CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.

Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDR ApaI, VDR FokI and PMOP susceptibility. Subgroup analysis showed that VDR ApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDR BsmI and VDR FokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying the ApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women with FokI Ff genotype. PMOP women with the Cdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.

MicroRNAs play pivotal roles in cancer stem cell regulation. Previous studies have shown that microRNA-34a (miR-34a) is downregulated in human breast cancer. However, it is unknown whether and how miR-34a regulates breast cancer stem cells. Notch signaling is one of the most important pathways in stem cell maintenance and function. In this study, we verified that miR-34a directly and functionally targeted Notch1 in MCF-7 cells. We reported that miR-34a negatively regulated cell proliferation, migration, and invasion and breast cancer stem cell propagation by downregulating Notch1. The expression of miR-34a was negatively correlated with tumor stages, metastasis, and Notch1 expression in breast cancer tissues. Furthermore, overexpression of miR-34a increased chemosensitivity of breast cancer cells to paclitaxel (PTX) by downregulating the Notch1 pathway. Mammosphere formation and expression of the stemness factor ALDH1 were also reduced in the cells treated with miR-34a and PTX compared to those treated with PTX alone. Taken together, our results indicate that miR-34a inhibited breast cancer stemness and increased the chemosensitivity to PTX partially by downregulating the Notch1 pathway, suggesting that miR-34a ⁄ Notch1 play an important role in regulating breast cancer stem cells. Thus miR-34a is a potential target for prevention and therapy of breast cancer. B reast cancer is the most common cancer among women worldwide.(1) Despite exciting developments in early detection and systemic therapy, it remains a major cause of cancerrelated death because of metastasis, relapse, and treatment resistance. Growing evidence indicated that one of the most important reasons behind this was the presence of a small population of stem-like cells called cancer stem cells (CSCs), such as breast cancer stem cells (BCSCs).(2) Breast cancer stem cells were the first CSCs to be reported and are among the best characterized.(3) Identification of BCSCs from tumor samples and breast cancer cells relies mainly on CD44 + ⁄ CD24 À or aldehyde dehydrogenase 1 (ALDH1) phenotypes.(4-6) Breast cancer stem cells are endowed with stem cell properties including the capacity of self-renewal and multilineage differentiation. They play important roles in tumor formation, progression, and therapy resistance in breast cancer. (7,8) Thus, effective targeting of BCSCs has the potential to improve outcomes for women with breast cancer. (9)

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Rice (Oryza sativa) grain shape, which is controlled by quantitative trait loci (QTL), has a strong effect on yield production and quality. However, the molecular basis for grain development remains largely unknown. In this study, we identified a novel QTL, Slender grain on chromosome 7 (SLG7), that is responsible for grain shape, using backcross introgression lines derived from 9311 and Azucena. The SLG7 allele from Azucena produces longer and thinner grains, although it has no influence on grain weight and yield production. SLG7 encodes a protein homologous to LONGIFOLIA 1 and LONGIFOLIA 2, both of which increase organ length in Arabidopsis. SLG7 is constitutively expressed in various tissues in rice, and the SLG7 protein is located in plasma membrane. Morphological and cellular analyses suggested that SLG7 produces slender grains by longitudinally increasing cell length, while transversely decreasing cell width, which is independent from cell division. Our findings show that the functions of SLG7 family members are conserved across monocots and dicots and that the SLG7 allele could be applied in breeding to modify rice grain appearance.KEYWORDS rice; quantitative trait loci; grain shape; cell elongation R ICE (Oryza sativa L.) is a staple food for half of the world's population (Khush 2001). Three major components, panicle number per plant, grain number per panicle, and grain weight, determine rice yield production. Grain weight is associated with grain size and shape, which are defined as grain length, grain width, and grain thickness (Duan et al. 2014). There is a striking diversity of grain size among the rice species worldwide. The grains of domesticated rice range from 3 to 11 mm in length and from 1.2 to 3.8 mm in width (Fitzgerald et al. 2009). Despite the influence of several environmental factors on plant growth and development, such as water supply and fertilizer level, the final grain size of rice is reasonably constant within a given species.Rice grain traits are quantitatively inherited. In the past decade, several quantitative trait loci (QTL) controlling grain size and shape have been cloned. GS3, encoding a transmembrane protein containing four putative domains, was the first characterized QTL that regulates grain length (Fan et al. 2006). qGL3 encodes a putative protein phosphatase with a Kelch-like repeat domain, and an aspartate-to-glutamate transition in the second Kelch domain leads to a long-grain phenotype (Zhang et al. 2012). GW6 encodes a GNAT-like protein that harbors intrinsic histone acetyltransferase activity, and an elevated expression enhances grain length and weight by enlarging spikelet hulls and accelerating grain filling (Song et al. 2015). GW2, GW5/qSW5, GS5, and GW8 were identified as regulators of rice grain width. GW2 encodes a previously unknown RING-type protein with E3 ubiquitin ligase, which negatively regulates cell division by degrading its substrate(s) through the ubiquitin-proteasome pathway (Song et al. 2007). GW5/qSW5 encodes a nuclearlocated protein t...

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Abstract. The purpose of this study was to investigate the activation of Hedgehog (Hh) signaling molecules and its involvement in triple-negative breast cancer (TNBC). A total of 123 cases of paraffin blocks, including 83 cases of primary breast carcinoma, 30 cases of mammary hyperplasia and 10 cases of normal breast tissue, were immunohistochemically analyzed for Sonic Hedgehog (SHH), Patched-1 (PTCH1), Smoothened (SMO) and glioma-associated oncogene homoglog 1 (GLI1) expression. The expression of SMO and GLI1 in TNBC was significantly increased in comparison to non-triple-negative breast cancer (nTNBC). GLI1 expression manifested an inverse association with the estrogen receptor. The levels of GLI1 expression were increased in lymph nodepositive cases. The expression of SHH and SMO was increased in high histological grades. Furthermore, the expression of SMO and GLI1 was correlated with superior tumor stage. The expression of SHH, SMO and GLI1 was significantly increased in breast cancer and mammary hyperplasia. PTCH1 expression was significantly decreased in breast cancer compared to mammary hyperplasia and normal breast tissue. For the first time, clinical evidence has been provided in support of significant roles of Hh signaling in TNBC. Hh signaling is involved in breast ductal changes and malignant transformation. Measures to inhibit Hh activity may improve the prognosis of TNBC patients.