Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss

Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs.Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor alpha (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio.These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism

PERAN ORANG TUA DALAM MEMBINA NILAI KARAKTER ANAK DI KECAMATAN SIMPANG TIGA ACEH BESAR

ABSTRAKRahmayanti KS, Sri. 2016. Peran Orang Tua Dalam Membina Nilai Karakter Anak di Kecamatan Simpang Tiga Kabupaten Aceh Besar. Skripsi, Jurusan Pendidikan Kesejahteraan Keluarga, Fakultas Keguruan dan Ilmu Pendidikan, Universitas Syiah Kuala. Pembimbing:(1)Dr. Anizar Ahmad, M.Pd., (2). Dra. Fitriana, M.SI.Kata Kunci: Nilai Karakter Anak, Peran Orang TuaPeran orang tua adalah partisipasi atau kesadaran jiwa orang tua untuk memperdulikan anaknya, terutama dalam hal memberikan dan memenuhi kebutuhan hidup anaknya baik dari segi sosial maupun material. Penelitian ini untuk mengetahui usaha orang tua dalam membina nilai karakter anak di Kecamatan Simpang Tiga Kabupaten Aceh Besar. Penelitian ini bertujuan untuk (1) mengetahui usaha yang dilakukan orang tua dalam membina nilai karakter anak dan (2) mengetahui sistem pengawasan yang diterapkan oleh orang tua terhadap anak. Metode yang digunakan dalam penelitian ini adalah metode deskriptif kuantitatif. Data penelitian ini bersumber dari orang tua yang memiliki anak usia 4 sampai 10 tahun berjumlah 28 keluarga, pengumpulan data menggunakan kuisioner. Pengolahan data penelitian ini menggunakan rumus persentase. Simpulan penelitian ini berpengaruh pada usaha orang tua dalam membina nilai karakter anak, walau sebagian kecil yang mengetahui nilai-nilai karakter, tetapi sebagian besar sudah berusaha menanamkan nilai karakter tersebut. Lebih dari setengah responden menanamkan nilai religius kepada anak dengan tujuan agar anak mempunyai akhlak yang mulia kedepannya. Sedangkan yang berperan dalam membina nilai karakter anak adalah suami dan istri. Sistem pengawasan yang diterapkan orang tua berpengaruh terhadap pembentukkan nilai karakter anak. Seluruh anak termasuk kedalam katagori anak yang mudah bersahabat. Penanaman nilai karakter pada anak di mulai pada awal masa kanak-kanak ketika berumur 2-6 tahun. Responden juga menerapkan perilaku disiplin kepada anak karena usia awal kanak-kanak merupakan usia yang masih rentan, dan akan meniru semua yang dikerjakan oleh orang tuanya. Saran untuk orang tua agar dapat mendidik anaknya dengan baik, tidak mengedepankan emosi, dapat meluangkan waktu, adanya komunikasi yang dibina orang tua dengan anak, dan jangan bersikap apatis terhadap apa yang dikerjakan sianak

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)