Publications by authors named "Tao Zhang"

5,572 Publications

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DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice.

Brain Res Bull 2022 Jun 29. Epub 2022 Jun 29.

College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071 Tianjin, PR China. Electronic address:

Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.
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http://dx.doi.org/10.1016/j.brainresbull.2022.06.016DOI Listing
June 2022

The Methylation Inhibitor 5-Aza-2'-Deoxycytidine Induces Genome-Wide Hypomethylation in Rice.

Rice (N Y) 2022 Jul 2;15(1):35. Epub 2022 Jul 2.

Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding/Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou, 225009, China.

DNA methylation is a conserved epigenetic modification which is vital for regulating gene expression and maintaining genome stability in both mammals and plants. Homozygous mutation of rice methyltransferase 1 (met1) gene can cause host death in rice, making it difficult to obtain plant material needed for hypomethylation research. To circumvent this challenge, the methylation inhibitor, 5-Aza-2'-deoxycytidine (AzaD), is used as a cytosine nucleoside analogue to reduce genome wide hypomethylation and is widely used in hypomethylation research. However, how AzaD affects plant methylation profiles at the genome scale is largely unknown. Here, we treated rice seedlings with AzaD and compared the AzaD treatment with osmet1-2 mutants, illustrating that there are similar CG hypomethylation and distribution throughout the whole genome. Along with global methylation loss class I transposable elements (TEs) which are farther from genes compared with class II TEs, were more significantly activated, and the RNA-directed DNA Methylation (RdDM) pathway was activated in specific genomic regions to compensate for severe CG loss. Overall, our results suggest that AzaD is an effective DNA methylation inhibitor that can influence genome wide methylation and cause a series of epigenetic variations.
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http://dx.doi.org/10.1186/s12284-022-00580-6DOI Listing
July 2022

Benzo[a]pyrene exposure promotes RIP1-mediated necroptotic death of osteocytes and the JNK/IL-18 pathway activation via generation of reactive oxygen species.

Toxicology 2022 Jun 28:153244. Epub 2022 Jun 28.

College of Medicine, Shaoxing University, Huancheng West Road 508, Shaoxing 312000, P.R. China. Electronic address:

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) of environmental pollutants, readily produced during the processing of petroleum and fatty foods. BaP exposure can cause skeletal deformities. However, whether BaP affects osteocytes, making up over 95% of all the bone cells, remains unknown. This study aimed to investigate the effect of BaP on osteocytes in vivo and in vitro, as well as explore the underlying mechanisms. The in vivo data showed that BaP (50mg/kg) exposure for 12 weeks could cause bone destruction, and increase osteocytes death in mouse cortical femur. Our in vitro results revealed that BaP (25-100 μmol/L) exposure inhibited cell viability of MLO-Y4 cells, and resulted in cell death in a dose-dependent manner. Furthermore, BaP exposure significantly triggered necroptosis of MLO-Y4 cells, as indicated by increased propidium iodide (PI)-positive cells and up-regulation of necroptosis-related protein expressions of receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). This necrotic effect was reversed by the RIP1 inhibitor necrostatin-1 (Nec-1). Simultaneously, BaP activated the downstream c-Jun N-terminal kinase (JNK)/ interleukin (IL)-18 signaling pathway, which was suppressed after the JNK inhibitor SP600125 or Nec-1 treatment. In addition, BaP exposure promoted the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), and elevated malondialdehyde (MDA) levels; while BaP decreased superoxide dismutase (SOD) activity and antioxidant enzymes including nuclear factor E-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, leading to oxidative damage. The ROS scavenger N-acetylcysteine (NAC) inhibited this necroptotic death and the JNK/IL-18 pathway activation. Collectively, BaP exposure may cause RIP1-mediated necroptotic death of osteocytes and activate the JNK/IL-18 pathway via ROS generation.
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http://dx.doi.org/10.1016/j.tox.2022.153244DOI Listing
June 2022

Adverse childhood experiences in offspring living with parental mental illness: a controlled study from China.

J Ment Health 2022 Jul 1:1-10. Epub 2022 Jul 1.

Peking University Sixth Hospital, Peking University Institute of Mental Health, National Clinical Research Center for Mental Disorders, Beijing, PR China.

Background: Adverse childhood experiences (ACEs) affect children's development, and their harm to health is pervasive throughout the life course.

Aims: To identify ACEs and their risk factors in Chinese household with or without parental mental illness.

Methods: A controlled study was conducted among 181 young adults with parental mental illness (positive group) and 201 demographically matched individuals without parental mental illness (negative group). Univariate and multivariate analyses were performed to study the correlation between ACEs and their risk factors.

Results: The positive group suffered emotional abuse, domestic violence, bullying, and cumulative ACEs more frequently than the negative group. In the positive group, living in rural areas and having a low household economic status during childhood were identified as risk factors for cumulative ACEs, whereas a higher education level of the mother was a protective factor for cumulative ACEs in univariate analyses. Low household economic status remained an independent risk factor for cumulative ACEs in the positive group in multivariate analyses.

Conclusions: Children living with parental mental illness are more vulnerable to ACEs, and our findings highlight the importance of socioeconomic factors in increasing the risk of ACEs. To alleviate the deleterious impact of parental mental illness on offspring, multidimensional supports are needed.
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http://dx.doi.org/10.1080/09638237.2022.2091765DOI Listing
July 2022

Transcriptome analysis of the ink sac and brain tissues from Sepiella inermis: A resource for discovering genes related to the inking of cephalopods.

Mar Genomics 2022 Jun 27;64:100968. Epub 2022 Jun 27.

Key Laboratory of Environment Change and Resources Use in Beibu Gulf, Ministry of Education, Nanning Normal University, Nanning 530001, China. Electronic address:

The common Chinese cuttlefish (Sepiella inermis) is an important cephalopod with nutritional and commercial value. Intensive inking stimulated by swilling seawater in transfer containers threatens the survival of cephalopods during transportation. However, the molecular basis for the inking behavior of S. inermis remains unclear. In the present study, transcriptome analysis was performed on ink sac and brain tissues from S. inermis under two different conditions, i.e. the control group (with individuals immersed in static seawater) and the experimental group (with individuals immersed in swilling seawater) to determine the global gene expression differences. The individuals from the experimental group ejected ink in response to the swilling of seawater. 330,699 unigenes were obtained from twelve transcriptome libraries via the Illumina Hiseq X platform, and the differentially expressed genes in the ink sac and brain tissues were identified respectively. Multiple upregulated genes in the ink sac were involved in cation transporter activity. Besides, an autocrine/paracrine factor wnt10b like and two important transcription factors (homeobox 1 and Hes-1-b-like) were also significantly upregulated in the ink sac. Moreover, a neuronal nitric oxide synthase (nNOS) was significantly downregulated in the brain. The findings from this study provide an important transcriptomic resource for discovering critical genes related to inking behavior of S. inermis, providing a basis for developing potential methods for protecting S. inermis from intensive inking.
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http://dx.doi.org/10.1016/j.margen.2022.100968DOI Listing
June 2022

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Front Pharmacol 2022 13;13:919652. Epub 2022 Jun 13.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor () mutations; however, clinical evidence of its activity on major uncommon mutations is currently limited. This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1-2 months. Adverse events were assessed by CTCAE 5.0. In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X ( = 24; 75%), followed by L861X ( = 10; 31.3%), and S768I ( = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1-14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1-2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon mutations.
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http://dx.doi.org/10.3389/fphar.2022.919652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234690PMC
June 2022

A 30,000-km journey by Apus apus pekinensis tracks arid lands between northern China and south-western Africa.

Mov Ecol 2022 Jun 29;10(1):29. Epub 2022 Jun 29.

State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China.

Background: As a widely distributed and aerial migratory bird, the Common Swift (Apus apus) flies over a wide geographic range in Eurasia and Africa during migration. Although some studies have revealed the migration routes and phenology of European populations, A. a. apus (from hereon the nominate apus), the route used by its East Asian counterpart A. a. pekinensis (from hereon pekinensis) remained a mystery.

Methods: Using light level geolocators, we studied the migration of adult pekinensis breeding in Beijing from 2014 to 2018, and analysed full annual tracks obtained from 25 individuals. In addition, we used the mean monthly precipitation to assess the seasonal variations in humidity for the distribution ranges of the nominate apus and pekinensis. This environmental variable is considered to be critically relevant to their migratory phenology and food resource abundance.

Results: Our results show that the swifts perform a round-trip journey of ca 30,000 km each year, representing a detour of 26% in autumn and 15% in spring compared to the shortest route between the breeding site in Beijing and wintering areas in semi-arid south-western Africa. Compared to the nominate apus, pekinensis experiences drier conditions for longer periods of time. Remarkably, individuals from our study population tracked arid habitat along the entire migration corridor leading from a breeding site in Beijing to at least central Africa. In Africa, they explored more arid habitats during non-breeding than the nominate apus.

Conclusions: The migration route followed by pekinensis breeding in Beijing might suggest an adaptation to semi-arid habitat and dry climatic zones during non-breeding periods, and provides a piece of correlative evidence indicating the historical range expansion of the subspecies. This study highlights that the Common Swift may prove invaluable as a model species for studies of migration route formation and population divergence.
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http://dx.doi.org/10.1186/s40462-022-00329-2DOI Listing
June 2022

Natural killer cell homing and trafficking in tissues and tumors: from biology to application.

Signal Transduct Target Ther 2022 Jun 29;7(1):205. Epub 2022 Jun 29.

Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China.

Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its "off-the-shelf" potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.
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http://dx.doi.org/10.1038/s41392-022-01058-zDOI Listing
June 2022

Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial.

Clin Cancer Res 2022 Jun 29:OF1-OF9. Epub 2022 Jun 29.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Experimental Design: In this single-center, single-arm, phase 2 trial, patients with resectable stage III-IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety.

Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%-57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%-88.9%). The median follow-up duration was 16.1 months (range, 8.3-28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%-99.4%). Grade 3 neoadjuvant therapy-related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%).

Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0666DOI Listing
June 2022

Potential-Driven Restructuring of Cu Single Atoms to Nanoparticles for Boosting the Electrochemical Reduction of Nitrate to Ammonia.

J Am Chem Soc 2022 Jun 29. Epub 2022 Jun 29.

Collaborative Innovation Center of Chemistry for Energy Materials (iChEM), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

Restructuring is ubiquitous in thermocatalysis and of pivotal importance to identify the real active site, yet it is less explored in electrocatalysis. Herein, by using X-ray absorption spectroscopy in conjunction with advanced electron microscopy, we reveal the restructuring of the as-synthesized Cu-N single-atom site to the nanoparticles of ∼5 nm during the electrochemical reduction of nitrate to ammonia, a green ammonia production route upon combined with the plasma-assisted oxidation of nitrogen. The reduction of Cu to Cu and Cu and the subsequent aggregation of Cu single atoms is found to occur concurrently with the enhancement of the NH production rate, both of them are driven by the applied potential switching from 0.00 to -1.00 V versus RHE. The maximum production rate of ammonia reaches 4.5 mg cm h (12.5 mol g h) with a Faradaic efficiency of 84.7% at -1.00 V versus RHE, outperforming most of the other Cu catalysts reported previously. After electrolysis, the aggregated Cu nanoparticles are reversibly disintegrated into single atoms and then restored to the Cu-N structure upon being exposed to an ambient atmosphere, which masks the potential-induced restructuring during the reaction. The synchronous changes of the Cu percentage and the ammonia Faradaic efficiency with the applied potential suggests that the Cu nanoparticles are the genuine active sites for nitrate reduction to ammonia, which is corroborated with both the post-deposited Cu NP catalyst and density functional theory calculations.
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http://dx.doi.org/10.1021/jacs.2c02262DOI Listing
June 2022

Endometrial thickness is an independent risk factor of hypertensive disorders of pregnancy: a retrospective study of 13,458 patients in frozen-thawed embryo transfers.

Reprod Biol Endocrinol 2022 Jun 28;20(1):93. Epub 2022 Jun 28.

Center for Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.

Background: Hypertensive disorders of pregnancy (HDP) are an important cause of maternal and fetal mortality, and its potential risk factors are still being explored. Endometrial thickness (EMT), as one of the important monitoring indicators of endometrial receptivity, has been confirmed to be related to the incidence of HDP in fresh embryo transfer. Our study was designed to investigate whether endometrial thickness is associated with the risk of hypertensive disorders of pregnancy in frozen-thawed embryo transfer (FET).

Methods: This respective cohort study enrolled 13,458 women who received vitrified embryo transfer and had a singleton delivery in the Reproductive Hospital affiliated to Shandong University from January 2015 to December 2019. We set strict screening criteria and obtained the information from the hospital electronic medical system. Statistical methods including logistic regression analysis, receiver operating characteristic curve and restricted cubic spline were used to evaluate the relationship between endometrial thickness and the incidence of pregnancy-induced hypertension.

Results: The incidences of HDP in a thin endometrial thickness group (< 0.8 cm) and a thick endometrial thickness group (> 1.2 cm) were significantly greater than in a reference group (0.8 cm-1.2 cm) (7.98 and 5.24% vs 4.59%, P <  0.001). A nonlinear relationship between endometrial thickness and risk of hypertensive disorders of pregnancy was examined by restricted cubic spline (P <  0.001). The thin endometrial thickness and thick endometrial thickness groups were significantly associated with the risk of HDP after adjusting for confounding variables by stepwise logistic regression analysis. Subsequently, subgroup logistic regression analysis based on endometrial preparation regimens showed that thin endometria were still significantly associated with a higher morbidity rate in the artificial cycle group, while in the natural cycle group, thick endometria were closely associated with increased morbidity.

Conclusion: Our study manifested that both the thin and thick endometria were associated with an increased risk of hypertensive disorders of pregnancy in frozen embryo transfer cycles. Reproductive clinicians should focus on adjusting endometrial thickness in different preparation regimens; and obstetricians should be mindful of the risk of hypertension during pregnancy, when women with thin (< 0.8 cm) or excessively thicker (> 1.2 cm) endometrial thickness achieve pregnancy through frozen-thawed embryo transfer.
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http://dx.doi.org/10.1186/s12958-022-00965-8DOI Listing
June 2022

Single-cell transcriptional profiling reveals cellular and molecular divergence in human maternal-fetal interface.

Sci Rep 2022 Jun 28;12(1):10892. Epub 2022 Jun 28.

BGI-Shenzhen, Shenzhen, 518083, China.

Placenta plays essential role in successful pregnancy, as the most important organ connecting and interplaying between mother and fetus. However, the cellular characteristics and molecular interaction of cell populations within the fetomaternal interface is still poorly understood. Here, we surveyed the single-cell transcriptomic landscape of human full-term placenta and revealed the heterogeneity of cytotrophoblast cell (CTB) and stromal cell (STR) with the fetal/maternal origin consecutively localized from fetal section (FS), middle section (Mid_S) to maternal section (Mat_S) of maternal-fetal interface. Then, we highlighted a subpopulation of CTB, named trophoblast progenitor-like cells (TPLCs) existed in the full-term placenta and mainly distributed in Mid_S, with high expression of a pool of putative cell surface markers. Further, we revealed the putative key transcription factor PRDM6 that might promote the differentiation of endovascular extravillous trophoblast cells (enEVT) by inhibiting cell proliferation, and down-regulation of PRDM6 might lead to an abnormal enEVT differentiation process in PE. Together, our study offers important resources for better understanding of human placenta and stem cell-based therapy, and provides new insights on the study of tissue heterogeneity, the clinical prevention and control of PE as well as the maternal-fetal interface.
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http://dx.doi.org/10.1038/s41598-022-14516-zDOI Listing
June 2022

[Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia].

Zhen Ci Yan Jiu 2022 Jun;47(6):517-24

Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Objective: To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD.

Methods: A total of 48 young SD rats were randomly divided into control (=10), model (=9), taVNS (=9), subdiaphragmatic vagus nerve stimulation (SDVNS, =9) and sham SDVNS (=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot.

Results: In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1β and TNF-α were significantly increased (<0.05,<0.01, <0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (<0.05, <0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (<0.05, <0.01, <0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (<0.05, <0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (<0.01, <0.05,<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (<0.01, <0.001) in the both SDVNS and taVNS groups.

Conclusion: taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.
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http://dx.doi.org/10.13702/j.1000-0607.20220111DOI Listing
June 2022

Design, synthesis and biological evaluation of biphenyl-benzamides as potent FtsZ inhibitors.

Eur J Med Chem 2022 Jun 21;239:114553. Epub 2022 Jun 21.

Bioland Laboratory (Guangzhou Regenerative Medicine and Health - Guangdong Laboratory),Guangzhou, 510530, PR China. Electronic address:

The rapid emergence of antibiotic resistance has become a prevalent threat to public health, thereby development of new antibacterial agents having novel mechanisms of action is in an urgent need. Targeting at the cytoskeletal cell division protein filamenting temperature-sensitive mutant Z (FtsZ) has been validated as an effective and promising approach for antibacterial drug discovery. In this study, a series of novel biphenyl-benzamides as FtsZ inhibitors has been rationally designed, synthesized and evaluated for their antibacterial activities against various Gram-positive bacteria strains. In particular, the most promising compound 30 exhibited excellent antibacterial activities, especially against four different Bacillus subtilis strains, with an MIC range of 0.008 μg/mL to 0.063 μg/mL. Moreover, compound 30 also showed good pharmaceutical properties with low cytotoxicity (CC > 20 μg/mL), excellent human metabolic stability (T = 111.98 min), moderate pharmacokinetics (T = 2.26 h, F = 61.2%) and in vivo efficacy, which can be identified as a promising FtsZ inhibitor worthy of further profiling.
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http://dx.doi.org/10.1016/j.ejmech.2022.114553DOI Listing
June 2022

Characterization of a recombinant arginine deiminase from Halothermothrix orenii and its application in citrulline production.

Biotechnol Appl Biochem 2022 Jun 27. Epub 2022 Jun 27.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.

In recent years, arginine deiminase (ADI, EC 3.5.3.6) has attracted much attention as a biocatalyst that produces the functional amino acid l-citrulline from l-arginine and also as an anticancer enzyme. Here, we identified and characterized a putative ADI from the thermophilic bacterium Halothermothrix orenii. The H. orenii ADI (H-ADI) protein was expressed in Escherichia coli BL21(DE3) with a specific activity of 91.8 U/mg protein at 55°C and pH 6.5. The enzyme remained at 74% relative activity after incubation at 45°C for 180 min, only 25% at 50°C. The melting temperature was 56°C. H-ADI is not a metal-requiring enzyme; Ni slightly improved the catalytic activity. The K and V for l-arginine were 55.5 mM and 156.8 μmol/min/mg protein, respectively. Moreover, three residues (Arg183, Arg237, and His273) were key to the formation of l-citrulline, as analyzed by alanine-scanning mutagenesis. Finally, the enzymatic synthesis of l-citrulline was carried out at 50°C with a conversion ratio reaching 99.03%. Together, these findings show that H-ADI is a promising biocatalyst for the production of l-citrulline.
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http://dx.doi.org/10.1002/bab.2375DOI Listing
June 2022

Factors affecting the completion of concurrent chemotherapy and impact of non-completion on survival in locally advanced esophageal squamous cell carcinoma.

Esophagus 2022 Jun 27. Epub 2022 Jun 27.

Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100021, People's Republic of China.

Background: To investigate whether completion of concurrent chemotherapy (CCT) improves overall survival (OS) of patients with locally advanced esophageal squamous cell carcinoma (ESCC), and to identify predictors of non-completion of CCT.

Methods: Data of ESCC patients treated with definitive concurrent chemoradiotherapy from January 2012 to December 2017 were retrospectively analyzed. CCT completion was defined as receiving recommended cycles with at most 25% dose reduction. Propensity score matching (PSM) analysis was applied to adjust unbalanced covariates between groups. Multivariate logistic regression model was used to identify factors affecting CCT completion.

Results: Of the 487 patients in the study, 194 patients (39.8%) had completed CCT. The majority (90.7%) had stage III-IV disease. Three-year OS rate was significantly higher in the completion group than non-completion group (35.4% vs. 30.3%; p = 0.025). Multivariate Cox analysis showed CCT completion was independently associated with longer OS (p = 0.005). The independent risk factors for CCT non-completion were weekly CCT regimen [odds ratio (OR) = 4.35, 95% CI 2.26-8.37; p < 0.001], clinical target volume (CTV)-elective nodal irradiation (ENI) (OR = 3.86, 95% CI 2.41-6.18; p < 0.001), planning target volume (PTV)/50 cm (OR = 1.09, 95% CI 1.02-1.16; p = 0.017), age (OR = 1.04, 95% CI 1.01-1.07, p = 0.011), and tumor in middle/lower esophagus (OR = 1.59, 95% CI 1.05-2.43, p = 0.030).

Conclusion: CCT completion can provide superior OS for ESCC patients treated with definitive CCRT. Weekly CCT regimen, CTV-ENI, PTV, older age, and tumor location are independent predictors of non-completion of CCT.
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http://dx.doi.org/10.1007/s10388-022-00930-9DOI Listing
June 2022

microRNA-146a mediates distraction osteogenesis via bone mesenchymal stem cell inflammatory response.

Acta Histochem 2022 Jun 24;124(6):151913. Epub 2022 Jun 24.

Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China. Electronic address:

Distraction osteogenesis (DO) is a widely used surgical technique to repair bone defects, partly owing to its high efficiency in inducing osteogenesis; however, the process of osteogenesis is complex, and the precise mechanism is still unclear. Among the factors identified for an effective DO procedure, well-controlled inflammation is essential. We aimed to explore how microRNA(miR)-146a, a negative regulator of inflammation, influences osteogenesis in DO. First, we established canine right mandibular DO and bone fracture models to evaluate the expression level of miR-146a in response to these procedures. Second, bone marrow mesenchymal stem cells (BMSCs) were isolated from healthy puppies and cultured with lipopolysaccharide (LPS) to observe how inflammation affects osteogenesis. Finally, the osteogenesis activity of BMSCs transfected with lentiviral vector either overexpressing (miR-146a-up) or inhibited for miR-146a expression was evaluated. miR-146a-up-transfected BMSCs were injected locally into the distraction gaps of the DO model canines. On days 42 and 56 post-surgery, the bone volume/tissue volume and bone mineral density values were evaluated via using micro-computed tomography, and newly formed tissues were harvested and evaluated via histological staining. The expression of miR-146a in both the DO canine model and LPS-stimulated BMSCs increased. Overexpression of miR-146a enhanced cell proliferation, migration, and osteogenic differentiation. Additionally, the newly formed callus was improved in canine mandibles injected with miR-146a-up-transfected BMSCs. In summary, miR-146a regulates mandibular DO by improving osteogenesis, and can serve as a potential target to shorten the therapy period of DO.
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http://dx.doi.org/10.1016/j.acthis.2022.151913DOI Listing
June 2022

Convergent and Divergent Age Patterning of Gut Microbiota Diversity in Humans and Nonhuman Primates.

mSystems 2022 Jun 27:e0151221. Epub 2022 Jun 27.

State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan Universitygrid.440773.3, Kunming, Yunnan, China.

The gut microbiome has significant effects on healthy aging and aging-related diseases, whether in humans or nonhuman primates. However, little is known about the divergence and convergence of gut microbial diversity between humans and nonhuman primates during aging, which limits their applicability for studying the gut microbiome's role in human health and aging. Here, we performed 16S rRNA gene sequencing analysis for captive rhesus macaques (Macaca mulatta) and compared this data set with other freely available gut microbial data sets containing four human populations (Chinese, Japanese, Italian, and British) and two nonhuman primates (wild lemurs [Lemur catta] and wild chimpanzees [Pan troglodytes]). Based on the consistent V4 region of the 16S rRNA gene, beta diversity analysis suggested significantly separated gut microbial communities associated with host backgrounds of seven host groups, but within each group, significant gut microbial divergences were observed, and indicator bacterial genera were identified as associated with aging. We further discovered six common anti-inflammatory gut bacteria (, , , , and ) that had butyrate-producing potentials suggested by pangenomic analysis and that showed similar dynamic changes in at least two selected host groups during aging, independent of distinct host backgrounds. Finally, we found striking age-related changes in 66 plasma metabolites in macaques. Two highly changed metabolites, hydroxyproline and leucine, enriched in adult macaques were significantly and positively correlated with and . Furthermore, genus-level pangenome analysis suggested that those six common indicator bacteria can synthesize leucine and arginine as hydroxyproline and proline precursors in both humans and macaques. This study provides the first comprehensive investigation of age patterning of gut microbiota of four human populations and three nonhuman primates and found that , , , , , and may be common antiaging microbial markers in both humans and nonhuman primates due to their potential metabolic capabilities for host health benefits. Our results also provide key support for using macaques as animal models in studies of the gut microbiome's role during human aging.
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http://dx.doi.org/10.1128/msystems.01512-21DOI Listing
June 2022

Laser Navigation Combined With XperCT Technology Assisted Puncture of Brainstem Hemorrhage.

Front Neurol 2022 9;13:905477. Epub 2022 Jun 9.

Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.

Background: Brainstem hemorrhage has a rapid onset with high mortality and disability rates. In recent years, an increasing number of studies have reported on the surgical treatment of brainstem hemorrhage. The introduction of stereotaxic instruments and navigation systems has improved the accuracy of surgical treatment; however, the popularity of these devices in the primary hospitals is not high. In this study, we introduce laser navigation combined with the XperCT technology to assist in the puncture and drainage of brainstem hemorrhage, aiming to improve surgical accuracy and facilitate the drainage of brainstem hemorrhage in primary hospitals.

Material And Methods: A total of five patients (four men and one woman), aged 34-70 years, who underwent hematoma puncture drainage with the assistance of laser navigation combined with XperCT technology at the Binzhou Medical University Hospital, China, between June 2020 and Aug 2021 were included in the study. The brainstem hemorrhages had volumes of 7-18 ml. Statistical analyses of the postoperative puncture deviation distance (distance between the actual puncture end and simulated puncture end) and postoperative improvement were also performed.

Results: The operations were successfully completed in all five patients. The puncture deviation distance was <6 mm in all five patients and <2 mm in two patients. The postoperative hematoma clearance rate was about 70%-90%. Among four patients with respiratory failure, three had improved breathing and resumed spontaneous breathing. Out of three patients with high fever, one showed a substantial decrease in body temperature. There were no cases of postoperative infection. Of the five patients, two recovered consciousness, one died, and two voluntarily gave up further treatment and were discharged.

Conclusions: Laser navigation combined with the XperCT technology could improve the accuracy of surgical puncture. The technique might be convenient for widespread clinical application because of its low trauma, high precision, short operation time, and low operation cost.
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http://dx.doi.org/10.3389/fneur.2022.905477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218265PMC
June 2022

Intelligent Traffic Flow Prediction and Analysis Based on Internet of Things and Big Data.

Comput Intell Neurosci 2022 15;2022:6420799. Epub 2022 Jun 15.

College of Mathematics and Computer Science, Tongling University, Tongling 244061, Anhui, China.

Nowadays, the problem of road traffic safety cannot be ignored. Almost all major cities have problems such as poor traffic environment and low road efficiency. Large-scale and long-term traffic congestion occurs almost every day. Transportation has developed rapidly, and more and more advanced means of transportation have emerged. However, automobile is one of the main means of transportation for people to travel. In the world, there are serious traffic jams in almost all cities. The excessive traffic flow every day leads to the paralysis of the urban transportation system, which brings great inconvenience and impact to people's travel. Various countries have also actively taken corresponding measures, i.e., traffic diversion, number restriction, or expanding the scale of the road network, but these measures can bring little effect. Traditional intelligent traffic flow forecasting has some problems, such as low accuracy and delay. Aiming at this problem, this paper uses the model of the combination of Internet of Things and big data to apply and analyze its social benefits in intelligent traffic flow forecasting and analyzes its three-tier network architecture model, namely, perception layer, network layer, and application layer. Research and analyze the mode of combining cloud computing and edge computing. From the multiperspective linear discriminant analysis algorithm of the combination method of combining the same points and differences between data and data into multiple atomic services, intelligent traffic flow prediction based on the combination of Internet of Things and big data is performed. Through the monitoring and extraction of relevant traffic flow data, data analysis, processing and storage, and visual display, improve the accuracy and effectiveness and make it easier to improve the prediction accuracy of overall traffic flow. The traffic flow prediction of the system of Internet of Things and big data is given through the case experiment. The method proposed in this paper can be applied in intelligent transportation services and can predict the stability of transportation and traffic flow in real time so as to optimize traffic congestion, reduce manual intervention, and achieve the goal of intelligent traffic management.
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http://dx.doi.org/10.1155/2022/6420799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217570PMC
June 2022

Mass drug administration in response to vivax malaria resurgence in Anhui Province of Huanghuai Plain, China.

Adv Parasitol 2022 31;116:115-152. Epub 2022 May 31.

Anhui Provincial Center for Disease Control and Prevention, Anhui, PR China.

This article summarizes the background, specific conditions, main measures, steps and effects of the implementation of Mass Drug Administration (MDA) to control the local P. vivax malaria epidemic in Anhui Province in central China. Distributing medicines to the designated population quickly controlled the local epidemic of P. vivax. Implementing MDA to control P. vivax ensured the correct selection of medicines, clarification of the targeted population for receipt of medicines, and assurance of a high rate of compliance through government support and health education. These results provide a reference for countries and regions experiencing similar events and planning to implement MDA in malaria control.
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http://dx.doi.org/10.1016/bs.apar.2022.04.001DOI Listing
June 2022

Pectolinarigenin acts as a potential anti-osteosarcoma agent via mediating SHP-1/JAK2/STAT3 signaling.

Biomed Pharmacother 2022 Jun 22;153:113323. Epub 2022 Jun 22.

Department of Orthopedics, Shanghai Bone Tumor Institution, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China. Electronic address:

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.
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http://dx.doi.org/10.1016/j.biopha.2022.113323DOI Listing
June 2022

Molecular features of pancreaticobiliary neoplasms: Implications for diagnosis, prognostication, and therapy selection.

Diagn Cytopathol 2022 Jun 25. Epub 2022 Jun 25.

The Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Background: Molecular diagnostics has impacted the diagnosis, prediction of prognosis, and selection of targeted therapy for many tumor types. While pulmonary adenocarcinomas and melanomas are among the neoplasms most associated with molecular diagnostics and targeted therapy, malignancies of the pancreaticobiliary system have also been impacted by precision medicine.

Methods: We undertook an electronic search using PubMed and Embase to review the published literature to determine what forms of molecular testing, mutations and oncogenetic pathways are associated with neoplasms of the pancreaticobiliary system. Keywords utilized were pancreas, bile duct, mutations, ERCP, FNA, KRAS, SMAD4, TP53, next-generation sequencing, serous cystadenoma, pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm, cystic mucinous neoplasm, solid pseudo-papillary neoplasm.

Results: A search between 1999 and 2022 yielded 6874 manuscripts. Screening of these yielded 302 more focused manuscripts of which 55 were used for the study. Ductal adenocarcinoma of the pancreas is associated with a progression of mutations beginning wit KRAS mutations and ending with a set of mutations in the TP53, SMAD4, and DPC4 genes. Similar mutations are found in neoplastic mucinous cysts. Specific mutations characterize serous cystadenomas, solid, and pseudo papillary neoplasms and adenocarcinomas of the bile ducts.

Conclusions: Mutational analysis of cytologic specimens obtained by fine-needle aspiration, and duct brushings and washings are helpful in the diagnosis of pancreaticobiliary neoplasms and may supply prognostic information.
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http://dx.doi.org/10.1002/dc.25005DOI Listing
June 2022

GJA1 reverses arsenic-induced EMT via modulating MAPK/ERK signaling pathway.

Toxicol Appl Pharmacol 2022 Jun 21:116138. Epub 2022 Jun 21.

Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. Electronic address:

Arsenic is known as a well-established human carcinogen. Gap Junction Protein Alpha 1 (GJA1) is a multifunction protein that forms gap junction channels and is important for intercellular communication. Recently, its aberrant expression has been shown to associate with cancer recurrence and metastatic spread. However, whether GJA1 plays a role in arsenic carcinogenesis remains unknown. Here, we demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to sodium arsenite promoted epithelial-mesenchymal transition (EMT) via increasing the expression of EMT inducer S100A4 and activation of MAPK/ERK signaling. In vitro and in vivo experiments showed that chronic exposure to sodium arsenite reduced GJA1 expression. Forced expression of GJA1 inhibited sodium arsenite-induced EMT via suppressing MAPK/ERK signaling whereas GJA1 knockdown produced an opposite effect. Intriguingly, chronic exposure to sodium arsenite increased autophagy flux. Inhibition of autophagy by pharmacological intervention or genetic deletion of autophagy core gene Beclin-1 upregulated GJA1 expression. These results suggested that GJA1 restrained the carcinogenic effect of sodium arsenite by limiting MAPK/ERK signaling, and GJA1 expression was decreased by arsenic-activated autophagy. In addition, interventions directed at enhancing the level or functional activity of GJA1 could be of preventive and therapeutic interest.
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http://dx.doi.org/10.1016/j.taap.2022.116138DOI Listing
June 2022

Altered spontaneous brain activity in major depressive disorder: An activation likelihood estimation meta-analysis.

J Affect Disord 2022 Jun 21. Epub 2022 Jun 21.

Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China; Mental Health Research Center, Zigong Mental Health Center, Zigong, Sichuan Province, China; Mental Health Research Center, Zigong Institute of Brain Science, Zigong, Sichuan Province, China; Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China. Electronic address:

Background: Wide application of resting-state functional magnetic resonance imaging (fMRI) in psychiatric research has revealed that major depressive disorder (MDD) manifest abnormal neural activities in several brain regions involving key resting state networks. However, inconsistent results have hampered our understanding of the exact neuropathology associated with MDD. Therefore, our aim was to conduct a meta-analysis to identify the consistent vulnerable brain regions of MDD in resting state, and to reveal the potential pathogenesis of MDD.

Methods: A systematic review analysis was conducted on studies involving brain resting-state changes in MDD using low-frequency amplitude (ALFF), fractional low-frequency amplitude (fALFF) and regional homogeneity (ReHo) analysis. The meta-analysis was based on the activation likelihood estimation method, using the software of Ginger ALE 2.3.

Results: 25 studies (892 MDD and 799 healthy controls) were included. Based on the meta-analysis results of ReHo, we found robust reduction of resting-state spontaneous brain activity in MDD, including the left cuneus and right middle occipital gyrus (cluster size = 216, 256 mm, uncorrected P < 0.0001), while no increased spontaneous activation in any of the brain regions. We also found reduced ALFF in the left middle occipital gyrus (cluster size = 224 mm, uncorrected P < 0.0001), and no increased spontaneous brain activation in any regions.

Conclusion: Our meta-analysis study using the activation likelihood estimation method demonstrated that MDD showed significant abnormalities in spontaneous neural activity, compared with healthy controls, mainly in areas associated with visual processing, such as the cuneus and the middle occipital gyrus. Dysfunction of these brain regions may be one of the pathogenesis of MDD.
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http://dx.doi.org/10.1016/j.jad.2022.06.014DOI Listing
June 2022

Microstructure of Dolostones of Different Geological Ages and Dedolomitization Reaction.

Materials (Basel) 2022 Jun 9;15(12). Epub 2022 Jun 9.

College of Materials Science and Engineering, Nanjing Tech University, Nanjing 211800, China.

Dolostone is widely distributed and commonly used as concrete aggregates. A large number of studies have shown that there are significant differences in the expansibility of different dolostones, and the key factors determining the expansibility of alkali carbonate rocks have not been clarified. In this paper, rocks were selected from five different geological ages: Jixianian, Cambrian, Ordovician, Devonian, and Triassic ages. The ordering degree and the content of MgCO of dolomites in rocks of different geological ages were determined by X-ray diffraction (XRD). The degree of dedolomitization reaction in rocks cured in 80 °C, 1 mol/L NaOH solution was determined by quantitative X-ray diffraction (QXRD). The morphology of dolomites in rocks was determined by a polarizing microscope. The products of the dedolomitization reaction were determined by field emission electron microscopy (FESEM-EDS). According to the test results, the following conclusions are drawn. There is a good positive correlation between ordering degree and the molar fraction of MgCO of dolomites. When the MgCO mole fraction of dolomites varies from 47.17% to 49.60%, the higher the MgCO mole fraction, the greater the ordering degree of dolomite. By analyzing the degree of the dedolomitization reaction of different dolostone powders cured at 80 °C in 1 mol/L NaOH solution, it is found that the older the geological age of dolostone, the slower the dedolomitization reaction rate and the lower the degree of dedolomitization reaction. The lower the ordering degree of dolomite crystal in the same geological age, the faster the rate of dedolomitization reaction and the higher the degree of dedolomitization reaction.
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http://dx.doi.org/10.3390/ma15124109DOI Listing
June 2022

TRX2/Rab35 Interaction Impairs Exosome Secretion by Inducing Rab35 Degradation.

Int J Mol Sci 2022 Jun 12;23(12). Epub 2022 Jun 12.

College of Life Sciences, Sichuan University, Chengdu 610065, China.

Given that exosomes mediate intercellular communication by delivering cellular components to recipient cells or tissue, they have the potential to be engineered to deliver therapeutic payloads. However, the regulatory mechanism of exosome secretion is poorly understood. In addition, mitochondrial components have been found in exosomes, suggesting communication between mitochondria and exosomes. However, the molecular mechanism of the mitochondria and vesicle interaction remains unclear. Here, we showed that mitochondrial thioredoxin 2 (TRX2) decreased exosome concentrations and inhibited HCT116 cell migration. Coimmunoprecipitation/mass spectrometry (Co-IP/MS) showed that TRX2 interacted with Rab35. TRX2 and Rab35 bound to each other at their N-terminal motifs and colocalized on mitochondria. Furthermore, TRX2 induced Rab35 degradation, resulting in impaired exosome secretion. Additionally, Rab35 mediated the suppressive effects of TRX2 on cell migration, and TRX2 suppressed cell migration through exosomes. Taken together, this study first found an interaction between TRX2 and Rab35. These results revealed a new role for TRX2 in the regulation of exosome secretion and cell migration and explained the upstream regulatory mechanism of Rab35. Furthermore, these findings also provide new molecular evidence for communication between mitochondria and vesicles.
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http://dx.doi.org/10.3390/ijms23126557DOI Listing
June 2022

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Int J Mol Sci 2022 Jun 7;23(12). Epub 2022 Jun 7.

Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.
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http://dx.doi.org/10.3390/ijms23126370DOI Listing
June 2022

Serum miR-204 and miR-451 Expression and Diagnostic Value in Patients with Pulmonary Artery Hypertension Triggered by Congenital Heart Disease.

Comput Math Methods Med 2022 13;2022:9430708. Epub 2022 Jun 13.

Qingdao Fuwai Cardiovascular Hospital, Qingdao, Shandong 266034, China.

Objective: To determine the level of expression and clinical importance of serum miR-204 and miR-451 in patients with pulmonary arterial hypertension caused by congenital heart disease (CHD-PAH).

Methods: From July 2019 to January 2021, 114 infants with congenital heart disease (CHD) were hospitalized at Qingdao's Fuwai Cardiovascular Hospital. They were grouped into categories: CHD (53 cases) and CHD-PAH (61 cases) based on whether they had pulmonary hypertension (PAH). In addition, 60 healthy children were selected as the control group. All children underwent routine biochemical examination, echocardiography, and pulmonary arterial pressure examination. By using an enzyme-linked immunosorbent assay (ELISA), the levels of brain natriuretic peptide (BNP) and asymmetric dimethylarginine (ADMA) in the blood were measured. Additionally, reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression levels of miR-204 and miR-451 in peripheral blood. The correlation between miR-204, miR-451, BNP, ADMA, and mPAP was investigated using Pearson correlation analysis.

Results: Consequently, the TC, BNP, and ADMA serum levels were considerably higher in the CHD and CHD-PAH groups than in the control group ( < 0.05), whereas BNP and ADMA serum levels were significantly higher in the CHD-PAH group than in the CHD group ( < 0.05). According to RT-PCR data, the expression levels of miR-204 and miR-451 in the peripheral blood of children in the CHD and CHD-PAH groups were significantly lower ( < 0.05) when compared to the control group. The expression levels of miR-204 and miR-451 in the peripheral blood of children in the CHD-PAH group were substantially lower ( < 0.05) than in the CHD group. Significantly, the findings of the ROC curve revealed that the area under the curve (AUC) of CHD-PAH diagnosed by miR-204 and miR-451 alone was 0.737 and 0.725, respectively, and the AUC of joint diagnosis was 0.840, which was greater than that of single diagnosis ( < 0.05). Patients with CHD-PAH had lower levels of miR-204 and miR-451 in their blood, and this was found to be associated with BNP, ADMA, and mPAP, analyzed by Pearson correlation.

Conclusions: Children with CHD-PAH can be diagnosed based on aberrant expressions of miR-204 and miR-451 in their peripheral blood serum. Moreover, CHD-PAH can be diagnosed if the combination of miR-204 and miR-451 is detected as a biomarker, which has a higher diagnostic value.
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http://dx.doi.org/10.1155/2022/9430708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208944PMC
June 2022

High levels of TDO2 in relation to pro-inflammatory cytokines in synovium and synovial fluid of patients with osteoarthritis.

BMC Musculoskelet Disord 2022 Jun 22;23(1):604. Epub 2022 Jun 22.

Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Anhui, 230022, Hefei, China.

Background: Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme that catabolizes tryptophan to kynurenine. Numerous studies have suggested that TDO2 is involved in inflammation-related diseases. However, its role in osteoarthritis (OA) has not yet been investigated. The aim of the present study was to explore the levels of TDO2 in the synovium and synovial fluid (SF) of patients with OA and its correlation with clinical manifestations and levels of pro-inflammatory cytokines.  METHODS : Synovium and SF samples were collected from patients with OA and patients with joint trauma (controls) during surgery. An enzyme-linked immunosorbent assay (ELISA) was used to measure TDO2, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Diagnostic performance of TDO2 in the synovium to discriminate between controls and OA patients was assessed using receiver operating characteristic (ROC) curve analysis. Correlations between TDO2 levels, OA clinical features, and pro-inflammatory cytokines were evaluated using Pearson correlation analysis. Effects of IL-1β or TNF-α stimulation on TDO2 expression in OA-fibroblast-like synoviocytes (OA-FLS) were also examined.

Results: The levels of TDO2, IL-1β, and TNF-α in the synovium of patients with OA were found to be significantly higher than those in controls. ROC curve analysis revealed an area under the curve (AUC) of 0.800 with 64.3% sensitivity and 85.0% specificity of TOD2 in the synovium, which enabled discriminating patients with OA from controls. Moreover, protein expression of TDO2 was upregulated to a greater extent in OA-FLS than in normal synovial fibroblasts (NSF). Furthermore, the levels of TDO2 showed significantly positive correlation with IL-1β and TNF-α levels in the synovium and SF. TDO2 levels in the synovium were also positively correlated with the Kellgren-Lawrence score. Additionally, TDO2 protein expression was significantly increased in IL-1β‒ or TNF-α‒stimulated OA-FLS than in control FLS.

Conclusion: These data indicate that highTDO2 levels in the synovium can be correlated with pro-inflammatory cytokines and severity of OA.
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http://dx.doi.org/10.1186/s12891-022-05567-4DOI Listing
June 2022
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