Synaptodendritic recovery following HIV Tat exposure: Neurorestoration by phytoestrogens

HIV‐1 infects the brain and, despite antiretroviral therapy, many infected individuals suffer from HIV‐1‐associated neurocognitive disorders (HAND). HAND is associated with dendritic simplification and synaptic loss. Prevention of synaptodendritic damage may ameliorate or forestall neurocognitive decline in latent HIV‐1 infections. The HIV‐1 transactivating protein (Tat) is produced during viral latency in the brain and may cause synaptodendritic damage. This study examined the integrity of the dendritic network after exposure to HIV‐1 Tat by labeling filamentous actin (F‐actin)‐rich structures (puncta) in primary neuronal cultures. After 24 h of treatment, HIV‐1 Tat was associated with the dendritic arbor and produced a significant reduction of F‐actin‐labeled dendritic puncta as well as loss of dendrites. Pre‐treatment with either of two plant‐derived phytoestrogen compounds (daidzein and liquiritigenin), significantly reduced synaptodendritic damage following HIV‐1 Tat treatment. In addition, 6 days after HIV‐1 Tat treatment, treatment with either daidzein, or liquiritigenin enhanced recovery, via the estrogen receptor, from HIV‐1 Tat‐induced synaptodendritic damage. These results suggest that either liquiritigenin or daidzein may not only attenuate acute synaptodendritic injury in HIV‐1 but may also promote recovery from synaptodendritic damage.

     

Lutetian calcareous nannofossil events in the Agost section (Spain): implications toward a revision of the Middle Eocene biomagnetostratigraphy

This paper presents a detailed calcareous nannofossil biostratigraphy of the entire Lutetian of the Agost section (Betic Cordillera, SE Spain). This investigation integrates and improves on previous study performed through the Ypresian/Lutetian boundary by the authors on this succession. The new revision of the integrated bio‐magnetobiochronology of the Early/Middle Eocene interval revealed highly diversified calcareous nannofossil assemblages, characterizing more than 8 Myr of climatic variability. The studied interval spans from Zone CP11 to Subzone CP14a and from the upper part of Zone NP13 to the base of Zone NP16 of calcareous nannofossil standard zonations. The revision of the calcareous nannofossil content enabled the identification of numerous secondary events which greatly improved the stratigraphic resolution of this time interval. An important re‐organization of the nannoflora was observed during the Y/L transition, when Reticulofenestra and Dictyococcites (Noelaerhabdaceae) became the most important genera in terms of abundance and dispersal, dominating the Middle Eocene nannofossil assemblages and replacing Toweius and Discoaster taxa characteristic of the lower Eocene. Pentaliths and Blackites experience a great expansion and diversification, whereas Discoaster and Chiasmolithus which are well diversified but never abundant during the Lutetian show a slow turnover. A reassessment of the major bio‐events observed in the Noelaerhabdaceae family as well as revision and correlation of these events with the classical Italian sections (Contessa and Bottaccione) are presented. The new results show that biostratigraphic problems related to the Middle Eocene chronology are not limited to the correlation between calcareous nannofossils and planktonic foraminiferans at the Y/L transition but extend to calcareous nannofossil events commonly used for correlating the Bartonian.     

IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4⁺ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection.     

Growth factors and chemotactic factors from parasitic helminths: Molecular evidence for roles in host-parasite interactions versus parasite development

For decades molecular helminthologists have been interested in identifying proteins expressed by the parasite that have roles in modulating the host immune response. In some cases, the aim was targeting parasite-derived orthologues of mammalian cytokines and growth factors known to have functions in immune modulation. In others, novel proteins without homology to mammalian cytokines were isolated by investigating effects of purified worm extracts on various immunological processes. Often, the role parasite-derived growth factors play in worm development was ignored. Here, we review growth factors and chemotactic factors expressed by parasitic helminths and discuss their recognised and potential roles in immunomodulation and/or parasite development.     

Carbon Source Preference in Chemosynthetic Hot Spring Communities

Rates of dissolved inorganic carbon (DIC), formate, and acetate mineralization and/or assimilation were determined in 13 high-temperature (>73°C) hot springs in Yellowstone National Park (YNP), Wyoming, in order to evaluate the relative importance of these substrates in supporting microbial metabolism. While 9 of the hot spring communities exhibited rates of DIC assimilation that were greater than those of formate and acetate assimilation, 2 exhibited rates of formate and/or acetate assimilation that exceeded those of DIC assimilation. Overall rates of DIC, formate, and acetate mineralization and assimilation were positively correlated with spring pH but showed little correlation with temperature. Communities sampled from hot springs with similar geochemistries generally exhibited similar rates of substrate transformation, as well as similar community compositions, as revealed by 16S rRNA gene-tagged sequencing. Amendment of microcosms with small (micromolar) amounts of formate suppressed DIC assimilation in short-term (<45-min) incubations, despite the presence of native DIC concentrations that exceeded those of added formate by 2 to 3 orders of magnitude. The concentration of added formate required to suppress DIC assimilation was similar to the affinity constant (K_m) for formate transformation, as determined by community kinetic assays. These results suggest that dominant chemoautotrophs in high-temperature communities are facultatively autotrophic or mixotrophic, are adapted to fluctuating nutrient availabilities, and are capable of taking advantage of energy-rich organic substrates when they become available.     

Cations Form Sequence Selective Motifs within DNA Grooves via a Combination of Cation-Pi and Ion-Dipole/Hydrogen Bond Interactions

The fine conformational subtleties of DNA structure modulate many fundamental cellular processes including gene activation/repression, cellular division, and DNA repair. Most of these cellular processes rely on the conformational heterogeneity of specific DNA sequences. Factors including those structural characteristics inherent in the particular base sequence as well as those induced through interaction with solvent components combine to produce fine DNA structural variation including helical flexibility and conformation. Cation-pi interactions between solvent cations or their first hydration shell waters and the faces of DNA bases form sequence selectively and contribute to DNA structural heterogeneity. In this paper, we detect and characterize the binding patterns found in cation-pi interactions between solvent cations and DNA bases in a set of high resolution x-ray crystal structures. Specifically, we found that monovalent cations (Tl⁺) and the polarized first hydration shell waters of divalent cations (Mg²⁺, Ca²⁺) form cation-pi interactions with DNA bases stabilizing unstacked conformations. When these cation-pi interactions are combined with electrostatic interactions a pattern of specific binding motifs is formed within the grooves.     

1H NMR spectra of (25s)-steroidal sapogenins. Reassignments of the C-20 and C-25 methyl signals

¹H NMR spectra of ten (25$\text{S}$)-steroidal sapogenins (I–X) and their acetates (Ia–Xa) in deuteriochloroform and pentadeuterio-pyridine were examined. The C-20 and C-25 methyl signal ass?ignments were revised. Some other features including benzene-induced shifts are described.     

Identification of MAGE-C1 (CT-7) epitopes for T-cell therapy of multiple myeloma

Multiple myeloma is incurable with standard therapies but is susceptible to a T-cell-mediated graft versus myeloma effect after allogeneic stem cell transplantation. We sought to identify myeloma-specific antigens that might be used for T-cell immunotherapy of myeloma. MAGE-C1 (CT-7) is a cancer-testis antigen that is expressed by tumor cells in >70% of myeloma patients and elicits a humoral response in up to 93% of patients with CT-7⁺ myeloma. No CD8⁺ T-cell epitopes have been described for CT-7, so we used a combination of reverse immunology and immunization of HLA-A2 transgenic mice with a novel cell-based vaccine to identify three immunogenic epitopes of CT-7 that are recognized by human CD8⁺ T-cells. CT-7-specific T-cells recognizing two of these peptides are able to recognize myeloma cells as well as CT-7 gene-transduced tumor cells, demonstrating that these epitopes are naturally processed and presented by tumor cells. This is the first report of the identification of immunogenic CD8⁺ T-cell epitopes of MAGE-C1 (CT-7), which is the most commonly expressed cancer-testis antigen found in myeloma, and these epitopes may be promising candidate targets for vaccination or T-cell therapy of myeloma or other CT-7⁺ malignancies.