RNA-seq liver transcriptome analysis reveals an activated MHC-I pathway and an inhibited MHC-II pathway at the early stage of vaccine immunization in zebrafish

BACKGROUND: Zebrafish (Danio rerio) is a prominent vertebrate model of human development and pathogenic disease and has recently been utilized to study teleost immune responses to infectious agents threatening the aquaculture industry. In this work, to clarify the host immune mechanisms underlying the protective effects of a putative vaccine and improve its immunogenicity in the future efforts, high-throughput RNA sequencing technology was used to investigate the immunization-related gene expression patterns of zebrafish immunized with Edwardsiella tarda live attenuated vaccine. RESULTS: Average reads of 18.13 million and 14.27 million were obtained from livers of zebrafish immunized with phosphate buffered saline (mock) and E. tarda vaccine (WED), respectively. The reads were annotated with the Ensembl zebrafish database before differential expressed genes sequencing (DESeq) comparative analysis, which identified 4565 significantly differentially expressed genes (2186 up-regulated and 2379 down-regulated in WED; p<0.05). Among those, functional classifications were found in the Gene Ontology database for 3891 and in the Kyoto Encyclopedia of Genes and Genomes database for 3467. Several pathways involved in acute phase response, complement activation, immune/defense response, and antigen processing and presentation were remarkably affected at the early stage of WED immunization. Further qPCR analysis confirmed that the genes encoding the factors involved in major histocompatibility complex (MHC)-I processing pathway were up-regulated, while those involved in MHC-II pathway were down-regulated. CONCLUSION: These data provided insights into the molecular mechanisms underlying zebrafish immune response to WED immunization and might aid future studies to develop a highly immunogenic vaccine against gram-negative bacteria in teleosts

Identification and functional characterization of EseH, a new effector of the type III secretion system of Edwardsiella piscicida

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135199/1/cmi12638_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135199/2/cmi12638.pd

Physical activity and liver health among urban and rural Chinese adults: results from two independent surveys

Background Increased physical activity has been associated with reduced risks of various physical and mental conditions. However, the association between physical activity and liver health in the Chinese general adult population is not clear. This study investigated whether physical activity, stratified by intensity (i.e. walking (light), moderate-to-vigorous), was associated with alanine aminotransferase (ALT) level in middle-aged and older Chinese adults. Methods Two independent surveys of urban (n = 5,824, males 44%, mean (standard deviation) age 52 (10) years) and rural populations (n = 20,269, males 41%, mean (standard deviation) age 51 (10) years) were undertaken. Physical activity was measured using the International Physical Activity Questionnaire, and in metabolic equivalents of task (MET) × minutes. Elevated serum level of ALT, a clinical surrogate of abnormal liver function, was defined as >40 IU/L (males) and >30 IU/L (females). Multivariable regression models were used. Results Amount of moderate-to-vigorous activity was inversely associated with serum level of ALT (β = −0.147 per 1k MET-minutes, p < 0.001), whereas walking was not associated. People who reached the lower limit of WHO recommendation (≥600 MET-minutes per week) had a reduced odds of ALT elevation, compared to those who did not (adjusted odds ratio: 0.85 95%CI (0.76, 0.95)). Conclusions Meeting the moderate-to-vigorous recommendations for physical activity in adults may be associated with decreased likelihood of abnormal liver function both in Chinese urban and rural populations. Promoting such activities could be a low-cost strategy in maintaining liver health as well as providing many other health-related benefits

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Constituent Parameter Identification of Braided Composite Based on Sensitivity Analysis

Mechanical properties of the constituent material of fiber-reinforced braided composites will inevitably change after the manufacturing process. An approach to constituent parameters&rsquo; identification of braided composites was proposed to obtain the basic information of composites for structural analysis. Identification of the constituent parameters was transformed as an optimization problem, which was solved by adopting the sensitivity analysis method, iteratively minimizing the discrepancies between the numerically calculated displacement field and the measured displacement field. The sensitivity matrix of displacements with respect to the constituent parameters was directly derived based on the constitutive material model for the first time. Considering that the large magnitude differences between parameters will lead to an ill-posed problem of the sensitivity matrix, the identification was susceptible to noise from the experimental data, the relative sensitivity was adopted, and a condition number-based response point selection was applied to improve the robustness of the parameter identification. A 2.5-dimensional braided composite was employed to illustrate the constituent parameter identification method by comparing with the finite difference method. In addition, the influence of selected measuring points and measuring errors on the proposed method were discussed. The results showed that the proposed method can be used to identify the constituent parameters efficiently and accurately. When the measured displacements are polluted by noise, the condition number of the sensitivity matrix is an effective indicator of preceding information to enhance the identification accuracy

Thermal Performance Analysis on the Seasonal Heat Storage by Deep Borehole Heat Exchanger with the Extended Finite Line Source Model

Deep borehole heat exchanger is promising and competitive for seasonal heat storage in the limited space underground with great efficiency. However, seasonal heat storage performance of the essentially deep borehole heat exchanger reaching kilometers underground was seldom studied. In addition, previous research rarely achieved comprehensive assessment for its thermal performance due to seasonal heat storage. Insight into the complicated heat transfer characteristics during the whole process of prior charging and subsequent discharging of deep borehole heat exchanger is in urgent need to be clarified. To this end, an extended finite line source model is proposed to investigate thermal performance of the deep borehole heat exchanger during charging and discharging stages. It is developed with modifications of classical finite line source model to consider the spatio-temporally non-uniform distribution of heat flux density and anisotropic thermal conductivity of deep rock. In general, simulation results demonstrate that thermal performance of the deep borehole heat exchanger deteriorates rapidly both during charging and discharging stages, making it impossible to sustain long-term efficient operation. Specifically, it was discovered that low temperature heat storage utilized only upper section of the borehole as effective heat storage section, and enhancement for heat extraction potential during the heating season was not significant. While high temperature heat storage by deep borehole heat exchanger could only enhance the heat extraction potential for 30 to 40 days in the initial stage of heating. Throughout the discharging, maximum thermal performance enhancement up to 11.27 times was achieved and the heat storage efficiency was evaluated at 2.86 based on average heat exchange rate. The findings of this study are intended to provide a guidance for decisionmakers to determine the most suitable seasonal heat storage strategy for the deep borehole heat exchanger and facilitate the application in engineering practice

Dialysate Creatinine Response Patterns During Peritoneal Equilibration Test and the Association Between Cardiovascular Mortality: Findings from a Prospective Cohort Study

Background/Aims: During peritoneal equilibrium test (PET), intermediate measures of Dt/P (dialysate/plasma creatinine ratio), D0/P, D2/P and D4/P ratios might provide additional information regarding a patient’s cardiovascular mortality. We aimed to characterise heterogeneity of dialysate creatinine response patterns based on three ratios and compare cardiovascular mortality risks by response patterns. Methods: 3,477 patients initialising peritoneal dialysis (PD) between 2007-2015 were measured D0/P, D2/P and D4/P at baseline and 2-year cardiovascular mortality was defined as the primary outcome. Latent class mixed-effect models were fitted to identify distinct patterns of dialysate creatinine response. Multivariable Logistic regression model with adjustment of cardiometabolic factors were used to compare cardiovascular mortality by latent classes. Results: The 1st latent class including 36% of participants was characterised by consistently increasing and high Dt/P ratios both at 2-hour and 4-hour. The 2nd class including 61% of participants characterised by sharply increased ratio at 2-hour and slightly increased ratio at 4-hour. The 3rd class included 3% of participants with decreased ratio at 2-hour and increased ratio at 4-hour. Comparing the 1st class, the lower cardiovascular mortality risk was identified in the 2nd and 3rd class with adjusted odds ratio 0.65 (95% confidence interval: 0.62-0.69) and 0.48 (0.41-0.57), respectively. Conclusion: Patients with decreased Dt/P ratio between 0-hour and 2-hour and low ratios at 2-hour and 4-hour tend to have low cardiovascular mortality. Latent class analysis seems to be a promising method to reveal unidentified subgroups that do not fit into the risk category defined by Dt/P ratio at 4-hour