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Clinical evidence suggests that there are correlations between activity within the anterior cingulate cortex (ACC) following re-exposure to drug-associated contexts and drug craving. However, there are limited data contributing to our understanding of ACC function at the cellular level during re-exposure to drug-context associations as well as whether the ACC is directly related to context-induced drug seeking. Here, we addressed this issue by employing our novel behavioral procedure capable of measuring the formation of drug-context associations as well as context-induced drug-seeking behavior in male mice (8–12 weeks of age) that orally self-administered oxycodone. We found that mice escalated oxycodone intake during the long-access training sessions and that conditioning with oxycodone was sufficient to evoke conditioned place preference (CPP) and drug-seeking behaviors. Additionally, we found that thick-tufted, but not thin-tufted pyramidal neurons (PyNs) in the ACC as well as ventral tegmental area (VTA)-projecting ACC neurons had increased intrinsic membrane excitability in mice that self-administered oxycodone compared to controls. Moreover, we found that global inhibition of the ACC or inhibition of VTA-projecting ACC neurons was sufficient to significantly reduce oxycodone-induced CPP, drug seeking, and spontaneous opioid withdrawal. These results demonstrate a direct role of ACC activity in mediating context-induced opioid seeking among other behaviors, including withdrawal, that are associated with the DSM-V criteria of opioid use disorder.

Objective(s): The central nucleus of the amygdala (CeA) is one of the most important areas for the morphine reward system. This study investigated the effect of electrical stimulation of CeA on morphine conditioned place preference (CPP) in male rats. Materials and Methods: After anesthetizing male Wistar rats, both electrode and cannula were implanted into CeA for stimulating (low intensity: 25 ÎA, and high intensity: 150 ÎA) and injecting (lidocaine and dopamine D2 receptor antagonist), respectively. Then, CPP induced by effective (5 mg/kg) and ineffective (0.5 mg/kg) doses of morphine was evaluated for five consecutive days (n = 6 / group). Results: The low electrical stimulation intensity of 25 ÎA suppressed both acquisition and expression phases, but the high intensity of 150 ÎA attenuated only the expression phase. On the other hand, intra-CeA administration of dopamine D2 receptor antagonist, eticlopride (2 Îg/rat), with the effective dose of morphine, decreased CPP. In addition, infusion of lidocaine into the CeA inhibited morphineinduced CPP in both acquisition and expression phases with the effective dose of morphine. Conclusion: Electrical stimulation of the CeA may play an important role in attenuating morphine induced CPP via possible changes in neurotransmitters involved in the reward system such as dopamine (DA) and gamma-aminobutyric acid (GABA). [ABSTRACT FROM AUTHOR]

Cell-penetrating peptides (CPPs) are small peptides that can transfer other materials into a cellular compartment. In this research, we studied the effect of fusion of new CPPs to the N-terminal of enhanced Green Fluorescent Protein eGFP on the ability of the latter to fluoresce. Results showed that the recombinant protein CPPs-eGFP could be successfully ex-pressed in Escherichia coli. In contrast to E. coliexpressing wild-type eGFP, which could fluoresce under ultraviolet (UV) or visible light, E. coliexpressing CPPs-eGFP lost their ability to fluoresce. PyMol, a molecular visualization system, revealed that fusion of the new CPPs to the N-terminal of eGFP alters interactions between chromophore-forming tripeptides and the adjacent amino acids of other tripeptides. Disrupting peptide interactions induced structural changes in eGFP that caused it to lose its fluorescence ability. We suggest performing computational analyses to predict the biological function of new fusion proteins prior to starting laboratory work.

Abstract Aims G protein‐activated inwardly rectifying potassium (GIRK) channels are related to rewarding effects of addictive drugs. The GIRK2 subunit is thought to play key roles in the reward system. Weaver mutant mice exhibit abnormal GIRK2 function and different behaviors that are caused by several addictive substances compared with wild‐type mice. However, mechanisms of reward‐related alterations in weaver mutant mice remain unclear. The present study investigated changes in the rewarding effects of methamphetamine (METH) in weaver mutant mice. Methods The rewarding effects of METH (4.0 mg/kg) were investigated using the conditioned place preference (CPP) paradigm. Extracellular dopamine level in the nucleus accumbens (NAc) was measured by in vivo microdialysis. To identify brain regions that were associated with these changes in rewarding effects, METH‐induced alterations of Fos expression were investigated by immunohistochemical analysis. Results Weaver mutant mice exhibited a significant decrease in METH‐induced CPP and dopamine release in the NAc. Methamphetamine significantly increased Fos expression in the posterior NAc (pNAc) shell in wild‐type but not in weaver mutant mice. Conclusions Methamphetamine did not induce rewarding effects in weaver mutant mice. The pNAc shell exhibited a significant difference in neuronal activity between wild‐type and weaver mutant mice. The present results suggest that the absence of METH‐induced CPP in weaver mutant mice is probably related to an innate reduction of dopamine and decreased neural activity in the pNAc shell that is partially attributable to the change of GIRK channel function. GIRK channels, especially those containing the GIRK2 subunit, appear to be involved in METH dependence.

Jinhui Ser1 ,* Ji Yeon Lee2 ,* Yong Ho Kim,3 Hoonsung Cho1 1School of Materials Science & Engineering, Chonnam National University, Gwangju 61186, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Incheon 21565, Republic of Korea; 3Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea*These authors contributed equally to this workCorrespondence: Yong Ho KimGachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of KoreaTel +82-32-899-6691Fax +82-32-724-9071Email euro16@gachon.ac.krHoonsung ChoSchool of Materials Science & Engineering, Chonnam National University, Gwangju 61186, Republic of KoreaTel +82-62-530-1717Fax +82-62-530-1699Email cho.hoonsung@jnu.ac.krIntroduction: Photodynamic therapy (PDT), which induces tissue damage by exposing tissue to a specific wavelength of light in the presence of a photosensitizer and oxygen, is a promising alternative treatment that could be used as an adjunct to chemotherapy and surgery in oncology. Cell-penetrating peptides (CPPs) with high arginine content, such as protamine, have membrane translocation and lysosome localization activities. They have been used in an extensive range of drug delivery applications.Methods: We conjugated cell-penetrating peptides (CPPs) with methylene blue (MB) and then purification by FPLC. Synthesis structure was characterized by the absorbance spectrum, FPLC, Maldi-TOF, and then evaluated cell viability by cytotoxicity assay after photodynamic therapy (PDT) assay. An uptake imaging assay was used to determine the sites of MB and MB-Pro in subcellular compartments.Results: In vitro assays showed that MB-Pro has more efficient photodynamic activities than MB alone for the colon cancer cells, owing to lysosome rupture causing the rapid necrotic cell death. In this study, we coupled protamine with MB for high efficacy PDT. The conjugates localized in the lysosomes and enhanced the efficiency of PDT by inducing necrotic cell death, whereas PDT with non-coupled MB resulted in only apoptotic processes.Discussion: Our research aimed to enhance PDT by engineering the photosensitizers using CPPs coupled with methylene blue (MB). MB alone permeates through the cell membrane and distributes into the cytoplasm, whereas coupling of MB dye with CPPs localizes the MB through an endocytic mechanism to a specific organelle where the localized conjugates enhance the generation of reactive oxygen species (ROS) and induce cell damage.Keywords: methylene blue, protamine, CPP, photodynamic therapy, bioconjugation, anticancer, fluorescent

Background: Delta-like non-canonical notch ligand 1 (DLK1) is negatively associated with bodyweight. DLK1 pathogenic variants cause central precocious puberty (CPP) and obesity, suggesting that DLK1 link the well-established association between higher BMI and earlier pubertal onset. However, little is known about the trajectories of circulating DKL1 in healthy girls as well as in girls with precocious puberty., Objective: To evaluate longitudinal changes in circulating DLK1 concentrations in 1) full-term, singleton healthy infant girls 2) healthy girls during pubertal transition 3) girls with CPP during treatment with gonadotropin-releasing hormone agonist (GnRHa)., Method: Three longitudinal studies of 1) healthy, infant girls (n=85), 2) healthy, peripubertal girls (n=15), 3) girls with CPP before and after GnRHa treatment (n=15).Body fat percentage (BF%) by Slaughter equation. Serum concentrations of DLK1 by ELISA., Results: Serum concentration of DLK1 in healthy infant girls declined significantly through the first year of life (17.6 ng/mL to 9.9 nh/mL, p=0.020). DLK1 was inversely correlated with birth weight and BF%: r=-0.220, p=0.044 and r=-0.503, p<0.001, respectively. DLK1 declined from one year prior to pubertal onset to time of first examination after pubertal onset (10.4 ng/mL to 9.2 n/mL, p=0.004) as well as to time at the last pubertal evaluation (10.4 ng/mL to 9.8 ng/mL, p=0.006). DLK1 levels were not affected by GnRHa treatment., Conclusion: Circulating DLK1 levels declined steeply during infancy and less pronounced through pubertal development. Due to considerable inter-individual variation, DLK1 is not useful as a diagnostic marker of pubertal onset. Importantly, DLK1 was negatively associated with birth weight and body fat percentage., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

• Morphine activate the 5-HT neurons. • Optogenetic activate 5-HT neurons encode reward. • Optogenetic inhibit 5-HT neurons reverse morphine CPP. Morphine rewarding properties are the main reasons for drug-craving in behaviors occurring during morphine addiction. It has been suggested that morphine addiction relies on signals to the mesolimbic dopamine system, although the mechanisms outside the dopaminergic system are still unclear. Notably, the role of the dorsal raphe nucleus (DRN) serotoninergic (5-hydroxytryptamine, 5-HT) system remains unexplored. Using in vivo electrophysiological and optogenetic approaches, we found that morphine treatment increased DRN 5-TH neurons firing rate and optogenetic activation of DRN 5-HT neurons induced a rewarding effect, indicating that morphine reward is related to DRN 5-HT neurons. Accordingly, optogenetic inhibition of DRN 5-HT neurons following morphine injection reversed conditioned place preference (CPP) during chronic morphine treatment. These findings aid our understanding of the new functions of the DRN 5-HT neurons for morphine rewarding effect and provide a potential approach for the treatment of morphine addiction. [ABSTRACT FROM AUTHOR]

This review concentrates on the research concerning conjugates of anticancer drugs with versatile cell-penetrating peptides (CPPs). For a better insight into the relationship between the components of the constructs, it starts with the characteristic of the peptides and considers its following aspects: mechanisms of cellular internalization, interaction with cancer-modified membranes, selectivity against tumor tissue. Also, CPPs with anticancer activity have been distinguished and summarized with their mechanisms of action. With respect to the conjugates, the preclinical studies (in vitro, in vivo) indicated that they possess several merits in comparison to the parent drugs. They concerned not only better cellular internalization but also other improvements in pharmacokinetics (e.g. access to the brain tissue) and pharmacodynamics (e.g. overcoming drug resistance). The anticancer activity of the conjugates was usually superior to that of the unconjugated drug. Certain anticancer CPPs and conjugates entered clinical trials. [ABSTRACT FROM AUTHOR]

The safety issues like immunogenicity and unacceptable cancer risk of viral vectors for DNA/mRNA vaccine delivery necessitate the development of non-viral vectors with no toxicity. Among the non-viral strategies, cell-penetrating peptides (CPPs) have been a topic of interest recently because of their ability to cross plasma membranes and facilitate nucleic acids delivery both in vivo and in vitro. In addition to the application in the field of gene vaccine and gene therapy, CPPs based nucleic acids delivery have been proved by its potential application like gene editing, RNA-sequencing, and imaging. Here, we focus on summarizing the recent applications and progress of CPPs-mediated nucleic acids delivery and discuss the current problems and solutions in this field. [Display omitted] [ABSTRACT FROM AUTHOR]

The objectives of Russian Social Democratic Labour Party (RSDLP), established in 1898, included: empowering Russian working classes, without a clearly determined Socialist Programme. In 1903, diverse approaches towards revolutionary change in Russia led to RSDLP’s split into two factions: Bolshevik (Majority) and Menshevik (Minority). The divergence in approach surfaced during 2nd Congress of RSDLP held in Brussels-London 17th July - August 10th 1903. This research attempts to describe and distinguish both, Bolshevik and Menshevik approaches to revolution in Russia. It also compares approaches to revolutionary change in less developed countries, particularly Pakistan. It examines fragmentation and split of leftist political parties in Pakistan due to approaches towards revolution. [ABSTRACT FROM AUTHOR]

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations. [ABSTRACT FROM AUTHOR]

Sweden has tried to speed up the process of early cancer detection by standardization of care. This increased focus on early cancer detection provides people with a conflicting norm regarding the importance of recognizing possible cancer symptoms and the responsibility of not delaying seeking care. Based on existing norms about patients' responsibility and care seeking, this study explores how patients experience encounters with primary care physicians when they seek care for symptoms potentially indicating cancer. Thirteen semi-structured interviews were conducted with patients receiving care for symptoms indicative of cancer in one county in northern Sweden. Data was analysed with thematic analysis. The common notion of describing patients as customers in a healthcare context does not sufficiently capture all aspects of what counts as being a person seeking care. Instead, people interacting with primary care face a twofold role in where they are required to take the role not only of customer but also of seller. Consequently, people shift between these two roles in order to legitimize their care seeking. Standardization oversimplifies the complexity underlying patients' experience of care seeking and interaction with healthcare. Hence, healthcare must acknowledge the individual person within a standardized system. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) is a condition that causes early gonadotropin-dependent sexual development; CPP is idiopathic in girls in most cases, whereas more than 50% of boys have an identifiable etiology. We conducted a qualitative systematic review following the ENTREQ (enhancing transparency in reporting the synthesis of qualitative research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms "precocious puberty" AND "brain tumor" OR "posterior fossa tumor" OR "cerebellar tumor" OR "infratentorial tumor", identifying five cases of pediatric patients with infratentorial tumors and CPP and a case of cerebellar ganglioglioma without hypothalamic−pituitary−gonadal axis involvement and/or intracranial hypertension. Our work highlights the importance of a multidisciplinary approach and extensive central nervous system imaging for patients presenting with CPP in order to detect possible tumor association. Moreover, we believe that this manuscript could contribute to stimulate other research because the exact mechanism of CPP in infratentorial brain lesions has not been understood yet. [ABSTRACT FROM AUTHOR]

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations.

BACKGROUND: Casein-Phosphopeptide of Amorphous-Calcium-Phosphate (CPP-ACP) promotes dental remineralization and revers of early carious lesion; however, the clinical evidence is limited. OBJECTIVE: Compare the preventive and remineralizing effect of CPP-ACP in two presentations: chewing gum and cream for self-application on permanent teeth. MATERIALS AND METHODS: Clinical trial carried out in students aged 11 to 13 years, with a duration of three months. Permanent premolar and molar surfaces were included: free of caries and with incipient carious lesions. Participants were randomly assigned to three groups: a) Chewing gum with CPP-ACP; b) Self-apply cream with CPP-ACP and, c) control. They brushed their teeth with a sodium fluoride toothpaste. For data analysis, median and percentile were calculated and Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests were used. RESULTS: Ninety students aged 11 to 13 years were studied for three months. A total of 971 permanent premolar and molar surfaces were included: 843 caries-free and 128 with incipient carious lesions. A decrease in fluorescence values was found. The medians of the differences between the baseline value and after each treatment in teeth without caries were: chewing gum: -2 (-5.0)); cream group: -1 (-3.1) and control group: -1 (-3.1). p = 0.001. For those teeth with incipient lesions, the medians were: gum: -15 (-19, -2), cream: -10 (-14, -5) and control -10 (-16, -4) with significant differences between the gum group with that of pasta and control (p = 0.001). CONCLUSION: CPP-ACP plus brushing with fluoridated-toothpaste showed remineralizing effect and limited the advancement of incipient carious lesions, with greater efficacy for chewing gum. [ABSTRACT FROM AUTHOR]

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain. [ABSTRACT FROM AUTHOR]

Neuroadaptive changes in the hippocampus underlie addictive-like behaviors in humans or animals chronically exposed to cocaine. miR-181a, which is widely expressed in the hippocampus, acts as a regulator for synaptic plasticity, while its role in drug reinstatement is unclear. In this study, we found that miR-181a regulates the reinstatement of cocaine conditioned place preference(CPP), and altered miR-181a expression changes the complexity of hippocampal neurons and the density and morphology of dendritic spines. By using a luciferase gene reporter, we found that miR-181a targets PRKAA1, an upstream molecule in the mTOR pathway. High miR-181a expression reduced the expression of the PRKAA1 mRNA and promoted mTOR activity and the reinstatement of cocaine CPP. These results indicate that miR-181a is involved in neuronal structural plasticity induced by reinstatement of cocaine CPP, possibly through the activation of the mTOR signaling pathway. This study provides new microRNA targets and a theoretical foundation for the prevention of cocaine-induced reinstatement. [ABSTRACT FROM AUTHOR]

The chirality of CPP, a prominent N -methyl- d -aspartate (NMDA) antagonist, and Anap, a notable genetically encoded fluorescent unnatural amino acid, have a significantly influence on their biological activities. Enantiospecific synthesis of CPP and Anap has been achieved through an improved strategy of ring opening of chiral aziridine, accomplished in 6 steps with a total yield of 50 % for CPP and in 4 steps with a total yield of 59 % for Anap. This unified method significantly shortened the synthetic process, improved overall yield, and demonstrated the potential for industrial-scale development. Based on the improved strategy of ring opening of chiral aziridine, enantiospecific synthesis of N -methyI- d -aspartate antagonist (R)-2-carboxy-4-(3-phosphonopropyl)piperazine [(R)-CPP] and genetically encoded fluorescent unnatural amino acid (S)-3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid [(S)-Anap] has been accomplished. This unified synthetic method has notably reduced the synthetic steps and improved the total yield in contrast with previous methodologies. [Display omitted] • (R)-CPP and (S)-Anap have been enantiospecifically synthesized based on ring opening of chiral aziridine. • More optimized process route has been accomplished. • This synthetic strategy has high yield and scalability. [ABSTRACT FROM AUTHOR]

Abstract Background Esophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~ 30% patients can survive this disease for more than 5 years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity. Methods We used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo. Results In our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions. For the first time, we identified FoxP3 as a key transcriptional repressor for both DR4 and DR5. By down-regulating FoxP3, CPP increases the expression of DR4/DR5 and renders ESCC cells much more sensitive to TRAIL. We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/β-catenin pathway. All these contributed to synergistic activity of CPP and TRAIL on ESCC cells in vitro and in vivo. Conclusion Our data suggest that CPP and TRAIL could be further explored as potential therapeutic approach for esophageal cancer.

Abstract Background Methionine has been proven to inhibit addictive behaviors of cocaine dependence. However, the mechanism of methionine response to cocaine CPP is unknown. Recent evidence highlights piRNAs to regulate genes via a miRNA‐like mechanism. Here, next‐generation sequencing is used to study mechanism on methionine response to drug‐induced behaviors though piRNA. Methods l‐methionine treatment cocaine CPP animal model was used to do non‐coding RNA sequencing. There were four groups to sequence: saline+saline (SS), MET+saline (MS), MET+cocaine (MC), and cocaine+saline. Combining mRNA sequencing data, the network and regulation of piRNA were analyzed with their corresponding mRNA and miRNA. Results Analysis of the piRNAome reveals that piRNAs inversely regulated their target mRNA genes. KEGG analysis of DE‐piRNA target mRNA genes were enriched in Morphine addiction, GABAergic synapse and Cholinergic synapse pathway. Furthermore, four significantly differential expressed genes Cacna2d3, Epha6, Nedd4l, and Vav2 were identified and regulated by piRNAs in the process of l‐methionine inhibits cocaine CPP. Thereinto, Vav2 was regulated by multiple DE piRNAs by sharing the common sequence: GTCTCTCCAGCCACCTT. Meanwhile, it was found that piRNA positively regulates miRNA and three genes Bcl3, Il20ra, and Insrr were identified and regulated by piRNA through miRNA. Conclusion The results showed that piRNA negatively regulated target mRNA genes and positively regulated target miRNA genes. Genes located in substance dependence, signal transduction and also nervous functions pathways were identified. When taken together, these data may explain the roles of l‐methionine in counteracting the effects of cocaine CPP via piRNAs.

BackgroundGonadotropin-releasing hormone agonist (GnRHa) is the gold standard in the treatment of Central Precocious Puberty (CPP) with progressive puberty and accelerative growth. However, GnRHa treatment is reported to result in growth deceleration and prevents growth plate development which leads to a reduction in height velocity. Stanozolol (ST) has been used to stimulate growth in patients with delayed growth and puberty, nevertheless, the effects and mechanisms of ST on CPP with GnRHa treatment are currently unclear.Methods and ResultsIn the current study, we recorded the following vital observations that provided insights into ST induced chondrogenic differentiation and the maintenance of normal growth plate development: (1) ST efficiently prevented growth deceleration and maintained normal growth plate development in rats undergoing GnRHa treatment; (2) ST suppressed the inhibitory effect of GnRHa to promote chondrogenic differentiation; (3) ST induced chondrogenic differentiation through the activation of the JNK/c-Jun/Sox9 signaling pathway; (4) ST promoted chondrogenic differentiation and growth plate development through the JNK/Sox9 signaling pathway in vivo.ConclusionsST mitigated the inhibitory effects of GnRHa and promoted growth plate development in rats. ST induced the differentiation of chondrocytes and maintained normal growth plate development through the activation of JNK/c-Jun/Sox9 signaling. These novel findings indicated that ST could be a potential agent for maintaining normal bone growth in cases of CPP undergoing GnRHa treatment.

Titanium (Ti) and its alloys have attractive properties like high strength-to-weight ratio, excellent formability, biocompatibility, and corrosion resistance. These alloys are conventionally produced via subtractive manufacturing (SM) method, but recently new additive manufacturing (AM) method has been developed and can fabricate desired products by melting and stacking powders using a laser, electron beam, or a plasma arc. From a mechanical perspective, the strength and ductility of AM Ti alloys are comparable to or above those fabricated via SM because of their unique microstructure. However, AM Ti alloys corrosion resistance is still unknown, because of their defects and formation of martensite phase resulting from rapid solidification, hence new strategies were developed to evaluate localized corrosion resistance Consequently, a measurement method based on electrochemical critical localized corrosion temperature (E-CLCT) was adopted as ISO 22,910:2020 but its application should be limited at normal ranges of pH and temperatures corresponding to the human body because of the temperature scan during the E-CLCT testing. Therefore, electrochemical critical localized corrosion potential (E-CLCP) was introduced and proposed in this paper as a new criterion in evaluating the resistance against localized corrosions in biomedical AM Ti alloys in human body environments. AM Ti alloy samples without a hole and crevice former as well as an electrochemical polarization cell were used in the artificial physiological fluids. This study explores how to efficiently evaluate the localized corrosion resistance of AM Ti alloys such as Ti-6Al-4 V by measuring E-CLCP values in the artificial physiological fluids. [ABSTRACT FROM AUTHOR]

A combination of doxorubicin (DOX) and small interfering RNA (siRNA) is proven effective for the reverse of multidrug resistance. However, rapid degradation and poor cellular internalization of siRNA hinder their synergistic action. To improve the combination effect, asparagine–glycine–arginine peptide (NGR) -modified nanobubbles (NBs) containing cell-penetrating peptide (CPP) decorated DOX and CPP decorated c-myc siRNA were constructed. Diameters of these NBs were about 245 nm and zeta potentials were about −3 mV. Encapsulation efficiencies (EE) of DOX exceeded 80%. Release of DOX could be triggered by ultrasound (US) since above 80% DOX was released from NBs after sonication while less than 5% DOX was discharged without treatment of US. These NBs were considered stable during 24 h since the decrease of particle size was no more than 10 nm, variances of EE were less than 5%, and changes of transmission (ΔT) were less than 3%. More drugs in formulation decorated with CPP and NGR were accumulated in the tumor when combined with sonication. The evident synergistic action of DOX, siRNA, NBs, and US was verified in mice with strong antitumor efficacy. Taken together, NGR-modified NBs containing CPP-DOX and CPP-siRNA are able to realize time- and spatial-controlled drug delivery and show potential application prospects. [ABSTRACT FROM AUTHOR]

Background: Gonadotropin-releasing hormone agonist (GnRHa) is the gold standard in the treatment of Central Precocious Puberty (CPP) with progressive puberty and accelerative growth. However, GnRHa treatment is reported to result in growth deceleration and prevents growth plate development which leads to a reduction in height velocity. Stanozolol (ST) has been used to stimulate growth in patients with delayed growth and puberty, nevertheless, the effects and mechanisms of ST on CPP with GnRHa treatment are currently unclear. Methods and Results: In the current study, we recorded the following vital observations that provided insights into ST induced chondrogenic differentiation and the maintenance of normal growth plate development: (1) ST efficiently prevented growth deceleration and maintained normal growth plate development in rats undergoing GnRHa treatment; (2) ST suppressed the inhibitory effect of GnRHa to promote chondrogenic differentiation; (3) ST induced chondrogenic differentiation through the activation of the JNK/c-Jun/Sox9 signaling pathway; (4) ST promoted chondrogenic differentiation and growth plate development through the JNK/Sox9 signaling pathway in vivo. Conclusions: ST mitigated the inhibitory effects of GnRHa and promoted growth plate development in rats. ST induced the differentiation of chondrocytes and maintained normal growth plate development through the activation of JNK/c-Jun/Sox9 signaling. These novel findings indicated that ST could be a potential agent for maintaining normal bone growth in cases of CPP undergoing GnRHa treatment. [ABSTRACT FROM AUTHOR]

Bacillus amyloliquefaciens Q-426 with strong antifungal activity was isolated from the compost samples in Dalian of China. Four kinds of diketopiperazines were extracted from the strain including cyclo(Pro-Phe) (cPP), which had cyclo(L-Pro-L-Phe), cyclo(D-Phe-L-Pro), cyclo(D-Pro-D-Phe) and cyclo(L-Pro-D-Phe) isomers. Results showed that (1) cPP production reached the maximum at 12 h and then maintained the constant yield; (2) cPP maintained a stable production in a wide temperature range of 31–42°C; (3) cPP production were quite different for various carbon sources because of the different growth rate of the strain; (4) cPP maintained a higher level yield in neutral and weakly alkaline environment (pH 6–10) than acid (pH 3–5) environment. Moreover, cPP played a negative effect on the synthesis of antifungal substance when the bacteria maintained a good growth, and the previous studies found that cPP showed a positive response to biosensors which were used to detect signal molecules. Based on these studies, diketopiperazines were suspected as the signal molecule of B. amyloliquefaciens Q-426. [ABSTRACT FROM AUTHOR]

Software Defined Network (SDN) is a programmable network which separates the control logic-plane and hardware data-plane. The SDN centrally manages different Internet of Things (IoT) enabled smart devices like, actuators and sensors connected in the networks. Smart city infrastructure is an application of IoT network which purpose is to manage the city network without human interventions. To collect the real time data, such smart devices generate large amount of data and increasing the traffic in network. To maintain the quality of services (QoS) of smart city IoT networks, the SDN needs to deploy the multi-controllers. But the communication performance reduces due to unbalance load distribution on controllers. To balance the traffic load of controller an intelligent cluster based Grey Wolf Optimization Affinity Propagation (GWOAP) Algorithm is proposed when deploying the multiple controllers in SDN-IoT enabled smart city networks. The proposed algorithm is simulated and the experimental results able to calculates the minimum overall communication cost in comparison with Genetic Algorithm (GA), Particle Swarm Optimization (PSO) and Affinity Propagation (AP). The proposed GWOAP better balance the IoT enabled smart switches among clusters and node equalization is balanced for each controller in deployed topology. By using the proposed methodology, the traffic load of IoT enabled devices in smart city networks intelligently better balance among controllers. [ABSTRACT FROM AUTHOR]

Hallucinations and illusions are two instances of perceptual experiences illustrating how perception might diverge from external sensory stimulations and be generated or altered based on internal brain states. The occurrence of these phenomena is not constrained to patient populations. Similar experiences can be elicited in healthy subjects by means of suitable experimental procedures. Studying the neural mechanisms underlying these experiences not only has the potential to expand our understanding of the brain’s perceptual machinery but also of how it might get impaired. In the current study, we employed an auditory signal detection task to induce auditory illusions by presenting speech snippets at near detection threshold intensity embedded in noise. We investigated the neural correlates of auditory false perceptions by examining the EEG activity preceding the responses in speech absent (false alarm, FA) trials and comparing them to speech present (hit) trials. The results of the comparison of event-related potentials (ERPs) in the activation period vs. baseline revealed the presence of an early negativity (EN) and a late positivity (LP) similar in both hits and FAs, which were absent in misses, correct rejections (CR) and control button presses (BPs). We postulate that the EN and the LP might represent the auditory awareness negativity (AAN) and centro-parietal positivity (CPP) or P300, respectively. The event-related spectral perturbations (ERSPs) exhibited a common power enhancement in low frequencies (

Hallucinations and illusions are two instances of perceptual experiences illustrating how perception might diverge from external sensory stimulations and be generated or altered based on internal brain states. The occurrence of these phenomena is not constrained to patient populations. Similar experiences can be elicited in healthy subjects by means of suitable experimental procedures. Studying the neural mechanisms underlying these experiences not only has the potential to expand our understanding of the brain's perceptual machinery but also of how it might get impaired. In the current study, we employed an auditory signal detection task to induce auditory illusions by presenting speech snippets at near detection threshold intensity embedded in noise. We investigated the neural correlates of auditory false perceptions by examining the EEG activity preceding the responses in speech absent (false alarm, FA) trials and comparing them to speech present (hit) trials. The results of the comparison of event-related potentials (ERPs) in the activation period vs. baseline revealed the presence of an early negativity (EN) and a late positivity (LP) similar in both hits and FAs, which were absent in misses, correct rejections (CR) and control button presses (BPs). We postulate that the EN and the LP might represent the auditory awareness negativity (AAN) and centro-parietal positivity (CPP) or P300, respectively. The event-related spectral perturbations (ERSPs) exhibited a common power enhancement in low frequencies (<4 Hz) in hits and FAs. The low-frequency power enhancement has been frequently shown to be accompanied with P300 as well as separately being a marker of perceptual awareness, referred to as slow cortical potentials (SCP). Furthermore, the comparison of hits vs. FAs showed a significantly higher LP amplitude and low frequency power in hits compared to FAs. Generally, the observed patterns in the present results resembled some of the major neural correlates associated with perceptual awareness in previous studies. Our findings provide evidence that the neural correlates associated with conscious perception, can be elicited in similar ways in both presence and absence of externally presented sensory stimuli. The present findings did not reveal any pre-stimulus alpha and beta modulations distinguishing conscious vs. unconscious perceptions. [ABSTRACT FROM AUTHOR]

Arginine (R)-rich peptides constitute the most relevant class of cell-penetrating peptides and other membrane-active peptides that can translocate across the cell membrane or generate defects in lipid bilayers such as water-filled pores. The mode of action of R-rich peptides remains a topic of controversy, mainly because a quantitative and energetic understanding of arginine effects on membrane stability is lacking. Here, we explore the ability of several oligo-arginines R n and of an arginine side chain mimic R Side to induce pore formation in lipid bilayers employing MD simulations, free-energy calculations, breakthrough force spectroscopy and leakage assays. Our experiments reveal that R Side but not R n reduces the line tension of a membrane with anionic lipids. While R n peptides form a layer on top of a partly negatively charged lipid bilayer, R Side leads to its disintegration. Complementary, our simulations show R Side causes membrane thinning and area per lipid increase beside lowering the pore nucleation free energy. Model polyarginine R 8 similarly promoted pore formation in simulations, but without overall bilayer destabilization. We conclude that while the guanidine moiety is intrinsically membrane-disruptive, poly-arginines favor pore formation in negatively charged membranes via a different mechanism. Pore formation by R-rich peptides seems to be counteracted by lipids with PC headgroups. We found that long R n and R Side but not short R n reduce the free energy of nucleating a pore. In short R n , the substantial effect of the charged termini prevent their membrane activity, rationalizing why only longer R n are membrane-active. [ABSTRACT FROM AUTHOR]

Analysis of error correction performance for error correcting codes is very important when using such codes in digital communication systems. At medium-to-high signal-to-noise ratios, the distance spectrum of the error correcting code represents a good indicator for the error correction performance of the code. It is desired that the minimum distance of the code is as large as possible and that the corresponding multiplicity (i.e. the number of codewords having the weight equal to the minimum distance) is as small as possible. If we know an upper bound of the minimum distance of the code, then we have a good indication about the capabilities and the limitations of the code. One of the classes of the error correcting codes with the best performance is that of turbo codes. For such codes, establishing upper bounds on the minimum distance is challenging because it depends on the interleaver component of the turbo code. In this paper we consider turbo codes with component convolutional codes as in the Long Term Evolution standard. The interleaver lengths are of the form 16 Ψ or 48 Ψ , with Ψ a product of different prime numbers greater than three. The first achievement in the paper is that for these interleaver lengths, we show that cubic permutation polynomials (CPP), with some constraints on the coefficients, when 3 ∤ (p i - 1) for a prime p i > 3 , always have a true inverse CPP. The most accurate upper bounds on the minimum distance for turbo codes are achieved by identifying bit information sequences leading to a certain weight of the corresponding turbo-codeword. In this paper we have indentified such bit information sequences by means of the full range dual impulse method to estimate the weight of the turbo-codewords. For the previously mentioned turbo codes and CPP interleavers, we show that the minimum distance is upper bounded by the values of 38, 36, and 28, for three different classes of coefficients. Previously, it was shown that for the same interleaver lengths and for quadratic PP (QPP) interleavers, the upper bound of the minimum distance is equal to 38. Several examples show that d min -optimal CPP interleavers are better than d min -optimal QPP interleavers because the multiplicities corresponding to the minimum distances for CPPs are about a half of those for QPPs. A theoretical explanation in terms of nonlinearity degrees for this result is given for all considered interleaver lengths and for the class of CPPs for which the upper bound is equal to 38. [ABSTRACT FROM AUTHOR]

Background: Available therapeutic options are currently limited by their modest efficacy. As a result, novel pharmacotherapeutic treatments with different mechanisms have recently attracted empirical attention. Magnesium, a divalent cation, is postulated to provide analgesic and anti-nociceptive effect through its action at the N-methyl-D-aspartate (NMDA) receptor., Objective: Considering the evidence surrounding magnesium's potential as a therapeutic modality for chronic pain, we conducted a narrative review on the evidence of magnesium's therapeutic effects in chronic pain., Methods: A review of the PubMed, and Google scholar databases was undertaken in May 2022 to identify completed studies that investigated the effectiveness of magnesium in the treatment of chronic pain from database inception to May 2022., Results: A total of 33 studies were included in the narrative review, out of which 26 were randomized controlled trials. Findings on available studies suggest that intravenous infusion of magnesium is an emerging and promising option that may alleviate pain in some clinical populations. Our narrative synthesis showed that evidence for intravenous magnesium is currently equivocal for a variety of chronic pain syndrome. Findings indicate that evidence for efficacy is poor or equivocal for: CRPS, neuropathic pain, chronic low back pain, and migraine prophylaxis. However, there is good evidence supporting the efficacy of intravenous magnesium for treating renal colic pain and pelvic pain related to endometriosis., Conclusion: Magnesium may be a promising pharmacologic solution for chronic pain. Future investigation is warranted on elucidating the neurobiological mechanisms of magnesium in attenuating pain signaling pathways., (Copyright © 1964–2024 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Chondrosarcoma (CS) is a rare malignant bone sarcoma that primarily affects cartilage cells in the femur and pelvis. While most subtypes exhibit slow growth with a very good prognosis, some aggressive subtypes have a poorer overall survival. CS is known for its resistance to chemotherapy and radiotherapy, leaving surgery as the sole effective therapeutic option. Cold physical plasma (CPP) has been explored in vitro as a potential therapy, demonstrating positive anti-tumor effects on CS cells. This study investigated the synergistic effects of combining CPP with cytostatics on CS cells. The chemotherapeutic agents cisplatin, doxorubicin, and vincristine were applied to two CS cell lines (CAL-78 and SW1353). After determining their IC 20 and IC 50 , they were combined with CPP in both cell lines to assess their impact on the cell proliferation, viability, metabolism, and apoptosis. This combined approach significantly reduced the cell proliferation and viability while increasing the apoptosis signals compared to cytostatic therapy alone. The combination of CPP and chemotherapeutic drugs shows promise in targeting chemoresistant CS cells, potentially improving the prognosis for patients in clinical settings.

The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

Developing non-viral gene therapy vectors that both protect and functionally deliver nucleic acid cargoes will be vital if gene augmentation and editing strategies are to be effectively combined with advanced regenerative medicine approaches. Currently such methodologies utilize high concentrations of recombinant growth factors, which result in toxicity and off-target effects. Herein we demonstrate the use of modified cell penetrating peptides (CPPs), termed Glycosaminoglycan (GAG)-binding Enhanced Transduction (GET) peptides with plasmid DNA (pDNA) encapsulated poly (lactic-co-glycolic acid) PLGA nanoparticles (pDNA-encapsulated PLGA NPs). In order to encapsulate the pDNA, it was first condensed with a cationic low molecular weight Poly L-Lysine (PLL) into 30–60 nm NPs followed by encapsulation in PLGA NPs by double emulsion; yielding encapsulation efficiencies (EE) of ∼30%. PLGA NPs complexed with GET peptides show enhanced intracellular delivery (up to sevenfold) and transfection efficiencies (up to five orders of magnitude). Moreover, the pDNA cargo has enhanced protection from nucleases (such as DNase I) promoting their translatability. As an example, we show these NPs efficiently deliver pBMP2 which can promote osteogenic differentiation in vitro. Gene delivery to human Mesenchymal Stromal Cells (hMSCs) inducing their osteogenic programming was confirmed by Alizarin red calcium staining and bone lineage specific gene expression (Q RT-PCR). By combining simplistic and FDA-approved PLGA polymer nanotechnology with the GET delivery system, therapeutic non-viral vectors could have significant impact in future cellular therapy and regenerative medicine applications.

Morphine is one of the most severely abused drugs in the world. Previous research on morphine addiction has focused on the central nervous system (CNS). Studies have shown that a two-way regulation of the brain and gut microbiota (GM), suggesting a link between GM and CNS disease. However, the functional mechanism underlying the relationship between intestinal flora and morphine dependence is unclear. In this study, the effect of sinomenine on morphine addiction was evaluated based on the microbiota-gut-brain axis (MGBA). The results show that the GM plays an important role in morphine dependence. Morphine treatment induced zebrafish conditional position preference (CPP), and significantly changed zebrafish GM characteristics and the expression of MGBA-related genes in the zebrafish brain and intestine. Importantly, sinomenine, an alkaloid with a similar structure to morphine, can reverse these morphine-induced changes. Subsequently, morphine-dependent CPP training was performed after antibiotic administration. After antibiotic treatment, zebrafish CPP behavior, the composition and proportions of the zebrafish GM, and the expression of MGBA-related genes in zebrafish were changed. More interestingly, sinomenine was no longer effective in treating morphine dependence, indicating that antibiotic-driven intestinal flora imbalance alters the efficacy of sinomenine on morphine-dependent zebrafish. This study confirms that the MGBA is bidirectionally regulated, highlighting the key role of the GM in the formation and treatment of morphine dependence, and may provide new treatment strategies for using traditional Chinese medicine to treat drug addiction.

Microwave assisted extraction technique was employed to extract pectin from citron peel. Box-Behnken design was applied to investigate the influence of irradiation time, microwave power and pH on the yield and DE of pectin. The finding indicated that the optimal conditions for the maximum yield of pectin (30.71%) were achieved at irradiation time of 3 min, microwave power of 700 W and pH of 1.5. DE of pectin ranged from 45.08 to 72.19% demonstrating that extracted pectin was classified as high methoxyl pectin. The emulsifier activity of extracted pectin under optimal conditions was 40.7%. Besides, the emulsions were 86.7 and 86.6% stable at 4°C and, 79.5 and 79.2 at 23°C after 1 and 30 days, respectively. The flow behavior of pectin solutions indicated that solutions in low (0.1, 0.5 and 1.0 %w/v) and high (2.0 %w/v) concentrations had Newtonian and pseudoplastic behaviors, respectively.