Acid-Promoted Multicomponent Reaction To Synthesize 4-Phosphorylated 4H-Chromenes.

An effective multicomponent reaction for the synthesis of 4-phosphorylated 4H-chromenes via a tandem phosphorylation/alkylation/cyclization/dehydration sequence with water as the only byproduct was developed. Extensive mechanistic investigations involving in situ NMR experiments, time control experiments, and in situ HRMS experiment allowed us to elucidate the order of each subreaction to arrive at a complete understanding of the underlying mechanism of this multicomponent reaction. Mechanistic data confirm that the reaction begins with a phospha-aldol-elimination, followed by addition of a ketone enolate, intermolecular alkylation, intramolecular cyclization, and dehydration under acidic conditions.

Lewis-acid-catalyzed phosphorylation of alcohols.

An efficient method has been developed for reacting dialkyl H-phosphonates or diarylphosphine oxides with alcohols for constructing C-P bonds. This reaction was catalyzed by Lewis acid and involved nucleophilic substitution. A series of diphenylphosphonates and diphenylphosphine oxides were obtained, from the phosphorylation of alcohols, with good-to-excellent yields.

Three-Component Direct Phosphorylation of Aldehydes and Alkylation of Ketones: Synthesis of γ-Ketophosphine Oxides under Acidic Conditions.

An effective and economical acid-promoted three-component reaction for the construction of C-P and C-C bonds for the synthesis of γ-ketophosphine oxides with water as the only byproduct was developed. Detailed mechanistic experiments confirmed that the reaction proceeds by phospha-aldol elimination, in which a benzylic carbocation is generated from the phosphorylation of aldehydes, which then reacts with ketone enolates under acidic conditions.

Diamond nitrogen-vacancy color-centered thermometer for integrated circuit application.

With the advancement of the chip industry, accurate temperature measurement and thermal management have become crucial. Traditional infrared temperature imaging has limitations in terms of resolution and accuracy. ln recent years, quantum diamond nitrogen-vacancy centers have emerged as a promising option for temperature sensing, but separating temperature from magnetic field effects remains a challenge. This paper presents a numerical approach to decouple temperature and magnetic fields using an ensemble Hamiltonian in high-current density Integrated Circuit (IC) applications. The proposed method demonstrates a temperature sensitivity of 22.9 mK/Hz1/2 and the ability to perform scanning temperature imaging with a spatial resolution of 20 µm on a typical IC.

Alterations of the intestinal microbiota in age-related macular degeneration.

Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss in those over the age of 50. Recently, intestinal microbiota has been reported to be involved in the pathogenesis of ocular diseases. The purpose of this study was to discover more about the involvement of the intestinal microbiota in AMD patients. Methods: Fecal samples from 30 patients with AMD (AMD group) and 17 age- and sex-matched healthy controls (control group) without any fundus disease were collected. DNA extraction, PCR amplification, and 16S rRNA gene sequencing of the samples were performed to identify intestinal microbial alterations. Further, we used BugBase for phenotypic prediction and PICRUSt2 for KEGG Orthology (KO) as well as metabolic feature prediction. Results: The intestinal microbiota was found to be significantly altered in the AMD group. The AMD group had a significantly lower level of Firmicutes and relatively higher levels of Proteobacteria and Bacteroidota compared to those in the control group. At the genus level, the AMD patient group showed a considerably higher proportion of Escherichia-Shigella and lower proportions of Blautia and Anaerostipes compared with those in the control group. Phenotypic prediction revealed obvious differences in the four phenotypes between the two groups. PICRUSt2 analysis revealed KOs and pathways associated with altered intestinal microbiota. The abundance of the top eight KOs in the AMD group was higher than that in the control group. These KOs were mainly involved in lipopolysaccharide biosynthesis. Conclusion: The findings of this study indicated that AMD patients had different gut microbiota compared with healthy controls, and that AMD pathophysiology might be linked to changes in gut-related metabolic pathways. Therefore, intestinal microbiota might serve as non-invasive indicators for AMD clinical diagnosis and possibly also as AMD treatment targets.

Investigating the role of tartaric acid in wine astringency.

Previous studies acknowledged that tartaric acid-imparted low-pH contributed to the enhancement of astringency, but in-depth studies are lacking and the underlying mechanisms are not clearly understood. This work introduced new insight into the effect of tartaric acid on astringency perception from the perspectives of complex formation, protein secondary structure, chemical bond type and salivary layer fluidity by establishing models using proteins (α-amylase, salivary proteins) and tannic acid. Results demonstrated that tartaric acid affects wine astringency by two mechanisms: a) Tartaric acid compound directly affects the wine astringency by forming ternary complexes and causing the protein structure to stretch by changing the hydrogen bond and hydrophobic bond between protein-polyphenol complexes. b) pH affected astringency by increasing the fluidity of the salivary layer rather than increasing the consumption of the salivary layer. The findings provide valuable information to the wine industry to regulate wine astringency by the management of tartaric acid.

Association of cognitive function with Neurofilament light chain in the aqueous humor of human eye.

Objectives: To evaluate the predictive clinical role of neurofilament light chain (NfL), amyloid-ß (Aß), glial fibrillary acidic protein (GFAP), and phosphorylated tau at threonine 181 (p-tau181) proteins in human aqueous humor (AH) and quantify the retinal macular microvascular parameters by optical coherence tomography angiography (OCTA) as early diagnostic markers of Alzheimer's disease (AD). Methods: This prospective, single-site, cross-sectional, cohort study enrolled 55 participants, including 38 patients with neovascular age-related macular degeneration (nAMD) and 17 individuals with senile cataracts. The single-molecule array platform was used to quantitatively measure the levels of AH NfL, Aß40, Aß42, GFAP, and p-tau181 proteins in AH. The mini-mental state examination (MMSE) score was used to assess the global cognitive function. OCTA scan with 6 × 6 mm macular area was used to quantify the retinal thickness and microvascular densities of superficial retinal capillary plexuses and deep retinal capillary plexuses. Results: NfL, Aß40, Aß42, GFAP, and p-tau181 were detected in all AH samples by Simoa platform. Individuals with cataract had higher concentrations of NfL and p-tau181 but lower Aß40 and Aß42 and similar GFAP compared to those with nAMD. Lower MMSE scores showed a negative correlation with NfL concentration of AH not only in the nAMD group (p = 0.043), but also in the cataract group (p = 0.032). However, the MMSE scores were not associated with the levels of Aß40, Aß42, GFAP, or p-Tau181. Further analysis found that the Aß40 and Aß42 concentrations showed a strong positive correlation (p < 0.0001). In addition, the NfL concentration showed a mild positive correlation with that of GFAP in the cataract group (p = 0.021). Although it has not reached statistical significance, there was a correlation between the levels of NfL and Aß42 in the nAMD group (p = 0.051). Moreover, the macular superficial vessel density values had a negative correlation with the concentration of NfL (p = 0.004) but a positive correlation with MMSE scores (p = 0.045). The macular deep vessel density values were negatively correlated with the concentration of p-tau181 (p = 0.031) and positively correlated with MMSE scores (p = 0.020). Conclusion: The examination of AD-related biomarkers in human AH and OCTA may improve the ocular-based AD detection methods and contribute to forestalling the progression of preclinical AD.

The prevalence and characteristics of extended-spectrum ß-lactamase Escherichia coli in raw milk and dairy farms in Northern Xinjiang, China.

In this study, extended-spectrum ß-lactamase (ESBL) Escherichia coli were isolated from five dairy farms in three areas of northern Xinjiang, China. Molecular biological techniques were used to systematically analyze drug resistance phenotypes and genotypes, virulence genes, phylogenetics, biofilm formation (BF), and pulsed field gel electrophoresis (PFGE) typing of isolated ESBL E. coli strains. A total of 766 samples were collected from five dairy farms in Shihezi, Urumqi and Yili, from which 149 (19.5 %, 95 % CI: 16.65 %-22.25 %) ESBL E. coli strains were isolated. Their distribution and contamination levels varied from region to region, with 16.2 % (68/419) in Urumqi, 22.4 % (60/268) in Shihezi, and 26.6 % (21/79) in Yili. The majority of isolates (97.3 %, 145/149) harbored the ß-lactamase blaCTX-M gene; while blaCTX-M-1 was the dominant phylogenetic group. The analysis of 21 resistance genes and the susceptibility to 13 different antibiotics showed that 91.3 % (136/149) of strains were resistant to three or more antibiotics. Thirty-six strains (24.2 %) belonged to extraintestinal pathogenic E. coli (ExPEC), and phylogenetic typing results were mainly grouped A (50.3 %) and B1 (37.6 %). Also, the biofilm assay revealed that 112 strains (75.2 %) could form biofilms. PFGE results showed that the 49 isolates revealed 21 major pulsotypes (P1-P21) and 28 subtypes with 80 % similarity, indicating the overall genetic diversity in the distribution area and sources of the samples.

Composition and diversity of gut microbiota in diabetic retinopathy.

Objective: Diabetic retinopathy (DR) is one of the most common complications of type 2 diabetes mellitus. The current study investigates the composition, structure, and function of gut microbiota in DR patients and explores the correlation between gut microbiota and clinical characteristics of DR. Methods: A total of 50 stool samples were collected from 50 participants, including 25 DR patients and 25 healthy controls (HCs). 16S ribosomal RNA gene sequencing was used to analyze the gut microbial composition in these two groups. DNA was extracted from the fecal samples using the MiSeq platform. Results: The microbial structure and composition of DR patients were different from that of HCs. The microbial richness of gut microbiota in DR was higher than that of normal individuals. The alterations of microbiome of DR patients were associated with disrupted Firmicutes, Bacteroidetes, Synergistota, and Desulfobacterota phyla. In addition, increased levels of Bacteroides, Megamonas, Ruminococcus_torques_group, Lachnoclostridium, and Alistipes, and decreased levels of Blautia, Eubacterium_ hallii_group, Collinsella, Dorea, Romboutsia, Anaerostipes, and Fusicatenibacter genera were observed in the DR groups. Additionally, a stochastic forest model was developed to identify a set of biomarkers with seven bacterial genera that can differentiate patients with DR from those HC. The microbial communities exhibited varied functions in these two groups because of the alterations of the above-mentioned bacterial genera. Conclusion: The altered composition and function of gut microbiota in DR patients indicated that gut microbiome could be used as non-invasive biomarkers, improve clinical diagnostic methods, and identify putative therapeutic targets for DR.

Reducing Virus Infection Risk in Space Environments through Nutrient Supplementation.

Space exploration has brought many challenges to human physiology. In order to evaluate and reduce possible pathological reactions triggered by space environments, we conducted bioinformatics analyses on the methylation data of the Mars 520 mission and human transcriptome data in the experiment simulating gravity changes. The results suggest that gene expression levels and DNA methylation levels were changed under the conditions of isolation and gravity changes, and multiple viral infection-related pathways were found in the enrichment analysis results of changed genes including Epstein Barr virus (EBV) infection, Hepatitis B virus (HBV) infection, Herpes simplex virus (HSV) infection and Kaposi's sarcoma-associated herpesvirus (KHSV) infection. In this study, we found that Epigallocatechin-3-gallate (EGCG) and vitamin D are helpful in reducing viral infection risk. In addition, the causal associations between nutrients and viral infections were calculated using Two sample Mendelian Randomization (2SMR) method, the results indicated that vitamin D can reduce EBV infection and HBV infection risk. In summary, our study suggests that space environments increase the risk of human viral infection, which may be reduced by supplementing EGCG and vitamin D. These results can be used to formulate medical plans for astronauts, which have practical application value for future space exploration.

N6-Methyladenosine regulator RBM15B acts as an independent prognostic biomarker and its clinical significance in uveal melanoma.

Uveal melanoma (UM) is the most frequent intraocular malignant tumor in adults. N6-Methyladenosine (m6A) methylation is recognized as the most critical epigenetic change and is implicated in the development of many malignancies. However, its prognostic value in UM is poorly understood. RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) help us better understand the relationship between m6A regulators and UM patients. Herein, four UM groups established by consensus clustering were shown to have different immune cell infiltrations and prognostic survival. Five m6A regulators, including RBM15B, IGF2BP1, IGF2BP2, YTHDF3, and YTHDF1, were associated with the prognosis of UM patients. Intriguingly, RBM15B was confirmed to be the only independent prognostic factor for UM and it was significantly correlated with clinicopathologic characteristics of UM. Notably, RBM15B expression was significantly negatively correlated with immune checkpoints. Furthermore, LINC00665/hsa-let-7b-5p/RBM15B axis and LINC00638/hsa-miR-103a-3p/RBM15B axis were found to be potential prognostic biomarkers in UM. In a nutshell, this work, through bioinformatics analysis, systematically described the gene signatures and prognostic values of m6A regulators. RBM15B is an independent protective prognostic factor, which may help us better understand the crosstalk within UM.

Pan-cancer analysis of the prognostic and immunological role of BRCA1-associated protein 1 gene (BAP1): Friend or foe?

BACKGROUND: BRCA1-associated protein 1 gene (BAP1) plays a key role in some cancers. However, it has not yet been elucidated whether BAP1 modulates the pathogenesis and progression of human cancers through some common cellular and molecular mechanisms, and a pan-cancer analysis for the roles of BAP1 has not yet been conducted. METHODS: A systematic assessment of the BAP1 gene was presented using bioinformatics analysis and R software. Based on gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, differential expression of BAP1, survival prognosis and genetic alterations of BAP1, correlations between BAP1 expression and immune infiltrates, enrichment analysis and receiver operating curves (ROC) were performed across 33 TCGA cancers. RESULTS: BAP1 was highly expressed in several cancers and high BAP1 expression resulted in different survival prognoses. BAP1 DNA methylation status was changed in uveal melanoma (UVM) cases and a high level of BAP1 phosphorylation was found at the S292 locus in several cancers (colon cancer, lung adenocarcinoma, breast cancer, ovarian cancer, and uterine cancer). The statistically significant correlations of BAP1 expression and immune infiltration may contribute to the prognostic survivals in several cancers including UVM, skin cutaneous melanoma (SKCM), and lung adenocarcinoma (LUAD). Additionally, the correlations between BAP1 expression and tumor mutation burden (TMB)/microsatellite instability (MSI) across TCGA cancers were also explored. Finally, the analysis revealed that BAP1 expression level had high sensitivity and specificity for liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), and pancreatic adenocarcinoma (PAAD) patients. CONCLUSION: This study has revealed statistically significant correlations of BAP1 expression with survival analysis, DNA methylation, protein phosphorylation, genetic alteration, and immune infiltration across multiple TCGA cancers, suggesting that BAP1 may potentially serve as a potential therapeutic target and prognostic biomarker for several cancers.

MMP1 and MMP9 are potential prognostic biomarkers and targets for uveal melanoma.

BACKGROUND: Uveal melanoma (UVM) is the leading cause of eye-related mortality worldwide. This study aimed to explore the expression and prognostic value of matrix metalloproteinases (MMPs) in UVM. METHODS: Gene expression levels were obtained from the Gene Expression Omnibus (GEO) and Oncomine databases. Functional and pathway enrichment analyses were performed using the Metascape database. GeneMANIA was then applied to construct a protein-protein interaction network and identify the hub genes. Moreover, overall survival (OS) and disease-free survival (DFS) analysis for the hub genes was performed using the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) online tool. Furthermore, TRRUST was used to predict the targets of the MMPs. RESULTS: Our results revealed that the transcriptional levels of MMP1, MMP9, MMP10, MMP11, MMP13, MMP14, and MMP17 were upregulated in UVM tissues compared to normal tissues. A protein-protein interaction (PPI) network was constructed and the top 50 hub genes were identified. The functions of MMPs and their neighboring proteins are mainly associated with ECM-receptor interaction, proteoglycans in cancer, the IL-17 signaling pathway, and microRNAs in cancer. Among the MMPs, MMP1/2/9/11/14/15/16/17/24 played significant roles in the progression of UVM from stage 3 to stage 4. We also found that the expression of MMP1, MMP2, MMP9, and MMP16 positively correlated with OS and DFS in patients with UVM. Additionally, 18 transcription factors associated with nine MMPs were identified. CONCLUSIONS: The results of this study may provide potential biomarkers and targets for UVM. However, further studies are required to confirm these results.

ncRNA-eQTL: a database to systematically evaluate the effects of SNPs on non-coding RNA expression across cancer types.

Numerous studies indicate that non-coding RNAs (ncRNAs) have critical functions across biological processes, and single-nucleotide polymorphisms (SNPs) could contribute to diseases or traits through influencing ncRNA expression. However, the associations between SNPs and ncRNA expression are largely unknown. Therefore, genome-wide expression quantitative trait loci (eQTL) analysis to assess the effects of SNPs on ncRNA expression, especially in multiple cancer types, will help to understand how risk alleles contribute toward tumorigenesis and cancer development. Using genotype data and expression profiles of ncRNAs of >8700 samples from The Cancer Genome Atlas (TCGA), we developed a computational pipeline to systematically identify ncRNA-related eQTLs (ncRNA-eQTLs) across 33 cancer types. We identified a total of 6 133 278 and 721 122 eQTL-ncRNA pairs in cis-eQTL and trans-eQTL analyses, respectively. Further survival analyses identified 8312 eQTLs associated with patient survival times. Furthermore, we linked ncRNA-eQTLs to genome-wide association study (GWAS) data and found 262 332 ncRNA-eQTLs overlapping with known disease- and trait-associated loci. Finally, a user-friendly database, ncRNA-eQTL (http://ibi.hzau.edu.cn/ncRNA-eQTL), was developed for free searching, browsing and downloading of all ncRNA-eQTLs. We anticipate that such an integrative and comprehensive resource will improve our understanding of the mechanistic basis of human complex phenotypic variation, especially for ncRNA- and cancer-related studies.

In vitro thermosensitivity of rat lateral parabrachial neurons.

The lateral parabrachial (LPB) neurons play a pivotal role in the thermoregulatory afferent pathway by transmitting cutaneous thermosensory signals received from spinal neurons directly to the thermoregulatory command center, the preoptic area (POA). The present study was conducted to electrophysiologically characterize the local temperature responsiveness of rat LPB neurons in brain slices to evaluate their local thermosensitivity and permit comparison with thermosensitive neurons in POA and spinal cord slices under consistent experimental conditions. In current clamp, warm- and cold-sensitive neurons were recorded in LPBel, LPBc and LPBd, the three LPB subnuclei responsible for the transmission of cutaneous feedforward signals. Of the 92 spontaneously firing LPB neurons, 27% were warm sensitive, 10% were cold sensitive, and 63% were temperature insensitive, and the spontaneous firing rate of the warm-sensitive neurons was significantly greater than that of the temperature-insensitive neurons. These proportions and spontaneous activity are similar to results obtained in the POA and spinal cord. Furthermore, the thermosensitivity was also present in 38% of silent neurons evoked by injection of a small amount of depolarizing current. Warm-sensitive neurons in the LPB were similar in thermoresponsiveness to those in the POA and spinal cord. However, cold sensitivity in the LPB was distinct from that in the POA. The firing rate of most cold-sensitive neurons changed steeply at a relatively narrow band of temperature, and some of them were silent near thermoneutrality. The percentages of thermosensitive and insensitive neurons within the three LPB subnuclei were not significantly different, nor were the mean maximal thermal coefficients of the thermosensitive neurons. These results suggest that LPB have local thermosensory functions as POA and spinal cord, and might be an important extrahypothalamic "thermoregulator".