Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning.

After ischemic stroke (IS), secondary injury is intimately linked to endoplasmic reticulum (ER) stress and body-brain crosstalk. Nonetheless, the underlying mechanism systemic immune disorder mediated ER stress in human IS remains unknown. In this study, 32 candidate ER stress-related genes (ERSRGs) were identified by overlapping MSigDB ER stress pathway genes and DEGs. Three Key ERSRGs (ATF6, DDIT3 and ERP29) were identified using LASSO, random forest, and SVM-RFE. IS patients with different ERSRGs profile were clustered into two groups using consensus clustering and the difference between 2 group was further explored by GSVA. Through immune cell infiltration deconvolution analysis, and middle cerebral artery occlusion (MCAO) mouse scRNA analysis, we found that the expression of 3 key ERSRGs were closely related with peripheral macrophage cell ER stress in IS and this was further confirmed by RT-qPCR experiment. These ERS genes might be helpful to further accurately regulate the central nervous system and systemic immune response through ER stress and have potential application value in clinical practice in IS.

Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage.

Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation of substantial amounts of lactate to maintain the energy demand for neurons and other brain cells. Lactate has garnered increasing attention in recent years because of its emerging role in critical biological processes such as inflammation regulation and neuroprotection, particularly through its histone lactylation. Bromodomain-containing protein 4 (BRD4) plays a crucial role in maintaining neural development and promoting memory formation in the central nervous system. Nonetheless, the function and regulatory mechanism of BRD4 and histone lactylation in astrocytes following SAH remain elusive. Our findings indicate that BRD4, a crucial epigenetic regulator, plays a definitive role in histone lactylation. Both in vitro and in vivo, these results demonstrated that targeted silencing of BRD4 in astrocytes can significantly reduce H4K8la lactylation, thereby aggravating the A1 polarization of astrocytes and ultimately affecting the recovery of neural function and prognosis in mice after SAH. In summary, BRD4 plays a pivotal role in modulating astrocyte polarization following SAH via histone lactylation. Targeting this mechanism might offer an efficient therapeutic strategy for SAH.

Optical design and fabrication of a multi-channel imaging spectrometer for combustion flame monitoring.

We design and construct a broadband integrated multi-channel imaging spectrometer (MCIS) from visible light to near-infrared. This system can directly obtain spectral images that conform to the consistent visual habits of the human eyes through a single exposure of the detector. The genetic algorithm is used to calculate system parameters to minimize pixel waste between spectral channels, achieving nearly 100% utilization of detector pixels. The field stop suppresses stray light in the system. This device is used for imaging an optical-resolution target, an object, and a furnace to verify the basic principles of the system. The results indicate that the system can effectively utilize detectors to monitor high-temperature objects in the visible to near-infrared wavelength range.

Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF-κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.

Facile and eco-friendly fabrication of biocompatible hydrogel containing CuS@Ser NPs with mechanical flexibility and photothermal antibacterial activity to promote infected wound healing.

Bacterial infections can significantly impede wound healing and pose a serious threat to the patient's life. The excessive use of antibiotics to combat bacterial infections has led to the emergence of multi-drug-resistant bacteria. Therefore, there is a pressing need for alternative approaches, such as photothermal therapy (PTT), to address this issue. In this study, for the first time, CuS NPs with photothermal properties were synthesized using sericin as a biological template, named CuS@Ser NPs. This method is simple, green, and does not produce toxic and harmful by-products. These nanoparticles were incorporated into a mixture (XK) of xanthan gum and konjac glucomannan (KGM) to obtain XK/CuS NPs composite hydrogel, which could overcome the limitations of current wound dressings. The composite hydrogel exhibited excellent mechanical flexibility, photothermal response, and biocompatibility. It also demonstrated potent antibacterial properties against both Gram-positive and negative bacteria via antibacterial experiments and accelerated wound healing in animal models. Additionally, it is proved that the hydrogel promoted tissue regeneration by stimulating collagen deposition, angiogenesis, and reducing inflammation. In summary, the XK/CuS NPs composite hydrogel presents a promising alternative for the clinical management of infected wounds, offering a new approach to promote infected wound healing.

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases.

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone's attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.

Using Computational Drug-Gene Analysis to Identify Novel Therapeutic Candidates for Retinal Neuroprotection.

Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the retina using a computational bioinformatics approach. We queried the National Center for Biotechnology Information (NCBI) to identify genes associated with retinal neuroprotection. Enrichment analysis was performed using ToppGene to identify compounds related to the identified genes. This analysis constructs a Pharmacome from multiple drug-gene interaction databases to predict compounds with statistically significant associations to genes involved in retinal neuroprotection. Compounds with known deleterious effects (e.g., asbestos, ethanol) or with no clinical indications (e.g., paraquat, ozone) were manually filtered. We identified numerous drug/chemical classes associated to multiple genes implicated in retinal neuroprotection using a systematic computational approach. Anti-diabetics, lipid-lowering medicines, and antioxidants are among the treatments anticipated by this analysis, and many of these drugs could be readily repurposed for retinal neuroprotection. Our technique serves as an unbiased tool that can be utilized in the future to lead focused preclinical and clinical investigations for complex processes such as neuroprotection, as well as a wide range of other ocular pathologies.

Absence of Gut Microbiota Is Associated with RPE/Choroid Transcriptomic Changes Related to Age-Related Macular Degeneration Pathobiology and Decreased Choroidal Neovascularization.

Studies have begun to reveal significant connections between the gut microbiome and various retinal diseases, including age-related macular degeneration (AMD). As critical supporting tissues of the retina, the retinal pigment epithelium (RPE) and underlying choroid play a critical role in retinal homeostasis and degeneration. However, the relationship between the microbiome and RPE/choroid remains poorly understood, particularly in animal models of AMD. In order to better elucidate this role, we performed high-throughput RNA sequencing of RPE/choroid tissue in germ-free (GF) and specific pathogen-free (SPF) mice. Furthermore, utilizing a specialized laser-induced choroidal neovascularization (CNV) model that we developed, we compared CNV size and inflammatory response between GF and SPF mice. After correction of raw data, 660 differentially expressed genes (DEGs) were identified, including those involved in angiogenesis regulation, scavenger and cytokine receptor activity, and inflammatory response-all of which have been implicated in AMD pathogenesis. Among lasered mice, the GF group showed significantly decreased CNV lesion size and microglial infiltration around CNV compared to the SPF group. Together, these findings provide evidence for a potential gut-RPE/choroidal axis as well as a correlation with neovascular features of AMD.

Breakage and displacement of the high-speed hand-piece bur during impacted mandibular third molar extraction: three cases.

BACKGROUND: The high-speed hand-piece bur is one of the methods to perform tooth sectioning during the minimally traumatic extraction of impacted mandibular third molars. During tooth sectioning, the breakage of the bur might take place when it is improperly used. Three cases of the breakage and displacement of a high-speed hand-piece bur during extraction are reported, aiming to remind dental surgeons of this complication. CASE PRESENTATION: The bur fragment in case 1 was embedded in the mandibular bone under the previously removed crown of tooth 48 and distal to tooth 47. The bur fragment in case 2 was embedded in the lingual edge of the socket and partly beneath the mucosa on the lingual side. The position of the bur fragment in case 3 was similar to that of case 1 but was completely embedded in the spongious bone. The three cases were performed by first-year residents, and all of the bur fragments were successfully removed by attending doctors after accurately locating them by radiological examination. CONCLUSIONS: In order to avoid breakage of the high-speed hand-piece bur, the number of uses of the bur should be monitored and the integrity and state of the bur should be carefully checked. Moreover, light pressure with little lateral force should be used during tooth sectioning. If bur breakage and displacement occur, the retrieval protocol should be determined based on the imaging findings and conducted as soon as possible to avoid serious consequences.

Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources.

In recent years, the emphasis of scientific inquiry has shifted from whole-genome analyses to an understanding of cellular responses specific to tissue, developmental stage or environmental conditions. One of the central mechanisms underlying the diversity and adaptability of the contextual responses is alternative splicing (AS). It enables a single gene to encode multiple isoforms with distinct biological functions. However, to date, the functions of the vast majority of differentially spliced protein isoforms are not known. Integration of genomic, proteomic, functional, phenotypic and contextual information is essential for supporting isoform-based modeling and analysis. Such integrative proteogenomics approaches promise to provide insights into the functions of the alternatively spliced protein isoforms and provide high-confidence hypotheses to be validated experimentally. This manuscript provides a survey of the public databases supporting isoform-based biology. It also presents an overview of the potential global impact of AS on the human canonical gene functions, molecular interactions and cellular pathways.

Recent Advances on Functional Nucleic-Acid Biosensors.

In the past few decades, biosensors have been gradually developed for the rapid detection and monitoring of human diseases. Recently, functional nucleic-acid (FNA) biosensors have attracted the attention of scholars due to a series of advantages such as high stability and strong specificity, as well as the significant progress they have made in terms of biomedical applications. However, there are few reports that systematically and comprehensively summarize its working principles, classification and application. In this review, we primarily introduce functional modes of biosensors that combine functional nucleic acids with different signal output modes. In addition, the mechanisms of action of several media of the FNA biosensor are introduced. Finally, the practical application and existing problems of FNA sensors are discussed, and the future development directions and application prospects of functional nucleic acid sensors are prospected.

DEEPre: sequence-based enzyme EC number prediction by deep learning.

Motivation: Annotation of enzyme function has a broad range of applications, such as metagenomics, industrial biotechnology, and diagnosis of enzyme deficiency-caused diseases. However, the time and resource required make it prohibitively expensive to experimentally determine the function of every enzyme. Therefore, computational enzyme function prediction has become increasingly important. In this paper, we develop such an approach, determining the enzyme function by predicting the Enzyme Commission number. Results: We propose an end-to-end feature selection and classification model training approach, as well as an automatic and robust feature dimensionality uniformization method, DEEPre, in the field of enzyme function prediction. Instead of extracting manually crafted features from enzyme sequences, our model takes the raw sequence encoding as inputs, extracting convolutional and sequential features from the raw encoding based on the classification result to directly improve the prediction performance. The thorough cross-fold validation experiments conducted on two large-scale datasets show that DEEPre improves the prediction performance over the previous state-of-the-art methods. In addition, our server outperforms five other servers in determining the main class of enzymes on a separate low-homology dataset. Two case studies demonstrate DEEPre's ability to capture the functional difference of enzyme isoforms. Availability and implementation: The server could be accessed freely at http://www.cbrc.kaust.edu.sa/DEEPre. Contact: xin.gao@kaust.edu.sa. Supplementary information: Supplementary data are available at Bioinformatics online.

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death.

Bax∆2 is a functional pro-apoptotic Bax isoform having alterations in its N-terminus, but sharing the rest of its sequence with Baxα. Bax∆2 is unable to target mitochondria due to the loss of helix α1. Instead, it forms cytosolic aggregates and activates caspase 8. However, the functional domain(s) responsible for BaxΔ2 behavior have remained elusive. Here we show that disruption of helix α1 makes Baxα mimic the behavior of Bax∆2. However, the other alterations in the Bax∆2 N-terminus have no significant impact on aggregation or cell death. We found that the hallmark BH3 domain is necessary but not sufficient for aggregation-mediated cell death. We also noted that the core region shared by Baxα and Bax∆2 is required for the formation of large aggregates, which is essential for BaxΔ2 cytotoxicity. However, aggregation by itself is unable to trigger cell death without the C-terminus. Interestingly, the C-terminal helical conformation, not its primary sequence, appears to be critical for caspase 8 recruitment and activation. As Bax∆2 shares core and C-terminal sequences with most Bax isoforms, our results not only reveal a structural basis for Bax∆2-induced cell death, but also imply an intrinsic potential for aggregate-mediated caspase 8-dependent cell death in other Bax family members.

Lynx: a knowledge base and an analytical workbench for integrative medicine.

Lynx (http://lynx.ci.uchicago.edu) is a web-based database and a knowledge extraction engine. It supports annotation and analysis of high-throughput experimental data and generation of weighted hypotheses regarding genes and molecular mechanisms contributing to human phenotypes or conditions of interest. Since the last release, the Lynx knowledge base (LynxKB) has been periodically updated with the latest versions of the existing databases and supplemented with additional information from public databases. These additions have enriched the data annotations provided by Lynx and improved the performance of Lynx analytical tools. Moreover, the Lynx analytical workbench has been supplemented with new tools for reconstruction of co-expression networks and feature-and-network-based prioritization of genetic factors and molecular mechanisms. These developments facilitate the extraction of meaningful knowledge from experimental data and LynxKB. The Service Oriented Architecture provides public access to LynxKB and its analytical tools via user-friendly web services and interfaces.

Plasma Renalase is Not Associated with Blood Pressure and Brachial-Ankle Pulse Wave Velocity in Chinese Adults With Normal Renal Function.

BACKGROUND/AIMS: This study aimed to investigate the association of renalase with blood pressure (BP) and brachial-ankle pulse wave velocity (baPWV) in order to better understand the role of renalase in the pathogenesis of hypertension and atherosclerosis. METHODS: A total of 344 subjects with normal kidney function were recruited from our previously established cohort in Shaanxi Province, China. They were divided into the normotensive (NT) and hypertensive (HT) groups or high baPWV and normal baPWV on the basis of BP levels or baPWV measured with an automatic waveform analyzer. Plasma renalase was determined through an enzyme-linked immunosorbent assay. RESULTS: Plasma renalase did not significantly differ between HT and NT groups (3.71 ± 0.69 µg/mL vs. 3.72 ± 0.73 µg/mL, P = 0.905) and between subjects with and without high baPWV (3.67 ± 0.66 µg/mL vs. 3.73 ± 0.74 µg/mL, P = 0.505). However, baPWV was significantly higher in the HT group than in the NT group (1460.4 ± 236.7 vs. 1240.7 ± 174.5 cm/s, P < 0.001). Plasma renalase was not correlated with BP levels and baPWV in the entire group. Linear and logistic regression analysis revealed that plasma renalase was not significantly associated with hypertension and high baPWV. CONCLUSION: Plasma renalase may not be associated with BP and baPWV in Chinese subjects with normal renal function.

Lynx: a database and knowledge extraction engine for integrative medicine.

We have developed Lynx (http://lynx.ci.uchicago.edu)--a web-based database and a knowledge extraction engine, supporting annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Its underlying knowledge base (LynxKB) integrates various classes of information from >35 public databases and private collections, as well as manually curated data from our group and collaborators. Lynx provides advanced search capabilities and a variety of algorithms for enrichment analysis and network-based gene prioritization to assist the user in extracting meaningful knowledge from LynxKB and experimental data, whereas its service-oriented architecture provides public access to LynxKB and its analytical tools via user-friendly web services and interfaces.

Lynx web services for annotations and systems analysis of multi-gene disorders.

Lynx is a web-based integrated systems biology platform that supports annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Lynx has integrated multiple classes of biomedical data (genomic, proteomic, pathways, phenotypic, toxicogenomic, contextual and others) from various public databases as well as manually curated data from our group and collaborators (LynxKB). Lynx provides tools for gene list enrichment analysis using multiple functional annotations and network-based gene prioritization. Lynx provides access to the integrated database and the analytical tools via REST based Web Services (http://lynx.ci.uchicago.edu/webservices.html). This comprises data retrieval services for specific functional annotations, services to search across the complete LynxKB (powered by Lucene), and services to access the analytical tools built within the Lynx platform.

Effect of salt intake and potassium supplementation on urinary renalase and serum dopamine levels in Chinese adults.

OBJECTIVE: The aim of our study was to assess the effects of altered salt and potassium intake on urinary renalase and serum dopamine levels in humans. METHODS: Forty-two subjects (28­65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for an additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). RESULTS: Urinary renalase excretions were significantly higher during the high-salt diet intervention than during the low-salt diet. During high-potassium intake, urinary renalase excretions were not significantly different from the high-salt diet, whereas they were significantly higher than the low-salt levels. Serum dopamine levels exhibited similar trends across the interventions. Additionally, a significant positive relationship was observed between the urine renalase and serum dopamine among the different dietary interventions. Also, 24-hour urinary sodium excretion positively correlated with urine renalase and serum dopamine in the whole population. CONCLUSIONS: The present study indicates that dietary salt intake and potassium supplementation increase urinary renalase and serum dopamine levels in Chinese subjects.

Effects of Renin-Angiotensin System Inhibitors on Renal Expression of Renalase in Sprague-Dawley Rats Fed With High Salt Diet.

BACKGROUND/AIMS: The aim of our study was to investigate the effect of high-salt diet on the renal expression of renalase and the potential role of the local renin-angiotensin system in this process. METHODS: Sprague-Dawley (SD) rats were divided into groups according to salt content in diet and drug treatment as follows: normal-salt diet (NS), high-salt diet (HS), high-salt intake with hydralazine (HS+H), high-salt diet with enalapril (HS+E), and high-salt diet with valsartan (HS+V). The dietary intervention and drugs were given for four weeks. Renin activity and angiotensin II type 1 receptor (AT1R) levels were detected by real-time PCR. Renalase mRNA and protein were also measured. RESULTS: After four weeks, systolic blood pressure and proteinuria were significantly increased in the HS group with respect to the NS group. Dietary salt intake caused a dramatic decrease in renalase expression in the rat kidneys. Renal cortex renin and AT1R increased significantly in the HS and HS+H groups. Urinary protein was positively correlated with renal renin and AT1R levels. However, in the HS+E and HS+V groups, enalapril and valsartan failed to influence renal renalase expression but abolished the increase in proteinuria, renal cortex renin, and AT1R levels with respect to the HS group. CONCLUSION: This study indicates that high salt intake reduces renal expression, and renal RAS may be not involved in the regulation of renalase in SD rats fed with high-salt diet.

High-throughput translational medicine: challenges and solutions.

Recent technological advances in genomics now allow producing biological data at unprecedented tera- and petabyte scales. Yet, the extraction of useful knowledge from this voluminous data presents a significant challenge to a scientific community. Efficient mining of vast and complex data sets for the needs of biomedical research critically depends on seamless integration of clinical, genomic, and experimental information with prior knowledge about genotype-phenotype relationships accumulated in a plethora of publicly available databases. Furthermore, such experimental data should be accessible to a variety of algorithms and analytical pipelines that drive computational analysis and data mining. Translational projects require sophisticated approaches that coordinate and perform various analytical steps involved in the extraction of useful knowledge from accumulated clinical and experimental data in an orderly semiautomated manner. It presents a number of challenges such as (1) high-throughput data management involving data transfer, data storage, and access control; (2) scalable computational infrastructure; and (3) analysis of large-scale multidimensional data for the extraction of actionable knowledge.We present a scalable computational platform based on crosscutting requirements from multiple scientific groups for data integration, management, and analysis. The goal of this integrated platform is to address the challenges and to support the end-to-end analytical needs of various translational projects.