Metal-Carbon Bond Heterolysis Energy Scale for Model Palladium Catalysts.

Thermodynamic studies of transition-metal intermediates are crucial for understanding of metal-catalyzed transformations. Herein, a series of arylpalladium cyanomethanides were synthesized and characterized. Their palladium-carbon bond heterolysis energies (ΔGhet(Pd-C)) were determined in DMSO for the first time by equilibrium methods. ΔGhet(Pd-C) values of 7.9-19.1 kcal/mol, located between the ΔGhet(Pd-O) and ΔGhet(Pd-N) scales previously established, are much smaller than the corresponding ΔGhet(C-H)s of phenylacetonitrile (30.0 kcal/mol). Linear free energy relationship (LEFR) analysis reveals insights into the structure-property relationship and the factor dictating the thermodynamics of metalation. These ΔGhet(Pd-X)s in combination with ΔGhet(X-H)s are successfully used to diagnose the reaction feasibility and selectivity of X-H bond activation.

Halogen Bond Unlocks Ultra-High Birefringence.

Anisotropy is crucial for birefringence (Δn) in optical materials, but optimizing it remains a formidable challenge (Δn >0.3). Supramolecular frameworks incorporating π-conjugated components are promising for achieving enhanced birefringence because of their structural diversity and inherent anisotropy. Herein, we first synthesized (C6H6NO2)+Cl- (NAC) and then constructed a halogen-bonded supramolecular framework I+(C6H4NO2)- (INA) by halogen aliovalent substitution of Cl- with I+. The organic moieties are protonated and deprotonated nicotinic acid (NA), respectively. The antiparallel arrangement of birefringent-active units in NAC and INA leads to significant differences in the bonding characteristics between the interlayer and intralayer domains. Moreover, the [O⋅⋅⋅I+⋅⋅⋅N] halogen bond in 1D [I+(C6H4NO2)-] chain exhibits stronger interactions and stricter directionality, resulting in a more pronounced in-plane anisotropy between the intrachain and interchain directions. Consequently, INA exhibits exceptional birefringent performance, with a value of 0.778 at 550 nm, twice that of NAC (0.363 at 550 nm). This value significantly exceeds those of commercial birefringent crystals, such as CaCO3 (0.172 at 546 nm), and is the highest reported value among ultraviolet birefringent crystals. This work presents a novel design strategy that employs halogen bonds as connection sites and modes for birefringent-active units, opening new avenues for developing high-performance birefringent crystals.

Bonding Energetics of Palladium Amido/Aryloxide Complexes in DMSO: Implications for Palladium-Mediated Aniline Activation.

Thermodynamic knowledge of the metal-ligand (M-L) σ-bond strength is crucial to understanding metal-mediated transformations. Here, we developed a method for determining the Pd-X (X=OR and NHAr) bond heterolysis energies (ΔGhet (Pd-X)) in DMSO taking [(tmeda)PdArX] (tmeda=N,N,N',N'-tetramethylethylenediamine) as the model complexes. The ΔGhet (Pd-X) scales span a range of 2.6-9.0 kcal mol-1 for ΔGhet (Pd-O) values and of 14.5-19.5 kcal mol-1 for ΔGhet (Pd-N) values, respectively, implying a facile heterolytic detachment of the Pd ligands. Structure-reactivity analyses of a modeling Pd-mediated X-H bond activation reveal that the M-X bond metathesis is dominated by differences of the X-H and Pd-X bond strengths, the former being more influential. The ΔGhet (Pd-X) and pKa (X-H) parameters enable regulation of reaction thermodynamics and chemoselectivity and diagnosing the probability of aniline activation with Pd-X complexes.

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients.

Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5-15 ng mL-1. Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h-1 (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg-1 d-1 (q12h), respectively. Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.

[Effect of acupuncture on hippocampal inflammation in rats with intrauterine distress induced hypoxic-ischemic brain injury].

OBJECTIVE: To observe the effects of acupuncture on the behavior, serum inflammatory cytokines, hippocampal Nod-like receptor protein 3(NLRP3) inflammasome-related proteins and microglia activation in rats with intrauterine distress induced ischemia-hypoxic brain injury (HIBD), so as to explore the mechanism of acupuncture underlying treatment of HIBD by regulating hippocampal inflammation. METHODS: The HIBD model was established by clipping bilateral uterine arteries for 10 min and delaying caesarean delivery. HIBD rats were randomly divided into model group and acupuncture group according to body weight and litter factors, with 12 rats in each group. Twelve rats delivered normally were regarded as the normal group. Acupuncture was applied to bilateral "Benshen"(GB13) for 10 min, once a day for 14 consecutive days. H.E. staining was used to observe the pathological changes of hippocampus. The three chamber sociability test was used to determine the rat's social ability. The serum IL-1ß and IL-18 levels, the hippocampal expressions of NLRP3, apoptosis associated speck like protein containing CARD(ASC) and cysteinyl aspartate specific proteinase-1(Caspase-1), andionized calcium bindingadaptor molecule-1(IBA-1) were detected by ELISA，Western blot and Immunofluorescence, separately. RESULTS: Compared with the normal group, The hippocampal neurons in the model group are arranged loosely, and the cells are solidified and shrunk and the whole cells are deeply stained. The time of exploring the stranger rat in the model group was significantly reduced (P<0.01). The contents of IL-1ß and IL-18, the expressions of NLRP3, ASC, Caspase-1 and IBA-1 of the model group were higher than those of the normal group (P<0.01, P<0.05, P<0.001). Following acupuncture intervention, the cell structure of hippocampal neurons was improved, and there were fewer cases of cell solidification, atrophy, and deep staining. In comparison with the model group, the time of exploring stranger rat in the acupuncture group was significantly increased (P<0.01). The contents of IL-1ß and IL-18, the expressions of NLRP3, ASC and Caspase-1, and IBA-1 of the acupuncture group were significantly down-regulated than those of the model group (P<0.01, P<0.05). CONCLUSION: Acupuncture can effectively improve the social behavior deficits of HIBD rats，which may be related to inhibition of the expression of inflammatory response proteins NLRP3, ASC and Caspase-1 in the hippocampus, decrease the activation of microglia in the hippocampus, and reduce serum IL-1ß and IL-18, thereby alleviating inflammation.

Complete chloroplast genome sequence and phylogenetic analysis of winter oil rapeseed (Brassica rapa L.).

Winter oil rapeseed '18 R-1' (Brassica rapa L.) is a new variety that can survive in northern China where the extreme low temperature is -20 °C to -32 °C. It is different from traditional B. rapa and Brassica napus. In this study, the complete chloroplast (cp) genome of '18 R-1' was sequenced and analyzed to assess the genetic relationship. The size of cp genome is 153,494 bp, including one large single copy (LSC) region of 83,280 bp and one small single copy (SSC) region of 17,776 bp, separated by two inverted repeat (IR) regions of 26,219 bp. The GC content of the whole genome is 36.35%, while those of LSC, SSC, and IR are 34.12%, 29.20%, and 42.32%, respectively. The cp genome encodes 132 genes, including 87 protein-coding genes, eight rRNA genes, and 37 tRNA genes. In repeat structure analysis, 288 simple sequence repeats (SSRs) were identified. Cp genome of '18 R-1' was closely related to Brassica chinensis, B. rapa and Brassica pekinesis.

[Changes of serum matrix metalloproteinases-9 and tissue inhibitors of metalloproteinases-9 in coal workers' pneumoconiosis].

OBJECTIVE: To explore the changes and significance of matrix metalloproteinases (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-9 in serum of patients with coal workers' pneumoconiosis (CWP). METHODS: Serum MMP-9 and TIMP-9 were determined by sandwich ELISA in 188 cases of coal workers' pneumoconiosis (including 53 cases of coal pneumoconiosis, 67 cases of coal-silica pneumoconiosis and 68 cases of silicosis), 57 cases of 0+ miner (group 0+), 64 cases of healthy miner (dust exposed control) and 50 healthy people (healthy control) , and were further evaluated according to stage, complication, and the duration of exposure to dust in CWP group. RESULTS: The median of serum MMP-9 in coal pneumoconiosis, coal-silica pneumoconiosis and silicosis were 17.16, 15.14 and 17.50 ng/ml respectively. The levels of serum MMP-9 in silicosis and coal-silica pneumoconiosis were lower than that in dust exposed control and 0+ group (P < 0.05), and there were no differences among 3 groups of CWP. The levels of serum TIMP-9 in coal pneumoconiosis, coal-silica pneumoconiosis and silicosis were (330.00 +/- 108.42), (312.04 +/- 120.09) and (366.81 +/- 135.50) ng/ml respectively, and compared with dust exposed control and 0+ group, it increased in silicosis and coal pneumoconiosis significantly (P < 0.05). The levels of serum TIMP-9 in silicosis were higher significantly than that of coal-silica pneumoconiosis (P < 0.05). No significant difference was observed in the levels of serum MMP-9 and TIMP-9 in CWP according to CWP stage, complications and the duration of exposure to dust (P > 0.05). There was a positive correlation between age and the concentration of TIMP-9 in silicosis (r = 0.249, P < 0.05). A positive correlation was shown between the levels of serum MMP-9 and TIMP-9 only in dust exposed control (r = 0.294, P < 0.05). CONCLUSIONS: The levels of serum MMP-9 and TIMP-9 are associated with the harmful effect to miner resulted from dust. The apparent disturbance of MMP-9 and TIMP-9 might take part in the pathogenesis of CWP. Dynamic observation of its concentration in group 0+ and health miners might contribute to the prevention, early diagnosis and differential diagnosis of CWP.

Counterintuitive solvation effect of ionic-liquid/DMSO solvents on acidic C-H dissociation and insight into respective solvation.

How would acidic bond dissociation be affected by adding a small quantity of a weakly polar ionic liquid IL (the "apparent" or "measured" dielectric constant ε of the IL is around 10-15) into a strongly polar molecular solvent (e.g., ε of DMSO: 46.5), or vice versa? The answer is blurred, because no previous investigation was reported in this regard. Toward this, we, taking various IL/DMSO mixtures as representatives, have thoroughly investigated the effects of the respective solvent in ionic-molecular binary systems on self-dissociation of C-H acid phenylmalononitrile PhCH(CN)2 via pK a determination. As disclosed, in this category of binary media, (1) no linear correspondence exists between pK a and molar fractions of the respective solvent components; (2) only ∼1-2 mol% of weakly polar ILs in strongly polar DMSO make C-H bonds even more dissociative than in neat DMSO; (3) a small fraction of DMSO in ILs (<10 mol%) can dramatically ease acidic C-H-dissociation; and (4) while the DMSO fraction further increases, its acidifying effect becomes much attenuated. These findings, though maybe counterintuitive, have been rationalized on the basis of the precise pK a measurement of this work in relation to the respective roles of each solvent component in solvation.

Interaction of sodium loading and enalapril on renin mRNA and renin release in hydronephrotic mice.

The present study investigated the interaction between sodium loading and enalapril on renin synthesis and secretion in hydronephrotic mice. Four different experimental groups (n=10 each) were used: sham-operated animals with normal diet (control group); sodium loading (SL group); enalapril treatment with normal diet (E group), and sodium loading combined with enalapril treatment (SL+E group). The hydronephrotic left kidney was induced by unilateral ureteral ligation in mice in the latter three groups. Plasma renin concentration (PRC) in the aorta, both the left and right renal veins, tissue renin concentration (TRC) and renin mRNA levels in the kidneys were examined under different procedures. In hydronephrotic mice treated with sodium loading, PRC in the left and right renal veins was lower than that in control mice (P<0.05), and TRC and renin mRNA levels in the hydronephrotic kidney were also suppressed (P<0.05). In hydronephrotic mice treated with enalapril, there were significant increases in PRC, TRC and renin mRNA levels in the hydronephrotic and right kidneys compared to the normal control (P<0.01). In hydronephrotic animals treated with sodium loading and enalapril, the increasing response was attenuated, and PRC in the hydronephrotic vein was similar to the level in the aorta. There was an interaction between sodium loading and enalapril on renin-angiotensin system (RAS) in both hydronephrotic and normal kidneys. The mechanism in control of renin synthesis is independent of the macula densa, but the latter is critical in the control of renin secretion.

Proton-coupled electron transfer oxidation of O-H bond by the N-radical cation of Wurster's blue salt (TMPDA˙+).

Here, we report the proton-coupled electron transfer reaction between TEMPO-H and Wurster's blue salt (TMPDA˙+). TMPDA˙+ could abstract a hydrogen atom from 2,2,6,6-tetramethyl-1-hydroxy-piperidine (TEMPO-H) via concerted electron-proton transfer and displayed a large KIE (7.05 ± 0.07 at 298 K). This work shows that a nitrogen-centered radical cation (R3N˙+) such as TMPDA˙+ is more than a weak single-electron oxidant, and can also be an effective PCET reagent for oxidative bond activation.

Clinical significance of spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia in Epstein-Barr virus-associated and Epstein-Barr virus-negative gastric cancer.

Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians.

[Safe wintering and economic and ecological benefit of winter rapeseed in dry and cold areas of northern China].

The purpose of this study was to realize the security of safe wintering of winter rapeseed in dry and cold regions of northern China. Experiments were conducted with 18 winter rapeseed (Brassica campestris) varieties at 57 sites from 2008 to 2013 to statistically analyze the wintering rate variation of different varieties in dry and cold regions of northern China. The results showed that, the wintering rate varied from 70% to 90% during the study period in different regions, which had no significant difference between different years and varieties, and had high stability and remarkable economic benefit. With Tianshui as a starting point of winter rapeseed planting, the wintering-safe regions included all Gansu Province , the south of Lasa and Linzhi of Xizang, the east of Minhe of Qinghai, up to Urumqi and Baicheng, and the south of Aletai, Tacheng, the east of Kashi of Xinjiang, it also included the regions along Yellow River eastward to Ningxia, the south of Linhe of Inner Mongolia, the north of Shaanxi, the vicinage of Qixian in Shanxi, Daming in Hebei, Tianjin, Beijing, the north of Weifang of Shandong, the south of Huludao of Liaoning and Yanbian of Jilin. Longyou 6, Longyou 7, Longyou 8 and Longyou 9 were the wintering-safe B. rapa varieties.

A systematic review of gemcitabine and taxanes combination therapy randomized trials for metastatic breast cancer.

PURPOSE: Gemcitabine/taxanes-based combination shows anti-tumor activity for the treatment of metastatic breast cancer, but there is a debate regarding the advantages of gemcitabine and taxanes regimens as a first-line or second-line treatment for metastatic breast cancer. Here we conducted a systematic review and meta-analysis to compare the efficacy and toxicity for patients receiving chemotherapy with or without GT-based regimens. METHODS: The randomized controlled trials were performed by searching Pubmed, MEDLINE, EMBASE, and conference proceedings. We identified eight randomized controlled trials and then extracted and combined the data using to calculate hazard ratios (HR). The primary outcomes were progression-free survival (PFS) and time to progression (TTP). The secondary outcomes were overall survival (OS) and acute toxicity. A meta-analysis was performed using Review Manager Version 4.2. RESULTS: Eight eligible trails were identified. These studies involved 2234 patients with metastatic breast cancer, (1122 patients received GT-based combination regimen and 1112 patients received a regimen without the combination). A fixed-effects model meta-analysis showed that ORR and TTP are superior for GT-treated patients ORR (OR = 1.28, 95% CI 1.07-1.53), TTP (HR = 0.80; 95% CI 0.71-0.89). And GT-based combination significantly improved OS in the first-line subgroup (HR = 0.84; 95% CI 0.71-0.99). However, there were significant differences regarding acute hematological toxicity, particularly thrombocytopenia. CONCLUSION: Gemcitabine/taxanes-treated patients with metastatic breast cancer showed a significant improvement in the ORR, TTP and OS (first-line background) compared to patients not treated with the combination regimen.

[Chemical constituents of the non-alkaloid fraction of Uncaria macrophylla].

OBJECTIVE: To analyze the chemical constituents of the non-alkaloid fraction of Uncaria macrophylla. METHODS: The constituents were separated and purified by silica gel chromatography and recrystalization, and their structures were identified by infrared, mass and nuclear magnetic resonance spectrometry. RESULTS: Six compounds were isolated from the non-alkaloid fraction of Uncaria macrophylla, whose structures were identified as beta-sitosterol, beta-daucosterol, ursolic acid, alpha-amyrin acetate, 3beta, 6beta, 23-trihydroxyurs-12-en-28-oic acid, 3beta-hydroxyurs-12-en-27, and 3beta-hydroxyurs-12-en-27, 28-dioic acid, respectively. CONCLUSIONS: Ursolic acid is the main component in the non-alkaloid fraction of Uncaria macrophylla. Alpha-amyrin acetate and 3beta-hydroxyurs-12-en-27, 28-dioic acid are isolated and characterized for the first time from this plant.