Biomineralized materials as bone ECM mimetics: From understanding molecular mechanisms to new therapeutic interventions

Bone extracellular matrix is a heterogeneous composite material consisting, of an inorganic (or mineral) phase, an organic phase and water. In an effort to mimic the mineral environment of bone tissue, we recently employed biomineralization and created mineralized biomaterials (1). Our studies showed that these biomineralized materials induced osteogenic differentiation of stem cells, including human pluripotent stem cells (which includes both embryonic stem cells and induced pluripotent stem cells), even in growth medium devoid of any osteogenic inducing molecules (2,3). By employing these mineralized materials, we have studied the molecular mechanism through which calcium phosphate minerals support osteogenesis with an emphasis on phosphate metabolism (4). Our studies show that extracellular phosphate (resulting from the dissolution of calcium phosphate minerals) uptake through solute carrier family 20 phosphate transporter member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SlC20a1 abrogates osteogenic differentiation by decreasing intra-mitochondrial phosphate and ATP synthesis. Our studies further show that the phosphate-ATP-adenosine signaling axis not only promotes osteogenic differentiation of multipotent progenitor cells but also inhibits their adipogenic differentiation (5). When implanted in vivo, these acellular mineralized biomaterials recruited endogenous cells and induced their differentiation to form vascularized bone tissues (6) and also supported donor bone marrow transplantation (7). Leveraging these understandings, we are currently studying the pivotal role of Adenosine A2b receptor, a G-protein coupled receptor on the cell membrane, in regulating bone-specific cells and treating bone metabolic disorders. In this talk, I will discuss these results and the identification of possible drug targets for osteoporosis. REFERENCES [1] Phadke A, Zhang C, Hwang YS, Vecchio K, Varghese S. “Templated mineralization of synthetic hydrogels for bone like composite material: Role of matrix hydrophobicity”, Biomacromolecules. 2010; 11, 2060 [2] Phadke A, Shig Y-R, Varghese, S. “Mineralized synthetic matrices as an instructive microenvironment for osteogenic differentiation of human mesenchymal stem cells” Macromol Biosci. 2012, 12, 1022 [3] Kang H, Shih Y-RV, Hwang YS, Wen C, Rao V, Seo T, and Varghese S. “Mineralized gelatin methacrylate-based matrices induce osteogenic differentiation of human induced pluripotent stem cells” Acta Biomater. 2014, 10, 4961 [4] Shih Y-RV, Hwang YS, Phadke A, Kang H, Hwang NS, Caro EJ, Nguyen S, Siu M, Theodorakis EA, Gianneschi NC, Vecchio KS, Chien S, Lee OK and Varghese S. “Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling” Proc. Natl. Acad. Sci. 2014, 111, 990. [5] Kang H, Shih Y-RV, Varghese S. “Biomineralized matrices dominate soluble cues to direct osteogenic differentiation of human mesenchymal stem cells through adenosine signaling” Biomacromolecules 2015, 16, 1050 [6] Shih Y-RV, Phadke A, Yamaguchi T, Kang H, Inoue N, Masuda K and Varghese S. “Synthetic bone mimetic matrix-mediated in situ bone tissue formation through host cell recruitment” Acta Biomater. 2015, 19, 1. [7] Shih Y-RV, Kang H, Rao V, Chu Y-J, Kown SK, and Varghese S. “In vivo engineering of bone organoids with hematopoietic functions” Proc. Natl. Acad. Sci, 2017, 114, 5419

Cellular senescence in neuroinflammation

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Synthesis, Crystal Structure and Photophysical Properties of Lanthanide Coordination Polymers of 4- 4-(9H-Carbazol-9-Yl)Butoxy Benzoate: The Effect of Bidentate Nitrogen Donors on Luminescence

A new aromatic carboxylate ligand, 4-[4-(9H-carbazol-9-yl)butoxy]benzoic acid (HL), has been synthesized by the replacement of the hydroxyl hydrogen of 4-hydroxy benzoic acid with a 9-butyl-9H-carbazole moiety. The anion derived from HL has been used for the support of a series of lanthanide coordination compounds [Ln = Eu (1), Gd (2) and Tb (3)]. The new lanthanide complexes have been characterized by a variety of spectroscopic techniques. Complex 3 was structurally authenticated by single-crystal X-ray diffraction and found to exist as a solvent-free 1D coordination polymer with the formula [Tb(L)(3)](n). The structural data reveal that the terbium atoms in compound 3 reside in an octahedral ligand environment that is somewhat unusual for a lanthanide. It is interesting to note that each carboxylate group exhibits only a bridging-bidentate mode, with a complete lack of more complex connectivities that are commonly observed for extended lanthanide-containing solid-state structures. Examination of the packing diagram for 3 revealed the existence of two-dimensional molecular arrays held together by means of CH-pi interactions. Aromatic carboxylates of the lanthanides are known to exhibit highly efficient luminescence, thus offering the promise of applicability as optical devices. However, due to difficulties that arise on account of their polymeric nature, their practical application is somewhat limited. Accordingly, synthetic routes to discrete molecular species are highly desirable. For this purpose, a series of ternary lanthanide complexes was designed, synthesized and characterized, namely [Eu(L)(3)(phen)] (4), [Eu(L)(3)(tmphen)] (5), [Tb(L)(3)(phen)] (6) and [Tb(L)(3)(tmphen)] (7) (phen = 1,10-phenanthroline and tmphen = 3,4,7,8-tetramethyl-1,10-phenanthroline). The photophysical properties of the foregoing complexes in the solid state at room temperature have been investigated. The quantum yields of the ternary complexes 4 (9.65%), 5 (21.00%), 6 (14.07%) and 7 (32.42%), were found to be significantly enhanced in the presence of bidentate nitrogen donors when compared with those of the corresponding binary compounds 1 (0.11%) and 3 (1.45%). Presumably this is due to effective energy transfer from the ancillary ligands.Council of Scientific and Industrial Research (CSIR-TAPSUN Project) SSL, NWP-55CSIR, New DelhiRobert A. Welch Foundation F-0003Chemistr

Metal-ion-mediated healing of gels

Several researchers have demonstrated the biomimicking attributes of stimuli responsive synthetic hydrogels such as sensitivity, selectivity, mobility, and memory. In this work we demonstrate yet another attribute, namely healing in hydrogels. We show that certain hydrogels having a flexible aliphatic side chain with a terminal carboxyl group can show healing in the presence of transition metal ions. On bringing two initially dried gel pieces into contact with each other in a dilute copper chloride solution the pieces were found to weld and the strength of the weld-line was found to increase gradually with time. The welded gel pieces could be separated by leaching out the metal ions and the separated gel pieces can be welded again by subsequent treatment with the metal ions

The effectiveness of video assisted teaching programme on knowledge and attitude of perimenopausal women regarding postmenopausal osteoporosis and its prevention in Marappadi Village at Kulasekharam, Kanyakumari

Osteoporosis occurred among elderly people and postmenopausal women. Lowestrogen has no effect on osteoporosis prevention. However, adequate diet and lifestyle can help to prevent osteoporosis from young age. It is important to store bone mass while the menstrual periods continue. Furthermore osteoporosis is not usually found until a bone has fractured so that many women are unaware that they are at risk of osteoporosis. (Curry & Hogstel 2002, 26.) The main objective of the study was to assess the effectiveness of video assisted teaching programme on assisted reproductive techniques among infertile women. The research design selected for the study was pre experimental one group pretest and posttest design. A purposive sampling technique was followed to obtain a sample of 50 perimenopausal woemn. During the data collection, a pretest was conducted on the first day, followed by video assisted teaching programme on osteoporosis and its prevention was given. Finally, posttest was done on the seventh day for the same perimenopausal women. Data were analyzed by descriptive and inferential statistics. The data were analyzed using both descriptive and inferential statistics. The pretests mean knowledge score was 9.32; the posttests mean knowledge score was 16.68. ‘t’ test was used to evaluate the effectiveness of the video assisted teaching programme at 0.05 level of significance.the pretest mean attitude score was 9.18 and post testmean attitude escore was 17.48. It was found that the ‘t’ test value was statistically significant at p<0.05 level (Table value=2.009). The study reveals that the level of knowledge and attitude among perimenopausal women has improved after video assisted teaching programme at 0.05 level of significance. Knowledge on osteoporosis and its prevention helps them to take preventive measures to get the risk of osteoporosis.Based on the findings this study concludes that teaching programme like video teaching will improve the knowledge on osteoporosis and its prevention among perimenopausal women

Effectiveness of Information, Education and Communication Package on Knowledge regarding Sexual Awareness among Adolescent Girls at Selected Schools in Kanniyakumari District

BACKGROUND OF THE STUDY: Adolescent is the period of transition between childhood and adulthood, a time of rapid physical, social, sexual and emotional maturation. Most adolescents deal with these changes without adequate knowledge and understanding which could cause issues such as, teenage pregnancy, sexual abuse, unhealthy sexual behaviour and HIV/AIDS. The nurses have an enabling role to help the adolescent to increase knowledge on sexual awareness by using IEC package. THE AIM OF THE STUDY: To evaluate the effectiveness of information education and Communication package on knowledge regarding sexual awareness among adolescent girls at selected schools in Kanyakumari District. MATERIALS AND METHOD: Quasi experimental pre-test post-test control group design was adopted. The sample size consisted of 100 adolescent girls, 50 in experimental group and 50 in control group. The conceptual frame work is based on Sister Callista Roy’s Adaptation Model. Purposive sampling technique was adopted. Demographic data and structured questionnaire on sexual awareness was used data collection. IEC was given for 30 minutes, once a week for 4 weeks. RESULT: In experimental group 52% of adolescent girls had inadequate awareness. After providing IEC package, no one had inadequate awareness and 100% had adequate awareness. There was a significant improvement in mean post test awareness score 20.08 in experimental group (MD = 12.36, t value =18.76 p<.000). The mean post-test level of awareness score 20.08 among adolescent girls in experimental group was greater than the mean post test level of awareness score 8.56 among adolescent girls in Control group (MD =11.52 t, =21.77 p<.000). CONCLUSION: The study proved that IEC programme is an effective teaching strategy in improving the knowledge regarding sexual awareness among adolescent girls

In vivo RNA editing of point mutations via RNA-guided adenosine deaminases.

We present in vivo sequence-specific RNA base editing via adenosine deaminases acting on RNA (ADAR) enzymes with associated ADAR guide RNAs (adRNAs). To achieve this, we systematically engineered adRNAs to harness ADARs, and comprehensively evaluated the specificity and activity of the toolsets in vitro and in vivo via two mouse models of human disease. We anticipate that this platform will enable tunable and reversible engineering of cellular RNAs for diverse applications

A Study on Insulin Resistance and Obesity Among Women at High Risk for Breast Cancer Using Cluster Analysis.

OBJECTIVE: The present study to stratify the female population based on their obesity and body fat distributions using cluster analysis without relating to conventional obesity cutoff values. To study insulin response (sensitivity x resistance) using indices of surrogate measures obtained from OGTT data. To identify the hormonal parameters that are significantly altered in obese breast cancer patients and to exploit them as screening markers along with body mass index (BMI) and body fat mass (BFM). To build a comprehensive questionnaire for breast cancer risk prediction using related variables and the symptoms associated with hormonal variations in breast cancer. PURPOSE OF STUDY: According to estimates of the International Obesity Task Force, 1,7 billion people are exposed to health risks related to body weight, while the increase in Body Mass Index (BMI) is responsible for more than 2.5 million deaths annually, which is expected to double by 2030. The aim is to define obesity using anthropometric measures particularly in obese post-menopausal women. Assessment of insulin resistance is of great importance in the study of epidemiology and pathophysiology of major public health problems and in following the clinical course of patients on various therapeutic regimens. It is also of our interest to evaluate the insulin resistance in obese post-menopausal women who are at high risk for breast cancer using a simple oral glucose tolerance test (OGTT). Studying about relevant risk factors of breast cancer and their prevalence is essential in the breast cancer risk prediction among individuals of high risk group.CONCLUSION: Obesity is a chronic disease which has spread all over the world and threatens public global health. Obesity in postmenopausal women was highly correlated with several disorders including type 2 diabetes mellitus, hypertension, coronary heart disease, arthritis, sleep apnea, and certain forms of obesity-related cancers, including breast, prostate, endometrium, colon and gallbladder cancer. However, defining an individual as overweight/obese using widely employed markers is a complex task. Cut-off points of these markers widely vary among the different sections of women population. In order to define obesity on a local level we stratified the female population based on their anthropometric measures using cluster analysis. We also clustered them based on their body fat distribution. Thus, we could identify through an alternative approach, the obese women who may be at high risk for breast cancer