Background
Fetal ethanol (EtOH) exposure can damage the developing central nervous system and lead to cognitive and behavioral deficits, known as fetal alcohol spectrum disorders (FASD). EtOH ...exposure to mouse pups during early neonatal development was used as a model of EtOH exposure that overlaps the human third‐trimester “brain growth spurt”—a model that has been widely used to study FASD in rats.
Methods
C57BL/6 male and female mice were exposed to EtOH (4 g/kg/d) on postnatal days (PD) 4 to 10 by oral intubation. Intubated and nontreated controls were also included. Behavioral testing of the offspring, including open field, elevated plus maze, and Morris water maze, was performed on PD 20 to 45.
Results
EtOH exposure during PD 4 to 10 resulted in hyperactivity and deficits in learning and memory in young mice with no apparent sex differences.
Conclusions
Based on these data, this neonatal intubation mouse model may be useful for future mechanistic and genetic studies of FASD and for screening of novel therapeutic agents.
Ethanol exposure via oral intubation on postnatal day (PD) 4–10 resulted in hyperactivity in open field test (A) and deficits in learning and memory in Morris water maze test (B) in young mice with no apparent sex differences.
Acinetobacter baumannii is a major causative agent of healthcare-associated infection and develops multidrug resistance rapidly. However, little is known in the host defense mechanisms against this ...infection. In this study, we examined if mice recovered from a previous intranasal A. baumannii infection (recovered mice) are fully protected against a subsequent reinfection. We found that, despite the presence of specific serum IgG and mucosal IgA responses prior to the reinfection, the recovered mice were only marginally better protected against intranasal challenge with low doses of homologous or heterologous A. baumannii strains than the naïve mice. Post-challenge immune and inflammatory (cells and cytokines) responses were generally comparable between recovered and naïve mice although the recovered mice produced significantly higher amounts of IFN-γ and IL-17 and had higher percentages and numbers of resident lung CD44hiCD62L–CD4+ and CD19+ B lymphocytes. Taken together, our results suggest that mice recovered from a previous A. baumannii infection remain susceptible to reinfection, indicating the complexity of immune protection mechanism for this Gram-negative, multidrug-resistant emerging pathogen.
Mice that recovered from an intranasal Acinetobacter infection are only marginally more resistant to a reinfection than naive mice, indicating the complexity of immune protection for this multidrug-resistant emerging pathogen.
Graphical Abstract Figure.
Mice that recovered from an intranasal Acinetobacter infection are only marginally more resistant to a reinfection than naive mice, indicating the complexity of immune protection for this multidrug-resistant emerging pathogen.
Cell death in lymphatic organs, such as the spleen, is in part responsible for immunosuppression and contributes to mortality during sepsis. An early and noninvasive detection of lymphoid cell death ...could thus have significant clinical implications. Here, we tested in vivo imaging of lymphoid cell death using a near-infrared annexin V (AV-750).
Animal study.
Laboratory investigation.
C57BL/6J wild-type and toll-like receptor 3 knockout mice.
Mild and severe polymicrobial sepsis was induced with cecum ligation and puncture. Serum cytokines and acute kidney injury markers were tested by immunoassay and quantitative reverse transcription-polymerase chain reaction, respectively. Sepsis-induced lymphoid cell death was detected by fluorescent AV-750 accumulation in the thorax and abdomen (in vivo), in isolated organs (ex vivo), and in isolated cells (flow cytometry). Caspase-3 cleavage/activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were tested for apoptosis.
Severe sepsis induced marked apoptosis in the thymus, spleen, and liver as demonstrated by cleaved caspase-3 and an increase in caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. A significant increase in fluorescent AV-750 signal was seen in the thoracic and upper abdominal fields and associated with the severity of sepsis. The in vivo thoracic and abdominal AV-750 fluorescent signal was attributed to the thymus, liver, and spleen as determined by ex vivo imaging and highly correlated with the levels of cell death in thymocytes and splenocytes, respectively, as measured by flow cytometry. Compared with wild-type septic mice, toll-like receptor 3 septic mice had attenuated abdominal AV-750 fluorescent signal, reduced ex vivo fluorescence in the spleen, and decreased splenocyte cell death.
In vivo AV-750 fluorescent imaging provides spatially resolved and organ-specific detection of lymphoid cell death during polymicrobial sepsis. The AV-750 fluorescent intensity in the thoracic and abdominal fields is associated with sepsis severity and well correlated with sepsis-induced cell death in the thymus and spleen, respectively.
Age of Information (AoI), a notion that measures the information freshness, is an essential performance measure for time-critical applications in Internet of Things (IoT). With the surge of computing ...resources at the IoT devices, it is possible to preprocess the information packets that contain the status update before sending them to the destination so as to alleviate the transmission burden. However, the additional time and energy expenditure induced by computing also make the optimal updating a nontrivial problem. In this article, we consider a time-critical IoT system, where the IoT device is capable of preprocessing the status update before the transmission. Particularly, we aim to jointly design the preprocessing and transmission so that the weighted sum of the average AoI of the destination and the energy consumption of the IoT device is minimized. Due to the heterogeneity in transmission and computation capacities, the durations of distinct actions of the IoT device are nonuniform. Therefore, we formulate the status updating problem as an infinite horizon average cost semi-Markov decision process (SMDP) and then transform it into a discrete-time Markov decision process. We demonstrate that the optimal policy is of threshold type with respect to the AoI. Equipped with this, a structure-aware relative policy iteration algorithm is proposed to obtain the optimal policy of the SMDP. Our analysis shows that preprocessing is more beneficial in regimes of high AoIs, given it can reduce the time required for updates. We further prove the switching structure of the optimal policy in a special scenario, where the status updates are transmitted over a reliable channel and derive the optimal threshold. Finally, simulation results demonstrate the efficacy of preprocessing and show that the proposed policy outperforms two baseline policies.
Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA ...and protein expression in paired tumor-normal tissues, and their relationship with survival.
PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124).
Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; Ptrend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; Ptrend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; Ptrend = 0.04).
Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis.
A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation.
•Acinetobacter baumannii is critical nosocomial pathogen resistant to multiple classes of antibiotics.•Through high-throughput screening, novel and potent isothiazolones were identified.•Several ...isothiazolones exhibit consistent and cidal activity against many clinical isolates of A. baumannii.•Presence of chloro-group on the heterocyclic ring or a fused benzene ring appears to be critical to activity.•These isothiazolones exhibit various degree of cytotoxicity to mammalian cells, with one compound possessing future development potential.
Acinetobacter baumannii has emerged as a globally important nosocomial pathogen characterized by an increased multi-drug resistance (MDR), leaving limited options for treating its infection. To identify novel antibacterial compounds with activity against clinical isolates of A. baumannii, we performed high-throughput screening against a chemical library of 42,944 compounds using nonpathogenic Escherichia coli MG1655 and identified 55 hit compounds. The antibacterial activities of 30 pure compounds were determined against MDR clinical isolates of A. baumannii obtained from Los Angeles County hospitals. Two isothiazolones identified, 5-chloro-2-(4-chloro-3-methylphenyl)-4-methyl-3(2H)-isothiazolone (Compound 6) and 5-chloro-2-(4-chlorophenyl)-4-methyl-3(2H)-isothiazolone (Compound 7), possess novel structure and exhibited consistent, potent and cidal activity against all 46 MDR A. baumannii clinical isolates and reference strains. Additionally, structure–activity relationship analysis involving several additional isothiazolones supports the link between a chloro-group on the heterocyclic ring or a fused benzene ring and the cidal activity. Attempts to obtain isothiazolone resistant mutants failed, consistent with the rapid cidal action and indicative of a complex mechanism of action. While cytotoxicity was observed with Compound 7, it had a therapeutic index value of 28 suggesting future therapeutic potential. Our results indicate that high-throughput screening of compound libraries followed by in vitro biological evaluations is a viable approach for the discovery of novel antibacterial agents to contribute in the fight against MDR bacterial pathogens.
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One of the challenges in antibiotic lead discovery is the difficulty and time-consuming task of determining the mechanism of action (MOA) of antibacterial compounds. In this report, we describe the ...development and validation of a facile and inexpensive assay system utilizing disk diffusion of inhibitors on solid agar medium embedded with mixed pools of a comprehensive collection of Escherichia coli clones each containing a plasmid-borne inducible essential gene from E. coli. From individual clones, pilot small-scale (48 or 50 clones) assays, to full-scale target identification platform for antibacterials (TIPA) system, involving a variety of assay formats (liquid vs solid media, individual vs mix clones), we demonstrate that elevated resistance phenotypes of relevant cell clones were highly specific. In particular, the TIPA system was able to reveal cellular targets of several known antibacterial inhibitors: cerulenin, diazaborine, indolmycin, phosphomycin, and triclosan. Complementary to several existing MOA profiling schemes, the TIPA system offers a simple and low-cost method for elucidating the target proteins of antibacterial inhibitors, thus will facilitate discovery and development of novel antibacterial compounds to combat multidrug-resistant bacterial pathogens.
The satellite-borne Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) is widely used to estimate ground-level fine ambient particulate matter (PM2.5) concentrations to ...evaluate their health effects. The associated estimation accuracy is often reduced by AOD missing values and by insufficiently accounting for the spatio-temporal PM2.5 variations. In this study, we aim to estimate ground-level PM2.5 concentrations at a fine resolution with improved accuracy by fusing fine-scale satellite and ground observations in the populated and polluted Beijing–Tianjin–Hebei (BTH) area of China in 2014. We employed a Bayesian-based statistical downscaler to model the spatio-temporal linear AOD-PM2.5 relationships. We used a 3km MODIS AOD product, which was resampled to a 4km resolution in a Lambert conic conformal projection, to assist comparison and fusion with predictions by atmospheric chemistry models. A two-step method was used to fill the missing AOD values to obtain a full AOD dataset with complete spatial coverage. The downscaler has a good performance in the fitting procedure (R2=0.75) and in the cross validation procedure (R2=0.58 by random method and R2=0.47 by city-specific method). The number of missing AOD values was serious and related to elevated PM2.5 concentrations. The gap-filled AOD values corresponded well with our understanding of PM2.5 pollution conditions in BTH. The prediction accuracy of PM2.5 concentrations were improved in terms of their annual and seasonal mean. As a result of its fine spatio-temporal resolution and complete spatial coverage, the daily PM2.5 estimation dataset could provide extensive and insightful benefits to related studies in the BTH area. This may include understanding the formation processes of regional PM2.5 pollution episodes, evaluating daily human exposure, and establishing pollution controlling measures.
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•Fine resolution PM2.5 concentrations are estimated in Beijing-Tianjin-Hebei area.•Downscaling method modeled time and space varied PM2.5-AOD associations.•Missing AOD values were filled using a two-step approach.•Derived PM2.5 products have multiple potential applications with high accuracy.
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