Publications by authors named "Ping Ren"

213 Publications

Hydroxysafflor yellow A acutely attenuates blood-brain barrier permeability, oxidative stress, inflammation and apoptosis in traumatic brain injury in rats1.

Acta Cir Bras 2021 20;35(12):e351202. Epub 2021 Jan 20.

PhD, Department of TCM-related comorbid depression, Nanjing University of Chinese Medicine, China.

Purpose: To investigate the therapeutic benefits of Hydroxysafflor yellow A (HSYA) on blood-brain barrier (BBB) vulnerability after traumatic brain injury (TBI) and identify its potential action of mechanisms on TBIinduced injuries.

Methods: The rat TBI model was performed by using a controlled cortical impact device. The BBB permeability induced by TBI was measured through Evans Blue dye superflux and western blotting or polymerase chain reaction (PCR) for tight junctional proteins (TJPs). The post-TBI changes in oxidative stress markers, inflammatory response and neuron apoptosis in brain tissue were also tested.

Results: Herein, the results showed that HSYA acutely attenuated BBB permeability via increasing the production of the TJPs, including occludin, claudin-1 and zonula occludens protein 24 h after TBI. Additionally, HSYA could suppress the secretion of proinflammatory factors, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α (IL-1β, IL-6, and TNF-α), and also concurrently down-regulate the expression of inflammation-related Toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-kB) protein. These HSYA challenged changes were accompanied by the decreased TBI induced oxidative stress markers and inhibited the expression of apoptosis proteins Bax, caspase-3 and caspase-9.

Conclusions: Taken together, all findings suggested that HSYA (30 mg/kg) are against TBI through improving the integrity in BBB, which are associated with the antioxidant, anti-inflammation and antiapoptosis via the probable mechanism of down-regulation of the TLR4/NF-kB pathway, and its in-detail protective mechanisms are under study.
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http://dx.doi.org/10.1590/ACB351202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819693PMC
January 2021

A -complementation system for SARS-CoV-2.

bioRxiv 2021 Jan 19. Epub 2021 Jan 19.

The biosafety level-3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research and countermeasure development. Here we report a -complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The -complementation system consists of two components: a genomic viral RNA containing a deletion of ORF3 and envelope gene, and a producer cell line expressing the two deleted genes. complementation of the two components generates virions that can infect naive cells for only one round, but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. The results suggest that the -complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.
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http://dx.doi.org/10.1101/2021.01.16.426970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836106PMC
January 2021

Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.

Nature 2021 Jan 25. Epub 2021 Jan 25.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.
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http://dx.doi.org/10.1038/s41586-021-03237-4DOI Listing
January 2021

Highly efficient and cheap treatment of dye by graphene-doped TiO microspheres.

Water Sci Technol 2021 Jan;83(1):223-232

Department of Chemistry and Material Science, Langfang Normal University, Langfang 065000, Hebei, China E-mail:

Highly efficient dye wastewater treatment by photocatalytic catalysis commonly requires expensive catalysts, long degradation time and a complicated procedure. Here, we for the first time prepared cheap graphene-doped titanium dioxide microspheres with a simple procedure to degrade dye with high efficiency. When the catalyst concentration was 0.2 g·L, the photocatalysis degradation extent of methylene blue solution, methylene green solution and 1,9-dimethyl methylene blue solution reached 96.4, 85.9 and 98.7%, respectively. The results showed that the degradation reactions accorded with the Langmuir-Hinshelwood model, and the photocatalytic reactions belonged to a first-order reaction in the primary stage. Furthermore, different photocatalytic degradation mechanisms were proposed, which have not been found in other literature. This work opened a new route for simple preparation of cheap microspheres in photocatalytic dye wastewater treatment with high efficiency.
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http://dx.doi.org/10.2166/wst.2020.545DOI Listing
January 2021

Interactive Effects of Copper Sources and a High Level of Phytase in Phosphorus-Deficient Diets on Growth Performance, Nutrient Digestibility, Tissue Mineral Concentrations, and Plasma Parameters in Nursery Pigs.

Biol Trace Elem Res 2021 Jan 11. Epub 2021 Jan 11.

Novus International, Inc., St. Charles, MO, 63304, USA.

The present study investigated the interactive effects of copper sources and a high level of phytase on growth performance, nutrient digestibility, tissue mineral concentrations, and plasma parameters in nursery pigs. Weaning piglets (N = 192; 6.06 ± 0.99 kg), blocked by body weight, were randomly allotted to 1 of 4 dietary treatments, with 12 pens per treatment and 4 pigs per pen. A basal diet for each phase was formulated to meet nutrient requirements for nursery pigs with the exception that standardized total tract digestibility (STTD) P was reduced by 0.12% and Ca was adjusted to achieve Ca/STTD P = 2.15. The 4 dietary treatments were arranged in a 2 × 2 factorial design, with 2 Cu sources (125 mg/kg Cu from copper methionine hydroxy analogue chelate (Cu-MHAC) or copper sulfate (CuSO)) and 2 phytase levels (0 or 1500 phytase units (FTU)/kg). Results showed that there was an interaction (P < 0.05) between Cu sources and phytase on ADG during days 0-41. When phytase was not present in the diets (P deficient), there was no difference between the two Cu sources in terms of ADG during days 0-41, whereas with phytase in the diets, Cu-MHAC tended to improve (P < 0.10) ADG during days 0-41 compared with CuSO. Pigs fed Cu-MHAC had greater apparent total tract digestibility (ATTD) of neutral and acid detergent fiber and STTD of P than those fed CuSO. Phytase increased (P < 0.05) growth performance, ATTD of Ca and P, and plasma inositol and growth hormone concentrations. In conclusion, Cu-MHAC may be more effective in improving growth rate than CuSO when phytase was supplemented at 1500 FTU/kg. Cu-MHAC enhanced fiber and P digestibility regardless of phytase, compared with CuSO. Phytase addition in P-deficient diets was effective in improving growth performance, Ca and P digestibility, and plasma inositol and growth hormone concentrations.
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http://dx.doi.org/10.1007/s12011-021-02580-xDOI Listing
January 2021

Effects of a novel phytase expressed in on growth, bone mineralization, and nutrient digestibility in pigs fed corn-soybean meal diets.

Transl Anim Sci 2020 Oct 4;4(4):txaa201. Epub 2020 Nov 4.

Department of Animal Sciences, University of Illinois, Urbana, IL.

Two studies were conducted to determine the effects of a novel phytase expressed in on growth performance, bone mineralization, and nutrient digestibility in pigs fed corn-soybean meal diets. In experiment 1, 160 nursery pigs (9.79 ± 1.22 kg) were randomly allotted to one of four treatments with 10 pens per treatment and four pigs per pen. Phase I and phase II diets were provided from d 0 to d 14 and d 14 to d 28, respectively. Treatments included: positive control (PC) with all nutrients meeting requirements; negative control (NC) with standardized total tract digestible (STTD) P reduced by 0.15% and 0.14% compared with PC in phase I and phase II, respectively; and NC diets containing 250 or 500 units of phytase (FTU) per kilogram. Results demonstrated that pigs fed PC had greater ( < 0.01) ADG and G:F for the overall experimental period, and greater ( < 0.01) bone ash and P concentrations, compared with pigs fed NC or diets with phytase supplementation. Pigs fed diets containing phytase had greater ( < 0.01) ADG and G:F for the overall experimental period compared with pigs fed the NC diet without phytase, and bone ash and P weights were increased ( < 0.01) as well. In experiment 2, 63 growing barrows (56.25 ± 2.54 kg) were blocked by BW and randomly allotted to one of seven treatments with nine pens per treatment and one pig per pen. A basal corn-soybean meal diet was formulated to meet nutrient requirements for growing pigs with the exception that STTD P was reduced by 0.18% compared with the requirement, and Ca was included to achieve a Ca:STTD P ratio of 2.15. Six additional diets were formulated by adding 250, 500, 750, 1,000, 1,500, or 2,000 FTU/kg of phytase to the basal diet. Pigs were fed experimental diets for 12 d with 7 d of adaptation and 5 d of fecal sample collection. Results indicated that there was a linear ( < 0.01) increase in apparent total tract digestibility of ash and ether extract, and STTD of Ca and P also increased (linear, < 0.05) in response to increasing doses of phytase. Increasing phytase levels in the diets resulted in increase (quadratic, < 0.05) in apparent ileal digestibility of Arg, His, Ile, Lys, Trp, Asp, and Glu. In conclusion, the novel phytase was effective in increasing growth performance, bone mineralization, and Ca and P digestibility in pigs fed corn-soybean meal-based diets. Results also indicated that this phytase had the potential to enhance the digestibility of fat and certain AA.
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http://dx.doi.org/10.1093/tas/txaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743475PMC
October 2020

The expression, modulation and use of cancer-testis antigens as potential biomarkers for cancer immunotherapy.

Am J Transl Res 2020 15;12(11):7002-7019. Epub 2020 Nov 15.

Department of Respiratory Medicine, The Second Hospital of Jilin University Changchun, P. R. China.

Cancer-testis antigens (CTA) are tumor antigens, present in the germ cells of testes, ovaries and trophoblasts, which undergo deregulated expression in the tumor and malignant cells. CTA genes are either X-linked or autosomal, favourably expressed in spermatogonia and spermatocytes, respectively. CTAs trigger unprompted humoral immunity and immune responses in malignancies, altering tumor cell physiology and neoplastic behaviors. CTAs demonstrate varied expression profile, with increased abundance in malignant melanoma and prostate, lung, breast and epithelial cell cancers, and a relatively reduced prevalence in intestinal cancer, renal cell adenocarcinoma and malignancies of immune cells. A combination of epigenetic and non-epigenetic agents regulates CTA mRNA expression, with the key participation of CpG islands and CpG-rich promoters, histone methyltransferases, cytokines, tyrosine kinases and transcriptional activators and repressors. CTA triggers gametogenesis, in association with mutated tumorigenic genes and tumor repressors. The CTAs function as potential biomarkers, particularly for prostate, cervical, breast, colorectal, gastric, urinary bladder, liver and lung carcinomas, characterized by alternate splicing and phenotypic heterogeneity in the cells. Additionally, CTAs are prospective targets for vaccine therapy, with the MAGE-A3 and NYESO-1 undergoing clinical trials for tumor regression in malignant melanoma. They have been deemed important for adaptive immunotherapy, marked by limited expression in normal somatic tissues and recurrent up-regulation in epithelial carcinoma. Overall, the current review delineates an up-dated understanding of the intricate processes of CTA expression and regulation in cancer. It further portrays the role of CTAs as biomarkers and probable candidates for tumor immunotherapy, with a future prospect in cancer treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724325PMC
November 2020

Analysis of sputum/tracheal aspirate and nasopharyngeal samples for SARS-CoV-2 detection by laboratory-developed test and Panther Fusion system.

Diagn Microbiol Infect Dis 2021 Jan 30;99(1):115228. Epub 2020 Sep 30.

Department of Pathology, University of Texas Medical Branch, Galveston, TX. Electronic address:

In this study, 127 sputum/tracheal aspirate specimens were evaluated by a laboratory-developed real-time RT-PCR method and Fusion SARS-CoV-2 assay. These specimens were collected from the patients who have nasopharyngeal swab (NPS) samples being used for SARS-CoV-2 detection previously or simultaneously. The overall agreement was 96% between the lower respiratory tract (LRT) and NPS samples, suggesting that LRT specimens could be an option for patients who develop a productive cough or those receiving invasive mechanical ventilation.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525323PMC
January 2021

Evaluation of a SARS-CoV-2 lateral flow assay using the plaque reduction neutralization test.

Diagn Microbiol Infect Dis 2021 Feb 16;99(2):115248. Epub 2020 Oct 16.

Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. Electronic address:

As new tests and technologies advance our understanding and diagnostic capabilities of the severe acute respiratory syndrome coronavirus 2 and the coronavirus disease 2019, they must be appropriately validated to make sure test performance is following manufacturer claims. In this study, we evaluated the Vazyme 2019-nCoV IgG/IgM Detection Kit, which is a lateral flow assay (LFA), by the plaque reduction neutralization test (PRNT) using 100 patient plasma/serum samples. As compared to the PRNT results, the Vazyme LFA had 95.9% sensitivity and 96.1% specificity. Along with the increased need for rapid, effective, and affordable point of care tests to help provide meaningful epidemiological data, we demonstrated that the Vazyme LFA performed well on IgG detection but cannot be judged on the performance of IgM detection using PRNT alone. However, our observation of the low IgM-positive rate supported the poor performance of IgM detection of this LFA which led to the disapproval of its Emergency Use Authorization recently.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562965PMC
February 2021

A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19.

Nat Commun 2020 10 15;11(1):5214. Epub 2020 Oct 15.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.

A high-throughput platform would greatly facilitate coronavirus disease 2019 (COVID-19) serological testing and antiviral screening. Here we present a high-throughput nanoluciferase severe respiratory syndrome coronavirus 2 (SARS-CoV-2-Nluc) that is genetically stable and replicates similarly to the wild-type virus in cell culture. SARS-CoV-2-Nluc can be used to measure neutralizing antibody activity in patient sera within 5 hours, and it produces results in concordance with a plaque reduction neutralization test (PRNT). Additionally, using SARS-CoV-2-Nluc infection of A549 cells expressing human ACE2 receptor (A549-hACE2), we show that the assay can be used for antiviral screening. Using the optimized SARS-CoV-2-Nluc assay, we evaluate a panel of antivirals and other anti-infective drugs, and we identify nelfinavir, rupintrivir, and cobicistat as the most selective inhibitors of SARS-CoV-2-Nluc (EC 0.77 to 2.74 µM). In contrast, most of the clinically approved antivirals, including tenofovir alafenamide, emtricitabine, sofosbuvir, ledipasvir, and velpatasvir were inactive at concentrations up to 10 µM. Collectively, this high-throughput platform represents a reliable tool for rapid neutralization testing and antiviral screening for SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-020-19055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567097PMC
October 2020

Rapid antidepressant-like effect of Fructus Aurantii depends on cAMP-response element binding protein/Brain-derived neurotrophic facto by mediating synaptic transmission.

Phytother Res 2021 Jan 12;35(1):404-414. Epub 2020 Oct 12.

Institute of TCM-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing, China.

Several studies reported the relative antidepressant effects of Fructus Aurantii (FRA) with repeated treatment, the rapid antidepressant effects of FRA and the underlying mechanisms remained unclear. We, therefore, examined the rapid antidepressant actions of FRA in behavioral tests in mice and tested the underlying molecular mechanisms. We found FRA, like ketamine, reversed the behavioral deficits both in lipopolysaccharide(LPS)-induced and learned helplessness (LH) models at 1 day after a single administration. FRA was also capable of increasing the expressions of protein kinase A/cAMP-response element-binding protein/brain-derived neurotrophic factor (PKA/CREB/BDNF) signaling in hippocampus. Consistent with ketamine, FRA up-regulated the expressions of GABAergic receptor (GAD67) and glutamatergic receptor 1 (GluR1) in mouse hippocampus both exposed to LPS and LH. Moreover, synaptic proteins such as postsynaptic density-95 (PSD95) and synapsin1 were also up-regulated by a single dose of FRA both in LH and LPS models, like ketamine. Finally, metadoxine (an antagonist of CREB) inhibited the antidepressant effects of FRA in tail suspension test (TST) and forced swimming test (FST) in LPS-induced mice, which also blocked the phosphorylation of CREB and the expressions of neurotransmitters and synaptic molecules. Therefore, FRA had rapid antidepressant effects, which depended on PKA/CREB/BDNF pathway, subsequently regulated the downstream synaptic transmission.
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http://dx.doi.org/10.1002/ptr.6812DOI Listing
January 2021

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Psychophysiology 2020 Oct 10. Epub 2020 Oct 10.

Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
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http://dx.doi.org/10.1111/psyp.13688DOI Listing
October 2020

Meranzin hydrate elicits antidepressant effects and restores reward circuitry.

Behav Brain Res 2021 Feb 6;398:112898. Epub 2020 Sep 6.

State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Institute of TCM-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address:

The burden of depression is enormous, and numerous studies have found that major depressive disorder (MDD) induces cardiovascular disorders (CVD) and functional dyspepsia (FD). Excitingly, meranzin hydrate (MH), an absorbed bioactive compound of Aurantii Fructus Immaturus, reverses psychosocial stress-induced mood disorders, gastrointestinal dysfunction and cardiac disease. Pharmacological methods have repeatedly failed in antidepressant development over the past few decades, but repairing aberrant neural circuits might be a reasonable strategy. This article aimed to explore antidepressant-like effects and potential mechanisms of MH in a rat model of unpredictable chronic mild stress (UCMS). Utilizing blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we sought to find reliable neurocircuits or a dominant brain region revealing the multiple effects of MH. The results show that compared with UCMS rats, MH (10 mg/kg/day for 1 week i.g.)-treated rats exhibited decreased depression-like behaviour; increased expression of brain-derived neurotrophic factor (BDNF) in the hippocampal dentate gyrus; and normalized levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and acylated ghrelin (AG). Additionally, the UCMS-induced rise in BOLD activation in the reward system was attenuated after MH treatment. A literature search shown that nucleus accumbens (NAc) and hypothalamus of the reward system might reveal multiple effects of MH on MDD-FD-CVD comorbidity. Further research will focus on the role of these two brain regions in treating depression associated with comorbidities.
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http://dx.doi.org/10.1016/j.bbr.2020.112898DOI Listing
February 2021

LncRNA PITPNA-AS1 boosts the proliferation and migration of lung squamous cell carcinoma cells by recruiting TAF15 to stabilize HMGB3 mRNA.

Cancer Med 2020 Oct 1;9(20):7706-7716. Epub 2020 Sep 1.

Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China.

Plenty of reports have probed the involvement of abnormally expressed lncRNAs in multiple cancers, including lung squamous cell carcinoma (LUSC). Through online database GEPIA, lncRNA PITPNA antisense RNA 1 (PITPNA-AS1) was highly expressed in LUSC samples, and these tendency was further affirmed in LUSC cells. The aim of current study was to investigate the related mechanism of PITPNA-AS1 in LUSC. Functional experiments verified that depletion of PITPNA-AS1 hampered the proliferative and migratory abilities, but accelerated apoptosis of LUSC cells. Additionally, we observed the increased expression of HMGB3 and its positive correlation with PITPNA-AS1 in LUSC samples. Interestingly, PITPNA-AS1 mainly located in the cytosol of LUSC cells, and also affected mRNA stability of HMGB3. Furthermore, the repressed mRNA stability of HMGB3 by PITPNA-AS1 via TAF15 was exposed through mechanism experiments. The mediatory function of PITPNA-AS1 on HMGB3 was validated via rescue assays. All in all, PITPNA-AS1 promoted the proliferation and migration of LUSC cells via stabilizing HMGB3 by TAF15. In conclusion, our study displayed a novel mechanism underlying PITPNA-AS1 in LUSC cells.
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http://dx.doi.org/10.1002/cam4.3268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571819PMC
October 2020

Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis.

bioRxiv 2020 Aug 26. Epub 2020 Aug 26.

SARS-CoV-2 has resulted in a global pandemic and shutdown economies around the world. Sequence analysis indicates that the novel coronavirus (CoV) has an insertion of a furin cleavage site (PRRAR) in its spike protein. Absent in other group 2B CoVs, the insertion may be a key factor in the replication and virulence of SARS-CoV-2. To explore this question, we generated a SARS-CoV-2 mutant lacking the furin cleavage site (ΔPRRA) in the spike protein. This mutant virus replicated with faster kinetics and improved fitness in Vero E6 cells. The mutant virus also had reduced spike protein processing as compared to wild-type SARS-CoV-2. In contrast, the ΔPRRA had reduced replication in Calu3 cells, a human respiratory cell line, and had attenuated disease in a hamster pathogenesis model. Despite the reduced disease, the ΔPRRA mutant offered robust protection from SARS-CoV-2 rechallenge. Importantly, plaque reduction neutralization tests (PRNT ) with COVID-19 patient sera and monoclonal antibodies against the receptor-binding domain found a shift, with the mutant virus resulting in consistently reduced PRNT titers. Together, these results demonstrate a critical role for the furin cleavage site insertion in SARS-CoV-2 replication and pathogenesis. In addition, these findings illustrate the importance of this insertion in evaluating neutralization and other downstream SARS-CoV-2 assays.

Importance: As COVID-19 has impacted the world, understanding how SARS-CoV-2 replicates and causes virulence offers potential pathways to disrupt its disease. By removing the furin cleavage site, we demonstrate the importance of this insertion to SARS-CoV-2 replication and pathogenesis. In addition, the findings with Vero cells indicate the likelihood of cell culture adaptations in virus stocks that can influence reagent generation and interpretation of a wide range of data including neutralization and drug efficacy. Overall, our work highlights the importance of this key motif in SARS-CoV-2 infection and pathogenesis.

Article Summary: A deletion of the furin cleavage site in SARS-CoV-2 amplifies replication in Vero cells, but attenuates replication in respiratory cells and pathogenesis in vivo. Loss of the furin site also reduces susceptibility to neutralization .
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http://dx.doi.org/10.1101/2020.08.26.268854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457603PMC
August 2020

Establishing In Situ Closed Circuit Perfusion of Lower Abdominal Organs and Hind Limbs in Mice.

J Vis Exp 2020 08 13(162). Epub 2020 Aug 13.

The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus.

Ex vivo perfusion is an important physiological tool to study the function of isolated organs (e.g. liver, kidneys). At the same time, due to the small size of mouse organs, ex vivo perfusion of bone, bladder, skin, prostate, and reproductive organs is challenging or not feasible. Here, we report for the first time an in situ lower body perfusion circuit in mice that includes the above tissues, but bypasses the main clearance organs (kidney, liver, and spleen). The circuit is established by cannulating the abdominal aorta and inferior vena cava above the iliac artery and vein and cauterizing peripheral blood vessels. Perfusion is performed via a peristaltic pump with perfusate flow maintained for up to 2 h. In situ staining with fluorescent lectin and Hoechst solution confirmed that the microvasculature was successfully perfused. This mouse model can be a very useful tool for studying pathological processes as well as mechanisms of drug delivery, migration/metastasis of circulating tumor cells into/from the tumor, and interactions of immune system with perfused organs and tissues.
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http://dx.doi.org/10.3791/60847DOI Listing
August 2020

Effects of mineral methionine hydroxy analog chelate in sow diets on epigenetic modification and growth of progeny.

J Anim Sci 2020 Sep;98(9)

Department of Animal Science, North Carolina State University, Raleigh, NC.

The study was conducted to determine the effects of mineral methionine hydroxy analog chelate (MMHAC) partially replacing inorganic trace minerals in sow diets on epigenetic and transcriptional changes in the muscle and jejunum of progeny. The MMHAC is zinc (Zn), manganese (Mn), and copper (Cu) chelated with methionine hydroxy analog (Zn-, Mn-, and Cu-methionine hydroxy analog chelate [MHAC]). On day 35 of gestation, 60 pregnant sows were allotted to two dietary treatments in a randomized completed block design using parity as a block: 1) ITM: inorganic trace minerals with zinc sulfate (ZnSO4), manganese oxide (MnO), and copper sulfate (CuSO4) and 2) CTM: 50% of ITM was replaced with MMHAC (MINTREX trace minerals, Novus International Inc., St Charles, MO). Gestation and lactation diets were formulated to meet or exceed NRC requirements. On days 1 and 18 of lactation, milk samples from 16 sows per treatment were collected to measure immunoglobulins (immunoglobulin G, immunoglobulin A, and immunoglobulin M) and micromineral concentrations. Two pigs per litter were selected to collect blood to measure the concentration of immunoglobulins in the serum, and then euthanized to collect jejunal mucosa, jejunum tissues, and longissimus muscle to measure global deoxyribonucleic acid methylation, histone acetylation, cytokines, and jejunal histomorphology at birth and day 18 of lactation. Data were analyzed using Proc MIXED of SAS. Supplementation of MMHAC tended to decrease (P = 0.059) body weight (BW) loss of sows during lactation and tended to increase (P = 0.098) piglet BW on day 18 of lactation. Supplementation of MMHAC increased (P < 0.05) global histone acetylation and tended to decrease myogenic regulatory factor 4 messenger ribonucleic acid (mRNA; P = 0.068) and delta 4-desaturase sphingolipid1 (DEGS1) mRNA (P = 0.086) in longissimus muscle of piglets at birth. Supplementation of MMHAC decreased (P < 0.05) nuclear factor kappa B mRNA in the jejunum and DEGS1 mRNA in longissimus muscle and tended to decrease mucin-2 (MUC2) mRNA (P = 0.057) and transforming growth factor-beta 1 (TGF-β1) mRNA (P = 0.057) in the jejunum of piglets on day 18 of lactation. There were, however, no changes in the amounts of tumor necrosis factor-alpha, interleukin-8, TGF-β, MUC2, and myogenic factor 6 in the tissues by MMHAC. In conclusion, maternal supplementation of MMHAC could contribute to histone acetylation and programming in the fetus, which potentially regulates intestinal health and skeletal muscle development of piglets at birth and weaning, possibly leading to enhanced growth of their piglets.
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http://dx.doi.org/10.1093/jas/skaa271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507415PMC
September 2020

A common partitivirus infection in United States and Czech Republic isolates of bat white-nose syndrome fungal pathogen Pseudogymnoascus destructans.

Sci Rep 2020 08 17;10(1):13893. Epub 2020 Aug 17.

Mycology Laboratory, Wadsworth Center, New York State Department of Health, Albany, NY, USA.

The psychrophilic (cold-loving) fungus Pseudogymnoascus destructans was discovered more than a decade ago to be the pathogen responsible for white-nose syndrome, an emerging disease of North American bats causing unprecedented population declines. The same species of fungus is found in Europe but without associated mortality in bats. We found P. destructans was infected with a mycovirus [named Pseudogymnoascus destructans partitivirus 1 (PdPV-1)]. The virus is bipartite, containing two double-stranded RNA (dsRNA) segments designated as dsRNA1 and dsRNA2. The cDNA sequences revealed that dsRNA1 dsRNA is 1,683 bp in length with an open reading frame (ORF) that encodes 539 amino acids (molecular mass of 62.7 kDa); dsRNA2 dsRNA is 1,524 bp in length with an ORF that encodes 434 amino acids (molecular mass of 46.9 kDa). The dsRNA1 ORF contains motifs representative of RNA-dependent RNA polymerase (RdRp), whereas the dsRNA2 ORF sequence showed homology with the putative capsid proteins (CPs) of mycoviruses. Phylogenetic analyses with PdPV-1 RdRp and CP sequences indicated that both segments constitute the genome of a novel virus in the family Partitiviridae. The purified virions were isometric with an estimated diameter of 33 nm. Reverse transcription PCR (RT-PCR) and sequencing revealed that all US isolates and a subset of Czech Republic isolates of P. destructans were infected with PdPV-1. However, PdPV-1 appears to be not widely dispersed in the fungal genus Pseudogymnoascus, as non-pathogenic fungi P. appendiculatus (1 isolate) and P. roseus (6 isolates) tested negative. P. destructans PdPV-1 could be a valuable tool to investigate fungal biogeography and the host-pathogen interactions in bat WNS.
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http://dx.doi.org/10.1038/s41598-020-70375-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431587PMC
August 2020

A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation.

Nat Commun 2020 08 13;11(1):4059. Epub 2020 Aug 13.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.

Virus neutralization remains the gold standard for determining antibody efficacy. Therefore, a high-throughput assay to measure SARS-CoV-2 neutralizing antibodies is urgently needed for COVID-19 serodiagnosis, convalescent plasma therapy, and vaccine development. Here, we report on a fluorescence-based SARS-CoV-2 neutralization assay that detects SARS-CoV-2 neutralizing antibodies in COVID-19 patient specimens and yields comparable results to plaque reduction neutralizing assay, the gold standard of serological testing. The fluorescence-based neutralization assay is specific to measure COVID-19 neutralizing antibodies without cross reacting with patient specimens with other viral, bacterial, or parasitic infections. Collectively, our approach offers a rapid platform that can be scaled to screen people for antibody protection from COVID-19, a key parameter necessary to safely reopen local communities.
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http://dx.doi.org/10.1038/s41467-020-17892-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426916PMC
August 2020

miR-365b regulates the development of non-small cell lung cancer via GALNT4.

Exp Ther Med 2020 Aug 10;20(2):1637-1643. Epub 2020 Jun 10.

Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.

Non-small cell lung cancer (NSCLC) is a type of cancer that is associated with high prevalence and high mortality rates in China. Therefore, it is of importance to identify the mechanisms underlying NSCLC progression. In the present study, reverse transcription-quantitative PCR was performed to measure the expression of microRNA (miR)-365b in NSCLC cell lines. In addition, the biological roles of miR-365b and N-acetylgalactosaminyltransferase 4 (GALNT4) were investigated by manipulating the expression levels of miR-365b and GALNT4 in NSCLC cells. It was found that miR-365b expression was reduced in NSCLC tissues and cells. Overexpression of miR-365b inhibited NSCLC cell proliferation whilst promoting apoptosis, but miR-365b knockdown promoted NSCLC cell proliferation. In addition, it was demonstrated that miR-365b regulated the proliferation and apoptosis of NSCLC cells by targeting GALNT4 expression. Collectively, the present study identified a miR-365b/GALNT4 regulatory axis in NSCLC, suggesting that miR-365b may serve as a therapeutic target for NSCLC.
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http://dx.doi.org/10.3892/etm.2020.8857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388555PMC
August 2020

Valine acts as a nutritional signal in brain to activate TORC1 and attenuate postprandial ammonia-N excretion in Chinese perch (Siniperca chuatsi).

Fish Physiol Biochem 2020 Dec 4;46(6):2015-2025. Epub 2020 Aug 4.

College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, No.1, Shizishan Street, Hongshan District, Wuhan, 430070, Hubei Province, China.

An emerging concept is that the hypothalamic nutrient sensor can regulate peripheral energy metabolism via a brain-liver circuit. Valine is an essential branched-chain amino acid (BCAA) that drives intracellular signaling cascades by the activation of target of rapamycin complex 1 (TORC1) which is critical to protein metabolism in mammals. However, in teleost fish, it remains scarce in this area especially about how the intraventricular (ICV) injection of valine can mediate the protein metabolism in peripheral organs. This study would tentatively explore the effects of ICV injection of valine on protein metabolism in peripheral organs through evaluating the postprandial ammonia-N excretion rate in Chinese perch. The control group was injected with 5-μL PBS, and the Val group was injected with 20-μg L valine dissolved into 5-μL PBS. The ammonia-N excretion rate of Val group was lower than control group at 4-, 12-, and 24-h postinjection, while the concertation of plasma glucose was increased sharply at 0.5-, 4-, 12-, and 24-h postinjection. We further checked both mRNA level and the enzyme activity of glutamate dehydrogenase (GDH) in the liver and adenosine monophosphate deaminase (AMPD) in muscle, and we found that they were obviously decreased in Val group at 4-, 12-, and 24-h postinjection. The phosphorylation level of ribosomal protein S6, a downstream target protein of TORC1, was markedly enhanced in the liver of Val group at 4-, 12-, and 24-h postinjection. Collectively, these results illustrated that ICV injection of valine can attenuate protein degradation in peripheral organs by depressing the GDH and AMPD enzyme activity; on the other hand, the injected valine can trigger the activation of TORC1 in the liver via a brain-liver circuit and then interdict proteolysis.
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http://dx.doi.org/10.1007/s10695-020-00767-yDOI Listing
December 2020

Antidepression and Prokinetic Effects of Paeoniflorin on Rats in the Forced Swimming Test via Polypharmacology.

Evid Based Complement Alternat Med 2020 11;2020:2153571. Epub 2020 Jul 11.

Institute of TCM-related Comorbid Depression, Nanjing University of Traditional Chinese Medicine, Nanjing 210023, China.

Paeoniflorin, an organic compound extracted from the roots of the white peony () plant, has previously been shown to exert antidepression and prokinetic effects. The traditional Chinese prescription Si-Ni-San, of which paeoniflorin is a constituent, is often used in treating depression and functional gastrointestinal disorders. The effectiveness of Si-Ni-San has been shown to be less effective in a paeoniflorin-deleted form. The present study further investigates whether paeoniflorin alone is as effective as herbal prescriptions in which the compound is a constituent, specifically any antidepressive and prokinetic effect on rats subjected to a forced swimming test (FST). The FST was used to establish the depression model. Sprague-Dawley rats were administrated with 10 mg/kg paeoniflorin by gastrogavage three times before the behavioral test and gastrointestinal motility tests, respectively. In antidepression studies, fluoxetine was used as the positive control. In order to determine the effect of paeoniflorin on the gastrointestinal movement, mosapride was used as the positive control. Plasma and hippocampus monoamine, hypothalamic-pituitary-adrenal axis, plasma brain-derived neurotrophic factor (BDNF), superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA), ghrelin, motilin, and hippocampus nitric oxide (NO) were assessed using an enzyme-linked immunosorbent assay (ELISA). Gastrointestinal (GI) motility was measured and . Rats subjected to FST showed decreased gastric emptying and intestinal transit , decreased plasma and hippocampus 5-hydroxytryptamine, norepinephrine, dopamine, ghrelin, motilin, and reduced plasma BDNF and SOD as well as increased plasma and hippocampus corticotropin-releasing hormone, adrenocorticotropic hormone, corticosterone, plasma MDA, and hippocampus NO. Paeoniflorin reversed these symptoms in a similar manner to fluoxetine and mosapride, respectively. , paeoniflorin can stimulate the jejunal contract of healthy rats dose-dependently. The results suggest that paeoniflorin can simultaneously exert antidepression and prokinetic effects via polypharmacology.
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http://dx.doi.org/10.1155/2020/2153571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369681PMC
July 2020

Interactive effects of zinc and copper sources and phytase on growth performance, mineral digestibility, bone mineral concentrations, oxidative status, and gut morphology in nursery pigs.

Transl Anim Sci 2020 Apr 20;4(2):txaa083. Epub 2020 Jun 20.

Novus International, Inc., St. Charles, MO.

This study investigated the interactive effects of zinc (Zn) and copper (Cu) sources and phytase on growth performance, oxidative status, mineral digestibility, tissue mineral concentrations, and gut morphology in nursery pigs. A total of 288 weaning barrows [body weight (BW) = 5.71 ± 0.81 kg], blocked by initial BW, were randomly allotted to one of eight dietary treatments, with nine pens per treatment and four pigs per pen. The eight dietary treatments were arranged in 2 × 2 × 2 factorial design, with two Zn sources [2,000, 2,000, and 100 mg/kg Zn from zinc oxide (ZnO) during phase 1 (days 1-14) and phase 2 (days 15-28), and phase 3 (days 29-42), respectively; 100 mg/kg Zn from zinc methionine hydroxy analogue chelate (Zn-MHAC) from phases 1 to 3], two Cu sources [150, 80, and 80 mg/kg Cu from copper sulfate (CuSO) or copper methionine hydroxy analogue chelate (Cu-MHAC) during phases 1-3, respectively], and two phytase inclusion levels (0 or 500 FTU/kg). Results showed that ZnO supplementation at 2,000 mg/kg Zn significantly increased average daily feed intake (ADFI; = 0.01) and average daily gain (ADG; = 0.03) during phase 1 compared to Zn-MHAC group; however, Zn-MHAC supplementation tended ( = 0.06) to improve gain to feed ratio (G:F) during phase 2 compared to ZnO group. There were no differences ( > 0.10) between ZnO and Zn-MHAC groups in terms of ADG, ADFI, and G:F during the entire nursery period. Compared with CuSO, Cu-MHAC tended to increase ADG ( = 0.07) and G:F ( = 0.08) during the entire nursery period. Phytase supplementation significantly increased ADG ( < 0.01), ADFI ( < 0.01), and G:F ( < 0.01) during the entire nursery period compared with no phytase supplementation. There was a significant interaction ( < 0.01) between Zn source and phytase on standardized total tract digestibility (STTD) of phosphorus (P), whereas there was no interaction ( = 0.21) between Cu sources and phytase on STTD of P. However, there was a significant interaction between Cu sources and phytase on calcium (Ca; = 0.02) and P ( = 0.03) concentrations in metacarpal bones and G:F in phase 2 ( = 0.09). Furthermore, pigs fed diets containing Zn-MHAC tended to have lower ileum villus width ( = 0.07), compared with those fed diets containing ZnO, and pigs fed diets containing Cu-MHAC tended to have lower plasma malondialdehyde concentration ( = 0.10) compared with those fed diets containing CuSO. In conclusion, under the conditions of the current study, ZnO supplementation at 2,000 mg/kg Zn was only effective in the first 2 wk postweaning, whereas Zn-MHAC supplementation at 100 mg/kg Zn could achieve better feed efficiency during phase 2 compared to pharmacological levels of ZnO, therefore, leading to no difference of growth performance in the entire nursery period. Low levels of Zn-MHAC may improve phytase efficacy on degrading phytate P compared to pharmacological levels of ZnO. Cu-MHAC may be more effective to promote growth compared to CuSO, which may be partially driven by reduced oxidative stress. Results also indicated that Cu-MHAC might exert a synergistic effect with phytase on improving feed efficiency and bone mineralization.
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http://dx.doi.org/10.1093/tas/txaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339880PMC
April 2020

Efficacy of copper-impregnated hospital linen in reducing healthcare-associated infections: A systematic review and meta-analysis.

PLoS One 2020 20;15(7):e0236184. Epub 2020 Jul 20.

Zaozhuang Hospital of Traditional Chinese Medicine, Zaozhuang, Shandong, P.R. China.

Background: Healthcare-associated infections (HAI) are a significant burden on the healthcare system. Recent research has suggested the role of copper in reducing HAI. The purpose of this study was to systematically search literature and pool data from studies evaluating the efficacy of copper-impregnated hospital linen in reducing HAI.

Methods: We carried out a systematic electronic search of PubMed, ScienceDirect, BioMed Central, Springer, Embase, and Google Scholar databases for controlled studies evaluating the efficacy of copper-impregnated linen in reducing the incidence of HAI. The last search was carried out on 15th February 2020.

Results: Six studies were included. There was no restriction on the type of organism causing HAI in three studies while three trials reported HAI from Clostridioides difficile and multi-drug resistant organisms (MDRO). A meta-analysis of six studies indicated the use of copper-impregnated linen did not reduce the risk of HAI [Incidence rate ratio (IRR):0.66, 95% CI:0.28-1.58, p = 0.36, I2 = 100%)]. On subgroup analysis, while pooled data from three studies HAI indicated a statistical significant reduction in all-HAI with copper-impregnated linen (IRR:0.76, 95% CI:0.75-0.77, p<0.00001, I2 = 0%), no such difference was seen when HAI was defined as infection by Clostridioides difficile and MDROs only (IRR:0.57, 95% CI:0.12-2.75, p = 0.48, I2 = 99%). Meta-regression analysis for study duration and number of days of hospitalization did not demonstrate any influence on the overall effect size. On sensitivity analysis, there was no change in the significance of results after the sequential exclusion of every study.

Conclusion: Current evidence on the use of copper-impregnated linen to reduce HAI is conflicting. Our results indicate that copper-impregnated linen may reduce HAI, but there is still no evidence of such an effect regarding infections caused by MDRO or Clostridioides difficile. The overall quality of evidence is not high. Homogenous high-quality studies are required to strengthen the evidence on this subject.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371175PMC
September 2020

Delivery of a model lipophilic membrane cargo to bone marrow via cell-derived microparticles.

J Control Release 2020 Oct 16;326:324-334. Epub 2020 Jul 16.

The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Bone marrow (BM) is the central immunological organ and the origin of hematological diseases. Efficient and specific drug delivery to the BM is an unmet need. We tested delivery of fluorescent indocarbocyanine lipids (ICLs, DiR, DiD, DiI) as a model lipophilic cargo, via different carriers. Systemically injected T-lymphocyte cell line Jurkat delivered ICLs to the BM more efficiently than erythrocytes, and more selectively than PEGylated liposomes. Near infrared imaging showed that the delivery was restricted to the BM, lungs, liver and spleen, with no accumulation in the kidneys, brain, heart, intestines, fat tissue and pancreas. Following systemic injection of ICL-labeled cells in immunodeficient or immunocompetent mice, few cells arrived in the BM intact. However, between 5 and 10% of BM cells were ICL-positive. Confocal microscopy of intact BM confirmed that ICLs are delivered independently of the injected cells. Flow cytometry analysis showed that the lipid accumulated in both CD11b + and CD11b- cells, and in hematopoietic progenitors. In a xenograft model of acute myeloid leukemia, a single injection of 10 million Jurkat cells delivered DiD to ~15% of the tumor cells. ICL-labeled cells disappeared from blood almost immediately post-intravenous injection, but numerous cell-derived microparticles continued to circulate in blood. The microparticle particle formation was not due to the ICL labeling or complement attack and was observed after injection of both syngeneic and xenogeneic cells. Injection of microparticles produced in vitro from Jurkat cells resulted in a similar ICL delivery as the injection of intact Jurkat cells. Our results demonstrate a novel delivery paradigm wherein systemically injected cells release microparticles that accumulate in the BM. In addition, the results have important implications for studies involving systemically administered cell therapies.
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http://dx.doi.org/10.1016/j.jconrel.2020.07.019DOI Listing
October 2020

How many are we missing with ID NOW COVID-19 assay using direct nasopharyngeal swabs? Findings from a mid-sized academic hospital clinical microbiology laboratory.

Diagn Microbiol Infect Dis 2020 Oct 4;98(2):115123. Epub 2020 Jul 4.

Department of Pathology, University of Texas Medical Branch, Galveston, TX. Electronic address:

Here, we retrospectively analyzed the comparative results of 182 paired dry nasopharyngeal swabs tested by Abbott ID NOW and nasopharyngeal swabs in viral transport medium by real-time RT-PCR methods. While the overall agreement was 96.2%, we found that of 15 samples that were tested positive with RT-PCR methods, 7 were missed by ID NOW, resulting in a false-negative rate of 47%.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334653PMC
October 2020

Altered complexity of resting-state BOLD activity in Alzheimer's disease-related neurodegeneration: a multiscale entropy analysis.

Aging (Albany NY) 2020 07 10;12(13):13571-13582. Epub 2020 Jul 10.

Shenzhen Mental Health Center, Shenzhen, Guangdong, China.

Brain complexity, which reflects the ability of the brain to adapt to a changing environment, has been found to be significantly changed with age. However, there is less evidence on the alterations of brain complexity in neurodegenerative disorders such as Alzheimer's disease (AD). Here we investigated the altered complexity of resting-state blood oxygen level-dependent signals in AD-related neurodegeneration using multiscale entropy (MSE) analysis. All participants were recruited from the Alzheimer's Disease Neuroimaging Initiative, including healthy controls (HC, n=62), amnestic mild cognitive impairment (aMCI, n =81) patients, and Alzheimer's disease (AD, n=25) patients. Our results showed time scale-dependent MSE differences across the three groups. In scale=1, significantly changed MSE patterns (HC>aMCI>AD) were found in four brain regions, including the hippocampus, middle frontal gyrus, intraparietal lobe, and superior frontal gyrus. In scale=4, reversed MSE patterns (HC
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http://dx.doi.org/10.18632/aging.103463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377896PMC
July 2020

Antidepressant-like Effect of Merazin Hydrate Depends on NO/ERK by Suppressing Its Downstream NF-κB or Nonactivating CREB/BDNF in Mouse Hippocampus.

ACS Chem Neurosci 2020 08 9;11(16):2472-2481. Epub 2020 Jul 9.

Institute of TCM-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.

Merazin hydrate (MH), an essential ingredient of Fructus aurantii, has been identified to have an antidepressant-like effect. However, the molecular mechanisms of MH modulate depressive behavior are largely uncharacterized. Here, in lipopolysaccharide-induced mice, we identified that a single administration of MH recovered depressive behaviors and down-regulated the expressions of neuronal nitric oxide synthase (nNOS) in the hippocampus after 1 day. Activation of nNOS by l-arginine led to depressive behaviors, and inhibition of nNOS contributed to antidepressive behaviors. Notably, MH only reversed the expression of nNOS's downstream NF-κB and not the CREB/BDNF pathway in the hippocampus, and MH's antidepressant-like effects were prevented by Asatone (an agonist of NF-κB) and not H89 (an antagonist of CREB). MH also normalized the expressions of GFAP and IB-1 in dentate gyrus in the hippocampus and inflammatory factors such as IL-1β, IL-10, and TNF-α in serum. Overall, our studies reveal the molecular mechanisms of MH's antidepressant-like effect.
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http://dx.doi.org/10.1021/acschemneuro.0c00246DOI Listing
August 2020

Let-7c regulated epithelial-mesenchymal transition leads to osimertinib resistance in NSCLC cells with EGFR T790M mutations.

Sci Rep 2020 07 8;10(1):11236. Epub 2020 Jul 8.

Department of Respiratory Medicine, The Second Hospital of Jilin University, 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People's Republic of China.

Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) have shown promise against non-small cell lung cancers (NSCLCs) in clinics but the utility is often short-lived because of T790M mutations in EGFR that help evade TKIs' action. Osimertinib is the third and latest generation TKI that targets EGFRs with T790M mutations. However, there are already reports on acquired resistance against Osimertinib. Recent work has revealed the role that miRNAs, particularly tumor suppressor let-7c, play in the invasiveness and acquired resistance of NSCLCs, but the mechanistic details, particularly in Osimertinib resistance, remain elusive. Using two cells lines, H1975 (endogenous T790M mutation) and HCC827-T790M (with acquired T790M mutation), we found that let-7c is a regulator of EMT, as well as it affects CSC phenotype. In both the cell lines, transfection with pre-let-7c led to reversal of EMT as studied through EMT markers e-cadherin and ZEB1. This resulted in reduced proliferation and invasion. Conversely, reduced expression of let-7c through anti-let-7c transfections significantly increased proliferation and invasion of lung cancer cells. Expression of let-7c was functionally relevant as EMT correlated with resistance to Osimertinib. High let-7c expression reversed EMT and made cells sensitive to Osimertinib, and vice versa. WNT1 and TCF-4 were found to be two targets of let-7c which were epigenetic suppressed by let-7c through increased methylation. In vivo, pre-let-7c inhibited while anti-let-7c potentiated tumor growth and WNT1 and TCF-4 were downregulated in xenografts with pre-let-7c. Silencing of both WNT1 and TCF-4 resulted in potentiation of Osimertinib action. Our results suggest an important role of let-7c in regulating EMT and the resulting Osimertinib resistance in T790M NSCLCs. More clinical studies need to be performed to fully understand the translational relevance of this novel mechanism.
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http://dx.doi.org/10.1038/s41598-020-67908-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343825PMC
July 2020

Histone Methylation of H3K4 Involved in the Anorexia of Carnivorous Mandarin Fish () After Feeding on a Carbohydrate-Rich Diet.

Front Endocrinol (Lausanne) 2020 19;11:323. Epub 2020 Jun 19.

College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, China.

Food intake of carnivorous fish decreases after feeding on a carbohydrate-rich diet. However, the molecular mechanism underlying the anorexia caused by high-carbohydrate diets has remained elusive. We domesticated the mandarin fish to feed on carbohydrate-rich (8%) diets. After 61 days of feeding, several fish (Group A) fed well on artificial diets during the whole feeding period; the other fish (Group B) fed well on artificial diets at the beginning of the feeding period, with their food intake then decreasing to half (anorexia) and then to zero for 5 days; and, finally, a negative control (Group C) fed on live prey fish throughout the experimental process. The plasma glucose was significantly higher in the mandarin fish of Group B than in those of Group A, whereas levels of hepatic glycogen and plasma triglyceride were significantly lower. Using transcriptome sequencing, we investigated the differentially expressed genes between Groups A and B and excluded the genes that were not differentially expressed between Groups A and C. The activation of mTOR and Jak/STAT pathways were found in the mandarin fish with anorexia, which was consistent with the higher expression levels of and genes. We found a higher expression of histone methyltransferase gene and an increased histone H3 tri-methylated at lysine 4 (H3K4me3) in the fish of Group B. Furthermore, using ChIP assay and inhibitor treatment, we found that the up-regulated H3K4me3 could activate expression, which might have contributed to the hyperglycemia and anorexia in the mandarin fish that fed on carbohydrate-rich diets. Our study initially indicated a link between histone methylation and expression, which might be a novel regulatory mechanism of fish who are fed a carbohydrate-rich diet.
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http://dx.doi.org/10.3389/fendo.2020.00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316955PMC
June 2020