Systematic studies on the kinetic process of 20(S)-protopanaxadiol in rats and dogs: absorption, distribution, metabolism and excretion.

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)-protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD.

Theoretical insights into the reduction of Azurin metal site with unnatural amino acid substitutions.

Copper-containing proteins play crucial roles in biological systems. Azurin is a copper-containing protein which has a Type 1 copper site that facilitates electron transfer in the cytochrome chain. Previous research has highlighted the significant impact of mutations in the axial Met121 of the copper site on the reduction potential. However, the mechanism of this regulation has not been fully established. In this study, we employed theoretical modeling to investigate the reduction of the Type 1 copper site, focusing on how unnatural amino acid substitutions at Met121 influence its behavior. Our findings demonstrated a strong linear correlation between electrostatic interactions and the reduction potential of the copper site, which indicates that the perturbation of the reduction potential is primarily influenced by electrostatic interactions between the metal ion and the ligating atom. Furthermore, we found that CF/π and CF…H interactions could induce subtle changes in geometry and hence impact the electronic properties of the systems under study. In addition, our calculations suggest the coordination mode and ion-ligand distance could significantly impact the reduction potential of a copper site. Overall, this study offers valuable insights into the structural and electronic properties of the Type 1 copper site, which could potentially guide the design of future artificial catalysts.

Global burden and trends of leukemia attributable to high body mass index risk in adults over the past 30 years.

Background: High BMI (Body Mass Index) is a significant factor impacting health, with a clear link to an increased risk of leukemia. Research on this topic is limited. Understanding the epidemiological trends of leukemia attributable to high BMI risk is crucial for disease prevention and patient support. Methods: We obtained the data from the Global Burden of Disease Study, analyzing the ASR (age-standardized rates), including ASDR (age-standardized death rate) and age-standardized disability-adjusted life years (DALYs) rate, and estimated annual percentage change (EAPC) by gender, age, country, and region from 1990 to 2019. Results: In 2019, deaths and DALYs have significantly increased to 21.73 thousand and 584.09 thousand. The global age-standardized death and DALYs rates have slightly increased over the past 30 years (EAPCs: 0.34 and 0.29). Among four common leukemia subtypes, only CML (Chronic Myeloid Leukemia) exhibited a significant decrease in ASDR and age-standardized DALYs rate, with EAPC of -1.74 and -1.52. AML (Acute Myeloid Leukemia) showed the most pronounced upward trend in ASDR, with an EAPC of 1.34. These trends vary by gender, age, region, and national economic status. Older people have been at a significantly greater risk. Females globally have borne a higher burden. While males have shown an increasing trend. The regions experiencing the greatest growth in ASR were South Asia. The countries with the largest increases were Equatorial Guinea. However, It is worth noting that there may be variations among specific subtypes of leukemia. Regions with high Socio-demographic Index (SDI) have had the highest ASR, while low-middle SDI regions have shown the greatest increase in these rates. All ASRs values have been positively correlated with SDI, but there has been a turning point in medium to high SDI regions. Conclusions: Leukemia attributable to high BMI risk is gradually becoming a heavier burden globally. Different subtypes of leukemia have distinct temporal and regional patterns. This study's findings will provide information for analyzing the worldwide disease burden patterns and serve as a basis for disease prevention, developing suitable strategies for the modifiable risk factor.

Biodegradable Ferroelectric Molecular Plastic Crystal HOCH2(CF2)7CH2OH Structurally Inspired by Polyvinylidene Fluoride.

Ferroelectric materials, traditionally comprising inorganic ceramics and polymers, are commonly used in medical implantable devices. However, their nondegradable nature often necessitates secondary surgeries for removal. In contrast, ferroelectric molecular crystals have the advantages of easy solution processing, lightweight, and good biocompatibility, which are promising candidates for transient (short-term) implantable devices. Despite these benefits, the discovered biodegradable ferroelectric materials remain limited due to the absence of efficient design strategies. Here, inspired by the polar structure of polyvinylidene fluoride (PVDF), a ferroelectric molecular crystal 1H,1H,9H,9H-perfluoro-1,9-nonanediol (PFND), which undergoes a cubic-to-monoclinic ferroelectric plastic phase transition at 339 K, is discovered. This transition is facilitated by a 2D hydrogen bond network formed through O-H···O interactions among the oriented PFND molecules, which is crucial for the manifestation of ferroelectric properties. In this sense, by reducing the number of -CF2- groups from ≈5 000 in PVDF to seven in PFND, it is demonstrated that this ferroelectric compound only needs simple solution processing while maintaining excellent biosafety, biocompatibility, and biodegradability. This work illuminates the path toward the development of new biodegradable ferroelectric molecular crystals, offering promising avenues for biomedical applications.

Reduced human fecundity attributable to ambient fine particles in low- and middle-income countries.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) has been associated with reduced human fecundity. However, the attributable burden has not been estimated for low- and middle-income countries (LMICs), where the exposure-response function between PM2.5 and the infertility rate has been insufficiently studied. OBJECTIVE: This study examined the associations between long-term exposure to PM2.5 and human fecundity indicators, namely the expected time to pregnancy (TTP) and 12-month infertility rate (IR), and then estimated PM2.5-attributable burden of infertility in LMICs. METHODS: We analyzed 164,593 eligible women from 100 Demographic and Health Surveys conducted in 49 LMICs between 1999 and 2021. We assessed PM2.5 exposures during the 12 months before a pregnancy attempt using the global satellite-derived PM2.5 estimates produced by Atmospheric Composition Analysis Group (ACAG). First, we created a series of pseudo-populations with balanced covariates, given different levels of PM2.5 exposure, using a matching approach based on the generalized propensity score. For each pseudo-population, we used 2-stage generalized Gamma models to derive TTP or IR from the probability distribution of the questionnaire-based duration time for the pregnancy attempt before the interview. Second, we used spline regressions to generate nonlinear PM2.5 exposure-response functions for each of the two fecundity indicators. Finally, we applied the exposure-response functions to estimate number of infertile couples attributable to PM2.5 exposure in 118 LMICs. RESULTS: Based on the Gamma models, each 10 µg/m3 increment in PM2.5 exposure was associated with a TTP increase by 1.7 % (95 % confidence interval [CI]: -2.3 %-6.0 %) and an IR increase by 2.3 % (95 %CI: 0.6 %-3.9 %). The nonlinear exposure-response function suggested a robust effect of an increased IR for high-concentration PM2.5 exposure (>75 µg/m3). Based on the PM2.5-IR function, across the 118 LMICs, the number of infertile couples attributable to PM2.5 exposure exceeding 35 µg/m3 (the first-stage interim target recommended by the World Health Organization global air quality guidelines) was 0.66 million (95 %CI: 0.061-1.43), accounting for 2.25 % (95 %CI: 0.20 %-4.84 %) of all couples affected by infertility. Among the 0.66 million, 66.5 % were within the top 10 % high-exposure infertile couples, mainly from South Asia, East Asia, and West Africa. CONCLUSION: PM2.5 contributes significantly to human infertility in places with high levels of air pollution. PM2.5-pollution control is imperative to protect human fecundity in LMICs.

Catalyst-free reaction of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates: synthesis of 1,2-dihydroquinolines and 2,3-dihydropyrroles.

Catalyst-free annulations of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates have been successfully achieved under mild conditions. Specifically, the reaction of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with sulfur ylides furnished various 1,2-dihydroquinolines in generally high yields. Furthermore, [3+2]-annulations of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with α,ß-unsaturated imines afforded a broad scope of polysubstituted 2,3-dihydropyrroles with high efficiency.

RUNX1 regulates MCM2/CDC20 to promote COAD progression modified by deubiquitination of USP31.

Colon adenocarcinoma (COAD) is the second leading cause of cancer death, and there is still a lack of diagnostic biomarkers and therapeutic targets. In this study, bioinformatics analysis of the TCGA database was used to obtain RUNX1, a gene with prognostic value in COAD. RUNX1 plays an important role in many malignancies, and its molecular regulatory mechanisms in COAD remain to be fully understood. To explore the physiological role of RUNX1, we performed functional analyses, such as CCK-8, colony formation and migration assays. In addition, we investigated the underlying mechanisms using transcriptome sequencing and chromatin immunoprecipitation assays. RUNX1 is highly expressed in COAD patients and significantly correlates with survival. Silencing of RUNX1 significantly slowed down the proliferation and migratory capacity of COAD cells. Furthermore, we demonstrate that CDC20 and MCM2 may be target genes of RUNX1, and that RUNX1 may be physically linked to the deubiquitinating enzyme USP31, which mediates the upregulation of RUNX1 protein to promote transcriptional function. Our results may provide new insights into the mechanism of action of RUNX1 in COAD and reveal potential therapeutic targets for this disease.

Influence of Temperatures on Physicochemical Properties and Structural Features of Tamarind Seed Polysaccharide.

Due to the high content of impurities such as proteins in tamarind seed polysaccharide (TSP), they must be separated and purified before it can be used. TSP can disperse in cold water, but a solution can only be obtained by heating the mixture. Therefore, it is important to understand the dispersion and dissolution process of TSP at different temperatures to expand the application of TSP. In this study, pasting behavior and rheological properties as a function of temperature were characterized in comparison with potato starch (PS), and their relationship with TSP molecular features and microstructure was revealed. Pasting behavior showed that TSP had higher peak viscosity and stronger thermal stability than PS. Rheological properties exhibited that G' and G'' of TSP gradually increased with the increase in temperature, without exhibiting typical starch gelatinization behavior. The crystalline or amorphous structure of TSP and starch was disrupted under different temperature treatment conditions. The SEM results show that TSP particles directly transformed into fragments with the temperature increase, while PS granules first expanded and then broken down into fragments. Therefore, TSP and PS underwent different dispersion mechanisms during the dissolution process: As the temperature gradually increased, TSP possibly underwent a straightforward dispersion and was then dissolved in aqueous solution, while PS granules initially expanded, followed by disintegration and dispersion.

Regio- and Diaseteroselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

An efficient labeled memory system for learned indexes.

The appearance and wide use of memory hardware bring significant changes to the conventional vertical memory hierarchy that fails to handle contentions for shared hardware resources and expensive data movements. To deal with these problems, existing schemes have to rely on inefficient scheduling strategies that also cause extra temporal, spatial and bandwidth overheads. Based on the insights that the shared hardware resources trend to be uniformly and hierarchically offered to the requests for co-located applications in memory systems, we present an efficient abstraction of memory hierarchies, called Label, which is used to establish the connection between the application layer and underlying hardware layer. Based on labels, our paper proposes LaMem, a labeled, resource-isolated and cross-tiered memory system by leveraging the way-based partitioning technique for shared resources to guarantee QoS demands of applications, while supporting fast and low-overhead cache repartitioning technique. Besides, we customize LaMem for the learned index that fundamentally replaces storage structures with computation models as a case study to verify the applicability of LaMem. Experimental results demonstrate the efficiency and efficacy of LaMem.

Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy. / å”¾æ¶²é ¸ç³–åŸºè½¬ç§»é ¶ST3GAL6的沉默可通过减少α2,3-å”¾æ¶²é ¸åŒ–èšç³–é™ä½ŽHSPB8-BAG3è¡¨è¾¾ä»Žè€Œè°ƒæŽ§è‚æ€§è„‘ç— å°é¼ å¤§è„‘ä¸­çš„è‡ªå™¬.

End-stage liver diseases, such as cirrhosis and liver cancer caused by hepatitis B, are often combined with hepatic encephalopathy (HE); ammonia poisoning is posited as one of its main pathogenesis mechanisms. Ammonia is closely related to autophagy, but the molecular mechanism of ammonia's regulatory effect on autophagy in HE remains unclear. Sialylation is an essential form of glycosylation. In the nervous system, abnormal sialylation affects various physiological processes, such as neural development and synapse formation. ST3 ß|-galactoside α2,|3-sialyltransferase 6 (ST3GAL6) is one of the significant glycosyltransferases responsible for adding α2,3-linked sialic acid to substrates and generating glycan structures. We found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction, and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3 (LC3) and Beclin-1 were upregulated in ammonia-induced astrocytes. These findings suggest that ST3GAL6 is related to autophagy in HE. Therefore, we aimed to determine the regulatory relationship between ST3GAL6 and autophagy. We found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-II (MAL-II) and neuraminidase can inhibit autophagy. In addition, silencing the expression of ST3GAL6 can downregulate the expression of heat shock protein ß8 (HSPB8) and Bcl2-associated athanogene 3 (BAG3). Notably, the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 expression. Our results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.

Study on the influence of water saturation on radon exhalation rates of rocks.

The radon exhalation characteristics of rocks will change significantly during water saturation treatment, and radon, as an important tracer, is of great significance in predicting rock activities. In this paper, the radon exhalation characteristics of rocks after saturated with different water contents were studied by centrifugal test, radon measurement test and other indoor tests. The results show that the radon exhalation rate of rocks shows a rising and then decreasing trend with the increase of rock water saturation. The radon precipitation rate peaked at 0.7 Sw âˆ¼ 0.8 Sw, and the high water saturation had an obvious inhibiting effect on the radon exhalation rate of rocks. The research results are of great significance in predicting the rock-water-based geological processes.

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.

Three polysaccharides (SnNG, SnFS and SnFG) were purified from the body wall of Stichopus naso. The physicochemical properties, including monosaccharide composition, molecular weight, sulfate content, and optical rotation, were analyzed, confirming that SnFS and SnFG are sulfated polysaccharides commonly found in sea cucumbers. The highly regular structure {3)-L-Fuc2S-(α1,}n of SnFS was determined via a detailed NMR analysis of its oxidative degradation product. By employing ß-elimination depolymerization of SnFG, tri-, penta-, octa-, hendeca-, tetradeca-, and heptadeca-saccharides were obtained from the low-molecular-weight product. Their well-defined structures confirmed that SnFG possessed the backbone of {D-GalNAc4S6S-ß(1,4)-D-GlcA}, and each GlcA residue was branched with Fuc2S4S. SnFS and SnFG are both structurally the simplest version of natural fucan sulfate and fucosylated glycosaminoglycan, facilitating the application of low-value sea cucumbers S. naso. Bioactivity assays showed that SnFG and its derived oligosaccharides exhibited potent anticoagulation and intrinsic factor Xase (iXase) inhibition. Moreover, a comparative analysis with the series of oligosaccharides solely branched with Fuc3S4S showed that in oligosaccharides with lower degrees of polymerization, such as octasaccharides, Fuc2S4S led to a greater increase in APTT prolongation and iXase inhibition. As the degree of polymerization increases, the influence from the sulfation pattern diminishes, until it is overshadowed by the effects of molecular weight.

Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement Enabled by Pyridine-Assisted Boronyl Radical Catalysis.

An unprecedented VCP-CP (vinylcyclopropane-cyclopentene) rearrangement approach has been established herein by virtue of the pyridine-boronyl radical catalyzed intramolecular ring expansions. This metal-free radical pathway harnesses readily available catalysts and unactivated vinylcyclopropane starting materials, providing an array of cyclopentene derivatives chemoselectively under relatively mild conditions. Mechanistic studies support the idea that the boronyl radical engages in the generation of allylic/ketyl radical species, thus inducing the ring opening of cyclopropanes and the following intramolecular cyclization processes.

Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review.

Rhodococcus equi, predominantly recognized as an opportunistic pathogen affecting immunocompromised hosts, and Brucella, a widespread zoonotic bacterium, infrequently co-infect immunocompetent adults, thereby posing a distinctive diagnostic challenge. Here, we describe a case involving a 53-year-old male with a history of goat farming, who presented with persistent chest tightness, cough, and notable weight loss, absent fever. Radiological and bronchoscopic assessments showed a right hilar mass, extensive vertebral destruction, and bronchial lesions, deviating from the typical symptoms associated with either pathogen. Laboratory analyses confirmed a co-infection involving R. equi and Brucella. Initial therapy with levofloxacin and vancomycin proved ineffective; however, a subsequent treatment regimen comprising azithromycin, etimicin, minocycline, and moxifloxacin resulted in substantial clinical improvement. This case accentuates the intricacies involved in diagnosing and managing atypical co-infections in immunocompetent individuals and underscores the importance of careful microbiological testing to inform effective therapeutic strategies.

A mild and efficient closed-loop recycling strategy for spent lithium-ion battery.

As lithium metal resource supply and demand stabilize and prices decrease, the efficient recovery of valuable metals other than lithium from spent lithium-ion batteries is receiving increasing attention. Currently, challenges remain in the selective lithium recovery efficiency and the high cost of regenerating valuable metal slag after lithium extraction, particularly for spent ternary cathode materials. To address these challenges, this study introduces a closed-loop recovery process for spent ternary cathode materials, employing sulfur-assisted roasting to achieve efficient lithium extraction and high-value direct regeneration of ternary leaching residues. At moderate temperatures (500 â„ƒ), LiNixCoyMn1-x-yO2 (NCM) materials undergo a directional transformation of lithium to Li2SO4 in synergy with sulfur and oxygen, achieving a lithium leaching extraction rate of 98.91 %. Additionally, the relatively mild reaction conditions preserve the secondary spherical morphology and uniform distribution of NiCoMn-based oxide residue without introducing adverse impurities, ensuring the successful regeneration of high-value NCM cathode materials (R-NCM). The R-NCM material exhibits good discharge capacity (144.3 mA·h/g at 1 C) and relatively stable cycling performance, with a capacity retention rate of 80 % after 150 cycles. This work provides a viable pathway for the efficient and environmental-friendly pyrometallurgical closed-loop recovery of spent lithium-ion batteries.

Suboptimal diet quality is associated with the incidence of type 2 diabetes mellitus in middle-aged and older populations in China: evidence from a population-based cross-sectional study.

The association between dietary quality and type 2 diabetes mellitus (T2DM) based on the Chinese Dietary Balance Index (DBI-16) is seldom reported. We hypothesized that poor dietary quality might increase the risk of T2DM in the middle-aged and older populations. A total of 1816 individuals (≥50 years) were included in the study. Demographic characteristics and dietary intake data were collected. Logistic regression and restricted cubic spline (RCS) analyses were conducted to explore the association between DBI-16 indexes and the risk of T2DM. The insufficient intake of vegetables and dairy might decrease the risk of T2DM (ORVegetable = 0.77, 95% CI = 0.60-0.97; ORDairy = 0.58, 95% CI = 0.35-0.96), but the individuals with insufficient intake of fruit were more likely to have a higher risk of T2DM (ORfruit = 2.26, 95% CI = 1.69-3.06). Compared with the subjects with the lowest quartile of Low Bound Score (LBS) or Diet Quality Distance (DQD), the individuals with Q2 and Q3 level of LBS (ORQ2 = 1.40, 95% CI = 1.03-1.90, P = .033; ORQ3 = 1.52, 95% CI = 1.11-2.08, P < .01) or DQD (ORQ2 = 1.45, 95% CI = 1.06-1.99, P = .021; ORQ3 = 1.64, 95% CI = 1.20-2.24, P < .01) showed increased risk of T2DM with a nonlinear association observed by RCS analysis. We concluded that imbalanced dietary intake, especially insufficient daily fruit intake, might predict an increased risk of T2DM in the middle-aged and elderly Chinese.

Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target.

Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.

Lewis Acid-Catalyzed Formal [2π+2σ] Cycloaddition of Bicyclobutanes with Quinoxalin-2(1H)-ones: Access to Quinoxaline-Fused Aza-Bicyclo[2.1.1]hexanes.

An efficient synthesis of quinoxaline-fused aza-bicyclo[2.1.1]hexanes bearing multiple quaternary carbon centers via the intermolecular [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes and quinoxalin-2(1H)-ones, facilitated by Lewis acid catalysis, is presented. This reaction is carried out under mild conditions and exhibits a broad substrate scope and excellent functional group tolerance.