Molybdenum isotopes unmask slab dehydration and melting beneath the Mariana arc.

How serpentinites in the forearc mantle and subducted lithosphere become involved in enriching the subarc mantle source of arc magmas is controversial. Here we report molybdenum isotopes for primitive submarine lavas and serpentinites from active volcanoes and serpentinite mud volcanoes in the Mariana arc. These data, in combination with radiogenic isotopes and elemental ratios, allow development of a model whereby shallow, partially serpentinized and subducted forearc mantle transfers fluid and melt from the subducted slab into the subarc mantle. These entrained forearc mantle fragments are further metasomatized by slab fluids/melts derived from the dehydration of serpentinites in the subducted lithospheric slab. Multistage breakdown of serpentinites in the subduction channel ultimately releases fluids/melts that trigger Mariana volcanic front volcanism. Serpentinites dragged down from the forearc mantle are likely exhausted at >200 km depth, after which slab-derived serpentinites are responsible for generating slab melts.

A Genetic Variant of the BTLA Gene is Related to Increased Risk and Clinical Manifestations of Breast Cancer in Chinese Women.

BACKGROUND: B and T lymphocyte attenuator (BTLA), an immunoinhibitory receptor, is shown to suppress the lymphocyte activation. Several studies addressed the relationship between the BTLA rs1982809 polymorphism and the risk of cancer. PATIENTS AND METHODS: To identify the effects of this polymorphism on the risk of breast cancer (BC), this study examined Chinese women from China, Jiangsu Province. This study involved 324 patients with BC and 412 controls. RESULTS: We observed that the BTLA rs1982809 polymorphism elevated the risk of BC. A similar finding was also shown in the subgroups of premenopausal women and those aged < 55 years old. In addition, this polymorphism was correlated with the estrogen receptor status, C-erbB-2 status, Ki-67 status, TNM stage, and tumor size of patients with BC. CONCLUSIONS: Collectively, the BTLA rs1982809 polymorphism shows a significant association with elevated risk and clinical features of BC in Chinese women. Further studies involving other races are urgently needed to replicate these findings.

Targeting ERß in Macrophage Reduces Crown-like Structures in Adipose Tissue by Inhibiting Osteopontin and HIF-1α.

Proinflammatory processes in adipose tissue contribute to development of breast cancer and insulin resistance. Crown-like structures (CLS) are histologic hallmarks of the proinflammatory process in adipose tissue. CLS are microscopic foci of dying adipocytes surrounded by macrophages mostly derived from monocytes in blood. Estrogen receptor ß (ERß) is expressed in microglia, macrophages within the central nervous system (CNS), where it evokes an anti-inflammatory response. The present study investigates the function of ERß in macrophages within CLS. We report that even though monocytes in the blood have no detectable levels of ERß, macrophages in CLS do express ERß. In ERß-/- mice, there was a significant increase in the number of CLS in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). CLS in these mice were dominated by pro-inflammatory macrophages (M1 macrophages) with higher expression of osteopontin (OPN) and an increase in number of proliferating macrophages. In mice made obese by Western diet, treatment with an ERß selective agonist (LY3201) reduced the number of CLS in both SAT and VAT with downregulation of OPN, activated hypoxia-inducible factor-1α (HIF-1α), proliferation and upregulation prolyl hydroxylase 2 (PHD2), the enzyme which prevents activation of HIF1α, in macrophages. We conclude that ERß expression is induced in macrophages in CLS within adipose tissue where it plays a pivotal role in suppression of CLS. Thus ERß agonists may be used to alleviate CLS-related breast cancer and insulin resistance in adipose tissue.

Adenovirus-mediated transduction with Histone Deacetylase 4 ameliorates disease progression in an osteoarthritis rat model.

BACKGROUND: Downregulation of histone deacetylase-4 (HDAC4) contributes to cartilage degeneration in osteoarthritis (OA) because it promotes upregulation of runt-related transcription factor-2 (Runx-2) and osteoarthritis-related genes. The effect of HDAC4 upregulation on cartilage damage in OA remains unknown. METHODS: Rat chondrocytes were infected with Ad-GFP or Ad-HDAC4-GFP for 48 h, stimulated with interleukin-1ß (IL-1ß, 10 ng/mL) for 24 h, and then harvested for RT-qPCR. Male Sprague-Dawley rats in 3 groups were given anterior cruciate ligament transection (ACLT) or sham operation, and knee injections with different adenovirus (Ad) vectors at 48 h after surgery and every 3 weeks thereafter: ACLT+Ad-GFP (n = 17); ACLT+Ad-HDAC4-GFP (n = 20); and sham+Ad-GFP (n = 15). Three ACLT-Ad-HDAC4-GFP rats were sacrificed at different times to examine the expression of HDAC4. Two ACLT-Ad-GFP rats and two ACLT-Ad-HDAC4-GFP rats were euthanized at week-2; articular cartilage was harvested and expression of HDAC4 was determined by RT-qPCR. All other rats were euthanized at week-8. Cartilage damage and OA progression was assessed using radiography, fluorescence molecular tomography (FMT), histology, immunohistochemistry (IHC), ELISA, and RT-qPCR. RESULTS: Overexpression of HDAC4 in chondrocytes stimulated by IL-1ß reduced the levels of Runx-2, MMP-13, and Collagen X, but increased the levels of Collagen II and Aggrecan. Upregulation of HDAC4 reduced osteophyte formation and cartilage damage, and increased articular cartilage anabolism. CONCLUSION: HDAC4 attenuated articular cartilage damage by repression of Runx-2, MMP-13, and collagen X and induction of collagen II and ACAN in this rat model of OA. Upregulation of HDAC4 may provide chondroprotection in OA patients.

Contribution of IL-1ß, 6 and TNF-α to the form of post-traumatic osteoarthritis induced by "idealized" anterior cruciate ligament reconstruction in a porcine model.

BACKGROUND: It has been noted that anterior cruciate ligament (ACL) injury-induced cartilage degeneration is the key risk factor for post-traumatic osteoarthritis (PTOA). However, whether the cartilage degeneration after ACL injury is caused by inflammation, abnormal biomechanics or both remains largely unknown, as there has been no animal model for separating the two factors so far. METHODS: Eighteen-month-old female mini-pigs were divided into an "idealized" anterior cruciate ligament reconstruction (IACLR) group and a control group (n = 16 limbs per group). Real-time PCR, safranine O staining and indian ink staining were performed to verify whether animal models were successfully established or not. Multiple linear regression analysis was used to evaluate the correlation between levels of the inflammatory factors (including interferon [IFN]-γ, interleukin [IL]-1ß, IL-4, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor [TNF]-α measured by the Luminex method) and changes in cartilage histology (quantified by morphological scoring) after surgery. RESULTS: A significant OA cartilage damage with increased MMP-1, MMP-13 mRNA levels and reduced aggrecan mRNA/protein levels was observed in IACLR groups. As a result, the IACLR gross morphology score was dramatically increased than control. Moreover, IACLR significantly increased the levels of IL-1ß, IL-4, IL-6 and TNF-α in the synovial fluid of the knee. Most importantly, a close relationship was found between IL-1ß, IL-6 and TNF-α concentrations and morphological score of PTOA, respectively. CONCLUSION: These results demonstrated that inflammatory factors are independently responsible for the onset of PTOA.