Publications by authors named "Jian Yan"

323 Publications

Combined scaffold hopping, molecular screening with dynamic simulation to screen potent CRBN ligands.

J Cell Biochem 2021 May 3. Epub 2021 May 3.

School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.

Thalidomide and its derivatives lenalidomide and pomalidomide, known as immunomodulatory drugs, (IMiDs) bind directly to cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase, resulting in the rapid ubiquitination and degradation of the substrate protein. With the discovery of the protein degradation mechanism of IMiDs, targeted protein degradation mediated by IMiDs via CRBN emerged and developed rapidly for the advantages of overcoming drug resistance and targeting undruggable. To date, almost all CRBN ligands are derived from thalidomide and there are few structural differences between them. Hence, we employed an accurate, effective, and rational approach to screen novel and potential CRBN ligands. In this study, we have built a molecular library by scaffold hopping with thalidomide. ADMET screening, virtual screening, and visual inspection screening were performed step-by-step to screen the molecular library and five molecules were hit. Furthermore, docking analysis and a period of 150 ns molecular dynamic (MD) simulation were performed to validate the accuracy of our screen. The docking results showed that molecular A (-10.42 kcal/mol), molecular B (-9.73 kcal/mol), molecular C (-9.25 kcal/mol), molecular D (-9.09 kcal/mol), and molecular E (-10.16 kcal/mol) have lower binding energy than thalidomide (-5.42 kcal/mol), lenalidomide (-5.74 kcal/mol), and pomalidomide (-5.51 kcal/mol). In the MD simulation, all the five screened molecules form key interactions with the active site amino acid residues (Trp380, Trp386, and Trp400) as well as the three marketed IMiDs. Besides, we found and explained that Pro352 was positive for ligand binding to CRBN and Glu377 in reverse, which has not been reported before. We believe that our findings and those five molecules can serve as further optimization of CRBN ligands and development of proteolysis targeting chimeras.
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http://dx.doi.org/10.1002/jcb.29941DOI Listing
May 2021

A Mediation Analysis to Identify Links between Gut Bacteria and Memory in Context of Human Milk Oligosaccharides.

Microorganisms 2021 Apr 15;9(4). Epub 2021 Apr 15.

Traverse Science, Inc., Champaign, IL 61820, USA.

Elucidating relationships between the gut and brain is of intense research focus. Multiple studies have demonstrated that modulation of the intestinal environment via prebiotics or probiotics can induce cognitively beneficial effects, such as improved memory or reduced anxiety. However, the mechanisms by which either act remain largely unknown. We previously demonstrated that different types of oligosaccharides affected short- and long-term memory in distinct ways. Given that the oligosaccharide content of human milk is highly variable, and that formula-fed infants typically do not consume similar amounts or types of oligosaccharides, their potential effects on brain development warrant investigation. Herein, a mediation analysis was performed on existing datasets, including relative abundance of bacterial genera, gene expression, brain volume, and cognition in young pigs. Analyses revealed that numerous bacterial genera in both the colon and feces were related to short- and/or long-term memory. Relationships between genera and memory appeared to differ between diets. Mediating variables frequently included GABAergic and glutamatergic hippocampal gene expression. Other mediating variables included genes related to myelination, transcription factors, brain volume, and exploratory behavior. Overall, this analysis identified multiple pathways between the gut and brain, with a focus on genes related to excitatory/inhibitory neurotransmission.
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http://dx.doi.org/10.3390/microorganisms9040846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071191PMC
April 2021

Bovine Milk Oligosaccharides and Human Milk Oligosaccharides Modulate the Gut Microbiota Composition and Volatile Fatty Acid Concentrations in a Preclinical Neonatal Model.

Microorganisms 2021 Apr 21;9(5). Epub 2021 Apr 21.

Department of Food Science & Human Nutrition, University of Illinois, Urbana, IL 61801, USA.

Milk oligosaccharides (OS) shape microbiome structure and function, but their relative abundances differ between species. Herein, the impact of the human milk oligosaccharides (HMO) (2'-fucosyllactose [2'FL] and lacto-N-neotetraose [LNnT]) and OS isolated from bovine milk (BMOS) on microbiota composition and volatile fatty acid (VFA) concentrations in ascending colon (AC) contents and feces was assessed. Intact male piglets received diets either containing 6.5 g/L BMOS (n = 12), 1.0 g/L 2'FL + 0.5 g/L LNnT (HMO; n = 12), both (HMO + BMOS; n = 10), or neither (CON; n = 10) from postnatal day (PND) 2 to 34. Microbiota were assessed by 16S rRNA gene sequencing and real-time PCR, and VFA were measured by gas chromatography. The microbiota was affected by OS in an intestine region-specific manner. BMOS reduced ( < 0.05) microbial richness in the AC, microbiota composition in the AC and feces, and acetate concentrations in AC, regardless of HMO presence. HMO alone did not affect overall microbial composition, but increased ( < 0.05) the relative proportion of specific taxa, including , compared to other groups. abundance was increased ( < 0.05) in the AC by BMOS and synergistically by BMOS + HMO in the feces. Distinct effects of HMO and BMOS suggest complementary and sometimes synergistic benefits of supplementing a complex mixture of OS to formula.
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http://dx.doi.org/10.3390/microorganisms9050884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143120PMC
April 2021

An atlas of the binding specificities of transcription factors in directs prediction of novel regulators in virulence.

Elife 2021 03 29;10. Epub 2021 Mar 29.

Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, China.

A high-throughput systematic evolution of ligands by exponential enrichment assay was applied to 371 putative TFs in , which resulted in the robust enrichment of 199 unique sequence motifs describing the binding specificities of 182 TFs. By scanning the genome, we predicted in total 33,709 significant interactions between TFs and their target loci, which were more than 11-fold enriched in the intergenic regions but depleted in the gene body regions. To further explore and delineate the physiological and pathogenic roles of TFs in , we constructed regulatory networks for nine major virulence-associated pathways and found that 51 TFs were potentially significantly associated with these virulence pathways, 32 of which had not been characterized before, and some were even involved in multiple pathways. These results will significantly facilitate future studies on transcriptional regulation in and other relevant pathogens, and accelerate to discover effective treatment and prevention strategies for the associated infectious diseases.
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http://dx.doi.org/10.7554/eLife.61885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041468PMC
March 2021

Genetic mapping identifies a rice naringenin O-glucosyltransferase that influences insect resistance.

Plant J 2021 Mar 20. Epub 2021 Mar 20.

Key Laboratory of Agro-Environment in the Tropics, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Eco-Circular Agriculture, Guangdong Engineering Research Centre for Modern Eco-Agriculture, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, People's Republic of China.

Naringenin, the biochemical precursor for predominant flavonoids in grasses, provides protection against UV damage, pathogen infection and insect feeding. To identify previously unknown loci influencing naringenin accumulation in rice (Oryza sativa), recombinant inbred lines derived from the Nipponbare and IR64 cultivars were used to map a quantitative trait locus (QTL) for naringenin abundance to a region of 50 genes on rice chromosome 7. Examination of candidate genes in the QTL confidence interval identified four predicted uridine diphosphate-dependent glucosyltransferases (Os07g31960, Os07g32010, Os07g32020 and Os07g32060). In vitro assays demonstrated that one of these genes, Os07g32020 (UGT707A3), encodes a glucosyltransferase that converts naringenin and uridine diphosphate-glucose to naringenin-7-O-β-d-glucoside. The function of Os07g32020 was verified with CRISPR/Cas9 mutant lines, which accumulated more naringenin and less naringenin-7-O-β-d-glucoside and apigenin-7-O-β-d-glucoside than wild-type Nipponbare. Expression of Os12g13800, which encodes a naringenin 7-O-methyltransferase that produces sakuranetin, was elevated in the mutant lines after treatment with methyl jasmonate and insect pests, Spodoptera litura (cotton leafworm), Oxya hyla intricata (rice grasshopper) and Nilaparvata lugens (brown planthopper), leading to a higher accumulation of sakuranetin. Feeding damage from O. hyla intricata and N. lugens was reduced on the Os07g32020 mutant lines relative to Nipponbare. Modification of the Os07g32020 gene could be used to increase the production of naringenin and sakuranetin rice flavonoids in a more targeted manner. These findings may open up new opportunities for selective breeding of this important rice metabolic trait.
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http://dx.doi.org/10.1111/tpj.15244DOI Listing
March 2021

Directed evolution of an enhanced POU reprogramming factor for cell fate engineering.

Mol Biol Evol 2021 Mar 15. Epub 2021 Mar 15.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Transcription factor-driven cell fate engineering in pluripotency induction, transdifferentiation, and forward reprogramming require efficiency, speed, and maturity for widespread adoption and clinical translation. Here, we used Oct4, Sox2, Klf4, c-Myc driven pluripotency reprogramming to evaluate methods for enhancing and tailoring cell fate transitions, through directed evolution with iterative screening of pooled mutant libraries and phenotypic selection. We identified an artificially evolved and enhanced POU factor (ePOU) that substantially outperforms wild-type Oct4 in terms of reprogramming speed and efficiency. In contrast to Oct4, ePOU can induce pluripotency with Sox2 alone and in the absence of Sox2 in three factor - ePOU/Klf4/c-Myc cocktails. Biochemical assays combined with genome-wide analyses show that ePOU acquires a new preference to dimerize on palindromic DNA elements. Yet, the moderate capacity of Oct4 to function as a pioneer factor, its preference to bind octamer DNA and its capability to dimerize with Sox2 and Sox17 proteins are not changed in ePOU. Compared to Oct4, ePOU is thermodynamically stabilized and persists longer in reprogramming cells. In consequence, ePOU: (1) differentially activates several genes hitherto not implicated in reprogramming, (2) reveals an unappreciated role of thyrotropin-releasing hormone signaling, and (3) binds a distinct class of retrotransposons. Collectively, these features enabled ePOU to accelerate the establishment of the pluripotency network. This demonstrates that the phenotypic selection of novel factor variants from mammalian cells with desired properties is key to advancing cell fate conversions with artificially evolved biomolecules.
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http://dx.doi.org/10.1093/molbev/msab075DOI Listing
March 2021

Mutagenicity of silver nanoparticles evaluated using whole-genome sequencing in mouse lymphoma cells.

Nanotoxicology 2021 04 12;15(3):418-432. Epub 2021 Mar 12.

Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA.

The increasing medical and food applications of silver nanoparticles (AgNPs) raise concerns about their safety, including the potential health consequences of human exposure. Previous studies found that AgNPs were negative in the Ames test due to both their microbicidal activity and the inability of nanoparticles to penetrate bacterial cell walls. Thus, the mutagenicity of AgNPs is still not completely clear, though they do induce chromosome damage, as suggested by many previous genotoxicity studies. In this study, whole-genome sequencing (WGS) was used to analyze the mutagenicity of AgNPs in mouse lymphoma cells expanded from single-cell clones. The cells were treated with AgNPs, 4-nitroquinolone-1-oxide (4-NQO) as the positive control, and vehicle controls. Both AgNPs and 4-NQO significantly increased mutation frequencies over their concurrent controls by 1.12-fold and 4.89-fold with mutation rates at 4-fold and 130-fold, respectively. AgNP-induced mutations mainly occurred at G:C sites with G:C > T:A transversions, G:C > A:T transitions, and deletions as the most commonly observed mutations. AgNPs also induced higher fold changes in tandem mutations. The results suggest that the WGS mutation assay conducted here can detect the low-level mutagenicity of AgNPs, providing substantial support for the use of the WGS method as a possible alternative assay with respect to the mutagenic assessment of nanomaterials.
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http://dx.doi.org/10.1080/17435390.2021.1894614DOI Listing
April 2021

Multivalent DNA Vaccines as A Strategy to Combat Multiple Concurrent Epidemics: Mosquito-Borne and Hemorrhagic Fever Viruses.

Viruses 2021 02 27;13(3). Epub 2021 Feb 27.

Inovio Pharmaceuticals Inc., Plymouth Meeting, PA 19462, USA.

The emergence of multiple concurrent infectious diseases localized in the world creates a complex burden on global public health systems. Outbreaks of Ebola, Lassa, and Marburg viruses in overlapping regions of central and West Africa and the co-circulation of Zika, Dengue, and Chikungunya viruses in areas with A. aegypti mosquitos highlight the need for a rapidly deployable, safe, and versatile vaccine platform readily available to respond. The DNA vaccine platform stands out as such an application. Here, we present proof-of-concept studies from mice, guinea pigs, and nonhuman primates for two multivalent DNA vaccines delivered using in vivo electroporation (EP) targeting mosquito-borne (MMBV) and hemorrhagic fever (MHFV) viruses. Immunization with MMBV or MHFV vaccines via intradermal EP delivery generated robust cellular and humoral immune responses against all target viral antigens in all species. MMBV vaccine generated antigen-specific binding antibodies and IFNγ-secreting lymphocytes detected in NHPs up to six months post final immunization, suggesting induction of long-term immune memory. Serum from MHFV vaccinated NHPs demonstrated neutralizing activity in Ebola, Lassa, and Marburg pseudovirus assays indicating the potential to offer protection. Together, these data strongly support and demonstrate the versatility of DNA vaccines as a multivalent vaccine development platform for emerging infectious diseases.
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http://dx.doi.org/10.3390/v13030382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997291PMC
February 2021

Self-Locomotive Soft Actuator Based on Asymmetric Microstructural TiCT MXene Film Driven by Natural Sunlight Fluctuation.

ACS Nano 2021 03 2;15(3):5294-5306. Epub 2021 Mar 2.

Key Laboratory of Advanced Functional Materials and Devices of Anhui Province, School of Materials Science and Engineering, Hefei University of Technology, Hefei 230009, P. R. China.

Soft actuators and microrobots that can move spontaneously and continuously without artificial energy supply and intervention have great potential in industrial, environmental, and military applications, but still remain a challenge. Here, a bioinspired MXene-based bimorph actuator with an asymmetric layered microstructure is reported, which can harness natural sunlight to achieve directional self-locomotion. We fabricate a freestanding MXene film with an increased and asymmetric layered microstructure through the graft of coupling agents into the MXene nanosheets. Owing to the excellent photothermal effect of MXene nanosheets, increased interlayer spacing favoring intercalation/deintercalation of water molecules and its caused reversible volume change, and the asymmetric microstructure, this film exhibits light-driven deformation with a macroscopic and fast response. Based on it, a soft bimorph actuator with ultrahigh response to solar energy is fabricated, showing natural sunlight-driven actuation with ultralarge amplitude and fast response (346° in 1 s). By utilizing continuous bending deformation of the bimorph actuator in response to the change of natural sunlight intensity and biomimetic design of an inchworm to rectify the repeated bending deformation, an inchwormlike soft robot is constructed, achieving directional self-locomotion without any artificial energy and control. Moreover, soft arms for lifting objects driven by natural sunlight and wearable smart ornaments that are combined with clothing and produce three-dimensional deformation under natural sunlight are also developed. These results provide a strategy for developing natural sunlight-driven soft actuators and reveal great application prospects of this photoactuator in sunlight-driven soft biomimetic robots, intelligent solar-energy-driven devices in space, and wearable clothing.
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http://dx.doi.org/10.1021/acsnano.0c10797DOI Listing
March 2021

Long Noncoding RNA LINC00526 Represses Glioma Progression via Regulating miR-5581-3p/BEX1.

J Oncol 2021 4;2021:8171250. Epub 2021 Feb 4.

Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.

The roles of long noncoding RNAs (lncRNAs) in regulating glioma progression have been widely recognized in recent years. This work was to investigate the roles and associated mechanisms of LINC00526 in glioma progression. LINC00526 expression in glioma tissues and cells and their normal counterparts was measured with quantitative real-time polymerase chain reaction method. Functions of LINC00526 in glioma were investigated with experiments. Moreover, competitive RNA (ceRNA) theory was employed to understand mechanisms of action of LINC00526 in glioma. LINC00526 was found to be decreased in glioma tissues and cell lines compared with their normal counterparts. Silencing the expression of LINC00526 promotes, while forcing its expression, inhibits glioma cell growth and invasion. Mechanism analyses showed LINC00526 functions as a sponge for microRNA-5581-3p (miR-5581-3p) to regulate brain-expressed X-linked 1 (BEX1) expression and, in the end, affects glioma progression. Collectively, our study indicated LINC00526 serves as a tumor-suppressive lncRNA and directly regulates miR-5581-3p/BEX1 axis in glioma.
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http://dx.doi.org/10.1155/2021/8171250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878094PMC
February 2021

Fabrication of graphitic carbon nitride functionalized P-CoFeO for the removal of tetracycline under visible light: Optimization, degradation pathways and mechanism evaluation.

Chemosphere 2021 Jul 27;274:129783. Epub 2021 Jan 27.

School of Civil Engineering and Architecture, East China Jiaotong University, Nanchang, 330013, Jiangxi Province, China. Electronic address:

In this study, nano-sized CoFeO composites were prepared through co-precipitation process. Then the phosphorus-doped strong magnetic graphitic carbon nitride hybrids composites ([email protected]) was stemmed from the CoFeO composites via the thermal polymerization method. The TEM results show that the CoFeO nanoparticles have been successfully embedded into the graphitic carbon nitride (GCN). The BET specific surface area of [email protected] could reach 36.91 m/g, which was 5.38 times higher than that of GCN. Thus, it provided sufficient reaction active sites to enhance the photocatalytic activity for tetracycline (TC) decomposition. The results from the photocatalytic experiments showed that the degradation efficiency of TC by [email protected] could reach 96.2% within 60 min, which is 3.19 times higher than that of GCN. The h, O• and •OH radicals detected by the electron spin resonance (ESR) were responsible for the TC decomposition in the photocatalytic reaction system. Persulfate (PS) can further activate the hybrid mixture system, and the fitting model predicted by the response surface methodology (RSM) indicated that the maximum tetracycline removal could reach 99.6% within 30 min. In addition, the degradation intermediates of TC were detected by HPLC-MS and the photodegradation mechanism was discussed.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129783DOI Listing
July 2021

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development.

Elife 2021 Feb 5;10. Epub 2021 Feb 5.

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes and . Knockdown of or in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.
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http://dx.doi.org/10.7554/eLife.59067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864636PMC
February 2021

Systematic analysis of binding of transcription factors to noncoding variants.

Nature 2021 03 27;591(7848):147-151. Epub 2021 Jan 27.

Ludwig Institute for Cancer Research, La Jolla, CA, USA.

Many sequence variants have been linked to complex human traits and diseases, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.
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http://dx.doi.org/10.1038/s41586-021-03211-0DOI Listing
March 2021

Intramuscular and Intradermal Electroporation of HIV-1 PENNVAX-GP DNA Vaccine and IL-12 Is Safe, Tolerable, Acceptable in Healthy Adults.

Vaccines (Basel) 2020 Dec 7;8(4). Epub 2020 Dec 7.

Wistar Institute, Philadelphia, PA 19104, USA.

Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety.

Methods: The HVTN 098 trial assessed the PENNVAX-GP DNA vaccine (encoding HIV , , ) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability.

Results: HVTN 098 enrolled 94 participants: 85 received PENNVAX-GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1-4.6 vs. 6-6.5, < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort.

Conclusions: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.
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http://dx.doi.org/10.3390/vaccines8040741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762306PMC
December 2020

Carbon quantum dots decorated heteroatom co-doped core-shell [email protected] for degradation of tetracycline via multiply synergistic mechanisms.

Chemosphere 2021 Apr 28;268:128806. Epub 2020 Oct 28.

School of Civil Engineering and Architecture, East China Jiaotong University, Nanchang, 330013, Jiangxi Province, China. Electronic address:

In this study, novel core-shell catalyst with a new ternary heterostructure was synthesized ([email protected]/CQDs) for the degradation of tetracycline (TC). The TEM results showed that the Fe particles were wrapped in POCN material and many nano CQDs were uniformly dispersed in the material. The new ternary nanocomposite exhibits excellent photocatalytic activity for the removal of TC, which was approximately 4.76 times higher than that of GCN. The enhancement of photocatalytic activity was attributed to the effective heterojunction as well as the multiply synergistic effects of POCN combined with Fe and CQDs, which was beneficial for retardation of recombination rate of photogenerated electron-hole pairs and generation of more free radicals for the oxidation of TC. Besides, the reactive oxygen species (ROS) of h, •O and •OH played pivotal roles in the degradation of TC by [email protected]/CQDs during the photocatalytic reaction. At the same times, sulfate radical (SO) and hydroxyl radical (•OH) highlighted the dominant role in the degradation process compared with other free radicals under persulfate hybrid mixture system (PS system), which was further confirmed by radical scavenger experiments and electron spin resonance (ESR) analysis. The response surface methodology (RSM) study indicated that the optimal removal parameters of tetracycline could reach 97.57% within 30 min under PS system. In addition, the possible degradation pathway intermediates of TC were studied by HPLC-MS and the reaction catalytic activity mechanism of [email protected]/CQDs/persulfate system was discussed.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128806DOI Listing
April 2021

A compendium of DNA-binding specificities of transcription factors in Pseudomonas syringae.

Nat Commun 2020 10 2;11(1):4947. Epub 2020 Oct 2.

Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, SAR, China.

Pseudomonas syringae is a Gram-negative and model pathogenic bacterium that causes plant diseases worldwide. Here, we set out to identify binding motifs for all 301 annotated transcription factors (TFs) of P. syringae using HT-SELEX. We successfully identify binding motifs for 100 TFs. We map functional interactions between the TFs and their targets in virulence-associated pathways, and validate many of these interactions and functions using additional methods such as ChIP-seq, electrophoretic mobility shift assay (EMSA), RT-qPCR, and reporter assays. Our work identifies 25 virulence-associated master regulators, 14 of which had not been characterized as TFs before.
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http://dx.doi.org/10.1038/s41467-020-18744-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532196PMC
October 2020

Non-pharmacological interventions for depressive disorder in patients after traumatic brain injury: A protocol for a systematic review and network meta-analysis.

Medicine (Baltimore) 2020 Sep;99(39):e22375

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

Background: Depressive disorder has gradually become one of the most commonly reported disabling psychiatric complication that occurs after traumatic brain injury (TBI). Currently classical antidepressant medications may not have the same effectiveness in patients with TBI as in patients without TBI. Non-pharmacological interventions have been considered to be effective for managing depressive symptoms or treating depressive disorder. But to date the comparative effectiveness of various types of non-pharmacological interventions has been synthesized in few studies, the evidence remains inconclusive. Thus, the purpose of this systematic review and network meta-analyses is to summarize high-quality evidence and identify the most effective non-pharmacological intervention when applied to treat the depressive disorder in patients after TBI.

Methods: The comprehensive literature search in electronic database including PubMed, Ovid Medline, Cochrane Library, Web of Science database, Embase Database, China National Knowledge Infrastructure (CNKI), and Wanfang Data Chinese database from inception to the search date. Only high-quality randomized controlled trials (RCTs) that have used non-pharmacological interventions to treat depressive disorder after TBI will be considered. Two independent reviewers will identify eligible studies, extract and manage data information, and then determine methodical quality of included studies. Overall efficacy will be assessed as primary outcome. Secondary outcomes involved treatment response, remission rate, overall acceptability, tolerability of treatment, social functioning, occurrence of adverse events, and suicide-related outcome. Cochrane risk of bias assessment tool will be adopted to assess the risk of bias. Study heterogeneity will be measured by the I statistic. Traditional pairwise meta-analyses will be performed using STATA, while WinBUGS with GeMTC package of R software will be used to carry out network meta-analysis.

Results: This systematic review will examine the relative efficacy, effectiveness, safety, tolerability and acceptability of non-pharmacological interventions, and then to identify the most effective non-pharmacological intervention for depressive disorder after TBI.

Expected Conclusion: Our work could be used to give clinical recommendations for practice guideline developers, psychiatrist, neurologist, policymakers, researchers as well as individual with depressive disorder after TBI, and will also identify gaps in knowledge that could be the subject of future research.

Ethics And Dissemination: Neither ethics approval nor patient informed consent is necessary since this protocol was designed based on the existing literature. The results will be disseminated electronically or in print through publications in peer-reviewed scientific journal.

Inplasy Registration: INPLASY202080022.
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http://dx.doi.org/10.1097/MD.0000000000022375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523874PMC
September 2020

Expression of miR-34a is a sensitive biomarker for exposure to genotoxic agents in human lymphoblastoid TK6 cells.

Mutat Res 2020 Aug - Sep;856-857:503232. Epub 2020 Jul 15.

Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, 72079, United States.

miR-34a has been identified as a tumor suppressor microRNA (miRNA) involved in the P53 network. Its expression levels correlate to carcinogenesis, which are generally lower in tumor tissue and higher in response to DNA damage. In this study, the response of miR-34a from exposure to genotoxic agents in human lymphoblastoid TK6 cells was evaluated to assess whether the expression of this miRNA could be used as an early indicator for genotoxic damage in mammalian cells. TK6 cells were treated with seven genotoxic agents with different mode-of-actions (cisplatin, N-ethyl-N-nitrosourea, etoposide, mitomycin C, methyl methanesulphonate, taxol, and X-ray radiation) and a non-genetic toxin (usnic acid) at different concentrations for four hours (except for X-rays) and the expression levels of miR-34a were measured 24 h after the beginning of the treatments. The expression levels of miR-34a were significantly increased by these genetic toxins in a dose-dependent manner, while no significant change in miRNA expression was found in the usnic acid-treated cells. These results suggest that miR-34a can respond to genotoxic insults sensitively; thus, miR-34a expression has the potential to be used to evaluate genotoxicity of agents.
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http://dx.doi.org/10.1016/j.mrgentox.2020.503232DOI Listing
November 2020

Human and Bovine Milk Oligosaccharides Elicit Improved Recognition Memory Concurrent With Alterations in Regional Brain Volumes and Hippocampal mRNA Expression.

Front Neurosci 2020 13;14:770. Epub 2020 Aug 13.

Piglet Nutrition and Cognition Laboratory, Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States.

Human milk contains a unique profile of oligosaccharides (OS) and preliminary evidence suggests they impact brain development. The objective of this study was to assess the impact of bovine and/or human milk oligosaccharides (HMO) (2'-fucosyllactose and Lacto-N-neotetraose) on cognition, brain development, and hippocampal gene expression. Beginning on postnatal day (PND) 2, male pigs received one of four milk replacers containing bovine milk oligosaccharides (BMOS), HMO, both (BMOS + HMO), or neither. Pigs were tested on the novel object recognition task using delays of 1- or 48-h at PND 22. At PND 32-33, magnetic resonance imaging procedures were used to assess structural brain development and hippocampal tissue was collected for analysis of mRNA expression. Pigs consuming only HMO exhibited recognition memory after a 1-h delay and those consuming BMOS + HMO exhibited recognition memory after a 48-h delay. Both absolute and relative volumes of cortical and subcortical brain regions were altered by diet. Hippocampal mRNA expression of , , , and were most strongly affected by diet. HMO and BMOS had distinct effects on brain structure and cognitive performance. These data suggest different mechanisms underlie their influence on brain development.
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http://dx.doi.org/10.3389/fnins.2020.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438728PMC
August 2020

Effects of herb-partitioned moxibustion for diarrhoea-predominant irritable bowel syndrome: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Aug;99(34):e21817

Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, China.

Background: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional intestinal disease characterized by abdominal pain and diarrhea. Herb-partitioned moxibustion (HPM), a characteristic external therapy, is effective in treating IBS-D. However, no systematic review has been carried out to assess the efficacy and safety of HPM for IBS-D. The aim of this study will systematically evaluate the efficacy and safety of HPM for the treatment of patients with IBS-D.

Methods: We will perform the comprehensive literature search in both English and Chinese electronic database including PubMed, Embase, Cochrane Library, Web of Science database, Medline, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, Wanfang database, Chongqing VIP information, and SinoMed from their inception to July 2020. All randomized controlled trials of HPM for the treatment of IBS-D will be included. RevManV5. 3 will be applied to analyze the data.

Results: This study will provide high-quality synthesis of current evidence of effectiveness and safety on HPM for patients with IBS-D.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether HPM is an effective intervention for IBS-D.

Trial Registration Number: 10.17605/OSF.IO/3JXCZ.
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http://dx.doi.org/10.1097/MD.0000000000021817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447470PMC
August 2020

Protection against infection mediated by a synthetically engineered DNA vaccine.

Hum Vaccin Immunother 2020 09 12;16(9):2114-2122. Epub 2020 Aug 12.

Department of Research and Development, Inovio Pharmaceuticals , Plymouth Meeting, PA, USA.

Lyme disease is the most common vector-borne disease in North America. The etiological agent is the spirochete burgdorferi, transmitted to mammalian hosts by the Ixodes tick. In recent years there has been an increase in the number of cases of Lyme disease. Currently, there is no vaccine on the market for human use. We describe the development of a novel synthetically engineered DNA vaccine, pLD1 targeting the outer-surface protein A (OspA) of burgdorferi. Immunization of C3 H/HeN mice with pLD1 elicits robust humoral and cellular immune responses that confer complete protection against a live burgdorferi bacterial challenge. We also assessed intradermal (ID) delivery of pLD1 in Hartley guinea pigs, demonstrating the induction of robust and durable humoral immunity that lasts at least 1 year. We provide evidence of the potency of pLD1 by showing that antibodies targeting the OspA epitopes which have been associated with protection are prominently raised in the immunized guinea pigs. The described study provides the basis for the advancement of pDL1 as a potential vaccine for Lyme disease control.
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http://dx.doi.org/10.1080/21645515.2020.1789408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553707PMC
September 2020

Dietary Oligofructose Alone or in Combination with 2'-Fucosyllactose Differentially Improves Recognition Memory and Hippocampal mRNA Expression.

Nutrients 2020 Jul 17;12(7). Epub 2020 Jul 17.

Piglet Nutrition and Cognition Laboratory, Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA.

Mounting evidence suggests that dietary oligosaccharides promote brain development. This study assessed the capacity of oligofructose (OF) alone or in combination with 2'-fucosyllactose (2'-FL) to alter recognition memory, structural brain development, and hippocampal gene expression. Beginning on postnatal day (PND) 2, male pigs received one of three milk replacers formulated to contain OF, OF + 2'-FL, or no oligosaccharides (CON). Pigs were tested on the novel object recognition task using delays of 1 or 48 h at PND 22. At PND 32-33, magnetic resonance imaging (MRI) procedures were used to assess structural brain development and hippocampal tissue was collected for analysis of mRNA expression. Pigs that consumed the OF diet demonstrated increased recognition memory after a 1 h delay, whereas those consuming diets containing OF + 2'-FL displayed increased recognition memory after a 48 h delay. Pigs fed OF or OF + 2'-FL exhibited a larger relative volume of the olfactory bulbs compared with CON pigs. Provision of OF or OF + 2'-FL altered gene expression related to dopaminergic, GABAergic, cholinergic, cell adhesion, and chromatin remodeling processes. Collectively, these data indicate that dietary OF and OF + 2'-FL differentially improve cognitive performance and affect olfactory bulb structural development and hippocampal gene expression.
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http://dx.doi.org/10.3390/nu12072131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400822PMC
July 2020

Prediction and optimization of adsorption properties for Cson [email protected] LDHs hollow spheres from aqueous solution: Kinetics, isotherms, and BBD model.

J Hazard Mater 2021 01 2;401:123374. Epub 2020 Jul 2.

School of Civil Engineering and Architecture, East China Jiaotong University, Nanchang, 330013, Jiangxi Province, China. Electronic address:

In this work, novel [email protected] layered double hydroxides (LDHs) hollow spheres were prepared by hydrothermal method. It was worth noting that LDHs' grafting towards NiSiO hollow spheres could avoid the LDHs' aggregation, and thus enhanced the material's adsorption capacity. Furthermore, adsorption kinetics, adsorption isotherms, and Box-Behnken Design (BBD) model were conducted. Results indicated that [email protected] LDHs hollow spheres had sufficient adsorption capability towards Cs. The adsorption kinetics satisfied the pseudo-second-order adsorption model, Temkin model and Langmuir isotherm model. The adsorption process was efficient at the alkaline condition (pH = 10). The adsorption kinetics indicated that the adsorption process could reach the equilibrium in only 20 min. The maximum adsorption capacity of Cs towards [email protected] LDHs hollow spheres was estimated to be 61.5 mg g. Moreover, the adsorption thermodynamics indicated that the adsorption process was exothermal, feasible and spontaneous. Thus, [email protected] LDHs hollow spheres presented a broad potential for treating cesium containing wastewater.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123374DOI Listing
January 2021

[Temporal and Spatial Variation Patterns of Picophytoplankton and Their Correlations with Environmental Factors During the Wet Season in East Lake Dongting].

Huan Jing Ke Xue 2020 Jun;41(6):2679-2687

Key Laboratory of Agro-Environment in Midstream of Yangtze Plain, Ministry of Agriculture, Hunan Institute of Agro-Environment and Ecology, Hunan Academy of Agricultural Sciences, Changsha 410125, China.

Picophytoplankton (<3 μm), comprising picocyanobacteria (PCY) and photosynthetic picoeukaryotes (PPEs), are considerably important in the material circulation and energy flow of aquatic ecosystems. To explore the temporal and spatial variation patterns of picophytoplankton and their correlations with environmental factors in lotic Yangtze-connected lakes, field investigations were performed on a monthly basis during the wet season (May to August) in 2019 in East Lake Dongting, a Yangtze-connected lake. The results indicated that both the Chla biomass and abundances of picophytoplankton exhibited significant spatial and temporal variability (<0.05). The picophytoplankton Chla biomass showed an average concentration of 8.52 μg·L and accounted for 41.6% to total phytoplankton on an average. From May to August, Chla biomass of picophytoplankton kept increasing with increasing temperature, especially in the north and south of the lake, and it was the lowest in the east of the lake. PCY dominated picophytoplankton abundance in East Lake Dongting and was 3.4 times the abundance of PPEs on an average. Similar spatial and temporal variation patterns were observed between PCY and PPEs. The abundances of PCY and PPEs both increased first and then decreased during the wet season. Spatially, picophytoplankton showed a trend to migrate from the northern lake to the southern lake from May to July, and the abundance significantly declined in August and peaked mainly in the north of the lake. The analysis results showed that picophytoplankton in East Lake Dongting exhibited significant spatial and temporal variability during the wet season; the water level and N:P ratio were determined to be the most important factors explaining the variation of the abundance proportion of PCY and PPEs.
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http://dx.doi.org/10.13227/j.hjkx.201912223DOI Listing
June 2020

CRISPR-assisted detection of RNA-protein interactions in living cells.

Nat Methods 2020 07 22;17(7):685-688. Epub 2020 Jun 22.

School of Medicine, Northwest University, Xi'an, China.

We have developed CRISPR-assisted RNA-protein interaction detection method (CARPID), which leverages CRISPR-CasRx-based RNA targeting and proximity labeling to identify binding proteins of specific long non-coding RNAs (lncRNAs) in the native cellular context. We applied CARPID to the nuclear lncRNA XIST, and it captured a list of known interacting proteins and multiple previously uncharacterized binding proteins. We generalized CARPID to explore binders of the lncRNAs DANCR and MALAT1, revealing the method's wide applicability in identifying RNA-binding proteins.
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http://dx.doi.org/10.1038/s41592-020-0866-0DOI Listing
July 2020

Clinical features and prognostic analysis of moyamoya disease associated with intracranial aneurysms.

Neurol Res 2020 Sep 20;42(9):767-772. Epub 2020 Jun 20.

Department of Neurosurgery, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi Province, China.

Objectives: To explore clinical features and compare of the difference between conservative treatment and surgical treatmentin prognosis of intracranial aneurysms associated with moyamoya disease (MMD).

Methods: 104 patients with MMD a ssociated with intracranial aneurysms diagnosed by digital subtraction angiography (DSA) or computed tomography angiography (CTA) were retrospectively analyzed.

Results: All patients of MMD with intracranial aneurysms had 129 aneurysms distributed at different sites. The distribution of the aneurysms was as follows: 28(21.71%) anterior communicating artery aneurysms, 21(16.28%) basilar artery aneurysms, 19(14.73%) middle cerebral artery aneurysms, 17(13.18%) posterior cerebral artery aneurysms, 12(9.30%)internal carotid artery aneurysms, 11(8.53%) posterior communicating artery aneurysms, 10(7.75%) anterior cerebral artery aneurysms, 5(3.88%) anterior choroidal artery aneurysms, 2(1.55%) moyamoya vessel aneurysms, and 4(3.1%) other location aneurysms. 82 cases (78.85%) had one aneurysm, and 21 cases (20.19%) had 2 or more aneurysms. 64 cases were treated surgically, and 40 cases were treated conservatively. 57 of 81 cases (70.37%) had a good outcome, 2 cases (2.47%) were in paralyzed, and 22 cases were died. The mortality rate was (27.16%). Death occurred in 16 (47.06%) of 34 patients with conservative treatment, and 6(12.77%) of 47 patients with surgical treatment. 7 cases (8.64%) had twice cerebral hemorrhage, and one case (1.23%) had third cerebral hemorrhage in the follow-up period. There were 5 deaths, two good outcomes, and one coma among 8 cases experienced re-hemorrhage.

Conclusion: Compared with conservative treatment, positive surgical treatment showed clinical significance for preventing cerebral hemorrhage and reducing mortality of MMD with intracranial aneurysms.

Abbreviations: MMD: moyamoya disease; DSA: digital subtraction angiography; CTA: computed tomography angiography.
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http://dx.doi.org/10.1080/01616412.2020.1773663DOI Listing
September 2020

Active immunoprophylaxis with a synthetic DNA-encoded monoclonal anti-respiratory syncytial virus scFv-Fc fusion protein confers protection against infection and durable activity.

Hum Vaccin Immunother 2020 09 16;16(9):2165-2175. Epub 2020 Jun 16.

Inovio Pharmaceuticals , Plymouth Meeting, PA, USA.

Respiratory Syncytial virus (RSV) is a major threat to many vulnerable populations. There are currently no approved vaccines, and RSV remains a high unmet global medical need. Here we describe the employment of a novel synthetic DNA-encoded antibody technology platform to develop and deliver an engineered human DNA-encoded monoclonal antibody (dMAb) targeting the fusion protein (F) of RSV as a new approach to prevention or therapy of at risk populations. In models, a single administration of synthetic DNA-encoding the single-chain fragment variable-constant fragment (scFv-Fc) RSV-F dMAb resulted in robust and durable circulating levels of a functional antibody systemically and in mucosal tissue. In cotton rats, which are the gold-standard animals to model RSV infection, we observed sustained scFv-Fc RSV-F dMAb in the sera and lung-lavage samples, demonstrating the potential for both long-lasting immunity to RSV and effective biodistribution. The scFv-Fc RSV-F dMAb harbored in the sera exhibited RSV antigen-specific binding and potent viral neutralizing activity. Importantly, delivery of synthetic DNA-encoding, the scFv-Fc RSV-F dMAb protected animals against viral challenge. Our findings support the significance of dMAbs as a potential platform technology for durable protection against RSV disease.
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http://dx.doi.org/10.1080/21645515.2020.1748979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553682PMC
September 2020

Activation of HIF-1 signaling ameliorates liver steatosis in zebrafish atp7b deficiency (Wilson's disease) models.

Biochim Biophys Acta Mol Basis Dis 2020 10 21;1866(10):165842. Epub 2020 May 21.

Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China. Electronic address:

Wilson's disease is an autosomal recessive disease characterized by excess copper accumulated in the liver and brain. It is caused by mutations in the copper transporter gene ATP7B. However, based on the poor understanding of the transcriptional program involved in the pathogenesis of Wilson's disease and the lack of more safe and efficient therapies, the identification of novel pathways and the establishment of complementary model systems of Wilson's disease are urgently needed. Herein, we generated two zebrafish atp7b-mutant lines using the CRISPR/Cas9 editing system, and the mutants developed hepatic and behavioral deficits similar to those observed in humans with Wilson's disease. Interestingly, we found that atp7b-deficient zebrafish embryos developed liver steatosis under low-dose Cu exposure, and behavioral deficits appeared under high-dose Cu exposure. Analyses of publicly available transcriptomic data from ATP7B-knockout HepG2 cells demonstrated that the HIF-1 signaling pathway is downregulated in ATP7B-knockout HepG2 cells compared with wildtype cells following Cu exposure. The HIF-1 signaling pathway was also downregulated in our atp7b-deficient zebrafish mutants following Cu exposure. Furthermore, we demonstrate that activation of the HIF-1 signaling pathway with the chemical compound FG-4592 or DMOG ameliorates liver steatosis and reduces accumulated Cu levels in zebrafish atp7b deficiency models. These findings introduce a novel prospect that modulation of the HIF-1 signaling pathway should be explored as a novel strategy to reduce copper toxicity in Wilson's disease patients.
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http://dx.doi.org/10.1016/j.bbadis.2020.165842DOI Listing
October 2020

Robust antibody and cellular responses induced by DNA-only vaccination for HIV.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.
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http://dx.doi.org/10.1172/jci.insight.137079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406303PMC
July 2020