Innate Antibodies, Murine Models, and Evolution: A Study of Trypanosome Lytic Factor Functions and Their Translational Applications

Trypanosome lytic factors (TLFs) are primate-specific antimicrobial protein complexes that lyse African trypanosome parasites by delivering the channel-forming toxin APOL1 to the invading microorganisms. Human serum contains two TLFs that are delivered to the parasite by separate mechanisms, only one of which has been characterized. TLF1 is endocytosed by a receptor that is typically blocked by other serum factors in vivo, suggesting that TLF2 is the more relevant lytic factor in the context of trypanosome immunity. TLF2 is non-covalently associated with polyclonal immunoglobulin M (IgM) antibodies, which we report here to be involved in the uptake mechanism. The TLF2-IgMs are polyreactive and can interact with both the TLF complex and the dominant surface protein of trypanosomes, the variant surface glycoprotein (VSG), which likely drives uptake of the APOL1. Once delivered to the parasite, human APOL1 forms cation selective pH-gated channels in membranes. However, relatively little is known about the channel forming properties of non-human primate APOL1 proteins or their TLF complexes. Here we also report that non-human primates, including the baboon, have both TLF1 and TLF2 complexes. We have investigated the channel forming properties of baboon APOL1 and have observed that it is less restricted by pH than human APOL1, which we have attributed to key amino acid differences between the two proteins. In order to better understand the function of human and primate TLFs, we have generated various mouse models allowing us to study them in vivo, including an array of targeted germline transgenic baboon APOL1-expressing animals. These mice have been used to model the possibility of creating genetically modified livestock with a similar strategy in order to potentially provide a novel method to limit the devastating agricultural burden imposed by trypanosomes on sub-Saharan Africa

A role for NRAGE in NF-κB activation through the non-canonical BMP pathway

<p>Abstract</p> <p>Background</p> <p>Previous studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab1 complex. Its effect on NF-κB has yet to be explored.</p> <p>Results</p> <p>Herein we report that NRAGE, via the same XIAP-Tak1-Tab1 complex, is required for the phosphorylation of IKK -α/β and subsequent transcriptional activation of the p65 subunit of NF-κB. Ablation of endogenous NRAGE by siRNA inhibited NF-κB pathway activation, while ablation of Tak1 and Tab1 by morpholino inhibited overexpression of NRAGE from activating NF-κB. Finally, cytokine profiling of an NRAGE over-expressing stable line revealed the expression of macrophage migration inhibitory factor.</p> <p>Conclusion</p> <p>Modulation of NRAGE expression revealed novel roles in regulating NF-κB activity in the non-canonical bone morphogenic protein signaling pathway. The expression of macrophage migration inhibitory factor by bone morphogenic protein -4 reveals novel crosstalk between an immune cytokine and a developmental pathway.</p

Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections

Funding: This work was supported in part by the National Institutes of Health (NIH) institutional training grants 5T32AI100853-03 and 5T32AI007180 to J.R.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Inducible Germline IgMs Bridge Trypanosome Lytic Factor Assembly and Parasite Recognition

Acknowledgments This work was supported by NSF Bread award IOS-1249166 and Hunter College (J.R.); CUNY Science Scholarship (J.V.); Hunter College HHMI UGRAD Science Education grant 52007535 (E.H.); NIH/NIAID award AI085973 (N.P.); Wellcome Trust award 082786 (J.S.). We thank George Cross and Ana Rodriguez for the parasite lines and VSG preparations used in this study.Peer reviewedPostprin

Expression of trk in MAH Cells Lacking the p75 Low-Affinty Nerve Growth Factor Receptor is Sufficient to Permit Nerve Growth Factor-Induced Differentiation to Postmitotic Neurons

We have transfected MAH cells, an immortalized sympathoadrenal progenitor cell line, with a plasmid encoding the 140-kDa Trk protein, a nerve growth factor (NGF) receptor with protein-tyrosine kinase activity. NGF promotes neurite outgrowth and proliferation from such cells, indicating that Trk is sufficient to mediate such responses in the absence of significant levels of the endogenous 75-kDa low-affinity NGF receptor (p75). These initial NGF responses are indistinguishable from those evoked by basic fibroblast growth factor (bFGF). However, NGF is sufficient to promote terminal differentiation of a {approx}8% of trk-transfected MAH cells to postmitotic, NGF-dependent neurons, whereas all cells eventually die in medium with bFGF. Other environmental signals (such as depolarization or ciliary neurotrophic factor) can cooperate with NGF to enhance production of postmitotic NGF-dependent neurons in trk-transfected MAH cells. The terminal differentiation of sympathetic neurons thus involves sequential and cooperative actions of different growth and neurotrophic factors, as well as cell-intrinsic changes in the response to these factors

Two novel human NUMB isoforms provide a potential link between development and cancer

We previously identified four functionally distinct human NUMB isoforms. Here, we report the identification of two additional isoforms and propose a link between the expression of these isoforms and cancer. These novel isoforms, NUMB5 and NUMB6, lack exon 10 and are expressed in cells known for polarity and migratory behavior, such as human amniotic fluid cells, glioblastoma and metastatic tumor cells. RT-PCR and luciferase assays demonstrate that NUMB5 and NUMB6 are less antagonistic to NOTCH signaling than other NUMB isoforms. Immunocytochemistry analyses show that NUMB5 and NUMB6 interact and complex with CDC42, vimentin and the CDC42 regulator IQGAP1 (IQ (motif) GTPase activating protein 1). Furthermore, the ectopic expression of NUMB5 and NUMB6 induces the formation of lamellipodia (NUMB5) and filopodia (NUMB6) in a CDC42- and RAC1-dependent manner. These results are complemented by in vitro and in vivo studies, demonstrating that NUMB5 and NUMB6 alter the migratory behavior of cells. Together, these novel isoforms may play a role in further understanding the NUMB function in development and cancer

Las visperas sicilianas

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Drama en cinc actes i sis quadres, música de Verdi amb llibret de Scribe i DuveyrierEmpresa: Juan A. Pamia

Financial Reporting Quality, Private Information, Monitoring, and the Lease-versus-Buy Decision

A flourishing stream of research suggests that liquidity-constrained firms with low accounting quality have limited access to capital for investments. We extend this research by investigating whether these firms are more likely to lease their assets. Lessors’ superior control rights allow them to provide capital to constrained firms with low-quality accounting reports. Consistent with this conjecture, we find that low accounting quality firms have a higher propensity to lease than purchase assets. To verify that leasing does not merely reflect these firms’ desire for off-balance-sheet accounting, we investigate whether banks’ access to private information and monitoring affect the relation between accounting quality and leasing. We find the association between accounting quality and leasing decreases when banks have higher monitoring incentives and when loans contain capital expenditure provisions. These results suggest that other mechanisms can substitute for the role of accounting quality in reducing information problems

Don Carlos

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Empresa: Juan A. PamiasIntèrpret : Montserrat CaballéMestre del cor : Riccardo BottinoOrquestra del Gran Teatre del Liceu dirigida per Anton GuadagnoÓpera de Verdi amb llibret de Méry i C. du Locl

Don Carlo

Empresa José F. ArquerOrquestra del Gran Teatre del Liceu; director Angelo QuestaPrograma del 9 de novembre de 1952 amb la representació de l'òpera en quatre actes Don Carlo, de Giuseppe Verdi amb llibret de Joseph Méry i Camille du LocleRegidor d'escena: A.C. Azzolini ; Mestre de Cor : J. AngladaDe cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents