We used data-independent acquisition (DIA) proteomics technology followed by ELISAs and automated biochemical analyses to identify and validate protein expression levels in Intrahepatic Cholestasis of Pregnancy (ICP) and healthy pregnant controls. We employed bioinformatics to identify metabolic processes associated with differentially expressed proteins.The expression levels of two proteins (S100-A9 and the L-lactate dehydrogenase A chain) were significantly higher in ICP patients than in controls; the areas under the receiver operating characteristic (ROC) curves (AUCs) were 0.774 and 0.828, respectively. The expression levels of two other proteins (apolipoprotein A-I and cholinesterase) were significantly lower in patients, with values of 0.900 and 0.842, respectively. Multiple logistic regression showed that a combination of the levels of the four proteins optimized the AUC (0.962), thus more reliably diagnosing ICP. The levels of all four proteins were positively associated with that of total bile acids. Bioinformatics analyses indicated that the four proteins principally affected neutrophil activation involved in the immune response, cell adhesion, lipoprotein metabolism, and the PPAR signaling pathway. SIGNIFICANCE: This preliminary work improves our understanding of changes in serum levels of protein in pregnant women with ICP. The four proteins may serve as novel noninvasive biomarkers for ICP.

Purpose. To measure the changes in fusional vergence in Chinese children with intermittent exotropia (IXT) and the association with the control of IXT. Methods. Ninety-two patients with IXT (8-15 years old) were compared with 86 controls. Exodeviation control was evaluated using the Revised Newcastle Control Score. Angle of deviation was measured using prism and alternate cover testing at distance and near. Fusional vergence was measured using prism bar and synoptophore. This study was registered with ChiCTR-RCC-13003920. Results. Using prism bar, convergence break points were lower whereas divergence break points were higher in children with IXT at distance (P < 0.001) and near (P < 0.001) compared with controls. There was no significant difference in mean divergence amplitudes between the two groups when testing using a synoptophore (P = 0.53). In children with IXT, the distance between recovery point and break point in both convergence (distance: P = 0.02; near: P = 0.02) and divergence (distance: P < 0.001; near: P < 0.001) was larger than controls when detected by prism bar and synoptophore (convergence: P = 0.005; divergence: P = 0.006). Conclusions. Children with IXT have reduced convergence amplitudes as detected by both prism bar and synoptophore.

In the past decade, hand, foot, and mouth disease (HFMD) has posed a serious threat to childhood health in China; however, no epidemiological data from large HFMD epidemics have been described since 2013. In the present study, we described the epidemiological patterns of HFMD in Shandong province during 2009-2016 from a large number of symptomatic cases (n = 839,483), including >370,000 HFMD cases since 2013. Our results revealed that HFMD activity has remained at a high level and continued to cause annual epidemics in Shandong province from 2013 onwards. Although the incidence rate was significantly higher in urban areas than in rural areas, no significantly higher case-severity and case-fatality rates were found in urban areas. Furthermore, the seventeen cities of Shandong province could be classified into three distinct epidemiological groups according to the different peak times from southwest (inland) to northeast (coastal) regions. Notably, a replacement of the predominant HFMD circulating agent was seen and non-EVA71/Coxsackievirus A16 enteroviruses became dominant in 2013 and 2015, causing approximately 30% of the severe cases. Our study sheds light on the latest epidemiological characteristics of HFMD in Shandong province and should prove helpful for the prevention and control of the disease in Shandong and elsewhere.

Old Chinese garden roses are the foundation of the modern rose, which is one of the best-selling ornamental plants. However, the horticultural grouping and evolution of old Chinese garden roses are unclear. Simple sequence repeat (SSR) markers were employed to survey genetic diversity in old Chinese garden roses and genetic differentiation was estimated among different rose groups. Fluorescence in situ hybridization was used to study the physical localization of 5 S rDNA genes and a karyotype analysis was performed. The SSR data suggest that old Chinese garden roses could be divided into Old Blush group, Odorata group and Ancient hybrid China group. The Old Blush group had the most primitive karyotype. The Ancient hybrid China group and modern rose had the most evolved karyotypes and the highest genetic diversity. During the evolution of rose cultivars, 5 S rDNA increased in number, partially weakened in signal intensity and exhibited variation in distance from the centromere. In conclusion, rose cultivars evolved from the Old Blush Group to the Odorata group, the Ancient Hybrid China group and the modern rose. This work provides a basis for the collection, identification, conservation and innovation of rose germplasm resources.

A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5'-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

Peripheral nerve regeneration remains one of the greatest challenges in regenerative medicine. Deprivation of sensory and/or motor functions often occurs with severe injuries even treated by the most advanced microsurgical intervention. Although electrical stimulation represents an essential nonpharmacological therapy that proved to be beneficial for nerve regeneration, the postoperative delivery at surgical sites remains daunting. Here, a fully biodegradable, self-electrified, and miniaturized device composed of dissolvable galvanic cells on a biodegradable scaffold is achieved, which can offer both structural guidance and electrical cues for peripheral nerve regeneration. The electroactive device can provide sustained electrical stimuli beyond intraoperative window, which can promote calcium activity, repopulation of Schwann cells, and neurotrophic factors. Successful motor functional recovery is accomplished with the electroactive device in behaving rodent models. The presented materials options and device schemes provide important insights into self-powered electronic medicine that can be critical for various types of tissue regeneration and functional restoration.

Hybridization and resulting introgression are important processes shaping the tree of life and appear to be far more common than previously thought. However, how the genome evolution was shaped by various genetic and evolutionary forces after hybridization remains unresolved. Here we used whole-genome resequencing data of 227 individuals from multiple widespread Populus species to characterize their contemporary patterns of hybridization and to quantify genomic signatures of past introgression. We observe a high frequency of contemporary hybridization and confirm that multiple previously ambiguous species are in fact F1 hybrids. Seven species were identified, which experienced different demographic histories that resulted in strikingly varied efficacy of selection and burdens of deleterious mutations. Frequent past introgression has been found to be a pervasive feature throughout the speciation of these Populus species. The retained introgressed regions, more generally, tend to contain reduced genetic load and to be located in regions of high recombination. We also find that in pairs of species with substantial differences in effective population size, introgressed regions are inferred to have undergone selective sweeps at greater than expected frequencies in the species with lower effective population size, suggesting that introgression likely have higher potential to provide beneficial variation for species with small populations. Our results, therefore, illustrate that demography and recombination have interplayed with both positive and negative selection in determining the genomic evolution after hybridization.

Obesity and its related metabolic disorders are closely correlated with gut dysbiosis. Montmorillonite is a common medicine used to treat diarrhea. We have previously found that dietary lipid adsorbent-montmorillonite (DLA-M) has an unexpected role in preventing obesity. The aim of this study was to further investigate whether DLA-M regulates intestinal absorption and gut microbiota to prevent obesity-related metabolic disorders. Here, we show that DLA-M absorbs free fatty acids (FFA) and endotoxins in vitro and in vivo. Moreover, the combination of fluorescent tracer technique and polarized light microscopy showed that DLA-M crystals immobilized BODIPY® FL C16 and FITC-LPS, respectively, in the digestive tract in situ. HFD-fed mice treated with DLA-M showed mild changes in the composition of the gut microbiota, particularly increases in short-chain fatty acids (SCFA)-producing Blautia bacteria and decreases in endotoxin-producing Desulfovibrio bacteria, these changes were positively correlated with obesity and inflammation. Our results indicated that DLA-M immobilizes FFA and endotoxins in the digestive tract via the adsorption-excretion axis and DLA-M may potentially be used as a prebiotic to prevent intestinal dysbiosis and obesity-associated metabolic disorders in obese individuals.

Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Using a meta-transcriptomic approach, we analysed the virome of 2,438 individual mosquitos (79 species), spanning ~4000 km along latitudes and longitudes in China. From these data we identified 393 core viral species associated with mosquitos, including seven (putative) arbovirus species. We identified potential species and geographic hotspots of viral richness and arbovirus occurrence, and demonstrated that host phylogeny had a strong impact on the composition of individual mosquito viromes. Our data revealed a large number of viruses shared among mosquito species or genera, expanding our knowledge of host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, possibly facilitated by long-distance mosquito migrations. Together, our results greatly expand the known mosquito virome, linked the viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the ecology of viruses of insect vectors.

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.