Although dexamethasone (Dex) substantially enhances the osteoblastic phenotype in osteogenic cells, including human periodontal ligament (PDL) cells, the basis for this response remains poorly understood. Since the accretion of a collagenous matrix is important for an osteoblastic response and dexamethasone is known to decrease collagenase expression, we examined whether osteoblastic differentiation mediated by Dex is linked to a decrease in collagenase expression in PDL cells. Early passage human PDL cells were exposed to Dex, or ascorbic acid (AA) or beta-glycerophosphate (betaGP) alone, or in various combinations in serum-free media for 3 or 5 days. Cells exposed to Dex alone or any combinations of treatments that included Dex demonstrated increased core binding factor alpha 1 (Cbfa1), alkaline phosphatase (AP), osteonectin (ON), osteopontin (OP), bone sialoprotein (BSP) and collagen I (alpha1) expression when compared to control cells or those exposed to AA or betaGP. The induction of these osteoblastic markers was accompanied by a decrease in collagenase-1 expression. Collagenase activity showed a statistically significant strong negative relationship to Cbfa1 (Pearson's r=-0.97), AP (r=-0.87), OP (r=-0.95) and BSP (r=-0.82) in 5-day cultures, and moderately strong relationship to ON (r=-0.74) from 3 days culture. Dex also produced a dose-dependent increase in AP that was paralleled by a decrease in collagenase activity (r=-0.98). Addition of collagenase inhibitors increased AP expression while concomitantly suppressing collagenase activity. Conversely, addition of exogenous collagenase decreased the AP phenotype of the cells, which was more marked in the absence then in the presence of Dex. The findings indicate that Dex enhances specific markers of osteoblastic differentiation in PDL cells by decreasing collagenase expression, and suggest that endogenous collagenase may regulate osteoblastic differentiation of these cells.

Influence measurement in social networks is vital to various real-world applications, such as online marketing and political campaigns. In this paper, we investigate the problem of measuring time-sensitive and topic-specific influence based on streaming texts and dynamic social networks. A user's influence can change rapidly in response to a new event and vary on different topics. For example, the political influence of Douglas Jones increased dramatically after winning the Alabama special election, and then rapidly decreased after the election week. During the same period, however, Douglas Jones' influence on sports remained low. Most existing approaches can only model the influence based on static social network structures and topic distributions. Furthermore, as popular social networking services embody many features to connect their users, multi-typed interactions make it hard to learn the roles that different interactions play when propagating information. To address these challenges, we propose a Time-sensitive and Topic-specific Influence Measurement (TTIM) method, to jointly model the streaming texts and dynamic social networks. We simulate the influence propagation process with a self-attention mechanism to learn the contributions of different interactions and track the influence dynamics with a matrix-adaptive long short-term memory. To the best of our knowledge, this is the first attempt to measure time-sensitive and topic-specific influence. Furthermore, the TTIM model can be easily adapted to supporting online learning which consumes constant training time on newly arrived data for each timestamp. We comprehensively evaluate the proposed TTIM model on five datasets from Twitter and Reddit. The experimental results demonstrate promising performance compared to the state-of-the-art social influence analysis models and the potential of TTIM in visualizing influence dynamics and topic distribution.

Maternal food restriction (MFR) during pregnancy leads to pulmonary dysplasia in the newborn period and increases susceptibility to diseases, such as asthma and chronic lung disease, later in life. Previous studies have shown that maternal electro-acupuncture (EA) applied to "Zusanli" (ST 36) could prevent the abnormal expression of key lung developmental signaling pathways and improve the lung morphology and function in perinatal nicotine exposed offspring. There is a significant overlap in lung developmental signaling pathways affected by perinatal nicotine exposure and MFR during pregnancy; however, whether maternal EA at ST 36 also blocks the MFR-induced lung phenotype is unknown. Here, we examined the effects of EA applied to maternal ST 36 on lung morphology and function and the expression of key lung developmental signaling pathways, and the hypercorticoid state associated with MFR during pregnancy. These effects were compared with those of metyrapone, an intervention known to block MFR-induced offspring hypercorticoid state and the resultant pulmonary pathology. Like metyrapone, maternal EA at ST 36 blocked the MFR-induced changes in key developmental signaling pathways and protected the MFR-induced changes in lung morphology and function. These results offer a novel and safe, nonpharmacologic approach to prevent MFR-induced pulmonary dysplasia in offspring.

Background

Maternal smoking and/or exposure to environmental tobacco smoke continue to be significant factors in fetal and childhood morbidity and are a serious public health issue worldwide. Nicotine passes through the placenta easily with minimal biotransformation, entering fetal circulation, where it results in many harmful effects on the developing offspring, especially on the developing respiratory system.

Objectives

Recently, in a rat model, electroacupuncture (EA) at maternal acupoints ST 36 has been shown to block perinatal nicotine-induced pulmonary damage; however, the underlying mechanism and the specificity of ST 36 acupoints for this effect are unknown. Here, we tested the hypothesis that compared with EA at ST 36, EA at LU 5 acupoints, which are on lung-specific meridian, will be equally or more effective in preventing perinatal nicotine-induced pulmonary changes.

Methods

Twenty-four pregnant rat dams were randomly divided into 4 groups: saline ("S"), nicotine ("N"), nicotine + ST 36 (N + ST 36), and nicotine + LU 5 (N + LU 5) groups. Nicotine (1 mg/kg, subcutaneously) and EA (at ST 36 or LU 5 acupoints, bilaterally) were administered from embryonic day 6 to postnatal day 21 once daily. The "S" group was injected saline. As needed, using ELISA, western analysis, q-RT-PCR, lung histopathology, maternal and offspring hypothalamic pituitary adrenal axes, offspring key lung developmental markers, and lung morphometry were determined.

Results

With nicotine exposure, alveolar count decreased, but mean linear intercept and septal thickness increased. It also led to a decrease in pulmonary function and PPARγ and an increase of β-catenin and glucocorticoid receptor expression in lung tissue and corticosterone in the serum of offspring rats. Electroacupuncture at ST 36 normalized all of these changes, whereas EA at LU 5 had no obvious effect.

Conclusion

Electroacupuncture applied to ST 36 acupoints provided effective protection against perinatal nicotine-induced lung changes, whereas EA applied at LU 5 acupoints was ineffective, suggesting mechanistic specificity and HPA axis' involvement in mediating EA at ST 36 acupoints' effects in mitigating perinatal nicotine-induced pulmonary phenotype. This opens the possibility that other acupoints, besides ST 36, can have similar or even more robust beneficial effects on the developing lung against the harmful effect of perinatal nicotine exposure. The approach proposed by us is simple, cheap, quick, easy to administer, and is devoid of any significant side effects.

Introduction. Environmental exposure of the developing offspring to cigarette smoke or nicotine is an important predisposing factor for many chronic respiratory conditions, such as asthma, emphysema, pulmonary fibrosis, and so forth, in the exposed offspring. Studies showed that electroacupuncture (EA) applied to maternal "Zusanli" (ST36) acupoints during pregnancy and lactation protects against perinatal nicotine exposure- (PNE-) induced lung damage. However, the most effective time period, that is, prenatal vs. postnatal, to attain this effect has not been determined.

Objective

To determine the most effective developmental timing of EA's protective effect against PNE-induced lung phenotype in the exposed offspring.

Methods

Pregnant rats were given (1) saline ("S" group); (2) nicotine ("N" group); (3) nicotine + EA, exclusively prenatally ("Pre-EA" group); (4) nicotine + EA, exclusively postnatally ("Post-EA," group); and (5) nicotine + EA, administered both prenatally and postnatally ("Pre- and Post-EA" group). Nicotine was injected once daily (1 mg/kg, 100 μl) and EA was administered to bilateral ST36 acupoints once daily during the specified time-periods. At the end of the experimental periods, key hypothalamic pituitary adrenal (HPA) axis markers in pups and dams, and lung function, morphometry, and the central molecular markers of lung development in the offspring were determined.

Results

After nicotine exposure, alveolar mean linear intercept (MLI) increased, but mean alveolar number (MAN) decreased and lung PPARγ level decreased, but glucocorticoid receptor (GR) and serum corticosterone (Cort) levels increased, in line with the known PNE-induced lung phenotype. In the nicotine exposed group, maternal hypothalamic corticotropin releasing hormone (CRH) level decreased, but pituitary adrenocorticotropic hormone (ACTH) and serum Cort levels increased. In the "Pre- and Post-EA" groups, PNE-induced alterations in lung morphometry, lung development markers, and HPA axis were blocked. In the "Pre-EA" group, PNE-induced changes in lung morphometry, GR, and maternal HPA axis improved; lung PPARγ level decreased, but glucocorticoid receptor (GR) and serum corticosterone (Cort) levels increased, in line with the known PNE-induced lung phenotype. In the nicotine exposed group, maternal hypothalamic corticotropin releasing hormone (CRH) level decreased, but pituitary adrenocorticotropic hormone (ACTH) and serum Cort levels increased. In the "Pre- and Post-EA" groups, PNE-induced alterations in lung morphometry, lung development markers, and HPA axis were blocked. In the "Pre-EA" group, PNE-induced changes in lung morphometry, GR, and maternal HPA axis improved; lung PPAR.

Conclusions

Maternal EA applied to ST36 acupoints during both pre- and postnatal periods preserves offspring lung structure and function despite perinatal exposure to nicotine. EA applied during the "prenatal period" affords only limited benefits, whereas EA applied during the "postnatal period" is ineffective, suggesting that the EA's effects in modulating PNE-induced lung phenotype are limited to specific time-periods during lung development.

Species of the Bos genus, including taurine cattle, zebu, gayal, gaur, banteng, yak, wisent and bison, have been domesticated at least four times and have been an important source of meat, milk and power for many human cultures. We sequence the genomes of gayal, gaur, banteng, wisent and bison, and provide population genomic sequencing of an additional 98 individuals. We use these data to determine the phylogeny and evolutionary history of these species and show that the threatened gayal is an independent species or subspecies. We show that there has been pronounced introgression among different members of this genus, and that it in many cases has involved genes of considerable adaptive importance. For example, genes under domestication selection in cattle (for example, MITF) were introgressed from domestic cattle to yak. Also, genes in the response-to-hypoxia pathway (for example, EGLN1, EGLN2 and HIF3a) have been introgressed from yak to Tibetan cattle, probably facilitating their adaptation to high altitude. We also validate that there is an association between the introgressed EGLN1 allele and haemoglobin and red blood cell concentration. Our results illustrate the importance of introgression as a source of adaptive variation and during domestication, and suggest that the Bos genus evolves as a complex of genetically interconnected species with shared evolutionary trajectories.

The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.

The heterogeneity of small extracellular vesicles and presence of non-vesicular extracellular matter have led to debate about contents and functional properties of exosomes. Here, we employ high-resolution density gradient fractionation and direct immunoaffinity capture to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material. Extracellular RNA, RNA-binding proteins, and other cellular proteins are differentially expressed in exosomes and non-vesicle compartments. Argonaute 1-4, glycolytic enzymes, and cytoskeletal proteins were not detected in exosomes. We identify annexin A1 as a specific marker for microvesicles that are shed directly from the plasma membrane. We further show that small extracellular vesicles are not vehicles of active DNA release. Instead, we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular-endosome-dependent but exosome-independent mechanism. This study demonstrates the need for a reassessment of exosome composition and offers a framework for a clearer understanding of extracellular vesicle heterogeneity.

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.