bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Levels of MiRNAs From 320 Family in Subjects With Lipodystrophy: Disclosing Novel Signatures of the Disease
Authors: Dattilo Alessia , Ceccarini Giovanni , Scabia Gaia , Magno Silvia , Quintino Lara , Pelosini Caterina , Salvetti Guido , Cusano Roberto , Massidda Matteo , Montanelli Lucia , Gilio Donatella , Gatti Gianluca , Giacomina Alessandro , Costa Mario , Santini Ferruccio , Maffei Margherita
Published: June 2022

Lipodystrophy (LD) indicates a group of rare disorders, with generalized or partial loss of white adipose tissue (WAT) often associated with metabolic derangements. Heterogeneity/wide spectrum of the disease and lack of biomarkers make diagnosis often difficult. MicroRNAs are important to maintain a correct WAT function and WAT is a source of circulating miRNAs (cmiRs). miRNAs from 320 family were previously detected in the WAT and variably associated to the metabolic syndrome. Our aim was then to investigate if LD can result in altered abundance of cmiRs-320. We collected samples from a cohort of LD subjects of various subtypes and from age matched controls. Use of quantitative PCR determined that cmiRs- 320a-3p, 320b, 320c, 320e are upregulated, while 320d is downregulated in LD. CmiRs-320 power as classifiers was more powerful in the most extreme and defined forms of LD, including the generalized and the Dunnigan subtypes. cmiR-320a-3p showed significant inverse relationships with plasma leptin (P < 0.0001), typically low in LD. The hepatic enzymes gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the marker of inflammation C-reactive protein (CRP) were inversely related to cmiR 320d (P < 0.05, for CRP and GGT; P < 0.01, for AST and ALT). Gene ontology analysis revealed cell-cell adhesion as a process regulated by 320 miRNAs targets, thus disclosing a novel route to investigate origin of WAT loss/dysfunction. In conclusion, cmiRs-320 constitute novel biomarkers of LD, abundance of miR320a-3p is inversely associated to indicators related to WAT function, while downregulation of cmiR-320d predicts an altered hepatic profile and higher inflammation.
Long Noncoding RNAs and Mitochondrial Homeostasis in the Development of Diabetic Retinopathy
Authors: Kowluru Renu A.
Published: June 2022

Retinopathy is one of the most devastating complications of diabetes, which a patient fears the most. Hyperglycemic environment results in many structural, functional, molecular and biochemical abnormalities in the retina, and overproduction of mitochondrial superoxide, induced by hyperglycemic milieu, is considered to play a central role in the development of diabetic retinopathy. Expression of many genes associated with maintaining mitochondrial homeostasis is also altered. Recent research has shown that several long noncoding RNAs, RNAs with more than 200 nucleotides but without any reading frames, are aberrantly expressed in diabetes, and altered expression of these long noncoding RNAs is now being implicated in the development of diabetes and its complications including retinopathy. This review focuses the role of long noncoding RNAs in the development of diabetic retinopathy, with a special emphasis on the maintenance of mitochondrial homeostasis.
Emerging Insight Into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence
Authors: Zhang Wenqian , Xiong Yuan , Tao Ranyang , Panayi Adriana C. , Mi Bobin , Liu Guohui
Published: June 2022

Cell senescence is a crucial process in cell fate determination and is involved in an extensive array of aging-associated diseases. General perceptions and experimental evidence point out that the decline of physical function as well as aging-associated diseases are often initiated by cell senescence and organ ageing. Therefore, regulation of cell senescence process can be a promising way to handle aging-associated diseases such as osteoporosis. The circadian clock regulates a wide range of cellular and physiological activities, and many age-linked degenerative disorders are associated with the dysregulation of clock genes. BMAL1 is a core circadian transcription factor and governs downstream genes by binding to the E-box elements in their promoters. Compelling evidence has proposed the role of BMAL1 in cellular senescence and aging-associated diseases. In this review, we summarize the linkage between BMAL1 and factors of cell senescence including oxidative stress, metabolism, and the genotoxic stress response. Dysregulated and dampened BMAL1 may serve as a potential therapeutic target against aging- associated diseases.
OMICs-Based Strategies to Explore Stress Tolerance Mechanisms of Saccharomyces cerevisiae for Efficient Fuel Ethanol Production
Authors: Xu Jian-Ren , Mehmood Muhammad Aamer , Wang Lan , Ahmad Niaz , Ma Hai-Jun
Published: June 2022

Efficient biotransformation of lignocellulosic biomass to second-generation (2G) bioethanol requires promising strains harboring built-in resistance against limitations imposed by pretreated lignocellulose-derived compounds. Ethanol fermentation and stress tolerance of yeast cells are almost simultaneously exposed to sequence variations and multiple inhibitory factors during the phases of proliferation, metabolism, and productivity. Several studies have extensively concentrated on identification or characterization of genes which confer resistance to various stresses and yeast tolerance enhancement through genetic breeding. However, the investigation of individual genes is inadequate to explain the global molecular mechanism. Herewith, “OMICs-approaches,” including genomics, transcriptomics, proteomics, and metabolomics, which are comprehensively aimed at comparative, functional profiling of the whole metabolic network, have elucidated complex cellular reactions under stressful conditions. This review briefly discusses the research progress in the field of multi-OMICs with a special focus on stress-responsive factors in frequently used S. cerevisiae. It also highlights how to promote metabolic-engineered strains for increased tolerance and higher production yield, which should be deeply exploited to achieve robustness during the lignocellulose-to-ethanol conversion process.
Artificial Regulation Effect of Plant Retardants on Leaf Anatomical Characteristics of Elaeagnus Angustifolia
Authors: Zhang Chao , Li Wanjiao , Gao Yong , Xu Zhengzheng , Tian Xiaoning
Published: June 2022

Aims: In order to explore the adaptation mechanisms of Elaeagnus angustifolia to the arid environment in desert areas under the treatment of artificial plant retardants, we used to investigate artificial regulation by using retardants of paclobutrazol (PP333), paclobutrazol+adhesive (NPP333), and chlormequat (CCC) based on multiple factors and multiple levels.

Methods: Orthogonal experimental design of L9 (34) was used to design the experimental treatment combinations. Leaf morphological and structural characteristics determined by the paraffin section method were used to explain the effect of different treatments and their combinations.

Results: The leaves of Elaeagnus angustifolia were iso-petalous with obvious stellate epidermal fuzzy borders on the upper epidermis. The palisade tissue was well developed and tightly arranged. The T1-T9 treatment significantly increased leaf thickness. Conversely, leaf length and width showed a delayed growth effect, while leaf growth developed as an elongated type after application. After plant retardant control, the upper epidermal, palisade tissue, and spongy tissue thickness of the leaves showed a significant trend to increase, at the same time, the number of xylem rows increased and the number of cells per row increased and were arranged closely. Meanwhile, there was a synergistic evolution phenomenon among the indexes. The best treatment combination of plant retardants to regulate the leaf configuration of plants was selecting the concentration of 600 mg/L of PP333, using the root application + leaf application method for two applications.

Conclusions: The study showed that plant retardants improved the ability of plants to resist external environmental stress by reducing leaf area, increasing leaf and epidermal thickness, and promoting the development of mesophyll and vein structures in order to improve water retention capacity and prevent transitional transpiration.
Spatial Differences and Influencing Factors of Energy Poverty: Evidence From Provinces in China
Authors: Jia Wenxing , Wu Shengnan
Published: June 2022

The complex and severe problem of energy poverty seriously affects the health and quality of life of residents and poses a significant challenge to the country’s macroeconomic development. The purpose of this paper is to analyze the spatial distribution of energy poverty and the characteristics of regional differences in 30 provinces in mainland China from 2008 to 2019 by constructing an energy poverty evaluation index system and explore the main reasons for the gap between energy poverty regions in China from the perspective of “relational data.” The results show that the spatial distribution of energy poverty in China is “high in the west and central area and low in the east,” and the spatial pattern is relatively stable. From the perspective of the time dimension, the problem of energy poverty in China has been alleviated during the sample period, and the overall gap in energy poverty has shown a decreasing trend. The difference in energy poverty between regions is the primary source of the overall gap, but its contribution is gradually decreasing. The empirical results suggest that reducing the imbalance of industrial structure, energy price, and energy investment among regions can effectively narrow the inter-regional energy poverty gap. Moreover, there are differences in the dominant factors that determine the difference in energy poverty within the eastern, central, and western regions. In this regard, it is recommended to further improve the relevant policies in developing new energy sources according to local conditions, reasonably increasing energy construction investment, strengthening technological innovation, establishing financial guarantee mechanisms, and guiding residents to consume modern, clean energy.
Identification of the Transcription Co-Factor–Related Gene Signature and Risk Score Model for Osteosarcoma
Authors: Jin Zhijian , Wu Jintao , Lin Jianwei , Wang Jun , Shen Yuhui
Published: June 2022

Osteosarcoma is a malignant tumor with a poor prognosis. Nowadays, there is a lack of good methods to assess the prognosis of osteosarcoma patients. Transcription co-factors (TcoFs) play crucial roles in transcriptional regulation through the interaction with transcription factors (TFs). Many studies have revealed that TcoFs are related to many diseases, especially cancer. However, few studies have been reported about prognostic prediction models of osteosarcoma by using TcoF-related genes. In order to construct a prognostic risk model with TcoF-related genes, the mRNA expression data and matched clinical information of osteosarcoma were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database and the Gene Expression Omnibus (GEO) database. TARGET was used as a training set and GSE21257 from GEO was used as a validation set. Univariate Cox regression was performed to select 13 TcoF-related candidate genes, of which five genes (LMO2, MAML3, MTF2, RBPMS, and SIRT1) were finally used to construct the prognostic risk model by LASSO Cox regression analysis. The Kaplan–Meier (K-M) survival curves showed an obvious difference between high- and low-risk groups. The receiver operating characteristic (ROC) curves based on TARGET demonstrated that this risk model was credible (1-year AUC: 0.607; 3-years AUC: 0.713; 5-years AUC: 0.736). Meanwhile, the risk model was associated with immune cells and immune-related functions. By combining the risk score and clinical factors, the nomogram of osteosarcoma was assessed with a C-index of 0.738 to further support the reliability of this 5-gene prognostic risk model. Finally, the expression of TcoF-related genes was validated in different cell lines by quantitative real-time PCR (qRT-PCR) and also in different tissue samples by immunohistochemistry (IHC). In conclusion, the model can predict the prognosis of osteosarcoma patients and may provide novel targets for the treatment of osteosarcoma patients.
p53 Regulates a miRNA-Fructose Transporter Axis in Brown Adipose Tissue Under Fasting
Authors: Reinisch Isabel , Klymiuk Ingeborg , Michenthaler Helene , Moyschewitz Elisabeth , Galhuber Markus , Krstic Jelena , Domingo Magnus , Zhang Fangrong , Karbiener Michael , Vujić Nemanja , Kratky Dagmar , Schreiber Renate , Schupp Michael , Lenihan-Geels Georgia , Schulz Tim J. , Malli Roland , Madl Tobias , Prokesch Andreas
Published: June 2022

Active thermogenic adipocytes avidly consume energy substrates like fatty acids and glucose to maintain body temperature upon cold exposure. Despite strong evidence for the involvement of brown adipose tissue (BAT) in controlling systemic energy homeostasis upon nutrient excess, it is unclear how the activity of brown adipocytes is regulated in times of nutrient scarcity. Therefore, this study aimed to scrutinize factors that modulate BAT activity to balance thermogenic and energetic needs upon simultaneous fasting and cold stress. For an unbiased view, we performed transcriptomic and miRNA sequencing analyses of BAT from acutely fasted (24 h) mice under mild cold exposure. Combining these data with in-depth bioinformatic analyses and in vitro gain-of-function experiments, we define a previously undescribed axis of p53 inducing miR-92a-1-5p transcription that is highly upregulated by fasting in thermogenic adipocytes. p53, a fasting-responsive transcription factor, was previously shown to control genes involved in the thermogenic program and miR-92a-1-5p was found to negatively correlate with human BAT activity. Here, we identify fructose transporter Slc2a5 as one direct downstream target of this axis and show that fructose can be taken up by and metabolized in brown adipocytes. In sum, this study delineates a fasting-induced pathway involving p53 that transactivates miR-92a-1-5p, which in turn decreases Slc2a5 expression, and suggests fructose as an energy substrate in thermogenic adipocytes.
Exploration of the Nurse Shark (Ginglymostoma cirratum) Plasma Immunoproteome Using High-Resolution LC-MS/MS
Authors: Bakke Fiona K. , Gundappa Manu Kumar , Matz Hanover , Stead David A. , Macqueen Daniel J. , Dooley Helen
Published: June 2022

Many animals of scientific importance lack species-specific reagents (e.g., monoclonal antibodies) for in-depth studies of immune proteins. Mass spectrometry (MS)-based proteomics has emerged as a useful method for monitoring changes in protein abundance and modifications in non-model species. It can be used to quantify hundreds of candidate immune molecules simultaneously without the generation of new reagents. Here, we used MS-based proteomics to identify and quantify candidate immune proteins in the plasma of the nurse shark (Ginglymostoma cirratum), a cartilaginous fish and representative of the most basal extant vertebrate lineage with an immunoglobulin-based immune system. Mass spectrometry-based LC-MS/MS was performed on the blood plasma of nurse sharks immunized with human serum albumin (n=4) or sham immunized (n=1), and sampled at days 0 (baseline control), 1, 2, 3, 5, 7, 14, 21, 28, 25, 42 and 49. An antigen-specific antibody response was experimentally confirmed post-immunization. To provide a high-quality reference to identify proteins, we assembled and annotated a multi-tissue de novo transcriptome integrating long- and short-read sequence data. This comprised 62,682 contigs containing open reading frames (ORFs) with a length >80 amino acids. Using this transcriptome, we reliably identified 626 plasma proteins which were broadly categorized into coagulation, immune, and metabolic functional groups. To assess the feasibility of performing LC-MS/MS proteomics in nurse shark in the absence of species-specific protein annotations, we compared the results to an alternative strategy, mapping peptides to proteins predicted in the genome assembly of a related species, the whale shark (Rhincodon typus). This approach reliably identified 297 proteins, indicating that useful data on the plasma proteome may be obtained in many instances despite the absence of a species-specific reference protein database. Among the plasma proteins defined against the nurse shark transcriptome, fifteen showed consistent changes in abundance across the immunized shark individuals, indicating a role in the immune response. These included alpha-2-macroglobulin (A2M) and a novel protein yet to be characterized in diverse vertebrate lineages. Overall, this study enhances genetic and protein-level resources for nurse shark research and vastly improves our understanding of the elasmobranch plasma proteome, including its remodelling following immune stimulation.
Effects and Molecular Regulation Mechanisms of Salinity Stress on the Health and Disease Resistance of Grass Carp
Authors: Fang Hong , Yang Yuan Yuan , Wu Xiao Man , Zheng Si Yao , Song Yun Jie , Zhang Jie , Chang Ming Xian
Published: June 2022

Though some freshwater fish have been successfully cultivated in saline-alkali water, the survival rates of freshwater fish are greatly affected by different saline-alkali conditions. The mechanisms of immune adaptation or immunosuppression of freshwater fish under different saline-alkali stress remain unclear. Here, grass carp were exposed to 3‰ and 6‰ salinity for 30 days. It was observed that salinity treatments had no obvious effects on survival rates, but significantly increased the percent of unhealthy fish. Salinity treatments also increased the susceptibility of grass carp against Flavobacterium columnare infection. The fatality rate (16.67%) of grass carp treated with 6‰ salinity was much lower than that treated with 3‰ salinity (40%). In the absence of infection, higher numbers of immune-related DEGs and signaling pathways were enriched in 6‰ salinity-treated asymptomatic fish than in 3‰ salinity-treated asymptomatic fish. Furthermore different from salinity-treated symptomatic fish, more DEGs involved in the upstream sensors of NOD-like receptor signaling pathway, such as NLRs, were induced in the gills of 6‰ salinity-treated asymptomatic fish. However in the case of F. columnare infection, more immune-related signaling pathways were impaired by salinity treatments. Among them, only NOD-like receptor signaling pathway was significantly enriched at early (1 and/or 2 dpi) and late (7 dpi) time points of infection both for 3‰ salinity-treated and 6‰ salinity-treated fish. Besides the innate immune responses, the adaptive immune responses such as the production of Ig levels were impaired by salinity treatments in the grass carp infected with F. columnare. The present study also characterized two novel NLRs regulated by salinity stress could inhibit bacterial proliferation and improve the survival rate of infected cells. Collectively, the present study provides the insights into the possible mechanisms why the percent of unhealthy fish in the absence of infection and mortality of grass carp in the case of F. columnare infection were much lower in the 6‰ salinity-treated grass carp than in 3‰ salinity-treated grass carp, and also offers a number of potential markers for sensing both environmental salinity stress and pathogen.
Signaling Crosstalks Drive Generation and Regeneration of the Thymus
Authors: Rosichini Marco , Catanoso Marialuigia , Screpanti Isabella , Felli Maria Pia , Locatelli Franco , Velardi Enrico
Published: June 2022

Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.
m6A-Regulator Expression Signatures Identify a Subset of Follicular Lymphoma Harboring an Exhausted Tumor Microenvironment
Authors: Zhang Tingting , Liu Hengqi , Gao Fenghua , Gong Wenchen , Cui Yaoli , He Jin , Li Lanfang , Qiu Lihua , Qian Zhengzi , Zhou Shiyong , Meng Bin , Ren Xiubao , Zhang Huilai , Wang Xianhuo
Published: June 2022

The role of N6-methyladenosine (m6A) modification in tumor microenvironment has rarely been explored in follicular lymphoma (FL). To examine the role of m6A modification in biological behavior, especially the immune landscape of FL, we utilized the Gene Expression Omnibus database to determine the expression signatures of m6A-regulators by unsupervised clustering, and then condense into a risk score, which was validated in an external cohort from the Tianjin Medical University Cancer Institute and Hospital. Finally, 16 m6A-regulators in 351 FL patients were evaluated and two m6A clusters were identified, characterized by differences in prognosis and biological behaviors. The m6A score was further developed based on 20-genes to quantify the m6A-regulator expression signature in each patient with FL. The low m6A score was associated with inferior prognosis of patients, with a median survival time of 8.84 (95% confidence interval [CI]: 7.251-10.429) years, which was remarkably shorter than that of patients with high m6A scores (15.73 years, 95% CI: 11.729-19.731; p<0.0001). Genes like TNFRSF14, CREBBP, and CARD11 were shown to be more often mutated in the low m6A group. This group was enriched with immune/inflammatory response but along with the abundant infiltration of exhausted T cells and the upregulated PD-1 and PD-L1 expression. Finally, we verified the m6A score could predict the response to anti-PD-L1 antibodies in an immunotherapy cohort. To conclude, the m6A score recognizes a section of FL patients harboring an exhausted tumor microenvironment and may help guide more effective immunotherapy strategies for patients with FL.
Invading the Occupied Niche: How a Parasitic Copepod of Introduced Oysters Can Expel a Congener From Native Mussels
Authors: Feis Marieke E. , Gottschalck Leo , Ruf Lena C. , Theising Franziska , Demann Felicitas , Wegner K. Mathias
Published: June 2022

In species introductions, non-native species are often confronted with new niches occupied by more specialized natives, and for introduced parasites this conflict can be amplified because they also face novel hosts. Despite these obstacles, invasions of introduced parasites occur frequently, but the mechanisms that facilitate parasite invasion success are only rarely explored. Here, we investigated how the parasitic copepod Mytilicola orientalis, that recently spilled over from its principal host - the Pacific oyster Crassostrea gigas, managed to invade the niche of blue mussel Mytilus edulis intestines, which is densely occupied by its specialist congener, Mytilicola intestinalis. From field observations demonstrating invasion dynamics in nature, we designed a series of experiments addressing potential mechanisms facilitating a successful occupation of the new niche. As expected the specialist M. intestinalis can only infect mussel hosts, but displayed higher infection success there than M. orientalis in both principal host species combined. In the absence of direct competitive interactions M. orientalis compensated its lower infection success (1) by recurrent spill-over from its high-fitness reservoir oyster host, and (2) by active aggregation interference enhancing its own mating success while limiting that of M. intestinalis. The introduced parasite could thus avoid direct competition by changing its own epidemiology and indirectly decreasing the reproductive success of its competitor in the new host. Such mechanisms outside of direct competition have seldom been considered, but are crucial to understand invasion success, parasite host range and community assembly in the context of species introductions.
Analytical Study on Time-Dependent Stiffness of Stud Shear Connectors
Authors: Liu Rong , Sun Xinyang , Ye Hengda , Liu Yuqing
Published: June 2022

Concrete creep weakens the spring stiffness of stud shear connectors (SSCs) and increases the long-term deflection of long-span composite beams. The time-dependent properties of SSC are of great importance for the long-term evaluation of composite steel construction. This paper proposes the time-dependent stiffness (TDS) method based on the analytical solution of the beam on a viscoelastic foundation to simulate the SSC under the sustained push-out load. TDS method combines beam theory and the viscoelastic property of hardened concrete. The long-term slip of SSC is predicted by hand calculation of the explicitly expressed governing equation, and it is close to the refined finite element analysis (FEA) results. The constants and parameters used to determine TDS seem to be insensitive regarding geometric and material variation. TDS may provide a simplified method to incorporate the time-dependent partial interaction into complex composite structures by saving the consumption of computer storage and advanced modeling time which are usually required in the refined modeling at the steel-concrete interface, especially when the long-term properties of concrete are of interest.
Feasibility of Extracting Meaningful Patient Centered Outcomes From the Electronic Health Record Following Critical Illness in the Elderly
Authors: Ahmad Sumera R. , Tarabochia Alex D. , Budahn Luann , Lemahieu Allison M. , Anderson Brenda , Vashistha Kirtivardhan , Karnatovskaia Lioudmila , Gajic Ognjen
Published: June 2022

Background

Meaningful patient centered outcomes of critical illness such as functional status, cognition and mental health are studied using validated measurement tools that may often be impractical outside the research setting. The Electronic health record (EHR) contains a plethora of information pertaining to these domains. We sought to determine how feasible and reliable it is to assess meaningful patient centered outcomes from the EHR.

Methods

Two independent investigators reviewed EHR of a random sample of ICU patients looking at documented assessments of trajectory of functional status, cognition, and mental health. Cohen's kappa was used to measure agreement between 2 reviewers. Post ICU health in these domains 12 month after admission was compared to pre- ICU health in the 12 months prior to assess qualitatively whether a patient's condition was “better,” “unchanged” or “worse.” Days alive and out of hospital/health care facility was a secondary outcome.

Results

Thirty six of the 41 randomly selected patients (88%) survived critical illness. EHR contained sufficient information to determine the difference in health status before and after critical illness in most survivors (86%). Decline in functional status (36%), cognition (11%), and mental health (11%) following ICU admission was observed compared to premorbid baseline. Agreement between reviewers was excellent (kappa ranging from 0.966 to 1). Eighteen patients (44%) remained home after discharge from hospital and rehabilitation during the 12- month follow up.

Conclusion

We demonstrated the feasibility and reliability of assessing the trajectory of changes in functional status, cognition, and selected mental health outcomes from EHR of critically ill patients. If validated in a larger, representative sample, these outcomes could be used alongside survival in quality improvement studies and pragmatic clinical trials.
Circ_0004951 Promotes Pyroptosis of Renal Tubular Cells via the NLRP3 Inflammasome in Diabetic Kidney Disease
Authors: Wang Yulin , Ding Li , Wang Ruiqiang , Guo Yanhong , Yang ZiJun , Yu Lu , Wang LiuWei , Liang Yan , Tang Lin
Published: June 2022

Background

Diabetic kidney disease (DKD) has become the leading cause of chronic kidney disease (CKD) in many countries. Recent studies have shown that circular RNA and pyroptosis play an important role in pathogenesis of DKD.

Methods

We analyzed expression patterns of circRNAs in human kidney biopsy tissues obtained from type 2 DKD (n = 9) and nephrectomy (n = 9) patients. Next, we cultured human renal tubular epithelial cells (HK2) in high glucose condition and detected circ_0004951, miR-93-5p, NLR Pyrin Domain Containing 3 (NLRP3) inflammasome-related indicators and pyroptosis. Furthermore, we performed Bioinformatics analysis and dual-luciferase reporter assay to analyze the relationship among circ_0004951, miR-93-5p and NLRP3.

Results

Circ_0004951 was significantly upregulated in kidney tissues from DKD patients and HK2 in high glucose condition vs. control. Knockdown of circ_0004951 mediated a significant suppression of HK2 pyroptosis, while results from bioinformatics analysis revealed that circ_0004951 has binding sites with miR-93-5p and miR-93-5p could bind to NLRP3. Results from dual-luciferase reporter assay further corroborated this finding. Finally, observations from rescue experiments showed that down-regulation of miR-93-5p and upregulation of NLRP3 markedly attenuated the anti-pyroptosis and anti-inflammatory effects of circ_0004951 knockdown on HK2.

Conclusion

Circ_0004951 promotes pyroptosis of renal tubular epithelial cells in DKD via the miR-93-5p/NLRP3 inflammasome pathway, suggesting its potential for clinical diagnosis and treatment of DKD.
Depressed Kallikrein Generation in Women With Preeclampsia: A Matched Cross-Sectional Study
Authors: Godtfredsen Anne Cathrine , Gram Jørgen Brodersen , Pham Stephanie Thuy Duong , Dolleris Britta Blume , Jørgensen Jan Stener , Sidelmann Johannes Jakobsen , Palarasah Yaseelan
Published: June 2022

Objective

The pathophysiology of preeclampsia is not fully understood. Disturbances in the contact system are associated with preeclampsia. Few studies have investigated the association between preeclampsia and alterations in the contact system in plasma. This study aims to elucidate whether this basic biological system is affected in preeclampsia using new methods focusing on the dynamic interactions and total capacity of the contact system in blood.

Design

Cross-sectional study matching women with preeclampsia and controls without preeclampsia regarding age, pregestational body mass index, and gestational age at onset of the disease.

Setting

Two Danish University hospitals.

Sample

A cohort of 117 women with preeclampsia and 117 controls.

Methods

The turnover and capacity of the contact system were determined with new methods. Paired t-test, Wilcoxon signed-pairs signed rank test, Mann-Whitney or Chi2-test were applied, as appropriate.

Main Outcome Measurements

Kallikrein generation (peak kallikrein concentration and endogenous kallikrein potential), coagulation factor XII, prekallikrein, H-kininogen, cleaved H-kininogen, and complement C1 esterase inhibitor.

Results

The endogenous kallikrein potential, peak kallikrein concentration, prekallikrein and cleaved H-kininogen were significantly lower in women with preeclampsia compared to the controls, p ≤ 0.005, whereas the concentration of coagulation factor XII, H-kininogen and complement C1 esterase inhibitor was not significantly different, p > 0.05.

Conclusion

This study demonstrates significant reduction in kallikrein generating capacity, prekallikrein and cleaved H-kininogen indicating that the contact system is affected in preeclampsia suggesting a link to the pathophysiology of the disease.
Case Report: Pirfenidone in the Treatment of Post-COVID-19 Pulmonary Fibrosis
Authors: Zhou Xianglin , Yang Danhui , Kong Xianglong , Wei Chengli , LvQiu Siqi , Wang Lin , Lin Yongkang , Yin Zhilan , Zhou Zhiguo , Luo Hong
Published: June 2022

Background

Pulmonary fibrosis is one of the sequelae of the COVID-19, which seriously affects the quality of life of survivors. Currently, there are no optimal evidence based guidelines targeting this population.

Case Presentation

We report a 66-year-old female patient without underlying comorbidities admitted to Changsha Public Health Center because of COVID-19. During hospitalization, she developed co-bacterial infection and acute respiratory distress syndrome, and received broad-spectrum antibacterial therapy, invasive mechanical ventilation and extracorporeal membrane oxygenation. After the acute phase, she developed post-COVID-19 pulmonary fibrosis subsequently treated with pirfenidone. Over 96 weeks after pirfenidone treatment, her modified Medical Research Council Dyspnea level improved to 2 from 4 at discharge. Her 6 minutes walk test distance, total lung capacity, and diffusion capacity for carbon monoxide all increased. Chest CT performed on 2 years after illness onset showed regressing fibrosis. The Hospital Anxiety and Depression Scale, Athens Insomnia Scale, and 36-Item Short Form Health Survey questionnaire all improved.

Conclusion

Post-COVID-19 pulmonary fibrosis is a challenging consequence of COVID-19, and our case suggests that pirfenidone may be an effective treatment option.
Visualizing Influenza A Virus vRNA Replication
Authors: Chiu Ya-Fang , Huang Yi-Wen , Chen Chi-Yuan , Chen Yu-Chia , Gong Yu-Nong , Kuo Rei-Lin , Huang Chung-Guei , Shih Shin-Ru
Published: June 2022

Influenza A virus (IAV) has caused recurrent epidemics and severe pandemics. In this study, we adapted an MS2-MCP live-cell imaging system to visualize IAV replication. A reporter plasmid, pHH-PB2-vMSL, was constructed by replacing a part of the PB2-coding sequence in pHH-PB2 with a sequence encoding 24 copies of a stem-loop structure from bacteriophage MS2 (MSL). Binding of MS2 coat protein (MCP) fused to green fluorescent protein (GFP) to MSL enabled the detection of vRNA as fluorescent punctate signals in live-cell imaging. The introduction of pHH-PB2-vMSL into A549 cells transduced to express an MCP-GFP fusion protein lacking the nuclear localization signal (MCP-GFPdN), subsequently allowed tracking of the distribution and replication of PB2-vMSL vRNA after IAV PR8 infection. Spatial and temporal measurements revealed exponential increases in vRNA punctate signal intensity, which was only observed after membrane blebbing in apoptotic cells. Similar signal intensity increases in apoptotic cells were also observed after MDCK cells, transduced to express MCP-GFPdN, were infected with IAV carrying PB2-vMSL vRNA. Notably, PB2-vMSL vRNA replication was observed to occur only in apoptotic cells, at a consistent time after apoptosis initiation. There was a lack of observable PB2-vMSL vRNA replication in non-apoptotic cells, and vRNA replication was suppressed in the presence of apoptosis inhibitors. These findings point to an important role for apoptosis in IAV vRNA replication. The utility of the MS2-imaging system for visualizing time-sensitive processes such as viral replication in live host cells is also demonstrated in this study.
Evaluating Starter Feeding on Ruminal Function in Yak Calves: Combined 16S rRNA Sequencing and Metabolomics
Authors: Wang Yin , Xia Hongze , Yang Qien , Yang Deyu , Liu Shujie , Cui Zhanhong
Published: June 2022

For young ruminants, starter feeding can effectively facilitate the growth and development of rumen in ruminants, but the development of rumen is an important physiological challenge as it remains unclear for the mechanism of starter feeding stimulating. In this study, we performed an analysis of ruminal microbiota and their metabolites in yak calves to explore how the ruminal microbiota and their metabolites stimulate the ruminal function. This study associated 16S rRNA sequencing with liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to evaluate the effects of starter feeding on ruminal microbiota diversity and metabolites in yak calves. We designed the experiment using 20 yak calves that were assigned equally into 2 groups, based on feeding milk replacer; the control (RA) group was fed with alfalfa hay while the treatment (RAS) group was fed with alfalfa hay and starter. After the experiment, we investigated the ruminal microbiota and metabolites through 16S rRNA sequencing and LC-MS-based metabolomics. During the preweaning period, the RAS group significantly promoted the growth performance and ruminal development in yak calves, including increases in body weight, chest girth, and development of rumen (P < 0.05). The RAS group increased the relative abundance of Bacteroidota, Proteobacteria, Chloroflexi, Synergistota, and Spirochaetota and decreased the abundance of Firmicutes, Desulfobacterota, Actinobacteriota, and Actinobacteriota at the phylum level (P < 0.05). At the genus level, the ruminal content of the RAS group was significantly enriched for Rikenellaceae_RC9_gut_group and Ruminococcus, while depleted for Prevotella, Christensenellaceae_R-7_group, and NK4A214_group (P < 0.05). A total of 37 metabolites were identified between the RA group and the RAS group, of which 15 metabolites were upregulated and 22 metabolites were downregulated compared with the RA group. Metabolic pathway analyses indicated that upregulated the metabolites of the RAS group yak calves were related to carbohydrate metabolism, ubiquinone, and other terpenoid-quinone biosynthesis, while the downregulated metabolic pathway was relevant to xenobiotic biodegradation, metabolism, and nucleotide metabolism. In summary, starter feeding before weaning significantly increased the dry matter intake and body weight of yak calves, changed the diversity and abundance of ruminal microbiota, and positively regulated the good development of ruminal morphology and function, providing an important basis for high-quality cultivation and the nutritional level of nutrition of yak calves in the Qinghai Tibet plateau. This study is based on the availability of 16S rRNA sequencing and LC-MS-based metabolomics in clarifying the function of starter feeding in the yak calves.
Maternal Fecal Microbes Contribute to Shaping the Early Life Assembly of the Intestinal Microbiota of Co-inhabiting Yak and Cattle Calves
Authors: Zhang Jianbo , Liang Zeyi , Ding Kao Renqing , Han Jianlin , Du Mei , Ahmad Anum Ali , Wang Shengyi , Salekdeh Ghasem Hosseini , Long Ruijun , Yan Ping , Ding Xuezhi
Published: June 2022

The Qinghai-Tibetan Plateau offers one of the most extreme environments for yaks (Bos grunniens). Although the genetic adaptability of yak and rumen metagenomes is increasingly understood, the relative contribution of host genetics and maternal symbiotic microbes throughout early intestinal microbial successions in yaks remains elusive. In this study, we assessed the intestinal microbiota succession of co-inhabiting yak and cattle (Bos taurus) calves at different weeks after birth as well as the modes of transmission of maternal symbiotic microbes (i.e., rumen fluid, feces, oral cavity, and breast skin) to their calves’ intestinal microbiota colonization. We found that the fecal microbiota of yak and cattle calves after birth was dominated by members of the families Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae. The Source Tracker model revealed that maternal fecal microbes played an important role (the average contribution was about 80%) in the intestinal microbial colonization of yak and cattle calves at different weeks after birth. Unlike cattle calves, there was no significant difference in the fecal microbiota composition of yak calves between 5 and 9 weeks after birth (Wilcoxon test, P > 0.05), indicating that yak may adapt to its natural extreme environment to stabilize its intestinal microbiota composition. Additionally, our results also find that the intestinal microbial composition of yak and cattle calves, with age, gradually tend to become similar, and the differences between species gradually decrease. The findings of this study are vital for developing strategies to manipulate the intestinal microbiota in grazing yaks and cattle for better growth and performance on the Qinghai-Tibetan Plateau.
Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy
Authors: Szu Jenny I. , Binder Devin K.
Published: June 2022

Epilepsy is a chronic brain disorder characterized by unprovoked seizures. Mechanisms underlying seizure activity have been intensely investigated. Alterations in astrocytic channels and transporters have shown to be a critical player in seizure generation and epileptogenesis. One key protein involved in such processes is the astrocyte water channel aquaporin-4 (AQP4). Studies have revealed that perivascular AQP4 redistributes away from astrocyte endfeet and toward the neuropil in both clinical and preclinical studies. This subcellular mislocalization significantly impacts neuronal hyperexcitability and understanding how AQP4 becomes dysregulated in epilepsy is beginning to emerge. In this review, we evaluate the role of AQP4 dysregulation and mislocalization in epilepsy.
Functional Connectivity and Complexity in the Phenomenological Model of Mild Cognitive-Impaired Alzheimer's Disease
Authors: Das Surya , Puthankattil Subha D.
Published: June 2022

Background

Functional connectivity and complexity analysis has been discretely studied to understand intricate brain dynamics. The current study investigates the interplay between functional connectivity and complexity using the Kuramoto mean-field model.

Method

Functional connectivity matrices are estimated using the weighted phase lag index and complexity measures through popularly used complexity estimators such as Lempel-Ziv complexity (LZC), Higuchi's fractal dimension (HFD), and fluctuation-based dispersion entropy (FDispEn). Complexity measures are estimated on real and simulated electroencephalogram (EEG) signals of patients with mild cognitive-impaired Alzheimer's disease (MCI-AD) and controls. Complexity measures are further applied to simulated signals generated from lesion-induced connectivity matrix and studied its impact. It is a novel attempt to study the relation between functional connectivity and complexity using a neurocomputational model.

Results

Real EEG signals from patients with MCI-AD exhibited reduced functional connectivity and complexity in anterior and central regions. A simulation study has also displayed significantly reduced regional complexity in the patient group with respect to control. A similar reduction in complexity was further evident in simulation studies with lesion-induced control groups compared with non-lesion-induced control groups.

Conclusion

Taken together, simulation studies demonstrate a positive influence of reduced connectivity in the model imparting a reduced complexity in the EEG signal. The study revealed the presence of a direct relation between functional connectivity and complexity with reduced connectivity, yielding a decreased EEG complexity.
Sensorimotor Responses in Post-Stroke Hemiplegic Patients Modulated by Acupuncture at Yanglingquan (GB34): A fMRI Study Using Intersubject Functional Correlation (ISFC) Analysis
Authors: Wang Yue , Wang Liping , Wang Yahui , Lu Mengxin , Xu Lingling , Liu Ruoyi , Wei Jingpei , Wan Jifeng , Zhang Hua , Zou Yihuai
Published: June 2022

Motor dysfunction is common in patients with stroke. Acupuncture has become an acceptable alternative method for stroke rehabilitation. Previous studies have shown various functional connectivity changes activated by acupuncture. We introduced intersubject correlation (ISC) and intersubject functional correlation (ISFC) analyses into the functional magnetic resonance imaging (fMRI) for ischemic stroke to seek a common activation and suppression pattern triggered by acupuncture. In this study, 63 ischemic stroke patients with motor dysfunction and 42 normal controls were analyzed. Three functional scans were conducted during the resting state, motor task, and acupuncture at Yanglingquan (GB34) task. Twenty-two sensory, motor, and movement-imagination cortices in the bilateral hemispheres were selected as the region of interest (ROI). We performed ISC and ISFC analyses among these ROIs in three fMRI runs on patients and controls. Subgroup analyses by course or severity were also conducted. The results showed that acupuncture at GB34 triggered ISFC among upper limb motor, upper limb/hand/face, lower limb, tongue/larynx sensory, and movement imagination regions in the patient group. Subgroup ISC and ISFC analyses showed that patients tended to have increasing responses in the early stage of stroke (within 1 month) and decreasing responses afterward (1–3 months). Patients with mild clinical functional damage (NIHSS 2–4) tended to generate more responses via acupuncture than those with moderate damage (NIHSS 5–15). Our findings may help understand the clinical effects and modulatory features of acupuncture based on the group-level post-stroke neuroplasticity.
Promising Effect of High Dose Ambroxol Treatment on Neurocognition and Motor Development in a Patient With Neuropathic Gaucher Disease 2
Authors: Aries Charlotte , Lohmöller Benjamin , Tiede Stephan , Täuber Karolin , Hartmann Guido , Rudolph Cornelia , Muschol Nicole
Published: June 2022

Gaucher Disease (GD) 2 is a rare inherited lysosomal disorder. Early-onset and rapid progression of neurovisceral symptoms lead to fatal outcome in early childhood. Treatment is symptomatic, a curative therapy is currently not available. This prospective study describes the clinical and biochemical outcome of a GD 2 patient treated with high dose ambroxol from the age of 4 months. Due to progressive hepatosplenomegaly additional enzyme replacement therapy was required 1 year after ambroxol monotherapy was initiated. Detailed clinical follow-up data demonstrated an age-appropriate neurocognitive and motor development but no clear benefit on peripheral organs. Glucosylsphingosine (Lyso-GL1) in cerebrospinal fluid decreased remarkably compared to pre-treatment, whereas Lyso-GL1 and chitotriosidase in blood increased. Ambroxol treatment of patient fibroblasts revealed a significant increase in β-glucocerebrosidase activity in vitro. To our knowledge, this is the first report of a GD 2 patient with age-appropriate cognitive and motor development at 3 years of age. Combination of high dose ambroxol with ERT proved to be a successful approach to manage both visceral and neurological manifestations.