bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the Association Between Toll-Like Receptors and T-Cell Activation in Takayasu’s Arteritis
Authors: Tian Yixiao , Huang Biqing , Li Jing , Tian Xinping , Zeng Xiaofeng
Published: January 2022

To explore the relationships between Toll-like receptors (TLRs) and the activation and differentiation of T-cells in Takayasu’s arteritis (TAK), using real-time fluorescence quantitative polymerase chain reaction, mRNA abundance of 29 target genes in peripheral blood mononuclear cells (PBMCs) were detected from 27 TAK patients and 10 healthy controls. Compared with the healthy control group, the untreated TAK group and the treated TAK group had an increased mRNA level of TLR2 and TLR4. A sample-to-sample matrix revealed that 80% of healthy controls could be separated from the TAK patients. Correlation analysis showed that the inactive-treated TAK group exhibited a unique pattern of inverse correlations between the TLRs gene clusters (including TLR1/2/4/6/8, BCL6, TIGIT, NR4A1, etc) and the gene cluster associated with T-cell activation and differentiation (including TCR, CD28, T-bet, GATA3, FOXP3, CCL5, etc). The dynamic gene co-expression network indicated the TAK groups had more active communication between TLRs and T-cell activation than healthy controls. BCL6, CCL5, FOXP3, GATA3, CD28, T-bet, TIGIT, IκBα, and NR4A1 were likely to have a close functional relation with TLRs at the inactive stage. The co-expression of TLR4 and TLR6 could serve as a biomarker of disease activity in treated TAK (the area under curve/sensitivity/specificity, 0.919/100%/90.9%). The largest gene co-expression cluster of the inactive-treated TAK group was associated with TLR signaling pathways, while the largest gene co-expression cluster of the active-treated TAK group was associated with the activation and differentiation of T-cells. The miRNA sequencing of the plasma exosomes combining miRDB, DIANA-TarBase, and miRTarBase databases suggested that the miR-548 family miR-584, miR-3613, and miR-335 might play an important role in the cross-talk between TLRs and T-cells at the inactive stage. This study found a novel relation between TLRs and T-cell in the pathogenesis of autoimmune diseases, proposed a new concept of TLR-co-expression signature which might distinguish different disease activity of TAK, and highlighted the miRNA of exosomes in TLR signaling pathway in TAK.
Case Report: Genetic Double Strike: VEXAS and TET2-Positive Myelodysplastic Syndrome in a Patient With Long-Standing Refractory Autoinflammatory Disease
Authors: Lötscher Fabian , Seitz Luca , Simeunovic Helena , Sarbu Adela-Cristina , Porret Naomi A. , Feldmeyer Laurence , Borradori Luca , Bonadies Nicolas , Maurer Britta
Published: January 2022

Somatic genetic mutations involving the innate and inflammasome signaling are key drivers of the pathogenesis of myelodysplastic syndromes (MDS). Herein, we present a patient, who suffered from a long-standing refractory adult-onset autoinflammatory syndrome (AIS), previously interpreted as various distinct rheumatic disorders. Developing pancytopenia and particularly macrocytic anemia prompted the screening for a hematological malignancy, which led to the diagnosis of a TET-2-positive MDS. The impressive and continuously changing range of organ involvement, with remarkable refractoriness to anti-inflammatory treatment, exceeded the common autoinflammatory phenotype of MDS patients. This prompted us to suspect a recently discovered disease, characterized by somatic mutations of the UBA1 gene: the VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, which was ultimately confirmed by genetic testing. Reevaluation of previous bone marrow biopsies showed the presence of characteristic vacuoles in myeloid- and erythroid progenitor cells. Our case illustrates that the triad of an unresponsive multisystemic autoinflammatory disease, hematological abnormalities and vacuoles in myeloid- and erythroid progenitors in the bone marrow biopsy should prompt screening for the VEXAS syndrome.
Sea-Level Rise: From Global Perspectives to Local Services
Authors: Durand Gaël , van den Broeke Michiel R. , Le Cozannet Goneri , Edwards Tamsin L. , Holland Paul R. , Jourdain Nicolas C. , Marzeion Ben , Mottram Ruth , Nicholls Robert J. , Pattyn Frank , Paul Frank , Slangen Aimée B. A. , Winkelmann Ricarda , Burgard Clara , van Calcar Caroline J. , Barré Jean-Baptiste , Bataille Amélie , Chapuis Anne
Published: January 2022

Coastal areas are highly diverse, ecologically rich, regions of key socio-economic activity, and are particularly sensitive to sea-level change. Over most of the 20th century, global mean sea level has risen mainly due to warming and subsequent expansion of the upper ocean layers as well as the melting of glaciers and ice caps. Over the last three decades, increased mass loss of the Greenland and Antarctic ice sheets has also started to contribute significantly to contemporary sea-level rise. The future mass loss of the two ice sheets, which combined represent a sea-level rise potential of ∼65 m, constitutes the main source of uncertainty in long-term (centennial to millennial) sea-level rise projections. Improved knowledge of the magnitude and rate of future sea-level change is therefore of utmost importance. Moreover, sea level does not change uniformly across the globe and can differ greatly at both regional and local scales. The most appropriate and feasible sea level mitigation and adaptation measures in coastal regions strongly depend on local land use and associated risk aversion. Here, we advocate that addressing the problem of future sea-level rise and its impacts requires (i) bringing together a transdisciplinary scientific community, from climate and cryospheric scientists to coastal impact specialists, and (ii) interacting closely and iteratively with users and local stakeholders to co-design and co-build coastal climate services, including addressing the high-end risks.
Planktonic Tintinnid Community Structure Variations in Different Water Masses of the Arctic Basin
Authors: Wang Chaofeng , Wang Xiaoyu , Xu Zhiqiang , Hao Qiang , Zhao Yuan , Zhang Wuchang , Xiao Tian
Published: January 2022

Information on tintinnid community structure variations in different water masses in the Arctic Basin is scarce. During the summer of 2020, tintinnid diversity and vertical distribution were investigated in the Arctic Ocean. A total of 21 tintinnid species were found in five water masses and each water mass had a unique tintinnid community structure. In the Pacific Summer Water (PSW), Salpingella sp.1 occupied the top abundance proportion (61.8%) and originated from the North Pacific. In the Remnant Winter Water (RWW), Acanthostomella norvegica occupied the top abundance proportion (85.9%) and decreased northward. In the Mixed Layer Water, Pacific Winter Water, and Atlantic-origin Water, Ptychocylis urnula had the highest abundance proportion (67.1, 54.9, and 52.2%, respectively). The high abundance distribution area of Salpingella sp.1 and A. norvegica were separated by the boundary of the Beaufort Gyre and Transpolar Drift. The above species could be indicator species of each water masses. The highest abundance proportion of Salpingella sp.1 contributes 81.9% to the dominance of 12–16 μm lorica oral diameter in the PSW, which indicated that the preferred food items of tintinnid were also getting smaller. The occurrence of North Pacific tintinnid in the PSW might be due to the increasing Pacific Inflow Water. Further studies are needed to explore the lasting period of this species and whether it can establish a local population under rapid Arctic warming progress.
Investigations on Zinc Isotope Fractionation in Breast Cancer Tissue Using in vitro Cell Culture Uptake-Efflux Experiments
Authors: Schilling Kathrin , Harris Adrian L. , Halliday Alex N. , Schofield Christopher J. , Sheldon Helen , Haider Syed , Larner Fiona
Published: January 2022

Zinc (Zn) accumulates in breast cancer tumors compared to adjacent healthy tissue. Clinical samples of breast cancer tissue show light Zn isotopic compositions (δ66Zn) relative to healthy tissue. The underlying mechanisms causing such effects are unknown. To investigate if the isotopic discrimination observed for in vivo breast cancer tissue samples can be reproduced in vitro, we report isotopic data for Zn uptake-efflux experiments using a human breast cancer cell line. MDA-MB-231 cell line was used as a model for triple receptor negative breast cancer. We determined Zn isotope fractionation for Zn cell uptake (Δ66Znuptake) and cell efflux (Δ66Znefflux) using a drip-flow reactor to enable comparison with the in vivo environment. The MDA-MB-231 cell line analyses show Zn isotopic fractionations in an opposite direction to those observed for in vivo breast cancer tissue. Uptake of isotopically heavy Zn (Δ66Znuptake = +0.23 ± 0.05‰) is consistent with transport via Zn transporters (ZIPs), which have histidine-rich binding sites. Zinc excreted during efflux is isotopically lighter than Zn taken up by the cells (Δ66Znefflux = −0.35 ± 0.06‰). The difference in Zn isotope fractionation observed between in vitro MDA-MB-231 cell line experiments and in vivo breast tissues might be due to differences in Zn transporter levels or intercellular Zn storage (endoplasmic reticulum and/or Zn specific vesicles); stromal cells, such as fibroblasts and immune cells. Although, additional experiments using other human breast cancer cell lines (e.g., MCF-7, BT-20) with varying Zn protein characteristics are required, the results highlight differences between in vitro and in vivo Zn isotope fractionation.
Utility of Trabecular Bone Score (TBS) in Bone Quality and Fracture Risk Assessment in Patients on Maintenance Dialysis
Authors: Poiana Catalina , Dusceac Roxana , Niculescu Dan Alexandru
Published: January 2022

Maintenance dialysis is associated with almost universal changes in bone metabolism collectively known as chronic kidney disease—mineral and bone disorder (CKD-MBD). These are accompanied in various proportions by bone loss and altered bone quality that led to an increased risk of fracture. Osteoporosis, age-related or postmenopausal, a condition that often coexists with CKD, is also a leading cause of fracture. Dual-energy X-ray densitometry (DXA) is the main tool for assessing the bone quantity and bone loss and the associated fracture risk. It has been validated in both CKD-MBD and osteoporosis. Trabecular bone score (TBS) is a DXA-derived algorithm for the evaluation of bone microarchitecture, and its clinical value has been repeatedly demonstrated in large cohorts of osteoporotic patients. However, its utility in patients on maintenance dialysis has not been conclusively shown. Published studies showed a lower TBS score and implicitly an altered bone microarchitecture in patients on maintenance dialysis, even after adjusting for various variables. Moreover, FRAX-based fracture risk is higher after adjusting for TBS, showing promise on an algorithm better estimating the clinical fracture risk in dialysis patients. However, TBS has not been demonstrated to independently predict clinical fractures in prospective studies on dialysis patients. Also, aortic calcifications and altered fluid balance could significantly affect TBS score and could hamper the widespread clinical use in patients on maintenance dialysis. In this mini-review, we focus on the benefits and pitfalls of TBS in the management of CKD-MBD and fracture risk assessment in patients on maintenance dialysis.
Trends of the Global, Regional, and National Incidence of Measles, Vaccine Coverage, and Risk Factors in 204 Countries From 1990 to 2019
Authors: Wang Ruitong , Jing Wenzhan , Liu Min , Liu Jue
Published: January 2022

Background

Measles is a highly contagious disease that has caused global morbidity and mortality. Though great progress has been made in measles elimination, the resurgence of measles has been observed in recent years. As extant literature were mainly confined to data of local area, we conducted a systematic analysis to explore the trends of the incidence of measles, coverage rate, and the risk factors from 1990 to 2019 on global, regional, and national levels.

Methods

Data on cases of incidence, age standardized rate (ASR), vaccine coverage, and risk factors of measles were retrieved from the Global Burden of Disease (GBD) Study 2019 database. Estimated averaged percentage change (EAPC) of ASR was calculated to quantify the trends of measles incidence. Pearson correlation was applied to assess the association of EAPC and measles-containing vaccine coverage rate with socio-demographic index (SDI) in 2019, and the correlation between ASR and measles-containing vaccine coverage rate.

Results

Globally, there was a significant decrease in the number (84.18%) and ASR (6.13%, 95% CI: 5.41–6.84%) of measles incidence from 1990 to 2019. More than 80% of incidence cases were attributed to children under 5 and the proportion was highest in low SDI region. Countries and territories with low ASRs are mostly clustered in North America, Southern Latin America, and Western Europe, whereas those with high ASRs are mainly clustered in Africa, East Asia, and South Asia. Lower SDI was associated with higher ASR and lower vaccine coverage rate. The more the SDI value was further away from 0.6, the smaller the absolute value did EAPC have. Child wasting accounted for the most measles-related death cases, followed by child underweight, child stunting, and vitamin A deficiency.

Conclusions

Measles eradication is feasible, but urgently demands political commitment, financial support, and public engagement. In the context of COVID-19 pandemic and the global resurgence of measles, surveillance systems and routine immunization programs should be improved, while vaccine hesitancy needs to be addressed.
Investigation on the Pathological Mechanism of Frequent Exacerbators With Chronic Obstructive Pulmonary Disease Based on the Characteristics of Respiratory Flora
Authors: Ke Li , Chen Luo , Yaling Yuan , Can Gao , Jun Lin , Chuan Zhang
Published: January 2022

Chronic obstructive pulmonary disease (COPD) is a common obstructive respiratory disease characterized by persistent respiratory symptoms and limited airflow due to airway obstruction. The present study investigates the distribution characteristics of respiratory tract flora in both frequent and infrequent exacerbators of COPD. The 16S sequencing technique was adopted to differentiate the inherent differences of respiratory tract flora between frequent exacerbators and infrequent exacerbators. Additionally, cell counting kit 8 (CCK8), lactate dehydrogenase (LDH) test, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and western blot were carried out in human bronchial epithelial cells cultured in vitro and the regulatory effects of differential flora were verified. The results revealed that the observed species index, Chao1 index, and the ACE estimator of COPD frequent exacerbators were markedly higher than those of COPD infrequent exacerbators. The top five strains of COPD frequent exacerbators included g_Streptococcus (15.565%), g_Prevotella (10.683%), g_Veillonella (6.980%), g_Haemophilus (5.601%), and g_Neisseria (4.631%). Veillonella parvula generated obvious cytotoxicity and substantially reduced the activity of human bronchial epithelial cells (p < 0.01). Furthermore, the results of flow cytometry indicated that the proportion of human bronchial epithelial cells in both the S phase and G2 phase decreased following Veillonella parvula treatment indicated that Veillonella parvula inhibited cell proliferation. Meanwhile, being treated using Veillonella parvula, the expressions of interleukin-1 (IL-1), IL-6, Tumor Necrosis Factor α (TNF-α), and p-nuclear factor kappa B (NF-κB) of the cells were increased markedly (p < 0.01). Taken together, the current research demonstrated that the relative abundance of Veillonella in COPD frequent exacerbators was higher than that of infrequent exacerbators. Veillonella parvula activated the inflammatory pathway, ultimately destroyed the cell viability, and greatly impaired the activity of human bronchial epithelial cells, thereby inhibiting cell proliferation.
Soil Microbial Community Response to Nitrogen Application on a Swamp Meadow in the Arid Region of Central Asia
Authors: Hu Yang , Chen Mo , Yang Zailei , Cong Mengfei , Zhu Xinping , Jia Hongtao
Published: January 2022

Although a large number of studies have reported the importance of microbial communities in terrestrial ecosystems and their response to nitrogen (N) application, it is not clear in arid alpine wetlands, and the mechanisms involved need to be clarified. Therefore, the response of the soil microbial community in a swamp meadow to short-term (1 year) N application (CK: 0, N1: 8, N2: 16 kg⋅N⋅hm–2⋅a–1) was studied using 16S/ITS rRNA gene high-throughput sequencing technology. Results showed that N application had no significant effect on soil microbial community diversity, but significantly changed soil bacterial community structure. N1 and N2 treatments significantly reduced the relative abundance of Chloroflexi (18.11 and 32.99% lower than CK, respectively). N2 treatment significantly reduced the relative abundance of Nitrospirae (24.94% lower than CK). Meanwhile, N application reduced the potential function of partial nitrogen (N) and sulfur (S) cycling in bacterial community. For example, compared with CK, nitrate respiration and nitrogen respiration decreased by 35.78–69.06%, and dark sulfide oxidation decreased by 76.36–94.29%. N application had little effect on fungal community structure and function. In general, short-term N application directly affected bacterial community structure and indirectly affected bacterial community structure and function through available potassium, while soil organic carbon was an important factor affecting fungal community structure and function.
HSV-2 Infection Enhances Zika Virus Infection of Primary Genital Epithelial Cells Independently of the Known Zika Virus Receptor AXL
Authors: Gornalusse Germán G. , Zhang Mengying , Wang Ruofan , Rwigamba Emery , Kirby Anna C. , Fialkow Michael , Nance Elizabeth , Hladik Florian , Vojtech Lucia
Published: January 2022

Zika virus (ZIKV) is transmitted to people by bite of an infected mosquito and by sexual contact. ZIKV infects primary genital epithelial cells, the same cells targeted by herpes simplex virus 2 (HSV-2). HSV-2 seroprevalence is high in areas where ZIKV is endemic, but it is unknown whether HSV-2 increases the risk for ZIKV infection. Here, we found that pre-infecting female genital tract epithelial cells with HSV-2 leads to enhanced binding of ZIKV virions. This effect did not require active replication by HSV-2, implying that the effect results from the immune response to HSV-2 exposure or to viral genes expressed early in the HSV-2 lifecycle. Treating cells with toll-like receptor-3 ligand poly-I:C also lead to enhanced binding by ZIKV, which was inhibited by the JAK-STAT pathway inhibitor ruxolitinib. Blocking or knocking down the well-studied ZIKV receptor AXL did not prevent binding of ZIKV to epithelial cells, nor prevent enhanced binding in the presence of HSV-2 infection. Blocking the α5 integrin receptor did not prevent ZIKV binding to cells either. Overall, our results indicate that ZIKV binding to genital epithelial cells is not mediated entirely by a canonical receptor, but likely occurs through redundant pathways that may involve lectin receptors and glycosaminoglycans. Our studies may pave the way to new interventions that interrupt the synergism between herpes and Zika viruses.
Screening of Phospholipids in Plasma of Large-Artery Atherosclerotic and Cardioembolic Stroke Patients With Hydrophilic Interaction Chromatography-Mass Spectrometry
Authors: Wang Haixing , Chen Siyan , Han Zhao , Li Ting , Ma Jianfeng , Chen Xi , Pang Jie , Wang Qingcheng , Shen Qing , Zhang Manman
Published: January 2022

Ischemic stroke (IS) is a deadly and debilitating disease with a high incidence and recurrence rate in elderly people worldwide. Large-artery atherosclerotic (LAA) and cardioembolic (CE) stroke are two leading subtypes and require different management. As a complementary biochemistry method for current diagnostic techniques, a sensitive and accurate phospholipid (PL) targeted lipidomic method was developed in this study. Plasma PLs were selectively extracted with titanium dioxide/fibrous silica nanosphere material, then characterized and quantified with hydrophilic interaction chromatography-mass spectrometry. A total of 31 molecular species of PLs were determined and ten biomarkers including seven molecular species of sphingomyelins (SM d18:1/18:1, d18:1/18:0, d18:1/24:1, d18:1/16:1, d18:1/22:1, d18:1/24:2, and d18:1/16:0) and three molecular species of phosphatidylcholines (16:0/18:1, 16:0/18:2 and 16:0/22:6) showed significant differences in LAA, CE, and healthy control (HC) groups. The independent diagnostic capabilities of these PL biomarkers were successfully evaluated and validated with receiver operating characteristic curves. Additionally, the oleic acid-enriched SMs, which can result in atherogenic lipoprotein aggregation, were proved to be positively related to IS and may perform as the potential risk factors in the future. Meanwhile, valuable suggestions for dietary interventions as an essential source of endogenous PLs could be obtained from this study.
Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases
Authors: Rickenbach Chiara , Gericke Christoph
Published: January 2022

The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.
Abnormal Static and Dynamic Functional Connectivity in Left and Right Temporal Lobe Epilepsy
Authors: Pang Xiaomin , Liang Xiulin , Zhao Jingyuan , Wu Peirong , Li Xinrong , Wei Wutong , Nie Liluo , Chang Weiwei , Lv Zongxia , Zheng Jinou
Published: January 2022

Objective

Temporal lobe epilepsy (TLE) can be conceptualized as a network disease. However, the network characteristics in lateralization remain controversial.

Methods

In this study, resting-state functional MRI scans were acquired from 53 TLE patients [22 with left-side TLE (LTLE) and 31 with right-side TLE (RTLE)] and 37 matched healthy controls. We focused on the characteristics of static and dynamic functional connectivity, including static connectivity patterns and topological properties, as well as temporal properties of the dynamic connectivity state and the variability of the dynamic connectivity and network topological organization. Correlation analyses were conducted between abnormal static and dynamic properties and cognitive performances.

Results

The static functional connectivity analysis presented a significantly decreased cortical-cortical connectivity pattern and increased subcortical-cortical connectivity pattern in RTLE. The global-level network in RTLE showed a significant decrease in global efficiency. The dynamic functional connectivity analysis revealed that RTLE patients exhibited aberrant connectivity states, as well as increased variability in the subcortical-cortical connectivity. The global-level network in RTLE revealed increased variance in global efficiency and local efficiency. The static or dynamic functional connectivity in LTLE did not show any significant abnormalities. The altered dynamic properties were associated with worsening cognitive performance in language and conceptual thinking by the TLE patients.

Conclusion

Our findings demonstrated the presence of abnormalities in the static and dynamic functional connectivity of TLE patients. RTLE patients exhibited more pronounced aberrant connectivity patterns and topological properties, which might represent a mechanism for reconfiguration of brain networks in RTLE patients. These observations extended our understanding of the pathophysiological network mechanisms of TLE.
Association Between Korean-Style Balanced Diet and Risk of Abdominal Obesity in Korean Adults: An Analysis Using KNHANES-VI (2013–2016)
Authors: Yang Hye Jeong , Kim Min Jung , Hur Haeng Jeon , Lee Byoung Kook , Kim Myung-Sunny , Park Sunmin
Published: January 2022

Abdominal obesity is a critical factor for metabolic diseases, and specific eating patterns such as the Mediterranean diet help prevent metabolic diseases. This study aimed to investigate the association between the modified Korean health eating index (MKHEI), including a Korean-balanced diet, and abdominal obesity risk according to genders in adults aged 20–64 years (4,886 males and 7,431 females), using the Korea National Health and Nutrition Examination Survey VI (2013–2016). Adjusted means and 95% confidence intervals of MKHEI scores and nutrient intake estimated using the 24-h recall method were calculated according to abdominal obesity (waist circumference ≥90 cm for men and ≥85 cm for women) after adjusting for age, residence area, region, education, income, drinking status, smoking status, marital status, and exercise. Adjusted odds ratios (ORs) for abdominal obesity were measured according to MKHEI tertiles using logistic regression analysis while controlling for covariates. Individuals aged >50 years, married, below high school, lower-income, heavy alcohol drinkers, past and current smokers, and males living in the southern areas had a higher risk of abdominal obesity. In both genders, the scores of all MKHEI components were lower in the abdominal obesity group (n = 2,895) than in the control group (n = 9,422). Further, the scores of fruits with and without fruit juice and those of beans, including fermented beans, were lower in the abdominal obesity group only in females but not in males. Further, the scores of fast foods were higher in the abdominal obesity group than in the control group only in females. After adjusting for covariates, the adjusted OR for abdominal obesity was inversely associated with Korean balanced diet (KBD) related to KHEI scores. Unlike KBD, MKHEI of Western-style diet was not associated with abdominal obesity in either gender. In conclusion, KBD can lower the risk of abdominal obesity in females and should thus be recommended to prevent abdominal obesity.
Lentinan Supplementation Protects the Gut–Liver Axis and Prevents Steatohepatitis: The Role of Gut Microbiota Involved
Authors: Yang Xiaoying , Zheng Mingxuan , Zhou Menglu , Zhou Limian , Ge Xing , Pang Ning , Li Hongchun , Li Xiangyang , Li Mengdi , Zhang Jun , Huang Xu-Feng , Zheng Kuiyang , Yu Yinghua
Published: January 2022

The microbiota–gut–liver axis has emerged as an important player in developing nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease (NAFLD). Higher mushroom intake is negatively associated with the prevalence of NAFLD. This study examined whether lentinan, an active ingredient in mushrooms, could improve NAFLD and gut microbiota dysbiosis in NAFLD mice induced by a high-fat (HF) diet. Dietary lentinan supplementation for 15 weeks significantly improved gut microbiota dysbiosis in HF mice, evidenced by increased the abundance of phylum Actinobacteria and decreased phylum Proteobacteria and Epsilonbacteraeota. Moreover, lentinan improved intestinal barrier integrity and characterized by enhancing intestinal tight junction proteins, restoring intestinal redox balance, and reducing serum lipopolysaccharide (LPS). In the liver, lentinan attenuated HF diet-induced steatohepatitis, alteration of inflammation–insulin (NFκB-PTP1B-Akt-GSK3β) signaling molecules, and dysregulation of metabolism and immune response genes. Importantly, the antihepatic inflammation effects of lentinan were associated with improved gut microbiota dysbiosis in the treated animals, since the Spearman's correlation analysis showed that hepatic LPS-binding protein and receptor (Lbp and Tlr4) and pro- and antiinflammatory cytokine expression were significantly correlated with the abundance of gut microbiota of phylum Proteobacteria, Epsilonbacteraeota and Actinobacteria. Therefore, lentinan supplementation may be used to mitigate NAFLD by modulating the microbiota–gut–liver axis.
Two Alkaloids From Delphinium brunonianum Royle, Their Anti-inflammatory and Anti-oxidative Stress Activity via NF-κB Signaling Pathway
Authors: Tang Qi , Chen Sitan , Rizvi Syed Arif Hussain , Qu Jiaojiao , Wang Li , Wang Senye , Ma Changyang , Liu Lijun , Kang Wenyi
Published: January 2022

In this study, we isolated and identified four compounds in Delphinium brunonianum Royle, and they were Delbrunine (1), 4-O-α-D-Glucosyl benzoic acid (2), Kaempferol 3-O-β-D-glucopyranoside 7-O-α-L-rhamnopyranoside (3) and Eldeline (4). Furthermore, the anti-inflammatory activity of these compounds was screened in RAW264.7 cells. The results showed that the anti-inflammatory activities of compounds 2 and 3 were weak, and 1, 4 had good anti-inflammatory activity. The macrophage inflammation model was established by lipopolysaccharide (LPS). Then, the anti-inflammatory activity was evaluated by ELISA kits, qRT-PCR experiment and western blot experiment. And the anti-oxidative stress activity was assessed by flow cytometry. The results showed that compounds 1, 4 could significantly inhibit the elevation of inflammatory factors nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and also had obvious inhibitory effects on the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). In addition, compounds 1 and 4 could effectively inhibit the overexpression of reactive oxygen species (ROS) in RAW264.7 cells that activated by LPS. These results indicated that compounds 1 and 4 may exert anti-inflammatory and anti-oxidative stress effects through the NF-κB signaling pathway.
Influence of Geographical Area and Living Setting on Children's Weight Status, Motor Coordination, and Physical Activity
Authors: Gallotta Maria Chiara , Zimatore Giovanna , Falcioni Lavinia , Migliaccio Silvia , Lanza Massimo , Schena Federico , Biino Valentina , Giuriato Matteo , Bellafiore Marianna , Palma Antonio , Battaglia Giuseppe , Baldari Carlo , Guidetti Laura
Published: January 2022

This study was aimed (i) to examine the effect of living setting (rural vs. urban), geographical area (North vs. Center vs. South), and gender (boys vs. girls) on weight status, motor coordination, and physical activity (PA) level of Italian school-age children; (ii) to examine differences in the neighborhood walkability of different school areas from different geographical areas and living settings; and (iii) to examine whether motor coordination, PA level, geographical areas, living setting, neighborhood walkability, and gender could predict children's weight status. We assessed anthropometric parameters, gross motor coordination, and PA level in 1,549 children aged between 8 and 13 years. Results revealed that Central children had higher BMI than Northern and Southern children (η2 = 0.01). Moreover, Northern children showed the highest motor quotient (η2 = 0.148) and PA level (η2 = 0.02), followed by Southern and Central children, respectively. Children from the South of Italy attended schools located in neighborhoods with the highest Walk Score®. Urban children attended schools located in neighborhoods with a higher Walk Score® than rural children. Lower motor quotient (MQ), lower PA level, and living in a rural setting and in a car-dependent neighborhood were associated with a higher relative risk for obesity. Being a girl was associated with a lower relative risk for obesity. The alarming high percentage of overweight and obesity in children as well as motor coordination impairments revealed the urgent need of targeted PA interventions in pediatric population.
Molecular Targets for Novel Therapeutics in Pediatric Fusion-Positive Non-CNS Solid Tumors
Authors: Chang Wen-I , Lin Claire , Liguori Nicholas , Honeyman Joshua N. , DeNardo Bradley , El-Deiry Wafik
Published: January 2022

Chromosomal fusions encoding novel molecular drivers have been identified in several solid tumors, and in recent years the identification of such pathogenetic events in tumor specimens has become clinically actionable. Pediatric sarcomas and other rare tumors that occur in children as well as adults are a group of heterogeneous tumors often with driver gene fusions for which some therapeutics have already been developed and approved, and others where there is opportunity for progress and innovation to impact on patient outcomes. We review the chromosomal rearrangements that represent oncogenic events in pediatric solid tumors outside of the central nervous system (CNS), such as Ewing Sarcoma, Rhabdomyosarcoma, Fibrolamellar Hepatocellular Carcinoma, and Renal Cell Carcinoma, among others. Various therapeutics such as CDK4/6, FGFR, ALK, VEGF, EGFR, PDGFR, NTRK, PARP, mTOR, BRAF, IGF1R, HDAC inhibitors are being explored among other novel therapeutic strategies such as ONC201/TIC10.
Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study
Authors: Cançado Guilherme Grossi Lopes , Couto Cláudia Alves , Guedes Laura Vilar , Braga Michelle Harriz , Terrabuio Débora Raquel Benedita , Cançado Eduardo Luiz Rachid , Ferraz Maria Lucia Gomes , Villela-Nogueira Cristiane Alves , Nardelli Mateus Jorge , Faria Luciana Costa , Oliveira Elze Maria Gomes de , Rotman Vivian , Mazo Daniel Ferraz de Campos , Borges Valéria Ferreira de Almeida e , Mendes Liliana Sampaio Costa , Codes Liana , Pessoa Mario Guimarães , Signorelli Izabelle Venturini , Levy Cynthia , Bittencourt Paulo Lisboa
Published: January 2022

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC.

Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria.

Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39–76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria.

Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients.
Acute/Chronic Responses of Combined Training on Serum Pro-thermogenic/Anti-inflammatory Inducers and Its Relation With Fed and Fasting State in Overweight Type 2 Diabetic Individuals
Authors: Bonfante Ivan Luiz Padilha , Duft Renata Garbellini , Mateus Keryma Chaves da Silva , Trombeta Joice Cristina dos Santos , Finardi Enrico Antonio Rautenberg , Ramkrapes Ana Paula Boito , Brunelli Diego Trevisan , Mori Marcelo Alves da Silva , Chacon-Mikahil Mara Patricia Traina , Velloso Licio Augusto , Cavaglieri Cláudia Regina
Published: January 2022

Concentrations of pro-thermogenic/anti-inflammatory inductors are influenced by fed/fasting, sedentary/trained states, and metabolic pattern. However, there is a lack of information on the interactions of these conditions, especially in humans. Thus, the present study aimed to evaluate the chronic and acute training responses as well as the fed/fasted states of serum pro-thermogenic/anti-inflammatory inducers in overweight type 2 diabetics individuals. Fifteen individuals with type 2 diabetes [body mass index (BMI): 29.61 ± 3.60 kg/m2; age: 50.67 ± 3.97 years] participated in the study. In the pre- and post-experimental periods, baseline clinical parameters analyses were performed. Pro-thermogenic/anti-inflammatory inductors were evaluated pre/post-baseline and before, shortly after, and after 30′ and 60′ in the first and last sessions of a 16-week combined training (CT) period. These inducers were also compared for fasting and feeding before and after the training period. CT has improved baseline physical fitness, metabolic pattern, and it has also increased interleukin (IL)33 and FNDC5/irisin. In the first training session, there was a decrease in IL4, IL13, and IL33, besides an increase in FNDC5/irisin, and natriuretic peptides. In the last training session, there was an increase in natriuretic peptides and bone morphogenic protein 4 (BMP4). Differences in responses between the first and last training sessions were observed at certain post-session times for IL4, IL33, and natriuretic peptides, always with higher concentrations occurring in the last session. In evaluating the area under the curve (AUC) of the first and last training session, FNDC5/irisin, natriuretics peptides, and meteorin-like showed increased areas in the last training session. The pre-training fed state showed an increase in IL4 and IL33, while in fasting there was an increase in meteorin-like, natriuretic peptides, and FNDC5/irisin. In the post-training, IL4, IL13, and IL33 were increased in the fed state, while meteorin-like, natriuretic peptides, and FNDC5/irisin remained increased in the fast. Adaptation to physical training and a better metabolic pattern favor an improvement in the acute secretory pattern in part of pro-thermogenic and anti-inflammatory substances analyzed. The fed and fasting states also interfere differently in these substances, where fasting interferes with the increase of myokines, while the fed state induces an increase in interleukins.

Clinical Trial Registration: [http://www.ensaiosclinicos.gov.br/rg/RBR-62n5qn/], identifier [U1111-1202-1476].
Exercise Capacity Is Improved by Levosimendan in Heart Failure and Sarcopenia via Alleviation of Apoptosis of Skeletal Muscle
Authors: Wang Di , Song Ming , Shen Long-fei , Han Lu , Zhu Ping , Jia Xu , Shang Guo-kai , Cao Yuan , Zhang Wei , Zhong Ming , Wang Zhi-hao
Published: January 2022

Background

Patients suffering from chronic heart failure (CHF) show an increased prevalence of sarcopenia. Levosimendan is an effective drug for the treatment of heart failure, but its effect on sarcopenia is still unclear. We aimed to explore whether levosimendan could enhance skeletal muscle contractibility, improve skeletal muscle atrophy, and thus improve exercise tolerance of individuals with heart failure.

Methods

C57BL6/J mice were used to establish the heart failure with sarcopenia model and injected of levosimendan. Mice were separated into control group, sham operation group, HF group, HF + solvent group, HF + levosimendan group, HF + sarcopenia group, HF + sarcopenia + solvent group, HF + sarcopenia + levosimendan group (n = 5–12). After the treatment, exercise capacity and cardiac function were evaluated. Muscle morphology, inflammation level and apoptosis levels were detected, in which mitochondrial function and oxidative stress level were also assessed.

Result

Levosimendan could increase forelimb grip strength/body weight, hanging impulse, maximum running distance and time in mice with HF and sarcopenia (P < 0.0001 for all), and these improvements were independent of EF (P = 0.0019 for hanging impulse, P < 0.001 for forelimb grip strength/body weight and maximum running distance). Levosimendan directly increased the CSA of gastrocnemius in mice with HF and sarcopenia (P < 0.0001). After levosimendan injection, the proportion of slow muscle fibers increased (P < 0.0001), but this improvement of muscle fiber typing might be attributed to improved cardiac function (P > 0.05). Levosimendan also maintained mitochondrial membrane potential, decreased cleaved caspase-3 (P = 0.034), cleaved caspase-9 (P < 0.0001), Bax expression (P < 0.0001), and increased Bcl2 expression (P = 0.0036). This effect is independent of improved cardiac function (P = 0.028 for bax, P < 0.001 for cleaved caspase-9 and Bcl2). IL-6, TNF-α expression (P < 0.0001 for both) decreased, and SOD activity (P = 0.0038), GSH/GSSG ratio (P = 0.002) significantly increased in skeletal muscle after injection of levosimendan. The improvement in oxidative stress level was attributed to improved cardiac function (P > 0.05).

Conclusion

Levosimendan reduce the loss of skeletal muscle mitochondrial membrane potential, decrease the apoptosis, alleviate the inflammation and oxidative stress, and ultimately improve the exercise capacity of mice with heart failure and sarcopenia. Therefore, levosimendan may be a potential drug for the treatment of heart failure with sarcopenia.
Identification and Pleiotropic Effect Analysis of GSE5 on Rice Chalkiness and Grain Shape
Authors: Jiang Liangrong , Zhong Hui , Jiang Xianbin , Zhang Jiaoping , Huang Rongyu , Liao Furong , Deng Yaqin , Liu Qingqing , Huang Yumin , Wang Houcong , Tao Yi , Zheng Jingsheng
Published: January 2022

Chalkiness is one of several major restricting factors for the improvement of rice quality. Although many chalkiness-related quantitative trait loci have been mapped, only a small number of genes have been cloned to date. In this study, the candidate gene GSE5 of a major quantitative trait locus (QTL) for rice chalkiness, qDEC5, was identified by map-based cloning. Phenotyping and haplotype analysis of proActin:GSE5 transgenic line, gse5-cr mutant, and 69 rice varieties further confirmed that GSE5 had the pleiotropic effects and regulated both chalkiness and grain shape. Genetic analysis showed GSE5 was a dominant gene for grain length and a semi-dominant gene for grain width and chalkiness. The DNA interval closely linked to GSE5 was introgressed to Zhenshan 97B (ZB) based on molecular marker-assisted selection, and the improved ZB showed lower chalkiness and longer but smaller grains, which showed that GSE5 played an important role in breeding rice varieties with high yield and good quality. Transcriptomics, proteomics, and qRT-PCR analyses showed that thirty-nine genes associated with carbon and protein metabolism are regulated by GSE5 to affect the formation of chalkiness, including some newly discovered genes, such as OsCESA9, OsHSP70, OsTPS8, OsPFK04, OsSTA1, OsERdj3A, etc. The low-chalkiness lines showed higher amino sugar and nucleotide sugar metabolism at 10 days after pollination (DAP), lower carbohydrate metabolism at 15 DAP, and lower protein metabolism at 10 and 15 DAP. With heat shock at 34/30°C, rice chalkiness increased significantly; OsDjC10 and OsSUS3 were upregulated at 6 and 12 DAP, respectively, and OsGSTL2 was downregulated at 12 DAP. Our results identified the function and pleiotropic effects of qDEC5 dissected its genetic characteristics and the expression profiles of the genes affecting the chalkiness formation, and provided a theoretical basis and application value to harmoniously pursue high yield and good quality in rice production.
L2 Learners Do Not Ignore Verb’s Subcategorization Information in Real-Time Syntactic Processing
Authors: Nakamura Chie , Arai Manabu , Hirose Yuki , Flynn Suzanne
Published: January 2022

This study addressed the question of whether L2 learners are able to utilize verb’s argument structure information in online structural analysis. Previous L2 research has shown that L2 learners have difficulty in using verb’s intransitive information to guide online syntactic processing. This is true even though L2 learners have grammatical knowledge that is correct and similar to that of native speakers. In the present study, we contrasted three hypotheses, the initial inaccessibility account, the intransitivity overriding account, and the fuzzy subcategorization frame account, to investigate whether L2 learner’s knowledge of intransitive verbs is in fact ignored in L2 online structural analysis. The initial inaccessibility account and the fuzzy subcategorization frame account predicted that L2 learners cannot access intransitivity information in building syntactic structures in any situation. The intransitivity overriding account predicted that intransitivity information is accessed in L2 parsing, but this process is overridden by the strong transitivity preference when a verb is followed by a noun phrase. Importantly, the intransitivity overriding account specifically predicted that L2 learners would be able to use intransitive information in online syntactic processing when a noun phrase does not appear immediately following a verb. We tested the three accounts in an eye-tracking reading experiment using filler-gap dependency structures. We manipulated verb’s transitivity information and lexically based plausibility information and tested English native speakers as a control L1 group (N = 29) and Japanese-English L2 participants (N = 32). The results showed that L2 learners as well as native speakers processed sentences differently depending on the subcategorization information of the verb, and adopted transitive analysis only when the verb was optionally transitive, providing support for the intransitivity overriding. The results further demonstrated that L2 learners had strong expectations for the transitive structure, which is consistent with the view proposed by the hyper-active gap-filling hypothesis. In addition, the results showed that the semantic mismatch in the incorrect transitive analysis facilitated native speaker’s processing but caused difficulty for L2 learners. Together, the current study provides evidence that L2 learners use intransitive information of the verbs to guide their structural analysis when there are no overriding constraints.