Publications by authors named "Min Xie"

479 Publications

Do Various Treatment Modalities of Vesicoureteral Reflux Have Any Adverse Effects in Pediatric Patients? A Meta-Analysis.

Urol Int 2021 Sep 23:1-9. Epub 2021 Sep 23.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Purpose: Vesicoureteral reflux (VUR) is a risk factor for various renal problems like recurrent urinary tract infections (UTIs), pyelonephritis, renal scarring, hypertension, and other renal parenchymal defects. The interventions followed by pediatricians include low-dose antibiotic treatment, surgical correction, and endoscopy. This meta-analysis aimed to assess the advantages and drawbacks of various primary VUR treatment options.

Search Strategy: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists of journals, and abstracts from conference proceedings were all used to find randomized controlled trials. The articles were retrieved from 1985 till 2020. Twenty articles were used for the data analysis. Criteria for Selection: Surgery, long-term antibiotic prophylaxis, noninvasive techniques, and any mix of therapies are also options for treating VUR. Collection and Interpretation of Data: Two authors searched the literature separately, determining research qualifications, assessing accuracy, and extracting and entering results. The odds ratio (OR) of these studies was used to construct the forest plot. The random-effects model was used to pool the data. Also, the random-effects model was used with statistical significance at a p value < 0.05 to assess the difference in side effects after treatment of VUR using different modalities.

Results: We found no statistically significant differences between surgery plus antibiotics and antibiotic alone-treated patients in terms of recurrent UTIs (OR = 0.581; 95% confidence interval [CI] 0.259-1.30), renal parenchymal defects (OR = 1.149; 95% CI 0.75-1.754), and renal scarring (OR = 1.042; 95% CI 0.72-1.50). However, the risk of developing pyelonephritis after surgical treatment of VUR was lesser than that in the conservative approach, that is, antibiotics (OR = 0.345; 95% CI 0.126-0.946.), positive urine culture (OR = 0.617; 95% CI 0.428-0.890), and recurrent UTIs were more common in the placebo group than in the antibiotic group (p < 0.05; OR = 0.639; 95% CI 0.436-0.936) which is statistically significant.

Conclusion: Based on current research, we recommend that a child with a UTI and significant VUR be treated conservatively at first, with surgical care reserved for children who have issues with antimicrobials or have clinically significant VUR that persists after several years of follow-up.
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http://dx.doi.org/10.1159/000518603DOI Listing
September 2021

The abnormal expression of Tim-3 is involved in the regulation of myeloid-derived suppressor cells and its correlation with preeclampsia.

Placenta 2021 Aug 26;114:108-114. Epub 2021 Aug 26.

Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, 130061, PR China. Electronic address:

Introduction: Maternal immune system tolerance to the semi-allogeneic fetus is critical to a successful pregnancy. We previously reported that myeloid-derived suppressor cells (MDSC) was associated with maternal immune imbalance. T cell immunoglobulin and mucin-containing protein 3 (Tim-3)/Galectin-9 (Gal-9) pathway modulates function of various immune cells in maternal-fetal interface. However, the regulatory effects of Tim-3/Gal-9 signaling on MDSCs and its role in preeclampsia (PE) remain unclear.

Methods: In the current study we investigated the expression of Tim-3 on MDSC in preeclampsia (PE) patients to further explore the pathogenesis of PE.

Results: The proportion of Tim-3 M-MDSC (monocytic MDSC) cells was higher in PE patients than in healthy control. Meanwhile, the protein expression of Gal-9, as the ligand of Tim-3, was increased in placenta of PE patients. M-MDSC also expressed a higher level of interferon-γ (IFN-γ) and a lower level of transforming growth factor-β (TGF-β) in PE. Furthermore, our study suggested that blocking Tim-3 could attenuate the inhibitory function of MDSC.

Discussion: The abnormal expression of Tim-3 on MDSC might be involved in the pathogenesis of PE, and could be a marker to evaluate the immune function in PE.
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http://dx.doi.org/10.1016/j.placenta.2021.08.060DOI Listing
August 2021

Parallel Metabolomic Profiling of Cerebrospinal Fluid, Plasma, and Spinal Cord to Identify Biomarkers for Spinal Cord Injury.

J Mol Neurosci 2021 Sep 9. Epub 2021 Sep 9.

Department of Orthopedics, The First Affiliated Hospital of Jinan University, No.601 West Huangpu Avenue, Tianhe, Guangzhou, 510630, China.

Loss of physical and emotional health due to spinal cord injury (SCI) has been rapidly increasing worldwide. Effective evaluation of the severity of SCI is crucial to its prognosis. Herein, we constructed rat models of SCI with four different degrees of injury (sham group, light injury group, moderate injury group, and heavy injury group), using the surgical approach. Cerebrospinal fluid (CSF), plasma, and spinal cord were sampled at the sub-acute spinal cord (72 h post-injury) from each rat. The LC-MS-based metabolic profiling of these samples was performed according to a universal metabolome standard (UMS). The results demonstrated that 130, 104, and 128 metabolites were significantly altered within the CSF, plasma, and spinal cord samples, respectively. Among them, there were four differential metabolites, including uric acid, phosphorycholine, pyridoxine, and guanidoacetic acid, which were commonly identified within the CSF, plasma, and spinal cord samples. Further pathway analysis of these differential metabolites demonstrated a disturbance in the metabolism of glyoxylate and dicarboxylate and glycine, serine, and threonine which were associated with pathophysiologic consequence of spinal cord injury. In particular, phosphorycholine, pyridoxine, and guanidoacetic acid demonstrated a relationship with SCI severity. Thus, they could be utilized as potential metabolite biomarkers for SCI severity assessment.
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http://dx.doi.org/10.1007/s12031-021-01903-wDOI Listing
September 2021

Impact of childbirth policy changes on obstetric workload over a 13-year period in a regional referral center in China - implications on service provision planning.

BMC Pregnancy Childbirth 2021 Sep 7;21(1):610. Epub 2021 Sep 7.

Department of Obstetrics and Gynecology, the First Affiliated Hospital of Kunming Medical University, China, PO Box 650032, No.295 Xi Chang Rd, Kunming, Yunnan, China.

Background: We aimed to appraise the impact of the changing national childbirth policy since 2002, currently allowing two children per family, on obstetric workload in a regional referral center in China.

Methods: In a retrospective cohort study, temporal changes were examined in relation with maternal demographics, incidence of women with high risk pregnancies and resource statistics in our hospital in managing singleton viable pregnancies (birth from 28 weeks gestational age onwards) for the period 2005-2017.

Results: During this 13-year period, the number of singleton livebirths from 28 weeks gestational age onwards was 49,479. Annual numbers of births increased from 1,941 to 2005 to 5,777 in 2017. There were concomitant and significant increases in the incidence of multiparous women (10.6-50.8 %), of age ≥35 years (6.5-24.3 %), with prior caesarean Sec. (2.6-23.6 %), with ≥3 previous pregnancy terminations (1.0-4.9 %), with pre-gestational diabetes (0.2-0.9 %), and with chronic hypertension (0.2-1.2 %). There were associated increases in beds and staff complement and reduced average hospital stay. Nevertheless, while the workload of medical staff remained stable with increasing staff complement, that of midwives increased significantly as reflected by the total births: midwife ratio which increased from 194.1:1 to 320.9:1 (p < 0.001).

Conclusions: In our hospital, progressively increasing numbers of annual births in combination with an increased incidence of women with high risk pregnancies took place following the revised national childbirth policy. Only the increase in medical and nursing, but not midwifery, staff was commensurate with workload. Remedial measures are urgently required before the anticipated progressive increase in care demand would overwhelm maternity care with potentially disastrous consequences.
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http://dx.doi.org/10.1186/s12884-021-04074-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424970PMC
September 2021

FBXO10 prevents chronic unpredictable stress-induced behavioral despair and cognitive impairment through promoting RAGE degradation.

CNS Neurosci Ther 2021 Sep 7. Epub 2021 Sep 7.

Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Aims: Depression is one of the leading causes of disability worldwide. The receptor for advanced glycosylation end products (RAGE) is closely related to chronic stress and is a target of F-box protein O10 (FBXO10) which promotes the degradation of RAGE by ubiquitination. Here, we explored the role of FBXO10 and RAGE in chronic unpredictable stress (CUS)-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization microglia.

Methods: Male C57BL/6 mice with or without infusion of viral in the medial prefrontal cortex (PFC) were subjected to CUS. Then the mice were exposed to forced swim test, sucrose consumption test, novelty-suppressed feeding test, and temporal object recognition task to assess the behavioral despair and cognitive impairment. Inflammatory cytokines and the neurotrophic factor brain-derived neurotrophic factor (BDNF) levels in PFC were assessed by enzyme-linked immunosorbent assay. Immunofluorescence and immunohistochemistry staining were performed to observe the activation and phenotypic transformation of microglia in PFC. LPS-induced cell model was constructed to explore the effect of FBXO10/RAGE axis in the polarization of microglia in vitro.

Results: FBXO10 promoted RAGE degradation by ubiquitination in BV2 cells. FBXO10 protein levels were reduced whereas RAGE protein levels were enhanced in CUS mice. FBXO10 overexpression or RAGE knockdown inhibited proinflammatory cytokine release, promoted BDNF expression, mitigated the depressive-like and cognitive impairment behaviors, and affected the polarization of microglia induced by CUS exposure. FBXO10/RAGE axis promoted the polarization of microglia from the M1 to the M2 phenotype in vitro. Moreover, p38 MAPK and NF-κΒ were identified to be the downstream effect factors for FBXO10/RAGE axis.

Conclusions: FBXO10 administration prevents CUS-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization of microglia through decreasing the accumulation of RAGE, p38 MAPK, and NF-κΒ, suggesting potential therapeutic strategies for the prevention and treatment of depression.
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http://dx.doi.org/10.1111/cns.13727DOI Listing
September 2021

Lipin1 Alleviates Autophagy Disorder in Sciatic Nerve and Improves Diabetic Peripheral Neuropathy.

Mol Neurobiol 2021 Aug 26. Epub 2021 Aug 26.

Department of Endocrinology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Ji'nan, Shandong, 250033, People's Republic of China.

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes, and its neural mechanisms underlying the pathogenesis remain unclear. Autophagy plays an important role in neurodegenerative diseases and nerve tissue injury. Lipin1 is a phosphatidic acid phosphatase enzyme that converts phosphatidic acid (PA) into diacylglycerol (DAG), a precursor of triacylglycerol and phospholipids which plays an important role in maintaining normal peripheral nerve conduction function. However, whether Lipin1 involved in the pathogenesis of DPN via regulation of autophagy is not elucidated. Here, we show that the Lipin1 expression was downregulated in streptozotocin (STZ)-induced DPN rat model. Interestingly, STZ prevented DAG synthesis, and resulted in autophagic hyperactivity, effects which may increase the apoptosis of Schwann cells and lead to demyelination in sciatic nerve in DPN rats. More importantly, upregulation of lipin1 in the DPN rats ameliorated autophagy disorders and pathological changes of the sciatic nerve, which associated with the increase of the motor nerve conductive velocity (MNCV) in DPN rats. In contrast, knockdown of lipin1 exacerbates neuronal abnormalities and facilitates the genesis of DPN phenotypes in rats. In addition, overexpression of lipin1 in RSC96 cells also significantly decreased the autophagic hyperactivity and apoptosis induced by hyperglycemia. These results suggest that lipin1 may exert neuroprotection within the sciatic nerve anomalies and may serve as a potential therapeutic target for the treatment of DPN.
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http://dx.doi.org/10.1007/s12035-021-02540-5DOI Listing
August 2021

Time-Dependent Internalization of S100B by Mesenchymal Stem Cells the Pathways of Clathrin- and Lipid Raft-Mediated Endocytosis.

Front Cell Dev Biol 2021 26;9:674995. Epub 2021 Jul 26.

Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China.

Mesenchymal stem cells (MSCs) are promising tools for cancer therapy, but there is a risk of malignant transformation in their clinical application. Our previous work revealed that the paracrine protein S100B in the glioma microenvironment induces malignant transformation of MSCs and upregulates intracellular S100B, which could affect cell homeostasis by interfering with p53. The purpose of this study was to investigate whether extracellular S100B can be internalized by MSCs and the specific endocytic pathway involved in S100B internalization. By using real-time confocal microscopy and structured illumination microscopy (SIM), we visualized the uptake of fluorescently labeled S100B protein (S100B-Alexa488) and monitored the intracellular trafficking of internalized vesicles. The results showed that S100B-Alexa488 was efficiently internalized into MSCs in a time-dependent manner and transported through endolysosomal pathways. After that, we used chemical inhibitors and RNA interference approaches to investigate possible mechanisms involved in S100B-Alexa488 uptake. The internalization of S100B-Alexa488 was inhibited by pitstop-2 or dyngo-4a treatment or RNA-mediated silencing of clathrin or dynamin, and the lipid raft-mediated endocytosis inhibitors nystatin and MβCD. In conclusion, our findings show that clathrin and lipid rafts contribute to the internalization of S100B-Alexa488, which provides promising interventions for the safe application of MSCs in glioma therapy.
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http://dx.doi.org/10.3389/fcell.2021.674995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351554PMC
July 2021

Perimyocarditis following first dose of the mRNA-1273 SARS-CoV-2 (Moderna) vaccine in a healthy young male: a case report.

BMC Cardiovasc Disord 2021 08 4;21(1):375. Epub 2021 Aug 4.

Department of Internal Medicine, University of Alabama at Birmingham (UAB), 1720 2nd Avenue S, BDB 327, Birmingham, AL, 35233, USA.

Background: Half of U.S. adults have received at least one dose of the COVID-19 vaccines produced by either Pfizer, Moderna, or Johnson and Johnson, which represents a major milestone in the ongoing pandemic. Given the emergency use authorizations for these vaccines, their side effects and safety were assessed over a compressed time period. Hence, ongoing monitoring for vaccine-related adverse events is imperative for a full understanding and delineation of their safety profile.

Case Presentation: An 22-year-old Caucasian male presented to our hospital center complaining of pleuritic chest pain. Six months prior he had a mild case of COVID-19, but was otherwise healthy. He had received his first dose of the Moderna vaccine three days prior to developing symptoms. Laboratory analysis revealed a markedly elevated troponin and multiple imaging modalities during his hospitalization found evidence of wall motion abnormalities consistent with a diagnosis of perimyocarditis. He was started on aspirin and colchicine with marked improvement of his symptoms prior to discharge.

Conclusions: We present a case of perimyocarditis that was temporally related to COVID-19 mRNA vaccination in an young male with prior COVID-19 infection but otherwise healthy. Our case report highlights an albeit rare but important adverse event for clinicians to be aware of. It also suggests a possible mechanism for the development of myocardial injury in our patient.
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http://dx.doi.org/10.1186/s12872-021-02183-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334333PMC
August 2021

IL-1β augments TGF-β inducing epithelial-mesenchymal transition of epithelial cells and associates with poor pulmonary function improvement in neutrophilic asthmatics.

Respir Res 2021 Aug 3;22(1):216. Epub 2021 Aug 3.

Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.

Background: Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA.

Methods: Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells.

Results: NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV compared to EA. For all asthmatics, sputum IL-1β mRNA was positively correlated with protein expression. Sputum IL-1β mRNA and protein levels were negatively correlated to FEV improvement. After subgrouping, the correlation between IL-1β mRNA and FEV improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1β augmenting TGF-β1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors.

Conclusions: IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways.

Trial Registration: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).
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http://dx.doi.org/10.1186/s12931-021-01808-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336269PMC
August 2021

Inhibition of miR-214-3p Protects Endothelial Cells from ox-LDL-Induced Damage by Targeting GPX4.

Biomed Res Int 2021 6;2021:9919729. Epub 2021 Jul 6.

Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China.

It is generally believed that excessive production of reactive oxygen species (ROS) during cardiovascular diseases impairs endothelial function. In this study, we aimed to investigate whether miR-214-3p is involved in the endothelial dysfunction induced by oxidized low-density lipoprotein (ox-LDL). In cultured vascular endothelial cells (VECs), the effects of miR-214-3p on endothelial injury induced by 100 mg/L ox-LDL were evaluated by knockdown of miR-214-3p. Western blotting was used to determine the expression of glutathione peroxidase 4 (GPX4) and endothelial nitric oxide synthase (eNOS) in VECs under different conditions. A luciferase reporter assay was used to identify GPX4 as the target of miR-214-3p. Our data showed that 100 mg/L ox-LDL significantly decreased the expression of GPX4 and eNOS, which was associated with increases in ROS levels and impairments of VEC viability and migration. Knockdown of miR-214-3p could partially reduce the increase in ROS, restore the decreased expression of GPX4 and eNOS, and thus rescue the impaired endothelial function caused by ox-LDL. Our data demonstrated that ox-LDL could induce upregulation of miR-214-3p and result in suppression of GPX4 in VECs. Downregulation of miR-214-3p could protect VECs from ROS-induced endothelial dysfunction by reversing its inhibitory effect on GPX4 expression.
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http://dx.doi.org/10.1155/2021/9919729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277498PMC
September 2021

Tumor-Derived Extracellular Vesicles Promote Activation of Carcinoma-Associated Fibroblasts and Facilitate Invasion and Metastasis of Ovarian Cancer by Carrying miR-630.

Front Cell Dev Biol 2021 30;9:652322. Epub 2021 Jun 30.

Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Ovarian cancer (OC) is a lethal gynecological malignancy. Extracellular vesicles (EVs) are crucial media in cell-to-cell communication by carrying microRNAs (miRs). The current study aims to investigate the underlying mechanism of miR-630 carried by OC cell-derived EVs in regard to invasion and metastasis of OC cells. miRs related to OC metastasis were searched and screened. The expression patterns of screened miRs in human normal fibroblasts (NFs) and carcinoma-associated fibroblasts (CAFs) were detected using RT-qPCR. miR-630 related to OC metastasis and CAFs activation was analyzed further. The levels of FAP and α-SMA were detected using Western blotting and immunofluorescence. The migration of NFs was measured using Transwell assay. OC cell-derived EVs were isolated and identified. Uptake of EVs by NFs was observed using immunofluorescence staining. The culture supernatant of NFs was collected and used to culture the low metastasis cell line OVCAR8. The migration and invasion of OC cells and epithelial mesenchymal transition (EMT) were measured. Moreover, a xenograft model was established by injecting OVCAR8 cells of different groups into nude mice. Lastly, the effect of EV-pretreated NFs on invasion and metastasis of OC cells was observed . miR-630 was upregulated in OC cells and CAFs, and further associated with CAF activation and OC metastasis. miR-630 overexpression increased the levels of FAP and α-SMA in NFs, resulting in the transformation of NFs into CAFs. EVs carried miR-630 into NFs and EVs promoted CAF activation. miR-630 targeted KLF6. miR-630 inhibition or KLF6 overexpression attenuated EVs-induced CAF activation. EVs activated the NF-κB pathway the miR-630/KLF6 axis. The conditioned medium of NFs pretreated with EVs promoted the invasion and metastasis of OVCAR8 cells, while downregulating miR-630 in EVs partially inhibited the promotive effect of NFs. EV-pretreated NFs promoted invasion and metastasis of OC . In conclusion, EVs carried miR-630 into NFs, thereby facilitating CAF activation and promoting invasion and metastasis of OC by inhibiting KLF6 and activating the NF-κB pathway. Our findings might offer a novel mechanism of invasion and metastasis of OC from the perspective of tumor microenvironment.
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http://dx.doi.org/10.3389/fcell.2021.652322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277948PMC
June 2021

Management and Clinical Outcome of Posterior Reversible Encephalopathy Syndrome in Pediatric Oncologic/Hematologic Diseases: A PRES Subgroup Analysis With a Large Sample Size.

Front Pediatr 2021 1;9:678890. Epub 2021 Jul 1.

Division of Hematology and Tumor, Children's Medical Center, The Second Xiangya Hospital, Central South University, Changsha, China.

This study investigated the management and clinical outcomes along with associated factors of posterior reversible encephalopathy syndrome (PRES) in childhood hematologic/oncologic diseases. We present data from children with hematologic/oncologic diseases who developed PRES after treatment of the primary disease with chemotherapy and hematopoietic stem cell transplantation (HSCT) at 3 medical centers in Changsha, China from 2015 to 2020, and review all previously reported cases with the aim of determining whether this neurologic manifestation affects the disease prognosis. In the clinical cohort of 58 PRES patients, hypertension [pooled odds ratio (OR) = 4.941, 95% confidence interval (CI): 1.390, 17.570; = 0.001] and blood transfusion (OR = 14.259, 95% CI: 3.273, 62.131; = 0.001) were significantly associated with PRES. Elevated platelet (OR = 0.988, 95% CI: 0.982, 0.995; < 0.001), hemoglobin (OR = 0.924, 95% CI: 0.890, 0.995; < 0.001), and blood sodium (OR = 0.905, 95% CI: 0.860, 0.953; < 0.001), potassium (OR = 0.599, 95% CI: 0.360, 0.995; = 0.048), and magnesium (OR = 0.093, 95% CI: 0.016, 0.539; = 0.008) were protective factors against PRES. Data for 440 pediatric PRES patients with hematologic/oncologic diseases in 21 articles retrieved from PubMed, Web of Science, and Embase databases and the 20 PRES patients from our study were analyzed. The median age at presentation was 7.9 years. The most common primary diagnosis was leukemia (62.3%), followed by solid tumor (7.7%) and lymphoma (7.5%). Most patients (65.0%) received chemotherapy, including non-induction (55.2%) and induction (44.8%) regimens; and 86.5% used corticosteroids before the onset of PRES. Although 21.0% of patients died during follow-up, in most cases (93.2%) this was not attributable to PRES but to severe infection (27.3%), underlying disease (26.1%), graft-vs.-host disease (14.8%), multiple organ dysfunction syndrome (8.0%), and respiratory failure (3.4%). PRES was more common with HSCT compared to chemotherapy and had a nearly 2 times higher mortality rate in patients with oncologic/hematologic diseases than in those with other types of disease. Monitoring neurologic signs and symptoms in the former group is therefore critical for ensuring good clinical outcomes following treatment of the primary malignancy.
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http://dx.doi.org/10.3389/fped.2021.678890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280768PMC
July 2021

Lesion Penetration and Activity Limit the Utility of Second-Line Injectable Agents in Pulmonary Tuberculosis.

Antimicrob Agents Chemother 2021 09 12;65(10):e0050621. Epub 2021 Jul 12.

Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.

Amikacin and kanamycin are second-line injectables used in the treatment of multidrug-resistant tuberculosis (MDR-TB) based on the clinical utility of streptomycin, another aminoglycoside and first-line anti-TB drug. While streptomycin was tested as a single agent in the first controlled TB clinical trial, introduction of amikacin and kanamycin into MDR-TB regimens was not preceded by randomized controlled trials. A recent large retrospective meta-analysis revealed that compared with regimens without any injectable drug, amikacin provided modest benefits, and kanamycin was associated with worse outcomes. Although their long-term use can cause irreversible ototoxicity, they remain part of MDR-TB regimens because they have a role in preventing emergence of resistance to other drugs. To quantify the contribution of amikacin and kanamycin to second-line regimens, we applied two-dimensional matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging in large lung lesions, quantified drug exposure in lung and in lesions of rabbits with active TB, and measured the concentrations required to kill or inhibit growth of the resident bacterial populations. Using these metrics, we applied site-of-action pharmacokinetic and pharmacodynamic (PK-PD) concepts and simulated drug coverage in patients' lung lesions. The results provide a pharmacological explanation for the limited clinical utility of both agents and reveal better PK-PD lesion coverage for amikacin than kanamycin, consistent with retrospective data of contribution to treatment success. Together with recent mechanistic studies dissecting antibacterial activity from aminoglycoside ototoxicity, the limited but rapid penetration of streptomycin, amikacin, and kanamycin to the sites of TB disease supports the development of analogs with improved efficacy and tolerability.
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http://dx.doi.org/10.1128/AAC.00506-21DOI Listing
September 2021

Increased copy number of gibberellin 2-oxidase 8 genes reduced trailing growth and shoot length during soybean domestication.

Plant J 2021 Jul 10. Epub 2021 Jul 10.

School of Life Sciences and the Centre for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Copy number variations (CNVs) play important roles in crop domestication. However, there is only very limited information on the involvement of CNVs in soybean domestication. Trailing growth and long shoots are soybean adaptations for natural habitats but cause lodging that hampers yield in cultivation. Previous studies have focused on Dt1/2 affecting the indeterminate/determinate growth habit, whereas the possible role of the gibberellin pathway remained unclear. In the present study, quantitative trait locus (QTL) mapping of a recombinant inbred population of 460 lines revealed a trailing-growth-and-shoot-length QTL. A CNV region within this QTL was identified, featuring the apical bud-expressed gibberellin 2-oxidase 8A/B, the copy numbers of which were positively correlated with expression levels and negatively with trailing growth and shoot length, and their effects were demonstrated by transgenic soybean and Arabidopsis thaliana. Based on the fixation index, this CNV region underwent intense selection during the initial domestication process.
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http://dx.doi.org/10.1111/tpj.15414DOI Listing
July 2021

Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors.

Sci Rep 2021 07 5;11(1):13854. Epub 2021 Jul 5.

Department of Respiratory and Critical Care MedicineTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.
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http://dx.doi.org/10.1038/s41598-021-93191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257634PMC
July 2021

Calycosin attenuates pulmonary fibrosis by the epithelial-mesenchymal transition repression upon inhibiting the AKT/GSK3β/β-catenin signaling pathway.

Acta Histochem 2021 Jul 30;123(5):151746. Epub 2021 Jun 30.

Department of General Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address:

The precise etiology and pathogenesis of idiopathic pulmonary fibrosis are not completely understood, and no satisfactory treatment exists. This work aimed to examine the effects of calycosin (CA, an isoflavone compound) on pulmonary fibrosis (PF) and explore the underlying mechanism. In this study, we established a mice model of PF induced by 5 mg/mL bleomycin (BLM), and mice were orally administrated with 7 mg/kg or 14 mg/kg CA once a day for three weeks. In vitro, after pretreated with 80 μM CA, MLE-12 cells were stimulated with 10 ng/mL transforming growth factor-β1 (TGF-β1) for inducing epithelial-mesenchymal transition (EMT). The results showed that CA treatment ameliorated the severity of fibrosis and the lung tissue damage, as well as suppressed the secretion of inflammation factors in a dose-dependent manner of the PF mice model induced by BLM. Subsequently, CA inhibited the BLM-induced PF progression by repressing EMT, evidenced by the reverse of the downregulation of E-cadherin and the upregulation of vimentin, α-SMA, and fibronectin. Moreover, the elevated phosphorylation of AKT and GSK3β induced by BLM (or TGF-β1) was decreased by CA treatment, leading to the rescue of the high expression of β-catenin. CA prevented the translocation of β-catenin from the cytoplasm to the nucleus. The repressed effects of CA on the TGF-β1-induced EMT and the AKT/GSK3β/β-catenin axis, as well as the translocation of β-catenin were all reversed by a AKT activator SC79. Taken together, CA ameliorated PF by the EMT inhibition upon suppressing the AKT/GSK3β/β-catenin signaling pathway.
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http://dx.doi.org/10.1016/j.acthis.2021.151746DOI Listing
July 2021

Serine hydroxymethyltransferase 2: a novel target for human cancer therapy.

Invest New Drugs 2021 Jul 3. Epub 2021 Jul 3.

Department of Pathology, Xuzhou Medical University, 209 Tong-shan Road, Xuzhou, 221004, Jiangsu, China.

Serine and glycine are the primary sources of one-carbon units that are vital for cell proliferation. Their abnormal metabolism is known to be associated with cancer progression. As the key enzyme of serine metabolism, Serine Hydroxymethyltransferase 2 (SHMT2) has been a research hotspot in recent years. SHMT2 is a PLP-dependent tetrameric enzyme that catalyzes the reversible transition from serine to glycine, thus promoting the production of one-carbon units that are indispensable for cell growth and regulation of the redox and epigenetic states of cells. Under a hypoxic environment, SHMT2 can be upregulated and could promote the generation of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione for maintaining the redox balance. Accumulating evidence confirmed that SHMT2 facilitates cell proliferation and tumor growth and is tightly associated with poor prognosis. In this review, we present insights into the function and research development of SHMT2 and summarize the possible molecular mechanisms of SHMT2 in promoting tumor growth, in the hope that it could provide clues to more effective clinical treatment of cancer.
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http://dx.doi.org/10.1007/s10637-021-01144-zDOI Listing
July 2021

Prevalence and Risk Factors of Mental Health Problems Among Healthcare Workers During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis.

Front Psychiatry 2021 15;12:567381. Epub 2021 Jun 15.

Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, China.

The purpose of this meta-analysis was to summarize the prevalence and risk factors of mental health problems among healthcare workers during the COVID-19 pandemic. We applied an optimized search strategy across the PubMed, EMBASE, Scopus, PsycINFO, and four Chinese databases, with hand searching supplemented to identify relevant surveys. Studies were eligible for inclusion if they were published in peer-reviewed literature and used a validated method to assess the prevalence and risk factors of mental health problems among healthcare workers during the COVID-19 pandemic. Heterogeneity was quantified using statistics and the statistics. The potential causes of heterogeneity were investigated using subgroup analysis and meta-regression analysis. Sensitivity analysis was performed to examine the robustness of the results. We pooled and analyzed data from 20 studies comprising 10,886 healthcare workers. The prevalence of depression, anxiety, insomnia, post-traumatic stress symptoms, phobia, obsessive-compulsive symptoms, and somatization symptoms was 24.1, 28.6, 44.1, 25.6, 35.0, 16.2, and 10.7%, respectively. Female and nurses had a high prevalence of depression and anxiety. Frontline healthcare workers had a higher prevalence of anxiety and a lower prevalence of depression than the those in the second-line. Furthermore, the proportion of moderate-severe depression and anxiety is higher in the frontline. Additionally, four studies reported on risk factors of mental health problems. In this systematic review, healthcare workers have a relatively high prevalence of depression, anxiety, insomnia, post-traumatic stress symptoms, phobia, obsessive-compulsive symptoms, and somatization symptoms during the COVID-19 pandemic, and focus should be on the healthcare workers at high risk of mental problems. Mental health problems in healthcare workers should be taken seriously, and timely screening and appropriate intervention for the high-risk group are highly recommended. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020179189.
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http://dx.doi.org/10.3389/fpsyt.2021.567381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239157PMC
June 2021

Effect of vitamin D supplementation on benign paroxysmal positional vertigo recurrence: A meta-analysis.

Sci Prog 2021 Apr-Jun;104(2):368504211024569

Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China.

Benign paroxysmal positional vertigo is characterized by recurrence, which exposes patients to repeated vertigo attacks. Vitamin D deficiency has been found to be a risk factor in benign paroxysmal positional vertigo, although effect of its elimination on recurrence reduction remains unknown. To determine the effect of vitamin D supplementation in preventing recurrence of benign paroxysmal positional vertigo patients with vitamin D deficiency using a meta-analysis study. We searched and retrieved relevant articles from several databases, then used the Cochrane evaluation system or Methodological Index for Non-Randomized Studies (MINORS) to assess the quality of studies. We adopted risk-ratio (RR) with corresponding 95% confidence interval (CI) to determine effect sizes, and further performed statistical analyses under a randomized- or fixed-effects model. Seven studies, comprising 602 and 731 participants in the case and control group respectively, met our inclusion criteria, and were therefore included in the meta-analysis. Assessment based on Cochrane evaluation system or MINORS revealed that most of the studies had high quality. Moreover, the randomized- model revealed that the vitamin D supplementation group had a lower recurrence rate than the control group which did not accepted vitamin D supplementation (RR = 0.41, 95% CI = 0.26-0.65,  < 0.01). Overall, these findings indicate that vitamin D supplementation can significantly lower recurrence in benign paroxysmal positional vertigo and vitamin D deficiency.
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http://dx.doi.org/10.1177/00368504211024569DOI Listing
June 2021

Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.

Circ Res 2021 Jul 11;129(3):435-450. Epub 2021 Jun 11.

Departments of Internal Medicine, Division of Cardiology (M.X., G.W.C., Y.K., D.L.L., F.A., X.L., C.R.M., N.J., G.G.S., H.I.M., J.M., J.M.S., A.F., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317428PMC
July 2021

Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy.

Front Immunol 2021 21;12:658698. Epub 2021 May 21.

Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.

Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is increasing evidence that extracellular vesicles (EVs) are involved in the antitumor activity of NK cells. NK cell-derived EVs (NKEVs) carrying cargo such as cytotoxic proteins, microRNAs, and cytokines employ multiple mechanisms to kill tumor cells, but also exhibit immunomodulatory activity by stimulating other immune cells. Several studies have reported that NKEVs can reverse immune suppression under tolerogenic conditions and contribute to NK-mediated immune surveillance against tumors. Thus, NKEVs are a promising tool for cancer immunotherapy. In this review, we describe the biological effects and potential applications of NKEVs in antitumor immunity.
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http://dx.doi.org/10.3389/fimmu.2021.658698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176011PMC
May 2021

Cellular Network Radio Monitoring and Management through Virtual UE Probes: A Study Case Based on Crowded Events.

Sensors (Basel) 2021 May 13;21(10). Epub 2021 May 13.

Instituto de Telecomunicación (TELMA), Universidad de Málaga, CEI Andalucía TECH, E.T.S. Ingeniería de Telecomunicación, Bulevar Louis Pasteur 35, 29010 Málaga, Spain.

Although log processing of network equipment is a common technique in cellular network management, several factors make said task challenging, especially during mass attendance events. The present paper assesses classic methods for cellular network measurement and acquisition, showing how the use of on-the-field user probes can provide relevant capabilities to the analysis of cellular network performance. Therefore, a framework for the deployment of this kind of system is proposed here based on the development of a new hardware virtualization platform with radio frequency capabilities. Accordingly, an analysis of the characteristics and requirements for the use of virtual probes was performed. Moreover, the impact that social events (e.g., sports matches) may have on the service provision was evaluated through a real cellular scenario. For this purpose, a long-term measurement study during crowded events (i.e., football matches) in a stadium has been conducted, and the performances of different services and operators under realistic settings has been evaluated. As a result, several considerations are presented that can be used for better management of future networks.
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http://dx.doi.org/10.3390/s21103404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153328PMC
May 2021

[Epidemiological and clinical features of children with mild coronavirus disease 2019].

Zhongguo Dang Dai Er Ke Za Zhi 2021 May;23(5):460-465

Children's Medical Center, Second Xiangya Hospital, Central South University, Changsha 410011, China.

Objective: To study the epidemiological and clinical features of children with mild coronavirus disease 2019 (COVID-19).

Methods: The children who were diagnosed with mild COVID-19 in the Wuchang Shelter Hospital in Wuhan from February 5 to March 10, 2020 were enrolled as subjects. The clinical, laboratory, and lung imaging data were collected during hospitalization and isolation. This was a retrospective single-center case series analysis.

Results: A total of 1 124 patients with mild COVID-19 were admitted from February 5 to March 10, 2020, including 13 children (1.16%). All the 13 children (7 boys and 6 girls) were residents of Wuhan in China, with a median age of 16 years (range: 10-18 years). Of all the 13 children, 9(69%) were from family clusters of COVID-19 and 4(31%) had unknown sources of infection. The mean time from exposure to onset was 6.8 days (range: 2-13 days) in 9 children with a definite history of exposure. There were 6 symptomatic children with the main manifestations of fever, cough, weakness, and myalgia, and the mean time from onset to hospitalization was 9.2 days. Of all the 13 children, 7(54%) were asymptomatic with positive nucleic acid test of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There were 4 children (31%) with abnormal lung CT findings, mainly patchy shadows or ground-glass opacities in the lung field, and 6 children (46%) had no symptoms with normal lung CT findings. All children had normal routine blood test results and C-reactive protein levels. Eight children underwent SARS-CoV-2 IgM and IgG tests at least once, among whom 6 had negative SARS-CoV-2 IgM but positive IgG, and 2 underwent SARS-CoV-2 IgM and IgG tests twice and had negative results. Of all the 13 children, 11(85%) had negative results of two SARS-CoV-2 nucleic acid tests during hospitalization and were discharged, and 2(15%) had positive results of four SARS-CoV-2 nucleic acid tests and were transferred to another hospital and lost to follow-up. Among the 11 children who were followed up, 1 had positive results of two SARS-CoV-2 nucleic acid tests at the isolation point, and 10 had negative results. The mean hospital stay was 10.9 days for the 13 children. Eleven children recovered during follow-up, with good living and learning conditions.

Conclusions: Children with mild COVID-19 often have an uncertain history of exposure and may not have any clinical symptoms. Etiological diagnosis is more important than clinical diagnosis. The disappearance of clinical manifestations may not parallel with the result of SARS-CoV-2 nucleic acid test. SARS-CoV-2 has a long detoxification time, and there may be recurrent cases of SARS-CoV-2 positivity. Further studies are needed to investigate the production patterns of SARS-CoV-2 IgM and IgG and their effect on the body.
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May 2021

PINK1 contained in huMSC-derived exosomes prevents cardiomyocyte mitochondrial calcium overload in sepsis via recovery of mitochondrial Ca efflux.

Stem Cell Res Ther 2021 05 6;12(1):269. Epub 2021 May 6.

Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China.

Background: Sepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death. Previous studies have shown that 40-50% of patients with sepsis have diverse myocardial injuries and 70 to 90% mortality rates compared to 20% mortality in patients with sepsis without myocardial injury. Therefore, uncovering the mechanism of sepsis-induced myocardial injury and finding a target-based treatment are immensely important.

Objective: The present study elucidated the mechanism of sepsis-induced myocardial injury and examined the value of human umbilical cord mesenchymal stem cells (huMSCs) for protecting cardiac function in sepsis.

Methods: We used cecal ligation and puncture (CLP) to induce sepsis in mice and detect myocardial injury and cardiac function using serological markers and echocardiography. Cardiomyocyte apoptosis and heart tissue ultrastructure were detected using TdT-mediated dUTP Nick-End Labeling (TUNEL) and transmission electron microscopy (TEM), respectively. Fura-2 AM was used to monitor Ca uptake and efflux in mitochondria. FQ-PCR and Western blotting detected expression of mitochondrial Ca distribution regulators and PTEN-induced putative kinase 1 (PINK1). JC-1 was used to detect the mitochondrial membrane potential (Δψm) of cardiomyocytes.

Results: We found that expression of PINK1 decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial Ca efflux disorder, mitochondrial calcium overload, and cardiomyocyte injury. In contrast, we found that exosomes isolated from huMSCs (huMSC-exo) carried Pink1 mRNA, which could be transferred to recipient cardiomyocytes to increase PINK1 expression. The reduction in cardiomyocyte mitochondrial calcium efflux was reversed, and cardiomyocytes recovered from injury. We confirmed the effect of the PINK1-PKA-NCLX axis on mitochondrial calcium homeostasis in cardiomyocytes during sepsis.

Conclusion: The PINK1-PKA-NCLX axis plays an important role in mitochondrial calcium efflux in cardiomyocytes. Therefore, PINK1 may be a therapeutic target to protect cardiomyocyte mitochondria, and the application of huMSC-exo is a promising strategy against sepsis-induced heart dysfunction.
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http://dx.doi.org/10.1186/s13287-021-02325-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101124PMC
May 2021

Cyclin D2 Overexpression Enhances the Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Myocardial Repair in a Swine Model of Myocardial Infarction.

Circulation 2021 Jul 6;144(3):210-228. Epub 2021 May 6.

Department of Biomedical Engineering (M.Z., Y.N., Y.W., W.B., A.V.B., Y.Z., G.P.W., J.Z.), the University of Alabama at Birmingham.

Background: Human induced pluripotent stem cells with normal (wild-type) or upregulated (overexpressed) levels of CCND2 (cyclin D2) expression were differentiated into cardiomyocytes (CCND2CMs or CCND2CMs, respectively) and injected into infarcted pig hearts.

Methods: Acute myocardial infarction was induced by a 60-minute occlusion of the left anterior descending coronary artery. Immediately after reperfusion, CCND2CMs or CCND2CMs (3×10 cells each) or an equivalent volume of the delivery vehicle was injected around the infarct border zone area.

Results: The number of the engrafted CCND2CMs exceeded that of the engrafted CCND2CMs from 6- to 8-fold, rising from 1 week to 4 weeks after implantation. In contrast to the treatment with the CCND2CMs or the delivery vehicle, the administration of CCND2CM was associated with significantly improved left ventricular function, as revealed by magnetic resonance imaging. This correlated with reduction of infarct size, fibrosis, ventricular hypertrophy, and cardiomyocyte apoptosis, and increase of vascular density and arterial density, as per histologic analysis of the treated hearts. Expression of cell proliferation markers (eg, Ki67, phosphorylated histone 3, and Aurora B kinase) was also significantly upregulated in the recipient cardiomyocytes from the CCND2CM-treated than from the CCND2CM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured human induced pluripotent stem cell cardiomyocytes were significantly greater after treatment with exosomes isolated from the CCND2CMs (CCND2Exos) than from the CCND2CMs (CCND2Exos). As demonstrated by our study, CCND2Exos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2Exos versus CCND2Exos identified 206 and 91 miRNAs that were significantly upregulated and downregulated, respectively. Gene ontology enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis.

Conclusions: We demonstrated that enhanced potency of CCND2CMs promoted myocyte proliferation in both grafts and recipient tissue in a large mammal acute myocardial infarction model. These results suggest that CCND2CMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292228PMC
July 2021

A Three-Dimensional Conductive Scaffold Microchip for Effective Capture and Recovery of Circulating Tumor Cells with High Purity.

Anal Chem 2021 05 28;93(18):7102-7109. Epub 2021 Apr 28.

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China.

Effective acquirement of highly pure circulating tumor cells (CTCs) is very important for CTC-related research. However, it is a great challenge since abundant white blood cells (WBCs) are always co-collected with CTCs because of nonspecific bonding or low depletion rate of WBCs in various CTC isolation platforms. Herein, we designed a three-dimensional (3D) conductive scaffold microchip for highly effective capture and electrochemical release of CTCs with high purity. The conductive 3D scaffold was prepared by dense immobilization of gold nanotubes (Au NTs) on porous polydimethylsiloxane and was functionalized with a CTC-specific biomolecule facilitated by a Au-S bond before embedding into a microfluidic device. The spatially distributed 3D macroporous structure compelled cells to change migration from linear to chaotic and the densely covered Au NTs enhanced the topographic interaction between cells and the substrate, thus synergistically improving the CTC capture efficiency. The Au NT-coated 3D scaffold had good electrical conductivity and the Au-S bond was breakable by voltage exposure so that captured CTCs could be specifically released by electrochemical stimulation while nonspecifically bonded WBCs were not responsive to this process, facilitating recovery of CTCs with high purity. The 3D conductive scaffold microchip was successfully applied to obtain highly pure CTCs from cancer patients' blood, benefiting the downstream analysis of CTCs.
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http://dx.doi.org/10.1021/acs.analchem.1c00785DOI Listing
May 2021

Aneuploid abortion correlates positively with MAD1 overexpression and miR-125b down-regulation.

Mol Cytogenet 2021 Apr 26;14(1):22. Epub 2021 Apr 26.

Central Laboratory of Birth Defects Prevention and Control, Ningbo Women & Children's Hospital, Ningbo, 315000, Zhejiang, China.

Background: Aneuploidy is the most frequent cause of early-embryo abortion. Any defect in chromosome segregation would fail to satisfy the spindle assembly checkpoint (SAC) during mitosis, halting metaphase and causing aneuploidy. The mitotic checkpoint complex (MCC), comprising MAD1, MAD2, Cdc20, BUBR1 and BUB3, plays a vital role in SAC activation. Studies have confirmed that overexpression of MAD2 and BUBR1 can facilitate correct chromosome segregation and embryo stability. Research also proves that miR-125b negatively regulates MAD1 expression by binding to its 3'UTR. However, miR-125b, Mad1 and Bub3 gene expression in aneuploid embryos of spontaneous abortion has not been reported to date.

Methods: In this study, embryonic villi from miscarried pregnancies were collected and divided into two groups (aneuploidy and euploidy) based on High-throughput ligation-dependent probe amplification (HLPA) and Fluorescence in situ hybridization (FISH) analyses. RNA levels of miR-125b, MAD1 and BUB3 were detected by Quantitative real-time PCR (qRT-PCR); protein levels of MAD1 and BUB3 were analysed by Western blotting.

Results: statistical analysis (p < 0.05) showed that miR-125b and BUB3 were significantly down-regulated in the aneuploidy group compared to the control group and that MAD1 was significantly up-regulated. Additionally, the MAD1 protein level was significantly higher in aneuploidy abortion villus, but BUB3 protein was only mildly increased. Correlation analysis revealed that expression of MAD1 correlated negatively with miR-125b.

Conclusion: These results suggest that aneuploid abortion correlates positively with MAD1 overexpression, which might be caused by insufficient levels of miR-125b. Taken together, our findings first confirmed the negative regulatory mode between MAD1 and miR-125b, providing a basis for further mechanism researches in aneuploid abortion.
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http://dx.doi.org/10.1186/s13039-021-00538-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074413PMC
April 2021

Small Airway Dysfunction in Asthma Is Associated with Perceived Respiratory Symptoms, Non-Type 2 Airway Inflammation, and Poor Responses to Therapy.

Respiration 2021;100(8):767-779. Epub 2021 Apr 23.

School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Background: Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma.

Objectives: The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF25-75%), with clinical and inflammatory profile and treatment responsiveness in asthma.

Method: In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness.

Results: SAD subjects had more elevated ΔVAS for dyspnea (p = 0.027) and chest tightness (p = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum (p < 0.05), and Spearman partial correlation found FEF25-75% significantly related to IFN-γ and interleukin-8 (both having p < 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) (p = 0.022 and p = 0.032).

Conclusions: This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.
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http://dx.doi.org/10.1159/000515328DOI Listing
April 2021

Branched chain amino acids selectively promote cardiac growth at the end of the awake period.

J Mol Cell Cardiol 2021 08 21;157:31-44. Epub 2021 Apr 21.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Essentially all biological processes fluctuate over the course of the day, manifesting as time-of-day-dependent variations with regards to the way in which organ systems respond to normal behaviors. For example, basic, translational, and epidemiologic studies indicate that temporal partitioning of metabolic processes governs the fate of dietary nutrients, in a manner in which concentrating caloric intake towards the end of the day is detrimental to both cardiometabolic and cardiovascular parameters. Despite appreciation that branched chain amino acids impact risk for obesity, diabetes mellitus, and heart failure, it is currently unknown whether the time-of-day at which dietary BCAAs are consumed influence cardiometabolic/cardiovascular outcomes. Here, we report that feeding mice a BCAA-enriched meal at the end of the active period (i.e., last 4 h of the dark phase) rapidly increases cardiac protein synthesis and mass, as well as cardiomyocyte size; consumption of the same meal at the beginning of the active period (i.e., first 4 h of the dark phase) is without effect. This was associated with a greater BCAA-induced activation of mTOR signaling in the heart at the end of the active period; pharmacological inhibition of mTOR (through rapamycin) blocked BCAA-induced augmentation of cardiac mass and cardiomyocyte size. Moreover, genetic disruption of the cardiomyocyte circadian clock abolished time-of-day-dependent fluctuations in BCAA-responsiveness. Finally, we report that repetitive consumption of BCAA-enriched meals at the end of the active period accelerated adverse cardiac remodeling and contractile dysfunction in mice subjected to transverse aortic constriction. Thus, our data demonstrate that the timing of BCAA consumption has significant implications for cardiac health and disease.
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http://dx.doi.org/10.1016/j.yjmcc.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319101PMC
August 2021

Proton Transfer in Nitromethane-Ammonia Clusters under VUV Single-Photon Ionization Explored by Infrared Spectroscopy and Theoretical Calculations.

J Phys Chem A 2021 Apr 20;125(16):3279-3287. Epub 2021 Apr 20.

MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China.

It is known that the acidity and reactivity of the CH bond can be enhanced after ionization. Also, this property plays a pivotal role in proton transfer reaction and in the formation of new molecules. Herein, infrared spectroscopy and high-precision quantum chemical calculations are used to study the neutral and cationic clusters of nitromethane-ammonia (CHNO-NH). It is found that in the neutral cluster, CHNO and NH are mainly bonded by three intermolecular hydrogen bonds, in which electrostatic contribution plays a major role. After vacuum ultraviolet (VUV) single-photon ionization of CHNO-NH, the positive charge redistributes from the ionized nitrogen atom of NH to the CHNO molecule immediately. Then, the proton of CHNO transfers to NH to form a proton-transferred type structure CHNO-NH, without any effective energy barrier, due to the positive hyperconjugation of cationic nitromethane. A closed loop of positive charge transfer takes place in the CHNO-NH cluster after VUV ionization. The present work demonstrates that both the proton transfer reaction and charge transfer process have occurred in the ionized CHNO-NH cluster. Moreover, it is found that the proton transfer reaction is a result of the highly acidic CH bond caused by hyperconjugation between the σ (CH) bond and π orbital.
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http://dx.doi.org/10.1021/acs.jpca.1c00255DOI Listing
April 2021
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