bluuebunny/crossref_metadata_2025 huggingface dataset:
The Lower Limit of Reference of Urinary Albumin/Creatinine Ratio and the Risk of Chronic Kidney Disease Progression in Patients With Type 2 Diabetes Mellitus
Authors: Tang Wei-Hua , Hung Wei-Chin , Wang Chao-Ping , Wu Cheng-Ching , Hsuan Chin-Feng , Yu Teng-Hung , Hsu Chia-Chang , Cheng Ya-Ai , Chung Fu-Mei , Lee Yau-Jiunn , Lu Yung-Chuan
Published: June 2022

A urine albumin/creatinine ratio (UACR) <30 mg/g is considered to be normal, while increased risk of incident hypertension and cardiovascular disease mortality in subjects with high normal UACR level had been observed. However, a mild elevated but normal UACR level was associated with the risk of initiating chronic kidney disease (CKD) is uncertain. We investigated whether higher normal UACR is associated with the risk of developing CKD. A total of 4821 subjects with type 2 diabetes mellitus (T2DM), an estimated glomerular filtration rate >60 ml/min/1.73 m2 and UACR <30 mg/g enrolled in a diabetes disease management program between 2006 and 2020 were studied. The optimal cutoff point for baseline UACR as a predictor for progression to CKD according to the 2012 KDIGO definition was calculated using receiving operating characteristic curve analysis. After a mean of 4.9 years follow-up, the CKD risk progression increased in parallel with the quartiles of baseline UACR <30 mg/g (p for trend <0.0001). UACR cutoff points of 8.44 mg/g overall, 10.59 mg/g in males and 8.15 mg/g in females were associated with the risk of CKD progression. In multivariate Cox regression analysis, the hazard ratios for the association between UACR (>8.44 mg/g, >10.9 mg/g, >8.15 mg/g in overall, male, and female patients, respectively) and the risk of CKD progression were significant. This study demonstrated that a cutoff UACR value of >10 mg/g could significantly predict the cumulative incidence and progression of CKD in patients with T2DM.
An Economical Optimization Method for Active Power With Variable Droop Control Considering Frequency Regulation Costs in Integrated Energy Systems
Authors: Zang Yuxiu , Ge Weichun , Wang Shunjiang , Zhao Long , Tan Che
Published: June 2022

As a high proportion of clean energy is connected to the power grid, the occupancy rate of the system synchronous machine decreases, the inertia constant of the system decreases, and the difficulty of frequency adjustment continues to increase. The imbalance of frequency is mainly caused by the imbalance of active power, so the problem of frequency can be transformed into the problem of active power balance. According to the droop control principle, the concept of the equivalent unit regulating power coefficient is proposed, and the equivalent unit regulating power is determined by determining the system parameters and frequency offset. In order to reduce the frequency regulation cost in the integrated energy system, a feasible method considering the frequency regulation cost is the proposed variable droop control active power economic optimization method. First, the integrated energy system in this study consists of carbon capture power plants, a wind turbine generator system (WTGS), a photovoltaic power generation system, and energy storage batteries. All four types of power supply leave spare capacity to participate in frequency regulation through droop control. Second, the concept of the equivalent unit regulating power coefficient (equivalent coefficient) and the mathematical model of the equivalent unit regulating power coefficient of the integrated energy system are put forward. Then, within the allowable range of frequency fluctuations, considering carbon trading and ancillary service markets and aiming at the lowest frequency regulation cost, an economical optimal distribution method is established for active power in an integrated energy system including carbon capture power plants, wind power, photovoltaic, and energy storage. Taking a city in the north as an example, the improved moth flame algorithm is used to solve the problem. The simulation results show that the proposed model can improve the frequency regulation characteristics and reduce the frequency regulation cost.
Case Report: A New Family With Pontocerebellar Hypoplasia 10 From Sudan
Authors: Amin Mutaz , Vignal Cedric , Hamed Ahlam A. A. , Mohammed Inaam N. , Elseed Maha A. , Abubaker Rayan , Bakhit Yousuf , Babai Arwa , Elbadi Eman , Eltaraifee Esraa , Mustafa Doua , Yahia Ashraf , Osman Melka , Koko Mahmoud , Mustafa Mohamed , Alsiddig Mohamed , Haroun Sahwah , Elshafea Azza , Drunat Severine , Elsayed Liena E. O. , Ahmed Ammar E. , Boespflug-Tanguy Odile , Dorboz Imen
Published: June 2022

Pontocerebellar hypoplasia type 10 (PCH10) is a very rare autosomal recessive neurodegenerative disease characterized by intellectual disability, microcephaly, severe developmental delay, pyramidal signs, mild cerebellar atrophy, and white matter changes in the brain, as shown by magnetic resonance imaging (MRI). The disease has been described in only twenty-one patients from ten Turkish families with a founder missense pathogenic variant in the CLP1 gene involved in tRNA processing and maturation. We analyzed three siblings from a consanguineous Sudanese family who presented with intellectual disability, dysmorphic features, developmental delay, regression of milestones, microcephaly, epilepsy, extrapyramidal signs, mild pontine, and cerebellar atrophy. We identified through whole-exome sequencing the same pathogenic variant (c.419G>A; p(Arg140His) reported before in all Turkish families. Our study extends the phenotypes of PCH10 and reports for the first time cases with PCH10 of non-Turkish origin.
Combining Z-Score and Maternal Copy Number Variation Analysis Increases the Positive Rate and Accuracy in Non-Invasive Prenatal Testing
Authors: Chen Liheng , Wang Lihong , Hu Zhipeng , Tao Yilun , Song Wenxia , An Yu , Li Xiaoze
Published: June 2022

Objective: To evaluate positive rate and accuracy of non-invasive prenatal testing (NIPT) combining Z-score and maternal copy number variation (CNV) analysis. To assess the relationship between Z-score and positive predictive value (PPV).

Methods: This prospective study included 61525 pregnancies to determine the correlation between Z-scores and PPV in NIPT, and 3184 pregnancies to perform maternal CNVs analysis. Positive results of NIPT were verified by prenatal diagnosis and/or following-up after birth. Z-score grouping, logistic regression analysis, receiver operating characteristic (ROC) curves, and S-curve trends were applied to correlation analysis of Z-scores and PPV. The maternal CNVs were classified according to the technical standard for the interpretation of ACMG. Through genetic counseling, fetal and maternal phenotypes and family histories were collected.

Results: Of the 3184 pregnant women, 22 pregnancies were positive for outlier Z-scores, suggesting fetal aneuploidy. 12 out of 22 pregnancies were true positive (PPV = 54.5%). 17 pregnancies were found maternal pathogenic or likely pathogenic CNVs (> 0.5 Mb) through maternal CNV analysis. Prenatal diagnosis revealed that 7 out of 11 fetuses carried the same CNVs as the mother. Considering the abnormal biochemical indicators during pregnancy and CNV-related clinical phenotypes after birth, two male fetuses without prenatal diagnosis were suspected to carry the maternally-derived CNVs. Further, we identified three CNV-related family histories with variable phenotypes. Statistical analysis of the 61525 pregnancies revealed that Z-scores of chromosomes 21 and 18 were significantly associated with PPV at 3 ≤ Z ≤ 40. Notably, three pregnancies with Z > 40 were both maternal full aneuploidy. At Z < -3, fetuses carried microdeletions instead of monosomies. Sex chromosome trisomy was significantly higher PPV than monosomy.

Conclusion: The positive rate of the NIPT screening model combining Z-score and maternal CNV analysis increased from 6.91‰ (22/3184) to 12.25‰ (39/3184) and true positives increased from 12 to 21 pregnancies. We found that this method could improve the positive rate and accuracy of NIPT for aneuploidies and CNVs without increasing testing costs. It provides an early warning for the inheritance of pathogenic CNVs to the next generation.
Identification of Differentially Expressed Genes and miRNAs for Ulcerative Colitis Using Bioinformatics Analysis
Authors: Hu Weitao , Fang Taiyong , Chen Xiaoqing
Published: June 2022

Introduction:Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine whose cause and underlying mechanisms are not fully understood. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) with diagnostic and therapeutic potential in UC.

Materials and methods:Three UC datasets (GSE179285, GSE75214, GSE48958) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and UC tissues were identified using the GEO2R online tool. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were performed using Metascape. Protein-protein interaction network (PPI) analysis and visualization using STRING and Cytoscape. Finally, the miRNA gene regulatory network was constructed by Cytoscape to predict potential microRNAs (miRNAs) associated with DEGs.

Results:A total of 446 DEGs were identified, consisting of 309 upregulated genes and 137 downregulated genes. The enriched functions and pathways of the DEGs include extracellular matrix, regulation of cell adhesion, inflammatory response, response to cytokine, monocarboxylic acid metabolic process, response to toxic substance. The analysis of KEGG pathway indicates that the DEGs were significantly enriched in Complement and coagulation cascades, Amoebiasis, TNF signaling pathway, bile secretion, and Mineral absorption. Combining the results of the PPI network and CytoHubba, 9 hub genes including CXCL8, ICAM1, CXCR4, CD44, IL1B, MMP9, SPP1, TIMP1, and HIF1A were selected. Based on the DEG-miRNAs network construction, 7 miRNAs including miR-335-5p, mir-204-5p, miR-93-5p, miR106a-5p, miR-21-5p, miR-146a-5p, and miR-155-5p were identified as potential critical miRNAs.

Conclusion:In summary, we identified DEGs that may be involved in the progression or occurrence of UC. A total of 446 DEGs,9 hub genes and 7 miRNAs were identified, which may be considered as biomarkers of UC. Further studies, however, are needed to elucidate the biological functions of these genes in UC.
Mechanism of COVID-19-Related Proteins in Spinal Tuberculosis: Immune Dysregulation
Authors: Chen Liyi , Liu Chong , Liang Tuo , Ye Zhen , Huang Shengsheng , Chen Jiarui , Sun Xuhua , Yi Ming , Zhou Chenxing , Jiang Jie , Chen Tianyou , Li Hao , Chen Wuhua , Guo Hao , Chen Wenkang , Yao Yuanlin , Liao Shian , Yu Chaojie , Wu Shaofeng , Fan Binguang , Gan Zhaoping , Zhan Xinli
Published: June 2022

Purpose

The purpose of this article was to investigate the mechanism of immune dysregulation of COVID-19-related proteins in spinal tuberculosis (STB).

Methods

Clinical data were collected to construct a nomogram model. C-index, calibration curve, ROC curve, and DCA curve were used to assess the predictive ability and accuracy of the model. Additionally, 10 intervertebral disc samples were collected for protein identification. Bioinformatics was used to analyze differentially expressed proteins (DEPs), including immune cells analysis, Gene Ontology (GO) and KEGG pathway enrichment analysis, and protein-protein interaction networks (PPI).

Results

The nomogram predicted risk of STB ranging from 0.01 to 0.994. The C-index and AUC in the training set were 0.872 and 0.862, respectively. The results in the external validation set were consistent with the training set. Immune cells scores indicated that B cells naive in STB tissues were significantly lower than non-TB spinal tissues. Hub proteins were calculated by Degree, Closeness, and MCC methods. The main KEGG pathway included Coronavirus disease-COVID-19. There were 9 key proteins in the intersection of COVID-19-related proteins and hub proteins. There was a negative correlation between B cells naive and RPL19. COVID-19-related proteins were associated with immune genes.

Conclusion

Lymphocytes were predictive factors for the diagnosis of STB. Immune cells showed low expression in STB. Nine COVID-19-related proteins were involved in STB mechanisms. These nine key proteins may suppress the immune mechanism of STB by regulating the expression of immune genes.
Identification and Isolation of Type II NKT Cell Subsets in Human Blood and Liver
Authors: Yang Zhou Jordi , Werner Jens M. , Glehr Gunther , Geissler Edward K. , Hutchinson James A. , Kronenberg Katharina
Published: June 2022

Background

Steatotic livers are more prone to rejection, but are often transplanted owing to the shortage of available organs. Type II NKT (T2NKT) cells are liver-resident lymphocytes that react to lipids presented by CD1d. The role of T2NKT cells in rejection of fatty liver transplants is unclear, partly because of a lack of T2NKT cell markers and their very low frequency in blood. Here, we quantify human T2NKT cells in blood and liver tissue by flow cytometry and provide a strategy for their enrichment and expansion.

Methods

Human T2NKT cells were identified as CD3+ CD56+ CD161+ TCR-γᵹ- TCRVα7.2- and TCRVα24- cells. T2NKT cells were enriched from blood by sequential positive selection using CD56 and CD3 microbeads. These were subsequently FACS-sorted to purity then expanded in vitro for 3 weeks using anti-CD3/CD28 beads and TGF-β1.

Results

The frequency of human T2NKT cells in blood was very low (0.8 ± 0.4% of CD3+ T cells) but they were a more abundant population in liver (6.3 ± 0.9%). Enriched T2NKT cells expressed the transcription factor PLZF. A novel subset of FoxP3+ T2NKT cells was discovered in blood and liver tissue. T2NKT cells were expanded in culture by 15- to 28-fold over 3 weeks, during which time they maintained expression of all identifying markers, including PLZF and FoxP3.

Conclusions

Our work defines new strategies for identifying and isolating T2NKT cells from human blood and liver tissue. We showed that this rare population can be expanded in vitro in order to obtain experimentally amenable cell numbers. Further, we identified a novel T2NKT cell subset that stably expresses FoxP3, which might play a role in regulating innate-like lymphocyte responses in steatotic liver transplants.
Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues
Authors: Yang Kai
Published: June 2022

Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.
Sargassum wightii Aqueous Extract Improved Salt Stress Tolerance in Abelmoschus esculentus by Mediating Metabolic and Ionic Rebalance
Authors: Khan Zawar , Gul Humaira , Rauf Mamoona , Arif Muhammad , Hamayun Muhammad , Ud-Din Aziz , Sajid Zahoor Ahmad , Khilji Sheza Ayaz , Rehman Aliya , Tabassum Asma , Parveen Zahida , Lee In-Jung
Published: June 2022

Salinity stress has hindered the growth and yield of crops globally. The demands for inducing salt stress tolerance by natural and biological sources with potent antioxidants and growth-promoting metabolites have been the main focus of the recent era. Therefore, the current research was conducted to extract salt stress tolerance-ameliorating metabolites and growth-promoting hormones from the marine brown macroalgaeSargassum wightiiGreville ex J. Agardh with maximum antioxidant potential used as a liquid fertilizer for okra (Abelmoschus esculentusL.). In the current study, the biochemical analysis showed thatSargassumaqueous extract (SAE) was rich in growth-promoting metabolites, antioxidants, and hormones. Meanwhile, overaccumulation of glycine betaine attracted the focus of the current research dealing with salt stress tolerance amelioration inA. esculentus. The plants supplemented with SAE (2% and 4%) and 0.04% ascorbic acid (AsA) alone and in combinations were subjected to sodium salt stress (NaCl; 75 mM). Results revealed that SAE efficiently promoted the vegetative and reproductive growth of plants by elevating the growth-promoting metabolites and hormones in comparison to control plants. Ionic contents (Na+, K+, Ca2+, and Mg2+) and ratios (K+/Na+, Mg2+/Na+, and Ca2+/Na+) were modulated in SAE-treated plants. SAE also increased the level of carbohydrates, proteins, lipids, carotenoids, and proline and decreased the level of hydrogen peroxide and abscisic acid in salt-treated plants compared with the control groups. Enzymatic activities of catalase, ascorbate peroxidase, and guaiacol peroxidase were also enhanced by SAE treatment upon salt stress. The SAE-mediated stress tolerance amelioration and the positive growth response ofA. esculentuswere further accelerated by AsA (0.04%) supplementation used in combination with SAE (2% and 4%). The current study revealed a novel report of the antioxidant and metabolite-rich algal extract (S. wightii) formulation along with AsA that induced salt stress tolerance and promoted the overall growth performance ofA. esculentusby rebalancing the ionic and metabolic status.
Growth Performance, Immune Response, Antioxidative Status, and Antiparasitic and Antibacterial Capacity of the Nile Tilapia (Oreochromis niloticus) After Dietary Supplementation With Bottle Gourd (Lagenaria siceraria, Molina) Seed Powder
Authors: Radwan Mahmoud , Abbas Mahmoud Mahrous M. , Mohammadein Amaal , Al Malki Jamila S. , Elraey Said M. A. , Magdy Mohammad
Published: June 2022

Medicinal plants are a potential safe source of bioactive compounds. Fish diet supplemented with the medicinal plant bottle gourd (Lagenaria siceraria) seed powder was evaluated in this study for the potential effect on growth performance, antioxidative status, immunological response, and resistance to infectious pathogens in the Nile tilapia (Oreochromis niloticus). Nile tilapia fingerlings with mean weight ( ± SD)= (25.64 ± 0.17 g), were fed four L. siceraria seed supplemented diets (LSSD) at 0.0, 1, 2, and 3% for 60 days. Specimens were then challenged with the bacterium Aeromonas hydrophila for 10 days. Also, three different concentrations (2.5, 5, and 10 ml/L) of Lagenaria siceraria ethanolic extract (LSEE) were tested for their antibacterial and antiparasitic efficacy on four selected bacterial and one parasitic species. All parameters’ values generally improved with elevating the content of the L. siceraria seed powder in the diet. Dietary administration of LSSD-3% enabled significant (P < 0.05) higher growth performance, and feed utilization efficiency. It reduced the mortality induced by A. hydrophila infection, increased crude protein content in the fish body and exhibited the highest in vitro antibacterial and antiparasitic efficiency. RBCs, WBCs, Hb, PCV, MCV, MCH, and total serum protein values in pre- and post-challenge groups were significantly higher (P < 0.05) in the LSSD-3% group. While MCHC, ALT, AST and glucose levels were significantly lower (P < 0.05) than those of the other groups. Lysozyme and antioxidant enzyme activities in pre- and post-challenge groups were also higher (P < 0.05) in the LSSD-3% group compared to the other groups. LSEE provided good efficacy against Gram-negative bacterial strains, mild efficacy against Gram-positive bacterial strains, and an antagonistic effect on the parasite Cichlidogyrus Tilapiae. The 10 ml/L concentration was the most effective against the pathogens followed by the 5 ml/L concentration and then 2.5 ml/L. Our findings suggest the feasibility of supplementation of Nile tilapia (O. niloticus) diet with L. siceraria seed powder by 3% to improve the growth performance, immunity, and vital parameters.
Participating in Negotiation of a New Ocean Treaty Under the Law of the Sea Convention – Experiences of and Lessons From a Group of Small-Island Developing States
Authors: Hassanali Kahlil
Published: June 2022

Negotiations are currently underway into establishing a new international agreement under the United Nations Convention on the Law of the Sea (UNCLOS) on the conservation and sustainable use of marine biological diversity of areas beyond national jurisdiction. This paper discusses some of the experiences and challenges faced by the Caribbean Community (CARICOM), a regional group of small island developing States, in the negotiation of this agreement. The group has been engaged as a bloc since the preparatory stage of the process. The process has now advanced well into an inter-governmental conference, which had an original mandate for four sessions, but will be extended for at least one more session in August 2022. CARICOM has managed to innovate, adapt and access and pool resources in order to be relevant and impactful participants throughout the ongoing negotiations and in face of the Covid-19 pandemic. Some suggestions are offered with a view to ensuring continued meaningful involvement of the group in the remainder of the negotiations, as well as in future ocean related multilateral processes.
A Prospective Study to Evaluate the Impact of Golimumab Therapy on Work Productivity and Activity, and Quality of Life in Patients With Rheumatoid Arthritis, Psoriasis Arthritis and Axial Spondyloarthritis in a Real Life Setting in AUSTRIA. The GO-ACTIVE Study
Authors: Dejaco Christian , Mueller Thomas , Zamani Omid , Kurtz Ulrike , Egger Stefan , Resch-Passini Johannes , Totzauer Anna , Yazdani-Biuki Babak , Schwingenschloegl Thomas , Peichl Peter , Kraus Angelika , Naerr Gerhard W.
Published: June 2022

Objective

To analyze real-world evidence on work productivity and daily activity impairment (WPAI) and health-related quality of life (HRQoL) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients treated with golimumab in Austria.

Methods

This was a prospective, non-interventional, multi-center study conducted in RA, PsA and axSpA patients initiating golimumab between April 2016 and May 2020 in 40 centers in Austria. WPAI, HRQoL (RAQoL, ankylosing spondylitis (AS)QoL and PsAQoL) questionnaires and disease activity (Clinical Disease Activity Index, CDAI, in RA and PsA; Bath Ankylosing Spondylitis Disease Activity Index, BASDAI, in axSpA) were assessed at baseline and months 3, 6, 12, 18, and 24. Association between WPAI and disease activity was tested using linear regression.

Results

We enrolled 233 patients (RA, n = 95; axSpA, n = 69; PsA, n = 69), 110 patients were followed up to month 24. Mean age was 50.2 ± 14.2 years; 64% were female. Disease activity decreased from baseline to month 24 (RA: CDAI −24.3 ± 13.5; axSpA: BASDAI −4.4 ± 2.1, and PsA: CDAI −21.7 ± 8.5, p < 0.0001, each). Total work productivity impairment (TWPI), activity impairment and presenteeism subscores continuously decreased throughout month 24 in all indications: RA (−58.3 ± 23%, −62.6 ± 23.8% and −61.7 ± 23.3%, respectively as compared to baseline; p < 0.0001, each), axSpA (−34.4 ± 38.3%, p = 0.0117; −60.9 ± 25.9%, and −43.8 ± 26.6%, respectively, p ≤ 0.0001 both) and PsA (−35.8 ± 43.7%, p = 0.0186; −52.3 ± 25.4%, p < 0.0001; and −43.3 ± 33.5%, p = 0.0007, respectively). Absenteeism scores decreased only in RA patients (−9.2 ± 24.9%, p = 0.0234). HRQoL improved between baseline and month 24 (RAQoL: −12.6 ± 7.5; ASQoL: −8.0 ± 4.3; PsAQoL; −8.3 ± 6.4, p < 0.0001, each). TWPI, presenteeism and activity impairment strongly associated with disease activity throughout the study.

Conclusions

This real-world study confirms the benefit of golimumab on work productivity/daily activity impairment in Austrian RA, PsA, and axSpA patients.
Insight Into Novel Anti-tuberculosis Vaccines by Using Immunoinformatics Approaches
Authors: Khan Zafran , Ualiyeva Daniya , Amissah Obed Boadi , Sapkota Sanjeep , Hameed H. M. Adnan , Zhang Tianyu
Published: June 2022

Tuberculosis (TB), an infectious disease, has been a leading cause of morbidity and mortality for decades. The causative agent of TB is the Mycobacterium tuberculosis (Mtb) which can infects various parts of the body, mainly the lungs in pulmonary TB cases. Mycobacterium bovis Bacillus Calmette–Guerin (BCG) is the only approved vaccine for TB, but its efficiency to combat pulmonary TB is limited. Multidrug-resistant (MDR) TB and extensive drug-resistant (XDR) TB requires the evolution of more potent vaccines. Therefore, this research aims to generate a universal TB subunit vaccine using advanced immunoinformatics techniques. In generating a novel multiepitope subunit vaccine, we selected the conserved and experimentally confirmed antigens Rv0058, Rv0101, and Rv3343. After a rigorous evaluation, the top candidates from predicted Helper T-lymphocytes (HTL), Cytotoxic T-lymphocytes (CTL), and B-cell epitopes were considered potential vaccine candidates. Immunogenicity was enhanced by the addition of an adjuvant to the ultimate construct of the vaccine. B-cell epitopes predictions guaranteed the eventual induction of a humoral response. Thereafter, dynamics simulations and molecular docking validated the vaccine-receptor complex’s stability and high affinity for the immune receptor TLR-3. Also, immune simulations revealed the significantly elevated levels of immunoglobulins such as IgM, cytokines such as interleukin-2, helper T (Th) cells, and cytotoxic T-cell populations. These results agreed with the actual inflammatory response and showed rapid antigen clearance after manifold exposure. Finally, the E. coli K12 strain was confirmed via in-silico cloning for quality expression. Nevertheless, in vivo experiments should be performed to validate the safety of the proposed vaccine and its inherent ability to prevent TB infection.
Resveratrol Inhibits Pseudorabies Virus Replication by Targeting IE180 Protein
Authors: Chen Xiangxiu , Song Xu , Li Lixia , Chen Yaqin , Jia Renyong , Zou Yuanfeng , Wan Hongping , Zhao Ling , Tang Huaqiao , Lv Cheng , Zhao Xinghong , Yin Zhongqiong
Published: June 2022

Resveratrol is a natural polyphenolic product in red wine and peanuts and has many pharmacological activities in humans. Our previous studies showed that resveratrol has good antiviral activity against the pseudorabies virus (PRV). However, little is known about the antiviral mechanism of resveratrol against PRV. In this study, we found that resveratrol inhibited the nuclear localization of IE180 protein, which is an important step for activating early/late genes transcription. Interestingly, the results show that resveratrol inhibited the activity of IE180 protein by dual-luciferase assay. Furthermore, molecular docking analysis shows that resveratrol could bind to the Thr601, Ser603, and Pro606 of IE180 protein. Point mutation assay confirmed that resveratrol lost its inhibition activity against the mutant IE180 protein. The results demonstrate that resveratrol exerts its antiviral activity against PRV by targeting the Thr601/Ser603/Pro606 sites of IE180 protein and inhibiting the transcriptional activation activity of IE180 protein. This study provides a novel insight into the antiviral mechanism of resveratrol against herpes viruses.
The Function and the Affecting Factors of the Zebrafish Gut Microbiota
Authors: Li Pingping , Zhang Jinhua , Liu Xiaoyi , Gan Lu , Xie Yi , Zhang Hong , Si Jing
Published: June 2022

Gut microbiota has become a topical issue in unraveling the research mechanisms underlying disease onset and progression. As an important and potential “organ,” gut microbiota plays an important role in regulating intestinal epithelial cell differentiation, proliferation, metabolic function and immune response, angiogenesis and host growth. More recently, zebrafish models have been used to study the interactions between gut microbiota and hosts. It has several advantages, such as short reproductive cycle, low rearing cost, transparent larvae, high genomic similarity to humans, and easy construction of germ-free (GF) and transgenic zebrafish. In our review, we reviewed a large amount of data focusing on the close relationship between gut microbiota and host health. Moreover, we outlined the functions of gut microbiota in regulating intestinal epithelial cell differentiation, intestinal epithelial cell proliferation, metabolic function, and immune response. More, we summarized major factors that can influence the composition, abundance, and diversity of gut microbiota, which will help us to understand the significance of gut microbiota in regulating host biological functions and provide options for maintaining the balance of host health.
Functional Comparison of Clostridium butyricum and Sodium Butyrate Supplementation on Growth, Intestinal Health, and the Anti-inflammatory Response of Broilers
Authors: Liu Ling , Ling Huayun , Zhang Wei , Zhou Ying , Li Youguo , Peng Nan , Zhao Shumiao
Published: June 2022

Butyrate has been reported to promote proliferation of colonic epithelial cells and maintain intestinal barrier integrity in broilers. Although supplementation of Clostridium butyricum and sodium butyrate have been shown to confer benefits on broilers, their effects and mechanisms have not been compared. In this study, C. butyricum and sodium butyrate were added into the basal diet of broilers and their effects on growth performance, intestinal health, and anti-inflammatory response were analyzed. It was found that both C. butyricum and sodium butyrate showed good probiotic effects on broilers. Their effects on growth rate and expression of inflammation related genes were superior to that of the antibiotic oxytetracycline. Besides, the two dietary supplements improved intestinal structure integrity and secretion of inflammatory cytokines, whereas the antibiotic had negative effects. Comparison of the two supplements revealed that sodium butyrate more effectively improved the growth and intestinal structure of broilers than C. butyricum. On the contrary, C. butyricum was superior to sodium butyrate in promoting tight junction protein expression and anti-inflammatory response. In summary, this study demonstrates the positive effects of C. butyricum and sodium butyrate on broilers, and will serve as a reference for selection of appropriate butyrate supplementation for broilers in the breeding industry.
Microbial Community Structure Is Most Strongly Associated With Geographical Distance and pH in Salt Lake Sediments
Authors: Santini Talitha C. , Gramenz Lucy , Southam Gordon , Zammit Carla
Published: June 2022

Salt lakes are globally significant microbial habitats, hosting substantial novel microbial diversity and functional capacity. Extremes of salinity and pH both pose major challenges for survival of microbial life in terrestrial and aquatic environments, and are frequently cited as primary influences on microbial diversity across a wide variety of environments. However, few studies have attempted to identify spatial and geochemical contributions to microbial community composition, functional capacity, and environmental tolerances in salt lakes, limiting exploration of novel halophilic and halotolerant microbial species and their potential biotechnological applications. Here, we collected sediment samples from 16 salt lakes at pH values that ranged from pH 4 to 9, distributed across 48,000 km2 of the Archaean Yilgarn Craton in southwestern Australia to identify associations between environmental factors and microbial community composition, and used a high throughput culturing approach to identify the limits of salt and pH tolerance during iron and sulfur oxidation in these microbial communities. Geographical distance between lakes was the primary contributor to variation in microbial community composition, with pH identified as the most important geochemical contributor to variation in microbial community composition. Microbial community composition split into two clear groups by pH: Bacillota dominated microbial communities in acidic saline lakes, whereas Euryarchaeota dominated microbial communities in alkaline saline lakes. Iron oxidation was observed at salinities up to 160 g L–1 NaCl at pH values as low as pH 1.5, and sulfur oxidation was observed at salinities up to 160 g L–1 NaCl between pH values 2–10, more than doubling previously observed tolerances to NaCl salinity amongst cultivable iron and sulfur oxidizers at these extreme pH values. OTU level diversity in the salt lake microbial communities emerged as the major indicator of iron- and sulfur-oxidizing capacity and environmental tolerances to extremes of pH and salinity. Overall, when bioprospecting for novel microbial functional capacity and environmental tolerances, our study supports sampling from remote, previously unexplored, and maximally distant locations, and prioritizing for OTU level diversity rather than present geochemical conditions.
The Prognostic Model and Drug Sensitivity of LKB1-Mutant Lung Adenocarcinoma Based on Immune Landscape
Authors: Wang Guanghui , Zheng Haotian , Zhao Xiaogang , Wang Yadong , Zeng Yukai , Du Jiajun
Published: June 2022

Background: Lung cancer is the most common cause of cancer-related deaths worldwide. LKB1-mutant lung adenocarcinoma (LUAD) is a unique subtype of this deadly cancer. LKB1 mutations cause functional changes in a variety of cell processes, including immune functions, that affect prognosis. To date, the potential role of immunity in the prognosis of LKB1-mutant LUAD is not well understood.

Methods: We systematically analyzed immune-related genes in LUAD samples from The Cancer Genome Atlas (TCGA) database. ESTIMATE and CIBERSORT algorithms were used to explore the immune microenvironment. A prognostic risk model was constructed, and prognostic, immune function, drug sensitivity, and model specificity analyses were performed to identify the effectiveness of the model.

Results: Our results showed that LKB1 mutations suppressed immune function in LUAD. A three-gene signature was constructed to stratify patients into two risk groups. The risk score was an independent predictor for overall survival (OS) in multivariate Cox regression analyses [hazard ratio (HR) > 1, p = 0.002]. Receiver operating characteristic (ROC) curve analyses confirmed that the risk score has better performance than clinicopathological characteristics. Functional analysis revealed that the immune status was different between the risk groups. ZM.447439 was an appropriate treatment for the high-risk group of patients. This risk model is only suitable for LKB1-mutant tumors; it performed poorly in LUAD patients with wild-type LKB1.

Conclusion: Our findings indicate the potential role of immunity in LKB1-mutant LUAD, providing novel insights into prognosis and guiding effective immunotherapy.
Hierarchical Virtual Screening Based on Rocaglamide Derivatives to Discover New Potential Anti-Skin Cancer Agents
Authors: dos Santos Igor V.F. , Borges Rosivaldo S. , Silva Guilherme M. , de Lima Lúcio R. , Bastos Ruan S. , Ramos Ryan S. , Silva Luciane B. , da Silva Carlos H. T. P. , dos Santos Cleydson B. R.
Published: June 2022

Skin Cancer (SC) is among the most common type of cancers worldwide. The search for SC therapeutics using molecular modeling strategies as well as considering natural plant-derived products seems to be a promising strategy. The phytochemical Rocaglamide A (Roc-A) and its derivatives rise as an interesting set of reference compounds due to their in vitro cytotoxic activity with SC cell lines. In view of this, we performed a hierarchical virtual screening study considering Roc-A and its derivatives, with the aim to find new chemical entities with potential activity against SC. For this, we selected 15 molecules (Roc-A and 14 derivatives) and initially used them in docking studies to predict their interactions with Checkpoint kinase 1 (Chk1) as a target for SC. This allowed us to compile and use them as a training set to build robust pharmacophore models, validated by Pearson’s correlation (p) values and hierarchical cluster analysis (HCA), subsequentially submitted to prospective virtual screening using the Molport® database. Outputted compounds were then selected considering their similarities to Roc-A, followed by analyses of predicted toxicity and pharmacokinetic properties as well as of consensus molecular docking using three software. 10 promising compounds were selected and analyzed in terms of their properties and structural features and, also, considering their previous reports in literature. In this way, the 10 promising virtual hits found in this work may represent potential anti-SC agents and further investigations concerning their biological tests shall be conducted.
Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit
Authors: Scalia Federica , Barone Rosario , Rappa Francesca , Marino Gammazza Antonella , Lo Celso Fabrizio , Lo Bosco Giosuè , Barone Giampaolo , Antona Vincenzo , Vadalà Maria , Vitale Alessandra Maria , Donato Mangano Giuseppe , Amato Domenico , Sentiero Giusy , Macaluso Filippo , Myburgh Kathryn H. , Conway de Macario Everly , Macario Alberto J. L. , Giuffrè Mario , Cappello Francesco
Published: June 2022

Recognition of diseases associated with mutations of the chaperone system genes, e.g., chaperonopathies, is on the rise. Hereditary and clinical aspects are established, but the impact of the mutation on the chaperone molecule and the mechanisms underpinning the tissue abnormalities are not. Here, histological features of skeletal muscle from a patient with a severe, early onset, distal motor neuropathy, carrying a mutation on the CCT5 subunit (MUT) were examined in comparison with normal muscle (CTR). The MUT muscle was considerably modified; atrophy of fibers and disruption of the tissue architecture were prominent, with many fibers in apoptosis. CCT5 was diversely present in the sarcolemma, cytoplasm, and nuclei in MUT and in CTR and was also in the extracellular space; it colocalized with CCT1. In MUT, the signal of myosin appeared slightly increased, and actin slightly decreased as compared with CTR. Desmin was considerably delocalized in MUT, appearing with abnormal patterns and in precipitates. Alpha-B-crystallin and Hsp90 occurred at lower signals in MUT than in CTR muscle, appearing also in precipitates with desmin. The abnormal features in MUT may be the consequence of inactivity, malnutrition, denervation, and failure of protein homeostasis. The latter could be at least in part caused by malfunction of the CCT complex with the mutant CCT5 subunit. This is suggested by the results of thein silicoanalyses of the mutant CCT5 molecule, which revealed various abnormalities when compared with the wild-type counterpart, mostly affecting the apical domain and potentially impairing chaperoning functions. Thus, analysis of mutated CCT5in vitroandin vivois anticipated to provide additional insights on subunit involvement in neuromuscular disorders.
Mice Lacking Cerebellar Cortex and Related Structures Show a Decrease in Slow-Wave Activity With Normal Non-REM Sleep Amount and Sleep Homeostasis
Authors: Fujiyama Tomoyuki , Takenaka Henri , Asano Fuyuki , Miyanishi Kazuya , Hotta-Hirashima Noriko , Ishikawa Yukiko , Kanno Satomi , Seoane-Collazo Patricia , Miwa Hideki , Hoshino Mikio , Yanagisawa Masashi , Funato Hiromasa
Published: June 2022

In addition to the well-known motor control, the cerebellum has recently been implicated in memory, cognition, addiction, and social behavior. Given that the cerebellum contains more neurons than the cerebral cortex and has tight connections to the thalamus and brainstem nuclei, it is possible that the cerebellum also regulates sleep/wakefulness. However, the role of the cerebellum in sleep was unclear, since cerebellar lesion studies inevitably involved massive inflammation in the adjacent brainstem, and sleep changes in lesion studies were not consistent with each other. Here, we examine the role of the cerebellum in sleep and wakefulness using mesencephalon- and rhombomere 1-specific Ptf1a conditional knockout (Ptf1a cKO) mice, which lack the cerebellar cortex and its related structures, and exhibit ataxic gait. Ptf1a cKO mice had similar wake and non-rapid eye movement sleep (NREMS) time as control mice and showed reduced slow wave activity during wakefulness, NREMS and REMS. Ptf1a cKO mice showed a decrease in REMS time during the light phase and had increased NREMS delta power in response to 6 h of sleep deprivation, as did control mice. Ptf1a cKO mice also had similar numbers of sleep spindles and fear memories as control mice. Thus, the cerebellum does not appear to play a major role in sleep-wake control, but may be involved in the generation of slow waves.
Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis
Authors: Liu Qing , Mai Lijia , Yang Shengyan , Jia Shilin , Chu Yanhao , He Hongwen , Fan Wenguo , Huang Fang
Published: June 2022

Orofacial inflammation leads to transcriptional alterations in trigeminal ganglion (TG) neurons. However, diverse alterations and regulatory mechanisms following orofacial inflammatory pain in different types of TG neurons remain unclear. Here, orofacial inflammation was induced by injection of complete Freund’s adjuvant (CFA) in mice. After 7 days, we performed single-cell RNA-sequencing on TG cells of mice from control and treatment groups. We identified primary sensory neurons, Schwann cells, satellite glial cells, oligodendrocyte-like cells, immune cells, fibroblasts, and endothelial cells in TG tissue. After principal component analysis and hierarchical clustering, we identified six TG neuronal subpopulations: peptidergic nociceptors (PEP1 and PEP2), non-peptidergic nociceptors (NP1 and NP2), C-fiber low-threshold mechanoreceptors (cLTMR) and myelinated neurons (Nefh-positive neurons, NF) based on annotated marker gene expression. We also performed differential gene expression analysis among TG neuronal subtypes, identifying several differential genes involved in the inflammatory response, neuronal excitability, neuroprotection, and metabolic processes. Notably, we identified several potential novel targets associated with pain modulation, including Arl6ip1, Gsk3b, Scn7a, and Zbtb20 in PEP1, Rgs7bp in PEP2, and Bhlha9 in cLTMR. The established protein–protein interaction network identified some hub genes, implying their critical involvement in regulating orofacial inflammatory pain. Our study revealed the heterogeneity of TG neurons and their diverse neuronal transcriptomic responses to orofacial inflammation, providing a basis for the development of therapeutic strategies for orofacial inflammatory pain.
Soluble Insulin Receptor Levels in Plasma, Exosomes, and Urine and Its Association With HIV-Associated Neurocognitive Disorders
Authors: Cantres-Rosario Yisel M. , Wojna Valerie , Ruiz Rafael , Diaz Bexaida , Matos Miriam , Rodriguez-Benitez Rosa J. , Rodriguez Elaine , Skolasky Richard L. , Gerena Yamil
Published: June 2022

Background

HIV-associated neurocognitive disorders (HAND) are one of the HIV-associated comorbidities affecting 20–50% of the people with HIV (PWH) infection. We found that the soluble insulin receptor (sIR) levels in plasma and cerebrospinal fluid (CSF) were significantly higher in HIV-infected women. The mechanism of sIR release into the plasma remains unknown, but the detection of the sIR in exosomes may uncover novel mechanisms of sIR secretion from HIV-infected cells and its contribution to HIV disease progression and HAND development. Quantification of sIR in urine may represent a less invasive and more accessible diagnostic tool. Our objective was to quantify sIR levels in plasma, plasma-derived exosomes, and urine, and evaluate their association with HAND and renal function.

Methods

We measured full-length sIR in the plasma and urine of 38 controls and 76 HIV-infected women by ELISA, and sIR, HIV-1 Tat, and reactive oxygen species (ROS) in exosomes by flow cytometry.

Results

Plasma and exosomes with sIR were significantly higher in HIV-infected women when compared with controls and HAND. Exosomal sIR positively correlated with exosomal ROS and exosomal HIV-1 Tat in HIV-infected women. Exosomal ROS was significantly higher in HIV-infected women with more symptomatic cognitive impairment. Plasma-derived exosomes exhibited significantly higher levels of astrocyte (GFAP) and neuronal (L1CAM) markers in HIV-infected women, confirming the presence of circulating CNS-derived exosomes in the blood of HIV-infected women. Urine sIR positively correlated with eGFR in controls, but not in HIV-infected women, regardless there was no significant difference in renal function as determined by the estimated glomerular filtration rate (eGFR, p = 0.762). In HIV-infected women, higher plasma sIR correlated with lower urine sIR that could suggest sIR retention in blood or decreased renal filtration.

Discussion

Higher plasma sIR levels and their correlation with ROS in plasma-derived exosomes with HAND suggest a combined role of metabolic disturbances, oxidative stress, exosome release, and cognitive decline. Communication between CNS and periphery is compromised in PWH, thus plasma-derived exosomes may shed light on disrupted cellular mechanisms in the brain of PWH. High plasma and low urine sIR levels could suggest sIR retention in blood or decreased renal filtration.