bluuebunny/crossref_metadata_2025 huggingface dataset:
GREM1 is a novel serum diagnostic marker and potential therapeutic target for pancreatic ductal adenocarcinoma
Authors: Yang Sen , Zhang Yalu , Hua Yuze , Cui Ming , Wang Mengyi , Gao Junyi , Liu Qiaofei , Liao Quan
Published: August 2022

Objective

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm with rising incidence worldwide. Gremlin 1 (GREM1), a regulator of bone morphogenetic protein (BMP) signaling, fine-tunes extensive biological processes, including organ morphology, cellular metabolism, and multiple pathological developments. The roles of GREM1 in PDAC remain unknown.

Methods

Varieties of public databases and online software were employed to analyze the expressions at transcription and protein levels of GREM1 in multiple malignant neoplasms including PDAC, and in addition, its potential pro-tumoral functions in PDAC were further evaluated. A total of 340 serum samples of pancreatic disease, including PDAC, low-grade malignant pancreatic neoplasm, benign pancreatic neoplasm, pancreatitis, and 132 healthy controls, were collected to detect GREM1. The roles of serum GREM1 in the diagnosis and prediction of survival of PDAC after radical resection were also analyzed.

Results

Bioinformatics analyses revealed that GREM1 was overexpressed in PDAC and predicted a poorer survival in PDAC. A higher protein level of GREM1 in PDAC correlated with stroma formation and immunosuppression by recruiting varieties of immunosuppressive cells, including T regulatory cells (Tregs), M2 macrophages, myeloid-derived suppressor cells (MDSCs), and exhaustion T cells into the tumor microenvironment. A higher level of serum GREM1 was observed in PDAC patients, compared to healthy control (p < 0.001). Serum GREM1 had a good diagnostic value (area under the curve (AUC) = 0.718, p < 0.001), and its combination with carbohydrate antigen 199 (CA199) achieved a better diagnostic efficacy (AUC = 0.914, p < 0.001), compared to CA199 alone. The cutoff value was calculated by receiver operating characteristic (ROC) analysis, and PDAC patients were divided into two groups of low and high GREM1. Logistic analyses showed serum GREM1 positively correlated with tumor size (hazard ratio (HR) = 7.097, p = 0.032) and histopathological grades (HR = 2.898, p = 0.014). High-level serum GREM1 (1,117.8 pg/ml) showed a shorter postoperative survival (p = 0.0394).

Conclusion

Higher intra-tumoral expression of GREM1 in PDAC contributes to tumor stroma and immunosuppressive tumor microenvironment, presenting its therapeutic potential. High-level serum GREM1 predicts poorer survival after resection. A combination of serum CA199 and GREM1 shows a stronger diagnostic efficacy in PDAC.
Prevalence and associated factors of psychosocial and behavioral problems in Indonesian adolescent students during the COVID-19 pandemic
Authors: Sutomo Retno , Ramadhani Fadhila Pratama Rizqi , Hanifa Intan Noor
Published: August 2022

Background

The COVID-19 pandemic and the subsequent measures to control it, such as social distancing, school closure, and online learning, put adolescent students at higher risk of psychosocial and behavioral problems (PSBP). The adverse potential is more concerning as the outbreak continues, especially in limited-resource countries, and requires further mitigation.

Objective

To assess the prevalence and factors associated with PSBP in Indonesian adolescent students in the COVID-19 pandemic

Subject/methods

We conducted a cross-sectional study in Yogyakarta Province, Indonesia, involving junior high school students. An anonymous online questionnaire in google form format was used to collect demographic data and the potential variables and screen the PSBP with the Strengths and Difficulties Questionnaire (SDQ). Logistic regression was applied to determine the independent variables.

Results

Six hundred seventy-six subjects participated, including 237 males (35.1%) and 439 females (64.9%). There were 34.6% subjects with PSBP, with a peer-relation problem as the most common one. The multivariable logistic regression showed that subjects with longer screen time duration and more family conflicts were more likely to have PSBP, with an adjusted odds ratio (OR) of 1.5 (95% CI: 1.1–2.1, p = 0.025) and 2.4 (95% CI: 1.5–3.8, p < 0.001), respectively, whereas whom with better family cohesion are less likely to have the problem with an adjusted OR of 0.4 (95% CI: 0.3–0.6, p < 0.001).

Conclusions

There is a high prevalence of PSBP among Indonesian adolescent students during the COVID-19 pandemic. Longer screen time duration and more family conflict are associated with higher prevalence, whereas better family cohesion with lower prevalence of PSBP.
Barriers and enablers to kangaroo mother care prior to stability from perspectives of Gambian health workers: A qualitative study
Authors: Cho Ying Chun , Gai Abdou , Diallo Brahima A. , Samateh Ahmadou Lamin , Lawn Joy E. , Martinez-Alvarez Melisa , Brotherton Helen
Published: August 2022

Aims

Kangaroo mother care (KMC) is an evidence-based intervention recommended for stable newborns <2,000 g. Recent trials have investigated survival benefits of earlier initiation of KMC, including prior to stability, with WHO's iKMC trial showing 25% relative risk reduction for mortality of neonates 1–1.8 kg at tertiary Indian and African neonatal units (NNU). However, evidence is lacking about how to safely deliver this intervention to the most vulnerable neonates in resource limited settings (RLS). Our study aimed to understand barriers and enablers for early KMC prior to stability from perspectives of neonatal health care workers (HCW) in a high neonatal mortality RLS.

Methods

This qualitative study was conducted at Edward Francis Small Teaching Hospital (EFSTH), the main neonatal referral unit in The Gambia. It was ancillary study to the eKMC clinical trial. Ten semi-structured interviews were conducted with all neonatal HCW cadres (4 nurses; 1 nurse attendant; 5 doctors; all Gambian). Study participants were purposively selected, and saturation was reached. Thematic analysis was conducted using Atun's conceptual framework for evaluation of new health interventions with methods to ensure data reliability and trustworthiness.

Results

HCW's perceptions of early KMC prior to stability included recognition of potential benefits as well as uncertainty about effectiveness and safety. Barriers included: Unavailability of mothers during early neonatal unit admission; safety concerns with concomitant intravenous fluids and impact on infection prevention control; insufficient beds, space, WASH facilities and staffing; and lack of privacy and respectful care. Enablers included: Education of HCW with knowledge transfer to KMC providers; paternal and community sensitization and peer-to-peer support.

Conclusions

Addressing health systems limitations for delivery of KMC prior to stability is foundational with linkage to comprehensive HCW and KMC provider education about effectiveness, safe delivery and monitoring. Further context specific research into safe and respectful implementation is required from varied settings and should include perceptions of all stakeholders, especially if there is a shift in global policy toward KMC for all small vulnerable newborns.
Hemostasis in neonatal ECMO
Authors: Cortesi Valeria , Raffaeli Genny , Amelio Giacomo S. , Amodeo Ilaria , Gulden Silvia , Manzoni Francesca , Cervellini Gaia , Tomaselli Andrea , Colombo Marta , Araimo Gabriella , Artoni Andrea , Ghirardello Stefano , Mosca Fabio , Cavallaro Giacomo
Published: August 2022

Extracorporeal membrane oxygenation (ECMO) is a life-saving support for cardio-respiratory function. Over the last 50 years, the extracorporeal field has faced huge technological progress. However, despite the improvements in technique and materials, coagulation problems are still the main contributor to morbidity and mortality of ECMO patients. Indeed, the incidence and survival rates of the main hemorrhagic and thrombotic complications in neonatal respiratory ECMO are relevant. The main culprit is related to the intrinsic nature of ECMO: the contact phase activation. The exposure of the human blood to the non-endothelial surface triggers a systemic inflammatory response syndrome, which chronically activates the thrombin generation and ultimately leads to coagulative derangements. Pre-existing illness-related hemostatic dysfunction and the peculiarity of the neonatal clotting balance further complicate the picture. Systemic anticoagulation is the management's mainstay, aiming to prevent thrombosis within the circuit and bleeding complications in the patient. Although other agents (i.e., direct thrombin inhibitors) have been recently introduced, unfractionated heparin (UFH) is the standard of care worldwide. Currently, there are multiple tests exploring ECMO-induced coagulopathy. A combination of the parameters mentioned above and the evaluation of the patient's underlying clinical context should be used to provide a goal-directed antithrombotic strategy. However, the ideal algorithm for monitoring anticoagulation is currently unknown, resulting in a large inter-institutional diagnostic variability. In this review, we face the features of the available monitoring tests and approaches, mainly focusing on the role of point-of-care (POC) viscoelastic assays in neonatal ECMO. Current gaps in knowledge and areas that warrant further study will also be addressed.
Interleukin-6-derived cancer-associated fibroblasts activate STAT3 pathway contributing to gemcitabine resistance in cholangiocarcinoma
Authors: Kittirat Yingpinyapat , Suksawat Manida , Thongchot Suyanee , Padthaisong Sureerat , Phetcharaburanin Jutarop , Wangwiwatsin Arporn , Klanrit Poramate , Sangkhamanon Sakkarn , Titapun Attapol , Loilome Watcharin , Saya Hideyuki , Namwat Nisana
Published: August 2022

Cancer-associated fibroblasts (CAFs) are the dominant component of the tumor microenvironment (TME) that can be beneficial to the generation and progression of cancer cells leading to chemotherapeutic failure via several mechanisms. Nevertheless, the roles of CAFs on anti-cancer drug response need more empirical evidence in cholangiocarcinoma (CCA). Herein, we examined the oncogenic roles of CAFs on gemcitabine resistance in CCA cells mediated via IL-6/STAT3 activation. Our findings showed that CCA-derived CAFs promote cell viability and enhance gemcitabine resistance in CCA cells through the activation of IL-6/STAT3 signaling. High expression of IL-6R was correlated with a poor overall survival rate and gemcitabine resistance in CCA, indicating that IL-6R can be a prognostic or predictive biomarker for the chemotherapeutic response of CCA patients. Blockade of IL-6R on CCA cells by tocilizumab, an IL-6R humanized antihuman monoclonal antibody, contributed to inhibition of the CAF-CCA interaction leading to enhancement of gemcitabine sensitivity in CCA cells. The results of this study should be helpful for modifying therapeutic regimens aimed at targeting CAF interacting with cancer cells resulting in the suppression of the tumor progression but enhancement of drug sensitivity.
Cathepsin L promotes chemresistance to neuroblastoma by modulating serglycin
Authors: Du Xiaohuan , Ding Leyun , Huang Shungen , Li Fang , Yan Yinghui , Tang Ruze , Ding Xinyuan , Zhu Zengyan , Wang Wenjuan
Published: August 2022

Cathepsin L (CTSL), a lysosomal acid cysteine protease, is found to play a critical role in chemosencitivity and tumor progression. However, the potential roles and molecular mechanisms of CTSL in chemoresistance in neuroblastoma (NB) are still unclear. In this study, the correlation between clinical characteristics, survival and CTSL expression were assessed in Versteeg dataset. The chemoresistant to cisplatin or doxorubicin was detected using CCK-8 assay. Western blot was employed to detect the expression of CTSL, multi-drug resistance proteins, autophagy-related proteins and apoptosis-related proteins in NB cells while knocking down CTSL. Lysosome staining was analyzed to access the expression levels of lysosomes in NB cells. The expression of apoptosis markers was analyzed with immunofluorescence. Various datasets were analyzed to find the potential protein related to CTSL. In addition, a subcutaneous tumor xenografts model in M-NSG mice was used to assess tumor response to CTSL inhibition in vivo. Based on the validation dataset (Versteeg), we confirmed that CTSL served as a prognostic marker for poor clinical outcome in NB patients. We further found that the expression level of CTSL was higher in SK-N-BE (2) cells than in IMR-32 cells. Knocking down CTSL reversed the chemoresistance in SK-N-BE (2) cells. Furthermore, combination of CTSL inhibition and chemotherapy potently blocked tumor growth in vivo. Mechanistically, CTSL promoted chemoresistance in NB cells by up-regulating multi-drug resistance protein ABCB1 and ABCG2, inhibiting the autophagy level and cell apoptpsis. Furthermore, we observed six datasets and found that Serglycin (SRGN) expression was positively associated with CTSL expresssion. CTSL could mediate chemoresistance by up-regulating SRGN expression in NB cells and SRGN expression was positively correlated with poor prognosis of NB patients. Taken together, our findings indicate that the CTSL promotes chemoresistance to cisplatin and doxorubicin by up-regulating the expression of multi-drug resistance proteins and inhibiting the autophagy level and cell apoptosis in NB cells. Thus, CTSL may be a therapeutic target for overcoming chemoresistant to cisplatin and doxorubicin in NB patients.
Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma
Authors: Yu Jing , Wu Xi , Song Jinen , Zhao Yujie , Li Huifang , Luo Min , Liu Xiaowei
Published: August 2022

Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.
Therapeutic effect of modified zengye decoction on primary Sjogren’s syndrome and its effect on plasma exosomal proteins
Authors: Zeng Yimin , Peng Xin , Wang Yun , Hou Lei , Ma Wukai , Yang Peng
Published: August 2022

Background: Modified Zengye Decoction (MZD), a traditional Chinese medicine, is an effective treatment for patients with primary Sjögren’s syndrome (pSS).

Purpose: To evaluate the efficacy of MZD and investigate its effect on plasma exosomal proteins.

Methods: Eighteen pSS patients were treated with MZD for 2 weeks. The therapeutic effect was evaluated by observing the changes in clinical symptoms, laboratory parameters, and plasma cytokines before and after treatment. Then, the differentially expressed proteins (DEPs) in the plasma exosomes before and after treatment were identified via label-free proteomics, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the possible biological functions and signaling pathways involved in the exosomal DEPs.

Results: MZD can effectively relieve the clinical symptoms of pSS patients, downregulate the plasma IgG and IgM levels, and inhibit plasma cytokine production. Thirteen DEPs were identified via label-free proteomics in the plasma exosomes before and after MZD treatment, of which 12 were downregulated proteins. GO analysis showed that these downregulated proteins were mainly related to the insulin response involved in dryness symptoms and the Gram-negative bacterial defense response and proteoglycan binding involved in infection. KEGG enrichment analysis showed that these downregulated proteins were primarily associated with the porphyrin metabolism involved in oteoarthrosis and the NF-κB and TLR4 pathways involved in infection.

Conclusion: MZD can effectively alleviate SS symptoms, while its mechanism may be associated with the reduced protein expression in insulin response, porphyrin metabolism, and the TLR4/NF-κB pathway.
Efficacy and safety of targeted therapeutics for patients with radioiodine-refractory differentiated thyroid cancer: Systematic review and network meta-analysis
Authors: Ji Xiaoyu , Liang Weili , Lv Guixu , Ding Changyuan , Lai Hong , Li Luchuan , Zeng Qingdong , Lv Bin , Sheng Lei
Published: August 2022

Background: Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to achieve long-term survival.

Methods: A systematic search of the PubMed, Embase, and ClinicalTrials.gov databases was conducted to identify eligible randomized controlled trials (RCTs) comparing the efficacy and safety of targeted treatments for patients with RAIR-DTC from inception to April, 2022. Data were extracted by following the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. We calculated the odds ratio (OR) or hazard ratio (HR), its corresponding 95% credible intervals (CrI), and the surface under the cumulative ranking curve (SUCRA) to indicate ranking probability using Bayesian network meta-analyses. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events.

Results: A total of 12 eligible RCTs involved 1,959 patients and 13 treatments: apatinib, cabozantinib, anlotinib, nintedanib, lenvatinib, lenvatinib with low dose (LD), sorafenib, sorafenib plus everolimus, donafenib (200 mg), donafenib (300 mg), pazopanib (continuous), pazopanib (intermittent), and vandetanib. Pooled analyses indicated that targeted therapeutics significantly prolonged PFS and OS in patients with RAIR-DTC (0.31, 0.21–0.41; 0.69, 0.53–0.85, respectively) compared with placebo. Network meta-analyses indicated that lenvatinib showed the most favorable PFS, with significant differences versus sorafenib (0.33, 0.23-0.48), vandetanib (0.31, 0.20–0.49), nintedanib (0.30, 0.15–0.60), and placebo (0.19, 0.15–0.25), while apatinib was most likely to be ranked first for prolonging OS with a SUCRA of 0.90. Lenvatinib showed the highest ORR (66%, 61%–70%), followed by anlotinib (59%, 48%–70%) and apatinib (54%, 40%–69%). Lenvatinib caused the most adverse events of grade 3 or higher, followed by lenvatinib (LD) and apatinib. Different toxicity profiles of individual treatment were also revealed.

Conclusion: This network meta-analysis suggests that lenvatinib and apatinib were associated with the best progression-free survival and overall survival benefits, respectively, for patients with RAIR-DTC, compared with other targeted therapeutics. Patients who received lenvatinib or apatinib also had more grade 3 or higher adverse events.

Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=302249], identifier [CRD42022302249].
Vitamin D3 preserves blood retinal barrier integrity in an in vitro model of diabetic retinopathy
Authors: Lazzara Francesca , Longo Anna Maria , Giurdanella Giovanni , Lupo Gabriella , Platania Chiara Bianca Maria , Rossi Settimio , Drago Filippo , Anfuso Carmelina Daniela , Bucolo Claudio
Published: August 2022

The impairment of the blood retinal barrier (BRB) represents one of the main features of diabetic retinopathy, a secondary microvascular complication of diabetes. Hyperglycemia is a triggering factor of vascular cells damage in diabetic retinopathy. The aim of this study was to assess the effects of vitamin D3 on BRB protection, and to investigate its regulatory role on inflammatory pathways. We challenged human retinal endothelial cells with high glucose (HG) levels. We found that vitamin D3 attenuates cell damage elicited by HG, maintaining cell viability and reducing the expression of inflammatory cytokines such as IL-1β and ICAM-1. Furthermore, we showed that vitamin D3 preserved the BRB integrity as demonstrated by trans-endothelial electrical resistance, permeability assay, and cell junction morphology and quantification (ZO-1 and VE-cadherin). In conclusion this in vitro study provided new insights on the retinal protective role of vitamin D3, particularly as regard as the early phase of diabetic retinopathy, characterized by BRB breakdown and inflammation.
Impairment of glutamate homeostasis in the nucleus accumbens core underpins cross-sensitization to cocaine following chronic restraint stress
Authors: Avalos María P. , Guzman Andrea S. , Garcia-Keller Constanza , Mongi-Bragato Bethania , Esparza María A. , Rigoni Daiana , Sanchez Marianela A. , Calfa Gastón D. , Bollati Flavia A. , Cancela Liliana M.
Published: August 2022

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.
Telerehabilitation proposal of mind-body technique for physical and psychological outcomes in patients with fibromyalgia
Authors: Paolucci Teresa , de Sire Alessandro , Ferrillo Martina , di Fabio Dania , Molluso Aurora , Patruno Antonia , Pesce Mirko , Lai Carlo , Ciacchella Chiara , Saggino Aristide , Agostini Francesco , Tommasi Marco
Published: August 2022

Fibromyalgia (FM) syndrome is characterized by the close correlation of chronic widespread pain and other non-pain related symptoms. Aim of this study was to investigate whether telerehabilitation that provides physical and psychological support services of the mind-body techniques can affect the clinical profile and pain relief of FM patients. The study included twenty-eight female FM patients, mean aged 56.61 ± 8.56 years. All patients underwent a rehabilitation treatment (8 sessions, 1/week, 1 h/each) through Zoom platform, with the following principles of rehabilitation treatment: Anchoring to a positive emotion; listen and perceive your “own” body; conscious breathing; improve interoceptive awareness; relax. All patients then underwent clinical assessment of the physical distress and fear of movement for the Numeric Rating Scale (NRS); the Fatigue Assessment Scale (FAS); the Fear Avoidance Belief Questionnaire (FABQ); with measures of physical and mental disability for the Fibromyalgia Impact Questionnaire (FIQ); the 12-Items Short Form Survey; the Resilience Scale for Adults and the Coping Strategies Questionnaire-Revised. The evaluations were performed at T0 (baseline), T1 (after 8 weeks of treatment), and T2 (after 1 month of follow-up). The main finding was that telerehabilitation reduced physical and mental distress, fear, and disability (p < 0.001). Resilience and coping ability were less affected by the rehabilitative treatment. Our attempt of mind-body technique telerehabilitation has shown good results in the improvement of painful symptoms and quality of life for the FM patients but showed fewer positive impacts for the resilience and coping abilities aspects.
Long term high glucose exposure induces premature senescence in retinal endothelial cells
Authors: Bertelli Pietro Maria , Pedrini Edoardo , Hughes David , McDonnell Shannon , Pathak Varun , Peixoto Elisa , Guduric-Fuchs Jasenka , Stitt Alan W , Medina Reinhold J.
Published: August 2022

Purpose: Features of cellular senescence have been described in diabetic retinal vasculature. The aim of this study was to investigate how the high glucose microenvironment impacts on the senescence program of retinal endothelial cells.

Methods: Human retinal microvascular endothelial cells were cultured under control and high glucose conditions of 5 mM and 25 mM D-glucose, respectively. Isomeric l-glucose was used as the osmotic control. Cells were counted using CASY technology until they reached their Hayflick limit. Senescence-associated β-Galactosidase was used to identify senescent cells. Endothelial cell functionality was evaluated by the clonogenic, 3D tube formation, and barrier formation assays. Cell metabolism was characterized using the Seahorse Bioanalyzer. Gene expression analysis was performed by bulk RNA sequencing. Retinal tissues from db/db and db/+ mice were evaluated for the presence of senescent cells. Publicly available scRNA-sequencing data for retinas from Akimba and control mice was used for gene set enrichment analysis.

Results: Long term exposure to 25 mM D-Glucose accelerated the establishment of cellular senescence in human retinal endothelial cells when compared to 5 mM D-glucose and osmotic controls. This was shown from 4 weeks, by a significant slower growth, higher percentages of cells positive for senescence-associated β-galactosidase, an increase in cell size, and lower expression of pRb and HMGB2. These senescence features were associated with decreased clonogenic capacity, diminished tubulogenicity, and impaired barrier function. Long term high glucose-cultured cells exhibited diminished glycolysis, with lower protein expression of GLUT1, GLUT3, and PFKFB3. Transcriptomic analysis, after 4 weeks of culture, identified downregulation of ALDOC, PFKL, and TPI1, in cells cultured with 25 mM D-glucose when compared to controls. The retina from db/db mice showed a significant increase in acellular capillaries associated with a significant decrease in vascular density in the intermediate and deep retinal plexuses, when compared to db/+ mice. Senescent endothelial cells within the db/db retinal vasculature were identified by senescence-associated β-galactosidase staining. Analysis of single cell transcriptomics data for the Akimba mouse retina highlighted an enrichment of senescence and senescence-associated secretory phenotype gene signatures when compared to control mice.

Conclusion: A diabetic-like microenvironment of 25 mM D-glucose was sufficient to accelerate the establishment of cellular senescence in human retinal microvascular endothelial cells.
Analysis of the potential ferroptosis mechanism and multitemporal expression change of central ferroptosis-related genes in cardiac ischemia–reperfusion injury
Authors: Wang Zuoxiang , He Zhisong , Xuan Qinkao , Zhang Yue , Xu Jialiang , Lin Jia , Li Hongxia , Chen Weixiang , Jiang Tingbo
Published: August 2022

Acute myocardial infraction is the most severe type of coronary artery disease and remains a substantial burden to the health care system globally. Although myocardial reperfusion is critical for ischemic cardiac tissue survival, the reperfusion itself could cause paradoxical injury. This paradoxical phenomenon is known as ischemia–reperfusion injury (IRI), and the exact molecular mechanism of IRI is still far from being elucidated and is a topic of controversy. Meanwhile, ferroptosis is a nonapoptotic form of cell death that has been reported to be associated with various cardiovascular diseases. Thus, we explored the potential ferroptosis mechanism and target in cardiac IRI via bioinformatics analysis and experiment. GSE4105 data were obtained from the GEO database and consist of a rat IRI model and control. After identifying differentially expressed ferroptosis-related genes (DEFRGs) and hub genes of cardiac IRI, we performed enrichment analysis, coexpression analysis, drug–gene interaction prediction, and mRNA–miRNA regulatory network construction. Moreover, we validated and explored the multitemporal expression of hub genes in a hypoxia/reoxygenation (H/R)-induced H9C2 cell injury model under different conditions via RT-qPCR. A total of 43 DEFRGs and 7 hub genes (tumor protein p53 [Tp53], tumor necrosis factor [Tnf], hypoxia-inducible factor 1 subunit alpha [Hif1a], interleukin 6 [Il6], heme oxygenase 1 [Hmox1], X-box binding protein 1 [Xbp1], and caspase 8 [Casp8]) were screened based on bioinformatics analysis. The functional annotation of these genes revealed apoptosis, and the related signaling pathways could have association with the pathogenesis of ferroptosis in cardiac IRI. In addition, the expression of the seven hub genes in IRI models were found higher than that of control under different H/R conditions and time points. In conclusion, the analysis of 43 DEFRGs and 7 hub genes could reveal the potential biological pathway and mechanism of ferroptosis in cardiac IRI. In addition, the multitemporal expression change of hub genes in H9C2 cells under different H/R conditions could provide clues for further ferroptosis mechanism exploring, and the seven hub genes could be potential biomarkers or therapeutic targets in cardiac IRI.
Peripheral chemoreflex modulation of renal hemodynamics and renal tissue PO2 in chronic heart failure with reduced ejection fraction
Authors: Kious Kiefer W. , Philipose Andrew , Smith Luke J. , Kemble Jayson P. , Twohey Stephanie C. E. , Savage Kalie , Díaz Hugo S. , Del Rio Rodrigo , Marcus Noah J.
Published: August 2022

Aberrant carotid body chemoreceptor (CBC) function contributes to increased sympathetic nerve activity (SNA) and reduced renal blood flow (RBF) in chronic heart failure (CHF). Intermittent asphyxia (IA) mimicking sleep apnea is associated with additional increases in SNA and may worsen reductions in RBF and renal PO2 (RPO2) in CHF. The combined effects of decreased RBF and RPO2 may contribute to biochemical changes precipitating renal injury. This study sought to determine the role of CBC activity on glomerular filtration rate (GFR), RBF and RPO2 in CHF, and to assess the additive effects of IA. Furthermore, we sought to identify changes in gene expression that might contribute to renal injury. We hypothesized that GFR, RBF, and RPO2 would be reduced in CHF, that decreases in RBF and RPO2 would be worsened by IA, and that these changes would be ameliorated by CBC ablation (CBD). Finally, we hypothesized that CHF would be associated with pro-oxidative pro-fibrotic changes in renal gene expression that would be ameliorated by CBD. CHF was induced in adult male Sprague Dawley rats using coronary artery ligation (CAL). Carotid body denervation was performed by cryogenic ablation. GFR was assessed in conscious animals at the beginning and end of the experimental period. At 8-weeks post-CAL, cardiac function was assessed via echocardiography, and GFR, baseline and IA RBF and RPO2 were measured. Renal gene expression was measured using qRT-PCR. GFR was lower in CHF compared to sham (p < 0.05) but CBD had no salutary effect. RBF and RPO2 were decreased in CHF compared to sham (p < 0.05), and this effect was attenuated by CBD (p < 0.05). RBF and RPO2 were reduced to a greater extent in CHF vs. sham during exposure to IA (p < 0.05), and this effect was attenuated by CBD for RBF (p < 0.05). Downregulation of antioxidant defense and fibrosis-suppressing genes was observed in CHF vs. sham however CBD had no salutary effect. These results suggest that aberrant CBC function in CHF has a clear modulatory effect on RBF during normoxia and during IA simulating central sleep apnea.
Characteristics of members of IGT family genes in controlling rice root system architecture and tiller development
Authors: Zhao Jianping , Jiang Lihui , Bai Hanrui , Dai Yuliang , Li Kuixiu , Li Saijie , Wang Xiaoran , Wu Lixia , Fu Qijing , Yang Yanfen , Dong Qian , Yu Si , Wang Meixian , Liu Haiyan , Peng Ziai , Zhu Haiyan , Zhang Xiaoyan , He Xie , Lei Yan , Liang Yan , Guo Liwei , Zhang Hongji , Yu Decai , Liu Yixiang , Huang Huichuan , Liu Changning , Peng Sheng , Du Yunlong
Published: August 2022

Root system architecture (RSA) and tiller are important agronomic traits. However, the mechanisms of the IGT family genes regulate RSA and tiller development in different rice varieties remain unclear. In this study, we demonstrated that 38 rice varieties obtained from Yuanyang Hani’s terraced fields with different RSA and could be classified into six groups based on the ratio of root length and width. We found a positive correlation between RSA (including root width, length, and area) and tiller number in most of rice varieties. Furthermore, the IGT family genes Deeper Rooting 1 (DRO1), LAZY1, TAC1, and qSOR1 showed different expression patterns when rice grown under irrigation and drought conditions. Moreover, the qSOR1 gene had higher levels in the roots and tillers, and accompanied with higher levels of PIN1b gene in roots when rice grown under drought environmental condition. DRO1 gene had two single nucleotide polymorphisms (SNPs) in the exon 3 sequences and showed different expression patterns in the roots and tillers of the 38 rice varieties. Overexpression of DRO1 with a deletion of exon 5 caused shorter root length, less lateral roots and lower levels of LAZY1, TAC1, and qSOR1. Further protein interaction network, microRNA targeting and co-expression analysis showed that DRO1 plays a critical role in the root and tiller development associated with auxin transport. These data suggest that the RSA and tiller development are regulated by the IGT family genes in an intricate network way, which is tightly related to rice genetic background in rice adapting to different environmental conditions.
Development and application of a relative soil water content – transpiration efficiency curve for screening high water use efficiency wheat cultivars
Authors: Qiao Yunzhou , Li Dongxiao , Qiao Wenjun , Li Yongpeng , Yang Hong , Liu Wenwen , Liu Mengyu , Zhang Xiying , Dong Baodi
Published: August 2022

Improving water use efficiency (WUE) has been proven to be a prosperous way to produce more grain in drought-prone areas. Transpiration efficiency (TE) has been proposed as a criterion for screening cultivars with high WUE. This study quantifies the relations of TE to relative soil water content (RSWC) gradients using pot experiments and evaluates the capability of the relations of TE-RSWC on assessing the cultivar performance in field yield and WUE. Twelve winter wheat cultivars were grown at 6 RSWC, 12.1, 24.2, 36.3, 48.4, 60.5, and 72.6% of field capacity (FC = 24.8 g/g) for 33 days in tightly sealed pots preventing soil evaporation. The results showed that TE decreased power functionally following the increase in RSWC for all cultivars. The relationship could be described as TE = TE FC × (RSWC) b, named TE–RSWC curve. This curve could be divided into an orderly area where the rank of cultivars was stable when RSWC ≤ 12.1% or RSWC ≥ 72.6% and a disorderly area where the rank was unstable when 12.1% < RSWC < 72.6%. To assess the consistency of pot TE to field yield and WUE, the same 12 varieties were grown under rainfed and two irrigations (75 mm at the jointing and flowering stages, respectively). TE FC was found to be positively related to field yield and WUE independent of irrigation. TE measured near the wilting point was negatively related to field yield and WUE. These results indicated that TE FC could be used as a surrogate for screening high-yield and high-WUE cultivars. The consistency and inconsistency can be attributed to the orderly area and disorderly area of the TE–RSWC curves.
Comparative transcriptome analysis revealed differential gene expression involved in wheat leaf senescence between stay-green and non-stay-green cultivars
Authors: Li Qing , Yang Huai , Guo Jingwei , Huang Qianglan , Zhong Shengfu , Tan Feiquan , Ren Tianheng , Li Zhi , Chen Chen , Luo Peigao
Published: August 2022

Breeders agree that leaf senescence is a favorable process for wheat seed yield improvement due to the remobilization of leaf nutrients. However, several studies have suggested that staying green may be an important strategy for further increasing wheat yields. In this study, we performed a comparative transcriptome analysis between wheat cultivars CN17 and CN19 after heading and also measured photosynthetic parameters, chlorophyll (Chl) contents, and antioxidant enzyme activities at various time points after heading. The physiological and biochemical indexes revealed that CN17 exhibited a functionally stay-green phenotype while CN19 did not. We identified a total of 24,585 and 34,410 differential expression genes between genotypes at two time-points and between time-points in two genotypes, respectively, and we also found that 3 (37.5%) genes for leaf senescence, 46 (100%) for photosynthesis – antenna protein, 33 (70.21%) for Chl metabolism and 34 (68%) for antioxidative enzyme activity were upregulated in CN17 compared with CN19 during leaf senescence, which could be regulated by the differential expression ofSAG39(senescence-associated gene 39), while 22 (100%) genes for photosynthesis – antenna proteins, 6 (46.15%) for Chl metabolism and 12 (80%) for antioxidative enzyme activity were upregulated in CN17 compared with CN19 before the onset of leaf senescence. Here, we further clarified the expression profiles of genes associated with a functional stay-green phenotype. This information provides new insight into the mechanism underlying delayed leaf senescence and a new strategy for breeders to improve wheat yields.
Comparative analyses of the metabolite and ion concentrations in nectar, nectaries, and leaves of 36 bromeliads with different photosynthesis and pollinator types
Authors: Göttlinger Thomas , Lohaus Gertrud
Published: August 2022

Floral nectar contains mainly sugars as well as smaller amounts of amino acids and further compounds. The nectar composition varies between different plant species and it is related to the pollination type of the plant. In addition to this, other factors can influence the composition. Nectar is produced in and secreted from nectaries. A few models exist to explain the origin of nectar for dicotyl plant species, a complete elucidation of the processes, however, has not yet been achieved. This is particularly true for monocots or plant species with CAM photosynthesis. To get closer to such an elucidation, nectar, nectaries, and leaves of 36 bromeliad species were analyzed for sugars, starch, amino acids, and inorganic ions. The species studied include different photosynthesis types (CAM/C3), different pollination types (trochilophilous/chiropterophilous), or different live forms. The main sugars in nectar and nectaries were glucose, fructose, and sucrose, the total sugar concentration was about twofold higher in nectar than in nectaries, which suggests that sugars are actively transported from the nectaries into the nectar. The composition of amino acids in nectar is already determined in the nectaries, but the concentration is much lower in nectar than in nectaries, which suggests selective retention of amino acids during nectar secretion. The same applies to inorganic ions. Statistical analyses showed that the photosynthesis type and the pollination type can explain more data variation in nectar than in nectaries and leaves. Furthermore, the pollinator type has a stronger influence on the nectar or nectary composition than the photosynthesis type. Trochilophilous C3 plants showed significant correlations between the nitrate concentration in leaves and the amino acid concentration in nectaries and nectar. It can be assumed that the more nitrate is taken up, the more amino acids are synthesized in leaves and transported to the nectaries and nectar. However, chiropterophilous C3 plants show no such correlation, which means that the secretion of amino acids into the nectar is regulated by further factors. The results help understand the physiological properties that influence nectaries and nectar as well as the manner of metabolite and ion secretion from nectaries to nectar.
Equity Reform and High-Quality Development of State-Owned Enterprises: Evidence From China in the New Era
Authors: Liao Hongwei , Wang Dingqing , Zhu Lei , Zhao Jing
Published: August 2022

How to improve the development quality of state-owned enterprises is of great significance to the economic and social development in the transition period. And promoting the reform of mixed ownership is an important path for state-owned enterprises to achieve high-quality development. Based on the micro-data of China’s A-share listed state-owned companies, the paper explores the impact of mixed ownership reform on the high-quality development of state-owned enterprises. It clarifies the importance and moderation of equity reform and the heterogeneity of impact effects from the theoretical mechanism analysis and empirical test. It also analyzes the reasons of inverted U-shape from the perspective of the transmission mechanism of the internal competition atmosphere and non-state-owned capital speculation motivation. It is found that the relationship between equity reform and state-owned enterprises’ high-quality development is inverted U-shaped with multi-dimensional heterogeneity. From the analysis of conduction mechanism, on the one hand, the equity reform can enhance the internal competitive atmosphere, stimulate the vitality of enterprises and improve the development quality for state-owned enterprises. On the other hand, it enhances the speculation motivation of enterprises and slows down the high-quality development process.
Processing speed mediates the association between physical activity and executive functioning in elderly adults
Authors: Silva-Fernandes Anabela , Cruz Sara , Moreira Célia Sofia , Pereira Diana R. , Sousa Sónia S. , Sampaio Adriana , Carvalho Joana
Published: August 2022

Advanced aging is associated with cognitive decline. To decrease the healthcare system and socio-economic burdens as well as to promote better quality of life, is important to uncover the factors that may be related to the delay of cognitive impairments in older adults. This study investigated the relationship between physical activity levels, sedentary behavior and cardiorespiratory fitness with cognitive functioning in healthy older adults. Furthermore, it examined the mediating role of processing speed on the association between physical activity and executive functions and long-term memory. Thirty-two individuals aged between 63 and 77 years (M = 68.16, SD = 3.73) underwent measurements of maximal oxygen uptake (VO2peak), 1-week of PA accelerometer measurement and a comprehensive cognitive assessment. Significant associations were observed between MVPA and cognitive processing speed. Equally, a significant positive indirect effect of MVPA on executive functioning and long-term memory was mediated by processing speed. Also, MVPA levels differentiated cognitive functioning in older adults – the physical active group outperformed the physical inactive group in processing speed, executive functions, and language abilities. Our results contribute to the literature on the MVPA levels as an important tool to promote healthier cognitive aging.
Physical giftedness/talent: A systematic review of the literature on identification and development
Authors: Jung Jae Yup
Published: August 2022

In this study, a systematic review was undertaken of the international scholarly literature on the identification and development of giftedness/talent in the physical domain, to establish the scope of current knowledge in the area. To identify relevant research, a search that involved the creation of a search string and the manual examination of the titles and abstracts of potentially relevant research, was conducted using two databases—Web of Science Core Collection and SportDiscus—and six inclusion/exclusion criteria (i.e., relevance to identification or development of physical giftedness/talent, an empirical study, publication in a reputable academic peer-reviewed journal, publication from 2000 to 2021, an English language publication, and authorship by scholars based in any part of the world). The 101 journal articles that met the inclusion/exclusion criteria were analyzed for key details, including the year of publication, methodological approaches, participants, and major findings. The five broad themes that emerged from the findings of these articles related to conceptions of physical giftedness/talent, identification characteristics/criteria, factors associated with identification, identification methods, and talent development interventions. An outline and discussion of the key issues and trends in the research, along with some recommendations for future research, conclude the systematic review.