Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

A Decision Support System for Land Allocation under Multiple Objectives in Public Production Forests in the Brazilian Amazon

Logging in natural forests is a vital economic activity in the Brazilian Amazon. However, illegal and unplanned logging is exhausting forests rapidly. In 2006, a new forestry law in Brazil (Lei 11,284/2006) established the legal framework to develop state and national public forests for multiple uses. To support public forest planning efforts, we combine spatially explicit data on logging profits, biodiversity, and potential for community use for use within a forest planning optimization model. While generating optimal land use configurations, the model enables an assessment of the market and nonmarket tradeoffs associated with different land use priorities. We demonstrate the model's use for Faro State Forest, a 636,000 ha forest embedded within a large mosaic of conservation units recently established in the state of Pará. The datasets used span the entire Brazilian Amazon, implying that the analysis can be repeated for any public forest planning effort within the region

A possible relationship between the Arctic Oscillation Index and atmosphere-triggered interannual long-wavelength

A host of geophysical processes contribute to temporal variations in the low-degree zonal harmonics of the Earth’s gravity field. The present paper focuses on atmosphere-based mass redistributions using global surface pressure data from the NOAA Climate Diagnostics Center for the period 1980-2002. We computed atmosphere-triggered temporal variations of the Earth’s low-degree zonal gravitational coefficients Jl (l = 2 : 4). Such atmosphere-triggered ΔJl(t) are compared with the Arctic Oscillation Index (AOI) and with the observed ΔJl(t) computed by the Italian Space Agency (ASI) so as to investigate a possible coupling. We show that there is a significant agreement between the AOI and atmosphere-triggered ΔJl(t), as well as a particularly interesting correlation between the winter ΔJl(t) series and the AOI active season series

Adenosine negatively regulates duodenal motility in mice: role of A1 and A2a receptors .

BACKGROUND AND PURPOSE: Adenosine is considered to be an important modulator of intestinal motility. This study was undertaken to investigate the role of adenosine in the modulation of contractility in the mouse duodenum and to characterize the adenosine receptor subtypes involved. EXPERIMENTAL APPROACH: RT-PCR was used to investigate the expression of mRNA encoding for A(1), A(2A), A(2B) and A(3) receptors. Contractile activity was examined in vitro as changes in isometric tension. KEY RESULTS: In mouse duodenum, all four classes of adenosine receptors were expressed, with the A(2B) receptor subtype being confined to the mucosal layer. Adenosine caused relaxation of mouse longitudinal duodenal muscle; this was antagonized by the A(1) receptor antagonist and mimicked by N(6)-cyclopentyladenosine (CPA), selective A(1) agonist. The relaxation induced by A(1) receptor activation was insensitive to tetrodotoxin (TTX) or N(ω)-nitro-l-arginine methyl ester (l-NAME). Adenosine also inhibited cholinergic contractions evoked by neural stimulation, effect reversed by the A(1) receptor antagonist, but not myogenic contractions induced by carbachol. CPA and 2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680), A(2A) receptor agonist, both inhibited the nerve-evoked cholinergic contractions. l-NAME prevented only the CGS-21680-induced effects. S-(4-Nitrobenzyl)-6-thioinosine, a nucleoside uptake inhibitor, reduced the amplitude of nerve-evoked cholinergic contractions, an effect reversed by an A(2A) receptor antagonist or l-NAME. CONCLUSIONS AND IMPLICATIONS: Adenosine can negatively regulate mouse duodenal motility either by activating A(1) inhibitory receptors located post-junctionally or controlling neurotransmitter release via A(1) or A(2A) receptors. Both receptors are available for pharmacological recruitment, even if only A(2A) receptors appear to be preferentially stimulated by endogenous adenosine. LINKED ARTICLE: This article is commented on by Antonioli et al., pp. 1577–1579 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01529.

Investigating REPAIRv2 as a Tool to Edit CFTR mRNA with Premature Stop Codons

Cystic fibrosis (CF) is caused by mutations in the gene encoding the transmembrane conductance regulator (CFTR) protein. Some CF patients are compound heterozygous or homozygous for nonsense mutations in the CFTR gene. This implies the presence in the transcript of premature termination codons (PTCs) responsible for a truncated CFTR protein and a more severe form of the disease. Aminoglycoside and PTC124 derivatives have been used for the read-through of PTCs to restore the full-length CFTR protein. However, in a precision medicine framework, the CRISPR/dCas13b-based molecular tool “REPAIRv2” (RNA Editing for Programmable A to I Replacement, version 2) could be a good alternative to restore the full-length CFTR protein. This RNA editing approach is based on the targeting of the deaminase domain of the hADAR2 enzyme fused to the dCas13b protein to a specific adenosine to be edited to inosine in the mutant mRNA. Targeting specificity is allowed by a guide RNA (gRNA) complementarily to the target region and recognized by the dCas13b protein. Here, we used the REPAIRv2 platform to edit the UGA PTC to UGG in dierent cell types, namely IB3-1 cells, HeLa, and FRT cells engineered to express H2BGFPopal and CFTRW1282X, respectively

Burkitt's lymphoma in pregnant woman: Difficult management of a rare case

Introduction: Burkitt's lymphoma (BL), an aggressive subtype of non-Hodgkin lymphoma (NHL), is extremely rare during pregnancy. In the case of bowel localization, diagnosis can be very difficult. Moreover, signs and symptoms of the primary small intestine lymphoma are nonspecific, mostly attributable to the “mass effect” of the tumor. The most frequent symptom is abdominal cramp-like pain, associated with nausea and vomiting. Presentation of case: We report a rare case of a 37-year-old pregnant woman, at the 33rd week of gestation, with an abdominal-pelvic mass of uncertain nature. Surgical strategy consisted of a two-step procedure, which involved a cesarean section and typing of the mass: extemporaneous examination hypothesized intestinal lymphoma. The definitive histological examination confirmed the diagnosis of rare case of BL in pregnancy. Discussion: The clinical case reported, representing a rare occurrence of BL in pregnancy, was associated with difficult interpretation and complex management. Lymphoma of the small intestine is often overlooked in the early stages of the disease, due to the fact that symptoms are non-specific and consequently underestimated. In our case, based on gestational age, it was possible to perform a multidisciplinary approach, a cesarean section with surgical intestinal exploration, achieving at the same time delivery of the child and a definitive diagnosis of BL with intestinal involvement. Conclusion: The involvement of multiple professionals is undoubtedly the best way to deal with the above referred to situation, with the main point being to keep in mind the possibility of this type of occurrence

Elp3 and RlmN: A tale of two mitochondrial tail-anchored radical SAM enzymes in Toxoplasma gondii

Radical S-adenosylmethionine (rSAM) enzymes use a 5'-deoxyadensyl 5'-radical to methylate a wide array of diverse substrates including proteins, lipids and nucleic acids. One such enzyme, Elongator protein-3 (TgElp3), is an essential protein in Toxoplasma gondii, a protozoan parasite that can cause life-threatening opportunistic disease. Unlike Elp3 homologues which are present in all domains of life, TgElp3 localizes to the outer mitochondrial membrane (OMM) via a tail-anchored trafficking mechanism in Toxoplasma. Intriguingly, we identified a second tail-anchored rSAM domain containing protein (TgRlmN) that also localizes to the OMM. The transmembrane domain (TMD) on Toxoplasma Elp3 and RlmN homologues is required for OMM localization and has not been seen beyond the chromalveolates. Both TgElp3 and TgRlmN contain the canonical rSAM amino acid sequence motif (CxxxCxxC) necessary to form the 4Fe-4S cluster required for tRNA modifications. In E. coli, RlmN is responsible for the 2-methlyadenosine (m2A) synthesis at purine 37 in tRNA while in S. cerevisiae, Elp3 is necessary for the formation of 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) at the wobble tRNA position. To investigate why these two rSAM enzymes localize to the mitochondrion in Toxoplasma, and whether or not TgRlmN and TgElp3 possess tRNA methyltransferase activity, a series of mutational and biochemical studies were performed. Overexpression of either TgElp3 or TgRlmN resulted in a significant parasite replication defect, but overexpression was tolerated if either the TMD or rSAM domain was mutated. Furthermore, we show the first evidence that Toxoplasma tRNAGlu contains the mcm5s2U modification, which is the putative downstream product generated by TgElp3 activity

Comparative analysis of medicinal plants used in traditional medicine in Italy and Tunisia

<p>Abstract</p> <p>Background</p> <p>Italy and Tunisia (Africa for the Romans), facing each other on the opposite sides of the Mediterranean Sea, have been historically linked since the ancient times. Over the centuries both countries were mutually dominated so the vestiges and traces of a mutual influence are still present. The aim of the present study is to conduct a comparative analysis of the medicinal species present in the respective Floras in order to explore potential analogies and differences in popular phytotherapy that have come out from those reciprocal exchanges having taken place over the centuries</p> <p>Methods</p> <p>The comparative analysis based on the respective floras of both countries takes into consideration the bulk of medicinal species mutually present in Italy and Tunisia, but it focuses on the species growing in areas which are similar in climate. The medicinal uses of these species are considered in accordance with the ethnobotanical literature.</p> <p>Results</p> <p>A list of 153 medicinal species belonging to 60 families, present in both floras and used in traditional medicine, was drawn. A considerable convergence in therapeutic uses of many species emerged from these data.</p> <p>Conclusion</p> <p>This comparative analysis strengthens the firm belief that ethno-botanical findings represent not only an important shared heritage, developed over the centuries, but also a considerable mass of data that should be exploited in order to provide new and useful knowledge.</p