Phosphine-Catalyzed Ring-Opening Regioselective Addition of Cyclopropenones with Amides.

A series of amides, including α-bromo hydroxamates, N-alkoxyamides, and N-aryloxyamides, were subjected to phosphine-catalyzed ring-opening O-selective addition with cyclopropenones, producing various special α,ß-unsaturated esters containing oxime ether motif, in moderate to excellent yields, with high regioselectivity, and exclusive O-selectivity. The methodology is highly atom-economical, with simple operation procedures, and compatible with a wide substrate scope (more than 44 examples).

Total Synthesis of Brevitaxin.

Brevitaxin was prepared in nine steps from commercially available carnosic acid. The construction of the 1,4-benzodioxin moiety involved an unique stepwise ortho-quinone-engaged [4+2] cycloaddition. Two strategic stages were employed to prepare the highly unsaturated cycloaddition precursor 3: (1) synthesizing the diene moiety (C1-C2 and C10-C20 double bonds) by regioselective ortho-quinone tautomerization, and (2) installing four sp2-hybridized carbon atoms (C3, C5, C6 and C7) in one step using a SeO2-promoted chemo- and regioselective oxidation reaction.

Phosphine-catalyzed dearomative [3+2] cycloaddition of 4-nitroisoxazoles with allenoates or Morita-Baylis-Hillman carbonates.

An efficient phosphine-catalyzed dearomative [3+2] annulation of 4-nitroisoxazoles with allenoates or Morita-Baylis-Hillman carbonates has been established for the convenient synthesis of bicyclic isoxazoline derivatives. This reaction approach showed a broad substrate scope, high functional group compatibility, and excellent regioselectivity and diastereoselectivity. Furthermore, the success at the gram-scale and synthetic applications of the obtained compound 3a demonstrate the great potential of this methodology for practical applications in organic synthesis.

Functional metalloenzymes based on myoglobin and neuroglobin that exploit covalent interactions.

Globins, such as myoglobin (Mb) and neuroglobin (Ngb), are ideal protein scaffolds for the design of functional metalloenzymes. To date, numerous approaches have been developed for enzyme design. This review presents a summary of the progress made in the design of functional metalloenzymes based on Mb and Ngb, with a focus on the exploitation of covalent interactions, including coordination bonds and covalent modifications. These include the construction of a metal-binding site, the incorporation of a non-native metal cofactor, the formation of Cys/Tyr-heme covalent links, and the design of disulfide bonds, as well as other Cys-covalent modifications. As exemplified by recent studies from our group and others, the designed metalloenzymes have potential applications in biocatalysis and bioconversions. Furthermore, we discuss the current trends in the design of functional metalloenzymes and highlight the importance of covalent interactions in the design of functional metalloenzymes.

Unexpected mutations occurred in CRISPR/Cas9 edited Drosophila analyzed by deeply whole genomic sequencing.

CRISPR/Cas9 possesses the most promising prospects as a gene-editing tool in post-genomic researches. It becomes an epoch-marking technique for the features of speed and convenience of genomic modification. However, it is still unclear whether CRISPR/Cas9 gene editing can cause irreversible damage to the genome. In this study, we successfully knocked out the WHITE gene in Drosophila, which governs eye color, utilizing CRISPR/Cas9 technology. Subsequently, we conducted high-throughput sequencing to assess the impact of this editing process on the stability of the entire genomic profile. The results revealed the presence of numerous unexpected mutations in the Drosophila genome, including 630 SNVs (Single Nucleotide Variants), 525 Indels (Insertion and Deletion) and 425 MSIs (microsatellite instability). Although the KO (knockout) specifically occurred on chromosome X, the majority of mutations were observed on chromosome 3, indicating that this effect is genome-wide and associated with the spatial structure between chromosomes, rather than being solely limited to the location of the KO gene. It is worth noting that most of the mutations occurred in the intergenic and intron regions, without exerting any significant on the function or healthy of the animal. In addition, the mutations downstream of the knockout gene well beyond the upstream. This study has found that gene editing can lead to unexpected mutations in the genome, but most of these mutations are harmless. This research has deepened our understanding of CRISPR/Cas9 and broadened its application prospects.

Ultrafast underwater self-healing piezo-ionic elastomer via dynamic hydrophobic-hydrolytic domains.

The development of advanced materials capable of autonomous self-healing and mechanical stimulus sensing in aquatic environments holds great promise for applications in underwater soft electronics, underwater robotics, and water-resistant human-machine interfaces. However, achieving superior autonomous self-healing properties and effective sensing simultaneously in an aquatic environment is rarely feasible. Here, we present an ultrafast underwater molecularly engineered self-healing piezo-ionic elastomer inspired by the cephalopod's suckers, which possess self-healing properties and mechanosensitive ion channels. Through strategic engineering of hydrophobic C-F groups, hydrolytic boronate ester bonds, and ions, the material achieves outstanding self-healing efficiencies, with speeds of 94.5% (9.1 µm/min) in air and 89.6% (13.3 µm/min) underwater, coupled with remarkable pressure sensitivity (18.1 kPa-1) for sensing performance. Furthermore, integration of this mechanosensitive device into an underwater submarine for signal transmission and light emitting diode modulation demonstrates its potential for underwater robotics and smarter human-machine interactions.

A Probiotic Targets Bile Acids Metabolism to Alleviate Ulcerative Colitis by Reducing Conjugated Bile Acids.

SCOPE: Gut microbiota (GM) dysbiosis and dysregulated bile acids (BAs) metabolism have been linked to ulcerative colitis (UC) pathogenesis. The possibility of utilizing live probiotics with a defined BAs-metabolizing capability to modify the composition BAs for UC treatment remains unexplored. METHODS AND RESULTS: In this study, Strain GR-4 is sourced from traditional Chinese fermented food, "Jiangshui," and demonstrated the ability to deconjugate two common conjugated BAs by over 69% and 98.47%, respectively. It administers strain GR-4 to dextran sulfate sodium (DSS)-induced UC mice, and observes an overall alleviation of UC symptoms, as evidence by improved colon morphology, reduces inflammation and oxidative stress, and restores intestinal barrier function. Importantly, these effects are reliant on an intact commensal microbiota, as depletion of GM mitigated GR-4s efficacy. Metabolomics analysis unveils a decline in conjugated BAs and an increase in secondary BAs following GR-4 administration. GM analysis indicates that GR-4 selectively enriches bacterial taxa linked to BAs metabolism, enhancing GM's capacity to modify BAs. CONCLUSION: This research demonstrates the potential for natural fermented foods and probiotics to effectively manipulate BAs composition, including conjugated and secondary BAs, to alleviate UC symptoms, underscoring the benefits of these approaches for gut health.

Exogenous titanium dioxide nanoparticles alleviate cadmium toxicity by enhancing the antioxidative capacity of Tetrastigma hemsleyanum.

Nanotechnology is one of the most recent approaches employed to defend plants against both biotic and abiotic stress including heavy metals such as Cadmium (Cd). In this study, we evaluated the effects of titanium dioxide (TiO2) nanoparticles (TiO2 NPs) in alleviating Cd stress in Tetrastigma hemsleyanum Diels et Gilg. Compared with Cd treatment, TiO2 NPs decreased leaf Cd concentration, restored Cd exposure-related reduction in the biomass to about 69% of control and decreased activities of antioxidative enzymes. Integrative analysis of transcriptome and metabolome revealed 325 differentially expressed genes associated with TiO2 NP treatment, most of which were enriched in biosynthesis of secondary metabolites. Among them, the flavonoid and phenylpropanoid biosynthetic pathways were significantly regulated to improve the growth of T. hemsleyanum when treated with Cd. In the KEGG Markup Language (KGML) network analysis, we found some commonly regulated pathways between Cd and Cd+TiO2 NP treatment, including phenylpropanoid biosynthesis, ABC transporters, and isoflavonoid biosynthesis, indicating their potential core network positions in controlling T. hemsleyanum response to Cd stress. Overall, our findings revealed a complex response system for tolerating Cd, encompassing the transportation, reactive oxygen species scavenging, regulation of gene expression, and metabolite accumulation in T. hemsleyanum. Our results indicate that TiO2 NP can be used to reduce Cd toxicity in T. hemsleyanum.

In situ electrochemical potential-induced synthesis of metal organic framework membrane on polymer support for H2/CO2 separation.

Metal-Organic Framework (MOF) membranes act as selective layers have offered unprecedented opportunities for energy-efficient and cost-effective gas separation. Searching for the green and sustainable synthesis method of dense MOF membrane has received huge attention in both academia and industry. In this work, we demonstrate an in situ electrochemical potential-induced synthesis strategy to aqueously fabricate Metal Azolate Framework-4 (MAF-4) membranes on polypropylene (PP) support. The constant potential can induce the heterogeneous nucleation and growth of MAF-4, resulting an ultrathin membrane with the thickness of only 390 nm. This high-quality membrane exhibits a high H2/CO2 separation performance with the H2 permeance as high as 1565.75 GPU and selectivity of 11.6. The deployment of this environment friendly one-step fabrication method under mild reaction conditions, such as low-cost polymer substrate, water instead of organic solvent, room temperature and ambient pressure shows great promise for the scale-up of MOF membranes.

A comprehensive review of deep learning-based variant calling methods.

Genome sequencing data have become increasingly important in the field of personalized medicine and diagnosis. However, accurately detecting genomic variations remains a challenging task. Traditional variation detection methods rely on manual inspection or predefined rules, which can be time-consuming and prone to errors. Consequently, deep learning-based approaches for variation detection have gained attention due to their ability to automatically learn genomic features that distinguish between variants. In our review, we discuss the recent advancements in deep learning-based algorithms for detecting small variations and structural variations in genomic data, as well as their advantages and limitations.

Design, synthesis and evaluation of C-5 substituted pyrrolopyridine derivatives as potent Janus Kinase 1 inhibitors with excellent selectivity.

The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 âˆ¼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases.

Prognostic value of red blood cell distribution width combined with chloride in predicting short- and long-term mortality in critically ill patients with congestive heart failure: Findings from the MIMIC-IV database.

Background: Hypochloremia and red blood cell distribution width (RDW) play important roles in congestive heart failure (CHF) pathophysiology, and they were associated with the prognosis of CHF. However, the prognostic value of chloride combined with RDW in patients with CHF remains unknown. Methods: We retrospectively analyzed critically ill patients with CHF. The database was derived from the Medical Information Mart for Intensive Care IV v2.0 (MIMIC-IV-v2.0) database. Results: In the final analysis, 5376 critically ill patients with CHF were included, and 2428 patients (45.2 %) experienced 5-year mortality. The restricted cubic spline model revealed a positive correlation between RDW and 5-year mortality, whereas chloride showed a U-shaped correlation with 5-year mortality. The median values of RDW and chloride were used to classify patients into four groups: high chloride/low RDW, low chloride/low RDW, high chloride/high RDW, and low chloride/high RDW. We observed the prognostic value of RDW combined with chloride in the Cox proportional hazard model, in predicting 5-year mortality, in-hospital mortality and 1-year mortality. Furthermore, we discovered that patients with chronic kidney disease (CKD) had a higher 5-year mortality risk than patients without CKD. Conclusion: We found the translational potential role of chloride combined with RDW in prioritizing patients at high risk for short- and long-term mortality in a cohort of critically ill patients with CHF. Prospective multicenter investigations are warranted to validate our results.

Regulating the Heme Active Site by Covalent Modifications: Two Case Studies of Myoglobin.

Using myoglobin (Mb) as a model protein, we herein developed a facial approach to modifying the heme active site. A cavity was first generated in the heme distal site by F46 C mutation, and the thiol group of Cys46 was then used for covalently linked to exogenous ligands, 1H-1,2,4-triazole-3-thiol and 1-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione. The engineered proteins, termed F46C-triazole Mb and F46C-phenol Mb, respectively, were characterized by X-ray crystallography, spectroscopic and stopped-flow kinetic studies. The results showed that both the heme coordination state and the protein function such as H2 O2 activation and peroxidase activity could be efficiently regulated, which suggests that this approach might be generally applied to the design of functional heme proteins.

Advance in the pharmacological and comorbidities management of heart failure with preserved ejection fraction: evidence from clinical trials.

The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF.

Peroxidase activity of a Cu-Fe bimetallic hydrogel and applications for colorimetric detection of ascorbic acid.

A Cu-Fe bimetallic hydrogel (2-QF-CuFe-G) was constructed through a simple method. The 2-QF-CuFe-G metallohydrogel possesses excellent peroxidase-like activity to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2. The catalytic mechanism was confirmed by the addition of •OH radical scavenger isopropyl alcohol (IPA), tert-butyl alcohol (TBA) and ˙OH trapping agent terephthalic acid (TA). Remarkably, the resultant blue ox-TMB system can be used to selectively and sensitively detect ascorbic acid (AA) with an LOD of 0.93 µM in the range of 4-36 µM through the colorimetric method. Moreover, the assay based on the 2-QF-CuFe-G metallohydrogel can be successfully applied to detect AA in fresh fruits.

Based on the interaction between supramolecules of traditional Chinese medicine and enterobacteria to explore the material basis of combination of Rhei Radix et Rhizoma - Coptidis Rhizoma / 药学学报

Based on the interaction between supramolecule of traditional Chinese medicine and enterobacteria, the material basis of Rhei Radix et Rhizoma and Coptidis Rhizoma was explored. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) were used to characterize the morphological differences of Rhubarb single decoction, Coptis single decoction and Rhubarb and Coptis co-decoction. An in vitro antibacterial model (E. coli, E. faecium and B. subtilis) was established to evaluate the damage effect of the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma on enterobacteria. Ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the changes of chemical components of single decoctions and co-decoctions. The co-decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma was turbid after decocting. The spherical particles of 300-400 nm were observed under SEM, and the co-decoction was more uniform and stable than that of single decoction. The interaction between supramolecules formed after the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma and enterobacteria was significantly different from that of single decoction. In the process of interaction between supramolecules and enterobacteria, the spherical state was maintained, and the medicinal ingredients in Coptidis Rhizoma or Rhei Radix et Rhizoma were blocked, which could effectively alleviate the damage to enterobacteria. This study provided a reference for subsequent studies on the regulation of intestinal flora homeostasis by the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma.

Clinical characteristics and prognosis of 28 cases of infant acute lymphoblastic leukemia / 中华儿科杂志

Objective: To analyze the clinical characteristics and prognosis of patients with infant acute lymphoblastic leukemia (IALL). Methods: A retrospective cohort study.Clinical data, treatment and prognosis of 28 cases of IALL who have been treated at Beijing Children's Hospital, Capital Medical University and Baoding Children's Hospital from October 2013 to May 2023 were analyzed retrospectively. Based on the results of fluorescence in situ hybridization (FISH), all patients were divided into KMT2A gene rearrangement (KMT2A-R) positive group and KMT2A-R negative group. The prognosis of two groups were compared. Kaplan-Meier method and Log-Rank test were used to analyze the survival of the patients. Results: Among 28 cases of IALL, there were 10 males and 18 females, with the onset age of 10.9 (9.4,11.8) months. In terms of immune classification, 25 cases were B-ALL (89%), while the remaining 3 cases were T-ALL (11%). Most infant B-ALL showed pro-B lymphocyte phenotype (16/25,64%). A total of 22 cases (79%) obtained chromosome karyotype results, of which 7 were normal karyotypes, no complex karyotypes and 15 were abnormal karyotypes were found. Among abnormal karyotypes, there were 4 cases of t (9; 11), 2 cases of t (4; 11), 2 cases of t (11; 19), 1 case of t (1; 11) and 6 cases of other abnormal karyotypes. A total of 19 cases (68%) were positive for KMT2A-R detected by FISH. The KMT2A fusion gene was detected by real-time PCR in 16 cases (57%). A total of 24 patients completed standardized induction chemotherapy and were able to undergo efficacy evaluation, 23 cases (96%) achieved complete remission through induction chemotherapy, 4 cases (17%) died of relapse. The 5-year event free survival rate (EFS) was (46±13)%, and the 5-year overall survival rate (OS) was (73±10)%.The survival time was 31.3 (3.3, 62.5) months. There was no significant statistical difference in 5-year EFS ((46±14)% vs. (61±18)%) and 5-year OS ((64±13)% vs. (86±13)%) between the KMT2A-R positive group (15 cases) and the KMT2A-R negative group (9 cases) (χ2=1.88, 1.47, P=0.170, 0.224). Conclusions: Most IALL patients were accompanied by KMT2A-R. They had poor tolerance to traditional chemotherapy, the relapse rate during treatment was high and the prognosis was poor.

Application of engineered myoglobins for biosynthesis of clofazimine by integration with chemical synthesis.

Significant efforts have been made in the design of artificial metalloenzymes. Myoglobin (Mb), an O2 carrier, has been engineered to exhibit different functions. Herein, we applied a series of engineered Mb mutants with peroxidase activity for biosynthesis of clofazimine (CFZ), a potential drug with a broad-spectrum antiviral activity, by integration with chemical synthesis. Two of those mutants, F43Y Mb and F43Y/T67R Mb, have been shown to efficiently catalyze the oxidative coupling of 2-N-(4-chlorophenyl) benzene-1,2-diamine (N-4-CPBDA) in the presence of H2O2, with 97% yields. The overall catalytic efficiency (kcat/Km) is 46-fold and 82-fold higher than that of WT Mb, respectively. By further combination of this reaction with chemical synthesis, the production of CFZ was accomplished with an isolated yield of 72%. These results showed that engineered Mbs containing the Tyr-heme cross-link (F43Y Mb and F43Y/T67R Mb) exhibit enhanced activity in the oxidative coupling reaction. This study also indicates that the combination of biocatalysis and chemical synthesis avoids the need for the separation of intermediate products, which offers a convenient approach for the total synthesis of the biological compound CFZ.

Effects of systemic Bifidobacterium longum and Lactobacillus rhamnosus probiotics on the ligature-induced periodontitis in rat.

Background/purpose: Probiotics might be beneficial in preventing periodontitis. Effects of Bifidobacterium and Lactobacillus on periodontitis were examined using the ligature-induced rat model. Materials and methods: Thirty-five male Sprague-Dawley rats were divided into control, ligation, Bifidobacterium longum (BL986), Lactobacillus rhamnosus (LRH09), and combination groups. Periodontitis was induced in maxillary second molars. From the day before ligation, phosphate-buffered saline (for control and ligation groups) or probiotics (2 × 109 CFU/g for probiotic groups) were fed daily. On day 8, gingival mRNA expressions for interleukin (IL)-1ß, IL-6, tissue necrosis factor (TNF)-α, IL-10, and NF-κB were determined via qPCR. Micro-computed tomography (µCT) and histomorphometry were employed to examine periodontal destruction. Results: Compared to the ligation group, mRNA of IL-1ß, TNF-α, IL-6, and NF-κB in probiotic groups were significantly decreased, but IL-10 was increased. Besides, the IL-10 was more significant in the combination group than in single-use group. Through µCT, the cementoenamel junction (CEJ)-to-bone distance and trabecular separation in combination group were less than that in ligation group, although the bone volume fraction and trabecular number/thickness showed an increase in three probiotic groups. Histopathologically, the combination group had significantly smaller gingival inflammatory cell-infiltrated area and CEJ-to-epithelium distance than the ligation group and the group with BL986 or LRH09. Additionally, the CEJ-to-bone distance was significantly smaller in the combination group than in the ligation and BL986 groups. Conclusion: Systemic combination of BL986 and LRH09 had a synergistic effect on enhancing IL-10 and ameliorating the induced experimental periodontitis, although the single-use still presented partially alleviative effects.

Synthesis of CF3-Containing 2-Imidazolines and Imidazoles via a Iodide-Promoted [3 + 2] Cyclization Reaction.

We report herein a general and effective system achieving cyclization of ß-trifluoromethyl enones with amidines in the presence of 1,3-diiodo-5,5-dimethylhydantoin (DIH), which affords a range of trifluoromethylated 2-imidazolines in synthetically useful yields with good diastereoselectivities (up to 95% yield, up to 98:2 dr) and good functional group tolerance. Furthermore, the one-pot synthesis of trifluoromethylated imidazoles via sequential cyclization and oxidation is demonstrated. More significantly, the reaction mechanism was verified by ESI-MS studies of possible intermediates, and a reasonable reaction mechanism was proposed.