Faculty Bibliography

Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate analyses showed that a FH of schizophrenia was associated with longer LTL in both male and female cases. Later paternal age was also related to longer LTL in male cases, but with shorter LTL in female cases. Male cases with older fathers and a FH had the longest LTL. The genetic architecture associated with a familial risk for schizophrenia may include pathways that lengthen LTL. Paternal aging conferred an additional increase in LTL lengthening in male cases, but reduced LTL in female cases. The gender difference in LTL for paternal aging is consistent with the severe illness features reported for female cases with older fathers and could implicate epigenetic alterations in the paternal X chromosomal region with advanced paternal age in association with the risk for schizophrenia.

Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in cardiolipin, the specific phospholipid of mitochondrial membranes. Indeed, cardiolipin is a universal component of mitochondria in all eukaryotes. It has a unique dimeric structure comprised of two phosphatidic acid residues linked by a glycerol bridge, which gives rise to unique physicochemical properties. Cardiolipin plays an important role in the structural organization and the function of mitochondrial membranes. In this article, we review the literature on cardiolipin biology, focusing on the most important discoveries of the past decade. Specifically, we describe the formation, the migration, and the degradation of cardiolipin and we discuss how cardiolipin affects mitochondrial function. We also give an overview of the various phenotypes of cardiolipin deficiency in different organisms.

Human Med26 was originally purified in the Cofactor Required for Sp1 Activation complex (CRSP) as a 70 kilodalton component named CRSP70. This polypeptide was specific to metazoans and the "small" form of the Mediator complex. We report here that a Drosophila homologue of Med26 similarly interacts with other components of the core Drosophila Mediator complex but not with the kinase module, and is recruited to genes upon activation. Using a null allele of Med26, we show that Med26 is required for organismal viability but not for cell proliferation or survival. Clones lacking Med26 in the wing disc lead to loss of the adult wing margin and reduced expression of genes involved in wing margin formation. Surprisingly, when polytene chromosomes from the salivary gland were examined using antibodies to Med26, it was apparent that a fraction of the protein is associated with the chromocenter, which contains pericentric heterochromatin. This staining co-localizes with heterochromatin protein 1 (HP1). Immunoprecipitation experiments show that Med26 interacts with HP1. The interaction is mediated through the chromoshadow domain of HP1 and through the conserved motif in the carboxy-terminus of the Med26 protein. This work is the first characterization of the metazoan-specific Mediator subunit in an animal model.

Mutations in proteins of the desmosome are associated with arrhythmogenic cardiomyopathy (AC; also referred to as "ARVC" or "ARVD"). Life-threatening ventricular arrhythmias often occur in the concealed phase of the disease before the onset of structural changes. Among the various potential mechanisms for arrhythmogenesis in AC, in this article, we concentrate on the relation between desmosomes and sodium channel function. We review evidence indicating that (1) loss of desmosomal integrity (including mutations or loss of expression of plakophilin-2; PKP2) leads to reduced sodium current (INa), (2) the PKP2-INa relation could be partly consequent to the fact that PKP2 facilitates proper trafficking of proteins to the intercalated disc, and (3) PKP2 mutations can be present in patients diagnosed with Brugada syndrome (BrS), thus supporting the previously proposed notion that AC and BrS are not two completely separate entities, but "bookends" in a continuum of variable sodium current deficiency and structural disease.

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

Animal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection.

As phylogenetic data becomes increasingly available, along with associated data on species' genomes, traits, and geographic distributions, the need to ensure data availability and reuse become more and more acute. In this paper, we provide ten "simple rules" that we view as best practices for data sharing in phylogenetic research. These rules will help lead towards a future phylogenetics where data can easily be archived, shared, reused, and repurposed across a wide variety of projects.

We have designed lectin functionalized Lipo-polymerosome bearing Amphotericin B (Lec-AmB-L-Psome) for specific internalization via lectin receptors over-expressed on infected macrophages of mononuclear phagocytic system (MPS) for the effective management of intramacrophage diseases such as Visceral Leishmaniasis. The lipo-polymerosome composed of glycol chitosan-stearic acid copolymer (GC-SA25%) and model lipid cholesterol, was surface functionalized with lectin by EDC/NHS carbodiimide coupling method. Our designed Lec-AmB-L-Psome showed >2 fold enhanced uptake and significantly higher internalization in macrophages as compared to AmB-L-Psome. Importantly, pharmacokinetic and organ distribution studies illustrate significantly higher accumulation of Lec-AmB-L-Psome in MPS especially in liver, spleen and lung as compared to AmB-L-Psome, Ambisome and Fungizone. The IC50 value demonstrated that Lec-AmB-L-Psome has 1.63, 2.23 and 3.43 times higher activity as compared to AmB-L-Psome (p<0.01), Ambisome (p<0.05) and Fungizone (p<0.05), respectively. Additionally, the Lec-AmB-L-Psome showed significantly higher splenic parasite inhibition (78.66+/-3.08%) compared to Fungizone and Ambisome that caused only 56.54+/-3.91% (p<0.05) and 66.46+/-2.08% (p<0.05) parasite inhibition, respectively in Leishmania-infected hamsters. The toxicity profile revealed that Lec-AmB-L-Psome is safe delivery system with diminished nephrotoxicity which is a limiting factor of Fungizone application. Taken together these studies suggest this surface functionalized self assembled Lec-AmB-L-Psome can open new platform to specifically target macrophages for effective management of intramacrophage diseases.

INTRODUCTION: Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity. METHODS: In this study, we examined the impact of diabetes on the murine ASC niche, as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting. RESULTS: Our results demonstrate that diabetes alters the ASC niche in situ, and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth. CONCLUSIONS: Perturbations in specific cellular subpopulations, visible only on a single cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in diabetic patients may be limited, and that interventions to improve cell function before application are warranted.