Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents

Exploring the longitudinal relationships between the use of grammar in text messaging and performance on grammatical tasks

Research has demonstrated that use of texting slang (textisms) when text messaging does not appear to impact negatively on children's literacy outcomes and may even benefit children's spelling attainment. However, less attention has been paid to the impact of text messaging on the development of children's and young people's understanding of grammar. This study therefore examined the interrelationships between children's and young adults' tendency to make grammatical violations when texting and their performance on formal assessments of spoken and written grammatical understanding, orthographic processing and spelling ability over the course of 1 year. Zero-order correlations showed patterns consistent with previous research on textism use and spelling, and there was no evidence of any negative associations between the development of the children's performance on the grammar tasks and their use of grammatical violations when texting. Adults' tendency to use ungrammatical word forms ('does you') was positively related to performance on the test of written grammar. Grammatical violations were found to be positively associated with growth in spelling for secondary school children. However, not all forms of violation were observed to be consistently used in samples of text messages taken 12 months apart or were characteristic of typical text messages. The need to differentiate between genuine errors and deliberate violation of rules is discussed, as are the educational implications of these findings

Effects of orthographic, morphological and semantic overlap on short-term memory for words in typical and atypical development

Little is known about implicit morphological processing in typical and atypical readers. These studies investigate this using a probe detection task with lures sharing morphological, orthographic or semantic overlap with the probe. Intermediate and advanced readers (reading ages 9;1-12;9) perform more poorly when there is more linguistic overlap. Novice readers (reading ages 5;7-8;0) were influenced only by orthographic overlap and not by semantics, indicating that use of orthographic processes typically precedes integration of semantic and morphological skills. Children with Otitis Media (repeated ear infections) had phonological awareness difficulties but performed age appropriately on the probe detection task indicating that morphological processing is not constrained by phonology. In contrast, dyslexic children’s performance reflected a failure to remember distinctions between words sharing root morphemes. Dyslexic children are sensitive to morphology but may over rely on root morphemes. This pattern differed from reading-ability matched children and children with circumscribed phonological difficulties. Publisher statement: This research was funded by a Nuffield Foundation Grant for Research and Innovation (reference EDU/40250). This project was funded by the Nuffield Foundation but the views expressed are those of the authors and not necessarily those of the Foundation. Published with license by Taylor & Francis Group, LLC© 2016 Helen L. Breadmore and Julia M. Carrol

Talking about food choices of former homeless young people: making sense of conflicting discourses of blame through social worlds theory.

After a pilot study at a charitable youth organisation in the North East of Scotland found no considerable improvements in the food choices of former homeless young people accommodated by the organisation (Perry, 2013), the Foodways and Futures project (2013-2016) set out to explore why. Both members of staff at the same organisation as well as young people were invited to voice their views and opinions on the factors influencing young people’s food choices. Whilst everyone’s contribution was considered equally informative for our findings, I was attentive to where the information originated from. In this, I found that three conflicting discourses of blame pervade the participants’ expressions of the rationales underlying young people’s food choices. Trying to make sense of these, I employ Strauss’ Social Worlds Theory (1978). I find that the different discourses of blame make sense in the context of the complex organisational structures. In objecting to a tendency in the literature to assign standardised discourse of blame primarily to youth workers’ practice, these discourses showcase mutual understanding instead

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Optimization of lipase production by solid-state fermentation of olive pomace: from flask to laboratory-scale packed-bed bioreactor

Lipases are versatile catalysts with many applications and can be produced by solid-state fermentation (SSF) using agro-industrial wastes. The aim of this work was to maximize the production of Aspergillus ibericus lipase under SSF of olive pomace (OP) and wheat bran (WB), evaluating the effect on lipase production of C/N ratio, lipids, phenols, content of sugars of substrates and nitrogen source addition. Moreover, the implementation of the SSF process in a packed-bed bioreactor and the improvement of lipase extraction conditions were assessed. Low C/N ratios and high content of lipids led to maximum lipase production. Optimum SSF conditions were achieved with a C/N mass ratio of 25.2 and 10.2% (w/w) lipids in substrate, by the mixture of OP:WB (1:1) and supplemented with 1.33% (w/w) (NH4)2SO4. Studies in a packed-bed bioreactor showed that the lower aeration rates tested prevented substrate dehydration, improving lipase production. In this work, the important role of Triton X-100 on lipase extraction from the fermented solid substrate has been shown. A final lipase activity of 223 ± 5 U g1 (dry basis) was obtained after 7 days of fermentation.Felisbela Oliveira acknowledges the financial support from Fundação para a Ciência e Tecnologia (FCT) of Portugal through grant SFRH/BD/87953/2012. José Manuel Salgado was supported by grant CEB/N2020–INV/01/2016 from Project ‘‘BIOTECNORTE-Underpinning Biotechnology to foster the north of Portugal bioeconomy’’ (NORTE-01-0145-FEDER-000004). Luı ´s Abrunhosa was supported by grant UMINHO/BPD/51/2015 from project UID/BIO/04469/2013 financed by FCT/MEC (OE). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684) and BioTecNorte operation (NORTE-01-0145-FEDER000004) funded by the European Regional Development Fund under the scope of Norte2020–Programa Operacional Regional do Norte. Noelia Pérez-Rodríguez acknowledges the financial support of FPU fellowship from the Spanish Ministry of Education, Culture and Sports. The authors thank the Spanish Ministry of Economy and Competitiveness for the financial support of this work (Project CTQ2015-71436-C2-1-R), which has partial financial support from the FEDER funds of the European Union.info:eu-repo/semantics/publishedVersio

On natural metalinguistic abilities in aphasia: a preliminary study

Natural metalinguistic abilities, which are put into play without explicit instructions, constitute the cognitive basis for a 'reflexive' use of language, a particular manifestation of the executive function when applied to language and verbal behaviour. This reflexive use entails a specific attentional activity by speakers and hearers with regard to linguistic outputs, and an intentional experience-based control over the language use. Putting into play natural metalinguistic abilities can be considered a significant factor for explaining different kinds of adaptive processes. Our results permit us to conclude that an impairment of metalinguistic abilities is involved in aphasia to different degrees. Moreover, the examination of preserved metalinguistic abilities provides an alternative way for assessing the degree of severity of impaired communicative behaviour by people with aphasia. Our procedure, presumably, will also be useful for suggesting new factors when designing therapeutic programmes

Surrogate waste streams for use in MWFA funded research and development

Researchers developing technologies for treatment of mixed (both hazardous and radioactive) wastes are strongly encouraged to test using materials representative of the wastes targeted by their processes. Using actual wastes is essential for treatability studies and demonstrations prior to implementation, but is excessively costly and impractical during development. Thus, it is a responsibility of the focus area to provide researchers with surrogate recipes for use in development. Data from tests with standardized recipes will also facilitate comparison of results for competing technologies by potential end users and industry. Due to the wide range of waste materials in the DOE inventory and the scope of technology covered by the focus area, no one surrogate will accurately represent all wastes in all applications. The surrogates described are based on generic base compositions representative of that class of wastes, with variable constituents to be added over a recommended test range. Not all of the additives must be tested for each technology; focus should be directed to the constituents and physical forms present in the waste streams targeted by the developer. Excluding some parameters, or reducing the parametric testing rather than using the full range of concentration recommended simply limits the scope of potential application when the data is considered by a potential user. Surrogates are described for debris, sludges, and caustic scrub solution. Soils are recognized as a fourth class, and are considered too complex to represent with a surrogate. Descriptive text is also included to explain how the recipes were developed, and why each test additive is prescribed

Lasing mechanisms in organic photonic crystal lasers with two-dimensional distributed feedback

We present a detailed experimental and theoretical investigation of the lasing characteristics of organic photonic crystal lasers. These lasers are based on strongly modulated two-dimensional polymer surface relief structures on which thin films of optically active organic materials have been deposited. We determine the in-plane photonic band structure of the corresponding quasiguided modes within an effective two-dimensional model. In addition, we calculate the total (three-dimensional) losses associated with these modes. This allows us to identify the lasing thresholds for square lattice geometries and to understand the emission pattern

Imaging features of retroperitoneal extra-adrenal paragangliomas in 10 dogs

Retroperitoneal paragangliomas are rare tumors of the neuroendocrine system. Only a few canine case reports are available with rare descriptions of their imaging features. The objectives of this multi-center, retrospective case series study were to describe the diagnostic imaging features of confirmed retroperitoneal paragangliomas and specify their location. Medical records and imaging studies of 10 affected dogs with cytological or histopathologic results concordant with retroperitoneal paragangliomas were evaluated. Dogs had a median age of 9 years. Four of them had clinical signs and laboratory reports compatible with excessive production of catecholamines. Six ultrasound, four CT, four radiographic, and one MRI studies were included. The paragangliomas did not have a specific location along the aorta. They were of various sizes (median 33 mm, range: 9–85 mm of length). Masses had heterogeneous parenchyma in six of 10 dogs, regardless of the imaging modality. Strong contrast enhancement was found in all CT studies. Encircling of at least one vessel was detected in six of 10 masses, clear invasion of a vessel was identified in one of 10 masses. In five of 10 cases, the masses were initially misconstrued as lymph nodes by the on-site radiologist. Retroperitoneal paragangliomas appear along the abdominal aorta, often presenting heterogeneous parenchyma, possibly affecting the local vasculature, and displaying strong contrast enhancement on CT. Clinical signs can be secondary to mass effects or excessive catecholamine production. Underdiagnosis and misdiagnosis of this tumor are suspected as they can be silent, of small size, or confused with other structures