Publications by authors named "Yan Guo"

1,574 Publications

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Dynamic changes of phosphatidylinositol and phosphatidylinositol 4-phosphate levels modulate H-ATPase and Na/H antiporter activities to maintain ion homeostasis in Arabidopsis under salt stress.

Mol Plant 2021 Jul 30. Epub 2021 Jul 30.

Plant metabolites are dynamically modified and distributed under environmental changes. However, it is poorly understood how metabolites change functions in plant stress responses. Maintaining ion homeostasis under salt stress requires coordinately activating two type central regulators: PM H-ATPase and Na/H antiporter. Here, we used a bioassay-guided isolation approach to identify endogenous small molecules, which affect PM H-ATPase and Na/H antiporter activities, and found phosphatidylinositol (PI), which inhibits PM H-ATPase activity in non-stress conditions in Arabidopsis by directly binding to the C-terminus of the PM H-ATPase AHA2. Under salt stress, the PI4P-to-PI ratio increased, PI4P bound and activated PM Na/H antiporter activity. PI prefers binding to the inactive form of PM H-ATPase, while PI4P tends to bind the active form of Na/H antiporter. Consistently, pis1 mutants, with reduced levels of PI, displayed increased PM H-ATPase activity and salt stress tolerance, while pi4kβ1 mutant, with reduced levels of PI4P, displayed reduced PM Na/H antiporter activity and salt stress tolerance. Collectively, we have revealed a dynamic change between PI and PI4P in response to salt stress in Arabidopsis, which is crucial for maintaining ion homeostasis to protect plants from unfavorable environmental conditions.
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http://dx.doi.org/10.1016/j.molp.2021.07.020DOI Listing
July 2021

Study Progress of Noninvasive Imaging and Radiomics for Decoding the Phenotypes and Recurrence Risk of Bladder Cancer.

Front Oncol 2021 15;11:704039. Epub 2021 Jul 15.

School of Biomedical Engineering, Air Force Medical University, Xi'an, China.

Urinary bladder cancer (BCa) is a highly prevalent disease among aged males. Precise diagnosis of tumor phenotypes and recurrence risk is of vital importance in the clinical management of BCa. Although imaging modalities such as CT and multiparametric MRI have played an essential role in the noninvasive diagnosis and prognosis of BCa, radiomics has also shown great potential in the precise diagnosis of BCa and preoperative prediction of the recurrence risk. Radiomics-empowered image interpretation can amplify the differences in tumor heterogeneity between different phenotypes, i.e., high-grade low-grade, early-stage vs. advanced-stage, and nonmuscle-invasive muscle-invasive. With a multimodal radiomics strategy, the recurrence risk of BCa can be preoperatively predicted, providing critical information for the clinical decision making. We thus reviewed the rapid progress in the field of medical imaging empowered by the radiomics for decoding the phenotype and recurrence risk of BCa during the past 20 years, summarizing the entire pipeline of the radiomics strategy for the definition of BCa phenotype and recurrence risk including region of interest definition, radiomics feature extraction, tumor phenotype prediction and recurrence risk stratification. We particularly focus on current pitfalls, challenges and opportunities to promote massive clinical applications of radiomics pipeline in the near future.
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http://dx.doi.org/10.3389/fonc.2021.704039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321511PMC
July 2021

Acupotomy Contributes to Suppressing Subchondral Bone Resorption in KOA Rabbits by Regulating the OPG/RANKL Signaling Pathway.

Evid Based Complement Alternat Med 2021 26;2021:8168657. Epub 2021 Apr 26.

School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China.

Subchondral bone lesions, as the crucial inducement for accelerating cartilage degeneration, have been considered as the initiating factor and the potential therapeutic target of knee osteoarthritis (KOA). Acupotomy, the biomechanical therapy guided by traditional Chinese meridians theory, alleviates cartilage deterioration by correcting abnormal mechanics. Whether this mechanical effect of acupotomy inhibits KOA subchondral bone lesions is indistinct. This study aimed to investigate the effects of acupotomy on inhibiting subchondral bone resorption and to define the possible mechanism in immobilization-induced KOA rabbits. After KOA modeling, 8 groups of rabbits (4w/6w acupotomy, 4w/6w electroacupuncture, 4w/6w model, and 4w/6w control groups) received the indicated intervention for 3 weeks. Histological and bone histomorphometry analyses revealed that acupotomy prevented both cartilage surface erosion and subchondral bone loss. Further, acupotomy suppressed osteoclast activity and enhanced osteoblast activity in KOA subchondral bone, showing a significantly decreased expression of tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinases-9 (MMP-9), and cathepsin K (Ctsk) and a significantly increased expression of osteocalcin (OCN); this regulation may be mediated by blocking the decrease in osteoprotegerin (OPG) and the increase in NF- receptor activated protein ligand (RANKL). These findings indicated that acupotomy inhibited osteoclast activity and promoted osteoblast activity to ameliorate hyperactive subchondral bone resorption and cartilage degeneration in immobilization-induced KOA rabbits, which may be mediated by the OPG/RANKL signaling pathway. Taken together, our results indicate that acupotomy may have therapeutic potential in KOA by restoring the balance between bone formation and bone resorption to attenuate subchondral bone lesions.
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http://dx.doi.org/10.1155/2021/8168657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298142PMC
April 2021

Analysis of the main soft tissue stress associated with flexible flatfoot deformity: a finite element study.

Biomech Model Mechanobiol 2021 Jul 30. Epub 2021 Jul 30.

Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China.

A better understanding of soft tissue stress and its role in supporting the medial longitudinal arch in flexible flatfoot could help to guide the clinical treatment. In this study, a 3-Dimensional finite element (FE) foot model was reconstructed to measure the stress of the soft tissue, and its variation in different scenarios related to flexible flatfoot. All bones, cartilages, ligaments and related tendons around the ankle, and fat pad were included in the finite element model. The equivalent stress on the articular surface of the joints in the medial longitudinal arch and the maximum principal stress of the ligaments around the ankle were obtained. The results show that the plantar fascia (PF) is the main tissue in maintaining the medial longitudinal arch. The equivalent stress of all the joints in the medial longitudinal arch increases when the PF attenuation and the talonavicular joint increases, while other joints decreases when all the three tissue attenuation. Moreover, the maximum principal stress variation of calcaneofibular ligament is largest when the PF attenuation and the tibionavicular ligament and posterior tibiotalar ligament are largest when the posterior tibial tendon (PTT) attenuation. The maximum principal stress variation of tibionavicular ligament and posterior tibiotalar ligament are even larger when all the three tissue attenuation. These findings support that the PF is the main factor in maintaining the medial longitudinal arch. The medial longitudinal arch collapse mainly affects the talonavicular joint and the calcaneofibular ligament, the tibionavicular ligament and the posterior tibiotalar ligament. This approach could help to improve the understanding of adult-acquired flatfoot deformity (AAFD).
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http://dx.doi.org/10.1007/s10237-021-01500-1DOI Listing
July 2021

The impact of the COVID-19 pandemic on health services utilization in China: Time-series analyses for 2016-2020.

Lancet Reg Health West Pac 2021 Apr 24;9:100122. Epub 2021 Mar 24.

Public Health Sciences Division, Fred Hutchison Cancer Research Center, Seattle, WA, United States.

Background: The aim of this study is to quantify the effects of the SARS-CoV-2 pandemic on health services utilization in China using over four years of routine health information system data.

Methods: We conducted a retrospective observational cohort study of health services utilization from health facilities at all levels in all provinces of mainland China. We analyzed monthly all-cause health facility visits and inpatient volume in health facilities before and during the SARS-CoV-2 outbreak using nationwide routine health information system data from January 2016 to June 2020. We used interrupted time series analyses and segmented negative binomial regression to examine changes in healthcare utilization attributable to the pandemic. Stratified analyses by facility type and by provincial Human Development Index (HDI) - an area-level measure of socioeconomic status - were conducted to assess potential heterogeneity in effects.

Findings: In the months before the SARS-CoV-2 outbreak, a positive secular trend in patterns of healthcare utilization was observed. After the SARS-CoV-2 outbreak, we noted statistically significant decreases in all indicators, with all indicators achieving their nadir in February 2020. The magnitude of decline in February ranged from 63% (95% CI 61-65%; <0•0001) in all-cause visits at hospitals in regions with high HDI and 71% (95% CI 70-72%; <0•0001) in all-cause visits at primary care clinics to 33% (95% CI 24-42%; <0•0001) in inpatient volume and 10% (95% CI 3-17%;  = 0•0076) in all-cause visits at township health centers (THC) in regions with low HDI. The reduction in health facility visits was greater than that in the number of outpatients discharged (51% versus 48%; <0•0079). The reductions in both health facility visits and inpatient volume were greater in hospitals than in primary health care facilities (<0•0001) and greater in developed regions than in underdeveloped regions (<0•0001). Following the nadir of health services utilization in February 2020, all indicators showed statistically significant increases. However, even by June 2020, nearly all indicators except outpatient and inpatient volume in regions with low HDI and inpatient volume in private hospitals had not achieved their pre-SARS-COV-2 forecasted levels. In total, we estimated cumulative losses of 1020.5 (95% CI 951.2- 1089.4; <0.0001) million or 23.9% (95% CI 22.5-25.2%; <0.0001) health facility visits, and 28.9 (95% CI 26.1-31.6; <0.0001) million or 21.6% (95% CI 19.7-23.4%; <0.0001) inpatients as of June 2020.

Interpretation: Inpatient and outpatient health services utilization in China declined significantly after the SARS-CoV-2 outbreak, likely due to changes in patient and provider behaviors, suspension of health facilities or their non-emergency services, massive mobility restrictions, and the potential reduction in the risk of non-SARS-COV-2 diseases. All indicators rebounded beginning in March but most had not recovered to their pre-SARS-COV-2 levels as of June 2020.

Funding: The National Natural Science Foundation of China (No. 72042014).
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http://dx.doi.org/10.1016/j.lanwpc.2021.100122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315657PMC
April 2021

Risk factors for implant failure of intertrochanteric fractures with lateral femoral wall fracture after intramedullary nail fixation.

Injury 2021 Jul 18. Epub 2021 Jul 18.

Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China; Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing 100191, China.

Introduction: Few studies have specifically evaluated the comminution extent of lateral femoral wall (LFW) fracture and risk factors of implant failure in intertrochanteric fractures with LFW fracture. The aim of present study was to evaluate the influence of comminution extent of LFW fracture on implant failure and identify risk factors of implant failure in cases with LFW fracture after intramedullary fixation.

Methods: This retrospective study included 130 intertrochanteric fracture with LFW fracture treated with intramedullary fixation at a teaching hospital over a 13-year period from January 2006 to December 2018. Demographic information, cortical thickness index, the reduction quality, status of medial support, position of the screw/blade and status of lateral femoral wall were collected and compared. The logistic regression analyzes was performed to evaluate risk factors of implant failure in intertrochanteric fractures with LFW fracture after intramedullary nail fixation.

Results: 10 patients (7.69%) suffered from mechanical failure after intramedullary fixation. Univariate analyzes showed that comminuted LFW fracture (OR, 7.625; 95%CI, 1.437~40.446; p = 0.017), poor reduction quality (OR, 49.375; 95%CI, 7.217~337.804; p < 0.001) and loss of medial support (OR, 17.818; 95%CI, 3.537~89.768; p < 0.001) were associated with implant failure. After adjustment for confounding variables, the multivariable logistic regression analyzes showed that poor reduction quality (OR, 11.318; 95%CI, 1.126~113.755; p = 0.039) and loss of medial support (OR, 7.734; 95%CI, 1.062~56.327; p = 0.043) were independent risk factors for implant failure. Whereas, comminuted LFW fracture was not associated with implant failure (p = 0.429).

Conclusions: The comminution extent of the LFW fracture might influence the stability of intertrochanteric fractures; and intramedullary fixation might be an effective treatment method. Furthermore, poor reduction quality and loss of medial support could increaze the risk of implant failure in intertrochanteric fractures with LFW fractures after intramedullary fixation. Therefore, we should pay great emphasis on fracture reduction quality in future.
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http://dx.doi.org/10.1016/j.injury.2021.07.025DOI Listing
July 2021

Prediction of lymphovascular space invasion using a combination of tenascin-C, cox-2, and PET/CT radiomics in patients with early-stage cervical squamous cell carcinoma.

BMC Cancer 2021 Jul 28;21(1):866. Epub 2021 Jul 28.

Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.

Background: Lymphovascular space invasion is an independent prognostic factor in early-stage cervical cancer. However, there is a lack of non-invasive methods to detect lymphovascular space invasion. Some researchers found that Tenascin-C and Cyclooxygenase-2 was correlated with lymphovascular space invasion. Radiomics has been studied as an emerging tool for distinguishing tumor pathology stage, evaluating treatment response, and predicting prognosis. This study aimed to establish a machine learning model that combines radiomics based on PET imaging with tenascin-C (TNC) and cyclooxygenase-2 (COX-2) for predicting lymphovascular space invasion (LVSI) in patients with early-stage cervical cancer.

Methods: One hundred and twelve patients with early-stage cervical squamous cell carcinoma who underwent PET/CT examination were retrospectively analyzed. Four hundred one radiomics features based on PET/CT images were extracted and integrated into radiomics score (Rad-score). Immunohistochemical analysis was performed to evaluate TNC and COX-2 expression. Mann-Whitney U test was used to distinguish differences in the Rad-score, TNC, and COX-2 between LVSI and non-LVSI groups. The correlations of characteristics were tested by Spearman analysis. Machine learning models including radiomics model, protein model and combined model were established by logistic regression algorithm and evaluated by ROC curve. Pairwise comparisons of ROC curves were tested by DeLong test.

Results: The Rad-score of patients with LVSI was significantly higher than those without. A significant correlation was shown between LVSI and Rad-score (r = 0.631, p < 0.001). TNC was correlated to both the Rad-score (r = 0.244, p = 0.024) and COX-2 (r = 0.227, p = 0.036). The radiomics model had the best predictive performance among all models in training and external dataset (AUCs: 0.914, 0.806, respectively, p < 0.001). However, in testing dataset, the combined model had better efficiency for predicting LVSI than other models (AUCs: 0.801 vs. 0.756 and 0.801 vs. 0.631, respectively).

Conclusion: The machine learning model of the combination of PET radiomics with COX-2 and TNC provides a new tool for detecting LVSI in patients with early-stage cervical cancer. In the future, multicentric studies on larger sample of patients will be used to test the model.

Trial Registration: This is a retrospective study and there is no experimental intervention on human participants. The Ethics Committee has confirmed that retrospectively registered is not required.
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http://dx.doi.org/10.1186/s12885-021-08596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317359PMC
July 2021

-mediated angiogenesis in retinopathy of prematurity is co-regulated by miR-17-5p and miR-20a-5p.

Biochem Cell Biol 2021 Jul 28:1-10. Epub 2021 Jul 28.

Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, Central South University, P.R. China.

The microRNAs miR-17-5p and miR-20a-5p play important roles on angiogenesis; however, it is arguable whether they regulate the formation of retinal blood vessels in retinopathy of prematurity (ROP). We used a mouse model of oxygen-induced retinopathy (OIR) to simulate the development of retinas in mice suffering from ROP, and the expression levels of miR-20a-5p, miR-17-5p, hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) were measured by RT-qPCR and Western blotting. Cell proliferation, apoptosis, and angiogenesis in the OIR model mice were measured using MTT assays, flow cytometry, and Matrigel assays, respectively. The interaction between HIF-1α/VEGF and miR-20a-5p/miR-17-5p were further validated using dual-luciferase reporter assays, biotin-labeled RNA-pulldown, and RNA immunoprecipitation (RIP) assays. In our OIR model, retinal angiogenesis in the mice was associated with down-regulation of miR-20a-5p and miR-17-5p, as well as up-regulation of HIF-1α and VEGF. In addition, the miR-20a-5p and miR-17-5p inhibited cell proliferation and angiogenesis through regulating HIF-1α and VEGF in the retinal cells of the OIR model mice. Moreover, it was found that miR-20a-5p and miR-17-5p bind to HIF-1α and VEGF at the 3'UTR, and there was a combined effect between miR-20a-5p and miR-17-5p on the regulation of HIF-1α and VEGF. It is worth noting that miR-17-5p and miR-20a-5p can preferentially regulate HIF-1α, then act on VEGF, thereby affecting the angiogenesis associated with ROP.
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http://dx.doi.org/10.1139/bcb-2020-0357DOI Listing
July 2021

RNA editing affects cis-regulatory elements and predicts adverse cancer survival.

Cancer Med 2021 Jul 28. Epub 2021 Jul 28.

Guizhou Provincial People's Hospital, Guiyang, China.

Background: RNA editing exerts critical impacts on numerous biological processes and thus are implicated in crucial human phenotypes, including tumorigenesis and prognosis. While previous studies have analyzed aggregate RNA editing activity at the sample level and associated it with overall cancer survival, there is not yet a large-scale disease-specific survival study to examine genome-wide RNA editing sites' prognostic value taking into account the host gene expression and clinical variables.

Methods: In this study, we solved comprehensive Cox proportional models of disease-specific survival on individual RNA-editing sites plus host gene expression and critical demographic covariates. This allowed us to interrogate the prognostic value of a large number of RNA-editing sites at single-nucleotide resolution.

Results: As a result, we identified 402 gene-proximal RNA-editing sites that generally predict adverse cancer survival. For example, an RNA-editing site residing in ZNF264 indicates poor survival of uterine corpus endometrial carcinoma, with a hazard ratio of 2.13 and an adjusted p-value of 4.07 × 10 . Some of these prognostic RNA-editing sites mediate the binding of RNA binding proteins and microRNAs, thus propagating their impacts to extensive regulatory targets.

Conclusions: In conclusion, RNA editing affects cis-regulatory elements and predicts adverse cancer survival.
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http://dx.doi.org/10.1002/cam4.4146DOI Listing
July 2021

A systematic view of computational methods for identifying driver genes based on somatic mutation data.

Brief Funct Genomics 2021 Jul 23. Epub 2021 Jul 23.

School of Computer Science and Engineering, Central South University, Changsha, China.

Abnormal changes of driver genes are serious for human health and biomedical research. Identifying driver genes, exactly from enormous genes with mutations, promotes accurate diagnosis and treatment of cancer. A lot of works about uncovering driver genes have been developed over the past decades. By analyzing previous works, we find that computational methods are more efficient than traditional biological experiments when distinguishing driver genes from massive data. In this study, we summarize eight common computational algorithms only using somatic mutation data. We first group these methods into three categories according to mutation features they apply. Then, we conclude a general process of nominating candidate cancer driver genes. Finally, we evaluate three representative methods on 10 kinds of cancer derived from The Cancer Genome Atlas Program and five Chinese projects from the International Cancer Genome Consortium. In addition, we compare results of methods with various parameters. Evaluation is performed from four perspectives, including CGC, OG/TSG, Q-value and QQQuantile-Quantileplot. To sum up, we present algorithms using somatic mutation data in order to offer a systematic view of various mutation features and lay the foundation of methods based on integration of mutation information and other types of data.
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http://dx.doi.org/10.1093/bfgp/elab032DOI Listing
July 2021

The signaling role of extracellular ATP in co-culture of Shiraia sp. S9 and Pseudomonas fulva SB1 for enhancing hypocrellin A production.

Microb Cell Fact 2021 Jul 23;20(1):144. Epub 2021 Jul 23.

College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.

Background: Adenosine 5'-triphosphate (ATP) plays both a central role as an intracellular energy source, and a crucial extracellular signaling role in diverse physiological processes of animals and plants. However, there are less reports concerning the signaling role of microbial extracellular ATP (eATP). Hypocrellins are effective anticancer photodynamic therapy (PDT) agents from bambusicolous Shiraia fungi. The co-culture of Shiraia sp. S9 and a bacterium Pseudomonas fulva SB1 isolated from Shiraia fruiting bodies was established for enhanced hypocrellin A (HA) production. The signaling roles of eATP to mediate hypocrellin biosynthesis were investigated in the co-culture.

Results: The co-culture induced release of eATP at 378 nM to the medium around 4 h. The eATP release was interdependent on cytosolic Ca concentration and reactive oxygen species (ROS) production, respectively. The eATP production could be suppressed by the Ca chelator EGTA or abolished by the channel blocker La, ROS scavenger vitamin C and NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). The bacterium-induced HO production was strongly inhibited by reactive blue (RB), a specific inhibitor of membrane purinoceptors, but dependent on the induced Ca influx in the co-culture. On the other hand, the application of exogenous ATP (exATP) at 10-300 µM to Shiraia cultures also promoted fungal conidiation and HA production, both of which were blocked effectively by the purinoceptor inhibitors pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS) and RB, and ATP hydrolase apyrase. Both the induced expression of HA biosynthetic genes and HA accumulation were inhibited significantly under the blocking of the eATP or Ca signaling, and the scavenge of ROS in the co-culture.

Conclusions: Our results indicate that eATP release is an early event during the intimate bacterial-fungal interaction and eATP plays a signaling role in the bacterial elicitation on fungal metabolites. Ca and ROS are closely linked for activation of the induced ATP release and its signal transduction. This is the first report on eATP production in the fungal-bacterial co-culture and its involvement in the induced biosynthesis of fungal metabolites.
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http://dx.doi.org/10.1186/s12934-021-01637-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305905PMC
July 2021

Fabrication of an Anti-Reflective Microstructure on ZnS by Femtosecond Laser Bessel Beams.

Molecules 2021 Jul 14;26(14). Epub 2021 Jul 14.

State Key Laboratory of Transient Optics and Photonics, Xi'an Institute of Optics and Precision Mechanics of CAS, Xi'an 710119, China.

As an important mid-infrared to far-infrared optical window, ZnS is extremely important to improve spectral transmission performance, especially in the military field. However, on account of the Fresnel reflection at the interface between the air and the high-strength substrate, surface optical loss occurs in the ZnS optical window. In this study, the concave antireflective sub-wavelength structures (ASS) on ZnS have been experimentally investigated to obtain high transmittance in the far-infrared spectral range from 6 μm to 10 μm. We proposed a simple method to fabricate microhole array ASS by femtosecond Bessel beam, which further increased the depth of the microholes and suppressed the thermal effects effectively, including the crack and recast layer of the microhole. The influence of different Gaussian and Bessel beam parameters on the microhole morphology were explored, and three ASS structures with different periods were prepared by the optimized Bessel parameters. Ultimately, the average transmittance of the sample with the ASS microhole array period of 2.6 μm increased by 4.1% in the 6 μm to 10 μm waveband, and the transmittance was increased by 5.7% at wavelength of 7.2 μm.
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http://dx.doi.org/10.3390/molecules26144278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307567PMC
July 2021

Bie Jia Jian pill enhances the amelioration of bone mesenchymal stem cells on hepatocellular carcinoma progression.

J Nat Med 2021 Jul 23. Epub 2021 Jul 23.

Teaching and Research Office of Internal Medicine of Traditional Chinese Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9, Dongge Road, Qingxiu District, Nanning, 530200, Guangxi, P.R. China.

Background: The therapeutic efficiency of Traditional Chinese Medicine (TCM) in suppressing the recurrence and metastasis of hepatocellular carcinoma (HCC) has been well proved.

Objective: The aim of this study is to investigate the role of Bie Jia Jian pill (BJJP) combined with bone mesenchymal stem cells (BMSCs) in HCC progression.

Methods: Flow cytometry was used to identify BMSCs isolated from BALB/c mice. The expressions of biomarkers and apoptosis rate of cancer stem cells (CSCs) enriched from Huh7 cells were also measured. The osteogenic differentiation and adipogenic differentiation ability of isolated BMSCs was determined by oil red O staining and Alizarin Red Staining. CSCs were used to establish the orthotopic HCC model. Histological changes in the liver tissues were examined by hematoxylin-eosin (H&E) staining and Van Gieson (VG) staining. The cell apoptotic rate in the cancer tissues was detected by TUNEL staining. The cell proliferation antigen Ki67 in the cancer tissues were detected by immunofluorescence assay and PCR, respectively. The levels of CSCs cellular surface markers (CD24, CD133 and EpCAM) and Wnt/β-catenin signal pathway related proteins were detected by PCR and western blot.

Results: Treatment of BJJP or BMSCs both improved the morphology induced by HCC and suppressed the differentiation ability of CSCs, as evidenced by down-regulated expressions of CD24, CD133, EpCAM and Ki67. The protective effect of BJJP or BMSCs in cancer tissues can be enhanced by the combination of BJJP and BMSCs. In addition to that, BJJP or BMSCs alone was found to increase the expression of miR-140 and promote cell apoptosis in CSCs, while down-regulation of miR-140 partially reversed the protective effect of BMSCs or BJJP + BMSCs on cancer tissues. BJJP + BMSCs treatment together also can down-regulate the expressions of Wnt3a and β-catenin.

Conclusions: These results proved the inhibitory role of BJJP + BMSCs in HCC development through regulating miR-140 and Wnt/β-catenin signal pathway.
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http://dx.doi.org/10.1007/s11418-021-01548-4DOI Listing
July 2021

Prognostic value of splenic volume in hepatocellular carcinoma patients receiving transarterial chemoembolization.

J Gastrointest Oncol 2021 Jun;12(3):1141-1151

Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Liver function is a key determinant for the survival of hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE). However, establishing robust prognostic indicators for liver insufficiencies and patient survival remains an unmet demand. This retrospective study evaluated the prognostic value of splenic volume (SV) in HCC patients undergoing TACE.

Methods: A total of 67 HCC patients who underwent at least two consecutive TACE procedures were retrospectively included in this study. Comprehensive clinical information and follow-up data were collected, and the SV was measured based on dynamic contrast enhanced images. Risk factors of SV enlargement were assessed. The prognostic value of SV on survival was analyzed and compared with Child-Pugh (CP) classification and albumin-bilirubin (ALBI) grade.

Results: The baseline SV was 299.74±143.63 cm, and showed a moderate and statistically significant correlation with CP classification (R=0.31, P<0.05). The SV increased remarkably after the first and second TACE procedures (330.16±155.38 cm, P<0.01, and 355.63±164.26 cm, P<0.01, respectively). In survival analysis, the optimal cut-off value of SV was determined as 373 cm using X-tile software, and the patients were divided into the small SV group and the large SV groups accordingly. Based on the pre-TACE SV, the median overall survival (mOS) for patients in the small SV group and the large SV group was 458 days and 249 days, respectively (P<0.05). After the first and second TACE, the mOS in the small SV group and the large SV group were 454 266 days (P<0.05) and 526 266 days (P<0.05), respectively. No prognostic value of CP classification and ALBI grade was identified for these patients. Furthermore, there were no significant differences between the small and large SV groups in age, tumor stage, and ALBI grade, except for CP classification (P<0.05).

Conclusions: SV was correlated with CP classification and was a robust predictor for HCC patients undergoing TACE treatment.
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http://dx.doi.org/10.21037/jgo-21-226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261322PMC
June 2021

In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan "boosted" charge-reversal nanoformulation.

Carbohydr Polym 2021 Oct 31;269:118268. Epub 2021 May 31.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China; State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai 264003, PR China. Electronic address:

Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/[email protected]) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged [email protected] could escape from lysosomes via "proton sponge effect" and "cationic-anionic interaction with lysosome membranes". Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/CMCS/[email protected] was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/[email protected] in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.
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http://dx.doi.org/10.1016/j.carbpol.2021.118268DOI Listing
October 2021

Indigoidine biosynthesis triggered by the heavy metal-responsive transcription regulator: a visual whole-cell biosensor.

Appl Microbiol Biotechnol 2021 Jul 22. Epub 2021 Jul 22.

National Key Clinical Specialty of Occupational Diseases, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China.

During the last few decades, whole-cell biosensors have attracted increasing attention for their enormous potential in monitoring bioavailable heavy metal contaminations in the ecosystem. Visual and measurable output signals by employing natural pigments have been demonstrated to offer another potential choice to indicate the existence of bioavailable heavy metals in recent years. The biosynthesis of the blue pigment indigoidine has been achieved in E. coli following heterologous expression of both BpsA (a single-module non-ribosomal peptide synthetase) and PcpS (a PPTase to activate apo-BpsA). Moreover, we demonstrated herein the development of the indigoidine-based whole-cell biosensors to detect bioavailable Hg(II) and Pb(II) in water samples by employing metal-responsive transcriptional regulator MerR and PbrR as the sensory elements, and the indigoidine biosynthesis gene cluster as a reporter element. The resulting indigoidine-based biosensors presented a good selectivity and high sensitivity to target metal ions. High concentration of target metal exposure could be clearly recognized by the naked eye due to the color change by the secretion of indigoidine, and quantified by measuring the absorbance of the culture supernatants at 600 nm. Dose-response relationships existed between the exposure concentrations of target heavy metals and the production of indigoidine. Although fairly good linear relationships were obtained in a relatively limited concentration range of the concentrations of heavy metal ions, these findings suggest that genetically controlled indigoidine biosynthesis triggered by the MerR family transcriptional regulator can enable a sensitive, visual, and qualitative whole-cell biosensor for bioindicating the presence of bioaccessible heavy metal in environmental water samples. KEY POINTS: • Biosynthesis pathway of indigoidine reconstructed in a high copy number plasmid in E. coli. • Visual and colorimetric detection of Hg(II) and Pb(II) by manipulation of indigoidine biosynthesis through MerR family metalloregulator. •Enhanced detection sensitivity toward Hg(II) and Pb(II) achieved using novel pigment-based whole-cell biosensors.
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http://dx.doi.org/10.1007/s00253-021-11441-5DOI Listing
July 2021

Transcriptome analysis reveals potential mechanisms of the effects of dietary Enteromorpha polysaccharides on bursa of Fabricius in broilers.

Vet Med Sci 2021 Jul 15. Epub 2021 Jul 15.

Department of Animal Science, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, Guangdong Province, P. R. China.

The present study was conducted to evaluate the effects of dietary supplementation of Enteromorpha polysaccharides (EP) on relative organ weight of broilers, and RNA-seq technique was used to reveal the potential molecular mechanisms of the positive effects of EP on relative organ weight. A total of 396 1-day-old male chicks (Arbor Acres) were randomly assigned to six dietary treatments containing EP at 0 (EP0), 1000 (EP1000), 2500 (EP2500), 4000 (EP4000), 5500 (EP5500), and 7000 (EP7000) mg/kg levels for a 35-day feeding trial. At the end of feeding trail, six birds (one bird from each replicate cage) were randomly selected from each treatment and then slaughtered for relative organ weight analysis. The results showed that the relative weight of bursa of Fabricius were increased in the EP1000 group (p < 0.05), and then three bursa of Fabricius samples from each group (EP0 and EP1000) were randomly selected for RNA-seq analysis. The results of RNA-seq analysis showed that there were 20 differentially expressed genes (DEGs) between EP0 and EP1000 groups, among the DEGs, 6 genes were upregulated and 14 genes were downregulated by EP1000 supplementation (p-adjust < 0.05). Gene ontology (GO) enrichment analysis suggested that the DEGs were mainly enriched in negative regulation of toll-like receptor 9 signaling pathway (p-corrected < 0.05). Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the DEGs were mainly enriched in phagosome, mitophagy-animal, Salmonella infection, autophagy-animal signaling pathways (p-corrected = 0.081). Taken together, dietary EP supplementation at 1000 mg/kg level promoted the relative weight of bursa of Fabricius may be involved in improving the immune function of broilers. These findings provided a reference for further exploring the specific molecular mechanism of EP that affecting the organ development in broilers.
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http://dx.doi.org/10.1002/vms3.573DOI Listing
July 2021

In vitro affinity maturation of broader and more-potent variants of the HIV-1-neutralizing antibody CAP256-VRC26.25.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458

Three variable 2 (V2) loops of HIV-1 envelope glycoprotein (Env) trimer converge at the Env apex to form the epitope of an important classes of HIV-1 broadly neutralizing antibodies (bNAbs). These V2-glycan/apex antibodies are exceptionally potent but less broad (∼60 to 75%) than many other bNAbs. Their CDRH3 regions are typically long, acidic, and tyrosine sulfated. Tyrosine sulfation complicates efforts to improve these antibodies through techniques such as phage or yeast display. To improve the breadth of CAP256-VRC26.25 (VRC26.25), a very potent apex antibody, we adapted and extended a B cell display approach. Specifically, we used CRISPR/Cas12a to introduce VRC26.25 heavy- and light-chain genes into their respective loci in a B cell line, ensuring that each cell expresses a single VRC26.25 variant. We then diversified these loci through activation-induced cytidine deaminase-mediated hypermutation and homology-directed repair using randomized CDRH3 sequences as templates. Iterative sorting with soluble Env trimers and further randomization selected VRC26.25 variants with successively improving affinities. Three mutations in the CDRH3 region largely accounted for this improved affinity, and VRC26.25 modified with these mutations exhibited greater breadth and potency than the original antibody. Our data describe a broader and more-potent form of VRC26.25 as well as an approach useful for improving the breadth and potency of antibodies with functionally important posttranslational modifications.
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http://dx.doi.org/10.1073/pnas.2106203118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307357PMC
July 2021

DDRS: Detection of drug response SNPs specifically in patients receiving drug treatment.

Comput Struct Biotechnol J 2021 18;19:3650-3657. Epub 2021 Jun 18.

Biomedical Informatics & Genomics Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, PR China.

Detecting SNPs associated with drug efficacy or toxicity is helpful to facilitate personalized medicine. Previous studies usually find SNPs associated with clinical outcome only in patients received a specific treatment. However, without information from patients without drug treatment, it is possible that the detected SNPs are associated with patients' clinical outcome even without drug treatment. Here we aimed to detect drug response SNPs based on data from patients with and without drug treatment through combing the cox proportional-hazards model and pairwise Kaplan-Meier survival analysis. A pipeline named Detection of Drug Response SNPs (DDRS) was built and applied to TCGA breast cancer data including 363 patients with doxorubicin treatment and 321 patients without any drug treatment. We identified 548 doxorubicin associated SNPs. Drug response score derived from these SNPs were associated with drug-resistant level (indicated by IC) of breast cancer cell lines. Enrichment analyses showed that these SNPs were enriched in active epigenetic regulation markers (e.g., H3K27ac). Compared with random genes, the -eQTL genes of these SNPs had a shorter protein-protein interaction distance to doxorubicin associated genes. In addition, linear discriminant analysis showed that the eQTL gene expression levels could be used to predict clinical outcome for patients with doxorubicin treatment (AUC = 0.738). Specifically, we identified rs2817101 as a drug response SNP for doxorubicin treatment. Higher expression level of its -eQTL gene is associated with poorer survival. This approach can also be applied to identify new drug associated SNPs in other cancers.
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http://dx.doi.org/10.1016/j.csbj.2021.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254081PMC
June 2021

Predicting factors of central lymph node metastasis and BRAF mutation in Chinese population with papillary thyroid carcinoma.

World J Surg Oncol 2021 Jul 13;19(1):211. Epub 2021 Jul 13.

Department of Pathology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, 7# Weiwu Road, Zhengzhou, 450003, Henan Province, China.

Objective: The aim of this study was to evaluate the predictive factors of central lymph node metastasis (CLNM) and BRAF mutation in Chinese patients with papillary thyroid carcinoma (PTC).

Methods: A total of 943 PTC patients who underwent thyroidectomy from 2014 to 2016 at our hospital were enrolled. Those patients were divided into PTC > 10 mm and papillary thyroid microcarcinoma (PTMC) groups by tumor size. The BRAF mutation was examined by quantitative real-time PCR. Univariate and multivariate analyses were used to examine risk factors associated with CLNM and the BRAF mutation.

Results: The frequency of CLNM was 53% (505/943). Both univariate and multivariate analyses suggested that the risk factors for CLNM in PTC patients were male, younger age, and larger tumor size (P < 0.05). Coexistent Hashimoto thyroiditis (HT) was an independent protective factor against CLNM when the tumor was > 10 mm (P = 0.006). Stratified analysis revealed that male, age ≤ 30 years, and tumor size > 5 mm were independent risk factors for CLNM. The BRAF mutation rate was 85%. Multivariate logistic regression analysis revealed that age (P < 0.001) and coexistent HT (P = 0.005) were independent predictive factors of BRAF mutation in PTC patients. Only age was a risk factor for the BRAF mutation when the tumor was > 10 mm (P = 0.004). In the PTMC group, the BRAF mutation was significantly correlated with tumor size (P < 0.001) and coexistent HT (P = 0.03). Stratified analysis revealed that age > 30 years and tumor size > 5 mm were independent predictive factors of BRAF mutation. Furthermore, the incidence of CLNM was significantly higher in BRAF mutation-positive patients (P = 0.009) when the tumor was ≤ 5 mm.

Conclusion: The factors male, younger age (≤ 30 years), large tumor size (> 5 mm), and coexistent HT are independent predicative factors for CLNM. The BRAF mutation is associated with both large size and without HT in PTMC patients, age > 30 years in the PTC > 10 mm group. The BRAF mutation was an independent risk factor for CLNM when the tumor was ≤ 5 mm. For optimal management, these features should be comprehensively evaluated to determine the initial surgical approach for PTC patients.
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http://dx.doi.org/10.1186/s12957-021-02326-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278623PMC
July 2021

CSE-Derived HS Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK Pathway.

ACS Chem Neurosci 2021 07 12;12(14):2580-2590. Epub 2021 Jul 12.

Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.

The effect of cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (HS) on the reactive proliferation of astrocytes and neural functional recovery over 30 d after acute cerebral ischemia and reperfusion (I/R) was determined by applying wild-type (WT) and CSE knockout (KO) mice. The changes of glial fibrillary acidic protein (GFAP) expression in hippocampal tissues was tested. Besides, we assessed the changes of mice spatial learning memory ability, neuronal damage, RhoA, Rho kinase 2 (ROCK), and myelin basic protein (MBP) expressions in hippocampal tissues. The results revealed that cerebral I/R resulted in obvious increase of GFAP expression in hippocampal tissues. Besides, we found the neuronal damage, learning, and memory deficits of mice induced by cerebral I/R as well as revealed the upregulation of RhoA and ROCK expressions and reduced MBP expression in hipppcampal tissues of mice following cerebral I/R. Not surprisingly, the GFAP expression and cerebral injury as well as the upregulation of the RhoA/ROCK pathway were more remarkable in CSE KO mice, compared with those in WT mice over 30 d following acute cerebral I/R, which could be blocked by NaHS treatment, a donor of exogenous HS. In addition, the ROCK inhibitor Fasudil also inhibited the reactive proliferation of astrocytes and ameliorated the recovery of neuronal function over 30 d after cerebral I/R. For the purpose of further confirmation of the role of HS on the astrocytes proliferation following cerebral I/R, the immunofluorescence double staining: bromodeoxyuridine (BrdU) and GFAP was evaluated. There was a marked upregulation of BrdU-labeled cells coexpressed with GFAP in hippocampal tissues at 30 d after acute cerebral I/R; however, the increment of astrocytes proliferation could be ameliorated by both NaHS and Fasudil. These findings indicated that CSE-derived HS could inhibit the reactive proliferation of astrocytes and promote the recovery of mice neural functional deficits induced by a cerebral I/R injury via inhibition of the RhoA/ROCK signal pathway.
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http://dx.doi.org/10.1021/acschemneuro.0c00674DOI Listing
July 2021

Establishment of epidemiological cut-off values for cefoselis, a new fourth-generation cephalosporin, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa.

J Antimicrob Chemother 2021 Jul 3. Epub 2021 Jul 3.

Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.

Objectives: To establish the epidemiological cut-off values (ECOFFs) for cefoselis against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa.

Methods: We collected 2288 non-repetitive clinical isolates from five laboratories throughout four cities in China. The cefoselis MICs and inhibition zone diameters for all isolates were established using the broth microdilution method and the disc diffusion method following EUCAST guidelines. MIC ECOFFs were determined by visual estimation and ECOFFinder software. Zone diameter ECOFFs were set if a high correlation of MICs and inhibition zone diameters was found by Pearson correlation. Zone diameter ECOFFs were finally determined by the visual estimate method.

Results: MICs of cefoselis were distributed from 0.008 to >256 mg/L for the four Enterobacterales species and from 0.25 to >256 mg/L for P. aeruginosa. MIC ECOFFs were 0.125 mg/L for E. coli, K. pneumoniae and P. mirabilis, 0.25 mg/L for E. cloacae and 32 mg/L for P. aeruginosa. A high correlation of MICs and zone diameters was observed for all Enterobacterales (|r| > 0.8, P < 0.001) and a relatively high correlation was found for P. aeruginosa (|r| = 0.71, P < 0.001). The zone diameter ECOFF was 24 mm for E. cloacae, E. coli and K. pneumoniae, 26 mm for P. mirabilis and 21 mm for P. aeruginosa.

Conclusions: We determined MIC and zone diameter ECOFFs for cefoselis against four Enterobacterales species and P. aeruginosa. The establishment of ECOFFs for cefoselis provides clinicians with helpful guidance to differentiate WT and non-WT pathogens.
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http://dx.doi.org/10.1093/jac/dkab216DOI Listing
July 2021

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy.

Cells 2021 Jun 9;10(6). Epub 2021 Jun 9.

Department of Ophthalmology and Visual Sciences, School of Medicine, University of Maryland at Baltimore (UMB), 10 S. Pine St., MSTF Room 5-77B, Baltimore, MD 21201, USA.

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ's effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ and MAGL inhibitor KML29, or PGJ + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ alone. KML29's failure to suppress PGE ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ has been shown to be neuroprotective, treatments combining PGJ with these PG synthesis inhibitors do not enhance PGJ's neuroprotection.
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http://dx.doi.org/10.3390/cells10061440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228425PMC
June 2021

5-HT3 Signaling Alters Development of Sacral Neural Crest Derivatives That Innervate the Lower Urinary Tract.

Int J Mol Sci 2021 Jun 25;22(13). Epub 2021 Jun 25.

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by and ). We determined that is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.
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http://dx.doi.org/10.3390/ijms22136838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269166PMC
June 2021

MdWRKY11 improves copper tolerance by directly promoting the expression of the copper transporter gene MdHMA5.

Hortic Res 2020 Jul 1;7(1):105. Epub 2020 Jul 1.

College of Horticulture, China Agricultural University, 100193, Beijing, China.

Overuse of fungicides and fertilizers has resulted in copper (Cu) contamination of soils and toxic levels of Cu in apple fruits. To breed Cu-resistant apple (Malus domestica) cultivars, the underlying molecular mechanisms and key genes involved in Cu resistance must be identified. Here, we show that MdWRKY11 increases Cu tolerance by directly promoting the transcription of MdHMA5. MdHMA5 is a Cu transporter that may function in the storage of excess Cu in root cell walls and stems for Cu tolerance in apple. The transcription factor MdWRKY11 is highly induced by excess Cu. MdWRKY11 overexpression in transgenic apple enhanced Cu tolerance and decreased Cu accumulation. Apple calli transformed with an MdWRKY11-RNAi construct exhibited the opposite phenotype. Both an in vivo chromatin immunoprecipitation assay and an in vitro electrophoretic mobility shift assay indicated that MdWRKY11 binds to the promoter of MdHMA5. Furthermore, MdWRKY11 promoted MdHMA5 expression in transgenic apple plants, as revealed by quantitative PCR. Moreover, inhibition of MdWRKY11 expression by RNA interference led to a significant decrease in MdHMA5 transcription. Thus, MdWRKY11 directly regulates MdHMA5 transcription. Our work resulted in the identification of a novel MdWRKY11-MdHMA5 pathway that mediates Cu resistance in apple.
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http://dx.doi.org/10.1038/s41438-020-0326-0DOI Listing
July 2020

Development of a bioavailable Hg(II) sensing system based on MerR-regulated visual pigment biosynthesis.

Sci Rep 2021 Jun 29;11(1):13516. Epub 2021 Jun 29.

National Key Clinical Specialty of Occupational Diseases, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China.

Engineered microorganisms have proven to be a highly effective and robust tool to specifically detect heavy metals in the environment. In this study, a highly specific pigment-based whole-cell biosensor has been investigated for the detection of bioavailable Hg(II) based on an artificial heavy metal resistance operon. The basic working principle of biosensors is based on the violacein biosynthesis under the control of mercury resistance (mer) promoter and mercury resistance regulator (MerR). Engineered biosensor cells have been demonstrated to selectively respond to Hg(II), and the specific response was not influenced by interfering metal ions. The response of violacein could be recognized by the naked eye, and the time required for the maximum response of violacein (5 h) was less than that of enhanced green fluorescence protein (eGFP) (8 h) in the single-signal output constructs. The response of violacein was almost unaffected by the eGFP in a double-promoter controlled dual-signals output construct. However, the response strength of eGFP was significantly decreased in this genetic construct. Exponentially growing violacein-based biosensor detected concentrations as low as 0.39 μM Hg(II) in a colorimetric method, and the linear relationship was observed in the concentration range of 0.78-12.5 μM. Non-growing biosensor cells responded to concentrations as low as 0.006 μM Hg(II) in a colorimetric method and in a Hg(II) containing plate sensitive assay, and the linear relationship was demonstrated in a very narrow concentration range. The developed biosensor was finally validated for the detection of spiked bioavailable Hg(II) in environmental water samples.
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http://dx.doi.org/10.1038/s41598-021-92878-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242042PMC
June 2021

Neonatal maple syrup urine disease in China: two novel mutations in the BCKDHB gene and literature review.

J Pediatr Endocrinol Metab 2021 Jun 29. Epub 2021 Jun 29.

Department of Nephrology, Nanjing Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Objectives: To report two novel mutations in the BCKDHB gene with Maple syrup urine disease (MSUD) and compare their data with 52 cases of MSUD reported in the available Chinese literature.

Methods: Clinical data of a case of a newborn with MSUD was retrospectively studied. Literatures on MSUD in the local medical journals from January 1990 till December 2019 in China were reviewed.

Results: Two novel BCKDHB mutations c.90_91insCTGGCGCGGGG (p.Phe35TrpfsTer41) and c.80_90del (p.Ala32PhefsTer48) were identified. We found a total of 52 cases of MSUD reports so far. A total of 49 cases had the symptom of poor feeding (94.2%), 50 cases showed poor responses to stimulation (96.2%), 21 cases had odor of maple syrup (40.3%), 29 cases had seizures (55.7%), and 13 cases had respiratory failure (25.0%). The average of the blood ammonia was 127.2 ± 75.0 μmol/L. A total of 18 cases reported the gene testing, among of them 9 cases of BCKDHA mutations, 6 cases of BCKDHB mutations, and 2 cases of DBT mutations. A total of 13 cases (25%) were treated with mechanical ventilation, 50 cases (96.2%) with protein-restricted diet and l-carnitine, 29 cases with thiamine, and only 2 cases were treated with blood purification. Finally, 19 patients (36.5%) were died, 21 cases (40.4%) were improved after treatments.

Conclusions: The clinical phenotype of neonatal MSUD in China belongs to the classical type currently. Suspected patients should have blood or urine branched-chain amino acid levels tested and brain MRI as early as possible to enable early diagnosis, thus improvement in prognosis.
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http://dx.doi.org/10.1515/jpem-2020-0746DOI Listing
June 2021

SP2509, an inhibitor of LSD1, exerts potential antitumor effects by targeting the JAK/STAT3 signaling.

Acta Biochim Biophys Sin (Shanghai) 2021 Jul;53(8):1098-1105

School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun 130117, China.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling promotes tumorigenesis and cancer progression. STAT3 participates in the essential processes of cell proliferation, survival, and differentiation in many types of tumors. In the present study, SP2509 was identified as a potent inhibitor of the JAK/STAT3 signaling pathway by high-throughput drug screening based on a STAT3-driven luciferase expression system. Our results indicated that SP2509 inhibits constitutive STAT3 activation and the expression of STAT3-driven downstream genes. Bcl-xL, c-Myc, and Cyclin D1 were downregulated after treatment with SP2509. In addition, SP2509 specifically inhibits JAK activity, which could cause cell cycle arrest, inhibit cell growth, and induce apoptosis of various cancer cells. These results confirmed that SP2509 inhibits tumor progression by suppressing the expression of JAK/STAT3 signaling and STAT3-related downstream genes. Moreover, we demonstrated that SP2509 inhibits tumor growth in vivo and induces cell death in vitro. SP2509-mediated inhibition of STAT3 phosphorylation is dependent on its original target lysine-specific demethylase 1 in cancer cells. In summary, our results indicate that SP2509 is a novel inhibitor of JAK/STAT3 signaling.
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http://dx.doi.org/10.1093/abbs/gmab083DOI Listing
July 2021

Solvent-Free Lithium/Sodium-Based Metal-Organic Frameworks with Versatile Nitrogen-Rich Ligands: Insight for the Design of Promising Superheat-Resistant Explosives.

Inorg Chem 2021 Jul 24;60(13):9282-9286. Epub 2021 Jun 24.

School of Chemical Engineering, College of Chemistry and Materials Science, Northwest University, Xi'an, Shaanxi 710069, China.

Energetic metal-organic frameworks (EMOFs) are very promising as heat-resistant explosives, affording both thermal stability and energy properties. In this work, the self-assembly of high-energy nitrogen-rich linkers with nontoxic alkali-metal lithium/sodium leads to four new solvent-free EMOFs. Because of unparalleled decomposition temperature ( = 403 °C) and heats of detonation (3.475 kcal·g), a 3D Li(I)-EMOF can be considered to be a superheat-resistant explosive candidate.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01658DOI Listing
July 2021

Metabolomics-based understanding of the olanzapine-induced weight gain in female first-episode drug-naïve patients with schizophrenia.

J Psychiatr Res 2021 08 9;140:409-415. Epub 2021 Jun 9.

Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China. Electronic address:

Previous studies have demonstrated that patients with schizophrenia (SZ) have greater rate of metabolic disorder as compared with the control population, which likely be the consequence of use of atypical antipsychotics. Olanzapine is a widely used antipsychotic, which increases the weight of SZ patients. However, the underlying mechanism remains poorly understood. Here we report the metabolomics-based understanding of the weight gain induced by olanzapine. 57 first-episode drug-naïve patients (FEDN) were recruited, of whom 27 patients completed a 4-week clinical trial. We then profiled the metabolomes of their plasma with the LC-MS-based nontargeted metabolomics approach at the baseline and after olanzapine monotherapy for 4 weeks. We observed that the plasma of the olanzapine-treated patient had significantly higher lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE) and lower carnitine as compared with that of the baseline plasma samples. Moreover, regression analyses indicated that the change of LysoPC(14:0) level was an independent contributor to the olanzapine-induced weight gain. Our study suggests that the metabolomics-based approach may facilitate the identification of biomarkers associated with the metabolic disorder causing by antipsychotic in schizophrenia patients.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.001DOI Listing
August 2021
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