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Background. Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs. Methods. We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%. Results. At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group. Conclusions. The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure. Trial registration. ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov. Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx

The endocannabinoid system (ECS) is involved in a wide range of biological functions and is comprised of cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Besides its physiological role, the ECS has been implicated in the development and pathophysiology of a number of central nervous system and peripheral diseases. Over the past two decades, significant advances towards developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made, some of which have entered clinical trials. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Given the importance of the ECS for neuronal function, particular focus will be devoted to neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling strategies, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.

Monoacylglycerol lipase (MAGL) is a serine hydrolase, which metabolizes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) in the central nervous system (CNS). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[18F]fluoropyridinyl scaffold. Excellent blood−brain barrier penetration and high in vivo binding specificity was validated for radioligand [18F]14 (also named as [18F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers. KEY WORDS Monoacylglycerol lipase (MAGL); Central nervous system (CNS); 2-Arachidonylglycerol (2-AG); Arachidonic acid (AA); Positron emission tomography (PET); Fluorine-18

As the numbers of medium- to high-entropy alloys being studied and impressive structural properties they exhibit increase rapidly, questions regarding the role played by their complex chemical fluctuations rise concomitantly. Here, using a combination of large-scale molecular dynamics (MD), a hybrid MD and Monte-Carlo simulation method, and crystal defect analysis, we investigate the role lattice distortion (LD) and chemical short-range order (CSRO) play in the nucleation and evolution of dislocations and nanotwins with straining in single crystal and nanocrystalline CoCrNi, a medium entropy alloy (MEA). LD and CSRO effects are elucidated by comparisons with responses from a hypothetical pure A-atom alloy, which bears the same bulk properties of the nominal MEA but no LD and no CSRO. The analysis reveals that yield strengths are determined by the strain to nucleate Shockley partial dislocations, and LD lowers this strain, while higher degrees of CSRO increase it. We show that while these partials prefer to nucleate in the CoCr clusters, regardless of their size, they find it increasingly difficult to propagate away from these sites as the level of CSRO increases. After yield, nanotwin nucleation occurs via reactions of mobile Shockley partials and is promoted in MEAs, due to the enhanced glide resistance resulting from LD and CSRO.

In this study, a high methyl ester pectin polysaccharide, AER-A3 (Mw, 1.12 × 105 g/mol; O-methyl ester groups (wt%), 3.81%), was isolated and purified from the root bark of Aralia elata by ion exchange and gel-filtration chromatography. Its planar structure was investigated in combination with UPLC-ESI+-MS, FT-IR, HILIC-UPLC-ESI−-HCD-MS/MS, GC–MS and NMR techniques. The main chain of AER-A3 was unambiguously determined to be smooth region and hairy region with a chain length ratio of 1:1, characterized by occurrence of (1 → 2)-α-Rhap, (1 → 2,3)-α-Rhap, (1 → 2,4)-α-Rhap, (1 → 2,3,4)-α-Rhap, and (1 → 4)-α-GalpA, whereas the branched chain included T-α-Rhap, T-α-Araf, (1 → 5)-α-Araf, (1 → 3,5)-α-Araf, T-β-Galp, (1 → 3)-β-Galp, (1 → 3,4,6)-β-Galp, (1 → 4)-Glcp, (1 → 3)-Glcp, and (1 → 3)-Manp. Meanwhile, SEC-MALLS-RID, CD and Congo red assays showed that AER-A3 had no helical conformations but existed as a globular shape with branching. In addition, AER-A3 had good scavenging activities against DPPH, hydroxyl, and superoxide radicals. Anti-tumor assay investigated the effects of AER-A3 on human A549 and HepG2 cancer cell lines in vitro. These results provided a scientific basis for the use of the polysaccharides in A. elata root barks in pharmaceuticals.

Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson’s disease (PD), Alzheimer’s disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. However, to date, few successful efforts have been disclosed to visualize mGlu2 in vivo, indicating an unmet and urgent clinical need. Herein we report the synthesis and preclinical evaluation of a focused library of mGlu2 modulators amenable for radiolabeling. The promising candidate 4-(2,4-difluorophenyl)-7-((2-methoxypyridin -4-yl)methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxamide (21b), exhibited high potency and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging studies after labeling with carbon-11. Ligand [11C]21b (also known as [11C]MG2-1904) demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2 in vivo derived from negative allosteric modulators (NAMs), which represents a promising chemotype for further development and optimization aimed for clinical translation.

BACKGROUND Oral appliance (OA) treatment for obstructive sleep apnea syndrome (OSAS) has attracted more and more attention due to its low price, comfort, portable and non-invasion. This study aimed to investigate the clinical effectiveness of adjustable oral appliance on older adult patients with OSAS. METHODS Thirty older adult patients diagnosed with OSAS were chosen as the study participants and received an adjustable OA for 6 months. Then, the patients were subjected to a polysomnographic examination, Berlin Questionnaire (BQ) scale questionnaire, and cone beam computer tomography (CBCT) analytical measurement to evaluate their symptom improvement and the morphologic changes of the upper airway. RESULTS After treatment with adjustable oral appliance for six months, the results showed that there was an improvement of different degrees in the subjective symptoms. Apnea hypopnea index (AHI) had decreased from (27.65±1.31) per hour to (6.74±0.75) per hour (P

Objectives: Although Helicobacter pylori (H. pylori) infection is one of the most important risk factors for gastric cancer, the molecular mechanisms underlying the progression of H. pylori-induced...

Both the NMDA receptor (NMDAR) positive allosteric modulator (PAM), and antagonist, can exert rapid antidepressant effects as shown in several animal and human studies. However, how this bidirectional modulation of NMDARs causes similar antidepressant effects remains unknown. Notably, the initial cellular trigger, specific cell-type(s), and subunit(s) of NMDARs mediating the antidepressant-like effects of a PAM or an antagonist have not been identified. Here, we used electrophysiology, microdialysis, and NMR spectroscopy to evaluate the effect of a NMDAR PAM (rapastinel) or NMDAR antagonist, ketamine on NMDAR function and disinhibition-mediated glutamate release. Further, we used cell-type specific knockdown (KD), pharmacological, and behavioral approaches to dissect the cell-type specific role of GluN2B, GluN2A, and dopamine receptor subunits in the actions of NMDAR PAM vs. antagonists. We demonstrate that rapastinel directly enhances NMDAR activity on principal glutamatergic neurons in medial prefrontal cortex (mPFC) without any effect on glutamate efflux, while ketamine blocks NMDAR on GABA interneurons to cause glutamate efflux and indirect activation of excitatory synapses. Behavioral studies using cell-type-specific KD in mPFC demonstrate that NMDAR-GluN2B KD on Camk2a- but not Gad1-expressing neurons blocks the antidepressant effects of rapastinel. In contrast, GluN2B KD on Gad1- but not Camk2a-expressing neurons blocks the actions of ketamine. The results also demonstrate that Drd1-expressing pyramidal neurons in mPFC mediate the rapid antidepressant actions of ketamine and rapastinel. Together, these results demonstrate unique initial cellular triggers as well as converging effects on Drd1-pyramidal cell signaling that underlie the antidepressant actions of NMDAR-positive modulation vs. NMDAR blockade.

We previously reported that the serotonergic system is important for the antidepressant-like effects of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, which produces rapid and long-lasting antidepressant effects in patients with major depressive disorder (MDD). In particular, selective stimulation of the 5-HT1A receptor in the medial prefrontal cortex (mPFC), as opposed to the somatic 5-HT1A autoreceptor, has been shown to play a critical role in the antidepressant-like actions of ketamine. However, the detailed mechanisms underlying mPFC 5-HT1A receptor-mediated antidepressant-like effects are not fully understood. Here we examined the involvement of the glutamate AMPA receptor and brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of 5-HT1A receptor activation in the mPFC. The results show that intra-mPFC infusion of the 5-HT1A receptor agonist 8-OH-DPAT induces rapid and long-lasting antidepressant-like effects in the forced swim, novelty-suppressed feeding, female urine sniffing, and chronic unpredictable stress tests. In addition, the results demonstrate that the antidepressant-like effects of intra-mPFC infusion of 8-OH-DPAT are blocked by co-infusion of an AMPA receptor antagonist or an anti-BDNF neutralizing antibody. In addition, mPFC infusion of 8-OH-DPAT increased the phosphorylation of signaling proteins downstream of BDNF, including mTOR, ERK, 4EBP1, and p70S6K. Finally, selective stimulation of the 5-HT1A receptor increased levels of synaptic proteins and synaptic function in the mPFC. Collectively, these results indicate that selective stimulation of 5-HT1A receptor in the mPFC exerts rapid and sustained antidepressant-like effects via activation of AMPA receptor/BDNF/mTOR signaling in mice, which subsequently increase synaptic function in the mPFC, and provide evidence for the 5-HT1A receptor as a target for the treatment of MDD.

In order to obtain the effect of second phases on Charpy impact energy and crack propagation behavior of Hastelloy N sheet, Charpy notched impact toughness test have been accomplished with different directions (RD, ND) of V-notch after solution treatment. The fracture morphology and microstructure are observed by optical microscopy (OM), scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS). It is shown that the dominant second phases in Hastelloy N after solution treatment includes molybdenum-riched Ni-Mo phase, which dissolve some elements such as chromium, silicon and ferrum, and a few carbides. The Charpy impact energy of sample 2# (RD) is 225J, almost twice as much as sample 1# (ND). Based on the reconstruction of morphology and distribution of second phases, the mechanism for effect of second phases on crack propagation behavior is discussed. The islands of second phase particles modify the stress triaxiality state, resulting in the propagation path of crack in 2# is totally different from that in 1#.

Purpose Our study aimed to construct a visible model to evaluate the risk of infectious complications after gastrectomy. Methods The clinical data of 856 patients who underwent gastrectomy were used to retrieve medical records. Univariate and multivariate analyses were performed to correlate early postoperative NLR and operative variables with postoperative complications, and the construction of the nomogram was based on logistic regression. The concordance index and receiver operating characteristic curves were used to evaluate the model performance. Results The postoperative infectious and noninfectious complication rates after gastrectomy were 18.5% (158/856 cases) and 12.3% (105/856 cases) respectively. Postoperative NLR (within 24 h) independently predicted the development of postoperative infectious complication. Multivariate analysis revealed that age, diabetes, body mass index (BMI), intraoperative blood transfusion and postoperative NLR were independent risk factors. The nomogram model showed a good performance in terms of predicting infectious complications after gastrectomy (concordance index=0.718). Conclusion Age, diabetes, BMI, intraoperative blood transfusion and postoperative NLR were independent risk factors of postoperative infectious complications after gastrectomy, and a novel nomogram based on these results can be used to predict postoperative infection and has the advantages of simple application and easy access.

Concrete facilities in the severe-cold areas of western China (salt lake environments and heavy saline soils) are seriously damaged by the multiple corrosion effects of freeze–thaw cycles and sulfate corrosion. Magnesium phosphate cement (MPC) cement-based material has become an ideal concrete structural component because of its superior performance. Because concrete structural repair materials are used in heavy-corrosion environments, their durability in those environments should also be considered. Regarding the salt-freezing resistance of MPC, the existing studies have all used a NaCl solution as the heat transfer medium. In addition to chlorine salt, sulfate, especially Na2SO4, is also common in typical use environments such as oceans, salt lakes, and groundwater. To evaluate the sulfate freeze–thaw resistance of potassium magnesium phosphate cement (MKPC) mortar, in this study the strength development, weight loss, and water absorption of MKPC mortar specimens subjected to different freeze–thaw cycles were tested and compared with those for Portland cement (P.O) mortar specimens of the same strength grade. The results showed that the P.O mortar specimen completely lost its strength after 75 cycles of rapid water freezing and thawing and 50 cycles of sodium sulfate solution (5%) freezing and thawing. However, the residual strength rating of the MKPC mortar specimen after 75 cycles of water freezing and thawing and 100 cycles of sodium sulfate solution freezing and thawing was higher than 75%. After 50 rapid freeze–thaw cycles in water and a 5% Na2SO4 solution, the P.O mortar specimen’s mass loss exceeded the 5% failure standard, whereas the mass loss of the MKPC mortar specimens was much less than 5%. Before the freeze–thaw cycles, the water absorption of the P.O mortar specimen was close to 8 times that of the MKPC mortar specimen, and after 50 water freeze–thaw cycles and 25 sulfate solution freeze–thaw cycles, the water absorption reached 4.88% and 5.68%, respectively. However, after 225 freeze–thaw cycles in water and the sulfate solution, the water absorption rates of MKPC mortar specimens were 2.91% and 2.51% respectively. The test and analysis results show that the freeze–thaw resistance of MKPC mortar was much higher than that of Portland cement mortar specimens. Those results provide a prerequisite for applying and expanding the use of MKPC-based materials in severe-cold areas of western China (salt lake and heavily saline soil environments).