Ebronucimab in Chinese patients with hypercholesterolemia---A randomized double-blind placebo-controlled phase 3 trial to evaluate the efficacy and safety of ebronucimab.

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

Establishment of a Raman nanosphere based immunochromatographic system for the combined detection of influenza A and B viruses' antigens on a single T-line.

A simple and rapid system based on Raman nanosphere (R-Sphere) immunochromatography was developed in this study for the simultaneous detection of Influenza A, B virus antigens on a single test line (T-line). Two types of R-Sphere with different characteristic Raman spectrum were used as the signal source, which were labeled with monoclonal antibodies against FluA, FluB (tracer antibodies), respectively. A mixture of antibodies containing anti-FluA monoclonal antibody and anti-FluB monoclonal antibody (capture antibody) was sprayed on a single T-line and goat anti-chicken IgY antibody was coated as a C-line, and the antigen solution with known concentration was detected by the strip of lateral flow immunochromatography based on surface-enhanced Raman spectroscopy (SERS). The T-line was scanned with a Raman spectrometer and SERS signals were collected. Simultaneous specific recognition and detection of FluA and FluB were achieved on a single T-line by analyzing the SERS signals. The findings indicated that the test system could identify FluA and FluB in a qualitative manner in just 15 minutes, with a minimum detection threshold of 0.25 ng ml-1, excellent consistency, and specificity. There was no interference with the other four respiratory pathogens, and it exhibited 8 times greater sensitivity compared to the colloidal gold test strip method. The assay system is rapid, sensitive, and does not require repetitive sample pretreatment steps and two viruses can be detected simultaneously on a single T-line by titrating one sample, which improves detection efficiency, and provide a reference for developing multiplexed detection techniques for other respiratory viruses.

Prominin-1 controls stem cell activation by orchestrating ciliary dynamics.

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.

Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial.

BACKGROUND: PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC. METHODS: This randomised, double-blind, phase 3 trial was done in 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously] and paclitaxel [175 mg/m2, intravenously] for squamous NSCLC, or carboplatin [AUC 5 mg/mL per min, intravenously] and pemetrexed [500 mg/m2, intravenously] for non-squamous NSCLC; sugemalimab group) or placebo plus the same platinum-based chemotherapy regimens for squamous or non-squamous NSCLC as in the sugemalimab group; placebo group) for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC, and intravenous sugemalimab 500 mg/m2 or matching placebo plus pemetrexed for non-squamous NSCLC. Randomisation was done by an interactive voice-web-response system via permuted blocks (block size was a mixture of three and six with a random order within each stratum) and stratified by ECOG performance status, PD-L1 expression, and tumour pathology. The investigators, patients, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one treatment dose. Results reported are from a prespecified interim analysis (ie, when the study met the primary endpoint) and an updated analysis (prespecified final analysis for progression-free survival) with a longer follow-up. This study is registered with ClinicalTrials.gov (NCT03789604), is closed to new participants, and follow-up is ongoing. FINDINGS: Between Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility; 367 were ineligible, and the remaining 479 patients were randomly assigned to the sugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with significantly longer progression-free survival in the sugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months [4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p<0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p<0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patients in the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-related deaths were reported in ten (3%) patients in the sugemalimab group (pneumonia with respiratory failure in one patient; myelosuppression with septic shock in one patient; pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient each; the other two deaths had an unspecified cause) and in two (1%) patients in the placebo group (pneumonia and multiple organ dysfunction syndrome). INTERPRETATION: Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC. FUNDING: CStone Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.

Lentibacillus saliphilus. sp. nov., a moderately halophilic bacterium isolated from a saltern in Korea.

A novel moderately halophilic bacterial strain, designated YIM 93176T, was isolated from a saltern in Korea and subjected to a polyphasic taxonomic study. This isolate YIM 93176T was observed to grow in the presence of 0-22% (w/v) NaCl and at pH 6.0-10.0 and 10-45 °C; optimum growth was observed with 5-10% (w/v) NaCl and at pH 7.0-9.0 and 28-37 °C. Based on 16S rRNA gene sequences analysis, the nearest relatives were Lentibacillus alimentarius M2024T (96.5% similarity), followed by Virgibacillus carmonensis LMG 20964T (96.0%) and the other type strains of the family Bacillaceae, but phylogenetic analysis indicated that strain YIM 93176T belonged to the cluster comprising type species of the genus Lentibacillus. Genome sequencing of strain YIM 93176T revealed a genome size of 3.2 Mb and a DNA G + C content of 40.5 mol%. The major fatty acids were anteiso-C15:0 (40.7%) and iso-C15:0 (26.4%), while the predominant respiratory quinone was menaquinone 7. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. These genotypic and chemotaxonomic characteristics supported affiliation of strain YIM 93176T to the genus Lentibacillus. In addition, phenotypic characteristics could distinguish strain YIM 93176T from its closely related species in genus Lentibacillus. Based on the cumulative evidences from the polyphasic taxonomic study, strain YIM 93176T represents a novel species of the genus Lentibacillus, for which name Lentibacillus saliphilus sp. nov. (type strain YIM 93176T = CCTCC AB 208139T = DSM 21375T) is proposed.

HDAC1-mediated deacetylation of LSD1 regulates vascular calcification by promoting autophagy in chronic renal failure.

Chronic renal failure (CRF) is commonly associated with various adverse consequences including pathological vascular calcification (VC), which represents a significant clinical concern. Existing literature has suggested the involvement of histone deacetylases (HDACs) in the progression of CRF-induced VC. However, the underlying molecular mechanisms associated with HDACs remain largely unknown. Therefore, we established the adenine-induced CRF rat model and in vitro VC models based on vascular smooth muscle cells (VSMCs) to examine HDAC1/lysine demethylase 1A (LSD1)/SESN2 as a novel molecular pathway in CRF-induced VC. Our initial results demonstrated that HDAC1 reduced the formation of VC in vivo and in vitro. HDAC1 was found to deacetylate LSD1, which subsequently led to impaired transcriptional activity in CRF-induced VC. Moreover, our results illustrated that LSD1 diminished the enrichment of H3K4me2 at the SESN2 promoter. Autophagy was identified as a vasculo-protective element against calcification in VC. Finally, we found that the inhibitory effects of HDAC1 overexpression on VC were partially abolished via over-expressed LSD1 in adenine-induced CRF model rats and in high phosphate-induced VSMCs. Taken together, these results highlight the crucial role of HDAC1 as an antagonistic factor in the progression of VC in CRF, and also revealed a novel regulatory mechanism by which HDAC1 operates. These findings provide significant insight and a fresh perspective into promising novel treatment strategies by up-regulating HDAC1 in CRF.

Multi-molar CO2 capture beyond the direct Lewis acid-base interaction mechanism.

Some singly charged ionic liquids (ILs) have been reported to absorb multi-molar CO2. However, the conventional acid(CO2)-base(anion) interaction picture leads to too weak CO2 binding to support the high uptake. Later, a so-called "cation-channel" mechanism assuming the cation-to-anion proton transfer successfully explains the over equimolar CO2 uptake of some phosphonium-based ILs. Here, by employing the density functional theory (DFT) calculations, we extend the proton transfer mechanism to incorporate imidazole- and ammonium-based ILs as well. For imidazole-based ILs, carbene molecules formed after the proton transfer can react strongly with CO2. More importantly, for ammonium-based ILs, the proton transfer process is feasible only with the help of CO2 molecules. Furthermore, compared to the one IL ion pair model, the model consisting of two IL ion pairs can result in stronger CO2 absorption because it can describe the intermolecular hydrogen bonds more appropriately, especially after incorporating CO2 molecules. The relative acidity and basicity of cations and anions in ILs may be crucial for understanding their functionalization as ILs.

Exploration of tetra-branched multiple-site SO2 capture materials.

We designed a series of tetra-branched anionic structures centered with Al for more efficient SO2 capture. By using the home-made configuration search program coupled with electronic structure calculations, we have systematically explored the large reaction space consisting of these anions, cations, and SO2 molecules. Unique insertion structures of the reaction complexes featuring a SO2 molecule inserted into a branch were found to be prevalent and sometimes to be the ground states. Cations can either enhance or compress the anion-SO2 interactions, highly depending on the anion, as they have multiple ways to interact with anions and SO2 molecules. According to the calculated sequential SO2 binding energies (with the cation effect included), [Al(Im)4]- is expected to be the best among the designed structures for reversible SO2 capture. This approach can be easily extended to design and screen sorbents for other acidic gases.

Electronic structure of mono(Lewis base)-stabilized borylenes.

This work demonstrates that the mono(Lewis base)-stabilized three-center-six-electron (3c-6e) or LB → B-R type borylenes may have a ground state singlet (σ2π0 and σ0π2) or triplet (σ1π1) electronic structure, depending on the substitution group, Lewis base, and molecule topology (cyclic or acyclic). The singlet-triplet energy gap of a borylene increases with electron-donating substitution groups and decreases with Lewis bases of strong σ-donating and π-accepting feature (e.g., carbenes and pyridine). The gap can be widely varied (ranging up to about 300 kJ mol-1) and even inversed by the proper combination of substitution groups and Lewis bases. These borylenes may even have singlet-and-triplet coexisting ground state electronic structures, which imply their complex reactivity.

Designing tri-branched multiple-site SO2 capture materials.

SO2 capture materials usually have multiple reactive sites located within a limited space, thus absorptions (or adsorptions) of disparate strengths and low effective capacity per sorption-desorption cycle become the natural results of the so-called "coverage effects" (due to both the electronic and steric effects). Here, we propose a tri-branched framework with separated reactive sites and nearly uniform charge distribution on the reacting atoms. Through density functional theory (DFT)-based calculations and simulated isotherms, two N-centered anionic structures (terminated with amine (TAEA) and imidazolyl (TIA) groups, respectively) are selected from a series of representative tri-branched species. The TAEA-based ILs are predicted to exhibit the highest uptakes (about 6.1 mol SO2 per mole IL) at 1 bar of SO2 and 20 °C, which reach the ceiling capacity that a negative charge can provide. The TIA-based ILs have small differences in their SO2 sequential binding energies and they are estimated to have the best effective SO2 capacity during a sorption-desorption cycle (about 2.6 mol SO2 per mole IL, absorption at 1 bar of SO2 and 20 °C and desorption at 1 bar of SO2 and 120 °C). Moreover, we also find that the designed species can efficiently capture other gases like NO.

Pulmonary surfactant-associated proteins and inflammatory factors in obstructive sleep apnea.

PURPOSE: Pulmonary surfactant (PS) plays roles in promoting the removal of the liquid, host defense, and immune regulation in the tracheal, bronchial, and alveoli epithelium. PS protein expression level can be regulated by oxygen levels and related free radicals. Obstructive sleep apnea (OSA) is featured with oxygen free radical production for damaging epithelial tissues and thus may affect PS production. The study was to explore the relationship between PS protein and OSA severity. METHODS: We collected serum and bronchoalveolar lavage fluid (BALF) samples from 35 OSA patients and 22 healthy subjects. PS-associated proteins and inflammatory factors, including surfactant proteins, HIF-1α, NF-κB, and IL-6, were analyzed. Regression analysis was performed to reveal the relationship between biochemical factors and clinical indexes recorded during PSG monitor. RESULTS: Lower BALF and surfactant protein (except surfactant protein C or SPC) levels occurred in OSA patients (all p < 0.05 compared to control group). A strongly negative correlation was found between surfactant protein with apnea-hypopnea index (AHI) and other sleeping indexes including ODI3 and ODI4. Similar patterns were found in serum samples, which were strongly correlated with BALF counterparts. Surfactant proteins were further found to have negative regression with inflammatory factors such as HIF-1α, NF-κB, and IL-6. CONCLUSIONS: This study established the relationship between PS-related protein with severity of OSA, plus their relationship with inflammatory factors. Our results provided possibly novel markers in general circulation for disease evaluation of OSA.

Electrophilicity and Nucleophilicity of Boryl Radicals.

We carried out a survey of the relative reactivity of a collection of 91 neutral boryl radicals using density functional calculations. Their reactivities were characterized by four indices, i.e., the global electrophilicity, global nucleophilicity, local electrophilicity, and local nucleophilicity. Particularly, the global electrophilicity and nucleophilicity indices span over a moderately wider range than those of carbon radicals, indicating their potentially broader reactivity. Thus, boryl radicals may be utilized in electrophilic radical reactions, while traditionally they are only considered for nucleophilic radical reactions. In contrast, the local electrophilicity and nucleophilicity indices at the boron center show a different reactivity picture than their global counterparts. The inconsistency is rooted in the low and varying spin density on boron (for most radicals, less than 50%) in different boryl radicals, which is a combinative result of radical stabilization via electron delocalization and the low electronegativity of boron (compared to carbon). In short, the boron character in boryl radicals may be weak and their reactivity is not reflected by the local indices based on boron but by the global ones.

Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease.

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.

Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury.

Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular ß-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes.

Multiple-Site SO2 -Capture Ionic Liquids with Nearly Uniform Site Performance.

We propose a series of azolium poly(azolyl)borate ionic liquids (ILs) for reversible SO2 capture. Density functional calculations demonstrate that the designed borate anions can strongly bond to SO2 at multiple sites with nearly uniform binding energies. Thus, as well as high overall uptakes, the ILs can achieve much higher effective uptakes (the uptake difference between absorption and desorption conditions) than existing SO2 -capture reagents. The larger size of the borate anions, the evenly distributed negative charge among the azolyl rings, and the blocking of the conjugation by the tetrahedral boron concertedly reduce absorbate-absorbate repulsion, which leads to a large disparity among binding sites in other multiple-site SO2 sorbents.

Intramolecular Hydrogen Bonds Enhance Disparity in Reactivity between Isomers of Photoswitchable Sorbents and CO2 : A Computational Study.

Reducing the emission of greenhouse gases, such as CO2 , requires efficient and reusable capture materials. The energy for regenerating sorbents is critical to the cost of CO2 capture. Here, we design a series of photoswitchable CO2 capture molecules by grafting Lewis bases, which can covalently bond CO2 , to azo-based backbones that can switch configurations upon light stimulation. The first-principles calculations demonstrate that intramolecular hydrogen bonds are crucial for enlarging the difference of CO2 binding strengths to the cis and trans isomers. As a result, the CO2 -sorbent interaction can be light-adjusted from strong chemical bonding in one configuration to weak bonding in the other, which may lead to a great energy reduction in sorbent regeneration.

Theoretical survey of the ligand tunability of poly(azolyl)borates.

Using density functional calculations, we have systematically investigated a series of homoleptic poly(azolyl)borate ligands, which display unusual steadily declining bond strengths accompanied by bond contractions when the azolyl groups are sequentially substituted to the parent BH4(-). As ligands, their effects on the coordinated metal ions (Cu(i) and Mo(0)) are quantitatively represented by two ligand tunability descriptors: the vibration frequency (νCO) of the CO groups complexed to the metal ions and the charge of the metal-(CO)x moiety, between which a good linear correlation exists. For the same number of azolyl substitutions, the boundary of ligand tunability is always marked by the pyrazolyl and tetrazolyl groups at the two ends, which feature the lowest and the highest nitrogen content in the azolyl ring, respectively. With the increase of the azolyl substitution number in the borate ligands, the νCO range expands, indicating a higher tunability of the ligands. The type of metal ion and the charge they carry play minor roles in influencing the ligand tunability.

Cation-assisted interactions between N-heterocycles and CO2.

Cation-assisted interactions between N-containing heterocycles (NHCs) and CO2 have been systematically studied by using density functional theory (DFT). For neutral and anionic (non-carbenoid) NHCs, the effects of monovalent cations (i.e., alkali metal ions) are moderate to small (the NHC-CO2 binding energy change, ΔBE usually < 25 kJ mol(-1)). However, for NHC carbenes, due to their strong basicity, the effects are strong (ΔBE > 60 kJ mol(-1)) and the monovalent cations play a critical role in the single carboxylation of dicarbenes with CO2. In comparison, divalent alkali earth metal cations, due to both their smaller sizes and higher formal charges, exhibit a much stronger influence (ΔBE > 100 kJ mol(-1)). Divalent cations should be incorporated into next generation CO2 capture reagents. Other aspects including the reaction potential energy surface (PES), orbital-based analyses of interactions, substitution effects, and the reactivity descriptors (cation size, reacting N lone pair orbital energy, etc.) have been discussed in detail as well.