Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer.

OBJECTIVE: To investigate the impact of vasculogenic mimicry (VM) and postoperative adjuvant therapy on the prognosis and survival of patients with esophageal squamous cell carcinoma (ESCC), as well as to assess whether VM affects the clinical benefit of postoperative adjuvant therapy. METHODS: This single-center retrospective analysis included patients who underwent radical surgery for ESCC, which was documented in the medical record system. The presence or absence of VM in surgical specimens was determined using double staining with PAS/CD31. Stratification was applied based on adjuvant therapy and VM status. Survival curves and COX modeling were used to analyze the impact of the presence or absence of VM on the benefit of adjuvant therapy and the survival prognosis of patients. RESULTS: VM-positive patients were more prone to postoperative recurrence and metastasis. VM was identified as an independent risk factor for progression-free survival (PFS) (p < 0.001, 95% CI:1.809-3.852) and overall survival (OS) (p < 0.001, 95% CI:1.603-2.786) in postoperative ESCC. Postoperative adjuvant therapy significantly prolonged PFS (p = 0.008) and OS time (p < 0.001) in patients with stage II and III ESCC, with concurrent chemoradiotherapy being the most effective. However, the presence of VM significantly reduced the benefits of postoperative adjuvant therapy (p < 0.001). CONCLUSION: VM negatively impacts the prognosis of postoperative ESCC patients and reduces the efficacy of postoperative adjuvant therapy.

The role of residual inflammatory risk and LDL cholesterol in patients with in-stent restenosis undergoing percutaneous coronary intervention.

BACKGROUND: To evaluate the relationships between residual inflammatory risk [assessed by high-sensitivity C-reactive protein (hsCRP)], residual cholesterol risk [assessed by low-density lipoprotein cholesterol (LDL-C)] and clinical outcomes among patients who underwent percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) lesions. METHODS: Between January 2017 and December 2018, a total of 2079 patients who underwent PCI for ISR were consecutively enrolled. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite endpoint of all-cause death, spontaneous myocardial infarction (MI), or repeat revascularization. RESULTS: During a median follow-up of 36 months, 436 MACEs occurred. Baseline hsCRP was significantly associated with MACE (highest versus lowest quartile, adjusted hazard ratio [aHR] 1.90 [95 % CI, 1.39-2.59]; P < 0.001). By contrast, the baseline LDL-C quartile was not associated with MACE (highest versus lowest quartile, aHR 0.93 [95 % CI, 0.71- 1.22]; P = 0.59). Compared with patients without residual risk (hsCRP <2 mg/L and LDL-C < 70 mg/dL), participants with both residual inflammatory and LDL-C risk (hsCRP ≥2 mg/L and LDL-C ≥ 70 mg/dL) (aHR, 1.39 [95 % CI, 1.06-1.83]; P = 0.02) and those with residual inflammatory risk only (hsCRP ≥2 mg/L and LDL-C < 70 mg/dL) (aHR, 1.34 [95 % CI, 1.01-1.72]; P = 0.04) had significantly higher risks of MACE. CONCLUSIONS: In the current cohort of patients after ISR PCI, inflammation assessed by hsCRP predicted higher risk of adverse clinical outcomes, whereas the level of LDL-C was not associated with adverse prognosis.

Hydroborative Depolymerization of Polyesters and Polycarbonates to Diols Catalyzed by Heterogeneous Lanthanum Materials La(CH2C6H4NMe2-o)3@SBA-15.

Chemical recycling is a promising strategy to establish a circular plastic economy, and it is still in an early stage of development. In this work, the reductive depolymerization of polyesters and polycarbonates into their corresponding borylated alcohols promoted by heterogeneous lanthanum materials was described. Grafting the easily accessible lanthanum tris(aminobenzyl) complex La(CH2C6H4NMe2-o)3 (1) onto the partially dehydroxylated silica support SBA-15 (SBA-15500 or SBA-15700) gave the inorganic-organic hybrid materials 1@SBA-15500 and 1@SBA-15700. These hybrid lanthanum materials, in combination with pinacolborane (HBpin), could serve as highly active heterogeneous catalysts for the selective depolymerization of aliphatic and aromatic polyesters, as well as polycarbonates into their corresponding borylated diols through a hydroboration reaction under mild conditions. The lanthanum materials exhibited a practical application in plastic waste recycling for their easy preparation, high catalytic efficiency, and recyclable property.

[Transepithelial transport in vivo and in vitro and anti-inflammatory activity of cannabidiol].

This study used Caco-2 cells and normal rats to investigate the in vitro absorption characteristics and in vivo pharmacokinetic characteristics of cannabidiol(CBD) and explore the anti-inflammatory mechanism of CBD. The safe concentration range of CBD was determined by the CCK-8 assay, and then the effects of time, concentration, temperature, endocytosis inhibitors, and transport inhibitors on the transepithelial absorption and transport of CBD were assessed. The blood drug concentration was measured at different time points after oral administration in rats for pharmacokinetic profiling, and the pharmacokinetic parameters were calculated. The Caco-2 cell model of inflammation injury was established with lipopolysaccharide(LPS). The effects of CBD on lactate dehydrogenase(LDH) activity, transendothelial electrical resistance(TEER), and levels of inflammatory cytokines of the modeled cells were exami-ned, on the basis of which the anti-inflammatory mechanism of CBD was deciphered. The results showed that within the concentration range tested in this study, the CBD uptake by Caco-2 cells reached saturation at the time point of 2 h. Moreover, the CBD uptake was positively correlated with concentration and temperature and CBD could be endocytosed into the cells. CBD could penetrate Caco-2 cells through active transport pathways involving multidrug resistance-associate protein 2(MRP2) and breast cancer resistance protein(BCRP), while the addition of P-gp inhibitors had no effect on CBD transport. Rats exhibited rapid absorption of CBD, with the peak time(t_(max)) of(1.00±0.11) h, and fast elimination of CBD, with a half-life(t_(1/2)) of only(1.86±0.16) h. In addition, CBD significantly ameliorated the increased LDH activity and decreased TEER that were caused by inflammatory response. It maintained the intestinal barrier by down-regulating the expression of pro-inflammatory cytokines interleukin-8(IL-8), interleukin-1 beta(IL-1ß) and tumor necrosis factor-α(TNF-α), thus exerting anti-inflammatory effects.

Practices and outcomes of rotational atherectomy in China: The Rota China registry.

BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.

Preparation, optimisation, and properties of O-carboxymethyl chitosan-g-cholesterol succinic acid monoester polymer nanomicelles.

Polymer nanomicelles have the advantages of small particle size, improved drug solubility, retention effect and enhanced permeability, so they can be used in the treatment of tumour diseases. The aim of this study was to prepare and optimise a nanomicelle which can improve the solubility of insoluble drugs. Firstly, the carboxyl group of cholesterol succinic acid monoester was grafted with the side chain amino group of O-carboxymethyl chitosan-g-cholesterol succinic acid monoester (CCMC), and its structure was characterized by fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Particle size has an important impact on tissue distribution, cell uptake, permeability and inhibition of tumour tissue. In this study, particle size and polydispersity index (PDI) were selected as indexes to optimise the preparation process of CCMC nanomicelles through single factor experiment, Plackett-Burman experiment, the steepest climbing experiment and response surface design experiment. The optimised CCMC nanomicelles showed an average particle size of 173.9 ± 2.3 nm and a PDI of 0.170 ± 0.053. The Cell Counting Kit-8 assay showed no significant effect on cell viability in the range of 0-1000 µg ml-1concentration. Coumarin-6 (C6) was used as a fluorescent probe to investigate the drug-carrying ability of CCMC nanomicelles. C6-CCMC showed 86.35 ± 0.56% encapsulation efficiency with a drug loading of 9.18 ± 0.32%. Both CCMC and C6-CCMC demonstrated excellent stability in different media. Moreover, under the same conditions, the absorption effect of C6 in C6-CCMC nanomicelles was significantly higher than that of free C6 while also exhibiting good sustained-release properties. Therefore, this study demonstrates CCMC nanomicelles as a promising new drug carrier that can significantly improve insoluble drug absorption.

COE targets EphA2 to inhibit vasculogenic mimicry formation induced by hypoxia in hepatocellular carcinoma.

Background: Vasculogenic Mimicry (VM) can reduce the efficacy of anti-angiogenesis and promote distant metastasis in hepatocellular carcinoma (HCC). Our previous studies have found that Celastrus orbiculatus extract (COE) can inhibit the VM formation in HCC by reducing EphA2 expression. However the underlying mechanism related to EphA2 in VM formation is unclear. Purpose: This study aimed to confirm that EphA2 is one of the potential targets of COE, and to explore the effect of EphA2 in VM formation in hypoxia context in HCC. Methods: TCM Systems Pharmacology database and proteomics analysis were used to explore the key targets of COE in HCC treatment. CD31-PAS double staining and VE-CAD staining were used to indicate vasculogenic mimicry. The localization of EphA2 and VE-CAD was examined through fluorescent microscopy. CCK8 assay, cell invasion assay, and tube formation assay were used to indicate the formation of VM under hypoxic conditions. The regulatory relationship of EphA2 upstream and downstream molecules were evaluated through COIP and Western Blot. The nude mouse xenograft tumor models were used to observe the VM formation after knocking down or overexpressing EphA2. Results: EphA2 is identified to the target of COE, and the driving gene of HCC. In HCC surgical specimens, EphA2 expression is closely associated with the VM formation of HCC. COE-regulated EphA2 is involved in hypoxia-induced VM formation in HCC cells in vitro. EphA2 is regulated by HIF directly or indirectly by C-MYC. Overexpression of EphA2 can promote the VM formation of HCC in nude mice, while knocking down EphA2 can inhibit the VM formation. Conclusion: EphA2, as a target of COE, plays a crucial regulatory role in the formation of vasculogenic mimicry in HCC, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD expression regulation.

Exercise-Induced Central Fatigue: Biomarkers, and Non-Medicinal Interventions.

Fatigue, commonly experienced in daily life, is a feeling of extreme tiredness, shortage or lack of energy, exhaustion, and difficulty in performing voluntary tasks. Central fatigue, defined as a progressive failure to voluntarily activate the muscle, is typically linked to moderate- or light-intensity exercise. However, in some instances, high-intensity exercise can also trigger the onset of central fatigue. Exercise-induced central fatigue often precedes the decline in physical performance in well-trained athletes. This leads to a reduction in nerve impulses, decreased neuronal excitability, and an imbalance in brain homeostasis, all of which can adversely impact an athlete's performance and the longevity of their sports career. Therefore, implementing strategies to delay the onset of exercise-induced central fatigue is vital for enhancing athletic performance and safeguarding athletes from the debilitating effects of fatigue. In this review, we discuss the structural basis, measurement methods, and biomarkers of exercise-induced central fatigue. Furthermore, we propose non-pharmacological interventions to mitigate its effects, which can potentially foster improvements in athletes' performances in a healthful and sustainable manner.

Structural basis for the transport and regulation mechanism of the Multidrug resistance-associated protein 2.

Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Deficiencies in MRP2 function are associated with Dubin-Johnson Syndrome and increased vulnerability to liver injury from cytotoxic drugs. Using cryogenic electron microscopy (cryo-EM), we determined the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. These structures show that MRP2 functions through the classic alternating access model, driven by ATP binding and hydrolysis. Its cytosolic regulatory (R) domain serves as a selectivity gauge, wherein only sufficiently high concentrations of substrates can effectively compete with and disengage the R domain to initiate transport. Comparative structural analyses of MRP2 in complex with different substrates reveal how the transporter recognizes a diverse array of compounds, highlighting the transporter's role in multidrug resistance.

The influence of service performance in China's sci-tech commissioner system: Using social network analysis and interpretable machine learning.

The Sci-Tech Commissioner System (SCS) is a result of exploratory efforts by the Chinese government to use science and technology to strengthen the agricultural sector. Social network analysis (SNA) and machine learning (ML) techniques make it feasible to assess the service performance in China's SCS by using indicators such as group types and structure features. In this study, SNA and a clustering algorithm were employed to categorize service group types of sci-tech commissioners. By comparing the accuracy of different classification algorithms in predicting the clustering results, LightGBM algorithm was finally select to determine the clustering features of sci-tech commissioners and establish an interpretable ML model. Then, the SHAP was used to algorithm to analyze influences affecting service performance. Results show that the service forms of sci-tech commissioners are group-oriented, and that group types include small groups of young commissioners with close cooperation, larger groups of young and middle-aged commissioners, small groups of middle-aged and old commissioners with close cooperation, and isolated points of highly-influential commissioners. Furthermore, while group size is not the determinant of a commissioner's average performance, group structure and coordination ability were found to be more critical. Moreover, while differences in distinct types of service performance are caused by various factors, but good group structures and extensive social contacts are essential for high service performance.

Structure-based discovery of CFTR potentiators and inhibitors.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

Principles of peptide selection by the transporter associated with antigen processing.

Our ability to fight pathogens relies on major histocompatibility complex class I (MHC-I) molecules presenting diverse antigens on the surface of diseased cells. The transporter associated with antigen processing (TAP) transports nearly the entire repertoire of antigenic peptides into the endoplasmic reticulum for MHC-I loading. How TAP transports peptides specific for MHC-I is unclear. In this study, we used cryo-EM to determine a series of structures of human TAP, both in the absence and presence of peptides with various sequences and lengths. The structures revealed that peptides of eight or nine residues in length bind in a similarly extended conformation, despite having little sequence overlap. We also identified two peptide-anchoring pockets on either side of the transmembrane cavity, each engaging one end of a peptide with primarily main chain atoms. Occupation of both pockets results in a global conformational change in TAP, bringing the two halves of the transporter closer together to prime it for isomerization and ATP hydrolysis. Shorter peptides are able to bind to each pocket separately but are not long enough to bridge the cavity to bind to both simultaneously. Mutations that disrupt hydrogen bonds with the N and C termini of peptides almost abolish MHC-I surface expression. Our findings reveal that TAP functions as a molecular caliper that selects peptides according to length rather than sequence, providing antigen diversity for MHC-I presentation.

Association between the frontoparietal network, clinical symptoms and treatment response in individuals with untreated anorexia nervosa.

Background: Anorexia nervosa (AN) has been characterised as a psychiatric disorder associated with increased control. Currently, it remains difficult to predict treatment response in patients with AN. Their cognitive abilities are known to be resistant to treatment. It has been established that the frontoparietal control network (FPCN) is the direct counterpart of the executive control network. Therefore, the resting-state brain activity of the FPCN may serve as a biomarker to predict treatment response in AN. Aims: The study aimed to investigate the association between resting-state functional connectivity (RSFC) of the FPCN, clinical symptoms and treatment response in patients with AN. Methods: In this case-control study, 79 female patients with AN and no prior treatment from the Shanghai Mental Health Center and 40 matched healthy controls (HCs) were recruited from January 2015 to March 2022. All participants completed the Questionnaire Version of the Eating Disorder Examination (version 6.0) to assess the severity of their eating disorder symptoms. Additionally, RSFC data were obtained from all participants at baseline by functional magnetic resonance imaging. Patients with AN underwent routine outpatient treatment at the 4th and 12th week, during which time their clinical symptoms were evaluated using the same measures as at baseline. Results: Among the 79 patients, 40 completed the 4-week follow-up and 35 completed the 12-week follow-up. The RSFC from the right posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (dlPFC) increased in 79 patients with AN vs 40 HCs after controlling for depression and anxiety symptoms. By multiple linear regression, the RSFC of the PPC to the inferior frontal gyrus was found to be a significant factor for self-reported eating disorder symptoms at baseline and the treatment response to cognitive preoccupations about eating and body image, after controlling for age, age of onset and body mass index. The RSFC in the dlPFC to the middle temporal gyrus and the superior frontal gyrus may be significant factors in the treatment response to binge eating and loss of control/overeating in patients with AN. Conclusions: Alterations in RSFC in the FPCN appear to affect self-reported eating disorder symptoms and treatment response in patients with AN. Our findings offer new insight into the pathogenesis of AN and could promote early prevention and treatment.

Rare-Earth Metal Complexes Supported by A Tridentate Amidinate Ligand: Synthesis, Characterization, and Catalytic Comparison in Isoprene Polymerization.

To systematically investigate the dependence of the initiating group and metal size on polymerization performance, a family of rare-earth metal bis(alkyl)/bis(benzyl)/bis(amide) complexes supported by a monoanionic tridentate amidinate ligand [(2,6-iPr2C6H3)NC(Ph)N(C6H4-2-OMe]- (HL) were synthesized and well-characterized. Treatment of rare-earth metal tris(alkyl)/tris(benzyl)/tris(amide) complexes Y(CH2C6H4NMe2-o)3 or Y(CH2SiMe3)3(THF)2 or Ln[N(SiHMe2)2]3(THF)x (Ln = Sc, x = 1; Ln = Y, La, Sm, Lu, x = 2) with 1 equiv of HL gave the corresponding mono(amidinate) rare-earth metal bis(alkyl)/bis(benzyl)/bis(amide) complexes [(2,6-iPr2C6H4)NC(Ph)N(C6H4-2-OMe)]Y(CH2C6H4NMe2-o)2 (1), [(2,6-iPr2C6H4)NC(Ph)N(C6H4-2-OMe)]Y(CH2SiMe3)2(THF) (2), and [(2,6-iPr2C6H4)NC(Ph)N(C6H4-2-OMe)]Ln[N(SiHMe2)2]2(THF)n (Ln = Y, n = 1 (3); Ln = La, n = 1 (4); Ln = Sc, n = 0 (5); Ln = Lu, n = 0 (6); Ln = Sm, n = 0 (7)) in good isolated yields. These complexes were characterized by elemental analysis, NMR spectroscopy, and single-crystal X-ray diffraction. In the presence of excess AlMe3 and on treatment with 1 equiv of [Ph3C][B(C6F5)4], these complexes could serve as precatalysts for cationic polymerization of isoprene, in which the dependence of the polymerization activity and regioselectivity on the initiating group and metal size was observed.

DNAJA1­knockout alleviates heat stroke­induced endothelial barrier disruption via improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Endothelial barrier disruption plays a key role in the pathophysiology of heat stroke (HS). Knockout of DNAJA1 (DNAJA1­KO) is thought to be protective against HS based on a genome­wide CRISPR­Cas9 screen experiment. The present study aimed to illustrate the function of DNAJA1­KO against HS in human umbilical vein endothelial cells. DNAJA1­KO cells were infected using a lentivirus to investigate the role of DNAJA1­KO in HS­induced endothelial barrier disruption. It was shown that DNAJA1­KO could ameliorate decreased cell viability and increased cell injury, according to the results of Cell Counting Kit­8 and lactate dehydrogenase assays. Moreover, HS­induced endothelial cell apoptosis was inhibited by DNAJA1­KO, as indicated by Annexin V­FITC/PI staining and cleaved­caspase­3 expression using flow cytometry and western blotting, respectively. Furthermore, the endothelial barrier function, as measured by transepithelial electrical resistance and FITC­Dextran, was sustained during HS. DNAJA1­KO was not found to have a significant effect on the expression and distribution of cell junction proteins under normal conditions without HS. However, DNAJA1­KO could effectively protect the HS­induced decrease in the expression and distribution of cell junction proteins, including zonula occludens­1, claudin­5, junctional adhesion molecule A and occludin. A total of 4,394 proteins were identified using proteomic analysis, of which 102 differentially expressed proteins (DEPs) were activated in HS­induced wild­type cells and inhibited by DNAJA1­KO. DEPs were investigated by enrichment analysis, which demonstrated significant enrichment in the 'calcium signaling pathway' and associations with vascular­barrier regulation. Furthermore, the 'myosin light­chain kinase (MLCK)­MLC signaling pathway' was proven to be activated by HS and inhibited by DNAJA1­KO, as expected. Moreover, DNAJA1­KO mice and a HS mouse model were established to demonstrate the protective effects on endothelial barrier in vivo. In conclusion, the results of the present study suggested that DNAJA1­KO alleviates HS­induced endothelial barrier disruption by improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

New media facilitate adolescents' body dissatisfaction and eating disorders in Mainland China.

New media play a significant role in adolescents' body dissatisfaction and eating disorders in Mainland China, through shaping social standards, peers, and family dynamics. How to mitigate their adverse effects on adolescents, reduce body dissatisfaction, and prevent eating disorders is a significant social issue that demands serious consideration.

Structural identification of a selectivity filter in CFTR.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that regulates transepithelial salt and fluid homeostasis. CFTR dysfunction leads to reduced chloride secretion into the mucosal lining of epithelial tissues, thereby causing the inherited disease cystic fibrosis. Although several structures of CFTR are available, our understanding of the ion-conduction pathway is incomplete. In particular, the route that connects the cytosolic vestibule with the extracellular space has not been clearly defined, and the structure of the open pore remains elusive. Furthermore, although many residues have been implicated in altering the selectivity of CFTR, the structure of the "selectivity filter" has yet to be determined. In this study, we identify a chloride-binding site at the extracellular ends of transmembrane helices 1, 6, and 8, where a dehydrated chloride is coordinated by residues G103, R334, F337, T338, and Y914. Alterations to this site, consistent with its function as a selectivity filter, affect ion selectivity, conductance, and open channel block. This selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads us to propose a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer.

Structural basis for CFTR inhibition by CFTRinh-172.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease. Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTRinh-172 to an overall resolution of 2.7 Å by cryogenic electron microscopy. We observe that CFTRinh-172 binds inside the pore near transmembrane helix 8, a critical structural element that links adenosine triphosphate hydrolysis with channel gating. Binding of CFTRinh-172 stabilizes a conformation in which the chloride selectivity filter is collapsed, and the pore is blocked from the extracellular side of the membrane. Single-molecule fluorescence resonance energy transfer experiments indicate that CFTRinh-172 inhibits channel gating without compromising nucleotide-binding domain dimerization. Together, these data reconcile previous biophysical observations and provide a molecular basis for the activity of this widely used CFTR inhibitor.

QoS-driven resource allocation in fog radio access network: A VR service perspective.

While immersive media services represented by virtual reality (VR) are booming, They are facing fundamental challenges, i.e., soaring multimedia applications, large operation costs and scarce spectrum resources. It is difficult to simultaneously address these service challenges in a conventional radio access network (RAN) system. These problems motivated us to explore a quality-of-service (QoS)-driven resource allocation framework from VR service perspective based on the fog radio access network (F-RAN) architecture. We elaborated details of deployment on the caching allocation, dynamic base station (BS) clustering, statistical beamforming and cost strategy under the QoS constraints in the F-RAN architecture. The key solutions aimed to break through the bottleneck of the network design and to deep integrate the network-computing resources from different perspectives of cloud, network, edge, terminal and use of collaboration and integration. Accordingly, we provided a tailored algorithm to solve the corresponding formulation problem. This is the first design of VR services based on caching and statistical beamforming under the F-RAN. A case study provided to demonstrate the advantage of our proposed framework compared with existing schemes. Finally, we concluded the article and discussed possible open research problems.