第2卷，第3期

1136

Multiple sclerosis (MS), a leading cause of non-traumatic disability in young adults, is a chronic in flammatory demyelinating disease of the central nervous system (CNS) associated with aberrant autoimmune responses. It has long been thought that therapeutic development should be centered on immunomodulatory agents. However, none of the agents tested could prevent chronic progressive disease and disability. On the other hand, direct repair of injured myelin might represent an alternative strategy for treating MS. This may be achieved by either promoting the inherent repair mechanism of neurons or by recruiting cells derived from oligodendrocyte progenitor cells (OPCs), which are unfortunately silent in MS. The latter approach was recently demonstrated by Najm et al at Case Western Reserve University and Northwestern University. They demonstrated that miconazole and clobetasol, screened from a library of bioactive small molecules on mouse pluripotent epiblaststem cell-derived OPCs, promoted precocious myelination, significantly increased the number of new oligodendrocytes and enhanced remyelination. Strikingly, both small molecules reversed the disease severity in mouse models of MS.

1119

The interplay between virus and host has been an everlasting evolutionary dance, with some advantageous outcomes, and some not so advantageous outcomes, such as cancer and autoimmunity. It has been well recognized that the intertwinement of retroviral DNA regulatory elements, the remnants of retroviral infections, with the host genome is part of a lasting battle between pathogen replication/reinfection and the host defense. The high mutation rate of retro gene sequences has provided a means for viruses to escape suppression by the host, while also serving as a major driving force in host genome evolution. As an "unintended" consequence, the high mutation rate provides a vast retro-sequence repertoire for the host genome to domesticate to its own benefit, such as by regulating healthy biological processes, while also suppressing the harm. Endogenous retroviruses (ERV) with their functional open reading frames are rare post-infection legacies within the host genome that are inheritable through the germline. A recent article published in Nature highlighted a fresh example of the activities of a human endogenous retrovirus (HERV) in early embryonic development. The authors demonstrated that during certain stages of early human embryonic development, HERV-K is reactivated to generate infectious virions. However, this same retroviral replication rendered the early embryo resistant to re-infection by either endogenous or exogenous retrovirions through a series of intricate mechanisms. Further, one of the retroviral protein products, Rec, which acts to enhance the viral RNA transcription and translation, was found to actively participate in up-regulating the transcription and translation of host mRNA during normal embryonic development. Whether this is a novel case of nonharmful domestication by the host at the viral protein level or of viral hijacking of human machinery, regardless the outcome, the evolutionary tango continues.

1509

Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells. Despite three decades of research that have elucidated the transcriptional regulation, post-translational modifications and functions of Bmi-1 in regulating the DNA damage response, cellular bioenergetics, and pathologies, the entire potential of a protein with such varied functions remains to be realized. This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer. Additionally, since cancer stem cells are emerging as a new paradigm for therapy resistance, the role of Bmi-1 in this perspective is also highlighted. The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy. Nonetheless, new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.

1180

Y box binding protein-1 (YBX1) belongs to a DNA-and RNA-binding family of transcription factors, containing the highly conserved cold shock domain (CSD).YBX1 is involved in a number of cellular functions including transcription, translation, DNA damage repair etc., and it is upregulated during times of environmental stress. YBX1 is localized in both the cytoplasm and the nucleus. There, its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression. Additionally, YBX1 expression is upregulated in a variety of cancers, pointing towards its role as a potential oncogene. Under certain circumstances, YBX1 also promotes the expression of multidrug resistance 1 (MDR1) gene, which is involved in the development of drug resistance. Thus, it is critical to un-derstand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development. A number of recent studies have highlighted the mechanisms of YBX1 regulation. Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function. Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently, S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth. This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1. This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation, which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.

1190

This review considers available evidence for mechanisms of conferred adaptive advantages in the face of specific infectious diseases. In short, we explore a number of genetic conditions, which carry some benefits in adverse circumstances including exposure to infectious agents. The examples discussed are conditions known to result in resistance to a specific infectious disease, or have been proposed as being associated with resistance to various infectious diseases. These infectious diseasedgenetic disorder pairings include malaria and hemo-globinopathies, cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, mycotic abortions and phenylketonuria, infection by enveloped viruses and disorders of glycosylation, infection by filoviruses and NiemannePick C1 disease, as well as rabies and myasthenia gravis. We also discuss two genetic conditions that lead to infectious disease hypersusceptibility, although we did not cover the large number of immunologic defects leading to infectious disease hypersusceptibilities. Four of the resistance-associated pairings (malaria/hemogloginopathies, cholera/cystic fibrosis, tuberculosis/Tay-Sachs, and mycotic abortions/phenylketonuria) appear to be a result of selection pressures in geographic regions in which the specific infectious agent is endemic. The other pairings do not appear to be based on selection pressure and instead may be serendipitous. Nonetheless, research investigating these relationships may lead to treatment options for the aforementioned diseases by exploiting established mechanisms between genetically affected cells and infectious organisms. This may prove invaluable as a starting point for research in the case of diseases that currently have no reliably curative treatments, e.g., HIV, rabies, and Ebola.

1210

"Let's Move!" is a comprehensive initiative, launched by the First Lady, Michelle Obama, dedicates to solving problems of obesity, which is growing in child. The life behaviors do affect obesity; however, the mechanistic insight in molecular level is still not clear. In this study, by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic, physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System, we demonstrated that the platelet-activating factor receptor (PTAFR) contributes to modification of life behaviors. PTAFR does not affect metabolism of ingested dietary fat and carbohydrate in young animals; however, Ptafr ablation dramatically increased weight gain without affecting adipose tissue accumulation. Ptafr^-/- mice possess new habits that increased food intake and decreased movement. Our studies suggest that regulation of PTAFR activity may be a novel strategy to control obesity in children or young adults.

1158

NOTCH plays a role in regulating stem cell function and fate decision. It is involved in tooth development and injury repair. Information regarding NOTCH expression in human dental root apical papilla (AP) and its residing stem cells (SCAP) is limited. Here we investigated the expression of NOTCH3, its ligand JAG1, and mesenchymal stem cell markers CD146 and STRO-1 in the AP or in the primary cultures of SCAP isolated from AP. Our in situ immunostaining showed that in the AP NOTCH3 and CD146 were co-expressed and associated with blood vessels having NOTCH3 located more peripherally. In cultured SCAP, NOTCH3 and JAG1 were co-expressed. Flow cytometry analysis showed that 7%, 16% and 98% of the isolated SCAP were positive for NOTCH3, STRO-1 and CD146, respectively with a rare 1.5% subpopulation of SCAP co-expressing all three markers. The expression level of NOTCH3 reduced when SCAP underwent osteogenic differentiation. Our findings are the first step towards defining the regulatory role of NOTCH3 in SCAP fate decision.

1156

Critical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons. Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcome. Bone morphogenetic proteins (BMPs) provide a robust osteoinductive cue to stimulate bony growth and remodeling. Previous studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor cells. The aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell differentiation. Reversibly immortalized murine calvarial progenitor cells (iCALs) were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation studies. Significant elevations in alkaline phosphatase (ALP) activity, osteocalcin (OCN) mRNA transcription, osteopontin (OPN) protein expression, and matrix mineralization were detected in BMP-treated cells compared to control. Specifically, ALP activity was elevated on days 3, 7, 9, 11, and 13 post-infection and OCN mRNA expression was elevated on days 8, 10, and 14 in treated cells. Additionally, treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control groups. BMP-9 also facilitated the formation of new bone in vivo as detailed by gross, microcomputed tomography, and histological analyses. Therefore, we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs, and should be considered an effective agent for calvarial tissue regeneration.

1103

Type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) share a common pathophysiology. However, diabetes mellitus is a complex disease, and T2DM and PTDM have different etiologies. T2DM is a metabolic disorder, characterized by persistent hyperglycemia, whereas PTDM is a condition of abnormal glucose tolerance, with variable onset after organ transplant. The KCNQ1 and KCNJ11 gene encode potassium channels, which mediate insulin secretion from pancreatic β-cells, and KCN gene mutations are correlated with the development of diabetes. However, no studies have been carried out to establish an association between KCNQ1 and KCNJ11 gene polymorphisms and T2DM and PTDM. Therefore, our study was aimed at the identification of the role of KCNQ1 and KCNJ11 gene polymorphisms associated with T2DM and the risk of developing PTDM in the Asian Indian population. We have carried out a caseecontrol study including 250 patients with T2DM, 250 control subjects, 42 patients with PTDM and 98 subjects with non-PTDM. PCR-RFLP analysis was carried out following the isolation of genomic DNA from EDTA-blood samples. The results of the present study reveal that two single nucleotide polymorphisms (rs2283228 and rs5210, of the KCNQ1 and KCNJ11 genes, respectively) are associated with both T2DM and PTDM. The results of our study suggest a role of KCNQ1 and KCNJ11 gene variants in the increased risk of T2DM and PTDM in the Asian Indian population.

1113