Identification of potential therapeutic targets for plaque vulnerability based on an integrated analysis.

BACKGROUND AND AIMS: This study aimed to explore potential hub genes and pathways of plaque vulnerability and to investigate possible therapeutic targets for acute coronary syndrome (ACS). METHODS AND RESULTS: Four microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene coexpression networks (WGCNA) and immune cell infiltration analysis (IIA) were used to identify the genes for plaque vulnerability. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Disease Ontology, Gene Ontology annotation and protein-protein interaction (PPI) network analyses were performed to explore the hub genes. Random forest and artificial neural networks were constructed for validation. Furthermore, the CMap and Herb databases were employed to explore possible therapeutic targets. A total of 168 DEGs with an adjusted P < 0.05 and approximately 1974 IIA genes were identified in GSE62646. Three modules were detected and associated with CAD-Class, including 891 genes that can be found in GSE90074. After removing duplicates, 114 hub genes were used for functional analysis. GO functions identified 157 items, and 6 pathways were enriched for the KEGG pathway at adjusted P < 0.05 (false discovery rate, FDR set at < 0.05). Random forest and artificial neural network models were built based on the GSE48060 and GSE34822 datasets, respectively, to validate the previous hub genes. Five genes (GZMA, GZMB, KLRB1, KLRD1 and TRPM6) were selected, and only two of them (GZMA and GZMB) were screened as therapeutic targets in the CMap and Herb databases. CONCLUSION: We performed a comprehensive analysis and validated GZMA and GZMB as a target for plaque vulnerability, which provides a therapeutic strategy for the prevention of ACS. However, whether it can be used as a predictor in blood samples requires further experimental verification.

Osteoarthritis and hypertension: observational and Mendelian randomization analyses.

BACKGROUND: The association between osteoarthritis (OA) and hypertension is a subject of ongoing debate in observational research, and the underlying causal relationship between them remains elusive. METHODS: This study retrospectively included 24,871 participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2020. Weighted logistic regression was performed to investigate the connection between OA and hypertension. Additionally, Mendelian randomization (MR) analysis was conducted to explore the potential causal relationship between OA and hypertension. RESULTS: In the NHANES data, after adjusting for multiple confounding factors, there was no significant relationship between OA and hypertension (OR 1.30, 95% CI, 0.97-1.73, P = 0.089). However, among males, OA appeared to be associated with a higher risk of hypertension (OR 2.25, 95% CI, 1.17-4.32, P = 0.019). Furthermore, MR results indicate no relationship between multiple OA phenotypes and hypertension: knee OA (IVW, OR 1.024, 95% CI: 0.931-1.126, P = 0.626), hip OA (IVW, OR 0.990, 95% CI: 0.941-1.042, P = 0.704), knee or hip OA (IVW, OR 1.005, 95% CI: 0.915-1.105, P = 0.911), and OA from UK Biobank (IVW, OR 0.796, 95% CI: 0.233-2.714, P = 0.715). Importantly, these findings remained consistent across different genders and in reverse MR. CONCLUSIONS: Our study found that OA patients had a higher risk of hypertension only among males in the observational study. However, MR analysis did not uncover any causal relationship between OA and hypertension.

Adaptive evolution and co-evolution of chloroplast genomes in Pteridaceae species occupying different habitats: overlapping residues are always highly mutated.

BACKGROUND: The evolution of protein residues depends on the mutation rates of their encoding nucleotides, but it may also be affected by co-evolution with other residues. Chloroplasts function as environmental sensors, transforming fluctuating environmental signals into different physiological responses. We reasoned that habitat diversity may affect their rate and mode of evolution, which might be evidenced in the chloroplast genome. The Pteridaceae family of ferns occupy an unusually broad range of ecological niches, which provides an ideal system for analysis. RESULTS: We conducted adaptive evolution and intra-molecular co-evolution analyses of Pteridaceae chloroplast DNAs (cpDNAs). The results indicate that the residues undergoing adaptive evolution and co-evolution were mostly independent, with only a few residues being simultaneously involved in both processes, and these overlapping residues tend to exhibit high mutations. Additionally, our data showed that Pteridaceae chloroplast genes are under purifying selection. Regardless of whether we grouped species by lineage (which corresponded with ecological niches), we determined that positively selected residues mainly target photosynthetic genes. CONCLUSIONS: Our work provides evidence for the adaptive evolution of Pteridaceae cpDNAs, especially photosynthetic genes, to different habitats and sheds light on the adaptive evolution and co-evolution of proteins.

Growth associated protein 43 deficiency promotes podocyte injury by activating the calmodulin/calcineurin pathway under hyperglycemia.

Podocyte injury is a crucial factor in the pathogenesis of diabetic kidney disease (DKD), and finding potential therapeutic interventions that can mitigate podocyte injury holds significant clinical relevance. This study was to elucidate the role of growth associated protein-43(Gap43) in podocyte injury of high glucose (HG). We confirmed the expression of Gap43 in human glomerulus and found that Gap43 expression was downregulated in podocytes of patients with DKD and HG-treated podocytes in vitro. Gap43 knockdown in podocytes promoted podocyte apoptosis, increased migration ability and decreased nephrin expression, while overexpression of Gap43 markedly suppressed HG-induced injury. Moreover, the increased expression and activity of calcineurin (CaN) were also abrogated by overexpression Gap43 in HG. Pretreatment with a typical CaN inhibitor FK506 in Gap43 knockdown podocytes restored the injury. Mechanistically, co-immunoprecipitation experiments suggested that Gap43 could bind to calmodulin (CaM). Pull-down assay further demonstrated that Gap43 and CaM directly interacts with each other via amino acids 30-52 of Gap43 and amino acids 133-197 of CaM. In addition, we also identified Pax5 as potential transcription inhibitor factor mediating Gap43 expression. In conclusion, the study indicated that the Gap43/CaM-CaN pathway may be exploited as a promising therapeutic target for protecting against podocyte injury in high glucose.

Chloroplast gene expression level is negatively correlated with evolutionary rates and selective pressure while positively with codon usage bias in Ophioglossum vulgatum L.

BACKGROUND: Characterization of the key factors determining gene expression level has been of significant interest. Previous studies on the relationship among evolutionary rates, codon usage bias, and expression level mostly focused on either nuclear genes or unicellular/multicellular organisms but few in chloroplast (cp) genes. Ophioglossum vulgatum is a unique fern and has important scientific and medicinal values. In this study, we sequenced its cp genome and transcriptome to estimate the evolutionary rates (dN and dS), selective pressure (dN/dS), gene expression level, codon usage bias, and their correlations. RESULTS: The correlation coefficients between dN, dS, and dN/dS, and Transcripts Per Million (TPM) average values were -0.278 (P = 0.027 < 0.05), -0.331 (P = 0.008 < 0.05), and -0.311 (P = 0.013 < 0.05), respectively. The codon adaptation index (CAI) and tRNA adaptation index (tAI) were significantly positively correlated with TPM average values (P < 0.05). CONCLUSIONS: Our results indicated that when the gene expression level was higher, the evolutionary rates and selective pressure were lower, but the codon usage bias was stronger. We provided evidence from cp gene data which supported the E-R (E stands for gene expression level and R stands for evolutionary rate) anti-correlation.

LOEN: Lensless opto-electronic neural network empowered machine vision.

Machine vision faces bottlenecks in computing power consumption and large amounts of data. Although opto-electronic hybrid neural networks can provide assistance, they usually have complex structures and are highly dependent on a coherent light source; therefore, they are not suitable for natural lighting environment applications. In this paper, we propose a novel lensless opto-electronic neural network architecture for machine vision applications. The architecture optimizes a passive optical mask by means of a task-oriented neural network design, performs the optical convolution calculation operation using the lensless architecture, and reduces the device size and amount of calculation required. We demonstrate the performance of handwritten digit classification tasks with a multiple-kernel mask in which accuracies of as much as 97.21% were achieved. Furthermore, we optimize a large-kernel mask to perform optical encryption for privacy-protecting face recognition, thereby obtaining the same recognition accuracy performance as no-encryption methods. Compared with the random MLS pattern, the recognition accuracy is improved by more than 6%.

NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFß-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

Optical random speckle encoding based on hybrid wavelength and phase modulation.

Optical random speckle encoding suffers from a contradiction between the generation speed and pattern amount. Spatial light modulators are commonly used for random speckle generation at relatively low speeds. Wavelength scanning combined with a scattering medium has a fast speed, while the pattern amount is limited by the optical bandwidth. To increase the performance of optical random speckle encoding, a novel, to the best of our knowledge, scheme combining wavelength and phase hybrid modulation is proposed and demonstrated. Through optical encoding in the two dimensions of wavelength and phase, the number of speckle patterns can reach one million, which is over 10,000 times that generated by only wavelength scanning. This scheme can be used in ghost imaging systems to increase the resolution of reconstructed images.

Integrated DNA Methylation and Gene Expression Analysis Identified S100A8 and S100A9 in the Pathogenesis of Obesity.

Background: To explore the association of DNA methylation and gene expression in the pathology of obesity. Methods: (1) Genomic DNA methylation and mRNA expression profile of visceral adipose tissue (VAT) were performed in a comprehensive database of gene expression in obese and normal subjects. (2) Functional enrichment analysis and construction of differential methylation gene regulatory networks were performed. (3) Validation of the two different methylation sites and corresponding gene expression was done in a separate microarray dataset. (4) Correlation analysis was performed on DNA methylation and mRNA expression data. Results: A total of 77 differentially expressed mRNAs matched with differentially methylated genes. Analysis revealed two different methylation sites corresponding to two unique genes-s100a8-cg09174555 and s100a9-cg03165378. Through the verification test of two interesting different expression positions [differentially methylated positions (DMPs)] and their corresponding gene expression, we found that methylation in these genes was negatively correlated to gene expression in the obesity group. Higher S100A8 and S100A9 expressions in obese subjects were validated in a separate microarray dataset. Conclusion: This study confirmed the relationship between DNA methylation and gene expression and emphasized the important role of S100A8 and S100A9 in the pathogenesis of obesity.

Histone deacetylase 4 mediates high glucose-induced podocyte apoptosis via upregulation of calcineurin.

Hyperglycemia promotes podocyte apoptosis and plays an important role in the pathogenesis of diabetic nephropathy (DN). Calcium/calcineurin (CaN) signaling is critical for podocyte apoptosis. Therefore, it is essential to elucidate the mechanisms underlying the regulation of CaN signaling. Recent studies reported that histone deacetylase 4 (HDAC4) is involved in podocyte apoptosis in DN. The aim of this study was to determine whether HDAC4 mediates the regulation of CaN and to elucidate the function of HDAC4 in high glucose (HG)-induced podocyte apoptosis. First, we identified the expression of HDAC4 was upregulated in podocytes of patients with DN. In vitro, the results also indicate that the mRNA and protein expression levels of HDAC4 were increased in HG-cultured podocytes. Silencing and overexpression of HDAC4 markedly decreased and increased CaN expression, respectively. Meanwhile, HG-induced podocyte apoptosis was abrogated by HDAC4-knockdown with subsequent decreased Bax expression and increased Bcl-2 expression. In contrast, overexpression of HDAC4 increased podocyte apoptosis and Bax expression, as well as decreased Bcl-2 expression. In addition, podocyte apoptosis induced by HDAC4 overexpression was effectively rescued by FK506, a pharmacological inhibitor of CaN, which was accompanied by decreased Bax and increased Bcl-2 expression. As a novel finding, HG-induced podocyte apoptosis is mediated by the HDAC4/CaN signaling pathway, which presents a promising target for therapeutic intervention in DN.

Raised Plasma Levels of Asymmetric Dimethylarginine Are Associated with Pathological Type and Predict the Therapeutic Effect in Lupus Nephritis Patients Treated with Cyclophosphamide.

BACKGROUND: Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Asymmetric dimethylarginine (ADMA) has been associated with cardiovascular events in SLE patients and is a strong predictor of the progression of chronic kidney disease. However, whether ADMA can provide a predictive value for the diagnosis and treatment of LN patients remains unclear. This study evaluated the clinical significance of ADMA in LN patients. METHODS: Blood samples of 114 patients with LN, 52 patients with primary glomerular disease, and 20 healthy people were collected. Plasma ADMA was measured via enzyme-linked immunosorbent assay. The relationship between plasma ADMA levels and pathological types and renal function and efficacy in LN patients were further analyzed. RESULTS: There was no significant difference in plasma ADMA levels between LN and primary glomerular disease, but both were significantly higher than the values in healthy people (p < 0.05). Plasma ADMA levels in LN patients were negatively correlated with baseline estimated glomerular filtration rate (eGFR) and serum superoxide dismutase and positively correlated with serum cystatin C and serum ß2-microglobulin (p < 0.05). The plasma ADMA levels of diffuse proliferative LN patients were significantly higher than those of other histopathological classes of LN. High plasma ADMA levels in LN patients (OR = 1.012; 95% CI 1.003-1.022; p = 0.010) is a risk factor for diffuse proliferative LN. The area under the receiver operating characteristic (ROC) curve of diagnosing diffuse proliferative LN by plasma ADMA was 0.707 (95% CI 0.610-0.805). The area under the ROC curve of combination with plasma ADMA, serum complement C3, and eGFR for diffuse proliferative LN was 0.796 (95% CI 0.713-0.879), which was significantly higher than that of ADMA, complement C3, and eGFR for diffuse proliferative LN alone, respectively (p < 0.05). Low plasma ADMA is an independent protective factor for proliferative LN patients achieving complete remission with cyclophosphamide as induction therapy (OR = 0.978; 95% CI 0.961-0.996; p < 0.05). CONCLUSION: High plasma ADMA levels in combination with eGFR and complement C3 may be useful to diagnose diffuse proliferative LN. Low plasma ADMA may help to predict complete remission in proliferative LN patients treated with cyclophosphamide as induction therapy. Plasma ADMA may be a new biomarker to determine the pathological type of LN and predict the therapeutic effect.

Superwettable Microchips as a Platform toward Microgravity Biosensing.

The construction of the Space Station provides a spaceflight laboratory, which enables us to accomplish tremendous short- and long-duration research such as astronomy, physics, material sciences, and life sciences in a microgravity environment. Continuous innovation and development of spaceflight laboratory prompted us to develop a facile detection approach to meet stringent requirements in a microgravity environment that traditional experimental approaches cannot reach. Here we introduce superhydrophilic microwells onto superhydrophobic substrates that are capable of capturing and transferring microdroplets, demonstrating a proof-of-concept study of a biosensing platform toward microgravity application. The capability of manipulating microdroplets originates from the capillary force of the nanoscale dendritic coating in superhydrophilic microwells. Based on theoretical modeling, capillary forces of the superhydrophilic microwells can dominate the behavior of microdroplets against the gravity. Direct naked-eye observation monitoring of daily physiological markers, such as glucose, calcium, and protein can be achieved by colorimetric tests without the requirement of heavy optical or electrical equipment, which greatly reduced the weight, and will bring a promising clue for biodetection in microgravity environments.

Cell micropatterns based on silicone-oil-modified slippery surfaces.

We demonstrate a simple and environment-friendly strategy to fabricate cell micropatterns on a nanodendritic superhydrophilic silica substrate separated by silicone-oil-modified superhydrophobic barriers. The superhydrophilic spots exhibit excellent cell adhesion capability due to the enhanced local topographic interaction between cell filopodia and the nanodendritic substrate interface, and result in sensational cell micropatterns. In contrast, the anti-adhesion of silicone-oil-modified superhydrophobic barriers prevents cell migration and results in long-term cell-repellency. Such superhydrophilic spots and silicone-oil-modified superhydrophobic barriers are very helpful for the formation of cell micropatterns. Moreover, co-culture of different cells can be achieved on the silicone-oil-modified micropatterns. The unique properties of our silicone-oil-modified micropatterns hold considerable promise for a wide range of biological applications, such as cell-based bioassays, tissue engineering, high-throughput screening and fundamental studies of cell biology.

Superhydrophilic cotton thread with temperature-dependent pattern for sensitive nucleic acid detection.

Cotton thread is promising in fabricating biosensors for diagnostic application due to its excellent characteristics. However, the enrichment of the capture molecules on a narrow zone of the cotton thread based biosensor is a big challenge because of its superhydrophilicity. Here, we report a simple, low-cost and accurate cotton thread based nucleic acid biosensor with temperature-dependent pattern. Liquid wax is used to fabricate temperature-dependent pattern to restrict the test zone in a narrow area. This biosensor enables visual and quantitative detection of target DNA by accumulation of gold nanoparticles (GNPs) on the test zone with a detection limits of 0.75nM. In addition, the cotton thread based biosensor needs less sample than previous reported lateral flow strip and the sample solution wicks faster at the cotton thread which can lead to a shorter detection time. This simple, low-cost and fast detection method holds great potential to improve healthcare services in the developing regions.

Ultratrace DNA Detection Based on the Condensing-Enrichment Effect of Superwettable Microchips.

A sensitive nucleic acid detection platform based on superhydrophilic microwells spotted on a superhydrophobic substrate is fabricated. Due to the wettability differences, ultratrace DNA molecules are enriched and the fluorescent signals are amplified to allow more sensitive detection. The biosensing interface based on superwettable materials provides a simple and cost-effective way for ultratrace DNA sensing.