The genome-wide signature of short-term temporal selection.

Despite evolutionary biology's obsession with natural selection, few studies have evaluated multigenerational series of patterns of selection on a genome-wide scale in natural populations. Here, we report on a 10-y population-genomic survey of the microcrustacean Daphnia pulex. The genome sequences of [Formula: see text]800 isolates provide insights into patterns of selection that cannot be obtained from long-term molecular-evolution studies, including the following: the pervasiveness of near quasi-neutrality across the genome (mean net selection coefficients near zero, but with significant temporal variance about the mean, and little evidence of positive covariance of selection across time intervals); the preponderance of weak positive selection operating on minor alleles; and a genome-wide distribution of numerous small linkage islands of observable selection influencing levels of nucleotide diversity. These results suggest that interannual fluctuating selection is a major determinant of standing levels of variation in natural populations, challenge the conventional paradigm for interpreting patterns of nucleotide diversity and divergence, and motivate the need for the further development of theoretical expressions for the interpretation of population-genomic data.

A high-resolution haplotype-resolved Reference panel constructed from the China Kadoorie Biobank Study.

Precision medicine depends on high-accuracy individual-level genotype data. However, the whole-genome sequencing (WGS) is still not suitable for gigantic studies due to budget constraints. It is particularly important to construct highly accurate haplotype reference panel for genotype imputation. In this study, we used 10 000 samples with medium-depth WGS to construct a reference panel that we named the CKB reference panel. By imputing microarray datasets, it showed that the CKB panel outperformed compared panels in terms of both the number of well-imputed variants and imputation accuracy. In addition, we have completed the imputation of 100 706 microarrays with the CKB panel, and the after-imputed data is the hitherto largest whole genome data of the Chinese population. Furthermore, in the GWAS analysis of real phenotype height, the number of tested SNPs tripled and the number of significant SNPs doubled after imputation. Finally, we developed an online server for offering free genotype imputation service based on the CKB reference panel (https://db.cngb.org/imputation/). We believe that the CKB panel is of great value for imputing microarray or low-coverage genotype data of Chinese population, and potentially mixed populations. The imputation-completed 100 706 microarray data are enormous and precious resources of population genetic studies for complex traits and diseases.

Evolutionary Insights from a Large-Scale Survey of Population-Genomic Variation.

The field of genomics has ushered in new methods for studying molecular-genetic variation in natural populations. However, most population-genomic studies still rely on small sample sizes (typically, <100 individuals) from single time points, leaving considerable uncertainties with respect to the behavior of relatively young (and rare) alleles and, owing to the large sampling variance of measures of variation, to the specific gene targets of unusually strong selection. Genomic sequences of ∼1,700 haplotypes distributed over a 10-year period from a natural population of the microcrustacean Daphnia pulex reveal evolutionary-genomic features at a refined scale, including previously hidden information on the behavior of rare alleles predicted by recent theory. Background selection, resulting from the recurrent introduction of deleterious alleles, appears to strongly influence the dynamics of neutral alleles, inducing indirect negative selection on rare variants and positive selection on common variants. Temporally fluctuating selection increases the persistence of nonsynonymous alleles with intermediate frequencies, while reducing standing levels of variation at linked silent sites. Combined with the results from an equally large metapopulation survey of the study species, classes of genes that are under strong positive selection can now be confidently identified in this key model organism. Most notable among rapidly evolving Daphnia genes are those associated with ribosomes, mitochondrial functions, sensory systems, and lifespan determination.

AMDBNorm: an approach based on distribution adjustment to eliminate batch effects of gene expression data.

Batch effects explain a large part of the noise when merging gene expression data. Removing irrelevant variations introduced by batch effects plays an important role in gene expression studies. To obtain reliable differential analysis results, it is necessary to remove the variation caused by technical conditions between different batches while preserving biological variation. Usually, merging data directly with batch effects leads to a sharp rise in false positives. Although some methods of batch correction have been developed, they have some drawbacks. In this study, we develop a new algorithm, adjustment mean distribution-based normalization (AMDBNorm), which is based on a probability distribution to correct batch effects while preserving biological variation. AMDBNorm solves the defects of the existing batch correction methods. We compared several popular methods of batch correction with AMDBNorm using two real gene expression datasets with batch effects and analyzed the results of batch correction from the visual and quantitative perspectives. To ensure the biological variation was well protected, the effects of the batch correction methods were verified by hierarchical cluster analysis. The results showed that the AMDBNorm algorithm could remove batch effects of gene expression data effectively and retain more biological variation than other methods. Our approach provides the researchers with reliable data support in the study of differential gene expression analysis and prognostic biomarker selection.

Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression.

BACKGROUND: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. METHODS: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. RESULTS: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. CONCLUSIONS: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.

Evolutionary Genomics of a Subdivided Species.

The ways in which genetic variation is distributed within and among populations is a key determinant of the evolutionary features of a species. However, most comprehensive studies of these features have been restricted to studies of subdivision in settings known to have been driven by local adaptation, leaving our understanding of the natural dispersion of allelic variation less than ideal. Here, we present a geographic population-genomic analysis of 10 populations of the freshwater microcrustacean Daphnia pulex, an emerging model system in evolutionary genomics. These populations exhibit a pattern of moderate isolation-by-distance, with an average migration rate of 0.6 individuals per generation, and average effective population sizes of ∼650,000 individuals. Most populations contain numerous private alleles, and genomic scans highlight the presence of islands of excessively high population subdivision for more common alleles. A large fraction of such islands of population divergence likely reflect historical neutral changes, including rare stochastic migration and hybridization events. The data do point to local adaptive divergence, although the precise nature of the relevant variation is diffuse and cannot be associated with particular loci, despite the very large sample sizes involved in this study. In contrast, an analysis of between-species divergence highlights positive selection operating on a large set of genes with functions nearly nonoverlapping with those involved in local adaptation, in particular ribosome structure, mitochondrial bioenergetics, light reception and response, detoxification, and gene regulation. These results set the stage for using D. pulex as a model for understanding the relationship between molecular and cellular evolution in the context of natural environments.

Genetic Diversity, Heteroplasmy, and Recombination in Mitochondrial Genomes of Daphnia pulex, Daphnia pulicaria, and Daphnia obtusa.

Genetic variants of mitochondrial DNA at the individual (heteroplasmy) and population (polymorphism) levels provide insight into their roles in multiple cellular and evolutionary processes. However, owing to the paucity of genome-wide data at the within-individual and population levels, the broad patterns of these two forms of variation remain poorly understood. Here, we analyze 1,804 complete mitochondrial genome sequences from Daphnia pulex, Daphnia pulicaria, and Daphnia obtusa. Extensive heteroplasmy is observed in D. obtusa, where the high level of intraclonal divergence must have resulted from a biparental-inheritance event, and recombination in the mitochondrial genome is apparent, although perhaps not widespread. Global samples of D. pulex reveal remarkably low mitochondrial effective population sizes, <3% of those for the nuclear genome. In addition, levels of population diversity in mitochondrial and nuclear genomes are uncorrelated across populations, suggesting an idiosyncratic evolutionary history of mitochondria in D. pulex. These population-genetic features appear to be a consequence of background selection associated with highly deleterious mutations arising in the strongly linked mitochondrial genome, which is consistent with polymorphism and divergence data suggesting a predominance of strong purifying selection. Nonetheless, the fixation of mildly deleterious mutations in the mitochondrial genome also appears to be driving positive selection on genes encoded in the nuclear genome whose products are deployed in the mitochondrion.

Early Lactate/Albumin and Procalcitonin/Albumin Ratios as Predictors of 28-Day Mortality in ICU-Admitted Sepsis Patients: A Retrospective Cohort Study.

BACKGROUND Lactate/albumin (LA/ALB) and procalcitonin/albumin (PCT/ALB) ratios have been implicated in predicting mortality in sepsis patients. However, their prognostic value and relationship to sepsis severity require further investigation. This retrospective study aimed to assess the prognostic value of lactate/albumin (LA/ALB) and procalcitonin/albumin (PCT/ALB) ratios in septic patients admitted to the Intensive Care Unit (ICU). MATERIAL AND METHODS A total of 340 adult sepsis patients admitted to the ICU were included in the derivation cohort. LA/ALB and PCT/ALB ratios were calculated and analyzed in relation to sepsis severity and survival status. Additionally, a validation cohort of 75 sepsis patients from another medical center was selected. RESULTS In the derivation cohort, higher LA/ALB and PCT/ALB ratios and SOFA scores were significantly associated with increased mortality (P<0.001). The LA/ALB and PCT/ALB ratios positively correlated with SOFA score. Survival analysis revealed significantly higher 28-day mortality in sepsis patients with elevated PCT/ALB (≥0.256) and LA/ALB (≥0.079) ratios upon ICU admission. The constructed prediction model incorporating LA/ALB ratio, PCT/ALB ratio, and SOFA score yielded an AUC of 0.826, demonstrating good predictive ability. The associations between LA/ALB and PCT/ALB ratios and 28-day mortality in sepsis patients were validated in the validation cohort. CONCLUSIONS The LA/ALB and PCT/ALB ratios at ICU admission provide valuable prognostic information for predicting 28-day mortality in sepsis patients. Combining these ratios with SOFA score improves the assessment of prognosis in sepsis patients.

FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism.

Previous studies demonstrated that arginine biosynthesis was frequently impaired in acute liver injury. However, the underlying mechanisms remain elusive. In this study, we found that Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine metabolism, was downregulated in the TAA-induced liver injury model. Single-cell RNA-seq data found that ASS1 was highly enriched in the hepatocytes. The reduction of ASS1 was attributed to the decreased expression of Farnesoid X receptor (FXR), which is a bile acid-activated nuclear hormone receptor with high expression in the liver. Subsequent studies demonstrated that activation of FXR by its agonist obeticholic acid (OCA) directly promoted ASS1 transcription and enhanced arginine synthesis, leading to the alleviation of TAA-mediated liver injury. Further experiments found that OCA, ASS1, and arginine supplement can rescue TAA-mediated hepatocytes apoptosis by decreasing the protein levels of Cyto C, PARP, and Caspase 3. Taken together, our study illustrated a protective role of the FXR/ASS1 axis in TAA-induced liver injury by targeting arginine metabolism, which might shed light on the development of novel therapeutic approaches for acute liver injury.

Safety evaluation and pharmacodynamics of minocycline hydrochloride eye drops.

PURPOSE: This study evaluated the safe dosage of minocycline hydrochloride (Mino) eye drops and investigated the potential for the prevention or reduction of retinal damage in a diabetic rat model. METHODS: Various concentrations of Mino were applied to human corneal epithelial cells (HCECs) to determine the half maximal inhibitory concentration (IC50). The safety of Mino eye drops was evaluated on Sprague-Dawley (SD) rat eyes by slit-lamp examination, electroretinography (ERG), histology, and TUNEL assay. Eye drops (1 mg/ml) were applied to the streptozotocin-induced diabetic SD rats. Clinical observations, ERG analyses, and optical coherence tomography analyses were performed monthly for five months. Eyes were then analyzed via histology, blood-retinal barrier function assay, and retinal vascular staining. RESULTS: Cytotoxicity analysis using HCECs revealed that the IC50 was 250 µg/ml. Safety analyses in healthy SD rats showed that Mino eye drops did not demonstrate any ocular toxicity. Pharmacodynamics analysis showed that retinal thickness at three months was greater in the Mino group than in the non treated (NT) group. The peak times and amplitudes of each program were better in the Mino group than in the NT group at each time point by ERG analyses. Histology examinations showed a thinner ganglion cell layer, fewer ganglion cells, and more dilated blood vessels in the NT group than in the Mino group. CONCLUSION: Mino eye drops at 1 mg/ml were safe when used in SD rats. Mino eye drops can protect the retina from the development or progression of diabetic retinopathy.

Study Design and Baseline Profiles of Participants in the Tianjin Birth Cohort (TJBC) in China.

BACKGROUND: To investigate the causal link between early-life exposures and long-term health consequences, we established the Tianjin Birth Cohort (TJBC), a large-scale prospective cohort in northern China. METHODS: TJBC aims to enroll 10,000 families with follow-ups from pregnancy until children's six year-old. Pregnant women and their spouses were recruited through a three-tier antenatal healthcare system at early pregnancy, with follow-ups at mid-pregnancy, late pregnancy, delivery, 42 days after delivery, 6 months after delivery, and each year until 6 years old. Antenatal/neonatal examination, biological samples and questionnaires were collected. RESULTS: From August 2017 to January 2019, a total of 3,924 pregnant women have already been enrolled, and 1,697 women have given birth. We observed the prevalence of gestational diabetes mellitus as 18.1%, anemia as 20.4%, and thyroid hypofunction as 2.0%. In singleton live births, 5.6% were preterm birth (PTB), 3.7% were low birth weight, and 7.3% were macrosomia. Based on current data, we also identified maternal/paternal factors which increased the risk of PTB, including paternal age (OR 1.07; 95% CI, 1.01-1.14 for each year increase), vaginal bleeding during pregnancy (OR 2.82; 95% CI, 1.54-5.17) and maternal early-pregnancy BMI (OR 1.08; 95% CI, 1.01-1.15 for each kg/m2 increase). CONCLUSION: TJBC has the strength of collecting comprehensive maternal, paternal, and childhood information. With a diverse range of biological samples, we are also engaging with emerging new technologies for multi-omics research. The study would provide new insight into the causal link between macro/micro-environmental exposures of early life and short/long-term health consequences.

Genetic control of male production in Daphnia pulex.

Daphnia normally reproduce by cyclical parthenogenesis, with offspring sex being determined by environmental cues. However, some females have lost the ability to produce males. Our results demonstrate that this loss of male-producing ability is controlled by a dominant allele at a single locus. We identified the locus by comparing whole-genome sequences of 67 nonmale-producing (NMP) and 100 male-producing (MP) clones from 5 Daphnia pulex populations, revealing 132 NMP-linked SNPs and 59 NMP-linked indels within a single 1.1-Mb nonrecombining region on chromosome I. These markers include 7 nonsynonymous mutations, all of which are located within one unannotated protein-coding gene (gene 8960). Within this single gene, all of the marker-linked NMP haplotypes from different populations form a monophyletic clade, suggesting a single origin of the NMP phenotype, with the NMP haplotype originating by introgression from a sister species, Daphnia pulicaria Methyl farnesoate (MF) is the innate juvenile hormone in daphnids, which induces the production of males and whose inhibition results in female-only production. Gene 8960 is sensitive to treatment by MF in MP clones, but such responsiveness is greatly reduced in NMP clones. Thus, we hypothesize that gene 8960 is located downstream of the MF-signaling pathway in D. pulex, with the NMP phenotype being caused by expression change of gene 8960.

Subcritical Water Enhanced with Deep Eutectic Solvent for Extracting Polysaccharides from Lentinus edodes and Their Antioxidant Activities.

In the present study, subcritical water extraction (SWE) assisted with deep eutectic solvent (DES) is used to extract Lentinus edodes polysaccharides (LEP). In addition, the antioxidant activity of the polysaccharide samples was also investigated. Based on a single factor test and response surface test, the optimal extraction factors were a liquid-solid solvent of 40:1 mL/g, extraction temperature of 147.23 °C, water content of 39.76% and extraction time of 17.58 min. Under these extraction conditions, the yield of LEP was 6.26 ± 0.08%. Compared with the SWE and hot water extraction (HWE), it improved by 19.24% and 17.01%, respectively. In addition, the results of monosaccharide composition, molecular weight, FT-IR, UV and SEM confirmed that the extracts had the features of polysaccharides. Interestingly, the polysaccharides obtained with the SWE assisted with the DES procedure showed a higher DPPH scavenging activity, hydroxyl radical scavenging activity and hydrogen peroxide scavenging activity, which indicated that the polysaccharides with this method had a stronger antioxidant activity. These findings demonstrated that the SWE-assisted DES is a strong method to obtain polysaccharides from Lentinus edodes for food, biopharmaceutical and other industrial production.

IDRMutPred: predicting disease-associated germline nonsynonymous single nucleotide variants (nsSNVs) in intrinsically disordered regions.

MOTIVATION: Despite of the lack of folded structure, intrinsically disordered regions (IDRs) of proteins play versatile roles in various biological processes, and many nonsynonymous single nucleotide variants (nsSNVs) in IDRs are associated with human diseases. The continuous accumulation of nsSNVs resulted from the wide application of NGS has driven the development of disease-association prediction methods for decades. However, their performance on nsSNVs in IDRs remains inferior, possibly due to the domination of nsSNVs from structured regions in training data. Therefore, it is highly demanding to build a disease-association predictor specifically for nsSNVs in IDRs with better performance. RESULTS: We present IDRMutPred, a machine learning-based tool specifically for predicting disease-associated germline nsSNVs in IDRs. Based on 17 selected optimal features that are extracted from sequence alignments, protein annotations, hydrophobicity indices and disorder scores, IDRMutPred was trained using three ensemble learning algorithms on the training dataset containing only IDR nsSNVs. The evaluation on the two testing datasets shows that all the three prediction models outperform 17 other popular general predictors significantly, achieving the ACC between 0.856 and 0.868 and MCC between 0.713 and 0.737. IDRMutPred will prioritize disease-associated IDR germline nsSNVs more reliably than general predictors. AVAILABILITY AND IMPLEMENTATION: The software is freely available at http://www.wdspdb.com/IDRMutPred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis.

Interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) are increasingly recognized as key participants in various autoimmune diseases, including multiple sclerosis. Although sets of transcription factors and cytokines are known to regulate T(H)-17 differentiation, the role of noncoding RNA is poorly understood. Here we identify a T(H)-17 cell-associated microRNA, miR-326, whose expression was highly correlated with disease severity in patients with multiple sclerosis and mice with experimental autoimmune encephalomyelitis (EAE). In vivo silencing of miR-326 resulted in fewer T(H)-17 cells and mild EAE, and its overexpression led to more T(H)-17 cells and severe EAE. We also found that miR-326 promoted T(H)-17 differentiation by targeting Ets-1, a negative regulator of T(H)-17 differentiation. Our data show a critical role for microRNA in T(H)-17 differentiation and the pathogenesis of multiple sclerosis.

Neuroprotective effect of minocycline on rat retinal ischemia-reperfusion injury.

Purpose: To examine the neuroprotective effect of minocycline on retinal ischemia-reperfusion (IR) injury in rats and investigate its possible mechanism of action. Methods: Retinal IR injury was established by increasing the intraocular pressure in rats up to 110 mmHg for 60 min. The animals with retinal IR injury were intraperitoneally injected with 22.5 mg/kg minocycline twice a day for 14 days. The control group received the same amount of saline. Subsequently, funduscopic examination, retinal thickness measurement, retinal microvascular morphology, full-field electroretinography (ERG), retinal apoptotic cell count, and remaining retinal ganglion cell (RGC) count were performed. The expression of iNOS, Bax, Bcl2, IL-1α, IL-6, TNF-α, caspase-3, GFAP, Iba-1, Hif-1α, and Nrf2 was examined with real-time PCR and western blotting. Results: Minocycline treatment prevented IR-induced rat retinal edema and retinal cells apoptosis at the early stage and alleviated retina atrophy, blood vessel tortuosity, functional photoreceptor damage, and RGC degeneration at the late stage of the IR injury. At the molecular level, minocycline affected retinal gene and protein expression induced by IR. Conclusions: The results suggested that minocycline has a neuroprotective effect on rat retinal IR injury, possibly through anti-inflammation, antiapoptosis, antioxidation, and inhibition of microglial activation.

Folate-conjugated herpes simplex virus for retargeting to tumor cells.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-mediated oncolytic therapy is a promising cancer treatment modality. However, viral tropism is considered to be one of the major stumbling blocks to the development of HSV-1 as an anticancer agent. METHODS: The surface of oncolytic HSV-1 G207 was covalently modified with folate-poly (ethylene glycol) conjugate (FA-PEG). The specificities and tumor targeting efficiencies of modified or unmodified G207 particles were analyzed by a real-time polymerase chain reaction at the level of cell attachment and entry. Immune responses were assessed by an interleukin-6 release assay from RAW264.7 macrophages. Biodistribution and in vivo antitumoral activity after intravenous delivery was evaluated in BALB/c nude mice bearing subcutaneous KB xenograft tumors. RESULTS: FA-PEG-HSV exhibited enhanced targeting specificity for folate receptor over-expressing tumor cells and had lower immunogenicity than the unmodified HSV. In vivo, the FA-PEG-HSV group revealed an increased anti-tumor efficiency and tumor targeting specificity compared to the naked HSV. CONCLUSIONS: These results indicate that folate-conjugated HSV G207 presents a folate receptor-targeted oncolytic virus with a potential therapeutic value via retargeting to tumor cells.

WDSPdb: an updated resource for WD40 proteins.

SUMMARY: The WD40-repeat proteins are a large family of scaffold molecules that assemble complexes in various cellular processes. Obtaining their structures is the key to understanding their interaction details. We present WDSPdb 2.0, a significantly updated resource providing accurately predicted secondary and tertiary structures and featured sites annotations. Based on an optimized pipeline, WDSPdb 2.0 contains about 600 thousand entries, an increase of 10-fold, and integrates more than 37 000 variants from sources of ClinVar, Cosmic, 1000 Genomes, ExAC, IntOGen, cBioPortal and IntAct. In addition, the web site is largely improved for visualization, exploring and data downloading. AVAILABILITY AND IMPLEMENTATION: http://www.wdspdb.com/wdsp/ or http://wu.scbb.pkusz.edu.cn/wdsp/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Overexpression of miR-129-5p Mitigates Sepsis-Induced Acute Lung Injury by Targeting High Mobility Group Box 1.

BACKGROUND: MicroRNAs are dysregulated in sepsis. Acute lung injury is a progressive syndrome during sepsis. However, the role of miR-129-5p in the development of acute lung injury induced by sepsis remains unclear. METHODS: The acute lung injury of sepsis model was established by cecal ligation puncture (CLP)-treated mice and lipopolysaccharide (LPS)-treated murine alveolar epithelial cell line (MLE)-12 cells. The lung injury in vivo was investigated by hematoxylin and eosin staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling staining, enzyme-linked immunosorbent assay, lung wet-to-dry weight ratio, and myeloperoxidase activity. The lung injury in vitro was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide, flow cytometry, and enzyme-linked immunosorbent assay. The expression levels of miR-129-5p and high mobility group box 1 (HMGB1) were measured by quantitative real-time polymerase chain reaction and Western blot. The association between miR-129-5p and HMGB1 was validated by luciferase assay and RNA immunoprecipitation. RESULTS: The expression of miR-129-5p was decreased in CLP model and LPS-treated MLE-12 cells. Overexpression of miR-129-5p attenuated inflammatory response, apoptosis, lung wet/dry weight ratio, and myeloperoxidase activity induced by CLP surgery in vivo. Moreover, addition of miR-129-5p increased cell viability and suppressed cell apoptosis and inflammatory response in vitro. HMGB1 as a target of miR-129-5p alleviated miR-129-5p-mediated injury suppression in LPS-treated MLE-12 cells. CONCLUSIONS: miR-129-5p protects against sepsis-induced acute lung injury by decreasing HMGB1 expression, providing new target for sepsis treatment.

Antibiotic treatment enhances the genome-wide mutation rate of target cells.

Although it is well known that microbial populations can respond adaptively to challenges from antibiotics, empirical difficulties in distinguishing the roles of de novo mutation and natural selection have left several issues unresolved. Here, we explore the mutational properties of Escherichia coli exposed to long-term sublethal levels of the antibiotic norfloxacin, using a mutation accumulation design combined with whole-genome sequencing of replicate lines. The genome-wide mutation rate significantly increases with norfloxacin concentration. This response is associated with enhanced expression of error-prone DNA polymerases and may also involve indirect effects of norfloxacin on DNA mismatch and oxidative-damage repair. Moreover, we find that acquisition of antibiotic resistance can be enhanced solely by accelerated mutagenesis, i.e., without direct involvement of selection. Our results suggest that antibiotics may generally enhance the mutation rates of target cells, thereby accelerating the rate of adaptation not only to the antibiotic itself but to additional challenges faced by invasive pathogens.