Retraction Note: Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain.
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Journal Article↗
Biomedical subjects
Jinhua Wang
Publications and source records attributed to Jinhua Wang.
New insights into soil amendment: Impact of humic acid on typical antibiotic resistance in agricultural soil.
Humic acid (HA) addition can improve agricultural soil, but little is known about how it affects the soil resistome. In this study, we used selective agar plate combined with quantitative PCR (qPCR) and 16S rRNA gene sequencing to investigate how HA influences antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARGs) in soil contaminated with erythromycin and kanamycin. 0.1 % HA reduced the abundance of culturable erythromycin-resistant bacteria (ERB), while promoting the growth of kanamycin-resistant bacteria (KRB). Lysinibacillus and Paenibacillus were the dominant genera in ERB and KRB, respectively, governing the changes in their abundances. At this concentration, the Lysinibacillus abundance in ERB decreased from 96.74 % to 70.57 %. Meanwhile, that of Paenibacillus in KRB increased from 33.40 % to 77.44 %. The copy number of ermF decreased after HA addition, while that of ermB increased. Furthermore, 0.1 % HA significantly reduced the copy number and relative abundance of aadA1 and aac(6')-Ib (aka aacA4)-03 in the soil. Changes in these two types of ARB and ARGs were primarily driven by shifts in the microbial community structure. Soil physicochemical properties, particularly increased organic matter (OM), altered the absolute abundance of ermB. Meanwhile, changes in intI1 abundance determined the risk associated with aadA1 and aac(6')-Ib (aka aacA4)-03. These findings emphasize the dual role of HA in the dissemination of antibiotic resistance in agricultural soils and highlight the necessity of considering dose-dependent effects when applying HA as a soil amendment.
Soil Microbiology↗
Predicting Weight Loss After Vertical Sleeve Gastrectomy Using a Whole-genome Sequencing-derived Polygenic Risk Score in the All of Us Cohort.
OBJECTIVE: To create a genome-wide polygenic risk score (PRS) to improve prediction of a 12-month percentage weight loss (WL) after vertical sleeve gastrectomy (VSG). BACKGROUND: Variability in post-VSG WL is not well explained by clinical factors. The All of Us program provides access to a 414,830 short-read whole-genome sequencing resource, enabling unbiased discovery of genetic predictors after VSG. METHODS: VSG counts, demographic, anthropomorphic and vital sign information were obtained from the linked electronic health record. The discovery cohort (DC) included participants from version 7 carried into version 8 while the validation cohort (VC) included those newly added to v8. We defined good responders and nonresponders as having WL±1SD from the mean. Following quality filtering, we applied a 2-stage penalized-regression, followed by elastic-net logistic regression, to identify 1583 stable variants and derive β-weights. We then tested this PRS on the DC into a prediction model. RESULTS: We identified 395 participants in the DC and 336 participants in the VC, respectively. Of these, VSG, 44 were classified as good responders (≥37% WL) and 55 as nonresponders (≤19% WL). In the VC, 55 were classified as good responders and 48 as nonresponders. Adding the PRS to models to clinical predictors increased the area under the curve following logistic regression by 0.03; P <4.3 × 10 -14 , random forest by 0.03; P <9.1 × 10 -7 , decision tree by 0.05; P = 1.2 × 10 -3 , and gradient boosting by 0.08; P <8.3 × 10 -10 . CONCLUSIONS: Use of short-read whole-genome sequencing from All of Us (AoU) can be effectively used to generate PRS to enhance predictive WL accuracy. This work has implications for outcomes of both bariatric surgery and other surgical procedures.
Humans↗
Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.
Aminoglycosides↗
An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers.
Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations.
Alternative Splicing↗
Gene expression profiles of mouse retinas during the second and third postnatal weeks.
Mouse retina undergoes crucial changes during early postnatal development. By using Affymetrix microarrays, we analyzed gene expression profiles of wild-type 129SvEv/C57BL/6 mouse retinas at postnatal days (P) 7, 10, 14, 18, and 21 and found significantly altered expression of 355 genes. Characterization of these 355 genes provided insight into physiologic and pathologic processes of mouse retinal development during the second and third postnatal weeks, a period that corresponds to human embryogenesis between weeks 12 and 28. These genes formed 6 groups with similar change patterns. Among the genes, sixteen cause retinal diseases when mutated; most of these 16 genes were upregulated in retina during this period. Using the PathArt program, we identified the biological processes in which many of the 355 gene products function. Among the most active processes in the P7-P21 retina are those involved in neurogenesis, obesity, diabetes type II, apoptosis, growth and differentiation, and protein kinase activity. We examined the expression patterns of 58 genes in P7 and adult retinas by searching the Brain Gene Expression Map database. Although most genes were present in various cell types in retinas, many displayed high levels of expression specifically in the outer nuclear, inner nuclear, and/or ganglion cell layers. By combining our 3 analyses, we demonstrated that during this period of mouse retinal development, many genes play important roles in various cell types, multiple pathways are involved, and some genes in a pathway are expressed in coordinated patterns. Our results thus provide foundation for future detailed studies of specific genes and pathways in various genetic and environmental conditions during retinal development.
Aging↗
Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing.
Besides linear RNAs, pre-mRNA splicing generates three forms of RNAs: lariat introns, Y-structure introns from trans-splicing, and circular exons through exon skipping. To study the persistence of excised introns in total cellular RNA, we used three Escherichia coli 3' to 5' exoribonucleases. Ribonuclease R (RNase R) thoroughly degrades the abundant linear RNAs and the Y-structure RNA, while preserving the loop portion of a lariat RNA. Ribonuclease II (RNase II) and polynucleotide phosphorylase (PNPase) also preserve the lariat loop, but are less efficient in degrading linear RNAs. RNase R digestion of the total RNA from human skeletal muscle generates an RNA pool consisting of lariat and circular RNAs. RT-PCR across the branch sites confirmed lariat RNAs and circular RNAs in the pool generated by constitutive and alternative splicing of the dystrophin pre-mRNA. Our results indicate that RNase R treatment can be used to construct an intronic cDNA library, in which majority of the intron lariats are represented. The highly specific activity of RNase R implies its ability to screen for rare intragenic trans-splicing in any target gene with a large background of cis-splicing. Further analysis of the intronic RNA pool from a specific tissue or cell will provide insights into the global profile of alternative splicing.
Dystrophin↗
Large-scale sequence analysis of avian influenza isolates.
The spread of H5N1 avian influenza viruses (AIVs) from China to Europe has raised global concern about their potential to infect humans and cause a pandemic. In spite of their substantial threat to human health, remarkably little AIV whole-genome information is available. We report here a preliminary analysis of the first large-scale sequencing of AIVs, including 2196 AIV genes and 169 complete genomes. We combine this new information with public AIV data to identify new gene alleles, persistent genotypes, compensatory mutations, and a potential virulence determinant.
Animals↗
Biochemical and biophysical studies on the precursor cells of mouse erythrocytes at different stages.
The aim of this research is to study the biochemical and biophysical properties of the precursor cells of mouse erythrocytes at different stages and the molecular mechanisms of their regulation. We investigated the degree of terminal differentiation of splenic erythroblasts obtained from mice during the acute phase of disease caused by the anemia-inducing FVAstrain of Friend virus. We analyzed the transcription and protein levels of alpha-globin, beta-globin (erythroid special protein) and GATA-1 (a special erythroid transcription factor). We also have examined the Ca2+ concentration, the distribution and amount of F-actin, important cellular components such as nucleic acids, lipids, and proteins, and the adhesion of precursor cells of RBC at different stages to vascular endothelium. Our results indicated that Ca2+ concentration and the distribution and structure of F-actin changed with the development of proerythroblasts, and that the adhesion rate between the precursor cells and endothelial cells can be correlated with the expression levels of ICAM-1 and P-selectin. These alternations caused changes in biophysical properties of the cell, such as membrane fluidity and deformability.
Actins↗
Glycodiversification for the optimization of the kanamycin class aminoglycosides.
In an effort to optimize the antibacterial activity of kanamycin class aminoglycoside antibiotics, we have accomplished the synthesis and antibacterial assay of new kanamycin B analogues. A rationale-based glycodiversification strategy was employed. The activity of the lead is comparable to that of commercially available kanamycin. These new members, however, were found to be inactive against aminoglycoside resistant bacteria. Molecular modeling was used to provide the explanation. Thus, a new strategy for structural modifications of kanamycin class aminoglycosides is suggested.
Anti-Bacterial Agents↗
Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes.
Exonic splicing enhancers (ESEs) are pre-mRNA cis-acting elements required for splice-site recognition. We previously developed a web-based program called ESEfinder that scores any sequence for the presence of ESE motifs recognized by the human SR proteins SF2/ASF, SRp40, SRp55 and SC35 (http://rulai.cshl.edu/tools/ESE/). Using ESEfinder, we have undertaken a large-scale analysis of ESE motif distribution in human protein-coding genes. Significantly higher frequencies of ESE motifs were observed in constitutive internal protein-coding exons, compared with both their flanking intronic regions and with pseudo exons. Statistical analysis of ESE motif frequency distributions revealed a complex relationship between splice-site strength and increased or decreased frequencies of particular SR protein motifs. Comparison of constitutively and alternatively spliced exons demonstrated slightly weaker splice-site scores, as well as significantly fewer ESE motifs, in the alternatively spliced group. Our results underline the importance of ESE-mediated SR protein function in the process of exon definition, in the context of both constitutive splicing and regulated alternative splicing.
Alternative Splicing↗
Genome-wide promoter extraction and analysis in human, mouse, and rat.
Large-scale and high-throughput genomics research needs reliable and comprehensive genome-wide promoter annotation resources. We have conducted a systematic investigation on how to improve mammalian promoter prediction by incorporating both transcript and conservation information. This enabled us to build a better multispecies promoter annotation pipeline and hence to create CSHLmpd (Cold Spring Harbor Laboratory Mammalian Promoter Database) for the biomedical research community, which can act as a starting reference system for more refined functional annotations.
Animals↗
Impact of Fusarium culmorum on the polysaccharides of wheat flour.
To assess the effects of Fusarium infection on the polysaccharides of winter wheat grain (Triticum aestivum L.), grain samples obtained from plants artificially inoculated with Fusarium culmorum were analyzed. Microscopy revealed obvious damage to the starch granules in the seriously infected samples. The Fusarium infection had no analytically detectable influence on the starch and total insoluble dietary fiber content of the wheat grain. There were significantly positive relationships between alpha-amylase activity, cellulase activity, total soluble dietary fiber content, pentosan content, and degree of infection quantified by an enzyme-linked immunosorbant assay, which would indicate the importance of fungal enzymes. A distinct higher Hagberg falling number (FN) was determined in the seriously infected samples, while the viscosity and sucrose content of the flour decreased. However, the addition of a liquid medium contaminated with F. culmorum led to a significant decrease in the FN. Depending on the type of buffer used, the alpha-amylase of F. culmorum demonstrated its maximum activity between pH 5.5 and pH 7.0 at 30-50 degrees C. Remarkably, this fungal alpha-amylase showed a thermostable characteristic and was active over a wide range of temperatures, from 10 to 100 degrees C. This type of thermostability suggests that the alpha-amylase of F. culmorum may damage starch granules throughout the processing of wheat flour, thereby inducing weak dough properties and unsatisfactory bread quality.
Cellulase↗
Tuning the regioselectivity of the Staudinger reaction for the facile synthesis of kanamycin and neomycin class antibiotics with N-1 modification.
[reaction: see text] A novel method for achieving the desired regioselective reduction of the N-1 azido group on a tetraazidoneamine has been developed that leads to the synthesis of both kanamycin and neomycin class antibiotics bearing N-1 modification. Both classes of aminoglycosides are active against aminoglycoside-resistant bacteria carrying APH(3')-I and AAC(6')/APH(2'').
Amikacin↗
Synthesis of trehalose-based compounds and their inhibitory activities against Mycobacterium smegmatis.
The synthesis of a library of trehalose-based compounds has been accomplished, and their activities against Mycobacterium smegmatis have been determined. A preliminary structure-activity relationship (SAR) is reported. Despite not having a potent lead, one of the trehalose derivatives displays strong activity when applied with isoniazid (INH), which is known to have low sterilizing activity. The bacteriocidal nature of our compounds against Mycobacterium may be significant for the development of new therapies against tuberculosis.
Combinatorial Chemistry Techniques↗
Effect of fungicide treatment on the quality of wheat flour and breadmaking.
Fungicides are applied to crop plants to ensure disease protection and improve growth. To assess the effects of five commercial foliar and spike fungicides in four different combinations on wheat (Triticum aestivum L.), various quality parameters and flour processing properties, including baking quality, were determined. Three commonly used wheat cultivars with different quality classes (E, B, and C) were tested. Falling number, crude protein content, water absorption ability, protease activity, viscosity, and the free amino acid content were mainly lower in the fungicide-treated grains than in the untreated grains. None of the fungicides caused any significant changes in the wet gluten content, dough properties, the mono- and oligosaccharide content, or the breadmaking quality. In general, the commercial fungicide treatments did not cause any statistically significant differences between the treated and the untreated samples with respect to the quality parameters analyzed, although there were indeed significant differences between the three cultivars themselves.
Adsorption↗
Synthesis of an unusual branched-chain sugar, 5-C-methyl-L-idopyranose for SAR studies of pyranmycins: implication for the future design of aminoglycoside antibiotics.
The syntheses of a challenging branched-chain sugar and several L-sugars have been accomplished. Their application in studies of the antibacterial activity of pyranmycins is reported, which could provide new strategies for the future design of aminoglycoside antibiotics.
Aminoglycosides↗
Application of glycodiversification: expedient synthesis and antibacterial evaluation of a library of kanamycin B analogues.
[reaction: see text] The expedient synthesis of a library of kanamycin B analogues is reported. The revealed SAR will guide future designs in developing kanamycin-type aminoglycoside antibiotics against drug-resistant bacteria.
Anti-Bacterial Agents↗