The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current ...understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of ...patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy.
Formalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166-0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280-0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells.
Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.
Single‐walled carbon nanotubes and graphene hybrid films with complementary properties are combined for use in high‐performance transparent electrodes and field‐effect transistors (FETs). Based on ...the transfer characteristics for the hybrid film‐based FETs, an improved Ion/Ioff and on‐state current are achieved, compared with pristine graphene. Notably, the hybrid film has a sheet resistance of 300 Ω/sq with 96.4% transparency.
The burgeoning interest in intelligent transportation systems (ITS) and the widespread adoption of in-vehicle amenities like infotainment have spurred a heightened fascination with vehicular ad-hoc ...networks (VANETs). Multi-hop routing protocols are pivotal in actualizing these in-vehicle services, such as infotainment, wirelessly. This study presents a novel protocol called multiple junction-based traffic-aware routing (MJTAR) for VANET vehicles operating in urban environments. MJTAR represents an advancement over the improved greedy traffic-aware routing (GyTAR) protocol. MJTAR introduces a distributed mechanism capable of recognizing vehicle traffic and computing curve metric distances based on two-hop junctions. Additionally, it employs a technique to dynamically select the most optimal multiple junctions between source and destination using the ant colony optimization (ACO) algorithm. We implemented the proposed protocol using the network simulator 3 (NS-3) and simulation of urban mobility (SUMO) simulators and conducted performance evaluations by comparing it with GSR and GyTAR. Our evaluation demonstrates that the proposed protocol surpasses GSR and GyTAR by over 20% in terms of packet delivery ratio, with the end-to-end delay reduced to less than 1.3 s on average.
This study aimed to identify the candidate miRNAs in the carcinogenesis of endometrial carcinoma, and to explore whether FFPE material would be suitable for miRNA profiling. We identified the ...differences between miRNA expression profiles using human miRNA microarray in endometrioid endometrial adenocarcinomas (EECs) and normal endometria. Of those tested, miR-200a*, miR-200b*, miR-141, miR-182, and miR-205 were greatly enriched. The expressions of these five miRNAs were validated using quantitative real-time reverse transcription-PCR (qRT-PCR). We then performed qRT-PCR miR expression profiling in 30 FFPE specimens (20 EECs, 10 normal endometria) and re-confirmed the results of differential expression between cancer and normal tissue. Following this, we tested whether the specific inhibition of overexpressed miRNAs would alter chemosensitivity. In the in vitro cell viability assay, anti-miR200b* showed a trend toward enhanced cytotoxicity slightly in cisplatin compared to the negative control (p = 0.07). This information provided the candidate miRNAs for further confirmation of the role of miRNAs in the carcinogenesis of EECs, potentially serving as a diagnostic or therapeutic tool. FFPE specimens of endometrial tissues are suitable as a source for miRNA microarray profiling.
Viruses represent the most abundant life forms on the planet. Recent experimental and computational improvements have led to a dramatic increase in the number of viral genome sequences identified ...primarily from metagenomic samples. As a result of the expanding catalog of metagenomic viral sequences, there exists a need for a comprehensive computational platform integrating all these sequences with associated metadata and analytical tools. Here we present IMG/VR (https://img.jgi.doe.gov/vr/), the largest publicly available database of 3908 isolate reference DNA viruses with 264 413 computationally identified viral contigs from >6000 ecologically diverse metagenomic samples. Approximately half of the viral contigs are grouped into genetically distinct quasi-species clusters. Microbial hosts are predicted for 20 000 viral sequences, revealing nine microbial phyla previously unreported to be infected by viruses. Viral sequences can be queried using a variety of associated metadata, including habitat type and geographic location of the samples, or taxonomic classification according to hallmark viral genes. IMG/VR has a user-friendly interface that allows users to interrogate all integrated data and interact by comparing with external sequences, thus serving as an essential resource in the viral genomics community.
Small-for-gestational age (SGA) infants should be identified before birth because of an increased risk of adverse perinatal outcomes. The objective of this study was to assess the impact of fetal ...growth rate by gestational age on the prediction of SGA and to identify the optimal time to initiate intensive fetal monitoring to detect SGA in low-risk women. We also sought to determine which the ultrasonographic parameters that contribute substantially to the birthweight determination.
This was a retrospective study of 442 healthy pregnant women with singleton pregnancies. There were 328 adequate-for-gestational age (AGA) neonates and 114 SGA infants delivered between 37+0 and 41+6 weeks of gestation. We compared the biparietal diameters (BPD), head circumferences (HC), abdominal circumferences (AC), femur lengths (FL), and estimated fetal weights (EFW) obtained on each ultrasound to determine which of these parameters was the best indicator of SGA. We created receiver operating characteristic curves, calculated the areas under the curves (AUCs), and analyzed the data using multivariable logistic regressions to assess the ultrasound screening performances and identify the best predictive factor.
Among the four ultrasonographic parameters, the AC measurement between 24+0~28+6 weeks achieved a sensitivity of 79.5% and a specificity of 71.7%, with an AUC of 0.806 in the prediction of SGA. AC showed consistently higher AUCs above 0.8 with 64~80% sensitivities as gestational age progressed. EFW measurements from 33+0~35+6 gestational weeks achieved a sensitivity of 60.6% and a specificity of 87.6%, with an AUC of 0.826. In a conditional growth model developed from the linear mixed regression, the value differences between AC and EFW in the SGA and AGA groups became even more pronounced after 33+0~35+6 weeks.
Healthy low-risk women with a low fetal AC after 24 weeks' gestation need to be monitored carefully for fetal growth to identify SGA infants with a risk for adverse perinatal outcomes.
Problem
Preeclampsia (PE) is a serious pregnancy complication leading to high maternal, perinatal morbidity, and mortality. We aimed to investigate the clinical effectiveness of the ...platelet‐to‐lymphocyte ratio (PLR) in women with PE and compare this measurement to platelet indices as a diagnostic and prognostic marker of PE.
Method of study
A total of 471 healthy pregnant women, 126 women diagnosed with mild PE, and 227 with severe PE were included in this retrospective study. We analyzed PLR and platelet indices, mainly mean platelet volume (MPV) and platelet distribution width (PDW) among the 3 groups.
Results
Platelet distribution width, MPV, and PLR levels in women with PE were significantly different from those of healthy pregnant women. PLR was significantly lower in severe PE than mild PE (P = .001), but PDW and MPV increased as severity of PE progressed; however, the differences in PDW and MPV between women with mild and severe PE were not significant. Receiver operating characteristic curve analysis showed that PLR was more predictive of PE than PDW and MPV (Area under the curve = 0.759 vs 0.621, 0.638). Additionally, the time interval from admission to delivery was significantly shorter in women with PLR‐positive (≤116) than in women with PDW‐positive (>58) and MPV‐positive (>9).
Conclusion
The PLR is an easily accessible and cost‐effective parameter, which may be used as a more useful marker for prediction of PE compared to platelet indices. Our study showed that PLR can serve as a useful diagnostic marker of PE.
Mitochondrial NADP
-dependent isocitrate dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine ...whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2
) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2
mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2
mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H
O
-induced ototoxicity, as the survival rate of Idh2
hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨ
, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2
mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss.
Targeting specific cell types in the mammalian inner ear is important for treating genetic hearing loss due to the different cell type-specific functions. Adeno-associated virus (AAV) is an efficient ...in vivo gene transfer vector, and it has demonstrated promise for treating genetic hearing loss. Although more than 100 AAV serotypes have been identified, few studies have investigated whether AAV can be distributed to specific inner ear cell types. Here we screened three EGFP-AAV reporter constructs (serotypes DJ, DJ8, and PHP.B) in the neonatal mammalian inner ear by injection via the round window membrane to determine the cellular specificity of the AAV vectors. Sensory hair cells, supporting cells, cells in Reissner’s membrane, interdental cells, and root cells were successfully transduced. Hair cells in the cochlear sensory epithelial region were the most frequently transduced cell type by all tested AAV serotypes. The recombinant DJ serotype most effectively transduced a range of cell types at a high rate. Our findings provide a basis for improving treatment of hereditary hearing loss using targeted AAV-mediated gene therapy.
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