A comparison of scRNA-seq annotation methods based on experimentally labeled immune cell subtype dataset.

Cell-type annotation is a critical step in single-cell data analysis. With the development of numerous cell annotation methods, it is necessary to evaluate these methods to help researchers use them effectively. Reference datasets are essential for evaluation, but currently, the cell labels of reference datasets mainly come from computational methods, which may have computational biases and may not reflect the actual cell-type outcomes. This study first constructed an experimentally labeled immune cell-subtype single-cell dataset of the same batch and systematically evaluated 18 cell annotation methods. We assessed those methods under five scenarios, including intra-dataset validation, immune cell-subtype validation, unsupervised clustering, inter-dataset annotation, and unknown cell-type prediction. Accuracy and ARI were evaluation metrics. The results showed that SVM, scBERT, and scDeepSort were the best-performing supervised methods. Seurat was the best-performing unsupervised clustering method, but it couldn't fully fit the actual cell-type distribution. Our results indicated that experimentally labeled immune cell-subtype datasets revealed the deficiencies of unsupervised clustering methods and provided new dataset support for supervised methods.

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.

INTRODUCTION: Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. METHODS: Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. RESULTS: The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. CONCLUSION: Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

Effect of Individualized PEEP Guided by Driving Pressure on Diaphragm Function in Patients Undergoing Laparoscopic Radical Resection of Colorectal Cancer: A Randomized Controlled Trial.

BACKGROUND The concept of driving pressure (ΔP) has been established to optimize mechanical ventilation-induced lung injury. However, little is known about the specific effects of setting individualized positive end-expiratory pressure (PEEP) with driving pressure guidance on patient diaphragm function. MATERIAL AND METHODS Ninety patients were randomized into 3 groups, with PEEP set to 0 in group C; 5 cmH2O in group F; and individualized PEEP in group I, based on esophageal manometry. Diaphragm ultrasound was performed in the supine position at 6 consecutive time points from T0-T5: diaphragm excursion, end-expiratory diaphragm thickness (Tdi-ee), and diaphragm thickening fraction (DTF) were measured. Primary indicators included diaphragm excursion, Tdi-ee, and DTF at T0-T5, and the correlation between postoperative DTF and ΔP. Secondary indicators included respiratory mechanics, hemodynamic changes at intraoperative d0-d4 time points, and postoperative clinical pulmonary infection scores. RESULTS (1) Diaphragm function parameters reached the lowest point at T1 in all groups (P<0.001). (2) Compared with group C, diaphragm excursion decreased, Tdi-ee increased, and DTF was lower in groups I and F at T1-T5, with significant differences (P<0.05), but the differences between groups I and F were not significant (P>0.05). (3) DTF was significantly and positively correlated with mean intraoperative ΔP in each group at T3, and the correlation was stronger at higher levels of ΔP. CONCLUSIONS Individualized PEEP, achieved by esophageal manometry, minimizes diaphragmatic injury caused by mechanical ventilation based on lung protection, but its protection of the diaphragm during laparoscopic surgery is not superior to that of conventional ventilation strategies.

Emerging trends and hotspots of the itch research: A bibliometric and visualized analysis.

AIMS: Itch, a common uncomfortable sensory experience, occurs frequently in inflammatory or allergic disorders. In recent years, with the discovery of itch-specific pathways in the peripheral and central nervous system, the association between immunology and neural pathways has gradually emerged as the main mechanism of itch. Although many studies have been conducted on itch, no bibliometric analysis study focusing on this topic has been conducted. This study aimed to explore the research hotspots and trends in the itch field from a bibliometric perspective. METHODS: Publications relevant to itch, published from 2003 to 2022, were retrieved from the Science Citation Index-Expanded of Web of Science Core Collection. Publications were critically reviewed and analyzed with CiteSpace software, Vosviewer, and the bibliometric online analysis platform. Visual maps were conducted in terms of annual production, collaborating countries or institutions, productive authors, core journals, co-cited references, and keyword bursts. RESULTS: 2395 articles on itch that met our criteria were identified and the quantity of publications has been increasing rapidly since 2012. The USA was the most influential country. University Hospital Münster was the institution with the most publications. Gil Yosipovitch was the most prolific author. Atopic dermatitis (AD), intradermal serotonin, chronic pruritus, mechanical itch, gastrin-releasing peptide, substance p, interleukin-31 receptor, histamine-induced itch, bile acid, scratching behavior, and h-4 receptor were the top 11 clusters in co-citation cluster analysis. Keyword burst analysis suggested that treatment, inflammation, and AD are current research hotspots. CONCLUSION: Global publications on itch research have increased steadily and rapidly over the past 20 years. Inflammation and AD are current research hotspots. The neuroimmunological and neuroinflammatory mechanisms of itch, as well as clinical assessment methods and therapeutic targets, will be novel research directions in the future. This study provides guidance for further itch research.

The G protein-coupled estrogen receptor of the trigeminal ganglion regulates acute and chronic itch in mice.

AIMS: Itch is an unpleasant sensation that severely impacts the patient's quality of life. Recent studies revealed that the G protein-coupled estrogen receptor (GPER) may play a crucial role in the regulation of pain and itch perception. However, the contribution of the GPER in primary sensory neurons to the regulation of itch perception remains elusive. This study aimed to investigate whether and how the GPER participates in the regulation of itch perception in the trigeminal ganglion (TG). METHODS AND RESULTS: Immunofluorescence staining results showed that GPER-positive (GPER+ ) neurons of the TG were activated in both acute and chronic itch. Behavioral data indicated that the chemogenetic activation of GPER+ neurons of the TG of Gper-Cre mice abrogated scratching behaviors evoked by acute and chronic itch. Conversely, the chemogenetic inhibition of GPER+ neurons resulted in increased itch responses. Furthermore, the GPER expression and function were both upregulated in the TG of the dry skin-induced chronic itch mouse model. Pharmacological inhibition of GPER (or Gper deficiency) markedly increased acute and chronic itch-related scratching behaviors in mouse. Calcium imaging assays further revealed that Gper deficiency in TG neurons led to a marked increase in the calcium responses evoked by agonists of the transient receptor potential ankyrin A1 (TRPA1) and transient receptor potential vanilloid V1 (TRPV1). CONCLUSION: Our findings demonstrated that the GPER of TG neurons is involved in the regulation of acute and chronic itch perception, by modulating the function of TRPA1 and TRPV1. This study provides new insights into peripheral itch sensory signal processing mechanisms and offers new targets for future clinical antipruritic therapy.

Lidocaine aerosol preoperative application for improving the comfort of pediatric patients undergoing tonsillectomy and adenoidectomy: A prospective randomized controlled trial.

Background and Aims: The use of lidocaine aerosol for pediatric tonsil and adenoidectomy has been reported less frequently. We hope to improve the perioperative comfort of pediatric patients undergoing these procedures by applying lidocaine aerosol. Methods: A total of 122 pediatric patients receiving tonsil and adenoidectomy were randomly divided into a lidocaine aerosol group (Group L) and a saline group (Group C), with 61 patients in each group; 2.4% alkaline lidocaine aerosol and saline were sprayed in the pharynx before induction. Our primary outcome were the incidence and rate ratio (RR) of postoperative pharyngeal complications (oropharyngeal dryness, dysphagia, hoarseness, and sore throat) and the pharyngeal comfort score, the latter of which was assessed by the occurrence of the above complications (yes = 0 point, none = 1 point). The secondary outcomes included preoperative and intraoperative blood pressure and heart rate, the incidence of choking during the induction period, the intraoperative opioid dosage, and the pain level and depth of sedation at 2, 6, and 24 h postoperatively. Statistical software used in this study included PASS15.0, SPSS 26.0, and GraphPad Prism 9.3.1, and statistical methods used included the t-test, the χ² test, the Mann-Whitney U test, and the repeated measures analysis of variance. Results: The incidence and RR of postoperative pharyngeal complications such as oropharyngeal dryness (RR: 0.667, 95% confidence interval [CI]: 0.458-0.970, p = 0.03), dysphagia (RR: 0.333, 95% CI: 0.114-0.976, p = 0.03), hoarseness (RR: 0.647, 95% CI: 0.433-0.967, p = 0.03), and sore throat (RR: 0.727, 95% CI: 0.547-0.967, p = 0.03) were significantly lower in Group L than in Group C at 2 h postoperatively, and the incidence and RR of postoperative sore throat was significantly lower in Group L than in Group C at 6 h postoperatively (RR: 0.717, 95% CI: 0.547-0.942, p = 0.01). The postoperative pharyngeal comfort scores were significantly higher in Group L than in Group C at all postoperative time points (p < 0.05). The Ramsay sedation score was significantly higher (p < 0.01) and FLACC (face, legs, activity, crying, and consolability) score was significantly lower (p < 0.01) in Group L than in Group C at 2 h postoperatively. In Group C, the blood pressure and heart rate significantly faster at all time points immediately after intubation and afterward, except at the end of surgery (p < 0.05). Conclusions: In pediatric tonsil and adenoidectomy, the application of lidocaine aerosol before induction can reduce the incidence of postoperative pharyngeal complications, improve the child's postoperative pharyngeal comfort, and better realize perioperative "comfort medical treatment."

RDKG-115: Assisting drug repurposing and discovery for rare diseases by trimodal knowledge graph embedding.

Rare diseases (RDs) may affect individuals in small numbers, but they have a significant impact on a global scale. Accurate diagnosis of RDs is challenging, and there is a severe lack of drugs available for treatment. Pharmaceutical companies have shown a preference for drug repurposing from existing drugs developed for other diseases due to the high investment, high risk, and long cycle involved in RD drug development. Compared to traditional approaches, knowledge graph embedding (KGE) based methods are more efficient and convenient, as they treat drug repurposing as a link prediction task. KGE models allow for the enrichment of existing knowledge by incorporating multimodal information from various sources. In this study, we constructed RDKG-115, a rare disease knowledge graph involving 115 RDs, composed of 35,643 entities, 25 relations, and 5,539,839 refined triplets, based on 372,384 high-quality literature and 4 biomedical datasets: DRKG, Pathway Commons, PharmKG, and PMapp. Subsequently, we developed a trimodal KGE model containing structure, category, and description embeddings using reverse-hyperplane projection. We utilized this model to infer 4199 reliable new inferred triplets from RDKG-115. Finally, we calculated potential drugs and small molecules for each of the 115 RDs, taking multiple sclerosis as a case study. This study provides a paradigm for large-scale screening of drug repurposing and discovery for RDs, which will speed up the drug development process and ultimately benefit patients with RDs. The source code and data are available at https://github.com/ZhuChaoY/RDKG-115.

MDTips: a multimodal-data-based drug-target interaction prediction system fusing knowledge, gene expression profile, and structural data.

MOTIVATION: Screening new drug-target interactions (DTIs) by traditional experimental methods is costly and time-consuming. Recent advances in knowledge graphs, chemical linear notations, and genomic data enable researchers to develop computational-based-DTI models, which play a pivotal role in drug repurposing and discovery. However, there still needs to develop a multimodal fusion DTI model that integrates available heterogeneous data into a unified framework. RESULTS: We developed MDTips, a multimodal-data-based DTI prediction system, by fusing the knowledge graphs, gene expression profiles, and structural information of drugs/targets. MDTips yielded accurate and robust performance on DTI predictions. We found that multimodal fusion learning can fully consider the importance of each modality and incorporate information from multiple aspects, thus improving model performance. Extensive experimental results demonstrate that deep learning-based encoders (i.e. Attentive FP and Transformer) outperform traditional chemical descriptors/fingerprints, and MDTips outperforms other state-of-the-art prediction models. MDTips is designed to predict the input drugs' candidate targets, side effects, and indications with all available modalities. Via MDTips, we reverse-screened candidate targets of 6766 drugs, which can be used for drug repurposing and discovery. AVAILABILITY AND IMPLEMENTATION: https://github.com/XiaoqiongXia/MDTips and https://doi.org/10.5281/zenodo.7560544.

The Value of the Optic Nerve Sheath Diameter (ONSD) in Predicting Postdural Puncture Headache (PDPH): A Prospective Observational Study.

BACKGROUND: Postdural puncture headache (PDPH) is one of the serious complications after lumbar puncture, but there is no effective tool to predict it. OBJECTIVES: To explore whether ultrasound measurement of optic nerve sheath diameter (ONSD) as a predictor of PDPH can be a reliable tool supported by reliable protocols and data. STUDY DESIGN: A prospective observational study. SETTING: Department of Anesthesiology. METHODS: This prospective observational study was performed in 156 patients undergoing cesarean section (CS). The patient's ONSD was recorded before anesthesia (T0), 10 minutes after anesthesia (T1), at the end of the operation (T2), at the first postoperative day (T24), at the second postoperative day (T48), and the third postoperative day (T72). During the 3-day follow-up, the patients were evaluated, identified, and divided into a PDPH group and a non-PDPH group. Age, weight, height, ASA, lumbar puncture location, and the number of lumbar puncture attempts were also recorded. We mainly analyzed the changes and differences between the 2 groups of ONSD. RESULTS: Twenty-four patients (15%) developed PDPH. The ONSD was significantly lower in the PDPH group than in the non-PDPH group at T2, T24, T48, and T72. All patients showed a significant reduction in ONSD at T1 compared to T0. Women whose ONSD continued to fall without recovery from T0 to T2 were more likely to experience PDPH (RR 5. 022; 95 CI 3.343 to 7.508). The ONSD at T24 was the best predictor of PDPH (ACU 0. 9787, 95 CI 0.9578 to 0.9996), with a cutoff value of 0.40 cm (sensitivity 92%, specificity 94%). LIMITATIONS: This is a single-center study, and ONSD may vary in different regions or ethnic groups. CONCLUSIONS: We believe that continuous measurements of ONSD may be a useful tool for predicting PDPH.

Association between the reactivity of local cerebral oxygen saturation after hypo-to-hypercapnic tests and delirium after abdominal surgery in older adults: A prospective study.

Objective: This study aimed to investigate the correlation between changes in regional cerebral oxygen saturation (rSO2) and postoperative delirium in older adults undergoing major abdominal surgery. Materials and methods: This prospective study enrolled older adults scheduled for elective major abdominal surgery at the Second Affiliated Hospital of Anhui Medical University from August 2021 to January 2022. The change in rSO2 from baseline was determined using the hypo-to-hypercapnic test. The main study outcome was the occurrence of postoperative delirium. Results: A total of 101 participants were included for analysis, of whom 16 (15.8%) developed postoperative delirium. Compared with non-delirium participants, the mean arterial pressure and heart rate were not significantly different in the postoperative delirium group at T0, T1, T2, T3, T4, and T6 (all Pinteraction > 0.05), but the delirium group had lower pH, lower PaO2, and higher lactate levels at T4, T5, and T6 (all Pinteraction < 0.05). rSO2 at T0, T1, T2, T3, T4, and T6 was 69.0 (63.2-75.2), 70.7 ± 7.3, 68.2 ± 7.5, 72.1 ± 8.0, 69.9 ± 7.8, 67.4 ± 7.2, and 71.7 ± 8.1, respectively. The postoperative change in rSO2 during the hypercapnia test (TΔrSO2%) was 6.62 (5.31-9.36). Multivariable analysis showed that the Cumulative Illness Rating Scale (odd ratio, OR = 1.89, 95% confidence interval, CI: 1.10-3.25, P = 0.021), preoperative albumin levels (OR = 0.67, 95% CI: 0.48-0.94, P = 0.022), rSO2 at T4 (OR = 0.61, 95% CI: 0.41-0.89, P = 0.010), and postoperative TΔrSO2% (OR = 0.80, 95% CI: 0.66-0.98, P = 0.028) were independently associated with postoperative delirium in older adults undergoing elective abdominal surgery. Conclusion: The rSO2 measured at T4 and postoperative TΔrSO2% were independently associated with postoperative delirium in older adults undergoing elective abdominal surgery.

Applicability and effectiveness of ultrasound combined with nerve stimulator-guided lumbosacral plexus block in the supine versus lateral position during surgeries for lower limb fracture-a prospective randomized controlled trial.

BACKGROUND: Patients with lower limb fracture often have acute pain and discomfort from changes in position, and such pain affects early postoperative recovery. This study aimed to compare the applicability and effectiveness of ultrasound combined with nerve stimulator-guided lumbosacral plexus block (LSPB) in the supine versus lateral position during lower limb fracture surgery. METHODS: We included 126 patients who underwent elective internal fixation for lower limb fracture who were divided into the S group and the L group by the random number table method and underwent LSPB guided by ultrasound combined with a nerve stimulator in the supine and lateral positions, respectively. The primary outcome was the dose of sufentanil used in surgery. The secondary outcomes were the maximum VAS (visual analogue scale) pain score at position placing for LSPB, the time of position placing, the time for nerve block,the number of puncture attempts,the haemodynamic indicators, the VAS score at 1, 12, and 24 h following surgery, postoperative satisfactory degree to analgesia and adverse events related to nerve block. RESULTS: There was no statistically significant difference in dose of sufentanil used between the two groups(P = 0.142). The maximum VAS pain score at position placing(P < 0.01), the time of position placement(P < 0.01), the time for lumbar plexus block and the time of puncture attempts were significantly lower in the S group than in the L group (P < 0.01). However, the time for sacral plexus block was higher in the S group than in the L group (P = 0.029). There was no significant difference in haemodynamic indicators,number of puncture attempts for the sacral plexus, postoperative VAS scores, postoperative satisfactory degree to analgesia or adverse events related to nerve block between the two groups (all P > 0.05). CONCLUSIONS: Our study provides a more comfortable and better accepted anaesthetic regimen for patients undergoing lower limb fracture surgery. LSPB in the supine position is simple to apply and has definite anaesthetic effects. Additionally, it has a high level of postoperative analgesia and therefore should be widely applied. TRIAL REGISTRATION: The trial was registered prior to patient enrolment at the Chinese Clinical Trail Registry (Date:11/03/2021 Number: ChiCTR2100044117 ).

Comparison of Outcomes Following General Anesthesia and Spinal Anesthesia During Emergency Cervical Cerclage in Singleton Pregnant Women in the Second Trimester at a Single Center.

BACKGROUND Little information exists regarding the best anesthesia method for emergency cerclage. This single-center study aimed to compare the outcomes following general anesthesia and spinal anesthesia during emergency cervical cerclage in women in the second trimester of a singleton pregnancy. MATERIAL AND METHODS A total of 297 pregnant patients were recruited: 141 patients were assigned to the general anesthesia group and 156 patients were assigned to the spinal anesthesia group. Periprocedural data and obstetric outcomes were recorded and statistically analyzed. RESULTS Average duration of the cerclage procedure was shorter in the general anesthesia group than in the spinal anesthesia group (25.78±9.4 min versus 30.88±10.5 min; P<0.05). No severe maternal complications, such as hematosepsis or maternal death, occurred after the procedure for either group. The neutrophil-lymphocyte ratio and C-reactive protein (CRP) increased after emergency cerclage in both groups, but at no time did the 2 groups differ significantly (P>0.05). There was also no significant difference in the incidence of miscarriage or preterm delivery (delivery <34 gestational weeks) or in neonatal outcome between the 2 groups (P>0.05). CONCLUSIONS The results of this study showed that there were no significant differences in maternal and neonatal outcomes, rates of miscarriage, or preterm delivery between general anesthesia and spinal anesthesia during emergency cervical cerclage in women in the second trimester of a singleton pregnancy.

Multimodal reasoning based on knowledge graph embedding for specific diseases.

MOTIVATION: Knowledge Graph (KG) is becoming increasingly important in the biomedical field. Deriving new and reliable knowledge from existing knowledge by KG embedding technology is a cutting-edge method. Some add a variety of additional information to aid reasoning, namely multimodal reasoning. However, few works based on the existing biomedical KGs are focused on specific diseases. RESULTS: This work develops a construction and multimodal reasoning process of Specific Disease Knowledge Graphs (SDKGs). We construct SDKG-11, a SDKG set including five cancers, six non-cancer diseases, a combined Cancer5 and a combined Diseases11, aiming to discover new reliable knowledge and provide universal pre-trained knowledge for that specific disease field. SDKG-11 is obtained through original triplet extraction, standard entity set construction, entity linking and relation linking. We implement multimodal reasoning by reverse-hyperplane projection for SDKGs based on structure, category and description embeddings. Multimodal reasoning improves pre-existing models on all SDKGs using entity prediction task as the evaluation protocol. We verify the model's reliability in discovering new knowledge by manually proofreading predicted drug-gene, gene-disease and disease-drug pairs. Using embedding results as initialization parameters for the biomolecular interaction classification, we demonstrate the universality of embedding models. AVAILABILITY AND IMPLEMENTATION: The constructed SDKG-11 and the implementation by TensorFlow are available from https://github.com/ZhuChaoY/SDKG-11. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[Effects of low-dose dexmedetomidine combined with hydromorphone in postoperative analgesia and on the serum IL-6 and CRP levels of prostate cancer patients].

OBJECTIVE: To explore the effects of low-dose dexmedetomidine (DM) combined with hydromorphone (HM) in postoperative analgesia and on levels of serum interleukin-6 (IL-6) and C-reactive protein (CRP) in PCa patients. METHODS: Using the random number table, we divided 102 PCa patients undergoing radical prostatectomy from January 2019 to November 2020 into a trial group (n = 51) and a control group (n = 51), the former given HM and the latter low-dose DM + HM for postoperative analgesia. We recorded the postoperative resuscitation time, extubation time and pain, perioperative cognitive function, IL-6 and CRP levels, and drug-related adverse reactions of the patients, and compared them between the two groups. RESULTS: There was no statistically significant difference in postoperative resuscitation time and extubation time between the two groups of patients (P > 0.05). The frequency of patient-controlled epidural analgesia (PCEA) compressions was lower in the trial than in the control group within 24 hours after surgery (P < 0.05). The Visual Analogue Scale (VAS) scores were higher in both of the groups at 24 hours than at 4, 12, and 48 hours after surgery (P < 0.05), at 12 hours than at 4 and 48 hours (P < 0.05) and at 4 hours than at 48 hours (P < 0.05), but lower in the trial than in the control group at 4, 12 and 24 hours postoperatively (P < 0.05). No statistically significant difference was observed in the scores of the Mini Mental State Evaluation Scale between the two groups of patients (P > 0.05). The levels of IL-6 and CRP were higher in both of the groups at 24 hours after than before and at 4, 12 and 48 hours after surgery (P < 0.05), at 48 hours after than before and at 4 and 12 hours after surgery (P < 0.05), at 12 hours after than before and at 4 hours after surgery (P <0.05), and at 4 hours after than before surgery (P < 0.05), but lower in the trial than in the control group at 4, 12, 24 and 48 hours postoperatively (P < 0.05). There was no statistically significant difference in the total incidence rate of adverse reactions between the two groups (P > 0.05). CONCLUSIONS: Low-dose dexmedetomidine combined with hydromorphone is a safe and effective option for postoperative analgesia in PCa patients, and it can inhibit the expression of inflammatory factors.

Pan-Cancer Genome-Wide DNA Methylation Analyses Revealed That Hypermethylation Influences 3D Architecture and Gene Expression Dysregulation in HOXA Locus During Carcinogenesis of Cancers.

DNA methylation dysregulation during carcinogenesis has been widely discussed in recent years. However, the pan-cancer DNA methylation biomarkers and corresponding biological mechanisms were seldom investigated. We identified differentially methylated sites and regions from 5,056 The Cancer Genome Atlas (TCGA) samples across 10 cancer types and then validated the findings using 48 manually annotated datasets consisting of 3,394 samples across nine cancer types from Gene Expression Omnibus (GEO). All samples' DNA methylation profile was evaluated with Illumina 450K microarray to narrow down the batch effect. Nine regions were identified as commonly differentially methylated regions across cancers in TCGA and GEO cohorts. Among these regions, a DNA fragment consisting of ∼1,400 bp detected inside the HOXA locus instead of the boundary may relate to the co-expression attenuation of genes inside the locus during carcinogenesis. We further analyzed the 3D DNA interaction profile by the publicly accessible Hi-C database. Consistently, the HOXA locus in normal cell lines compromised isolated topological domains while merging to the domain nearby in cancer cell lines. In conclusion, the dysregulation of the HOXA locus provides a novel insight into pan-cancer carcinogenesis.

The Model of Aging Acceleration Network Reveals the Correlation of Alzheimer's Disease and Aging at System Level.

As the incidence of senile dementia continues to increase, researches on Alzheimer's disease (AD) have become more and more important. Several studies have reported that there is a close relationship between AD and aging. Some researchers even pointed out that if we wanted to understand AD in depth, mechanisms of AD based on accelerated aging must be studied. Nowadays, machine learning techniques have been utilized to deal with large and complex profiles, thus playing an important role in disease researches (i.e., modelling biological systems, identifying key modules based on biological networks, and so on). Here, we developed an aging predictor and an AD predictor using machine learning techniques, respectively. Both aging and AD biomarkers were identified to provide insights into genes associated with AD. Besides, aging scores were calculated to reflect the aging process of brain tissues. As a result, the aging acceleration network and the aging-AD bipartite graph were constructed to delve into the relationship between AD and aging. Finally, a series of network and enrichment analyses were also conducted to gain further insights into the mechanisms of AD based on accelerated aging. In a word, our results indicated that aging may contribute to the development of AD by affecting the function of the immune system and the energy metabolism process, where the immune system may play a more prominent role in AD.

Network analysis of aging acceleration reveals systematic properties of 11 types of cancers.

Cancers are known to be associated with accelerated aging, but to date, there has been a paucity of systematic and in-depth studies of the correlation between aging and cancer. DNA methylation (DNAm) profiles can be used as aging markers and utilized to construct aging predictors. In this study, we downloaded 333 paired samples of DNAm, expression and mutation profiles encompassing 11 types of tissues from The Cancer Genome Atlas public access portal. The DNAm aging scores were calculated using the Support Vector Machine regression model. The DNAm aging scores of cancers revealed significant aging acceleration compared to adjacent normal tissues. Aging acceleration-associated mutation modules and expression modules were identified in 11 types of cancers. In addition, we constructed bipartite networks of mutations and expression, and the differential expression modules related to aging-associated mutations were selected in 11 types of cancers using the expression quantitative trait locus method. The results of enrichment analyses also identified common functions across cancers and cancer-specific characteristics of aging acceleration. The aging acceleration interaction network across cancers suggested a core status of thyroid carcinoma and neck squamous cell carcinoma in the aging process. In summary, we have identified correlations between aging and cancers and revealed insights into the biological functions of the modules in aging and cancers.

The convergence of Chinese county government health expenditures: capitation and contribution.

BACKGROUND: The disparity between government health expenditures across regions is more severe in developing countries than it is in developed countries. The capitation subsidy method has been proven effective in developed countries in reducing this disparity, but it has not been tested in China, the world's largest developing country. METHODS: The convergence method of neoclassical economics was adopted to test the convergence of China's regional government health expenditure. Data were obtained from Provinces, Prefectures and Counties Fiscal Statistical Yearbook (2003-2007) edited by the Chinese Ministry of Finance, and published by the Chinese Finance & Economics Publishing House. RESULTS: The existence of σ-convergence and long-term and short-term ß-convergence indicated the effectiveness of the capitation subsidy method in the New Rural Cooperative Medical Scheme on narrowing county government health expenditure disparities. The supply-side variables contributed the most to the county government health expenditure convergence, and factors contributing to convergence of county government health expenditures per capita were different in three regions. CONCLUSION: The narrowing disparity between county government health expenditures across regions supports the effectiveness of the capitation subsidy method adopted by China's New Rural Cooperative Scheme. However, subsidy policy still requires further improvement.

Opioid-induced redistribution of 6TM and 7TM µ opioid receptors: A hypothesized mechanistic facilitator model of opioid-induced hyperalgesia.

Opioids are still the most popular form of pain treatment, but many unavoidable side effects make opioids a big challenge in effective pain management. Opioid-induced hyperalgesia (OIH), a paradoxical phenomenon, portrays an increased sensitivity to harmful stimuli caused by opioid exposure. Changes in the neural modulation are considered a major contributor to the development of OIH. Activation of opioid receptors (ORs) and corresponding downstream molecules are the vital composition of functional performance of opioids. Increasing interests were proposed of the interaction between ORs and other neural transmitter systems such as glutamatergic, GABAergic and adrenergic ones to the genesis of OIH. G protein coupled µ-opioid receptor (MOR) was studied comprehensively on its role in the development of OIH. In addition to the relationship between MOR and other neurotransmitter receptors, a new intracellular MOR that has six transmembrane (6TM) domains was identified, and found to perform a pro-nociceptive task in contrast to the counterpart 7TM isoform. A mechanistic model of OIH in which both 6TM and 7TM MORs undergoing membrane redistribution upon opioid exposure is proposed which eventually facilitates the neurons more sensitive to nociceptive stimulation than that of the preceding opioid exposure.

Postoperative cognitive dysfunction: current developments in mechanism and prevention.

Postoperative cognitive dysfunction (POCD) is a subtle disorder of thought processes, which may influence isolated domains of cognition and has a significant impact on patient health. The reported incidence of POCD varies enormously due to lack of formal criteria for the assessment and diagnosis of POCD. The significant risk factors of developing POCD mainly include larger and more invasive operations, duration of anesthesia, advanced age, history of alcohol abuse, use of anticholinergic medications, and other factors. The release of cytokines due to the systemic stress response caused by anesthesia and surgical procedures might induce the changes of brain function and be involved in the development of postoperative cognitive dysfunction. The strategies for management of POCD should be a multimodal approach involving close cooperation between the anesthesiologist, surgeon, geriatricians, and family members to promote early rehabilitation and avoid loss of independence in these patients.