SunM~aryT helper type 0 (Th0), Thl, and Th2 CD4 + T cell cloues derived from a T cell receptor cx/fl (TCR-alfl) transgenic mouse were activated by antigen presented on "artificial" antigen-presenting cells that expressed or lacked the costimulatory molecule B7-1, and were analyzed for single cell eytokine mRNA expression by in situ hybridization. There was significant heterogeneity in the frequency of T cells that expressed individual cytokine mRNAs within each donal population, suggesting that transcriptional control of each of the cytokine genes was not coordinate within an individual cell. The majority of antigen-stimulated Thl cells expressed mRNA for interferon "y (IFN-7), but far fewer cells in the same population expressed interleukin 2 (IL-2). Similarly, the frequency of IL-4-expressing cells was greater than that of IL-5-or IL-10-expressing cells in the same Th2 population, but the difference in expression frequencies was more variable between dones. The expression frequencies of each of the cytokines was quite heterogeneous in the antigenactivated Th0 population. The principal effect of increased antigen on the activation of individual cytokine genes in each of the clonal populations was to increase recruitment of mRNA-positive cells, with little or no effect on the level of cytokine mRNA expression in individual positive cells. The effects of B7 costimulation were variable depending on the cytokiue gene analyzed. B7 costimulation markedly increased the frequency and the level of IL-2 mRNA expression in individual positive cells in the Thl and Th0 populations, with less effect on the recruitment and single cell expression level of IFN-% IL-4 frequencies were modestly increased by B7 costimulation of the Th2 clones, but there was no detectable increase in single cell IL-4 expression level. The observed patterns of cytokine mRNA expression favor a model of T cell activation in which all-or-none, rather than graded, responses of cytokine genes are dominant.

CD4+ T cells from a8-T-cell receptor transgenic mice were analyzed for coexpression of cytokine mRNAs during phenotype development using a double-label in situ hybridization technique. T cells that produced cytokines in the primary response were a fraction of the activated population, and only a minority of the cytokine-positive cells coexpressed two cytokines. In secondary responses, frequencies of doublepositive cells increased, although they remained a minority of the total. Of the cytokine pairs examined, interleukin (IL)-4 and IL-5 were the most frequently coexpressed. IL-4 and interferon y showed the greatest tendency toward segregation of expression, being rarely coexpressed after the primary stimulation. These data indicate that there is significant heterogeneity of cytokine gene expression by individual CD4+ T cells during early antigenic responses. Coexpression of any pairs of cytokines, much less Thl and Th2 cytokines, is generally the exception. The ThO phenotype is a population phenotype rather than an individual cell phenotype.Regulation of immune responses by CD4+ T cells is mediated by antigen-induced production of cytokines. Naive CD4+ T cells have limited cytokine responses; hence, their regulatory capacity and effector function are limited (1-3). After antigendriven differentiation, there is significant diversification of CD4+ T-cell cytokine responses (3). At least two differentiation pathways can be distinguished-the so-called Thl/Th2 paradigm (4-6). Recent studies have begun to elucidate the mechanisms that control CD4+ T-cell phenotype development (3, 7-10) and have established a principal role for cytokines as determinants of Thl vs. Th2 development. Interleukin (IL)-4, IL-12, IL-10, interferon (IFN)-,y, and transforming growth factor ,B exert critical effects on phenotype development, albeit by distinct mechanisms (7-9, 11, 12 (14), who produced transgenic mice with a thymidine kinase (TK) cDNA linked to the IL-4 promoter and showed that in the presence of ganciclovir, the mitogen-stimulated development of both IL-4-and IFN-y-producing T-cell effectors was blocked. These data suggest that an IL-4-producing intermediate precedes development of both Thl and Th2 cells.In an effort to dissect single cell responses during development of cytokine phenotypes in an a,B-TCR transgenic system, we have developed a double-label in situ hybridization (ISH) method to detect the expression of pairs of cytokine mRNAs in individual cells. Our results demonstrate a marked heterogeneity of cytokine gene expression during primary and subsequent antigenic stimulations and indicate that coexpression of cytokines by the same cell is the exception. These data suggest that the ThO-like phenotype in early CD4+ T-cell differentiation is a population phenotype rather than an individual cell phenotype and emphasize the independent regulation of each of the cytokine genes.EXPERIMENTAL PROCEDURES Animals. The DO10 transgenic line has been described (15). These animals express a transgenic TCR with specificity...

Chalcopyrite compound CuGaTe2 is the focus of much research interest due to its high power factor. However, its high intrinsic lattice thermal conductivity seriously impedes the promotion of its thermoelectric performance. Here, it is shown that through alloying of isoelectronic elements In and Ag in CuGaTe2, a quinary alloy compound system Cu1−xAgxGa0.4In0.6Te2 (0 ≤ x ≤ 0.4) with complex nanosized strain domain structure is prepared. Due to strong phonon scattering mainly by this domain structure, thermal conductivity (at 300 K) drops from 6.1 W m−1 K−1 for the host compound to 1.5 W m−1 K−1 for the sample with x = 0.4. As a result, the optimized chalcopyrite sample Cu0.7Ag0.3Ga0.4In0.6Te2 presents an outstanding performance, with record‐high figure of merit (ZT) reaching 1.64 (at 873 K) and average ZT reaching 0.73 (between ≈300 and 873 K), which are ≈37 and ≈35% larger than the corresponding values for pristine CuGaTe2, respectively, demonstrating that such domain structure arising from isoelectronic multielement alloying in chalcopyrite compound can effectively suppress its thermal conductivity and elevate its thermoelectric performance remarkably.

The differences in angiographic characteristics and cardiovascular (CV) risk factors between coronary artery aneurysm (CAA) and coronary artery ectasia (CAE) have not been compared systematically. Of 10 876 patients undergoing coronary angiography, patients with CAA (n = 85) and CAE (n = 51) were screened. The prevalence of CAA was greater than that of CAE ( P < .05). The right coronary artery was the most involved (70.6%) in CAE compared with left circumflex (52.9%) and left anterior descending (41.2%). Coronary artery aneurysm coexisted with coronary artery disease (CAD) more frequently than CAE ( P = .002), and the modified Gensini score of CAA was also higher than that of CAE ( P < .001). The average maximum diameter was smaller, and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count was lower in CAA than CAE in all 3 coronary arteries ( P < .001). Multivariate analysis showed that hyperlipidemia ( P = .02), smoking ( P = .04), and family history of CAD ( P = .02) were the independent variables most strongly associated with CAA, but not CAE. This study suggests that there are significant differences in coronary angiographic characteristics and CV risk factors between CAA and CAE.

Objective The aim of this study was to investigate whether remedial hydration (RH) reduces the incidence of contrast-induced nephropathy (CIN) and short-term adverse events in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Methods A total of 216 consecutive STEMI patients were prospectively and randomly assigned into two groups: 108 patients in the RH group and 108 patients in the no RH (control) group. The serum creatinine (SCr) and creatinine clearance (CCr) levels were measured on admission and at 24, 48 and 72 hours after primary PCI. The rates of CIN and short-term adverse events were analyzed for each group. After surgery, the patients were categorized into four groups according to the Mehran risk score: low (! 5, n =98), moderate (6-10, n=56), high (11-15, n=40) or very high (" 16, n=22). Results The incidence of CIN in the RH group was lower than that observed in the control group (22/108; 20.4% vs. 38/108; 35.2%, p<0.05). The subgroup analysis showed that the rate of CIN was lower in the moderate (6/29; 20.7% vs. 13/30; 43.3%, p<0.10) and significantly lower in both the high (5/21; 23.8% vs. 10/18; 55.6%, p<0.05) and very high score groups (3/12; 25.0% vs. 8/12; 66.7%, p<0.05) among the RH patients compared to the controls. At 24, 48 and 72 hours after PCI, the patients in the RH group exhibited lower SCr levels and higher CCr levels than the patients in the control group (both p<0.05). A lower incidence of in-hospital clinical events was also observed in the RH group. Conclusion Remedial hydration decreases the occurrence of CIN and improves the short-term prognosis of STEMI patients undergoing primary PCI.

Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR-4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We then found that miR-4756 targeted the 3'-untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased 5' monophosphate-activated protein kinase activation. Thus, our study provides evidence that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR-4756 may be a novel strategy for DKD treatment.

Background:Oral cancer metastasis is a devastating process that contributes to poor prognosis and high mortality, yet its detailed underlying mechanisms remain unclear. Here, we aimed to evaluate metastasis-specific markers in oral cancer and to provide comprehensive recognition concerning functional roles of the specific target in oral cancer metastasis.Methods:Lectin, galactoside-binding, soluble, 1 (LGALS1) was identified by secretomic analysis. LGALS1 expression of patient samples with oral cancer on the tissue microarray were examined by immunochemical (IHC) staining. Small interfering RNA (siRNA)-mediated knockdown of LGALS1 revealed the role of LGALS1 in oral cancer metastasis in vitro and in vivo.Results:LGALS1 was observed to be upregulated in highly invasive oral cancer cells, and elevated LGALS1 expression was correlated with cancer progression and lymph node metastasis in oral cancer tissue specimens. Functionally, silencing LGALS1 resulted in suppressed cell growth, wound healing, cell migration, and cell invasion in oral cancer cells in vitro. Knockdown of LGALS1 in highly invasive oral cancer cells dramatically inhibited lung metastasis in an in vivo mouse model. Mechanistic studies suggested p38 mitogen-activated protein kinase (MAPK) phosphorylation, upregulated MMP-9, and mesenchymal phenotypes of epithelial-mesenchymal transition (EMT) in highly invasive oral cancer cells, whereas siRNA against LGALS1 resulted in the inactivation of p38 MAPK pathway, downregulated MMP-9, and EMT inhibition.Conclusions:These findings demonstrate that elevated LGALS1 is strongly correlated with oral cancer progression and metastasis, and that it could potentially serve as a prognostic biomarker and an innovative target for oral cancer therapy.

As an ecofriendly thermoelectric material with intrinsic low thermal conductivity, ternary diamond-like Cu2SnSe3 (CSS) has attracted much attention. Nevertheless, its figure of merit, ZT, is limited by its small thermopower (S) and power factor (PF). Here, we show that an increase in thermopower by 63% and a carrier-mobility rise of 81% at 300 K can be simultaneously achieved through 5% substitution of Fe for Sn due to both enhancement of electronic density of states and degeneracy of multiple valence band maxima, which lead to high PF = 10.3 μW·cm–1·K–2 at 823 K for Fe-doped CSS (CSFS). Besides, an ultrahigh PF of 14.8 μW·cm–1·K–2 (at 773 K) and 45% reduction of lattice thermal conductivity (at 823 K) are realized for CSFS-based composites with 0.125 wt % of MgO nanoinclusions, owing to further enhancement of S via energy-dependent scattering and strong phonon scattering by the embedded nanoparticles. Consequently, a maximum ZT = 1 at 823 K is reached for the CSFS/f MgO composite samples with f = 0.125 wt %, which is around 2.5 times larger than that of the CSS compound.