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Antibiotic tolerance has become an increasingly serious crisis that has seriously threatened global public health. However, little is known about the exogenous factors that can trigger the development of antibiotic tolerance, both in vivo and in vitro. Herein, we found that the addition of citric acid, which is used in many fields, obviously weakened the bactericidal activity of antibiotics against various bacterial pathogens. This mechanistic study shows that citric acid activated the glyoxylate cycle by inhibiting ATP production in bacteria, reduced cell respiration levels, and inhibited the bacterial tricarboxylic acid cycle (TCA cycle). In addition, citric acid reduced the oxidative stress ability of bacteria, which led to an imbalance in the bacterial oxidation–antioxidant system. These effects together induced the bacteria to produce antibiotic tolerance. Surprisingly, the addition of succinic acid and xanthine could reverse the antibiotic tolerance induced by citric acid in vitro and in animal infection models. In conclusion, these findings provide new insights into the potential risks of citric acid usage and the relationship between antibiotic tolerance and bacterial metabolism.

Bilayer graphene has been widely studied in recent years due to its intriguing physical properties and potential engineering applications. Here, we report on the stability measurements of isotope-labeled bilayer graphene with different stacking sequences. The results showed evidence of different defect intensity after the Ar plasma treatment. We found that the AB stacked bilayer graphene shows better stability when compared to twisted bilayer and monolayer graphene. However, for the protection of the under layer graphene, the twisted bilayer graphene showed better results. Our work demonstrates that the stability of bilayer graphene strongly depends on the layer stacking sequence.

Extracellular vesicles (EVs) contain thousands of proteins and nucleic acids, playing an important role in cell-cell communications. Sertoli cells have been essential in the testis as a "nurse cell". However, EVs derived from human Sertoli cells (HSerCs) have not been well investigated.EVs were isolated from HSerCs via ultracentrifugation and characterized by transmission electron microscopy, tunable resistive pulse sensing, and Western blotting. The cargo carried by HSerCs-EVs was measured via liquid chromatography-mass spectrometry and GeneChip miRNA Arrays. Bioinformatic analysis was performed to reveal potential functions of HSerCs-EVs.A total of 860 proteins with no less than 2 unique peptides and 88 microRNAs with high signal values were identified in HSerCs-EVs. Biological processes related to molecular binding, enzyme activity, and regulation of cell cycle were significantly enriched. Specifically, many proteins in HSerCs-EVs were associated with spermatogenesis and regulation of immune system, including Septins, Large proline-rich protein BAG6, Clusterin, and Galectin-1. Moreover, abundant microRNAs within HSerCs-EVs (miR-638, miR-149-3p, miR-1246, etc.) had a possible impact on male reproductive disorders such as asthenozoospermia and oligozoospermia.Our study has shown that HSerCs-EVs contain diverse components such as proteins and microRNAs. Further research is required to evaluate HSerCs-EVs in spermatogenesis, which are underutilized but highly potent resources with particular promise for male infertility.

We report a convenient process for synthesizing indolo-[2,1-a]isoquinoline tetracyclic skeletons in one pot via a low-cost copper-catalyzed tandem amino radical cyclization, in which one C–C bond and one C–N bond are synchronously established.

A novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp3)–H bonds in amides and meta-C(sp2)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished.

Readily available 2-chlorobenzoic acid or ethyl phenylpropiolate as the C2 insertion unit. High regioselectivity. Broad substrate scope. Mechanistic studies.

We report here a direct allenylation reaction of inactive cyclic ethers. The reaction proceeds through a copper-catalyzed 1,4-difunctionalization of 1,3-enynes, with cyano group installed at the allenes simultaneously. This methodology shows a broad functional group compatibility to 1,3-enynes. Diversified allene-modified cyclic ether derivatives were synthesized with high regioselectivity under mild conditions.

Pasteurella multocida capsular type A (PmA) is one of the main pathogens causing bovine respiratory disease in China. The prevention and control measures against Pm are traditionally based on the use of broad-spectrum antibiotics. Previous studies found that Pm was prone to antibiotic resistance and tolerance mutation under the action of low concentrations of antibiotics, ultimately causing difficulties in prevention and control against Pm. In this study, highly pathogenic Pm fluoroquinolone-sensitive strain P3 and fluoroquinolone-resistant strain P32 induced by sub-inhibitory concentration of enrofloxacin were selected as research objects. RNA-seq was used to screen the differential gene recO of SOS response of P3 and P32 for functional verification. In addition, through MIC, MBC, induced resistance time, time-kill curve analysis and antibiotic tolerance test, the effect of recO gene on the resistance and tolerance of Pm to fluoroquinolone was clarified. At the same time, using fluorescent reporter vector, it was found that recO gene affected SOS repair response. In conclusion, the inhibition of recO gene can not only reduce their resistance to fluoroquinolone, but also prolong the formation time of fluoroquinolone resistance. It is speculated that recO gene is a potential target of fluoroquinolone synergistic antibacterial agent.

Background Palmitic acid (PA) has a lipotoxic effect on blood vessels, leading to endothelial dysfunction and cell death. The underlying mechanisms are not yet fully understood. Aim We sought to investigate the effects of PA on endothelial cells, with an emphasis on ferroptosis. Methods Rat corpus cavernosum endothelial cells (RCCECs) and human umbilical vein endothelial cells (HUVECs) were treated with PA to induce a pattern of cell death, as evidenced by the evaluation of cell viability. The differentially expressed genes were measured via RNA sequencing to reveal potential mechanisms. The intracellular levels of glutathione (GSH), malondialdehyde (MDA), ferrous ion (Fe2+), and reactive oxygen species (ROS) were evaluated using commercial kits. Western blot was performed to determine the expressions of relative proteins. Outcomes At the end of the study period, the evaluated outcomes were cell viability, transcriptome profiles, the expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), as well as levels of GSH, MDA, Fe2+, and ROS. Results PA-induced cell death of RCCECs and HUVECs was demonstrated in a dose- and time-dependent manner. Based on the findings of RNA-sequencing (RNA-seq), enrichment of many biological processes associated with cell cycle and response to stimulus occurred. More importantly, ferroptosis was highlighted in the bioinformatic analysis of both endothelial cells. The levels of intracellular Fe2+, MDA, and ROS were significantly increased following PA exposure while GSH was decreased, suggesting excessive iron accumulation, development of lipid peroxidation, and imbalanced redox homeostasis. Mechanistically, PA decreased the protein expression levels of GPX4 and SLC7A11 in endothelial cells, both of which played crucial roles in ferroptotic cell death. Clinical Translation This study suggests that ferroptosis may be a useful target for novel therapeutic interventions for endothelial dysfunction and cell death in vascular diseases such as erectile dysfunction. Strengths and Limitations In this study, we found that ferroptosis could participate in PA-induced endothelial dysfunction and cell death. A limitation of the study is that it did not shed light on the overall mechanisms of this process. Therefore, further research on the intricate networks of regulating ferroptosis is needed. Conclusion Overall, the occurrence of ferroptosis was demonstrated in the PA-treated HUVECs and RCCECs in this study.

Herein, we describe a novel and efficient photo-redox catalytic difluorinated ester radical addition/defluoroalkylation coupling reaction between trifluoroacetic acid derivatives and α-trifluoromethyl alkenes. A series of polyfluorinated compounds were synthesized by...

The goal of this paper is to introduce and study a new class of fractional differential hemivariational inequality formulated by an evolutionary hemivariational inequality and a fractional differential equation in Banach spaces. By employing the Rothe method and the surjectivity result, we derive the existence of unique solution for such a problem under some mild conditions. Moreover, we use the fully discrete scheme to approximate the fractional differential hemivariational inequality and provide an error estimate for the approximation. Finally, the main results are applied to obtain the unique solvability as well as the numerical analysis for a viscoelastic frictional contact problem with adhesion.

Herein, we describe a novel and efficient photoredox catalytic radical addition/defluoroalkylation coupling reaction between primary amines and trifluoromethyl-substituted alkenes. A series of

Studying the impact of land-use changes in wetland systems on the community structure of bacteria in soil aggregates can provide a theoretical basis for elucidating the impact mechanisms of the stability of wetland soil aggregates. The soil samples (0-20 cm) were collected from a natural wetland and paddy field in the Huixian karst wetland. The bacterial community structure in soil aggregates (macroaggregates 0.25-2 mm, microaggregates 0.053-0.25 mm, and silt-clay0.053 mm) were analyzed using high-throughput sequencing and ecological network analysis. The results showed that ① the proportion of microaggregates in the paddy field was 29.64%, which was significantly higher than that in the natural wetland (22.20%), and ② there were differences in the relative abundance of bacteria between the natural wetland and paddy field. The relative abundance of Chloroflexi in macroaggregates, microaggregates, and silt-clay in the paddy field were 7.97%, 8.56%, and 7.40%, respectively, which were significantly higher than those in the natural wetland (4.93%, 4.81%, and 3.76%). The relative abundance of Anaerolineales in macroaggregates, microaggregates, and silt-clay in the paddy field were 2.35%, 3.03%, and 2.65%, respectively, which were significantly higher than those in the natural wetland (0.92%, 0.91%, and 0.43%).③ Ecological network analysis showed that the number of nodes, edges, and the average numbers of neighbors in microaggregates and the silt-clay network in the paddy field were higher than those in the natural wetland, the average connectivity of the network was greater in the two components, and the characteristic path length was shorter. There was a longer characteristic path length, higher modularity, and lower average connectivity in the macroaggregate network of the paddy field. The above results indicated that the bacterial community structure in soil aggregates was altered after a natural wetland was used as a paddy field. The material circulation and information transmission efficiency of bacterial communities was higher in both microaggregates and silt-clay of the paddy field, whereas the bacterial community structure with low network tightness and high modularity in macroaggregates was more stable.

It is important to suppress cavitation phenomenon for lower vibration and noise, which can be realized by structure optimization to reduce cavitation bubbles of flow field. Nonetheless, performance factors in hydrodynamic retarder are usually conflicted when conducting a structure design, it is hard to simultaneously restrain cavitation and improve the retarding performance. In our study, a combination of comprehensive CFD simulation and multi-objective optimization is developed to improve the retarding torque ([Formula: see text]), lessen the volume of Retarder ([Formula: see text]) and reduce the volume of bubbles ([Formula: see text]) in the internal flow field. First, the elaborate CFD simulation calculation, included a refined hexahedral mesh and the stress-blended eddy simulation (SBES), is proposed to investigate the unsteady flow field considering the cavitation, and its accuracy is validated by experimental data. Then, the RSM (Respond Surface Method) approximation model is constructed by combination of DOE (Design of Method) and CFD methods. The NSGA-II (Non-Dominated Sorting Genetic Algorithm) is selected as multi-objective optimization algorithm, and the weight and scale factor of each sub objective are specified. The optimization results, verified by theoretical calculation, show that [Formula: see text] is increased by 22%–24%, [Formula: see text] is reduced by 32%–45% and [Formula: see text] is reduced by 1%. Furthermore, the comparison of the vortex distributions before and after optimization demonstrates that the optimization improves the flow field impact and pressure loss in the retarder and reduces the number of bubbles resulting in the increasing vortex. Additionally, parameters’ effect on the cavitation and the braking performance are analyzed to efficiently achieve the best comprehensive performance of the retarder design. The newly-developed optimization method, which can understand the optimization principle and guide a balance between the cavitation and the retarding performance improvement, will reduce huge trial cost and time cost in the manufacture.

This study aimed to investigate the value and feasibility of combining fractional anisotropy (FA) values from diffusion tensor imaging (DTI) and total kidney volume (TKV) for the assessment of kidney function in chronic kidney disease (CKD). Fifty-one patients were included in this study. All MRI examinations were performed with a 3.0 T scanner. DTI was used to measure FA values, and TKV was obtained from DTI and T2-weighted imaging (T2WI). Patients were divided into three groups (mild, moderate, severe) according to eGFR, which was calculated with serum creatinine. Differences in the FA values of the cortex and medulla were analysed among the three groups, and the relationships of FA values, TKV, and the product of the FA values and TKV with eGFR were analysed. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficiency of the FA values, TKV, and the product of the FA values and TKV for kidney function in different CKD stages. Medullary FA values (m-FA), TKV, and the product of the m-FA values and TKV (m-FA-TKV) were significantly correlated with eGFR (r = 0.653, 0.685, and 0.797, respectively; all P

The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka-Heck/C(sp3 or sp2)-H activation reaction is reported here. The key step in this transformation is the activation of a δ-C-H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiro-palladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp3)-H activation step.

Mimecan encodes a secretory protein that is secreted into the human serum as two mature proteins with molecular masses of 25 and 12 kDa. We found 12-kDa mimecan to be a novel satiety hormone mediated by the upregulation of the expression of interleukin (IL)-1β and IL-6 in the hypothalamus. Mimecan was found to be expressed in human pituitary corticotroph cells and was up-regulated by glucocorticoids, while the secretion of adrenocorticotropic hormone (ACTH) in pituitary corticotroph AtT-20 cells was induced by mimecan. However, the effects of mimecan in adrenal tissue on the hypothalamic-pituitary-adrenal (HPA) axis functions remain unknown. We demonstrated that the expression of mimecan in adrenal tissues is significantly downregulated by hypoglycemia and scalded stress. It was down-regulated by ACTH, but upregulated by glucocorticoids through in vivo and in vitro studies. We further found that 12-kDa mimecan fused protein increased the corticosterone secretion of adrenal cells in vivo and in vitro. Interestingly, compared to litter-mate mice, the diurnal rhythm of corticosterone secretion was disrupted under basal conditions, and the response to restraint stress was stronger in mimecan knockout mice. These findings suggest that mimecan stimulates corticosterone secretion in the adrenal tissues under basal conditions; however, the down-regulated expression of mimecan by increased ACTH secretion after stress in adrenal tissues might play a role in maintaining the homeostasis of an organism's responses to stress.

We developed a new transition-metal-free intermolecular Claisen rearrangement process to introduce allyl and allenyl groups into the α position of tertiary amides. In this transformation, amides were activated by trifluoromethanesulfonic anhydride to produce the keteniminium ion intermediates that exhibit strong electrophilic activity. This atom-economical process delivers α position-modified amides under mild conditions in moderate to good yields and showcases a broad substrate compatibility.

Studying the similarities and differences in microbial community structure and functional groups in soil aggregates between karst areas (KA) and non-karst areas (NKA) can provide a theoretical basis for revealing the interaction mechanism between soil organic microorganisms and soil aggregate structure stability in KA. The surface soils (0-20 mm) were collected from paddy fields both in KA and NKA. The aggregates were divided into macro-aggregates (Mac, 0.25-2 mm), micro-aggregates (Mic, 0.053-0.25 mm), and silt-clay fractions (SC,0.053 mm) using the wet sieving method. The microbial community structure of soil aggregates was analyzed using high-throughput sequencing. The keystone taxa were analyzed by the co-occurrence network, and their functions were predicted by FAPROTAX. The results showed that:① the proportion of Mac, mean weight diameter, and geometric mean diameter of aggregates in KA were 30.94%, 0.41 mm, and 0.15 mm, respectively. These three factors in KA were significantly higher than those in NKA, indicating that the environment in the KA was conducive to the formation of aggregates. ② The relative abundances of Acidobacteria, Proteobacteria, Acidobacteria(Gp3, Gp4, and Gp6), and

A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration strategy. Specifically, the subsequent mechanism research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This transformation is identified as having good functional group applicability with two different quaternary stereocenter in a regioselective manner, which is controlled by the substituent group of the nitrogen.

This report describes palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs). smNBDs were proposed to regulate the reactivity of the aryl-norbornadiene-palladacycle (ANP), including its high chemoselectivity and regioselectivity, which were the key to constructing C2 and C3 unsubstituted C4-glycosidic indoles. The scope of this substrate is extensive; the halogenated six-membered and five-membered glycosides were applied to the reaction smoothly, and N-alkyl (primary, secondary and tertiary) C4-glycosidic indoles can also be obtained by this method. In terms of mechanism, the key ANP intermediates characterized by X-ray single-crystal diffraction and further controlled experiments proved that the migration-insertion of smNBDs with phenylpalladium intermediate endows them with high chemo- and regioselectivity. Finally, density functional theory (DFT) calculation further verified the rationality of the mechanism.

This article deals with a new fractional nonlinear delay evolution system driven by a hemi-variational inequality in a Banach space. Utilizing the KKM theorem, a result concerned with the upper semicontinuity and measurability of the solution set of a hemivariational inequality is established. By using a fixed point theorem for a condensing set-valued map, the nonemptiness and compactness of the set of mild solutions are also obtained for such a system under mild conditions. Finally, an example is presented to illustrate our main results.

Cavitation has a significant influence on the accurate control of the liquid filling rate and braking performance of a hydraulic retarder; however, previous studies of the flow field in hydraulic retarders have provided insufficient information in terms of considering cavitation. Here, the volume of fluid (VOF) method and a scale-resolving simulation (SRS) were employed to numerically and more comprehensively calculate and analyze the flow field in a retarder considering the cavitation phenomenon. The numerical models included the improved delayed detached eddy simulation (IDDES) model, stress-blended eddy simulation (SBES) model, dynamic large eddy simulation (DLES) model, and shear stress transport (SST) model in the Reynolds-averaged Navier-Stokes (RANS) model. All the calculations were typically validated by the brake torque in the impeller rather than the internal flow. The unsteady flow field indicated that the SBES and DLES models could better capture unsteady flow phenomena, such as the chord vortex. The SBES and DLES models could also better capture bubbles than the SST and IDDES models. Since the braking torque error of the SBES model was the smallest, the transient variation of the bubble volume fraction over time on a typical flow surface was analyzed in detail with the SBES model. It was found that bubbles mainly appeared in the center area of the blade suction surface, which coincided with the experiments. The accumulation of bubbles resulted in a larger bubble volume fraction in the center of the blade over time. In addition, the temperature variations of the pressure blade caused by heat transfer were further analyzed. More bubbles precipitated in the center of the blade, leading to a lower temperature in this area.

A novel visible-light-induced palladium-catalyzed Heck reaction for bromine sugars and aryl olefins with high regio- and stereochemistry selectivity for the preparation of C-glycosyl styrene is des...

The nanocrystalline CO-Ni-graphene composite coating were successfully fabricated onto the mild steel substrate by electrochemical co-deposition technique. The coating was prepared by changing the amount of added graphene at the bath temperature of 50°C, PH value of 4 and current density of 2A/dm2. Scanning electron microscopy (SEM), Energy dispersive spectroscopy (EDS) and X-ray diffractometer (XRD) were used to analyze the surface morphology, composition and phase structure of the coating. The prepared composite coating was then subjected to an impedance map in a 3.5% NaCl solution by a VersaSTAT3 electrochemical analyzer. The results show that the surface morphology of the coating was coarsened with the increase of graphene content in the electrolyte. The corrosion rate of the coating in the 3.5% NaCl solution first decreased and then increased, and the corrosion rate was 0.1998mA/cm2 at a content of 1.0 g/L.

Yong-Hang Li,1,* Wei Huang,1,* Man-Yu Xiao,2 Shi-Qing Huang,1 Hui Chen,1 Zai-Fang Li,1 Xue-Song Li,1 Yong Cheng1,2 1The Third People’s Hospital of Foshan, Foshan, Guangdong, People’s Republic of China; 2Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong Cheng; Xue-Song Li, Email yongcheng@muc.edu.cn; fs83315006@163.comBackground: It has been suggested that the pharmacogenomic response to antipsychotics in schizophrenia patients partially contributed by drug metabolism enzyme polymorphism, including P450 2D6 (CYP2D6). However, CYP2D6 gene polymorphism across populations is largely unknown.Materials and Methods: Here, we investigated the differences of CYP2D6 gene polymorphism between Chinese Han and Tibetan schizophrenia patients. We analyzed five CYP2D6 gene related polymorphic locus in 103 patients with schizophrenia, including 60 Han ethnicity and 43 of Tibetan ethnicity, by nucleic acid MALDI-TOF.Results: Polymorphisms of rs1065852, rs1135840 and rs16947 were significantly different between Han and Tibetan patients. rs1065852 AA genotype had a low frequency of 9.3% in Tibetan patients in comparison with a frequency of 41.7% in Han patients, whereas rs16947 AA genotype had a low frequency of 3.3% in Han patients in comparison with a frequency of 34.9% in Tibetan patients. Additionally, the two patient groups showed distinct distribution of CYP2D6 haplotypes, with the highest frequency of *10/*10 and *1/*2 in Han and Tibetan patients, respectively. Furthermore, Han and Tibetan patients showed differential CYP2D6 metabolic activity.Discussion: Taken together, this exploratory study showed the differences of CYP2D6 gene and metabolic polymorphism between Han and Tibetan schizophrenia patients, and therefore may improve our understanding of the pharmacogenomic response to antipsychotics in schizophrenia patients across populations.Keywords: schizophrenia, CYP2D6, Han, Tibetan

A novel palladium-catalyzed spirocyclization through sequential Narasaka-Heck cyclization, C-H activation and [4 + 2] annulation has been developed. In this reaction, cheap and readily available 2-chlorobenzoic acid or ethyl phenylpropiolate was employed as the C2 insertion unit to react with γ,δ-unsaturated oxime ester. The key step in this transformation is the regioselective insertion of the C2 synthon into the spiro-palladacycle intermediate that is formed by the δ-C-H activation process, thereby efficiently assembling a series of spirocyclic pyrrolines with high regiocontrol. Furthermore, density functional theory (DFT) calculations and control experiments were performed to gain some insights into the reaction mechanism.

Schizophrenia（SCZ）is a common clinically chronic psychiatric disease, and there have no effective specific therapeutic drugs in clinical practice currently. Studies have shown that the expression level of brain-derived neurotrophic factor (BDNF) in schizophrenics has decreased, so the expression level of BDNF has always been one of the evaluation indicators of SCZ. The neurotrophic factor hypothesis believes that increase or decrease of the expression level of BDNF may be one of the pathophysiological basis of SCZ.In this study, schizophrenic mice model with MK-801-induced glutamate dysfunction was established, and two doses of BDNF were administered to schizophrenic mice by intranasal administration. The four groups of mice: Control group, Model group, BDNF-20, BDNF-100 performed a series of behavioral tests to explore the effects of BDNF on sensory motor gating, anxiety, depression, social interaction, spontaneous activity, and memory in schizophrenic mice. Transcriptome sequencing of the BDNF high group and Model group in prefrontal cortex and hippocampus, using Metascape for gene function annotation and enrichment pathway analysis, to obtain BDNF transcription regulation information, understand the molecular mechanism of BDNF in SCZ further. Subsequently，immunofluorescence detected the effects of BDNF on neurons and glial cells in the prefrontal cortex and hippocampus.The results show that BDNF can improve the behavior of SCZ by regulating the construction of the nervous system, affecting the growth and distribution of neurons and glial cells, and changing inflammation and apoptosis in the brain.

PurposeTo assess the diverse cell populations of human corpus cavernosum in patients with severe erectile dysfunction (ED) at the single-cell level.MethodsPenile tissues collected from three patients were subjected to single-cell RNA sequencing using the BD Rhapsody™ platform. Common bioinformatics tools were used to analyze cellular heterogeneity and gene expression profiles from generated raw data, including the packages Seurat, Monocle, and CellPhoneDB.ResultsDisease-related heterogeneity of cell types was determined in the cavernous tissue such as endothelial cells (ECs), smooth muscle cells, fibroblasts, and immune cells. Reclustering analysis of ECs identified an arteriole ECs subcluster and another one with gene signatures of fibroblasts. The proportion of fibroblasts was higher than the other cell populations and had the most significant cellular heterogeneity, in which a distinct subcluster co-expressed endothelial markers. The transition trajectory of differentiation from smooth muscle cells into fibroblasts was depicted using the pseudotime analysis, suggesting that the expansion of corpus cavernosum is possibly compromised as a result of fibrosis. Cell-cell communications among ECs, smooth muscle cells, fibroblasts, and macrophages were robust, which indicated that inflammation may also have a crucial role in the development of ED.ConclusionsOur study has demonstrated a comprehensive single-cell atlas of cellular components in human corpus cavernosum of ED, providing in-depth insights into the pathogenesis. Future research is warranted to explore disease-specific alterations for individualized treatment of ED.

Construction of C(sp

Pasteurella multocida (Pm) is one of the major pathogens of bovine respiratory disease (BRD), which can develop drug resistance to many of the commonly used antibiotics. Our earlier research group found that with clinical use of enrofloxacin, Pm was more likely to develop drug resistance to enrofloxacin. In order to better understand the resistance mechanism of Pm to enrofloxacin, we isolated PmS and PmR strains with the same PFGE typing in vitro, and artificially induced PmR to obtain the highly resistant phenotype, PmHR. Then transcriptome sequencing of clinically isolated sensitive strains, resistant and highly drug-resistant strains, treated with enrofloxacin at sub-inhibitory concentrations, were performed. The satP gene, of which the expression changed significantly with the increase in drug resistance, was screened. In order to further confirm the function of this gene, we constructed a satP deletion (ΔPm) strain using suicide vector plasmid pRE112, and constructed the C-Pm strain using pBBR1-MCS, and further analyzed the function of the satP gene. Through a continuously induced resistance test, it was found that the resistance rate of ΔPm was obviously lower than that of Pm in vitro. MDK99, agar diffusion and mutation frequency experiments showed significantly lower tolerance of ΔPm than the wild-type strains. The pathogenicity of ΔPm and Pm was measured by an acute pathogenicity test in mice, and it was found that the pathogenicity of ΔPm was reduced by about 400 times. Therefore, this study found that the satP gene was related to the tolerance and pathogenicity of Pm, and may be used as a target of enrofloxacin synergistic effect.

This over 7-year case study is the first to compare the results of laparoscopic Glissonian pedicle approach hemihepatectomy (LGAH) and laparoscopic hilar dissection approach hemihepatectomy (LHAH) in a randomized controlled trial (RCT).Patients who had undergone laparoscopic hemihepatectomy, either LGAH or LHAH, between March 2012 and December 2019 at our center were prospectively enrolled and assigned to the LGAH or LHAH group. Both groups were stratified and compared, and the preoperative and follow-up outcomes were analyzed. The primary endpoint was total operative time.The groups were equally matched for age, sex, HBsAg, Child-Pugh class, benign disease, malignancy, liver cirrhosis, tumor diameter and type of resection. Ninety-six patients had undergone LGAH and 94 had undergone LHAH. No preoperative death occurred in the two groups. LGAH did not enhance the postoperative overall complication rates (P = .465) or intraoperative blood loss (P = .535) compared with LHAH. However, the overall operative time (P = .014) and hilar dissection time (P = .000) were significantly shorter in the LGAH group than in the LHAH group. No significant differences were found between the groups regarding the 1-year (P = .384), 3-year (P = .332), and 5-year overall survival rates (P = .662) or 1-year (P = .856), 3-year (P = .348), and 5-year disease-free survival rates (P = .573).LGAH and LHAH are both effective procedures for treating the hilar structures in selected patients. LGAH has advantages over LHAH in reducing total operation time under the condition where both procedures can be used. LGAH for selected patients is worthy of promotion owing to its simplicity and convenience.NCT01567631 (http://www.gov).

A new method for the efficient synthesis of hexahydro-1H-fluorene and octahydrobenzo[a]azulene derivatives through a ring-expansion strategy is reported. With an appropriate combination of thulium(III) trifluoromethanesulfonate and 13X molecular sieves, a range of unsaturated polycyclic compounds were obtained in good yields. Mechanism studies reveal that the reaction is more likely to undergo Meyer-Schuster rearrangement, ring expansion, and Friedel-Crafts-type pathways, which provide a conceptually different strategy for the ring opening of tertiary cycloalkanols.

Previous research has demonstrated aberrations in the levels of inflammatory cytokines in patients with schizophrenia (SCZ), but most of the respective studies have tested a narrow set of inflammatory cytokines. Here, we aimed to analyze broad immune profiles in the peripheral blood of the first-episode drug-free (FEDF) patients with SCZ at baseline and after an 8-week treatment with atypical antipsychotics. Serum samples from 24 FEDF patients with SCZ and 25 healthy control (HC) subjects were tested using Luminex multiplex analysis for 30 cytokines, chemokines, and growth factors. Multiple comparison tests demonstrated that interleukin-2 (IL-2), IL-4, interferon-gamma (IFN-γ), monokine induced by IFN-γ, and granulocyte colony-stimulating factor (G-CSF) levels were significantly increased, whereas those of the epidermal growth factor were significantly decreased in the FEDF patients with SCZ. Moreover, the levels of the 6 dysregulated cytokines as well as those of 12 additional soluble factors in FEDF patients with SCZ were significantly decreased after 8 weeks of antipsychotic treatment. Furthermore, the transcription of G-CSF and IFN-γ was significantly increased in FEDF patients with SCZ when compared with controls, and G-CSF and IFN-γ mRNA levels were highly correlated with their respective protein concentrations. Receiver operating characteristic curves showed that G-CSF and IFN-γ had good performance in differentiating between FEDF patients with SCZ and HC subjects. Taken together, our data revealed that FEDF patients with SCZ were accompanied by a unique pattern of immune profile, and antipsychotic medications seemed to suppress the immune function in these patients, which could be used to develop novel targets for the diagnosis and treatment of SCZ.

Bovine milk-derived extracellular vesicles (BM-EVs) are recognized as promising nanoscale delivery vectors owing to their large availability. However, few isolation methods can achieve high purity and yield simultaneously. Therefore, we developed a novel and cost-effective procedure to separate BM-EVs via “salting-out.” First, BM-EVs were isolated from skimmed milk using ammonium sulfate. The majority of BM-EVs were precipitated between 30 and 40% saturation and 34% had a relatively augmented purity. The separated BM-EVs showed a spherical shape with a diameter of 60–150 nm and expressed the marker proteins CD63, TSG101, and Hsp70. The purity and yield were comparable to the BM-EVs isolated via ultracentrifugation while ExoQuick failed to separate a relatively pure fraction of BM-EVs. The uptake of BM-EVs into endothelial cells was dose- and time-dependent without significant cytotoxicity. The levels of endothelial nitric oxide syntheses were regulated by BM-EVs loaded with icariside II and miRNA-155-5p, suggesting their functions as delivery vehicles. These findings have demonstrated that it is an efficient procedure to isolate BM-EVs via “salting-out,” holding great promise toward therapeutic applications.

In this paper, we introduce and study a new Stackelberg-population competition model which captures the desired features of both population games and Stackelberg competition model within the same framework. We obtain some characterization results for the Stackelberg-population equilibrium response set and the Stackelberg-population equilibrium leader set by using the variational inequality technique and Brouwer’s fixed point theorem. We also show an existence theorem of Nash equilibrium for Stackelbergpopulation competition model under some mild conditions. Finally, we give an example to illustrate our main results.

A silver-catalyzed formal [3 + 3] annulation of 3-methyleneisoindolin-1-one with alkynol for the synthesis of 1,5-dihydroindolizin-3(2H)-one derivatives is disclosed. The protocol allows practical synthesis of N-heterocyclic scaffolds with a broad scope of functional groups and could be efficiently scaled up to gram scale, which incarnates a potential application of this methodology. In addition, a range of chlorine anion substitution of alkenes can be constructed by adjusting the structure of the alkynol substrates with the use of TMSCl.

In this paper, we propose two new projection-type algorithms for solving the multi-valued variational inequality in finite dimensional spaces. We prove the convergence of the sequences generated by the proposed projection-type algorithms without any monotonicity. Moreover, we provide some numerical experiments to illustrate the efficiency of the proposed projection-type algorithms.

Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.

This report describes palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs). smNBDs were proposed to regulate the reactivity of the aryl-norbornadiene-palladacycle (ANP), including its high chemoselectivity and regioselectivity, which were the key to constructing C2 and C3 unsubstituted C4-glycosidic indoles. The scope of this substrate is extensive; the halogenated six-membered and five-membered glycosides were applied to the reaction smoothly, and N-alkyl (primary, secondary and tertiary) C4-glycosidic indoles can also be obtained by this method. In terms of mechanism, the key ANP intermediates characterized by X-ray single-crystal diffraction and further controlled experiments proved that the migration-insertion of smNBDs with phenylpalladium intermediate endows them with high chemo- and regioselectivity. Finally, density functional theory (DFT) calculation further verified the rationality of the mechanism., This report describes palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs).