCDC158 gene region on chromosome 4. In pathway association studies, forty significant pathways had FDR (false discovery rate) and or FWER (family-wise error rate) ≤ 0.001: spermatogenesis, leukocyte trans-endothelial migration, cell adhesion, glycoprotein, membrane lipid, steroid metabolic process, and insulin signaling pathways were among the most significant pathways that associated with the plasma cystatin C levels. We also performed Genome-wide association studies for eGFR, top associated genes were largely overlapped with those for cystatin C.
Identification and Validation of a Tumor Microenvironment-Related Gene Signature in Hepatocellular Carcinoma Prognosis
Authors: Huang Changjing , Zhang Chenyue , Sheng Jie , Wang Dan , Zhao Yingke , Qian Ling , Xie Lin , Meng Zhiqiang
Published: December 2021

Background: Hepatocellular carcinoma (HCC) is a typical inflammatory-related malignant tumor with complex immune tolerance microenvironment and poor prognosis. In this study, we aimed to construct a novel immune-related gene signature for the prognosis of HCC patients, exploring tumor microenvironment (TME) cell infiltration characterization and potential mechanisms.

Methods: A total of 364 HCC samples with follow-up information in the TCGA-LIHC dataset were analyzed for the training of the prognostic signature. The Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the IRGs was conducted to identify the prognostic genes and establish an immune risk signature. The immune cell infiltration in TME was estimated via the CIBERSORT method. Gene Set Variation Analysis (GSVA) was conducted to compare the biological pathways involved in the low-risk and high-risk groups. Furthermore, paraffin sections of HCC tissue microarrays containing 77 patients from Fudan University Shanghai Cancer Center were used for IHC staining. The clinical characteristics of the 77 HCC patients were collected and summarized for survival analysis validation via the Kaplan–Meier (KM) method.

Results: Three-gene signature with close immune correlation (Risk score = EPO * 0.02838 + BIRC5 * 0.02477 + SPP1 * 0.0002044) was constructed eventually and proven to be an effective prognostic factor for HCC patients. The patients were divided into a high-risk and a low-risk group according to the optimal cutoff, and the survival analysis revealed that HCC samples with high-risk immuno-score had significantly poorer outcomes than the low-risk group (p < 0.0001). The results of CIBERSORT suggested that the immune cell activation was relatively higher in the low-risk group with better prognosis. Besides, GSVA analysis showed multiple signaling differences between the high- and low-risk group, indicating that the three-gene prognostic model can affect the prognosis of patients by affecting immune-related mechanisms. Tissue microarray (TMA) results further confirmed that the expression of three genes in HCC tissues was closely related to the prognosis of patients, respectively.

Conclusion: In this study, we constructed and validated a robust three-gene signature with close immune correlation in HCC, which presented a reliable performance in the prediction of HCC patients’ survival.
A Genetic Map of the Modern Urban Society of Amsterdam
Authors: Ferwerda Bart , Abdellaoui Abdel , Nieuwdorp Max , Zwinderman Koos
Published: December 2021

Genetic differences between individuals underlie susceptibility to many diseases. Genome-wide association studies (GWAS) have discovered many susceptibility genes but were often limited to cohorts of predominantly European ancestry. Genetic diversity between individuals due to different ancestries and evolutionary histories shows that this approach has limitations. In order to gain a better understanding of the associated genetic variation, we need a more global genomics approach including a greater diversity. Here, we introduce the Healthy Life in an Urban Setting (HELIUS) cohort. The HELIUS cohort consists of participants living in Amsterdam, with a level of diversity that reflects the Dutch colonial and recent migration past. The current study includes 10,283 participants with genetic data available from seven groups of inhabitants, namely, Dutch, African Surinamese, South-Asian Surinamese, Turkish, Moroccan, Ghanaian, and Javanese Surinamese. First, we describe the genetic variation and admixture within the HELIUS cohort. Second, we show the challenges during imputation when having a genetically diverse cohort. Third, we conduct a body mass index (BMI) and height GWAS where we investigate the effects of a joint analysis of the entire cohort and a meta-analysis approach for the different subgroups. Finally, we construct polygenic scores for BMI and height and compare their predictive power across the different ethnic groups. Overall, we give a comprehensive overview of a genetically diverse cohort from Amsterdam. Our study emphasizes the importance of a less biased and more realistic representation of urban populations for mapping genetic associations with complex traits and disease risk for all.
Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias
Authors: Arnaud Pauline , Mougin Zakaria , Boileau Catherine , Le Goff Carine
Published: December 2021

The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.
Cognitive Process of Psoriasis and Its Comorbidities: From Epidemiology to Genetics
Authors: Gao Jing , Shen Xue , Ko Randy , Huang Cong , Shen Changbing
Published: December 2021

Psoriasis (PsO) is a chronic inflammatory skin disease that affects approximately 2% of the population all over the world. Comorbidities of PsO have increasingly garnered more interest in the past decades. Compared with the normal population, the incidences of comorbidities are higher among patients with PsO. In the last 20 years, researchers have focused on studying the genetic components of PsO, and genetic associations between PsO and its comorbidities were elucidated. This review provides an in-depth understanding and summarization of the connection between PsO and its comorbidities from the perspectives of epidemiology and genetics. Further understanding of PsO and its comorbidities will promote research on the pathogenesis, drug development, novel therapy methods, and personalized and precision treatment of PsO and its comorbidities.
Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex
Authors: Chen Fuying , Yao Lei , Zhang Xue , Gu Yan , Yu Hong , Yao Zhirong , Zhang Jia , Li Ming
Published: December 2021

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.
A Competitive Endogenous RNA Network Based on Differentially Expressed lncRNA in Lipopolysaccharide‐Induced Acute Lung Injury in Mice
Authors: Jia Xianxian , Huang Jinhui , Wu Bo , Yang Miao , Xu Wei
Published: December 2021

Non-coding RNAs have remarkable roles in acute lung injury (ALI) initiation. Nevertheless, the significance of long non-coding RNAs (lncRNAs) in ALI is still unknown. Herein, we purposed to identify potential key genes in ALI and create a competitive endogenous RNA (ceRNA) modulatory network to uncover possible molecular mechanisms that affect lung injury. We generated a lipopolysaccharide-triggered ALI mouse model, whose lung tissue was subjected to RNA sequencing, and then we conducted bioinformatics analysis to select genes showing differential expression (DE) and to build a lncRNA-miRNA (microRNA)- mRNA (messenger RNA) modulatory network. Besides, GO along with KEGG assessments were conducted to identify major biological processes and pathways, respectively, involved in ALI. Then, RT-qPCR assay was employed to verify levels of major RNAs. A protein-protein interaction (PPI) network was created using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and the hub genes were obtained with the Molecular Complex Detection plugin. Finally, a key ceRNA subnetwork was built from major genes and their docking sites. Overall, a total of 8,610 lncRNAs were identified in the normal and LPS groups. Based on the 308 DE lncRNAs [p-value < 0.05, |log2 (fold change) | > 1] and 3,357 DE mRNAs [p-value < 0.05, |log2 (fold change) | > 1], lncRNA-miRNA and miRNA-mRNA pairs were predicted using miRanda. The lncRNA-miRNA-mRNA network was created from 175 lncRNAs, 22 miRNAs, and 209 mRNAs in ALI. The RT-qPCR data keep in step with the RNA sequencing data. GO along with KEGG analyses illustrated that DE mRNAs in this network were mainly bound up with the inflammatory response, developmental process, cell differentiation, cell proliferation, apoptosis, and the NF-kappa B, PI3K-Akt, HIF-1, MAPK, Jak-STAT, and Notch signaling pathways. A PPI network on the basis of the 209 genes was established, and three hub genes (Nkx2-1, Tbx2, and Atf5) were obtained from the network. Additionally, a lncRNA-miRNA-hub gene subnetwork was built from 15 lncRNAs, 3 miRNAs, and 3 mRNAs. Herein, novel ideas are presented to expand our knowledge on the regulation mechanisms of lncRNA-related ceRNAs in the pathogenesis of ALI.
SVInterpreter: A Comprehensive Topologically Associated Domain-Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants
Authors: Fino Joana , Marques Bárbara , Dong Zirui , David Dezső
Published: December 2021

With the advent of genomic sequencing, a number of balanced and unbalanced structural variants (SVs) can be detected per individual. Mainly due to incompleteness and the scattered nature of the available annotation data of the human genome, manual interpretation of the SV’s clinical significance is laborious and cumbersome. Since bioinformatic tools developed for this task are limited, a comprehensive tool to assist clinical outcome prediction of SVs is warranted. Herein, we present SVInterpreter, a free Web application, which analyzes both balanced and unbalanced SVs using topologically associated domains (TADs) as genome units. Among others, gene-associated data (as function and dosage sensitivity), phenotype similarity scores, and copy number variants (CNVs) scoring metrics are retrieved for an informed SV interpretation. For evaluation, we retrospectively applied SVInterpreter to 97 balanced (translocations and inversions) and 125 unbalanced (deletions, duplications, and insertions) previously published SVs, and 145 SVs identified from 20 clinical samples. Our results showed the ability of SVInterpreter to support the evaluation of SVs by (1) confirming more than half of the predictions of the original studies, (2) decreasing 40% of the variants of uncertain significance, and (3) indicating several potential position effect events. To our knowledge, SVInterpreter is the most comprehensive TAD-based tool to identify the possible disease-causing candidate genes and to assist prediction of the clinical outcome of SVs. SVInterpreter is available at http://dgrctools-insa.min-saude.pt/cgi-bin/SVInterpreter.py.
Identification of Enzymes-specific Protein Domain Based on DDE, and Convolutional Neural Network
Authors: Sikander Rahu , Wang Yuping , Ghulam Ali , Wu Xianjuan
Published: December 2021

Predicting the protein sequence information of enzymes and non-enzymes is an important but a very challenging task. Existing methods use protein geometric structures only or protein sequences alone to predict enzymatic functions. Thus, their prediction results are unsatisfactory. In this paper, we propose a novel approach for predicting the amino acid sequences of enzymes and non-enzymes via Convolutional Neural Network (CNN). In CNN, the roles of enzymes are predicted from multiple sides of biological information, including information on sequences and structures. We propose the use of two-dimensional data via 2DCNN to predict the proteins of enzymes and non-enzymes by using the same fivefold cross-validation function. We also use an independent dataset to test the performance of our model, and the results demonstrate that we are able to solve the overfitting problem. We used the CNN model proposed herein to demonstrate the superiority of our model for classifying an entire set of filters, such as 32, 64, and 128 parameters, with the fivefold validation test set as the independent classification. Via the Dipeptide Deviation from Expected Mean (DDE) matrix, mutation information is extracted from amino acid sequences and structural information with the distance and angle of amino acids is conveyed. The derived feature maps are then encoded in DDE exploitation. The independent datasets are then compared with other two methods, namely, GRU and XGBOOST. All analyses were conducted using 32, 64 and 128 filters on our proposed CNN method. The cross-validation datasets achieved an accuracy score of 0.8762%, whereas the accuracy of independent datasets was 0.7621%. Additional variables were derived on the basis of ROC AUC with fivefold cross-validation was achieved score is 0.95%. The performance of our model and that of other models in terms of sensitivity (0.9028%) and specificity (0.8497%) was compared. The overall accuracy of our model was 0.9133% compared with 0.8310% for the other model.
Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy
Authors: Wan Jiayi , Hu Mingyang , Jiang Ziming , Liu Dongwei , Pan Shaokang , Zhou Sijie , Liu Zhangsuo
Published: December 2021

Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.
RNA m6A Methylation Regulators Multi-Omics Analysis in Prostate Cancer
Authors: Su Hao , Wang Yutao , Li Hongjun
Published: December 2021

RNA N6-methyladenosine (m6A) methylation is known to be the most popular RNA modification in animals. Many research reports have elaborated on the effects of m6A regulators in medical practice, such as diagnosis, prognosis, and treatment. M6A modification has evident impacts on many aspects of RNA metabolism, just like RNA splicing, processing, translation, and stability. M6A also has a magnificent role in numerous types of cancers. We analyzed the prostate cancer datasets, from The Cancer Genome Atlas (TCGA) database, for every recognized m6A regulator in their gene expression, DNA methylation status and copy number variations (CNVs). We also systematically analyzed the relationship between different m6A regulators and the prognosis of prostate cancer. The results illustrated considerable differences in the expression of various m6A regulators between the prostate and normal cancer samples. At the same time, there were evident differences in the expression of various m6A regulators in prostate cancers with different Gleason scores. Subsequently, we determined CBLL1, FTO, YTHDC1, HNRNPA2B1 as crucial m6A regulators of prostate cancer. Premised on the expression of CBLL1, we also identified potential therapeutic agents for prostate cancer, and knockdown of FTO prominently inhibited prostate cells migration and invasion in vitro experiment.
An Exploration of Non-Coding RNAs in Extracellular Vesicles Delivered by Swine Anterior Pituitary
Authors: Xiong Jiali , Zhang Haojie , Zeng Bin , Liu Jie , Luo Junyi , Chen Ting , Sun Jiajie , Xi Qianyun , Zhang Yongliang
Published: December 2021

Extracellular vesicles are lipid bilayer-delimited particles carrying proteins, lipids, and small RNAs. Previous studies have demonstrated that they had regulatory functions both physiologically and pathologically. However, information remains inadequate on extracellular vesicles from the anterior pituitary, a key endocrine organ in animals and humans. In this study, we separated and identified extracellular vesicles from the anterior pituitary of the Duroc swine model. Total RNA was extracted and RNA-seq was performed, followed by a comprehensive analysis of miRNAs, lncRNAs, and circRNAs. Resultantly, we obtained 416 miRNAs, 16,232 lncRNAs, and 495 circRNAs. Furthermore, GO and KEGG enrichment analysis showed that the ncRNAs in extracellular vesicles may participate in regulating intracellular signal transduction, cellular component organization or biogenesis, small molecule binding, and transferase activity. The cross-talk between them also suggested that they may play an important role in the signaling process and biological regulation. This is the first report of ncRNA data in the anterior pituitary extracellular vesicles from the duroc swine breed, which is a fundamental resource for exploring detailed functions of extracellular vesicles from the anterior pituitary.