Humans discriminate individual large-billed crows and individual cats by their respective vocalizations

Previous research has shown that human adults can easily discriminate two individual zebra finches (Taeniopygia guttata) by their signature songs, struggle to discriminate two individual rhesus monkeys (Macaca mulatta) by their calls, and are unable to discriminate two individual dogs (Canis familiaris) by their barks. The purpose of the present experiment was to examine whether acoustic discrimination of individual non-primate heterospecifics is limited to species producing stereotyped signature songs, or whether it is possible with the vocalizations of other species as well. This was tested here with the calls of individual large-billed crows (Corvus macrorhynchos) and the meows of individual domestic cats (Felis catus) using a forced-choice Same-Different Paradigm. Results show a high discrimination accuracy without prior training, although the scores obtained here for both species were lower than those in the zebra finch discrimination task. Discrimination accuracy of cat voices decreased when mean pitch was equalized between individuals, but was still possible without this cue. The removal of formant frequencies did not influence the discrimination, and there was no significant performance improvement across trials. These experiments suggest that individual acoustic discrimination is possible not only with species producing signature songs, but also with unlearned vocalizations of both birds and non-human mammals

Error in the Superior Temporal Gyrus? A Systematic Review and Activation Likelihood Estimation Meta-Analysis of Speech Production Studies

Evidence for perceptual processing in models of speech production is often drawn from investigations in which the sound of a talker's voice is altered in real time to induce “errors.” Methods of acoustic manipulation vary but are assumed to engage the same neural network and psychological processes. This paper aims to review fMRI and PET studies of altered auditory feedback and assess the strength of the evidence these studies provide for a speech error correction mechanism. Studies included were functional neuroimaging studies of speech production in neurotypical adult humans, using natural speech errors or one of three predefined speech manipulation techniques (frequency altered feedback, delayed auditory feedback, and masked auditory feedback). Seventeen studies met the inclusion criteria. In a systematic review, we evaluated whether each study (1) used an ecologically valid speech production task, (2) controlled for auditory activation caused by hearing the perturbation, (3) statistically controlled for multiple comparisons, and (4) measured behavioral compensation correlating with perturbation. None of the studies met all four criteria. We then conducted an activation likelihood estimation meta-analysis of brain coordinates from 16 studies that reported brain responses to manipulated over unmanipulated speech feedback, using the GingerALE toolbox. These foci clustered in bilateral superior temporal gyri, anterior to cortical fields typically linked to error correction. Within the limits of our analysis, we conclude that existing neuroimaging evidence is insufficient to determine whether error monitoring occurs in the posterior superior temporal gyrus regions proposed by models of speech production

Distinct neural systems recruited when speech production is modulated by different masking sounds

When talkers speak in masking sounds, their speech undergoes a variety of acoustic and phonetic changes. These changes are known collectively as the Lombard effect. Most behavioural research and neuroimaging research in this area has concentrated on the effect of energetic maskers such as white noise on Lombard speech. Previous fMRI studies have argued that neural responses to speaking in noise are driven by the quality of auditory feedback—that is, the audibility of the speaker's voice over the masker. However, we also frequently produce speech in the presence of informational maskers such as another talker. Here, speakers read sentences over a range of maskers varying in their informational and energetic content: speech, rotated speech, speech modulated noise, and white noise. Subjects also spoke in quiet and listened to the maskers without speaking. When subjects spoke in masking sounds, their vocal intensity increased in line with the energetic content of the masker. However, the opposite pattern was found neurally. In the superior temporal gyrus, activation was most strongly associated with increases in informational, rather than energetic, masking. This suggests that the neural activations associated with speaking in noise are more complex than a simple feedback response. I. INTRODUCTIO

The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation.

In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought

Characteristics of clinical trials in rare vs. common diseases : A register-based Latvian study

Publisher Copyright: © 2018 Logviss et al. This is an open ccess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and eproduction in any medium, provided the original author and source are credited.Background Conducting clinical studies in small populations may be very challenging; therefore quality of clinical evidence may differ between rare and non-rare disease therapies. Objective This register-based study aims to evaluate the characteristics of clinical trials in rare diseases conducted in Latvia and compare them with clinical trials in more common conditions. Methods The EU Clinical Trials Register (clinicaltrialsregister.eu) was used to identify interventional clinical trials related to rare diseases (n = 51) and to compose a control group of clinical trials in non-rare diseases (n = 102) for further comparison of the trial characteristics. Results We found no significant difference in the use of overall survival as a primary endpoint in clinical trials between rare and non-rare diseases (9.8% vs. 13.7%, respectively). However, clinical trials in rare diseases were less likely to be randomized controlled trials (62.7% vs. 83.3%). Rare and non-rare disease clinical trials varied in masking, with rare disease trials less likely to be double blind (45.1% vs. 63.7%). Active comparators were less frequently used in rare disease trials (36.4% vs. 58.8% of controlled trials). Clinical trials in rare diseases enrolled fewer participants than those in non-rare diseases: In Latvia (mean 18.3 vs. 40.2 subjects, respectively), in the European Economic Area (mean 181.0 vs. 626.9 subjects), and in the whole clinical trial (mean 335.8 vs. 1406.3 subjects). Although, we found no significant difference in trial duration between the groups (mean 38.3 vs. 36.4 months). Conclusions The current study confirms that clinical trials in rare diseases vary from those in non-rare conditions, with notable differences in enrollment, randomization, masking, and the use of active comparators. However, we found no significant difference in trial duration and the use of overall survival as a primary endpoint.publishersversionPeer reviewe

Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP

Integration Preferences of Wildtype AAV-2 for Consensus Rep-Binding Sites at Numerous Loci in the Human Genome

Adeno-associated virus type 2 (AAV) is known to establish latency by preferential integration in human chromosome 19q13.42. The AAV non-structural protein Rep appears to target a site called AAVS1 by simultaneously binding to Rep-binding sites (RBS) present on the AAV genome and within AAVS1. In the absence of Rep, as is the case with AAV vectors, chromosomal integration is rare and random. For a genome-wide survey of wildtype AAV integration a linker-selection-mediated (LSM)-PCR strategy was designed to retrieve AAV-chromosomal junctions. DNA sequence determination revealed wildtype AAV integration sites scattered over the entire human genome. The bioinformatic analysis of these integration sites compared to those of rep-deficient AAV vectors revealed a highly significant overrepresentation of integration events near to consensus RBS. Integration hotspots included AAVS1 with 10% of total events. Novel hotspots near consensus RBS were identified on chromosome 5p13.3 denoted AAVS2 and on chromsome 3p24.3 denoted AAVS3. AAVS2 displayed seven independent junctions clustered within only 14 bp of a consensus RBS which proved to bind Rep in vitro similar to the RBS in AAVS3. Expression of Rep in the presence of rep-deficient AAV vectors shifted targeting preferences from random integration back to the neighbourhood of consensus RBS at hotspots and numerous additional sites in the human genome. In summary, targeted AAV integration is not as specific for AAVS1 as previously assumed. Rather, Rep targets AAV to integrate into open chromatin regions in the reach of various, consensus RBS homologues in the human genome

HTLV-1 Tax Mediated Downregulation of miRNAs Associated with Chromatin Remodeling Factors in T Cells with Stably Integrated Viral Promoter

RNA interference (RNAi) is a natural cellular mechanism to silence gene expression and is predominantly mediated by microRNAs (miRNAs) that target messenger RNA. Viruses can manipulate the cellular processes necessary for their replication by targeting the host RNAi machinery. This study explores the effect of human T-cell leukemia virus type 1 (HTLV-1) transactivating protein Tax on the RNAi pathway in the context of a chromosomally integrated viral long terminal repeat (LTR) using a CD4+ T-cell line, Jurkat. Transcription factor profiling of the HTLV-1 LTR stably integrated T-cell clone transfected with Tax demonstrates increased activation of substrates and factors associated with chromatin remodeling complexes. Using a miRNA microarray and bioinformatics experimental approach, Tax was also shown to downregulate the expression of miRNAs associated with the translational regulation of factors required for chromatin remodeling. These observations were validated with selected miRNAs and an HTLV-1 infected T cells line, MT-2. miR-149 and miR-873 were found to be capable of directly targeting p300 and p/CAF, chromatin remodeling factors known to play critical role in HTLV-1 pathogenesis. Overall, these results are first in line establishing HTLV-1/Tax-miRNA-chromatin concept and open new avenues toward understanding retroviral latency and/or replication in a given cell type