Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human.

The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.

Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design, synthesis, and in vitro anti-mycobacterial activity evaluation.

The purpose of this study was to prepare various novel amide tethered ciprofloxacin-1,2,3-triazole-isatin hybrids 7a-l, and evaluate their in vitro anti-mycobacterial activity as well as cytotoxicity in VERO cells. The synthesized hybrids showed considerable in vitro activity against both MTB H37Rv and MDR-MTB with MIC of 0.12 to 32 µg/mL, and acceptable cytotoxicity in VERO cells (CC50: 8.0->128.0 µg/mL). In particular, the most active hybrid 7a (MICMTB H37Rv: 0.5 µg/mL and MICMDR-MTB: 0.12 µg/mL) had the activity in the same level with the first-line anti-tubercular agents isoniazid (MIC: 0.12 µg/mL) and rifampicin (MIC: 0.25 µg/mL), and it was 2-fold more active than the parent ciprofloxacin (MIC: 1.0 µg/mL) against MTB H37Rv, and ≥16 folds more potent than ciprofloxacin (MIC: 2.0 µg/mL), isoniazid (MIC: >64 µg/mL) and rifampicin (MIC: >64 µg/mL) against MDR-MTB. Moreover, hybrid 7a (CC50: 16.0 µg/mL) also displayed considerable cytotoxicity towards VERO cells. Thus, hybrid 7a could act as a platform for further investigations.

IoT service composition based on improved Shuffled Frog Leaping Algorithm.

In the complex Internet of Things (IoT) environment, a plethora of IoT services with akin functions but varying qualities of service exist. To meet diverse customer needs and drive widespread application, service composition optimization becomes crucial. In the current era of rapid development in artificial intelligence, intelligent algorithms play a significant role in optimizing service composition. However, algorithms applied to IoT service composition optimization face common challenges of low search efficiency and insufficient optimization precision, including the Shuffled Frog Leaping Algorithm (SFLA) and Genetic Algorithm (GA). Therefore, this study seeks to enhance the perception of service quality in IoT service composition. It proposes an improved SFLA (ISFLA) based on the original SFLA. The algorithm integrates chaos theory and reverse learning theory for the acquisition of the initial population. It utilizes Euclidean distance to partition the population into groups and employs Gaussian mutation to optimize the optimal individual of each group. Finally, the entire population undergoes evolution through a local update method based on two strategies. Simulated experiments were conducted to search for optimal IoT service composition solutions of different scales. The results indicate that, compared to the SFLA, GA, ISFLA*, IGSFLA and SFLAGA, ISFLA achieves superior fitness values, better composition solutions, and exhibits faster convergence, higher stability, and greater overall operational efficiency.

Tuning Surface Molecular Design of Porous Carbon for Blue Energy Harvesting.

Capacitive mixing is a promising blue energy technology due to its membrane-free electricity generation and long electrode life cycle. However, because of limited performance, existing systems do not lend themselves to practical implementation. Although it is a crucial factor directly influencing electrode behavior, surface chemistry has largely been overlooked in capacitive mixing. Here, we show that manipulating surface functionalization alone can tune the responses of electrodes to produce a high voltage rise without altering the pore structure of the electrodes. Our findings reveal that the spontaneous electrode potential of a surface-modified carbon electrode shifts negatively proportional to the surface charge due to the surface groups, which explains why and how manipulating the surface chemistry can improve the power generation capacity. Using electrodes fabricated with identical activated carbon material but with different surface treatments, we have achieved a remarkably high power density of 166 mW/m2 delivered to an electrical load under a 0.6 M to 0.01 M salinity gradient, with the total power generated of 225 mW/m2. The corresponding volumetric power densities were 0.88 kW/m3 net and 1.17 kW/m3 total. The volumetric power density of our prototype is comparable to or better than those of prevailing membrane technologies, such as pressure retarded osmosis and reverse electrolysis, whose volumetric power density values are 1.1 kW/m3 and 0.16 kW/m3, respectively. In the seawater stage, the net power density reached 432 mW/m2 or 2.3 kW/m3. Such performance far exceeds existing membrane-free systems, with the highest reported power density of 65 mW/m2 under a 0.5 M to 0.02 M salinity gradient (121 mW/m2 in this work). The device demonstrated unparalleled durability, maintaining 90% of the maximum energy capacity after 54,000 charge-discharge cycles.

Enhanced Photothermal Effect Assisted by Resonance Energy Transfer in Carbon/Covellite Core-Shell Nanoparticles toward a High-Performance Interfacial Water Evaporation Process.

Carbon and semiconductor nanoparticles are promising photothermal materials for various solar-driven applications. Inevitable recombination of photoinduced charge carriers in a single constituent, however, hinders the realization of a greater photothermal effect. Core-shell heterostructures utilizing the donor-acceptor pair concept with high-quality interfaces can inhibit energy loss from the radiation relaxation of excited species, thereby enhancing the photothermal effect. Here, core-shell structures composed of a covellite (CuS) shell (acceptor) and spherical carbon nanoparticle (CP) core (donor) (abbreviated as CP/CuS) are proposed to augment the photothermal conversion efficiency via the Förster resonance energy transfer (FRET) mechanism. The close proximity and spectral overlap of the donor and acceptor trigger the FRET mechanism, where the electronic excitation relaxation energy of the CP reinforces the plasmonic resonance and near-infrared absorption in CuS, resulting in boosting the overall photothermal conversion efficiency. CP/CuS core-shell coated on polyurethane (PU) foam exhibits a total solar absorption of 97.1%, leading to an elevation in surface temperature of 61.6 °C in dry conditions under simulated solar illumination at a power density of 1 kW m-2 (i.e., 1 sun). Leveraging the enhanced photothermal conversion emanated from the energy transfer effect in the core-shell structure, CP/CuS-coated PU foam achieves an evaporation rate of 1.62 kg m-2 h-1 and an energy efficiency of 93.8%. Thus, amplifying photothermal energy generation in core-shell structures via resonance energy transfer can be promising in solar energy-driven applications and thus merits further exploration.

Protection of toll-like receptor 9 against lipopolysaccharide-induced inflammation and oxidative stress of pulmonary epithelial cells via MyD88-mediated pathways.

Acute lung injury (ALI) caused by lipopolysaccharide (LPS) is a common, severe clinical syndrome. Injury caused by inflammation and oxidative stress in vascular endothelial and alveolar epithelial cells is a vital process in the pathogenesis of ALI. Toll-like receptor 9 (TLR9) is highly expressed in LPS-induced ALI rats. In this study, Beas-2B human pulmonary epithelial cells and A549 alveolar epithelial cells were stimulated by LPS, resulting in the upregulation of TLR9 in a concentrationdependent manner. Furthermore, TLR9 overexpression and interference vectors were transfected before LPS administration to explore the role of TLR9 in LPS-induced ALI in vitro. The findings revealed that inhibition of TLR9 reduced inflammation and oxidative stress while suppressing apoptosis of LPS-induced Beas-2B and A549 cells, whereas TLR9 overexpression aggravated these conditions. Moreover, TLR9 inhibition resulted in downregulated protein expression of myeloid differentiation protein 88 (MyD88) and activator activator protein 1 (AP-1), as well as phosphorylation of nuclear factor-?B (NF-kappaB), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). The phosphorylation of extracellular-regulated protein kinases 1/2 was upregulated compared to that of cells subjected to only LPS administration, and this was reversed by TLR9 overexpression. These results indicate that inhibition of TLR9 plays a protective role against LPS-induced inflammation and oxidative stress in Beas-2B and A549 cells, possibly via the MyD88/NF-kappaB and MyD88/MAPKs/AP-1 pathways.

Moxifloxacin Derivatives with Potential Antibacterial Activity against Methicillin- Resistant Staphylococcus Aureus (MRSA).

BACKGROUND: Methicillin-resistant S. aureus (MRSA) has already tormented humanity and the environment for a long time and is responsible for many difficult-to-treat infections. Unfortunately, there are limited therapeutic options, and MRSA isolates with complete resistance to vancomycin, the first-line drug for the treatment of MRSA infections, have already emerged in recent years. Moxifloxacin retained activity against mutant bacterial strains with various levels of fluoroquinolones resistance and had a lower potential to select for resistant mutants. Isatin is a versatile structure, and its derivatives are potent inhibitors of many enzymes and receptors. The fluoroquinolone- isatin derivatives demonstrated excellent antibacterial activity against both drug-sensitive and drug-resistant organisms. The structure-activity relationship elucidated that incorporation of 1,2,3-triazole moiety into the C-7 position of fluoroquinolone skeleton was favorable to the antibacterial activity. Accordingly, fluoroquinolone derivatives with isatin and 1,2,3-triazole fragments at the side chain on the C-7 position are promising candidates to fight against drug-resistant bacteria. OBJECTIVE: To explore more active moxifloxacin derivatives to fight against MRSA and enrich the structure-activity relationships. METHODS: The synthesized moxifloxacin derivatives 7a-i and 14a-f were evaluated for their antibacterial activity against a panel of MRSA strains by means of standard two-fold serial dilution method. RESULTS: The majority of the synthesized moxifloxacin derivatives were active against most of the tested MRSA strains with MIC values in a range of 1 to 64 µg/mL. The mechanistic investigations revealed that topoisomerase IV was one of the targets for antibacterial activity. CONCLUSION: These derivatives are useful scaffolds for the development of novel topoisomerase IV inhibitors.

Harvesting energy from low-frequency excitations through alternate contacts between water and two dielectric materials.

Recent studies have demonstrated the benefits of water-dielectric interfaces in electrostatic energy harvesting. Most efforts have been focused on extracting the kinetic energy from the motions of water drops on hydrophobic surfaces, and thus, the resulting schemes inherently prefer cases where the water drops move at a high speed, or vibrate at a high frequency. Here we report a method for directly harvesting ambient mechanical energy as electric potential energy through water droplets by making alternate contacts with CYTOP and PTFE thin films. Because CYTOP and PTFE acquire significantly different surface charge densities during contact with water, such a difference can be utilized to effectively generate electricity. We demonstrate this concept using prototype devices fabricated on silicon substrates with a simple procedure. In the experiments conducted, a water drop of 400 µL alone could generate a peak open-circuit voltage of 42 V under a 0.25 Hz vibration. Under a 2.5 Hz vibration, the peak open-circuit voltage reached 115 V under an external bias of 8 V. The demonstrated efficiency is orders of magnitude higher than those of existing devices of similar dimensions.

Epidemiology of varicella in Haidian district, Beijing, China-2007-2015.

BACKGROUND: 1-Dose varicella vaccination was recommended for children in Beijing before November 2012. To further control school-based outbreaks and decrease incidence, a 2-dose vaccination was implemented in 2013. We described the varicella epidemiology and assessed impact of the 2-dose vaccination in Haidian district, Beijing, 2007-2015. METHODS: We examined the estimated incidence and disease characteristics of varicella during 2007-2015 and obtained the 1-dose vaccination coverage for children born during 2005-2013. Number of vaccine doses given was used to indirectly reflect the second-dose vaccination coverage. Overall and age-specific estimated incidences were compared between 2007-2012 and 2013-2015. RESULTS: A total of 23,497 cases were reported during 2007-2015. Of the 23,497 cases, 13,440 (57.20%) were male, and 68.40% were <20years of age and 70.02% were students and children in kindergarten. The estimated incidence increased from 82 cases per 100,000 population in 2007 to 104 in 2011, before substantially decreasing from 86 in 2012 to 56 in 2015. The median age increased from 14years in 2007 to 18years in 2015. The 1-dose varicella coverage for children at ≥2years of age gradually increased from 74.21% in 2007 to 90.06% in 2015. Compared with 2007-2012, two-fold average vaccine doses were given during 2013-2015, and the overall estimated incidence declined by 34.4%, particularly in children aged 5-9years, with a significantly declined trend in children aged 1-9years and older adolescents aged 15-19years and non-significantly declined trend in adults aged ≥20years, but a significant increasing trend in infants. CONCLUSIONS: The overall incidence of varicella has decreased substantially in Haidian district since 2013, with largest decline in children aged 5-9years. The 2-dose varicella vaccination might not lead to increase in incidence in adults. Long-term surveillance is needed to fully evaluate the long-term impact of the 2-dose varicella vaccination.

GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

Synthesis and in vitro anti-HCV activity of beta-D- and 1-2'-deoxy-2'-fluororibonucleosides.

Based on the discovery of beta-D-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of beta-D- and L-2'-deoxy-2'-fluoroibonucleosides with modifications at 5 and/or 4 positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The introduction of the 2'-fluoro group was achieved by either fluorination of 2,2'-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compounds, namely beta-D-2'-deoxy-2',5-difluorocytidine (5), had anti-HCV activity in the subgenomic HCV replicon cell line, and inhibitory activity against ribosomal RNA. As beta-D-N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, the two functionalities of the N4-hydroxyl and the 2'-fluoro were combined into one molecule, yielding beta-D-2'-deoxy-2'-fluoro-N4-hydroxycytidine (12). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot reliably predict anti-HCV activity in vitro.

Roles of the Excitation in Harvesting Energy from Vibrations.

The study investigated the role of excitation in energy harvesting applications. While the energy ultimately comes from the excitation, it was shown that the excitation may not always behave as a source. When the device characteristics do not perfectly match the excitation, the excitation alternately behaves as a source and a sink. The extent to which the excitation behaves as a sink determines the energy harvesting efficiency. Such contradictory roles were shown to be dictated by a generalized phase defined as the instantaneous phase angle between the velocity of the device and the excitation. An inductive prototype device with a diamagnetically levitated seismic mass was proposed to take advantage of the well established phase changing mechanism of vibro-impact to achieve a broader device bandwidth. Results suggest that the vibro-impact can generate an instantaneous, significant phase shift in response velocity that switches the role of the excitation. If introduced properly outside the resonance zone it could dramatically increase the energy harvesting efficiency.

Outbreak of varicella in a highly vaccinated preschool population.

BACKGROUND: Varicella vaccine is available for private purchase in Beijing, with single dose recommended for children aged ≥12 months before 2013. Despite the success achieved in reducing varicella incidence, varicella outbreaks continued to occur, including in schools and kindergartens among highly vaccinated children. We investigated a varicella outbreak in a preschool with high varicella vaccination coverage in Haidian district, Beijing. METHODS: Through questionnaires, data including children's medical and vaccination history were collected from their parents. A case of varicella was defined as an acute, generalized, maculopapulovesicular rash without other apparent cause in a child in the preschool from March 10 through March 29, 2010. Attack rates in vaccinated and unvaccinated children were calculated, and the analyses of vaccine effectiveness (VE) and of risk factors for breakthrough disease (varicella occurring >42 days after vaccination) were conducted. RESULTS: A total of 12 cases occurred during the outbreak, and ten of them (83.3%) had breakthrough varicella. The index case with mild varicella occurred in a child who had been vaccinated four years previously. Questionnaires were returned for all of 150 children in the preschool. Of all the 150 children, 144 (96.0%) had no prior history of varicella disease. Among these children, 135(93.7%) had received single-dose varicella vaccine before the outbreak. VE was 84.5% [95% confidence interval (CI): 62.8%∼93.5%] in preventing varicella of any severity, and VE was 92.2% (95% CI: 81.4%∼96.8%) against moderate to severe varicella. Age at vaccination (<15 months vs. ≥15 months) and time since vaccination before the outbreak (<3 years vs. ≥3 years) were not associated with the increased risk of breakthrough varicella(P=0.124 and 1, respectively). All the varicella cases with vaccination history verified through immunization records had received varicella vaccine and measles-mumps-rubella vaccine >30 days apart. CONCLUSIONS: Breakthrough infection with fever in vaccinated person may be as infectious as varicella in unvaccinated persons. High single-dose varicella vaccination coverage is effective in reducing varicella incidence, but not sufficient to prevent outbreak. To control varicella outbreak a second dose may deserve additional consideration.

[Investigation on measles cases of new genotype D8 in Beijing, 2013].

OBJECTIVE: To investigate the epidemiological characteristics of measles cases of new genotype D8 in Beijing from January to June, 2013. METHODS: Epidemiological survey and descriptive analysis was conducted. RESULTS: 661 suspected measles were reported from January to June, 2013. 416 were confirmed measles cases by serology and etiology detection. 28 measles cases were caused by genotype D8 measles virus by genotype identification. There were 2 measles outbreak including 14 cases and 14 sporadic cases. The incidence peak was during April and May. 25 cases (89.3%, 25/28) occurred in downtown and suburban districts. 22 cases (78.5%, 22/28) were adults aged 15-39 years and 19 cases (67.9%, 19/28) were migrant population. 12 cases (85.7%, 12/14) in outbreak were migrant population working in clothing sales. There was epidemiological association between 2 outbreaks. CONCLUSION: Measles cases of genotype D8 were found for the first time in Beijing. Genotype D8 virus mainly infected migrant adults and caused local outbreak and endemic.

Synthesis and anti-viral activity of a series of d- and l-2'-deoxy-2'-fluororibonucleosides in the subgenomic HCV replicon system.

Based on the discovery of (2'R)-d-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of d- and l-2'-deoxy-2'-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2'-fluoro group, was achieved by either fluorination of 2,2'-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2'R)-d-2'-deoxy-2',5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N(4)-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N(4)-hydroxyl and the 2'-fluoro into one molecule, resulting (2'R)-d-2'-deoxy-2'-fluoro-N(4)-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the l-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.