Publications by authors named "Yanhua Huang"

93 Publications

Effects of Lyophilization on the Release Profiles of 3D Printed Delivery Systems Fabricated with Carboxymethyl Cellulose Hydrogel.

Polymers (Basel) 2021 Feb 28;13(5). Epub 2021 Feb 28.

Department of Industrial and Manufacturing Systems Engineering, Iowa State University, Ames, IA 50011, USA.

Recently, increasing numbers of researchers are becoming interested in 3D bioprinting because it provides customizability and structural complexity, which is difficult for traditional subtractive manufacturing to achieve. One of the most critical factors in bioprinting is the material. Depending on the bio-applications, materials should be bio-inert or bio-active, non-toxic, and along with those characteristics, mechanical properties should also meet the applicational or manufacturing requirement. As previously validated for bioprinting, carboxymethyl cellulose (CMC) hydrogel is focused on the printability and release control test in this study. With a differentiated weight percentage of CMC hydrogels were used to 3D print capsules filled with food degradable colorant at designated voids to mimic capsules manufactured for oral delivery. Standard USP (United States Pharmacopeia) dissolution apparatus II (Paddle) evaluations were performed both on lyophilized and non-lyophilized printed capsules. The first-order model was selected due to high linear fitting regression. Upon 24 h dissolution, non-lyophilized capsules showed a different release efficiency when the CMC percentage varied, while lyophilized capsules showed no significant difference. This study signifies the possibility of customizing oral drug delivery by printing capsules with CMC hydrogel. The improved delivery efficiency demonstrated by capsules with post-process lyophilizing proposed potential optimization options for pharmaceutical manufacturing industries.
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http://dx.doi.org/10.3390/polym13050749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957655PMC
February 2021

Nanopore long-read RNAseq reveals regulatory mechanisms of thermally variable reef environments promoting heat tolerance of scleractinian coral Pocillopora damicornis.

Environ Res 2021 Apr 24;195:110782. Epub 2021 Jan 24.

Guangxi Laboratory on the Study of Coral Reefs in the South China Sea, Coral Reef Research Center of China, School of Marine Sciences, Guangxi University, Nanning, China.

Some scleractinian corals exhibit high thermal adaptability to climate changes, although the mechanism of their adaptation is unclear. This study investigated the adaptability of scleractinian coral Pocillopora damicornis to thermally variable reef environments by applying a nanopore-based RNA sequencing method to characterize different transcription responses that promote heat tolerance of P. damicornis. We identified 1414 novel genes and optimized 6256 mis-annotated loci. Based on full-length transcriptome data, we identified complex alternative polyadenylation and alternative splicing events, which can improve our understanding of the genome annotation and gene structures of P. damicornis. Furthermore, we constructed differentially expressed lncRNA-mRNA co-expression networks, which may play a crucial role in the P. damicornis thermal adaptive response. KEGG function enrichment analysis revealed that P. damicornis from the high-temperature pool had a lower metabolic rate than that from the low-temperature pool. We hypothesize that metabolic readjustment, in the form of a lower metabolic rate, positively correlated with increased heat tolerance in P. damicornis in thermally variable reef environments. Our study provides novel insights into lncRNAs that promote thermally tolerance of scleractinian corals in the thermally variable reef environment, suggesting potential mechanisms for their adaptation to global warming in the future.
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http://dx.doi.org/10.1016/j.envres.2021.110782DOI Listing
April 2021

G Protein-Coupled Receptor 109A Maintains the Intestinal Integrity and Protects Against ETEC Mucosal Infection by Promoting IgA Secretion.

Front Immunol 2020 8;11:583652. Epub 2021 Jan 8.

Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China.

Several studies have reported an intricate link between the G protein-coupled receptor 109A (GPR109A) and intestinal health. Upon activation, induced by butyric acid and β-hydroxybutyric acid, GPR109A regulates the expression of tight junction proteins, exerts anti-inflammatory effects, and maintains the integrity of the intestinal barrier. However, its function and the mechanism of action in combating the infection caused by exogenous pathogenic microorganisms remain unclear. This study established an animal model of infection by oral enterotoxigenic (ETEC) gavage to examine the underlying mechanism(s) and protective effects of GPR109A on the intestinal tract. Experimental GPR109Aand GPR109A mice were orally administered with 1 × 10 colony-forming units (CFUs) of ETEC, and changes in body weight were then observed. The colonization and translocation of ETEC in the intestine were detected by the plate counting method. The expression of tight junction proteins and the levels of inflammatory factors and secretory IgA (SIgA) in the intestine were detected by quantitative real-time polymerase chain reaction (q-PCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The results demonstrated that GPR109Amice were more susceptible to ETEC infection, showing more severe inflammatory reactions and intestinal damage. Moreover, the secretion of IgA in the intestinal tract of GPR109A mice was significantly increased after ETEC infection, whereas the IgA levels in GPR109Amice did not change significantly. We added 5 g/L sodium butyrate to the drinking water of all mice. The GPR109A mice were protected against ETEC infection and no effect was observed in GPR109Amice. Similarly, sodium butyrate increased the SIgA content in the gut of the GPR109A mice and no effect was observed in GPR109Amice. In conclusion, activated GPR109A is effective against the colonization and translocation of ETEC in the gut and maintains the integrity of the intestinal barrier, possibly by promoting the secretion of intestinal IgA.
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http://dx.doi.org/10.3389/fimmu.2020.583652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821714PMC
January 2021

AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses.

J Neurosci 2021 Mar 12;41(9):1996-2011. Epub 2021 Jan 12.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subsequently internalized, resulting in the AMPAR-silent state on withdrawal day 1. Furthermore, GluN2B NMDARs functioned to maintain these cocaine-generated synapses in the AMPAR-silent state during drug withdrawal, until they were replaced by nonGluN2B NMDARs, a switch that allowed AMPAR recruitment and maturation of silent synapses. These results reveal dynamic interactions between AMPARs and NMDARs during the generation and maturation of silent synapses after cocaine experience and provide a mechanistic basis through which new synaptic contacts and possibly new neural network patterns created by these synapses can be manipulated for therapeutic benefit. Studies over the past decade reveal a critical role of AMPA receptor-silent, NMDA receptor-containing synapses in forming cocaine-related memories that drive cocaine relapse. However, it remains incompletely understood how AMPA and NMDA receptors traffic at these synapses during their generation and maturation. The current study characterizes a two-step AMPA receptor trafficking cascade that contributes to the generation of silent synapses in response to cocaine experience, and a two-step NMDA receptor trafficking cascade that contributes to the maturation of these synapses after cocaine withdrawal. These results depict a highly regulated cellular procedure through which nascent glutamatergic synapses are generated in the adult brain after drug experience and provide significant insight into the roles of glutamate receptors in synapse formation and maturation.
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http://dx.doi.org/10.1523/JNEUROSCI.1918-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939090PMC
March 2021

Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex.

Pain 2020 Nov 17. Epub 2020 Nov 17.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260.

Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become 'unsilenced' by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
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http://dx.doi.org/10.1097/j.pain.0000000000002149DOI Listing
November 2020

Activation and Assembly of Plasmonic-Magnetic Nanosurfactants for Encapsulation and Triggered Release.

Nano Lett 2020 12 13;20(12):8773-8780. Epub 2020 Nov 13.

Department of Materials Science and Engineering, Iowa State University, Ames, Iowa 50011, United States.

Multifunctional surfactants hold great potentials in catalysis, separation, and biomedicine. Highly active plasmonic-magnetic nanosurfactants are developed through a novel acid activation treatment of Au-FeO dumbbell nanocrystals. The activation step significantly boosts nanosurfactant surface energy and enables the strong adsorption at interfaces, which reduces the interfacial energy one order of magnitude. Mediated through the adsorption at the emulsion interfaces, the nanosurfactants are further constructed into free-standing hierarchical structures, including capsules, inverse capsules, and two-dimensional sheets. The nanosurfactant orientation and assembly structures follow the same packing parameter principles of surfactant molecules. Furthermore, nanosurfactants demonstrate the capability to disperse and encapsulate homogeneous nanoparticles and small molecules without adding any molecular surfactants. The assembled structures are responsive to external magnetic field, and triggered release is achieved using an infrared laser by taking advantage of the enhanced surface plasmon resonance of nanosurfactant assemblies. Solvent and pH changes are also utilized to achieve the cargo release.
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http://dx.doi.org/10.1021/acs.nanolett.0c03641DOI Listing
December 2020

Cocaine-induced neural adaptations in the lateral hypothalamic melanin-concentrating hormone neurons and the role in regulating rapid eye movement sleep after withdrawal.

Mol Psychiatry 2020 Oct 22. Epub 2020 Oct 22.

Departments of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague-Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
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http://dx.doi.org/10.1038/s41380-020-00921-1DOI Listing
October 2020

Cocaine Triggers Astrocyte-Mediated Synaptogenesis.

Biol Psychiatry 2021 Feb 25;89(4):386-397. Epub 2020 Aug 25.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens shell (NAcSh).

Methods: Using multidisciplinary approaches including astrocyte Ca imaging, genetic mouse lines, viral-mediated gene transfer, and operant behavioral procedures, we monitor the response of NAcSh astrocytes to cocaine administration and examine the role of astrocytic TSP-α2δ-1 signaling in cocaine-induced silent synapse generation as well as the behavioral impact of astrocyte-mediated synaptogenesis and silent synapse generation.

Results: Cocaine administration acutely increases Ca events in NAcSh astrocytes, while decreasing astrocytic Ca blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and synapse generation in NAcSh decreases cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction.

Conclusions: These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.
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http://dx.doi.org/10.1016/j.biopsych.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854999PMC
February 2021

High-performance humidity sensor based on a micro-nano fiber Bragg grating coated with graphene oxide.

Opt Express 2020 Aug;28(18):26395-26406

A high-performance relative humidity (RH) sensor based on a micro-nano fiber Bragg grating (MFBG) coated with a graphene oxide (GO) film is fabricated with a chemical corrosion technique and optically driven deposition method. The diameter of MFBG is corroded to about 12 µm. GO film with the thickness of about 2.5 µm is uniformly coated on the MFBG surface. The change of RH results in the change of refractive index (RI) of GO film, that is, the change of effective RI of MFBG, which will at last result in the shift of reflected wavelength. The experimental results show that there is a good linear relationship between the wavelength shift of MFBG and RH changes in the RH range of 20% to 80% at constant temperature. The sensitivity is 17.361 pm/RH% and the linear correlation coefficient is 99.89%. In order to eliminate the impact of temperature cross sensitivity, the relative measurement is adopted and similar results are obtained. The average response and recovery times are measured to be about 3.2 s and 8.3 s, respectively. The sensor has the advantages of long stability, reversibility, quick response and simple structure. With such high performance, it can be used in widespread potential fields, such as biology, chemical processing and food processing.
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http://dx.doi.org/10.1364/OE.402648DOI Listing
August 2020

Cortical and Thalamic Interaction with Amygdala-to-Accumbens Synapses.

J Neurosci 2020 09 6;40(37):7119-7132. Epub 2020 Aug 6.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

The nucleus accumbens shell (NAcSh) regulates emotional and motivational responses, a function mediated, in part, by integrating and prioritizing extensive glutamatergic projections from limbic and paralimbic brain regions. Each of these inputs is thought to encode unique aspects of emotional and motivational arousal. The projections do not operate alone, but rather are often activated simultaneously during motivated behaviors, during which they can interact and coordinate in shaping behavioral output. To understand the anatomic and physiological bases underlying these interprojection interactions, the current study in mice of both sexes focused on how the basolateral amygdala projection (BLAp) to the NAcSh regulates, and is regulated by, projections from the medial prefrontal cortex (mPFCp) and paraventricular nucleus of the thalamus (PVTp). Using a dual-color SynaptoTag technique combined with a backfilling spine imaging strategy, we found that all three afferent projections primarily targeted the secondary dendrites of NAcSh medium spiny neurons, forming putative synapses. We detected a low percentage of BLAp contacts closely adjacent to mPFCp or PVTp presumed synapses, and, on some rare occasions, the BLAp formed heterosynaptic interactions with mPFCp or PVTp profiles or appeared to contact the same spines. Using dual-rhodopsin optogenetics, we detected signs of dendritic summation of BLAp with PVTp and mPFCp inputs. Furthermore, high-frequency activation of BLAp synchronous with the PVTp or mPFCp resulted in a transient enhancement of the PVTp, but not mPFCp, transmission. These results provide anatomic and functional indices that the BLAp interacts with the mPFCp and PVTp for informational processing within the NAcSh. The nucleus accumbens regulates emotional and motivational responses by integrating extensive glutamatergic projections, but the anatomic and physiological bases on which these projections integrate and interact remain underexplored. Here, we used dual-color synaptic markers combined with backfilling of nucleus accumbens medium spiny neurons to reveal some unique anatomic alignments of presumed synapses from the basolateral amygdala, medial prefrontal cortex, and paraventricular nucleus of thalamus. We also used dual-rhodopsin optogenetics in brain slices, which reveal a nonlinear interaction between some, but not all, projections. These results provide compelling anatomic and physiological mechanisms through which different glutamatergic projections to the nucleus accumbens, and possibly different aspects of emotional and motivational arousal, interact with each other for final behavioral output.
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http://dx.doi.org/10.1523/JNEUROSCI.1121-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480237PMC
September 2020

Analysis of efficacy and prognosis of Osimertinib combined with docetaxel for non-small cell lung cancer.

J BUON 2020 Mar-Apr;25(2):805-810

Department of Pulmonary and Critical Care Medicine, the affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, China.

Purpose: To explore the therapeutic effects and prognosis of osimertinib combined with docetaxel for non-small cell lung cancer (NSCLC).

Methods: A total of 94 patients with NSCLC diagnosed in hospitals of Changzhou were selected and randomly divided into two groups of 47 patients each. Patients in the control group took osimertinib tablets, while patients in the drug combination group were given intravenous docetaxel in addition to the oral administration of osimertinib. The therapeutic effects, inflammatory factors, toxic and side effects and factors affecting prognosis were analyzed in the two groups.

Results: The overall response rate (RR) and disease control rate (DCR) in the drug combination group were 25.53% and 57.44%, respectively, which were higher than those in the control group. Before treatment, there were no obvious differences in terms of the levels of vascular endothelial growth factor (VEGF), matrix metallopeptidase-9 (MMP-9) and cytokeratin19 fragment antigen 21-1 (CYFRA21-1) between the two groups of patients. After treatment, the levels of the above indicators were lower in the drug combination group than in the control group. Patients in the two groups demonstrated significantly different degrees of side effects during treatment, including fatigue, thrombocytopenia and neutropenia. Smoking history, Karnofsky performance scale (KPS) score and TNM staging were important indicators affecting the prognosis of NSCLC patients. KPS score <70 and TNM stage IV were independent risk factors for the prognosis of NSCLC patients. After follow-up for 2 years, it was found that the survival rate was remarkably different between the two groups. The survival rate was notably higher in the drug combination group than in the control group.

Conclusions: The therapeutic effect of osimertinib combined with docetaxel is better than that of osimertinib alone, but the toxic and side effects of combined use are significantly higher, suggesting that enteral administration should be conducted during the medication period. Patients with smoking history, advanced TNM stage and high KPS score tend to have a poor prognosis.
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February 2021

Potential molecular traits underlying environmental tolerance of Pavona decussata and Acropora pruinosa in Weizhou Island, northern South China Sea.

Mar Pollut Bull 2020 Jul 11;156:111199. Epub 2020 May 11.

Guangxi Laboratory on the Study of Coral Reefs in the South China Sea, Guangxi University, Nanning 530004, China; Coral Reef Research Center of China, Guangxi University, Nanning 530004, China; School of Marine Sciences, Guangxi University, Nanning 530004, China.

Coral species display varying susceptibilities to biotic or abiotic stress. To address the causes underlying this phenomenon, we profiled the Symbiodiniaceae clade type, bacterial communities and coral transcriptome responses in Pavona decussata and Acropora pruinosa, two species displaying different environmental tolerances in the Weizhou Island. We found that C1 was the most dominant Symbiodiniaceae subclade, with no difference detected between A. pruinosa and P. decussata. Nevertheless, P. decussata exhibited higher microbial diversity and significantly different community structure compared with that of A. pruinosa. Transcriptome analysis revealed that coral genes with significantly high expression in P. decussata were mostly related to immune and stress-resistance responses, whereas, those with significantly low expression were metabolism-related. We postulate that the higher tolerance of P. decussata as compared with that of A. pruinosa is the result of several traits, such as higher microbial diversity, different dominant bacteria, higher immune and stress-resistant response, and lower metabolic rate.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111199DOI Listing
July 2020

Tunable mode-locked erbium-doped fiber laser based on a digital micro-mirror device.

Appl Opt 2020 Apr;59(11):3440-3446

A tunable mode-locked erbium-doped fiber laser with a digital micro-mirror device (DMD) as the wavelength tuner and nonlinear amplifying loop mirror as the mode-locked device is proposed and experimentally demonstrated. The mode-locked pulse with the center wavelength of 1538-1565 nm continuously tunable is achieved. The average power of the output pulse is 1.028 mW, the pulse repetition frequency is 1.7 MHz, the pulse duration is 616 fs, and the single pulse energy is 0.6 nJ. By controlling the DMD, the center wavelength can be fine-tuned with the tuning accuracy of 0.07 nm. With the increase of the pump power, the traditional soliton pulse is transformed into a noise-like pulse (NLP), and the power of the NLP can reach 34 mW. This mode-locked process can work for a long time and is almost unaffected by the external environment. These results are very useful for applications where pulsed lasers with different wavelengths are needed.
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http://dx.doi.org/10.1364/AO.388878DOI Listing
April 2020

Colonization of Trichoderma viride Tv-1511 in peppermint (Mentha × piperita L.) roots promotes essential oil production by triggering ROS-mediated MAPK activation.

Plant Physiol Biochem 2020 Jun 4;151:705-718. Epub 2020 Apr 4.

Agilent Technologies (China) Co., Ltd, Beijing, 100102, China.

Peppermint (Mentha × piperita L.) is a flavoring additive used worldwide, and Trichoderma species are beneficial fungi that can stimulate growth and disease resistance of these plants. Here the growth conditions and metabolic processes of essential oil (EO) biosynthesis in response to inoculation with Trichoderma viride Tv-1511 were investigated. The results showed that T. viride Tv-1511 was able to colonize roots of peppermint to promote its growth and photosynthetic activity and induce higher levels of glandular trichomes and elevated EO yield and composition. GC-MS analysis showed that T. viride Tv-1511-inoculated peppermint produced higher concentrations of menthone, menthol, and pulegone and lower concentrations of menthofuran than un-inoculated seedlings, and qRT-PCR showed that T. viride Tv-1511 inoculation induced upregulation of Pr (pulegone reductase encoding gene) and Mr (menthone reductase encoding gene), whereas it led to the downregulation of Mfs (menthofuran synthase encoding gene). Furthermore, a mitogen-activated protein kinase (MAPK) in peppermint, which was determined to be an analog of Arabidopsis MPK6 protein, was found to be responsible for the modulation of EO metabolism at the transcriptional level and for enzymatic activation in the T. viride Tv-1511-inoculated peppermint. Notably, NADPH oxidase-dependent reactive oxygen species (ROS) production played vital roles in the root colonization of T. viride Tv-1511 and was also involved in the induction of MAPK activation. These data showed the beneficial effects of T. viride Tv-1511 on the seedling growth and EO yield of peppermint, and they elucidated that T. viride Tv-1511 improved the quantity and quality of EOs by regulating the genes that encode the enzymes involved in EO metabolism through a potential MAPK-mediated signaling pathways.
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http://dx.doi.org/10.1016/j.plaphy.2020.03.042DOI Listing
June 2020

Knockdown of HSDL2 inhibits lung adenocarcinoma progression via down-regulating AKT2 expression.

Biosci Rep 2020 04;40(4)

Department of Respiratory and Critical Care Medicine, the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213003, Jiangsu Province, China.

The aims of the present study are to investigate the role of hydroxysteroid dehydrogenase-like 2 (HSDL2) in the progression of lung adenocarcinoma and illuminate the underlying molecular mechanisms. ShRNA targeting HSDL2 gene (siHSDL2) was utilized to knockdown (KD) HSDL2 expression. In vitro and in vivo experiments were carried out to investigate the effect of siHSDL2 on the progression of lung adenocarcinoma. Microarray hybridization and gene expression analysis were used to investigate effect of siHSDL2 on mRNA expression profile in lung cancer cell line H1299. Our data demonstrated that HSDL2 was up-regulated in lung adenocarcinoma tissue samples (P<0.001). Patients with high HSDL2 expression in cancer tissues had a worse overall survival (P<0.001). HSDL2 KD not only inhibited the proliferation, cell cycle, apoptosis, clone-formation, invasion and migration of lung adenocarcinoma cells in vitro (P<0.05), but also suppressed the growth and metastasis in vivo (P<0.05). HSDL2 KD resulted in up-regulation of 681 genes and down-regulation of 276 genes. HSDL2 KD down-regulated the protein expression and phosphorylation of protein kinase B β (AKT2) (P<0.001 and P<0.001, respectively) and protein expression of baculoviral IAP repeat-containing 3 (BIRC3; P=0.001), and up-regulated the phosphorylation of ERK (P<0.001). Rescue experiments showed that AKT2 overexpression reversed the suppression effect of siHSDL2 on cell proliferation (P<0.001), invasion (P<0.001) and migration (P<0.001) significantly. HSDL2 functions as an oncogene to promote the growth and metastasis of lung adenocarcinoma via promoting the expression of AKT2.
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http://dx.doi.org/10.1042/BSR20200348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138907PMC
April 2020

A Critical Role of Basolateral Amygdala-to-Nucleus Accumbens Projection in Sleep Regulation of Reward Seeking.

Biol Psychiatry 2020 06 9;87(11):954-966. Epub 2019 Nov 9.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Sleep impacts reward-motivated behaviors partly by retuning the brain reward circuits. The nucleus accumbens (NAc) is a reward processing hub sensitive to acute sleep deprivation. Glutamatergic transmission carrying reward-associated signals converges in the NAc and regulates various aspects of reward-motivated behaviors. The basolateral amygdala projection (BLAp) innervates broad regions of the NAc and critically regulates reward seeking.

Methods: Using slice electrophysiology, we measured how acute sleep deprivation alters transmission at BLAp-NAc synapses in male C57BL/6 mice. Moreover, using SSFO (stabilized step function opsin) and DREADDs (designer receptors exclusively activated by designer drugs) (Gi) to amplify and reduce transmission, respectively, we tested behavioral consequences following bidirectional manipulations of BLAp-NAc transmission.

Results: Acute sleep deprivation increased sucrose self-administration in mice and altered the BLAp-NAc transmission in a topographically specific manner. It selectively reduced glutamate release at the rostral BLAp (rBLAp) onto ventral and lateral NAc (vlNAc) synapses, but spared caudal BLAp onto medial NAc synapses. Furthermore, experimentally facilitating glutamate release at rBLAp-vlNAc synapses suppressed sucrose reward seeking. Conversely, mimicking sleep deprivation-induced reduction of rBLAp-vlNAc transmission increased sucrose reward seeking. Finally, facilitating rBLAp-vlNAc transmission per se did not promote either approach motivation or aversion.

Conclusions: Sleep acts on rBLAp-vINAc transmission gain control to regulate established reward seeking but does not convey approach motivation or aversion on its own.
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http://dx.doi.org/10.1016/j.biopsych.2019.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210061PMC
June 2020

Calcineurin Promotes Neuroplastic Changes in the Amygdala Associated with Weakened Cocaine-Cue Memories.

J Neurosci 2020 02 20;40(6):1344-1354. Epub 2019 Dec 20.

Department of Psychiatry,

Interfering with memory reconsolidation or inducing memory extinction are two approaches for weakening maladaptive memories in disorders such as addiction and post-traumatic stress disorder. Both extinction and reconsolidation are regulated by intracellular protein kinases and phosphatases, and interfering with these signaling molecules can alter memory strength. The calcium-dependent protein phosphatase, calcineurin (CaN), has been implicated in both the consolidation and extinction of fear memories. However, the role of CaN in regulating drug-cue associative memories has not been investigated. Prior studies have demonstrated that plasticity at thalamo-lateral amygdala (T-LA) synapses is critically involved in the regulation of cocaine-cue memories. Therefore, in the present study, we tested the effects of LA administration of an activator of CaN, chlorogenic acid (CGA), on behavioral and electrophysiological indices of cocaine cue memory reconsolidation and extinction. Male, Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. The cue memory was then either briefly reactivated, extinguished, or not manipulated, followed immediately by LA infusion of CGA. Rats were tested 24 h later for cue-induced reinstatement, or LA slices were prepared for electrophysiological recordings. We found that intra-LA infusions of CGA following cue extinction or reconsolidation reduced cue-induced reinstatement, which was blocked by co-infusion of the CaN inhibitor, FK-506. Similarly, CGA infusions following cue re-exposure significantly attenuated EPSC amplitude at T-LA synapses, suggesting that CaN affects cocaine-cue memory reconsolidation and extinction by altering T-LA synaptic strength. Therefore, CaN signaling in the LA may represent a novel target for disrupting cocaine-associated memories to reduce relapse. Repetitive drug use induces synaptic plasticity that underlies the formation of long-lasting associative memories for environmental cues paired with the drug. We previously identified thalamo-amygdala synapses (T-LA) that project via the interal capsule, as an important locus for the regulation of cocaine-cue memories. These synapses are strengthened by repeated cocaine-cue pairings, but this is reversed by extinction training or by optogenetic induction of long-term depression (LTD). Here, we demonstrate that activating calcineurin, a calcium-dependent phosphatase, following the reactivation or extinction of a cocaine-cue memory, induces LTD-like changes at T-LA synapses, and a corresponding decrease in cue-induced reinstatement, suggesting that calcineurin may be a potential therapeutic target for relapse prevention.
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http://dx.doi.org/10.1523/JNEUROSCI.0453-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002139PMC
February 2020

Silent synapses dictate cocaine memory destabilization and reconsolidation.

Nat Neurosci 2020 01 2;23(1):32-46. Epub 2019 Dec 2.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.

Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.
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http://dx.doi.org/10.1038/s41593-019-0537-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930359PMC
January 2020

Clinical Application Evaluation of a Fourth-Generation HIV Antigen Antibody Combination Screening Assay.

Clin Lab 2019 Oct;65(10)

Background: Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) are infectious diseases with high mortality. Early diagnosis is crucial. Combining HIV antibody and p24 antigen, the Elecsys HIV combi PT assay is a fourth generation HIV screening assay. The sensitivity and specificity of this assay was examined.

Methods: A total of 111,556 samples was conducted from January 1, 2016, to June 30, 2018 in Zhongshan Hospital of Yat-Sen University. We conducted a fourth-generation HIV test of retrospective HIV screening samples and assessed the reliability of using signal-to-cutoff (S/CO) ratios to distinguish false positive HIV antibody reactions and analyzed false positives.

Results: A total of 122 specimens were confirmed as HIV-1 infected by western blot (WB) and HIV nucleic acid assays. The median S/CO ratio for HIV false positive specimens was 3.27, while for the HIV-infected specimen it was 391.7. Receiver operating characteristic (ROC) analysis showed that the best diagnostic point for HIV was 22.85 S/CO. The sensitivity, specificity, and Youden index were 100%, 97.8%, and 0.978, respectively. The highest false positive rate of 26.4% was found in patients with malignant tumors and blood diseases.

Conclusions: The results of this study show that the fourth-generation Elecsys HIV combination PT test can identify early HIV infected and can be a useful adjunct to help clinicians to manage the disease by viral load testing and starting an appropriate therapy. Our research data provides a reference for subsequent research and HIV testing in the region.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190220DOI Listing
October 2019

Chronic sleep fragmentation enhances habenula cholinergic neural activity.

Mol Psychiatry 2021 03 12;26(3):941-954. Epub 2019 Apr 12.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca-activated K (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.
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http://dx.doi.org/10.1038/s41380-019-0419-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790161PMC
March 2021

Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2.

J Neurosci 2019 06 8;39(24):4657-4667. Epub 2019 Apr 8.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, and

The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using -tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of Cell-type-specific knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior. Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.
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http://dx.doi.org/10.1523/JNEUROSCI.2233-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561687PMC
June 2019

Cholinergic system in sleep regulation of emotion and motivation.

Pharmacol Res 2019 05 17;143:113-118. Epub 2019 Mar 17.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, 15219, PA, United States. Electronic address:

Sleep profoundly regulates our emotional and motivational state of mind. Human brain imaging and animal model studies are providing initial insights on the underlying neural mechanisms. Here, we focus on the brain cholinergic system, including cholinergic neurons in the basal forebrain, ventral striatum, habenula, and brain stem. Although much is learned about cholinergic regulations of emotion and motivation, less is known on their interactions with sleep. Specifically, we present an anatomical framework that highlights cholinergic signaling in the integrated reward-arousal/sleep circuitry, and identify the knowledge gaps on the potential roles of cholinergic system in sleep-mediated regulation of emotion and motivation. Sleep impacts every aspect of brain functions. It not only restores cognitive control, but also retunes emotional and motivational regulation [1]. Sleep disturbance is a comorbidity and sometimes a predicting factor for various psychiatric diseases including major depressive disorder, anxiety, post-traumatic stress disorder, and drug addiction [2-9]. Although it is well recognized that sleep prominently shapes emotional and motivational regulation, the underlying neural mechanisms remain elusive. The brain cholinergic system is essential for a diverse variety of functions including cognition, learning and memory, sensory and motor processing, sleep and arousal, reward processing, and emotion regulation [10-14]. Although cholinergic functions in cognition, learning and memory, motor control, and sleep and arousal have been well established, its interaction with sleep in regulating emotion and motivation has not been extensively studied. Here we review current evidence on sleep-mediated regulation of emotion and motivation, and reveal knowledge gaps on potential contributions from the cholinergic system.
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http://dx.doi.org/10.1016/j.phrs.2019.03.013DOI Listing
May 2019

Upregulation of interleukin-6 on Ca3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation.

Exp Neurol 2019 07 11;317:226-243. Epub 2019 Mar 11.

Neuroscience Research Institute, Peking University, Beijing 100083, China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100083, China; Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing 100083, China. Electronic address:

The T-type calcium channels Ca3.2, one of the low voltage-activated (LVA) calcium channels, have been found to play important roles in the neuronal excitability. Recently, we and others have demonstrated that accumulation of Ca3.2 channels in the dorsal root ganglion (DRG) neurons and sensory nerves contributes to neuropathic pain after peripheral nerve injury. In the present study, we aimed to further investigate the regulation of Ca3.2 channels by interleukin-6 (IL-6) in DRG neurons in neuropathic pain rats after spinal nerve ligation (SNL). The results showed that Ca3.2 channel protein expression in L5 DRG neurons was upregulated and blockade of this channel decreased the hyperexcitability of DRG neurons and mechanical allodynia in SNL neuropathic pain rats. Furthermore, inhibition of IL-6 trans-signaling reduced the upregulation of Ca3.2 T-type channel induced by FIL-6 (a fusion protein of IL-6 and sIL-6R) in primary cultured DRG neurons in vitro. In vivo, inhibition of IL-6 trans-signaling reversed the upregulation of Ca3.2, reduced the hyperexcitability of L5 DRG neurons and alleviated mechanical allodynia in SNL rats. Our results suggest that IL-6 upregulates Ca3.2 T-type channels expression and function through the IL-6/sIL-6R trans-signaling pathway in DRG neurons, thus contributes to the development of neuropathic pain in SNL rats.
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http://dx.doi.org/10.1016/j.expneurol.2019.03.005DOI Listing
July 2019

-: a novel rearrangement in one lung adenocarcinoma patient responding to crizotinib treatment.

Onco Targets Ther 2019 7;12:1071-1074. Epub 2019 Feb 7.

Department of Respiratory and Critical Care Medicine, Changzhou Second Affiliated People's Hospital of Nanjing Medical University, Changzhou 213003, China,

The heterogeneity of ALK tyrosine-kinase inhibitor (TKI) responses poses a puzzling question to clinicians. Different variants of rearrangements might be one of the mechanisms explaining this phenomenon. Therefore, identifying specific fusion forms is crucial to clinical practice. This case report assesses the clinical efficacy of an ALK-TKI in a new -rearrangement variant. Next-generation sequencing was performed in tumor tissue of one lung adenocarcinoma patient, and one new fusion form of an rearrangement (-) was identified. This patient had progression-free survival >18 months with crizotinib treatment. Our findings provide valuable information about responses to crizotinib in patients with this form of rearrangement and better understanding of ALK-TKI applications.
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http://dx.doi.org/10.2147/OTT.S192367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369846PMC
February 2019

Plasticity at Thalamo-amygdala Synapses Regulates Cocaine-Cue Memory Formation and Extinction.

Cell Rep 2019 01;26(4):1010-1020.e5

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address:

Repeated drug use has long-lasting effects on plasticity throughout the brain's reward and memory systems. Environmental cues that are associated with drugs of abuse can elicit craving and relapse, but the neural circuits responsible for driving drug-cue-related behaviors have not been well delineated, creating a hurdle for the development of effective relapse prevention therapies. In this study, we used a cocaine+cue self-administration paradigm followed by cue re-exposure to establish that the strength of the drug cue association corresponds to the strength of synapses between the medial geniculate nucleus (MGN) of the thalamus and the lateral amygdala (LA). Furthermore, we demonstrate, via optogenetically induced LTD of MGN-LA synapses, that reversing cocaine-induced potentiation of this pathway is sufficient to inhibit cue-induced relapse-like behavior.
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http://dx.doi.org/10.1016/j.celrep.2018.12.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392072PMC
January 2019

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Mol Psychiatry 2019 11 4;24(11):1668-1684. Epub 2018 May 4.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.
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http://dx.doi.org/10.1038/s41380-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215755PMC
November 2019

Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice.

Alcohol Clin Exp Res 2018 05 18;42(5):879-888. Epub 2018 Apr 18.

Research and Development Service, Portland Veterans Affairs Medical Center, Portland, Oregon.

Background: Chronic alcohol intake leads to long-lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. Here, we investigate the effects of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) on neuronal activity in the NAc and binge-like drinking.

Methods: C57BL/6J mice were stereotaxically injected with AAV2 hSyn-HA hM3Dq, -hM4Di, or -eGFP bilaterally into NAc [core + shell, core or shell]. We measured clozapine-n-oxide (CNO)-induced changes in NAc activity and assessed binge-like ethanol (EtOH) or tastant/fluid intake in a limited access Drinking in the Dark (DID) schedule.

Results: We found that CNO increased NAc firing in hM3Dq positive cells and decreased firing in hM4Di cells, confirming the efficacy of these channels to alter neuronal activity both spatially and temporally. Increasing NAc core + shell activity decreased binge-like drinking without altering intake of other tastants. Increasing activity specifically in the NAc core reduced binge-like drinking, and decreasing activity in the NAc core increased drinking. Manipulation of NAc shell activity did not alter DID. Thus, we find that increasing activity in the entire NAc, or just the NAc core is sufficient to decrease binge drinking.

Conclusions: We conclude that the reduction in EtOH drinking is not due to general malaise, altered perception of taste, or reduced calorie-seeking. Furthermore, we provide the first evidence for bidirectional control of NAc core and binge-like drinking. These findings could have promising implications for treatment.
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http://dx.doi.org/10.1111/acer.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034712PMC
May 2018

Transcriptomic analysis reveals vacuolar Na (K)/H antiporter gene contributing to growth, development, and defense in switchgrass (Panicum virgatum L.).

BMC Plant Biol 2018 Apr 10;18(1):57. Epub 2018 Apr 10.

College of Animal Science and Technology, China Agricultural University, Beijing, People's Republic of China.

Background: Intracellular Na (K)/H antiporters (NHXs) have pivotal functions in regulating plant growth, development, and resistance to a range of stresses. To gain insight into the molecular events underlying their actions in switchgrass (Panicum virgatum L.), we analyzed transcriptomic changes between PvNHX1-overexpression transgenic lines and wild-type (WT) plants using RNA sequencing (RNA-seq) technology.

Results: The comparison of transcriptomic data from the WT and transgenic plants revealed a large number of differentially expressed genes (DEGs) in the latter. Gene ontology (GO) and KEGG pathway analyses showed that these DEGs were associated with a wide range of functions, and participated in many biological processes. For example, we found that PvNHX1 had an important role in plant growth through its regulation of photosynthetic activity and cell expansion. In addition, PvNHX1 regulated K homeostasis, cell expansion and pollen development, indicating that it has unique and specific roles in flower development. We also found that transgenic switchgrass exhibited a higher level of transcription of defense-related genes, especially those involved in disease resistance.

Conclusion: We showed that PvNHX1 had an important role in plant growth and development through its regulation of photosynthetic activity, cell expansion, K homeostasis, and pollen development. Additionally, PvNHX1 overexpression activated a complex signal transduction network in response to various biotic and abiotic stresses. In relation to plant growth, development, and defense responses, PvNHX1 also had a vital regulatory role in the formation of a series of plant hormones and transcription factors (TFs). The reliability of the RNA-seq data was confirmed by quantitative real-time PCR. Our data provide a valuable foundation for further research into the molecular mechanisms and physiological roles of NHXs in plants.
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http://dx.doi.org/10.1186/s12870-018-1278-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892015PMC
April 2018

Circulating HOTAIR expression predicts the clinical response to neoadjuvant chemotherapy in patients with breast cancer.

Cancer Biomark 2018 ;22(2):249-256

Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Tianhe District, Guangzhou, Guangdong, China.

Background: Long noncoding RNA HOTAIR has been detected in the serum of patients with various malignances and may be served as novel biomarker for diagnosis and prognosis prediction of breast cancer. However, the value of circulating HOTAIR to predict the response to neoadjuvant chemotherapy (NAC) remains unclear.

Objective: In the present study, we analyzed whether pretreatment circulating HOTAIR levels predict the response to NAC and investigated prognostic impact of circulating HOTAIR on disease-free survival (DFS) in breast cancer patients treated with NAC.

Methods: Circulating HOTAIR levels in the serum of 112 breast cancer patients before NAC were measured using quantitative real-time PCR. The correlation of circulating HOTAIR with the clinicopathologic status and the response to NAC were analyzed. Kaplan-Meier survival analysis and log-rank test were used to estimate the DFS.

Results: In 112 serum samples obtained before NAC, high circulating HOTAIR was associated with larger tumor size, more positive lymph nodes as well as more distant metastasis. However, there was no significant correlation between the circulating HOTAIR levels and age, Ki67 status or hormone receptor. Furthermore, patients with high circulating HOTAIR achieved less clinical response as well as pathologic complete response than those with low circulating HOTAIR (p< 0.05). The Kaplan-Meier survival curve with a median follow-up of 48 months demonstrated that patients with high circulating HOTAIR expression had a worse disease-free survival than those with low circulating HOTAIR (log-rank p= 0.012).

Conclusions: High circulating HOTAIR level correlates with less response to neoadjuvant chemotherapy as well as a worse prognosis in breast cancer patients. Therefore, the present study provides a favorable basis to use circulating HOTAIR as a predictor of neoadjuvant chemotherapy response.
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http://dx.doi.org/10.3233/CBM-170874DOI Listing
October 2018

Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving.

J Neurosci 2018 05 6;38(18):4316-4328. Epub 2018 Apr 6.

Departments of Neuroscience,

In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal. Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.
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http://dx.doi.org/10.1523/JNEUROSCI.3291-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932642PMC
May 2018