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The goal of this study was to investigate the value of the long-term average spectrum in the acoustic analysis of snore sounds arising from different sources in the upper airway.Long-term average spectrum was used to analyze sequences of 10 consecutive snore sounds that had been divided into 2 groups, soft-palate type and lateral-wall type, according to the vibration site generating the snore sounds and the patterns of soft tissue collapse in the upper airway as identified by drug-induced sleep endoscopy. We calculated the first spectral peak, mean spectral energy, high-frequency energy, 0-1 kHz spectral energy, 1-5 kHz spectral energy, and 0-1 kHz/1-5 kHz difference from each group and compared the differences between them.All parameters except mean spectral energy showed significant differences between the 2 groups. The first spectral peak of less than 265.53 Hz, and the 0-1k/1-5 kHz difference of less than -11.6 dB strongly suggests soft-palate-type snore sounds.Long-term average spectrum has potential application for snore sound source identification. We recommend using first spectral peak and a 0-1 kHz/1-5 Hz difference to identify soft-palate-type snore sounds.Peng H, Xu H, Xu Z, Jia R, Yu H. Long-term average spectrum measures of consecutive snore sounds from different sources determined by drug-induced sleep endoscopy.

Although interscalene nerve block is the standard for shoulder analgesia, the risk of hemidiaphragmatic paralysis restricts its use in patients with compromised pulmonary function. We hypothesized that a novel subparaneural upper trunk block would provide noninferior postoperative analgesia but superior diaphragmatic sparing effect compared to interscalene block.This randomized controlled trial comprised 96 patients who underwent arthroscopic shoulder surgery under either subparaneural upper trunk block (5 mL of 0.5% ropivacaine) or interscalene block (15 mL of 0.5% ropivacaine), followed by supraclavicular nerve block (5 mL of 0.5% ropivacaine). General anesthesia was standardized. The coprimary outcomes were (1) recovery room resting pain score at 30 minutes, measured on an 11-point numerical rating scale, with a prespecified noninferiority margin of 1 point and (2) the incidence of hemidiaphragmatic paralysis, diagnosed using ultrasound. Among secondary outcomes, resting pain scores were assessed with numerical rating scale at 4, 8, and 24 hours postoperatively.Recovery room resting pain scores at 30 minutes were 0 (0-1) in the subparaneural upper trunk group versus 0 (0-0) in the interscalene group, with a median difference of 0 (95% CI, 0-0); the upper 95% CI limit was lower than the prespecified noninferiority margin (noninferiority P.001). Hemidiaphragmatic paralysis was observed in 16.7% of patients in the subparaneural upper trunk group versus 100% of those in the interscalene group (RR, 0.17; 95% CI, 0.09-0.31; P.001), with complete paralysis occurring in 6.3% and 93.7% of patients, respectively. In this study, any reported differences in pain scores at 4, 8, and 24 hours postoperatively were not clinically important.The subparaneural upper trunk block compared to interscalene block provided noninferior analgesia at 30 minutes in the recovery room after arthroscopic shoulder surgery but resulted in less hemidiaphragmatic paralysis.

A green fluorescent protein (GFP)-tagged isolate of Verticillium dahliae was used to study its colonization in potato plants and tubers. Three-week-old potato plants of the highly susceptible cultivar ‘Shepody’ were inoculated with a conidial suspension of a GFP-tagged isolate of V. dahliae using a wound inoculation method. Colonization was studied using confocal microscopy combined with tissue sections. Conidia germinated and hyphae grew along the root hairs, elongation zones, and root caps between 24 and 96 h postinoculation (HPI). At 7 days postinoculation (DPI), the pathogen advanced to cortical tissues and grew into the root vascular bundles. At 8 weeks postinoculation (WPI), the stem epidermal cells, cortical tissues, vascular elements, and petioles were fully colonized by the mycelium of V. dahliae. At 11 WPI, the pathogen was detected in the stolon and progeny tubers, as confirmed by both GFP signals in tissues and reisolation of the pathogen on the semiselective NP-10 medium. Progeny potato tubers were harvested from the inoculated potato plants, and the GFP-signal was observed in the epidermal cells and vascular elements of sprouting buds that emerged from the harvested tubers. The infection rate of progeny tubers detected on semiselective NP-10 medium ranged from 34.55 to 55.56%, with an average of 45.31%. In conclusion, we report, for the first time, the entire progression of colonization by V. dahliae in potato plant tissues, progeny tubers, as well as of the sprouting buds that emerged from progeny tubers.

Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.

Potato is one of the most important staple crops in the world. China is one of the leading producers of potato, but the industry faces soilborne diseases such as Verticillium wilt. The identification and comparison of the biological characteristics and pathogenicity of different mating types of Verticillium dahliae isolated from potato and sunflower in the major planting regions in China is of great importance. This is to help unravel the sudden increase in infected fields and the V. dahliae population diversity. Molecular techniques were used to isolate and identify the V. dahliae pathogens in sunflower and potato planting materials as well as field plants. The data obtained revealed that the mating type population in sunflower was MAT1-1 and that of potato was MAT1-2, but all the samples belonged to race two. There was a significant percentage of MAT1-1 isolates present in potato, which is a new trend. We conclude that the weather conditions and the conventional crop rotation practices of farmers using sunflower and potato could be the reason for the rise in infection and mating type transfer between sunflower and potato.

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.

Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C5–NH2 of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1–H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1–H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1–H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.

The HIV-1 capsid (CA) protein plays crucial roles in both early and late stages of the viral life cycle, which has intrigued researchers to target it to develop anti-HIV drugs. Accordingly, in this research, we report the design, synthesis and biological evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors using the Cu(I)-catalyzed azide and alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. Among this series of inhibitors, compound II-10c displayed a remarkable anti-HIV activity (EC(50) = 2.13 μM, CC(50) > 35.49 μM). Furthermore, surface plasmon resonance (SPR) binding assays showed that compounds II-10c and PF-74 (lead compound) have similar affinities to HIV-1 CA monomer. Further investigation showed that the weak permeability and water solubility of representative compounds were probably the important factors that restricted their cell-based activity. Preliminary structure-activity relationships (SARs) were inferred based on the activities of these compounds, and their known structure. The most promising new compound was studied with molecular dynamics simulation (MD) to determine the preferred interactions with the drug target. Finally, the activities of members of this series of inhibitors were deeply inspected to find the potential reasons for their anti-HIV-1 activity from various perspectives. This highlights the important factors required to design compounds with improved potency.

The Nuclear Factor-Y (NF-Y) transcription factor (TF), which includes three distinct subunits (NF-YA, NF-YB and NF-YC), is known to manipulate various aspects of plant growth, development, and stress responses. Although the NF-Y gene family was well studied in many species, little is known about their functions in potato. In this study, a total of 37 potato NF-Y genes were identified, including 11 StNF-YAs, 20 StNF-YBs, and 6 StNF-YCs. The genetic features of these StNF-Y genes were investigated by comparing their evolutionary relationship, intron/exon organization and motif distribution pattern. Multiple alignments showed that all StNF-Y proteins possessed clearly conserved core regions that were flanked by non-conserved sequences. Gene duplication analysis indicated that nine StNF-Y genes were subjected to tandem duplication and eight StNF-Ys arose from segmental duplication events. Synteny analysis suggested that most StNF-Y genes (33 of 37) were orthologous to potato's close relative tomato (Solanum lycopersicum L.). Tissue-specific expression of the StNF-Y genes suggested their potential roles in controlling potato growth and development. The role of StNF-Ys in regulating potato responses to abiotic stress (ABA, drought and salinity) was also confirmed: twelve StNF-Y genes were up-regulated and another two were down-regulated under different abiotic treatments. In addition, genes responded differently to pathogen challenges, suggesting that StNF-Y genes may play distinct roles under certain biotic stress. In summary, insights into the evolution of NF-Y family members and their functions in potato development and stress responses are provided.

On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

Sunflower (Helianthus annuus) can be infected by the fungal pathogen Sclerotinia sclerotiorum, but its susceptibility varies depending on the cultivars. The aim of this study was to characterize and compare the biochemical responses between the R and the S sunflower cultivars after inoculation with S. sclerotiorum. The biochemical activities were detected by measuring necrotic cell, callose deposition, soluble protein content, as well as ROS accumulation at the infection site. Antioxidant enzymatic activities, the transcripts of ROS related genes and marker genes in pathways of salicylic acid (SA) and jasmonic acid (JA) were also quantified to characterize the responses. Results showed that compared to the S cultivar, the R cultivar was characterized having reduced number of necrotic cell, more callose deposition on the cell wall, increased soluble protein content, higher levels of H2O2 and ROS scavenger enzyme activities, and upregulated transcript profile of marker genes of both SA and JA pathways.

From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5–NH2 position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5–NH2 position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly.

Sunflower White Mold caused by Sclerotinia sclerotiorum and Sclerotinia minor is a devastating disease worldwide. To investigate the effect of low temperature (4 °C) on biological characteristics and aggressiveness of isolates of the two species, which were collected from the same field in Baiyinchagan, Inner Mongolia, their mycelial growth rate, oxalic acid secretion level and polygalacturonase activity were compared under normal culture temperature (23 °C) and low temperature (4 °C). Aggressiveness was also evaluated on detached leaves by inoculating the isolates produced in both temperatures. The results suggested that culture of isolates at 4 °C not only promoted mycelial growth, but also enhanced secretion of oxalic acid and polygalacturonase activity of both S. sclerotiorum and S. minor isolates compared to that cultured at 23 °C. Additionally, the corresponding aggressiveness of tested isolates of the two species also increased after culture at 4 °C. However, S. sclerotiorum always showed faster mycelial growth, higher oxalic acid levels and greater polygalacturonase activity than S. minor at both 23 °C and 4 °C, indicating that S. sclerotiorum is generally the more aggressive species than S. minor.

A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 μM, 0.049 μM and 0.16 μM and EC50 values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.

The first reported case of Phoma macdonaldii Boerema that caused sunflower black stem disease in China was from Xinjiang Uygur Autonomous Region in 2008. Black spindle lesions were observed on sunflower stems in the fields of Inner Mongolia region in China. The causal agents were isolated from the infected stems. Cultures on potato dextrose agar (PDA) plates were whitish with black particles underneath. Dark and pear-like pycnidia with yellowish or dirty whitish exudates were also observed on the surface of the cultures. The cultures produce primarily non-septate conidia. The cultures could infect sunflowers stems by artificial inoculation and developed symptoms consistent with those in the field. Morphological characteristics and molecular identification indicated the isolated causal agents were P. macdonaldii. Phylogenetic analysis based on ITS1, 5.8 s RNA and ITS2 region confirmed the identification. Disease resistance assessments were performed on twenty sunflower varieties and the results suggested that the resistance of seven sunflower varieties to P. macdonaldii was above the average; SC89 and Longkuiza1 were susceptible to P. macdonaldii.

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5–NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1–H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 μM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1–H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

to investigate the origin characters of snore in simple snorers and provide the basis for its treatment.Thirty-two simple snorers diagnosed by polysomnography were induced to sleep by propofol and dexmedetomidine, then we observed the vibration sites, pattern and concomitant collapse of soft tissue in pharyngeal cavity by nasendoscopy.Thirteen cases showed palatal fluttering only, and 1 case showed vibration of epiglottis only. Six cases showed palatal fluttering with vibration of epiglottis, and 2 cases showed palatal fluttering with vibration of epiglottis and tongue base. Five cases showed palatal fluttering with vibration of pharyngeal lateral wall, and 5 cases showed palatal fluttering with vibration of lateral wall, epiglottis and tongue base together. Palate and pharyngeal lateral wall vibrated strongly and always collapsed with vibrating, but epiglottis and tongue base usually vibrated slightly and seldom collapsed.The palatal fluttering is the main source of snoring sounds for most simple snorers, then followed by vibration of palatal and pharyngeal lateral wall together. The site of collapse in pharyngeal cavity is consistent with the main site of vibration.