Asymmetric 1,4-Addition of Diarylphosphine Oxides to α, ß-Unsaturated 2-Acyl Imidazoles.

Here we introduce a metal-free, catalytic and enantioselective strategy from α,ß-unsaturated 2-acyl imidazoles to the chiral phosphorous 2-acyl imidazoles. Interestingly, this methodology was catalyzed by the classical and commercial oxazaborolidine under mild conditions. This strategy features a wide range of substrates scope with good yields and excellent enantioselectivities. The possible mechanism further suggests the key of this reaction through the cleavage of diarylphosphine oxides using Frustrated Lewis Pairs theory.

Metal-Free Enantioselective 1,4-Addition of Diarylphosphine Oxides to α,ß-Unsaturated Carboxylic Esters.

The catalytic asymmetric conjugate addition of phosphorus nucleophiles to unsaturated compounds, catalyzed by metallic or nonmetallic catalysts, has been extensively developed. However, the enantioselective transformations involving α,ß-unsaturated carboxylic esters for constructing chiral c-p bonds have been rarely reported, particularly in metal-free processes. In this study, we present a novel metal-free methodology for enantioselective 1,4-addition of diarylphosphine oxides to α,ß-unsaturated carboxylic esters using classical chiral oxazaborolidine catalysts. Remarkably high yields and enantioselectivities were obtained for most of the products. Furthermore, these valuable chiral phosphorus esters serve as crucial intermediates that can be transformed into various derivatives including amides, acids, and alcohols in a single step.

When transition-metal catalysis meets electrosynthesis: a recent update.

While aiming at sustainable synthesis, organic electrosynthesis has attracted increasing attention in the past few years. In parallel, with a deeper understanding of catalyst and ligand design, 3d transition-metal catalysis allows the conception of more straightforward synthetic routes in a cost-effective fashion. Owing to their intrinsic advantages, the merger of organic electrosynthesis with 3d transition-metal catalysis has offered huge opportunities for conceptually novel transformations while limiting ecological footprint. This review summarizes the key advancements in this direction published in the recent two years, with specific focus placed on strategy design and mechanistic aspects.

Enantioselective Transformations from Nitriles to NH2 -α-Tertiary Amines.

Organic molecules, containing one or more amine chiral centers, are very common to see in natural products and medicines. Although a large number of methods have been developed to afford enantiopure amines, most of the known approaches are limited with various reasons. For example, many methodologies start from nitrogen protected and activated substrates, which usually need multistep operations and seriously decrease the atom economy. Here we disclose a new catalytic strategy from commercial nitriles to high enantioselective α-tertiary primary amines in up to 90 % yield and 95 % enantiomeric excess. This transformation firstly undergoes an addition process of organolithium reagents to nitriles to generate the imine intermediates in situ. Subsequently, the most challenging step is by employing copper catalytic enantioselective addition of AllylBpin to the imine intermediates to form the final amines in one pot.

Mendelian Randomization Analysis Reveals No Causal Relationship Between Nonalcoholic Fatty Liver Disease and Severe COVID-19.

BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has witnessed more than 4.5 million deaths as of the time of writing. Whether nonalcoholic fatty liver disease (NAFLD) increases the risk for severe COVID-19 remains unclear. We sought to address this question using 2-sample Mendelian randomization (TSMR) analysis approaches in large cohorts. METHODS: We performed large-scale TSMR analyses to examine whether there is a causal relationship between NAFLD, serum alanine aminotransferase, grade of steatosis, NAFLD Activity Score, or fibrosis stage and severe COVID-19. To maximize the power of this analysis, we performed a genome-wide meta-analysis to identify single nucleotide polymorphisms associated with NAFLD. We also examined the impact of 20 major comorbid factors of NAFLD on severe COVID-19. RESULTS: Univariate analysis of the UK Biobank data demonstrated a significant association between NAFLD and severe COVID-19 (odds ratio [OR], 3.06; P = 1.07 × 10-6). However, this association disappeared after demographic and comorbid factors were adjusted (OR, 1.57; P = .09). TSMR study indicated that NAFLD (OR, 0.97; P = .61), alanine aminotransferase level (OR, 1.03; P = .47), grade of steatosis (OR, 1.08; P = .41), NAFLD Activity Score (OR, 1.02; P = .39), and fibrosis stage (OR, 1.01; P = .87) were not associated with severe COVID-19. Among all NAFLD-related comorbid factors, body mass index (OR, 1.73; P = 7.65 × 10-9), waist circumference (OR, 1.76; P = 2.58 × 10-5), and hip circumference (OR, 1.33; P = 7.26 × 10-3) were the only ones demonstrated a causal impact on severe COVID-19. CONCLUSIONS: There is no evidence supporting that NAFLD is a causal risk factor for severe COVID-19. Previous observational associations between NAFLD and COVID-19 are likely attributed to the correlation between NAFLD and obesity.

Brønsted Acid-Catalyzed Synthesis of 1,2,5-Trisubstituted Imidazoles via a Multicomponent Reaction of Vinyl Azides with Aromatic Aldehydes and Aromatic Amines.

A facile and efficient approach to the synthesis of 1,2,5-trisubstituted imidazoles is developed via a multicomponent reaction under metal-free catalysis. Under Brønsted acid catalysis, the desired products can be obtained from readily available vinyl azides, aromatic aldehydes, and aromatic amines without generating any toxic waste. The convenient operations and high functional group compatibility indicate that this approach offers an attractive alternative method for the synthesis of imidazole derivatives.

Synergistic denitrification, partial nitrification - Anammox in a novel A2/O2 reactor for efficient nitrogen removal from low C/N wastewater.

A biofilm-based anaerobic-aerobic (A2O2) reactor was constructed to treat manure-free piggery wastewater. The reactor contained four compartments, among which the first two were anaerobic (A phase) and the last two were aerobic (O phase). Throughout around one-year operation, high-level nutrient removal was demonstrated. At an optimal reflux ratio of 100%, the average NH4+-N, TN, and COD removal efficiencies were high as 99.4%, 91.7%, and 79.4%, respectively, with the influent concentration of 220.6, 231.6 and 332 mg/L, respectively. The NH4+-N, TN, and COD concentrations in the final effluent were only 1.4, 18.5 and 65 mg/L, respectively. COD and nitrogen removal were mainly removed in the A phase and O phase, respectively. This result revolutionizes the previous perception that nitrogen is only removed in the A phase of conventional A-O configuration. Achievement of PN/A in the O phase was critical to the efficient nitrogen removal. Heterotrophic denitrification in the anaerobic compartments removed the nitrate produced by anammox, ensuring the high-level nitrogen removal. Anaerobic organic degradation was a major pathway for COD removal, as abundant methanogens detected in the A phase. This study provides a feasible technical scheme for the efficient nutrient removal from ammonium-rich wastewater.

Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides.

An efficient, high-yielding and scalable procedure for the regioselective 3-acylation of indoles with anhydrides promoted by boron trifluoride etherate under mild conditions was reported. This novel protocol provided a simple way to prepare 3-(benzofuran-2-yl) indole in three steps.

Catalyst-free gem-chlorosulfurization of difluoromethyl-substituted diazo compounds with disulfide and PhICl2.

A series of gem-chlorosulfurization products bearing difluoromethyl substituents were synthesized in high to excellent yields directly from p-toluenesulfonyl difluorodiazoethane (TsCF2CHN2), disulfides and PhICl2 without any catalysts or additives. The mild reaction conditions and high functional group compatibility indicated the utility and sustainability of the method. In addition, the gem-chlorosulfurization products could be efficiently converted to sulfur-containing and aryl substituted difluoromethyl derivatives by a feasible multi-component operation.

gem-Difunctionalization of α-diazoarylketones with diaryldiselenides and N-halosuccinimides: facile synthesis of α-halo-α-arylseleno ketones.

An efficient synthesis of α-halo-α-arylseleno ketones has been developed via gem-difunctionalization of α-diazoarylketones with diaryldiselenides and N-halosuccinimides. With this multicomponent approach, a series of α-halo-α-arylseleno ketones were accessed in excellent yields and chemoselectivities under mild conditions. This transformation is proposed to proceed via the key intermediate arylselenenyl halide that generated from diaryldiselenides/N-halosuccinimides, followed by addition with α-diazoarylketones to give the desired gem-difunctionalization products.

Insights into complete nitrate removal in one-stage nitritation-anammox by coupling heterotrophic denitrification.

Nitritation-anammox has been considered to be the most promising process for nitrogen (N) removal from wastewater. However, the anammox reaction still produces an amount of nitrate, which cannot be removed further. This study hypothesizes that heterotrophic denitrification can be an appealing option to remove the residual nitrate in the one-stage nitritation-anammox process. Through monitoring N-removal performance and microbial community succession of a laboratory microaerobic reactor, the effect of four different levels of oxygen supply on nitrate removal was investigated. The reactor was continuously fed with real manure-free piggery wastewater containing ~240 mg NH4+-N/L and chemical oxygen demand (COD)/total nitrogen (TN) ratio of less than 1 for 180 days. With a high influent loading rate of 0.7 kg N/(m3·d), efficient total nitrogen removal (>80 %) was achieved during stable operation of dissolved oxygen (DO) concentrations between 0.3 and 0.6 mg O2/L, indicating N-removal via the nitritation-anammox pathway in the low-carbon wastewater treatment. At the same time, the effluent nitrate reduced with decreased oxygen supply and completely depleted at DO of 0.3 ± 0.1 mg O2/L. In addition to oxygen, preventing ammonia nitrogen from falling to very low levels (<10 mg/L) could be also useful for the complete nitrate removal and stable nitritation-anammox. 16S rRNA gene-based analyses confirmed a complex microbial community including nitrifiers, denitrifiers and anammox bacteria in the biomass of the reactor. Collectively, this study provides new insights into high-level N-removal of a nitritation-anammox process by complete nitrate depletion.

Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1.

Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.

Zinc promotes prostate cancer cell chemosensitivity to paclitaxel by inhibiting epithelial-mesenchymal transition and inducing apoptosis.

BACKGROUND: Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of prostate cancer. However, most patients develop resistance and metastasis, and thus new therapeutic approaches are urgently required. Recent studies have identified widespread anti-tumor effects of zinc (Zn) in various tumor cell lines, especially prostate cancer cells. In this study, we examined the effects of Zn as an adjuvant to PTX in prostate cancer cells. METHODS: PC3 and DU145 cells were treated with different concentrations of Zn and/or PTX. MTT assay was used to detect cell viability. Real-time cell analysis (RTCA) and microscopy were used to observe morphological changes in cells. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. qPCR (reverse transcription-polymerase chain reaction) was used to examine changes in TWIST1 mRNA levels. Cell invasion and migration were detected by scratch and transwell assays. shRNA against TWIST1 was used to knockdown TWIST1. Colony formation assay was used to detect cell proliferation, while Annexin V and propidium iodide (PI) staining was used to detect cell apoptosis. RESULTS: Zn and PTX increased proliferation inhibition in a dose- and time-dependent manner in prostate cancer cells, while Zn increased prostate cancer cell chemosensitivity to PTX. Combined Zn and PTX inhibited prostate cancer cell invasion and migration by downregulating the expression of TWIST1. Furthermore, knockdown of TWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, Zn and PTX reduced cell proliferation and induced apoptosis in prostate cancer cells. CONCLUSIONS: Our results demonstrated that Zn and PTX combined therapy inhibits EMT by reducing the expression of TWIST1, which reduces the invasion and migration of prostate cancer cells. SiTWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, with prolonged treatment, Zn and PTX inhibited proliferation and led to prostate cancer cell apoptosis. Therefore, Zn may be a potential adjuvant of PTX in treating prostate cancer and combined treatment may offer a promising therapeutic strategy for prostate cancer.

Exploring the ancestry differentiation and inference capacity of the 28-plex AISNPs.

Inferring an unknown DNA's ancestry using a set of ancestry-informative single nucleotide polymorphisms (SNPs) in forensic science is useful to provide investigative leads. This is especially true when there is no DNA database match or specified suspect. Thus, a set of SNPs with highly robust and balanced differential power is strongly demanded in forensic science. In addition, it is also necessary to build a genotyping database for estimating the ancestry of an individual or an unknown DNA. For the differentiation of Africans, Europeans, East Asians, Native Americans, and Oceanians, the Global Nano set that includes just 31 SNPs was developed by de la Puente et al. Its ability for differentiation and balance was evaluated using the genotype data of the 1000 Genomes Phase III project and the Stanford University HGDP-CEPH. Just 402 samples were genotyped and analyzed as a reference set based on statistical methods. To validate the differentiating capacity using more samples, we developed a single-tube 28-plex SNP assay in which the SNPs were chosen from the 31 allelic loci of the Global AIMs Nano set. Three tri-allelic SNPs used to differentiate mixed-source DNA contribute little to population differentiation and were excluded here. Then, 998 individuals from 21 populations were typed, and these genotypes were combined with the genotype data obtained from 1000 Genomes Phase III and the Stanford University HGDP-CEPH (3090 total samples,43 populations) to estimate the power of this multiplex assay and build a database for the further inference of an individual or an unknown DNA sample in forensic practice.

Nutrient removal from high ammonium swine wastewater in upflow microaerobic biofilm reactor suffered high hydraulic load.

To understand the ability of an upflow microaerobic biofilm reactor (UMBR) to remove nutrient from manure-free swine wastewater rich in NH4+ with a COD/TN ratio less than 1.00, effect of hydraulic loading rate (HLR) on the microaerobic process was evaluated with a constant reflux ratio of 25 at 25 °C. The results showed that changes in HLR had a remarkable effect on the performance of the UMBR in nutrient removal from the wastewater. With the favorable HLR 3.0 m3/(m3·d) (Hydraulic Retention Time (HRT) 8 h), average removal of COD, NH4+ and TN in the microaerobic process reached 59.3%, 87.7% and 84.7%, respectively, though the COD/TN ratio was as low as 0.84. With an over HLR of 4.0 m3/(m3·d) (HRT decreased to 6 h), bad performance of the UMBR was observed with an average removal of COD, NH4+ and TN as low as 45.0%, 59.0% and 57.5%, respectively. Since the HLR was decreased to 2.4 m3/(m3·d) (HRT 10 h), the microaerobic process regained the efficiency in nutrient removal with a removal of COD, NH4+ and TN averaged 59.0%, 95.3% and 87.8%, respectively. The microaerobic condition allowed anammox bacteria, ammonia-oxidizing bacteria and archaea, nitrite-oxidizing bacteria and denitrifiers to all thrive in the UMBR, resulting in the efficient synchronous removal of organic carbon and nitrogen. As the dominant approach to nitrogen removal, anaerobic ammonium oxidation (anammox) pathway contributing to the TN removal in the microaerobic process exceeded 59.5% at HLR 3.0 m3/(m3·d). The results demonstrated that the UMBR can remove nitrogen and carbon from swine wastewater, with a suitable HLR.

The role of COD/N ratio on the start-up performance and microbial mechanism of an upflow microaerobic reactor treating piggery wastewater.

This study investigated the role of COD/N ratio on the start-up and performance of an upflow microaerobic sludge reactor (UMSR) treating piggery wastewater at 0.5 mgO2/L. At high COD/N ratio (6.24 and 4.52), results showed that the competition for oxygen between ammonia-oxidizing bacteria, nitrite-oxidizing bacteria and heterotrophic bacteria limited the removal of nitrogen. Nitrogen removal efficiency was below 40% in both scenarios. Decreasing the influent COD/N ratio to 0.88 allowed achieving high removal efficiencies for COD (∼75%) and nitrogen (∼85%) due to the lower oxygen consumption for COD mineralization. Molecular biology techniques showed that nitrogen conversion at a COD/N ratio 0.88 was dominated by the anammox pathway and that Candidatus Brocadia sp. was the most important anammox bacteria in the reactor with a relative abundance of 58.5% among the anammox bacteria. Molecular techniques also showed that Nitrosomonas spp. was the major ammonia-oxidiser bacteria (relative abundance of 86.3%) and that denitrification via NO3- and NO2- also contributed to remove nitrogen from the system.

Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N-Substituted Coumarins with Coumarins and Azides.

A series of C3-N-substituted coumarins were synthesized in good yields directly from coumarins and azides in the presence of Pr(OTf)3 without any additives or ligands needed. The selected compounds 3a, 3c-e, 3g, 3i, 3q, 3u, and 3v exhibited good anticancer activities against MGC-803, A549, and NCI-H460 cell lines with IC50 in the range 8.75-38.54 µmol L-1.

Making waves: Knowledge and data fusion in urban water modelling.

Mathematical modeling plays a crucial role in understanding and managing urban water systems (UWS), with mechanistic models often serving as the foundation for their design and operations. Despite the wide adoptions, mechanistic models are challenged by the complexity of dynamic processes and high computational demands. Data-driven models bring opportunities to capture system complexities and reduce computational cost, by leveraging the abundant data made available by recent advance in sensor technologies. However, the interpretability and data availability hinder their wider adoption. This paper advocates for a paradigm shift in the application of data-driven models within the context of UWS. Integrating existing mechanistic knowledge into data-driven modeling offers a unique solution that reduces data requirements and enhances model interpretability. The knowledge-informed approach balances model complexity with dataset size, enabling more efficient and interpretable modeling in UWS. Furthermore, the integration of mechanistic and data-driven models offers a more accurate representation of UWS dynamics, addressing lingering uncertainties and advancing modelling capabilities. This paper presents perspectives and conceptual framework on developing and implementing knowledge-informed data-driven modeling, highlighting their potential to improve UWS management in the digital era.