Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata

HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterisation was undertaken for three and localisation confirmed for cytoplasmic (TA12105); endoplasmic reticulum (TA06470) and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin, were demonstrated for recombinant TA12105 and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilised to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform (s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation

Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma.

OBJECTIVE: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG. Here, the authors reviewed their institutional experience with using a personalized medicine approach to patients with newly diagnosed pLGGs. METHODS: All pediatric patients at the authors\u27 institution who had been treated with dabrafenib or trametinib for pLGG without first receiving conventional chemotherapy or radiation were retrospectively reviewed. Demographic, clinical, and radiological data were collected. RESULTS: Eight patients underwent targeted therapy as a first-line treatment for pLGG. Five patients had a BRAF alteration (1 with a BRAFV600E mutation, 4 with a KIAA1549:BRAF fusion), and 3 patients had an NF1 mutation. One of the 8 patients was initially treated with dabrafenib, and trametinib was added later. Seven patients were initially treated with trametinib; of these, 2 later transitioned to dual therapy, whereas 5 continued with trametinib monotherapy. Six patients (75%) demonstrated a partial response to therapy during their treatment course, whereas stable disease was identified in the remaining 2 patients (25%). One patient experienced mild disease progression after completing a course of trametinib monotherapy, but ultimately stabilized after a period of close observation. Another patient experienced tumor progression while on dabrafenib, but subsequently responded to dual therapy with dabrafenib and trametinib. The most common adverse reactions to targeted therapy were cutaneous toxicity (100%) and diarrhea (50%). CONCLUSIONS: Targeted therapies have the potential to become a standard treatment option for pLGG due to their favorable toxicity profile and oral route of administration. This case series provides preliminary evidence that targeted therapies can induce an early disease response as a first-line adjuvant treatment; however, large-scale studies are required to assess long-term durability and safety

A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites

Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection

An estimate of the cost of Lincoln Hall

Thesis (B.S.)--University of Illinois, 1912.Typescript

Depletion of emamectin residues following oral administration to rainbow trout, Oncorhynchus mykiss

The depletion of emamectin B1a in the edible tissues of rainbow trout (Oncorhynchus mykiss) was studied at two temperatures following treatment with emamectin benzoate (Slice®) in feed. Fish approaching market size (400–1500g) were held in tanks supplied with temperature-controlled seawater at 6±1°C (cold water) or 15±1°C (warm water). In each study the medicated group was offered feed containing emamectin benzoate at a nominal dose rate of 50μgkg−1 fish day−1 for 7 days and the control group was offered unmedicated feed. Actual dose rates, calculated from growth rate and feed consumption data, and measured emamectin benzoate concentrations in feed, were 88.6% nominal in the cold water study (96.6% adjusted for feed assay recovery) and 96.8% nominal in the warm water study (105.1% adjusted for feed assay recovery).  Concentrations of emamectin B1a were determined in fillet samples collected at intervals from 6h to 77 days post-treatment in the cold water study and 6h to 49 days post-treatment in the warm water study. In the cold water study, mean emamectin B1a residues ranged from 81.8±44.5ngg−1 at 1day post-treatment (102.3±55.7ngg−1 adjusted for recovery) to 13.7±10.5ngg−1 at 77 days post-treatment (17.2±13.1ngg−1). In the warm water study, mean residue concentrations ranged from 64.5±50.3ngg−1 at 6h post-treatment (80.7±62.9ngg−1 adjusted for recovery) to 1.6±1.6ngg−1 at 49 days post-treatment (2.0±2.0ngg−1). In the cold water study, residues in skin and muscle were also determined separately. On average, emamectin B1a concentrations in skin were approximately 1.8 times higher than in muscle.  Measured residue levels ranged widely and no detectable residues were found in at least a few individual fish at all time points. This high variability was considered to be due to differences in medicated feed consumption within the experimental population. Depletion of emamectin was faster at 15°C than at 6°C. In both studies the depletion curve showed a small secondary peak at around 90 degree-days. This observation is consistent with recirculation of the compound from a body store

Dissipative Irreversibility from Nose's Reversible Mechanics

Nose's Hamiltonian mechanics makes possible the efficient simulation of irreversible flows of mass, momentum and energy. Such flows illustrate the paradox that reversible microscopic equations of motion underlie the irreversible behavior described by the second law of thermodynamics. This generic behavior of molecular many-body systems is illustrated here for the simplest possible system, with only one degree of freedom: a one-body Frenkel-Kontorova model for isothermal electronic conduction. This model system, described by Nose-Hoover Hamiltonian dynamics, exhibits several interesting features: (1) deterministic and reversible equations of motion; (2) Lyapunov instability, with phase-space offsets increasing exponentially with time; (3) limit cycles; (4) dissipative conversion of work (potential energy) into heat (kinetic energy); and (5) phase-space contraction, a characteristic feature of steady irreversible flows. The model is particularly instructive in illustrating and explaining a paradox associated with steady-state statistical mechanics: the Gibbs entropy of a nonequilibrium steady state decreases continuously to minus infinity. © 1987, Taylor & Francis Group, LLC. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Redescription of Alatina alata (Reynaud, 1830) (Cnidaria: Cubozoa) from Bonaire, Dutch Caribbean

Lewis, Cheryl, Bentlage, Bastian, Yanagihara, Angel, Gillan, William, Blerk, Johan Van, Keil, Daniel P., Bely, Alexandra E., Collins, Allen G. (2013): Redescription of Alatina alata (Reynaud, 1830) (Cnidaria: Cubozoa) from Bonaire, Dutch Caribbean. Zootaxa 3737 (4): 473-487, DOI: http://dx.doi.org/10.11646/zootaxa.3737.4.