Facilitation of Behavioral and Cortical Emergence from Isoflurane Anesthesia by GABAergic Neurons in Basal Forebrain.

General anesthesia shares many similarities with natural sleep in behavior and electroencephalogram (EEG) patterns. The latest evidence suggests that general anesthesia and sleep-wake behavior may share overlapping neural substrates. The GABAergic neurons in the basal forebrain (BF) have recently been demonstrated to play a key role in controlling wakefulness. It was hypothesized that BF GABAergic neurons may participate in the regulation of general anesthesia. Here, using in vivo fiber photometry, we found that the activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia, having obviously decreased during the induction of anesthesia and being gradually restored during the emergence from anesthesia, in Vgat-Cre mice of both sexes. Activation of BF GABAergic neurons with chemogenetic and optogenetic approaches decreased sensitivity to isoflurane, delayed induction, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of BF GABAergic neurons decreased EEG δ power and the burst suppression ratio (BSR) during 0.8% and 1.4% isoflurane anesthesia, respectively. Similar to the effects of activating BF GABAergic cell bodies, photostimulation of BF GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. Collectively, these results showed that the GABAergic BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthesia via the GABAergic BF-TRN pathway. Our findings may provide a new target for attenuating the depth of anesthesia and accelerating emergence from general anesthesia.SIGNIFICANCE STATEMENT The basal forebrain (BF) is a key brain region controlling sleep-wake behavior. Activation of GABAergic neurons in the BF potently promotes behavioral arousal and cortical activity. Recently, many sleep-wake-related brain structures have been reported to participate in the regulation of general anesthesia. However, it is still unclear what role BF GABAergic neurons play in general anesthesia. In this study, we aim to reveal the role of BF GABAergic neurons in behavioral and cortical emergence from isoflurane anesthesia and elucidate the underlying neural pathways. Understanding the specific role of BF GABAergic neurons in isoflurane anesthesia would improve our understanding of the mechanisms of general anesthesia and may provide a new strategy for accelerating emergence from general anesthesia.

SEEI: spherical evolution with feedback mechanism for identifying epistatic interactions.

BACKGROUND: Detecting epistatic interactions (EIs) involves the exploration of associations among single nucleotide polymorphisms (SNPs) and complex diseases, which is an important task in genome-wide association studies. The EI detection problem is dependent on epistasis models and corresponding optimization methods. Although various models and methods have been proposed to detect EIs, identifying EIs efficiently and accurately is still a challenge. RESULTS: Here, we propose a linear mixed statistical epistasis model (LMSE) and a spherical evolution approach with a feedback mechanism (named SEEI). The LMSE model expands the existing single epistasis models such as LR-Score, K2-Score, Mutual information, and Gini index. The SEEI includes an adaptive spherical search strategy and population updating strategy, which ensures that the algorithm is not easily trapped in local optima. We analyzed the performances of 8 random disease models, 12 disease models with marginal effects, 30 disease models without marginal effects, and 10 high-order disease models. The 60 simulated disease models and a real breast cancer dataset were used to evaluate eight algorithms (SEEI, EACO, EpiACO, FDHEIW, MP-HS-DHSI, NHSA-DHSC, SNPHarvester, CSE). Three evaluation criteria (pow1, pow2, pow3), a T-test, and a Friedman test were used to compare the performances of these algorithms. The results show that the SEEI algorithm (order 1, averages ranks = 13.125) outperformed the other algorithms in detecting EIs. CONCLUSIONS: Here, we propose an LMSE model and an evolutionary computing method (SEEI) to solve the optimization problem of the LMSE model. The proposed method performed better than the other seven algorithms tested in its ability to identify EIs in genome-wide association datasets. We identified new SNP-SNP combinations in the real breast cancer dataset and verified the results. Our findings provide new insights for the diagnosis and treatment of breast cancer. AVAILABILITY AND IMPLEMENTATION: https://github.com/scutdy/SSO/blob/master/SEEI.zip .

Finite temperature string by K-means clustering sampling with order parameters as collective variables for molecular crystals: application to polymorphic transformation between ß-CL-20 and ε-CL-20.

Polymorphic transformation of molecular crystals is a fundamental phase transition process, and it is important practically in the chemical, material, biopharmaceutical, and energy storage industries. However, understanding of the transformation mechanism at the molecular level is poor due to the extreme simulating challenges in enhanced sampling and formulating order parameters (OPs) as the collective variables that can distinguish polymorphs with quite similar and complicated structures so as to describe the reaction coordinate. In this work, two kinds of OPs for CL-20 were constructed by the bond distances, bond orientations and relative orientations. A K-means clustering algorithm based on the Euclidean distance and sample weight was used to smooth the initial finite temperature string (FTS), and the minimum free energy path connecting ß-CL-20 and ε-CL-20 was sketched by the string method in collective variables, and the free energy profile along the path and the nucleation kinetics were obtained by Markovian milestoning with Voronoi tessellations. In comparison with the average-based sampling, the K-means clustering algorithm provided an improved convergence rate of FTS. The simulation of transformation was independent of OP types but was affected greatly by finite-size effects. A surface-mediated local nucleation mechanism was confirmed and the configuration located at the shoulder of potential of mean force, rather than overall maximum, was confirmed to be the critical nucleus formed by the cooperative effect of the intermolecular interactions. This work provides an effective way to explore the polymorphic transformation of caged molecular crystals at the molecular level.

Agonistic analog of growth hormone-releasing hormone promotes neurofunctional recovery and neural regeneration in ischemic stroke.

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone-releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 µg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation-reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Exosome-Mediated Communication in Thyroid Cancer: Implications for Prognosis and Therapeutic Targets.

Thyroid cancer (THCA) is one of the most common malignancies of the endocrine system. Exosomes have significant value in performing molecular treatments, evaluating the diagnosis and determining tumor prognosis. Thus, the identification of exosome-related genes could be valuable for the diagnosis and potential treatment of THCA. In this study, we examined a set of exosome-related differentially expressed genes (DEGs) (BIRC5, POSTN, TGFBR1, DUSP1, BID, and FGFR2) by taking the intersection between the DEGs of the TCGA-THCA and GeneCards datasets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the exosome-related DEGs indicated that these genes were involved in certain biological functions and pathways. Protein‒protein interaction (PPI), mRNA‒miRNA, and mRNA-TF interaction networks were constructed using the 6 exosome-related DEGs as hub genes. Furthermore, we analyzed the correlation between the 6 exosome-related DEGs and immune infiltration. The Genomics of Drug Sensitivity in Cancer (GDSC), the Cancer Cell Line Encyclopedia (CCLE), and the CellMiner database were used to elucidate the relationship between the exosome-related DEGs and drug sensitivity. In addition, we verified that both POSTN and BID were upregulated in papillary thyroid cancer (PTC) patients and that their expression was correlated with cancer progression. The POSTN and BID protein expression levels were further examined in THCA cell lines. These findings provide insights into exosome-related clinical trials and drug development.

Finite Temperature String with Order Parameter as Collective Variables for Molecular Crystal: A Case of Polymorphic Transformation of TNT under External Electric Field.

An external electric field is an effective tool to induce the polymorphic transformation of molecular crystals, which is important practically in the chemical, material, and energy storage industries. However, the understanding of this mechanism is poor at the molecular level. In this work, two types of order parameters (OPs) were constructed for the molecular crystal based on the intermolecular distance, bond orientation, and molecular orientation. Using the K-means clustering algorithm for the sampling of OPs based on the Euclidean distance and density weight, the polymorphic transformation of TNT was investigated using a finite temperature string (FTS) under external electric fields. The potential of mean force (PMF) was obtained, and the essence of the polymorphic transformation between o-TNT and m-TNT was revealed, which verified the effectiveness of the FTS method based on K-means clustering to OPs. The differences in PMFs between the o-TNT and transition state were decreased under external electric fields in comparison with those in no field. The fields parallel to the c-axis obviously affected the difference in PMF, and the relationship between the changes in PMFs and field strengths was found. Although the external electric field did not promote the convergence, the time of the polymorphic transformation was reduced under the external electric field in comparison to its absence. Moreover, under the external electric field, the polymorphic transformation from o-TNT to m-TNT occurred while that from m-TNT to o-TNT was prevented, which was explained by the dipole moment of molecule, relative permittivity, chemical potential difference, nucleation work and nucleation rate. This confirmed that the polymorphic transformation orientation of the molecular crystal could be controlled by the external electric field. This work provides an effective way to explore the polymorphic transformation of the molecular crystals at a molecular level, and it is useful to control the production process and improve the performance of energetic materials by using the external electric fields.

Anti-Inflammatory Peroxidized Chlorahololide-Type Dimers Are Artifacts of Shizukaol-Type Dimers: From Phenomena Discovery and Confirmation to Potential Underlying Mechanism.

In our research on naturally occurring sesquiterpenes, eight shizukaol-type dimers, one chlorahololide-type dimer, and one sarcanolide-type dimer were isolated from the roots of Chloranthus fortunei. As the project was implemented, we accidentally discovered that shizukaol-type dimers can be converted into peroxidized chlorahololide-type dimers. This potential change was discovered after simulations of the changes in corresponding shizukaols showed that three peroxide products were generated (1-3), indicating that peroxidation reactions occurred. HPLC-HR-MS analysis results obtained for the shizukaol derivatives further demonstrate that the reaction occurred, and the type of substituent of small organic ester moieties at positions C-15' and C-13' of unit B were not decisively related to the reaction. Quantum chemical calculations of the mode dimer further demonstrated this phenomenon. The highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy of the precursor and production revealed the advantageous yield of 4ß-hydroperoxyl production. Additionally, the potential reaction mechanism was speculated and validated using the free energy in the reaction which successfully explained the feasibility of the reaction. Finally, the anti-inflammatory activity of the precursors and products was evaluated, and the products of peroxidation showed better anti-inflammatory activity.

Clinical Value of Platelets and Coagulation Parameters in Predicting the Severity of Delta Variant SARS-CoV-2.

INTRODUCTION: The present study aimed to analyze the clinical features and laboratory markers of patients with Delta variant SARS-CoV-2 and explore the role of platelet in predicting the severity of Delta. METHODS: This retrospective, observational study was conducted on 863 patients laboratory-confirmed Delta variant SARS-CoV-2. These cases were sub-classified based on disease severity into mild (n = 304), moderate (n = 537), and severe (n = 22). A series of laboratory findings and clinical data were collected and analyzed during hospitalization. RESULTS: Of 863 hospitalized patients with Delta, the median age was 38 years (interquartile range, 30-51 years) and 471 (54.58%) were male. The most common clinical symptoms mainly included cough, fever, pharyngalgia, expectoration, dyspnea, fatigue, and headache, and the commonest comorbidities were hypertension and diabetes. Among the hematological variables, neutrophil count, red blood cell count, and hemoglobin, were found to be statistically significant with regard to subcategories based of disease severity (p < 0.05). Among coagulation parameters, there was a statistically significant difference in D-dimer, fibrinogen, international normalized ratio, and prothrombin time (p < 0.05). Statistically significant differences were observed in platelet markers including platelet count, large platelet count, and plateletcrit (p < 0.05). Additionally, there was strong correlation between platelet and other parameters with disease severity. Logistical regression analysis and ROC curves showed that D-dimer was a single best marker of disease severity (p = 0.005, p < 0.0001); however, platelet (p = 0.009, p = 0.002) and plateletcrit (p = 0.002, p = 0.001) could also predict severe disease. Platelet was identified as an independent risk factor for severe Delta. CONCLUSION: Low platelet may be a marker of disease severity in Delta variant SARS-CoV-2 and may contribute to determine the severity of patients infected with Delta.

Chemical Constituents of Thesium chinense Turcz and Their In Vitro Antioxidant, Anti-Inflammatory and Cytotoxic Activities.

Three novel compounds (1-3) along with twenty-six known compounds, two known steroids (4-5) and twenty-four known phenylpropanoids (6-29) were isolated from the whole plant of Thesium chinense Turcz. The structures of the three new compounds were elucidated on the basis of ESI-MS, HR-ESIMS, 1D and 2D NMR, IR, UV spectroscopic data. The absolute stereochemistry of compound 1 was determined by the Gauge-Including Atomic Orbitals (GIAO) method. The in vitro antioxidant, anti-inflammatory and cytotoxic activities of the isolated compounds were evaluated by DPPH radical-scavenging assay, LPS-activated RAW 264.7 cells model and CCK-8 kit, respectively. Compound 11 showed high antioxidant activity with an SC50 value of 16.2 ± 1.6 µM. Compound 21 showed considerable anti-inflammatory activity with an IC50 value of 28.6 ± 3.0 µM. Compounds 4 and 5 displayed potent cytotoxic activity against human NCI-H292, SiHa, A549, and MKN45 cell lines, with the compound 4 having IC50 values of 17.4 ± 2.4, 22.2 ± 1.1, 9.7 ± 0.9, 9.5 ±0.7 µM, and the compound 5 having all IC50 values less than 0.1 µM in vitro.

Strong External Electric Fields Reduce Explosive Sensitivity: A Theoretical Investigation into the Reaction Selectivity in NH2NO2∙∙∙NH3.

Controlling the selectivity of a detonation initiation reaction of explosive is essential to reduce sensitivity, and it seems impossible to reduce it by strengthening the external electric field. To verify this, the effects of external electric fields on the initiation reactions in NH2NO2∙∙∙NH3, a model system of the nitroamine explosive with alkaline additive, were investigated at the MP2/6-311++G(2d,p) and CCSD(T)/6-311++G(2d,p) levels. The concerted effect in the intermolecular hydrogen exchange is characterized by an index of the imaginary vibrations. Due to the weakened concerted effects by the electric field along the -x-direction opposite to the "reaction axis", the dominant reaction changes from the intermolecular hydrogen exchange to 1,3-intramolecular hydrogen transference with the increase in the field strengths. Furthermore, the stronger the field strengths, the higher the barrier heights become, indicating the lower sensitivities. Therefore, by increasing the field strength and adjusting the orientation between the field and "reaction axis", not only can the reaction selectivity be controlled, but the sensitivity can also be reduced, in particular under a super-strong field. Thus, a traditional concept, in which the explosive is dangerous under the super-strong external electric field, is theoretically broken. Compared to the neutral medium, a low sensitivity of the explosive with alkaline can be achieved under the stronger field. Employing atoms in molecules, reduced density gradient, and surface electrostatic potentials, the origin of the reaction selectivity and sensitivity change is revealed. This work provides a new idea for the technical improvement regarding adding the external electric field into the explosive system.

Deacetylation of Notch1 by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization.

Hepatic macrophages are involved in both pathogen clearance and immunopathogenesis. Emerging evidence demonstrates that macrophage polarization plays a critical role in hepatitis B virus (HBV)-induced immune impairment and liver pathology. However, it remains largely unknown as to how HBV infection facilitates M2 macrophage polarization. Here, a mouse HBV infection model was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome via the tail vein. Coculture experiments with HBV-producing HepG2.2.15 cells and macrophages were established in vitro. We found that HBV-inhibited M1 while enhancing M2 markers, which was accompanied by decreased proinflammatory tumor necrosis factor-α (TNF-α) and augmented anti-inflammatory IL-10 expression. Furthermore, both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion contributed to HBV-triggered macrophage polarization from M1 toward M2 phenotype. Mechanistically, HBsAg and HBeAg could upregulate the sirtuins 1 (SIRT1) deacetylase expression, which in turn promote deacetylation of the Notch1 intracellular domain (NICD), leading to increased Akt phosphorylation and decreased NF-κB nuclear translocation in macrophages. Our findings suggest that NICD deacetylation by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, raising the possibility of targeting SIRT1/Notch1 pathway in macrophages to treat HBV immune evasion and chronic HBV infection.NEW & NOTEWORTHY This study identified a previously unrecognized molecular mechanism of HBV-mediated suppression of innate immune responses. We demonstrate that deacetylation of NICD by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, which may aid in the development of new macrophage-based immunotherapy for chronic HBV infection and related diseases.

China's ecosystem service value in 1992-2018: Pattern and anthropogenic driving factors detection using Bayesian spatiotemporal hierarchy model.

Maintaining ecosystem services (ESs) and reducing ecosystem degradation are important goals for achieving sustainable development. However, under the influence of various anthropogenic factors, the total ecosystem service value (ESV) of China continues to decline, and the detailed processes involved in this decline are unclear. In this paper, a new long-term annual land cover dataset (the Climate Change Initiative Land Cover or CCI-LC dataset) with a spatial resolution of 300 m was employed to estimate the ESV of China, and Bayesian spatiotemporal hierarchy models were built to examine the detailed patterns and anthropogenic driving factors. From 1992 to 2018, the total ESV of China fluctuated and decreased from 3265.3 to 3253.29 billion US$ at an average rate of 0.55 billion US$ per year. Furthermore, the model revealed the spatiotemporal variations in the ESV pattern, and simultaneously detected the influences of 9 variables related to economic factors, population, infrastructure, energy, agriculture and ecological restoration, providing a convenient and effective method for ESV spatiotemporal analysis. The results enrich our understanding of the detailed spatiotemporal variation and anthropogenic driving factors underlying the declining ESV in China. These findings have substantial guiding implications for adjusting ecological regulation policies.

Anthraquinones from the Aerial Parts of Rubia cordifolia with Their NO Inhibitory and Antibacterial Activities.

The present study aimed to identify the composition of the aerial parts of Rubia cordifolia L. A chemical investigation on the EtOAc extracts from the aerial parts of Rubia cordifolia resulted in the isolation of four new anthraquinones, namely Cordifoquinone A-D (1-4), along with 16 known anthraquinones. Their structures were elucidated on the basis of NMR and HR-ESIMS data. All isolates were assessed for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 1, 3 and 10 exhibited significant inhibitory activities with IC50 values of 14.05, 23.48 and 29.23 µmol·L-1, respectively. Their antibacterial activities of four bacteria, Escherichia coli (ATCC 25922), Staphylococcus aureus subsp. aureus (ATCC 29213), Salmonella enterica subsp. enterica (ATCC 14028) and Pseudomonas aeruginosa (ATCC 27853), were also evaluated. Our results indicated that the antibacterial activity of these compounds is inactive.

Structure Revision of Four Classes of Prenylated Aromatic Natural Products Based on a Rule for Diagnostic 13C NMR Chemical Shifts.

Errors in elucidating the structures of four natural classes of prenylated aromatic compounds with 2,3-epoxy, 2,3-dihydroxy, and cyclization with an ortho-phenolic hydroxyl to give a pyran or furan ring moiety are frequent and inevitable. Based on rigorous literature research and a series of chemical transformation experiments, a rule for the rapid determination of these four classes of prenylated derivates based on 13C NMR data was formulated, and 57 corrections featuring these fragments were accordingly reported.

Outpatient Percutaneous Endovascular Abdominal Aortic Aneurysm Repair: A Single-Center Experience.

PURPOSE: To evaluate the safety of outpatient percutaneous endovascular abdominal aortic repair (PEVAR) versus inpatient PEVAR without or with adjunct procedures. MATERIALS AND METHODS: Between January 2012 and June 2019, a cohort of 359 patients comprising 168 (46.8%) outpatients and 191 (53.2%) inpatients who had undergone PEVAR were enrolled. All the patients were asymptomatic but had indications for endovascular aortic repair, ie, fit for intravenous anesthesia and anatomically feasible with standard devices. Patient sex, age, comorbidities, smoking status, type of anesthesia, adjunct procedures, type of graft device, operative times, mortality, complications, and readmissions were analyzed. RESULTS: Median follow-up period was 16.5 months (interquartile range, 9-31 months). Except for a higher percentage of tobacco use (42.6% vs 28.8%; P = .04), dyslipidemia (39.7% vs 19.2%; P < .01), and use of local anesthesia (99.4% vs 82.2%; P < .01) in the outpatients, there was no significant difference in the type of graft and adjunct procedures used. No outpatient mortality occurred. There was no difference in the number, severity, and onset of complications (all P > .05). Outpatient unexpected same-day admission, 30-day readmission, and emergency department visit rates were 4.8%, 2.4% (P = .13), and 10% (P < .01), respectively. Operative times for outpatient PEVAR without adjunct procedures were shorter (P < .01). CONCLUSIONS: Outpatient PEVAR can be performed with a safety profile similar to that of inpatient PEVAR. The unexpected same-day admission, 30-day readmission, and emergency department visit rates were low. The outpatient PEVARs without adjunct procedures took less time.

Antibacterial Prenylated p-Hydroxybenzoic Acid Derivatives from Oberonia myosurus and Identification of Putative Prenyltransferases.

Twelve hitherto unknown tandem prenylated p-hydroxybenzoic acid derivatives, namely, oberoniamyosurusins A-L, together with five known derivatives, were isolated from an EtOH extract of the whole parts of the plant Oberonia myosurus. Compounds 10, 13, and 17 exhibited moderate inhibitory activity against Staphylococcus aureus subsp. aureus ATCC29213 with MIC50 values ranging from 7.6 to 23 µg/mL. To determine the biosynthetic pathway of this class of tandem prenyl-substituted compounds, the full-length transcriptome of O. myosurus was sequenced, yielding 19.09 Gb of clean data and 10 949 nonredundant sequences. Two isoforms of p-hydroxybenzoic acid prenyltransferases were annotated and functionally characterized as the enzymes that might be involved in the biosynthesis of nervogenic acid (13) in Pichia pastoris.

MiR-328-3p inhibits cell proliferation and metastasis in colorectal cancer by targeting Girdin and inhibiting the PI3K/Akt signaling pathway.

MiR-328-3p has been reported to be downregulated and serve as a tumor suppressor in several cancers. Previous studies only have reported the downregulation of miR-328-3p in CRC. However, the roles of miR-328-3p in CRC growth and metastasis were unknown. In this study, we demonstrated that miR-328-3p overexpression inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). The PI3K/Akt signaling pathway was also inactivated by miR-328-3p overexpression. MiR-328-3p knockdown showed the opposite effects. In addition, we confirmed that miR-328-3p directly bound to 3'UTR of Girdin and negatively regulated its expression. Girdin knockdown or treatment with PI3K inhibitor LY294002 blocked the effects of miR-328-3p inhibitor on cell proliferation, metastasis, and the PI3K/Akt signaling pathway. Moreover, pre-miR-328 decreased numbers of liver metastatic nodules, and reduced the levels of p-Akt, p-Girdin, and Girdin in metastatic tissues in liver. In conclusion, miR-328-3p may inhibit proliferation and metastasis of CRC cells by targeting Girdin and inactivating the PI3K/Akt signaling pathway. MiR-328-3p may be a novel target in cancer therapy.

Inhibition of YAP activation attenuates renal injury and fibrosis in angiotensin II hypertensive mice.

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1ß, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor ß, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II-induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Comparison of clinicopathologic parameters and oncologic outcomes between type 1 and type 2 papillary renal cell carcinoma.

BACKGROUND: To compare the clinicopathologic parameters and oncologic outcomes between type 1 and type 2 papillary renal cell carcinoma (PRCC). METHODS: This study was approved by the review board (NO.XYFY2019-KL032-01). Between 2007 and 2018, 52 consecutive patients who underwent surgery at a single tertiary referral hospital were included. Clinicopathologic and survival data were collected and entered into a database. The Kaplan-Meier method, and univariate and multivariate Cox proportional hazard regression analyses were performed to estimate progression-free survival (PFS) and cancer-specific survival (CSS). RESULTS: Of the 52 patients, 24 (46.2%) were diagnosed with type 1 PRCC, and 28 (53.8%) had type 2 PRCC. The mean tumor size was 4.8 ± 2.5 cm. The two subtypes displayed different morphological features: foamy macrophages were more common in type 1 PRCC, while eosinophils and microvascular angiolymphatic invasion were more frequent in type 2 PRCC. Type 2 cases showed higher tumor stage and World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade than type 1 cases (T3-T4: 43% vs 17%, P = 0.041; G3-G4: 43% vs 8%, P = 0.005). In univariate analysis, type 2 PRCC had a lower probability for PFS and CSS than patients with type 1 PRCC (P = 0.016, P = 0.049, log-rank test, respectively). In multivariate analysis, only WHO/ISUP grade (HR 11.289, 95% CI 2.303-55.329, P = 0.003) and tumor size (HR 1.244, 95% CI 1.034-1.496, P = 0.021) were significantly associated with PFS. CONCLUSIONS: PRCC subtype displayed different morphological features: foamy macrophages, eosinophils and microvascular angiolymphatic invasion are pathologic features that may aid in the distinction of the two subtypes. Histologic subtype of PRCC is not an independent prognostic factor and only WHO/ISUP grade and tumor size were independent predictors for PFS.

Whole-exome sequencing identified four loci influencing craniofacial morphology in northern Han Chinese.

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.