Faculty Bibliography

Progranulin (PGRN) is a growth factor that has been implicated in wound healing, inflammation, infection, tumorigenesis, and is most known for its neuroprotective and proliferative properties in neurodegenerative disease. This pleiotropic growth factor has been found to be a key player and regulator of a diverse spectrum of multi-systemic functions. Its critical anti-inflammatory role in rheumatoid arthritis and other inflammatory disease models has allowed for the propulsion of research to establish its significance in musculoskeletal diseases, including inflammatory conditions involving bone and cartilage pathology. In this review, we aim to elaborate on the emerging role of PGRN in the musculoskeletal system, reviewing its particular mechanisms described in various musculoskeletal diseases, with special focus on osteoarthritis and inflammatory joint disease patho-mechanisms and potential therapeutic applications of PGRN and its derivatives in these and other musculoskeletal diseases.

For almost half a century researchers have attempted to determine the absolute ages of Neogene sedimentary units in the Sahabi area of Libya. The age of these sediments is of particular interest to paleontologists who have worked on important vertebrate remains in the area since the late 1970s. To date, several geochronological methods have been attempted; however, no precise ages have been obtained for the various units. In this paper we report data for calcareous nannofossils and strontium isotope (Sr-87/Sr-86) analysis of macrofossils, which can be used to infer age of deposition of part of the Neogene section (Formation M). Because most Sahabi fossils are extensively altered by various diagenetic processes, including gypsification and dolomitization, we carefully screened tens of samples to select unaltered material for analysis. Among the many fossils collected from Formation M and analyzed by XRD, only two, Balanus sp. and a Cubitostrea digitalina show no evidence of diagenetic alteration of their shells, and thus retain their original low-Mg calcite (LMC) mineralogy. The strontium isotopic values from these fossils were plotted against the marine strontium isotopic curve, in order to infer the absolute age. The Balanus sp. has a Sr-87/Sr-86 value of 0.708917, whereas C. digitalina has a Sr-87/Sr-86 value of 0.708908. Based on the current estimated error (0.000008), the value of 0.708917 indicates an ages between 9.33 Ma and 8.59 Ma, centered on 8.99 Ma, whereas the value of 0.708908 indicates ages between 9.61 and 9.03 Ma, centered on 9.36 Ma. The calcareous nannofossils found in this formation belong to biozone NN10b-NN11 a and provide an age of 8.23 Ma. These ages fall in the Late Miocene period (Tortonian Epoch). Therefore, Formation M should be considered Late Miocene (Tortonian) rather than Middle Miocene (Serravallian) as proposed by many previous workers. Age dating of Formation M will help in revising the stratigraphic nomenclature as well as in re-evaluating the stratigraphic po!

Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes that encode detoxifying enzymes, drug transporters, antiapoptotic proteins, and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase-mediated degradation of Nrf2. Chemicals, including antioxidants, tocopherols including alpha-tocopherol (vitamin E), and phytochemicals, and radiation antagonize the Nrf2:INrf2 interaction and lead to the stabilization and activation of Nrf2. The signaling events involve preinduction, induction, and postinduction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinases in a preinduction response that phosphorylates specific residues on Nrf2 negative regulators, INrf2, Fyn, and Bach1, leading to their nuclear export, ubiquitination, and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2 cysteine 151 followed by PKC phosphorylation of Nrf2 serine 40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus, resulting in a coordinated activation of gene expression. This is followed by a postinduction response that controls the "switching off" of Nrf2-activated gene expression. GSK3beta, under the control of AKT and PI3K, phosphorylates Fyn, leading to Fyn nuclear localization. Fyn phosphorylates Nrf2 Y568, resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provide protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance.

Vascularized composite allotransplantation (VCA) enables surgeons to address complex problems that exceed the possibilities of traditional autologous reconstruction. However, logistical and immunologic challenges currently limit the widespread application of VCA. Recent breakthroughs in the field of stem cells and tissue engineering have direct implications for the advancement of VCA. Specifically, the use of bioreactors may prolong ex vivo allograft survival and enable allograft modulations that mitigate immunogenicity and enhance graft function. Additionally, novel approaches utilizing bioreactor systems for stem cell seeding of vascularized bioscaffolds provide a blueprint for the de novo generation of complex tissues. These promising bioreactor-based strategies have the potential to expand the reconstructive applications of VCA, and could one day allow the fabrication of customized complex tissue grafts.

The proteome informatics research group of the Association of Biomolecular Resource Facilities conducted a study to assess the community's ability to detect and characterize peptides bearing a range of biologically occurring post-translational modifications when present in a complex peptide background. A data set derived from a mixture of synthetic peptides with biologically occurring modifications combined with a yeast whole cell lysate as background was distributed to a large group of researchers and their results were collectively analyzed. The results from the twenty-four participants, who represented a broad spectrum of experience levels with this type of data analysis, produced several important observations. First, there is significantly more variability in the ability to assess whether a results is significant than there is to determine the correct answer. Second, labile post-translational modifications, particularly tyrosine sulfation, present a challenge for most researchers. Finally, for modification site localization there are many tools being employed, but researchers are currently unsure of the reliability of the results these programs are producing.

Both mature BDNF and its precursor, proBDNF, play a crucial role in shaping neurons and contributing to the structural basis for neuronal connectivity. They do so in a largely opposing manner, and through differential engagement with their receptors. In this review, we will summarise the evidence that BDNF modulates neural circuit formation in vivo both within the central and peripheral nervous systems, through the control of neuronal morphology. The underlying intracellular mechanisms that translate BDNF signalling into changes of neuronal cell shape will be described. In addition, the signalling pathways that act either locally at the site of BDNF action, or over long distances to influence gene transcription will be discussed. These mechanisms begin to explain the diversity of actions that BDNF carries out on neuronal morphology. This article is part of a Special Issue entitled 'BDNF'.

One mechanism of the lipid-lowering effects of the fish oil n-3 fatty acids [e.g., docosahexaenoic acid (DHA)] in cell and animal models is induced hepatic apolipoprotein B100 (apoB) presecretory degradation. This degradation occurs post-endoplasmic reticulum, but whether DHA induces it before or after intracellular VLDL formation remains unanswered. We found in McA-RH7777 rat hepatic cells that DHA and oleic acid (OA) treatments allowed formation of pre-VLDL particles and their transport to the Golgi, but, in contrast to OA, with DHA pre-VLDL particles failed to quantitatively assemble into fully lipidated (mature) VLDL. This failure required lipid peroxidation and was accompanied by the formation of apoB aggregates (known to be degraded by autophagy). Preventing the exit of proteins from the Golgi blocked the aggregation of apoB but did not restore VLDL maturation, indicating that failure to fully lipidate apoB preceded its aggregation. ApoB autophagic degradation did not appear to require an intermediate step of cytosolic aggresome formation. Taken with other examples in the literature, the results of this study suggest that pre-VLDL particles that are competent to escape endoplasmic reticulum quality control mechanisms but fail to mature in the Golgi remain subject to quality control surveillance late in the secretory pathway.

Presenilin 1 (PSEN1) encodes the catalytic subunit of gamma-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Abeta42 to Abeta40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Abeta42/40, and have characterized novel expression changes.

The behavior of the Central African Kinda baboon (Papio kindae) is not well documented. Having previously noted distinctive grooming behavior in several Kinda baboon populations, we investigated the topic more systematically in the Kafue National Park, Zambia. We recorded the duration and details of male-female dyadic interactions (approaches, withdrawals and time spent grooming) in the early morning and late afternoon. Such interactions were more often initiated by the male and terminated by the female partner. The male groomed the female more often, and longer, than she groomed him, regardless of the female's reproductive state or the presence of an infant. The bias towards male grooming was stronger in morning than evening interactions. These behaviors, whose function is not immediately obvious, and which are unlike those previously reported in baboons, further exemplify the distinctiveness of the taxon. (c) 2014 S. Karger AG, Basel.

Background: Loss-of-function (LOF) mutations in FGFR1 are a frequent cause of congenital hypogonadotropic hypogonadism (CHH), a severe form of gonadotropin-releasing hormone (GnRH) deficiency, in males and females. They also predispose females to hypothalamic amenorrhea (HA), a milder and reversible form of GnRH deficiency associated with stress and/or energy deficits. FGF21 is an important metabolic regulator, which signals through a complex of FGFR1c with its co-receptor s-Klotho. Several lines of evidence support the hypothesis that mutations in KLB, which encodes s-Klotho, could also underlie CHH by compromising FGF21 signalling: 1) female Fgf21 transgenic(Tg) mice are resistant to high-fat diet and exhibit HH and infertility; 2) a CHH patient, obese with severe insulin-resistance carries a FGFR1 L342S mutation (1) that impairs FGF21 signalling in vitro. Methods: We screened 295 CHH patients for mutations in KLB and FGF21. The functionality of identified mutations were evaluated in vitro using cell-based reporter gene assays and expression assays, as well as in vivo using rescue experiments in C.elegans deficient of both worm KLB homologues. Klb deficient mice (Klb-/-) were evaluated for reproductive and metabolic phenotypes. Results: No mutations were identified in FGF21. We identified 9 heterozygous KLB mutations among 13/295 unrelated CHH patients (4%, 9 males and 4 females). Five patients harbor an identical KLB deletion (p.Phe777del) while the other mutations are missense. All mutations have a MAF<1% in EVS and 1000 genome database and are LOF in vitro and/or in vivo. Additional gene defects in CHH-associated genes were identified in 6/13 patients; these including 3 heterozygous FGFR1 mutations, consistent with an oligogenic model of inheritance. Notably, 10/13 subjects also exhibited metabolic defects, such as obesity, impaired fasting glucose, and/or severe dyslipidemia. Klb-/- mice are smaller in size than wild- type littermates. Female Klb-/- exhibit delayed sexual maturation and irregular estrous cycles, with reduced time spent in estrous. Further reproductive and metabolic phenotyping of the Klb-/-mice is underway. Conclusion: Loss-of-function KLB mutationsunderlie congenital GnRH deficiency. The delayed puberty phenotype of Klb-/- mice supports a role for KLB in reproduction. These findings highlight FGF21 as a probable important link between metabolism and reproduction