Publications by authors named "Hao Zhu"

579 Publications

Rich-Club Analysis of the Structural Brain Network in Cases with Cerebral Small Vessel Disease and Depression Symptoms.

Cerebrovasc Dis 2021 Sep 17:1-10. Epub 2021 Sep 17.

Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Background: Altered white matter brain networks have been extensively studied in cerebral small vessel disease (SVD). However, there exists currently a deficiency of comprehending the performance of changes within the structural networks of the brain in cases with cerebral SVD and depression symptoms. The main aim of the present research is to study the network topology behaviors and features of rich-club organization in SVD patients using graph theory and diffusion tensor imaging (DTI) to characterize changes in the microstructure of the brain.

Methods: DTI datasets were acquired from 26 SVD patients with symptoms of depression (SVD + D) and 26 SVD patients without symptoms of depression (SVD - D), and a series of neuropsychological assessments were completed. A structural network was created using a deterministic fiber tracking method. The analysis of rich-club was performed in company with analysis of the global network features of the network to characterize the topological properties of all subjects.

Results: DTI data were obtained from SVD patients who manifested symptoms of depression (SVD + D) and from control SVD patients (SVD - D). In comparison with SVD - D patients, SVD + D cases demonstrated a diminished coefficient of clustering along with lower global efficiencies and longer path length characteristics. Rich-club analysis showed SVD + D patients had decreased feeder connectivity and local connectivity strengths compared to SVD - D patients. Our data also showed that the feeder connections in the brain correlated significantly with the severity of depression in SVD + D patients.

Conclusions: Our study revealed that SVD patients with depressive symptoms have disrupted white matter networks that characteristically have reduced network efficiency compared to the networks in other SVD patients. Disrupted information interactions among the regions of nonrich-club and rich-club in SVD cases are related to the severity of depression. Our data suggest that DTI may be utilized as an appropriate biomarker for the diagnosis of depression in comorbid SVD patients.
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http://dx.doi.org/10.1159/000517243DOI Listing
September 2021

Author Correction: miR-93 functions as an oncomiR for the downregulation of PDCD4 in gastric carcinoma.

Sci Rep 2021 Sep 14;11(1):18601. Epub 2021 Sep 14.

State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, Jiangsu, China.

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http://dx.doi.org/10.1038/s41598-021-98187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440678PMC
September 2021

Spatially Graded Millimeter Sized MoWS Monolayer Alloys: Synthesis and Memory Effect.

ACS Appl Mater Interfaces 2021 Sep 8;13(37):44693-44702. Epub 2021 Sep 8.

Tianjin Key Laboratory of Photoelectric Materials and Devices, School of Materials Science and Engineering, Tianjin University of Technology, Tianjin 300384, P. R. China.

The band gap engineering of two-dimensional (2D) transition metal dichacogenides (TMDs) could significantly broaden their applications, especially in electronics and optoelectronics. Alloying is a more effective approach to synthesize 2D ternary TMD materials with tunable bandgaps by regulating the compositions. Whether the alloying could induce memory effects is of interest as a scientific problem and worthy to be studied. A thermal evaporation-assisted chemical vapor deposition (CVD) method was proposed to grow millimeter size gradient alloyed monolayer MoWS. This method reveals a promising and universal methodology for the development of gradient alloyed TMDs because of the precise controlling of each precursor. The synthesized MoWS monolayer crystal has a gradient composition with ranging from 0.1 to 1. The W and Mo atoms homogeneously alloyed with random distribution in the MoWS monolayer. As reported, the deep energy levels induced by sulfur vacancies can be effectively suppressed to shallow energy levels by alloying TMDs. The series distribution of the shallow energy levels in the band of the graded alloy semiconductor can act as multiple charge trapping states, which leads to obvious memory effects in the device. These results present a new opportunity for memory devices and related applications.
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http://dx.doi.org/10.1021/acsami.1c09176DOI Listing
September 2021

Corrigendum to "Tantalum nanoparticles reinforced polyetheretherketone shows enhanced bone formation" [Mater. Sci. Eng. C 101 (2019) 232-242].

Mater Sci Eng C Mater Biol Appl 2021 Sep 5;128:112332. Epub 2021 Aug 5.

Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China. Electronic address:

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http://dx.doi.org/10.1016/j.msec.2021.112332DOI Listing
September 2021

Growth Mechanisms and Morphology Engineering of Atomic Layer-Deposited WS.

ACS Appl Mater Interfaces 2021 Sep 2;13(36):43115-43122. Epub 2021 Sep 2.

State Key Laboratory of ASIC and System, School of Microelectronics, Fudan University, Shanghai 200433, China.

Transition-metal dichalcogenides (TMDs) have attracted intense research interest for a broad range of device applications. Atomic layer deposition (ALD), a CMOS compatible technique, can enable the preparation of high-quality TMD films on 8 to 12 in. wafers for large-scale circuit integration. However, the ALD growth mechanisms are still not fully understood. In this work, we systematically investigated the growth mechanisms for WS and found them to be strongly affected by nucleation density and film thickness. Transmission electron microscope imaging reveals the coexistence and competition of lateral and vertical growth mechanisms at different growth stages, and the critical thicknesses for each mechanism are obtained. The in-plane lateral growth mode dominates when the film thickness remains less than 5.6 nm (8 layers), while the vertical growth mode dominates when the thickness is greater than 20 nm. From the resulting understanding of these growth mechanisms, the conditions for film deposition were optimized and a maximum grain size of 108 nm was achieved. WS-based field-effect transistors were fabricated with electron mobility and on/off current ratio up to 3.21 cm V s and 10, respectively. Particularly, this work proves the capability of synthesis of TMD films in a wafer scale with excellent controllability of thickness and morphology, enabling many potential applications other than transistors, such as nanowire- or nanosheet-based supercapacitors, batteries, sensors, and catalysis.
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http://dx.doi.org/10.1021/acsami.1c13467DOI Listing
September 2021

Influence of Aerobic Fitness on White Matter Integrity and Inhibitory Control in Early Adulthood: A 9-Week Exercise Intervention.

Brain Sci 2021 Aug 18;11(8). Epub 2021 Aug 18.

College of Physical Education, Yangzhou University, Yangzhou 225127, China.

Previous cross-sectional studies have related aerobic fitness to inhibitory control and white matter (WM) microstructure in young adults, but there is no longitudinal study to confirm whether these relationships exist. We carried out a longitudinal study comparing aerobic fitness, inhibitory control, and WM integrity across time points, before versus after completing an exercise intervention in young adults (18-20 years old) relative to a control group. The exercise group ( = 35) participated in a 9-week exercise protocol, while the control group ( = 24) did not receive any regular exercise training. Behavioral data and diffusion tensor imaging (DTI) data were collected prior to and following the intervention. After the exercise intervention, aerobic fitness and inhibitory control performance were significantly improved for the exercise group, but not for the control group. Analyses of variance (ANOVA) of the DTI data demonstrated significantly increased fractional anisotropy (FA) in the right corticospinal tract and significantly decreased FA in the left superior fronto-occipital fasciculus in the exercise group after the intervention versus before. The enhanced aerobic fitness induced by exercise was associated with better inhibitory control performance in the incongruent condition and lower FA in the Left superior fronto-occipital fasciculus (SFOF). Regression analysis of a mediation model did not support Left SFOF FA as a mediator of the relationship between improvements in aerobic fitness and inhibitory control. The present data provide new evidence of the relationship between exercise-induced changes in aerobic fitness, WM integrity, and inhibitory control in early adulthood. Longer-duration intervention studies with larger study cohorts are needed to confirm and further explore the findings obtained in this study.
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http://dx.doi.org/10.3390/brainsci11081080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391670PMC
August 2021

Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes.

Nat Cancer 2020 Sep 7;1(9):909-922. Epub 2020 Sep 7.

Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical cBAF-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiologic and biochemical consequences of ARID1A/ARID1B loss. In double knockout liver and skin, aggressive carcinogenesis followed de-differentiation and hyperproliferation. In double mutant endometrial cancer, add-back of either induced senescence. Biochemically, residual cBAF subcomplexes resulting from loss of ARID1 scaffolding were unexpectedly found to disrupt polybromo containing pBAF function. 37 of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer caused complex disassembly, partially explaining their mutation spectra. ARID1-less, cBAF-less states promote carcinogenesis across tissues, and suggest caution against paralog-directed therapies for ARID1-mutant cancer.
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http://dx.doi.org/10.1038/s43018-020-00109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357309PMC
September 2020

Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Aug 10:159026. Epub 2021 Aug 10.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT impacts on the activity of brown adipocytes in a twofold manner: i) by elevating mitochondrial density plus maximal respiration capacity, and through that, by stimulating BAT oxidative metabolism along with the organelles` uncoupled respiration; and ii) by influencing the free fatty acids pool towards a palmitate-enriched composition and shifting the lipid droplet (LD) equilibrium towards higher counts of smaller droplets. These metabolic changes were accompanied by the up-regulated expression of thermogenesis markers UCP1, CIDEA, CIDEC, PGC1-α and PPAR-α in the BAT of MB wildtype (MBwt) mice. Along with the emergence of the "browning" BAT morphology, MBwt mice exhibited a leaner phenotype when compared to MBko littermates at 20 weeks of age. Our data shed novel insights into MB's role in linking oxygen and lipid-based thermogenic metabolism. The findings suggest potential new strategies of targeting the MB pathway to treat metabolic disorders related to diminishing energy expenditure.
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http://dx.doi.org/10.1016/j.bbalip.2021.159026DOI Listing
August 2021

Effect of a quality improvement intervention with safety-based checklists for perinatal health of hypertension disorders in pregnancy.

Int J Gynaecol Obstet 2021 Aug 9. Epub 2021 Aug 9.

Department of Obstetrics, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.

Objective: To improve perinatal management for hypertensive disorders in pregnancy (HDP) using checklists.

Methods: A pre-post evaluation of the implementation of checklists was performed. The checklist for HDP was adapted for the local context through expert consultations and had been used within peripartum since September 2017. Data of 763 women with singleton pregnancies diagnosed with HDP were collected between April 2016 and March 2019 at the Obstetrics & Gynecology Hospital of Fudan University. The monitoring and control groups consisted of 394 and 369 cases, respectively. Analysis was carried out by intention-to-treat with respect to maternal and fetal complications and delivery outcomes.

Results: After the implementation of the checklists, patients had a significant reduction in anti-hypertensive treatment both orally (P = 0.028) and intravenously (P = 0.003), and increased utilization rate of MgSO management (P < 0.001). Gestation was prolonged in the expectant treatment (P = 0.012) and the rate of elective and intrapartum cesarean delivery decreased (P < 0.001 and P = 0.001, respectively). The neonates of these patients had a low rate of admission to the neonatal intensive care unit (P < 0.001).

Conclusion: National clinical guidelines complied critically after the implementation of the checklists. These checklists could be used for improving the quality of the clinical strategy and treatment, which benefitted perinatal management.
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http://dx.doi.org/10.1002/ijgo.13862DOI Listing
August 2021

Detailed Avatar Recovery from Single Image.

IEEE Trans Pattern Anal Mach Intell 2021 Aug 4;PP. Epub 2021 Aug 4.

This paper presents a novel framework to recover detailed avatar from a single image. It is a challenging task due to factors such as variations in human shapes, body poses, texture and viewpoints. Prior methods typically attempt to recover the human body shape using a parametric based template that lacks the surface details. As such the resulting body shape appears to be without clothing. In this paper, we propose a novel learning-based framework that combines the robustness of parametric model with the flexibility of free-form 3D deformation. We use the deep neural networks to refine the 3D shape in a Hierarchical Mesh Deformation (HMD) framework, utilizing the constraints from body joints, silhouettes, and per-pixel shading information. We are able to restore detailed human body shapes with complete textures beyond skinned models. Experiments demonstrate that our method has outperformed previous state-of-the-art approaches, achieving better accuracy in terms of both 2D IoU number and 3D metric distance.
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http://dx.doi.org/10.1109/TPAMI.2021.3102128DOI Listing
August 2021

Interaction between polyene antifungal drug and saturated phospholipid monolayer regulated by calcium ions at the air-water interface.

Authors:
Juan Wang Hao Zhu

Colloids Surf B Biointerfaces 2021 Jul 22;207:111998. Epub 2021 Jul 22.

Shaanxi Engineering Research Center of Controllable Neutron Source, School of Science, Xijing University, Xi'an, 710123, China.

Amphotericin B (AmB) is a polyene antifungal drug, which could directly form pores on the sterol-free phospholipid monolayers. The interaction between AmB and phospholipid can be affected by calcium ions, but the mechanism is still unclear. DPPC is a saturated phospholipid with -PC group, which is often used to simulate the outer cell membrane leaflet. And DPPC is also the main constituent of pulmonary surfactants. In this work, the DPPC monolayer was used as a model membrane to study the effect of calcium ions on the interaction between AmB and phospholipid. The influence of different concentration of calcium ions on the elastic modulus, mean molecular area increment, excess Gibbs free energy and stability of the AmB/DPPC mixed monolayer has been researched at the surface pressure of 7.5 mN/m, 12.5 mN/m and 22.5 mN/m. The AmB/DPPC monolayers at the air-water interface have been observed in real-time by Brewster angle microscope and the microstructure of the Langmuir-Blodgett monolayer films transferred onto the mica have been researched by scanning electron microscope and atomic force microscope. The results showed that calcium ions had a significant influence on the elastic modulus, mean molecular area increment, excess Gibbs free energy, stability and microstructure of the AmB/DPPC monolayer. It has been indicated that the influence of calcium ions on the interaction between AmB and DPPC molecules mainly depended on the effect of calcium ions on the orientation of AmB molecules. The calcium ions could regulate the effect of AmB to the stability of the DPPC monolayer. This regulatory role changed with the different concentrations of calcium ions and the different phase states of the monolayer. This work provides useful information to further understand the influence mechanism of calcium ions on the interaction between AmB and saturated phospholipid with -PC group, which is helpful to find out the effect mechanism of calcium ion on the interaction between AmB and the outer layer of cell membrane or pulmonary surfactants in different phase states and to understand the toxicity mechanism of AmB on the cell membrane or lungs.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111998DOI Listing
July 2021

Revealing Adverse Outcome Pathways from Public High-Throughput Screening Data to Evaluate New Toxicants by a Knowledge-Based Deep Neural Network Approach.

Environ Sci Technol 2021 08 25;55(15):10875-10887. Epub 2021 Jul 25.

Center for Computational and Integrative Biology, Rutgers University Camden, Camden, New Jersey 08103, United States.

Traditional experimental testing to identify endocrine disruptors that enhance estrogenic signaling relies on expensive and labor-intensive experiments. We sought to design a knowledge-based deep neural network (k-DNN) approach to reveal and organize public high-throughput screening data for compounds with nuclear estrogen receptor α and β (ERα and ERβ) binding potentials. The target activity was rodent uterotrophic bioactivity driven by ERα/ERβ activations. After training, the resultant network successfully inferred critical relationships among ERα/ERβ target bioassays, shown as weights of 6521 edges between 1071 neurons. The resultant network uses an adverse outcome pathway (AOP) framework to mimic the signaling pathway initiated by ERα and identify compounds that mimic endogenous estrogens (i.e., estrogen mimetics). The k-DNN can predict estrogen mimetics by activating neurons representing several events in the ERα/ERβ signaling pathway. Therefore, this virtual pathway model, starting from a compound's chemistry initiating ERα activation and ending with rodent uterotrophic bioactivity, can efficiently and accurately prioritize new estrogen mimetics (AUC = 0.864-0.927). This k-DNN method is a potential universal computational toxicology strategy to utilize public high-throughput screening data to characterize hazards and prioritize potentially toxic compounds.
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http://dx.doi.org/10.1021/acs.est.1c02656DOI Listing
August 2021

Survival outcomes of patients with brain metastasis of osteosarcoma can be improved by aggressive multi-disciplinary interventions including chemotherapy.

Br J Neurosurg 2021 Jul 15:1-6. Epub 2021 Jul 15.

Jinling Hospital Department of Orthopaedics, Nanjing Medical University, Nanjing, China.

Background/objective: Brain metastasis in osteosarcoma (BMO) is rare and its clinical characteristics are often buried among studies on brain metastasis of bone and soft tissue sarcomas. The aim of the present study was to summarize the incidence, clinical characteristics, treatment and outcomes of patients with BMO.

Methods: This retrospective study included 7 patients with BMO who received treatment in our center between 2005 and 2019. The clinical medical records of the 7 patients, together with data of 70 BMO patients published in 33 articles and retrieved by means of PubMed and Medline, were analyzed, retrospectively.

Results: Data analysis of the 97 BMO patients showed a high correlation between the interval from the primary diagnosis to BMO occurrence and the interval from the primary diagnosis to prior metastases. Multivariate analysis showed that chemotherapy, radiotherapy and surgery were three main factors affecting the overall survival of BMO patients (HR = 0.427; HR = 0.372; HR = 0.296). Surgery combined with chemotherapy or radiotherapy offered a better overall survival than surgery alone.

Conclusion: Patients with BMO may obtain survival benefits from regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy.

Synopsis: This is a retrospective study describing the characteristics of metastasic intervals, locations, clinical features and prognosis in 97 patients with brain metastasis of osteosarcoma (BMO). Multivariate analysis showed that chemotherapy was effective as surgery and radiotherapy for the treatment of BMO. Our findings emphasize the importance of regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy.
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http://dx.doi.org/10.1080/02688697.2021.1950624DOI Listing
July 2021

Prevalence and treatment of high cardiovascular disease risk in Inner Mongolia, China.

Rev Cardiovasc Med 2021 Jun;22(2):521-529

School of Public Health, Inner Mongolia Medical University, 010110 Hohhot, Inner Mongolia, China.

Early identification of individuals with high risk is crucial to preventing cardiovascular disease (CVD). We aimed to determine the prevalence of high CVD risk in Inner Mongolia and to analyze the treatment of major risk factors among individuals with high CVD risk. We selected 70,380 participants aged 35-75 years in Inner Mongolia between 2015 and 2017 using multistage stratified sampling. All participants completed a questionnaire and their blood pressure, blood glucose and lipid levels, height, weight and waist circumference were measured. Participants without a history of CVD were defined as high CVD risk if the predicted 10-year risk for CVD exceeded 10%. We assessed rates of high CVD risk and the prevalence and treatment of major risk factors among individuals with high CVD risk. After excluding participants with previous CVD, 68,083 participants remained. The overall prevalence of high CVD risk was 24.96%. The age- and sex-standardized rate of high CVD risk was 22.92%. Among high-risk participants, the prevalence of risk factors was hypertension (91.9%), dyslipidemia (54.1%), obesity (34.6%), diabetes (27.6%), and smoking (24.5%); clustering of these risk factors was common. The percentage of high-risk individuals taking antihypertensive drugs was 45.94% in those with hypertension; 27.99% of those with diabetes took hypoglycemic drugs and only 5.01% of those with dyslipidemia took lipid-lowering drugs. Control rates of hypertension, diabetes, and dyslipidemia were 1.20%, 4.43%, and 2.78%, respectively. Therefore, the prevalence of high CVD risk was elevated in Inner Mongolia, and treatment and control rates were low.
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http://dx.doi.org/10.31083/j.rcm2202060DOI Listing
June 2021

Elucidate growth control mechanisms using reconstructed spatiotemporal distributions of signaling events.

Authors:
Hao Zhu

Comput Struct Biotechnol J 2021 18;19:3618-3627. Epub 2021 Jun 18.

Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Shatai Road, Guangzhou 510515, China.

A fundamental biological question is how diverse and complex signaling and patterning is controlled correctly to generate distinct tissues, organs, and body plans, but incorrectly in diseased cells and tissues. Signaling pathways important for growth control have been identified, but to identify the mechanisms their transient and context-dependent interactions encode is more difficult. Currently computational systems biology aims to infer the control mechanisms by investigating quantitative changes of gene expression and protein concentrations, but this inference is difficult in nature. We propose it is desirable to explicitly simulate events and orders of gene regulation and protein interactions, which better elucidate control mechanisms, and report a method and tool with three examples. The wing model includes Wnt, PCP, and Hippo pathways and mechanical force, incorporates well-confirmed experimental findings, and generates novel results. The other two examples illustrate the building of three-dimensional and large-scale models. These examples support that reconstructed spatiotemporal distributions of key signaling events help elucidate growth control mechanisms. As biologists pay increasing attention to disordered signaling in diseased cells, to develop new modeling methods and tools for conducting new computational studies is important.
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http://dx.doi.org/10.1016/j.csbj.2021.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249872PMC
June 2021

Construction of a Virtual Opioid Bioprofile: A Data-Driven QSAR Modeling Study to Identify New Analgesic Opioids.

ACS Sustain Chem Eng 2021 Mar 4;9(10):3909-3919. Epub 2021 Mar 4.

The Rutgers Center for Computational and Integrative Biology, Joint Health Sciences Center, Camden, New Jersey 08103, United States; Department of Chemistry, Rutgers University, Camden, New Jersey 08102, United States.

Compared to traditional experimental approaches, computational modeling is a promising strategy to efficiently prioritize new candidates with low cost. In this study, we developed a novel data mining and computational modeling workflow proven to be applicable by screening new analgesic opioids. To this end, a large opioid data set was used as the probe to automatically obtain bioassay data from the PubChem portal. There were 114 PubChem bioassays selected to build quantitative structure-activity relationship (QSAR) models based on the testing results across the probe compounds. The compounds tested in each bioassay were used to develop 12 models using the combination of three machine learning approaches and four types of chemical descriptors. The model performance was evaluated by the coefficient of determination ( ) obtained from 5-fold cross-validation. In total, 49 models developed for 14 bioassays were selected based on the criteria and were identified to be mainly associated with binding affinities to different opioid receptors. The models for these 14 bioassays were further used to fill data gaps in the probe opioids data set and to predict general drug compounds in the DrugBank data set. This study provides a universal modeling strategy that can take advantage of large public data sets for computer-aided drug design (CADD).
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http://dx.doi.org/10.1021/acssuschemeng.0c09139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259887PMC
March 2021

Investigation of the Mechanisms of Chuankezhi Injection in the Treatment of Asthma Based on the Network Pharmacology Approach.

Evid Based Complement Alternat Med 2021 10;2021:5517041. Epub 2021 Jun 10.

Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Chuankezhi injection (CKZI) was an effective traditional Chinese medicine (TCM) injection in adjuvant bronchial asthma therapy. In this report, we used a network pharmacology method to reveal the mechanisms of CKZI for the treatment of asthma.

Methods: The candidate compounds in CKZI were determined by searching the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and China National Knowledge Infrastructure website (CNKI). The targets of candidate compounds were searched in the TCMSP, DrugBank 5.0, and SwissTargetPrediction. The disease targets were screened from the Online Mendelian Inheritance in Man (OMIM) and GeneCards. The overlapping gene symbols between candidate compounds and disease were filtered via a Venn diagram and were considered as potential targets. A protein-protein interaction (PPI) network and disease-related candidate compound-target-pathway (DC-T-P) network were visualized by Cytoscape 3.6.1. Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by metascape to determine the pathways related to asthma.

Results: A total of 70 overlapping gene symbols were recognized as potential targets. Cytokines (IL6, TNF, and IL1B) and chemokines (CXCL8 and CCL2) could be recognized as hub genes. Asthma-related candidate compounds were mainly flavonoids, such as quercetin, luteolin, and kaempferol. The cytokine-mediated signaling pathway, cytokine receptor binding, and membrane craft were the most significant biological process (BP), molecular function (MF), and cellular component (CC) of GO function results, respectively. The relevant pathways of CKZI against asthma mainly include IL-17, NF-kappa B, HIF-1, calcium, and PI3K-Akt signaling pathways.

Conclusion: Our research provided a theoretical basis for further investigating the mechanisms of CKZI in the treatment of asthma.
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http://dx.doi.org/10.1155/2021/5517041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213469PMC
June 2021

Isovitexin attenuates tumor growth in human colon cancer cells through the modulation of apoptosis and epithelial-mesenchymal transition via PI3K/Akt/mTOR signaling pathway.

Biochem Cell Biol 2021 Jul 4. Epub 2021 Jul 4.

Yantaishan Hospital, 519688, Yantai, Shandong, China;

Isovitexin, a biologically active flavone C-glycosylated derivative, has a variety of biological activities. We aimed to identify the effect of isovitexin (Isov) on colon cancer. The human colonic epithelial cell (HCEC), and cancer cells were treated with Isov, Cell Counting Kit-8 (CCK8) was used to detect cell proliferation and calculate half-inhibitory concentration (IC50). The biological activity of cancer cells were assessed. The tumor size and volume were recorded. The expression levels of proteins were analyzed by western blot. Isov inhibited cancer cells proliferation, while had little cytotoxicity on HCEC. Isov significantly attenuated cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), induced cell apoptosis, and that trends were blocked by insulin-like growth factor-1 (IGF-1) treated. The expression levels of phosphorylated phosphatidylinositol 3-kinasep (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and B-cell lymphoma-2 (Bcl-2) evidently decreased when treated with Isov, while the levels of Bcl2-associated X (Bax), and caspase-3 significantly increased. After Isov treatment, the tumor volume and weight were decreased, the levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2 significantly decreased in tumor tissues. Our finding demonstrated that Isov could inhibit cancer cells migration, invasion and EMT. Isov maybe a new potentially treatment medicine for colon cancer.
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http://dx.doi.org/10.1139/bcb-2021-0045DOI Listing
July 2021

Anti-SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations.

CPT Pharmacometrics Syst Pharmacol 2021 09 1;10(9):973-982. Epub 2021 Aug 1.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs. Continuous development and expansion are feasible with the public availability of this database.
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http://dx.doi.org/10.1002/psp4.12681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420371PMC
September 2021

siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis.

Front Oncol 2021 14;11:662444. Epub 2021 Jun 14.

State Key Laboratory of Organ Failure Research, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells . 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.
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http://dx.doi.org/10.3389/fonc.2021.662444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236890PMC
June 2021

Model-Informed Drug Development in Pediatric Dose Selection.

J Clin Pharmacol 2021 06;61 Suppl 1:S60-S69

Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, Maryland, USA.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.
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http://dx.doi.org/10.1002/jcph.1848DOI Listing
June 2021

Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder.

J Clin Pharmacol 2021 06;61 Suppl 1:S117-S124

Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation Research, US Food and Drug Administration, White Oak, Silver Spring, Maryland, USA.

Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence-based literature to make critical therapeutic decisions for pediatric patients. Effective and scientifically justified dosing recommendations are needed to improve treatment outcomes in pediatric patients with schizophrenia and bipolar I disorder. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the US Food and Drug Administration (FDA) released a general advice letter to sponsors highlighting the acceptance of extrapolating efficacy of atypical antipsychotics to pediatric patients. This review provides insight into the FDA's justification for extrapolating efficacy from adult to pediatric patients and provides a rationale for dose selection in pediatric patients with schizophrenia and bipolar I disorder.
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http://dx.doi.org/10.1002/jcph.1836DOI Listing
June 2021

Catalytic asymmetric nucleophilic fluorination using BF·EtO as fluorine source and activating reagent.

Nat Commun 2021 06 25;12(1):3957. Epub 2021 Jun 25.

Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Fluorination using chiral catalytic methods could result in a direct access to asymmetric fluorine chemistry. However, challenges in catalytic asymmetric fluorinations, especially the longstanding stereochemical challenges existed in BF·EtO-based fluorinations, have not yet been addressed. Here we report the catalytic asymmetric nucleophilic fluorination using BF·EtO as the fluorine reagent in the presence of chiral iodine catalyst. Various chiral fluorinated oxazine products were obtained with good to excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Control experiments (the desired fluoro-oxazines could not be obtained when Py·HF or EtN·3HF were employed as the fluorine source) indicated that BF·EtO acted not only as a fluorine reagent but also as the activating reagent for activation of iodosylbenzene.
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http://dx.doi.org/10.1038/s41467-021-24278-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233348PMC
June 2021

Inverse identification of pollution source release information for surface river chemical spills using a hybrid optimization model.

J Environ Manage 2021 Sep 11;294:113022. Epub 2021 Jun 11.

School of Software, Harbin Institute of Technology, Harbin, 150090, China. Electronic address:

To evaluate the liability of the spilled contaminant and to design comprehensive emergency response schemes, it is essential to estimate the contaminant source characteristic and identify where, when and how much the spilled contaminant is injected into a surface river. In this study, an effective pollution source inverse method is developed to reconstruct the release history of the injection location, time, and quantity, and provide appropriate emergency response schemes for dealing with surface river environmental pollution. The pollution source inverse method IGSAA is developed by an integration of genetic algorithm (IGA) and simulated annealing algorithm (SAA) in order to guarantee both the global searching ability and convergence speed. The pollution source inverse method IGSAA is then applied to a hypothetical study, comparing with the traditional GA-based and SAA-based methods, to verify the accuracy and efficiency of the contaminant source inverse, and to a trace study of Truckee River in west America to identify the contaminant source release history and characteristic under different scenarios. The pollution source inversion results can help decision-makers (DMs) to identify the contaminant source characteristics of a chemical spill, and carry out emergency disposal scheme for an emergency rescue in a quick response, and enhance the supervision and management ability for a real surface river system.
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http://dx.doi.org/10.1016/j.jenvman.2021.113022DOI Listing
September 2021

Deficits in multi-scale top-down processes distorting auditory perception in schizophrenia.

Behav Brain Res 2021 Aug 11;412:113411. Epub 2021 Jun 11.

NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, 3663 Zhongshan Road North, Shanghai, 200062, China; Division of Arts and Sciences, New York University Shanghai, 1555 Century Avenue, Shanghai, 200122, China. Electronic address:

Cognitive models postulate that impaired source monitoring incorrectly weights the top-down prediction and bottom-up sensory processes and causes hallucinations. However, the underlying mechanisms of the interaction, such as whether the incorrectly weighting is ubiquitously on all levels of sensory features and whether different top-down processes have distinct effects in subgroups of schizophrenia are still unclear. This study investigates how multi-scale predictions influence perception of basic tonal features in schizophrenia. Sixty-three schizophrenia patients with and without symptoms of auditory verbal hallucinations (AVHs), and thirty healthy controls identified target tones in noise at the end of tone sequences. Predictions of different timescales were manipulated by either an alternating pattern in the preceding tone sequences (long-term regularity) or a repetition between the target tone and the tone immediately before (short-term repetition). The sensitivity index, d prime (d'), was obtained to assess the modulation of predictions on tone identification. Patients with AVHs showed higher d' when the target tones conformed to the long-term regularity of alternating pattern in the preceding tone sequence than when the target tones were inconsistent with the pattern. Whereas, the short-term repetition modulated the tone identification in patients without AVHs. Predictions did not influence tone identification in healthy controls. Our results suggest that impaired source monitoring in schizophrenia patients with AVHs heavily weights top-down predictions over bottom-up perceptual processes to form incorrect perception. The weighting function in source monitoring can extend to the processes of basic tonal features, and predictions at multiple timescales could differentially modulate perception in different clinical populations. The impaired interaction between top-down and bottom-up processes might underlie the development of hallucination symptoms in schizophrenia.
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http://dx.doi.org/10.1016/j.bbr.2021.113411DOI Listing
August 2021

An in-memory computing architecture based on two-dimensional semiconductors for multiply-accumulate operations.

Nat Commun 2021 06 7;12(1):3347. Epub 2021 Jun 7.

State Key Laboratory of ASIC and System, School of Microelectronics, Fudan University, Shanghai, China.

In-memory computing may enable multiply-accumulate (MAC) operations, which are the primary calculations used in artificial intelligence (AI). Performing MAC operations with high capacity in a small area with high energy efficiency remains a challenge. In this work, we propose a circuit architecture that integrates monolayer MoS transistors in a two-transistor-one-capacitor (2T-1C) configuration. In this structure, the memory portion is similar to a 1T-1C Dynamic Random Access Memory (DRAM) so that theoretically the cycling endurance and erase/write speed inherit the merits of DRAM. Besides, the ultralow leakage current of the MoS transistor enables the storage of multi-level voltages on the capacitor with a long retention time. The electrical characteristics of a single MoS transistor also allow analog computation by multiplying the drain voltage by the stored voltage on the capacitor. The sum-of-product is then obtained by converging the currents from multiple 2T-1C units. Based on our experiment results, a neural network is ex-situ trained for image recognition with 90.3% accuracy. In the future, such 2T-1C units can potentially be integrated into three-dimensional (3D) circuits with dense logic and memory layers for low power in-situ training of neural networks in hardware.
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http://dx.doi.org/10.1038/s41467-021-23719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184885PMC
June 2021

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat.

Clin Transl Sci 2021 Jun 3. Epub 2021 Jun 3.

Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO ). The current study used that model to assess the impact on respiration of non-benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO above the oxycodone effect. Analyses indicated that most pCO interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO recorded with oxycodone-paroxetine co-administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug-drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co-administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.
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http://dx.doi.org/10.1111/cts.13080DOI Listing
June 2021

Effects of Mini-Basketball Training Program on Social Communication Impairment and Executive Control Network in Preschool Children with Autism Spectrum Disorder.

Int J Environ Res Public Health 2021 05 12;18(10). Epub 2021 May 12.

College of Physical Education, Yangzhou University, Yangzhou 225127, China.

This study evaluated the effect of a 12-week mini-basketball training program (MBTP) on social communication (SC) and the executive control network (ECN) in preschool children with autism spectrum disorders (ASD). We finally assigned 30 preschool children with ASD to an experiment group ( = 15, 12 males, 3 females) or a control group ( = 15, 13 males, 2 females). The experiment group participated in a 12-week MBTP (40-min sessions per day, 5 days a week), while the control group only received the institutional routine behavioral rehabilitation intervention. The SC of preschool children with ASD was measured using the Social Responsiveness Scale, Second Edition (SRS-2), whereas functional connectivity (FC) of the ECN was assessed using resting-state functional magnetic resonance imaging (rs-fMRI) at pre-and post-test. Our results showed that SC exhibited significant improvement in the intervention group, especially in SRS-2 total score, social cognition, and social communication. We found significantly enhanced functional connectivity between the right cerebellum and left inferior frontal gyrus in the experimental group, while functional connectivity between the left middle temporal gyrus and right cerebellum were decreased in the control group. Furthermore, there were no significant correlations between the change in SC scores and FC of the ECN. Altogether, this study provides valuable insights that a 12-week MBTP improves SC and functional connectivity of the ECN in preschool children with ASD. We further inferred that neural mechanisms might be associated with changing the ECN of preschool ASD children caused by the 12-week MBTP.
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http://dx.doi.org/10.3390/ijerph18105132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150962PMC
May 2021
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