A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features.

Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.

Comparative analysis of craniofacial shape in two mouse models of Down syndrome: Ts65Dn and TcMAC21.

Mouse models are central to studying and understanding the genotypic-to-phenotypic outcomes of Down syndrome (DS), a complex condition caused by an extra copy of the long arm of human chromosome 21. The recently developed TcMAC21-a transchromosomic mouse strain with comparable gene dosage to human chromosome 21 (Hsa21)-includes more Hsa21 genes than any other model of DS. Recent studies on TcMAC21 have provided valuable insight into the molecular, physiological, and neuroanatomical aspects of the model. However, relatively little is known about the craniofacial phenotype of TcMAC21 mice, particularly as it compares to the widely studied Ts65Dn model. Here we conducted a quantitative study of the cranial morphology of TcMAC21 and Ts65Dn mice and their respective unaffected littermates. Our comparative data comprise forty three-dimensional cranial measurements taken on micro-computed tomography scans of the heads of TcMAC21 and Ts65Dn mice. Our results show that TcMAC21 exhibit similar patterns of craniofacial change to Ts65Dn. However, the DS-specific morphology is more pronounced in Ts65Dn mice. Specifically, Ts65Dn present with more medio-lateral broadening and retraction of the snout compared to TcMAC21. Our findings reveal the complexity of potential gene interaction in the production of craniofacial phenotypes.

Processes and patterns: Insights on cranial covariation from an Apert syndrome mouse model.

BACKGROUND: Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms. FGF/FGFRs are necessary to produce several "vertebrate-specific" structures, including the vertebrate head. Here, we examine the effects of the FGFR2 S252W mutation associated with Apert syndrome on patterns of cranial integration. Our data comprise micro-computed tomography images of newborn mouse skulls, bred to express the Fgfr2 S252W mutation exclusively in either neural crest or mesoderm-derived tissues, and mice that express the Fgfr2 S252W mutation ubiquitously. RESULTS: Procrustes-based methods and partial least squares analysis were used to analyze craniofacial integration patterns. We found that deviations in the direction and degree of integrated shape change across the mouse models used in our study were potentially driven by the modular variation generated by differing expression of the Fgfr2 mutation in cranial tissues. CONCLUSIONS: Our overall results demonstrate that covariation patterns can be biased by the spatial distribution and magnitude of variation produced by underlying developmental-genetic mechanisms that often impact the phenotype in disproportionate ways.

Structural connectivity predicts sequential processing differences in music perception ability.

To relate individual differences in music perception ability with whole brain white matter connectivity, we scanned a group of 27 individuals with varying degrees of musical training and assessed musical ability in sensory and sequential music perception domains using the Profile of Music Perception Skills-Short version (PROMS-S). Sequential processing ability was estimated by combining performance on tasks for Melody, Standard Rhythm, Embedded Rhythm, and Accent subscores while sensory processing ability was ascertained via tasks of Tempo, Pitch, Timbre, and Tuning. Controlling for musical training, gender, and years of training, network-based statistics revealed positive linear associations between total PROMS-S scores and increased interhemispheric fronto-temporal and parieto-frontal white matter connectivity, suggesting a distinct segregated structural network for music perception. Secondary analysis revealed two subnetworks for sequential processing ability, one comprising ventral fronto-temporal and subcortical regions and the other comprising dorsal fronto-temporo-parietal regions. A graph-theoretic analysis to characterize the structural network revealed a positive association of modularity of the whole brain structural connectome with the d' total score. In addition, the nodal degree of the right posterior cingulate cortex also showed a significant positive correlation with the total d' score. Our results suggest that a distinct structural network of connectivity across fronto-temporal, cerebellar, and cerebro-subcortical regions is associated with music processing abilities and the right posterior cingulate cortex mediates the connectivity of this network.

Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice.

BACKGROUND: In Ts65Dn, a mouse model of Down syndrome (DS), brain and craniofacial abnormalities that parallel those in people with DS are linked to an attenuated cellular response to sonic hedgehog (SHH) signaling. If a similarly reduced response to SHH occurs in all trisomic cells, then chronic up-regulation of the pathway might have a positive effect on development in trisomic mice, resulting in amelioration of the craniofacial anomalies. RESULTS: We crossed Ts65Dn with Ptch1(tm1Mps/+) mice and quantified the craniofacial morphology of Ts65Dn;Ptch(+/-) offspring to assess whether a chronic up-regulation of the SHH pathway rescued DS-related anomalies. Ts65Dn;Ptch1(+/-) mice experience a chronic increase in SHH in SHH-receptive cells due to haploinsufficiency of the pathway suppressor, Ptch1. Chronic up-regulation had minimal effect on craniofacial shape and did not correct facial abnormalities in Ts65Dn;Ptch(+/-) mice. We further compared effects of this chronic up-regulation of SHH with acute pathway stimulation in mice treated on the day of birth with a SHH pathway agonist, SAG. We found that SHH affects facial morphology differently based on chronic vs. acute postnatal pathway up-regulation. CONCLUSIONS: Our findings have implications for understanding the function of SHH in craniofacial development and for the potential use of SHH-based agonists to treat DS-related abnormalities.

Reading Research and Practice: Indian Perspective.

The authors outline the basic structure of akshara, the basic unit of writing in Indic writing systems used widely in South and Southeast Asia; present preliminary studies relating to reading, assessment, and instruction of akshara; and outline recommendations for future studies.

Brains of verbal memory specialists show anatomical differences in language, memory and visual systems.

We studied a group of verbal memory specialists to determine whether intensive oral text memory is associated with structural features of hippocampal and lateral-temporal regions implicated in language processing. Professional Vedic Sanskrit Pandits in India train from childhood for around 10years in an ancient, formalized tradition of oral Sanskrit text memorization and recitation, mastering the exact pronunciation and invariant content of multiple 40,000-100,000 word oral texts. We conducted structural analysis of gray matter density, cortical thickness, local gyrification, and white matter structure, relative to matched controls. We found massive gray matter density and cortical thickness increases in Pandit brains in language, memory and visual systems, including i) bilateral lateral temporal cortices and ii) the anterior cingulate cortex and the hippocampus, regions associated with long and short-term memory. Differences in hippocampal morphometry matched those previously documented for expert spatial navigators and individuals with good verbal working memory. The findings provide unique insight into the brain organization implementing formalized oral knowledge systems.

A case of Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim.

PURPOSE: To report a case of endogenous Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim. CASE REPORT: A 57-year-old man developed disseminated Lomentospora prolificans with right endophthalmitis on the background of immunosuppression following lung transplantation for interstitial lung disease. He was treated with early vitrectomy, intravitreal voriconazole, and systemic Olorofim, voriconazole and terbinafine. His symptoms improved and remained stable in the right eye. Eight weeks later the patient represented with Lomentopora prolificans endophthalmitis in the left eye when systemic voriconazole and terbinafine treatment were withdrawn. Despite aggressive treatment he ultimately succumbed due to vascular complications of extensive disseminated disease. CONCLUSION: We report a rare case of disseminated Lomentosporosis with panophthalmitis in an immunocompromised host with prolonged survival on systemic Olorofim, voriconazole and terbinafine in conjunction with pars plana vitrectomy and intravitreal voriconazole. Early suspicion of an opportunistic fungal infection is critical, as managing disseminated disease is often unsuccessful. Despite presumed inherent resistance, intravitreal and systemic voriconazole appeared to limit disease progression in the right eye. The potential synergistic effects of combined antifungal therapy with orotomides warrant further investigation.

The Humira in Ocular Inflammations Taper (HOT) Study.

PURPOSE: To assess factors that impact the risk of relapse in patients with noninfectious uveitis (NIU) who undergo adalimumab tapering after achieving remission. DESIGN: Retrospective study. METHODS: In this multicenter study, patients with NIU were treated with adalimumab and subsequently tapered. Patient demographics, type of NIU, onset and duration of disease, the period of inactivity before tapering adalimumab, and the tapering schedule were collected. The primary outcome measures were independent predictors of the rate of uveitis recurrence after adalimumab tapering. RESULTS: Three hundred twenty-eight patients were included (54.6% female) with a mean age of 34.3 years. The mean time between disease onset and initiation of adalimumab therapy was 35.2 ± 70.1 weeks. Adalimumab tapering was commenced after a mean of 100.8 ± 69.7 weeks of inactivity. Recurrence was observed in 39.6% of patients at a mean of 44.7 ± 61.7 weeks. Patients who experienced recurrence were significantly younger than those without recurrence (mean 29.4 years vs 37.5 years, P = .0005), and the rate of recurrence was significantly higher in younger subjects (hazard ratio [HR] = 0.88 per decade of increasing age, P = .01). The lowest rate of recurrence was among Asian subjects. A faster adalimumab taper was associated with an increased recurrence rate (HR = 1.23 per unit increase in speed, P < .0005). Conversely, a more extended period of remission before tapering was associated with a lower rate of recurrence (HR = 0.97 per 10-weeks longer period of inactivity, P = .04). CONCLUSIONS: When tapering adalimumab, factors that should be considered include patient age, race, and duration of disease remission on adalimumab. A slow tapering schedule is advisable.

Counterion Association of Ionic Drugs with Sodium Tetradecyl Sulfate in the Aqueous Medium.

This work highlighted the counterion association of diphenhydramine hydrochloride (DPC) and chlorpheniramine maleate (CPM) with anionic sodium tetradecyl sulfate (STS) by conductivity, fluorescence, and UV spectrophotometer measurements. The presence of drugs and the formation of premicellar aggregates of STS were highlighted. The modified Corrin-Harkins CH approaches assessed the STS counterion binding values B = 0.300 for DPC and 0.379 for CPM in the aqueous media at 25 °C. The counterion binding constant (ßc) and Gibb's free energy of micellization (ΔGmic°) were increased and became more negative, suggesting that the drug-surfactant interaction was controlled by electrostatic interaction. Furthermore, the spectral study evaluated that the three isosbestic points for CPM and one isosbestic point for DPC in the STS micelles were observed, which confirmed that CPM was more binding than DPC with the STS micelles. The differential absorbance spectra study was applied to UV spectra to determine the binding constants (Kb) of 2.232 and 2.837 and partition coefficients (Kx) of 286.64 and 3209.21 for DPC and CPM in the presence of STS micelles. The findings demonstrated that the CPM molecules have been associated with the Palisade layer of the STS micelles, and the DPC molecules were bound to the Stern layer of the STS micelles. Finally, we came to the conclusion that ionic drugs could improve the micellization capabilities of surfactants, which might be useful for choosing the best excipients for pharmaceutical applications.

Morphological evolution through integration: a quantitative study of cranial integration in Homo, Pan, Gorilla and Pongo.

Morphological integration refers to coordinated variation among traits that are closely related in development and/or function. Patterns of integration can offer important insight into the structural relationship between phenotypic units, providing a framework to address questions about phenotypic evolvability and constraints. Integrative features of the primate cranium have recently become a popular subject of study. However, an important question that still remains under-investigated is: what is the pattern of cranial shape integration among closely related hominoids? To address this question, we conducted a Procrustes-based geometric morphometrics study to quantify and analyze shape covariation patterns between different cranial regions in Homo, Pan, Gorilla and Pongo. A total of fifty-six 3D landmarks were collected on 407 adult individuals. We then sub-divided the landmarks corresponding to cranial units as outlined in the 'functional matrix hypothesis.' Sub-dividing the cranium in this manner allowed us to explore patterns of covariation between the face, basicranium and cranial vault, using the two-block partial least squares approach. Our results suggest that integrated shape changes in the hominoid cranium are complex, but that the overall pattern of integration is similar among human and non-human apes. Thus, despite having very distinct morphologies the way in which the face, basicranium and cranial vault covary is shared among these taxa. These results imply that the pattern of cranial integration among hominoids is conserved.

The case of the neglected alphasyllabary: orthographic processing in Devanagari.

We applaud Ram Frost for highlighting the need for multicultural perspectives while developing universal models of visual word recognition. We second Frost's proposal that factors like lexical morphology should be incorporated besides purely orthographic features in modeling word recognition. In support, we provide fresh evidence from Hindi (written in Devanagari), an example of hitherto under-represented alphasyllabic orthographies, in which flexible encoding of aksara (character) position is constrained by the morphological structure of words.

A simplicial analysis of the fMRI data from human brain dynamics under functional cognitive tasks.

The topological analysis of fMRI time series data has recently been used to characterize the identification of patterns of brain activity seen during specific tasks carried out under experimentally controlled conditions. This study uses the methods of algebraic topology to characterize time series networks constructed from fMRI data measured for adult and children populations carrying out differentiated reading tasks. Our pilot study shows that our methods turn out to be capable of identifying distinct differences between the activity of adult and children populations carrying out identical reading tasks. We also see differences between activity patterns seen when subjects recognize word and nonword patterns. The results generalize across different populations, different languages and different active and inactive brain regions.

Effects of a Digital Game-Based Course in Building Adolescents' Knowledge and Social-Emotional Competencies.

Objective: The purpose of this study was to investigate the efficacy of a digital game-based course to build domain knowledge and social emotional competencies of empathy and compassion in adolescents. Materials and Methods: The study used a digital game Bury me, my Love with an accompanying course which was administered to 201 participants between ages 13-18 across United Arab Emirates (UAE) and India. Standardized self-reports were used to score participants on measures of knowledge and attitudes, empathy, and compassion before and after the intervention. Mixed analyses of variance were conducted with 1 between-subjects factor (gender) and 1 within-subjects factor (time) to determine the impact of the intervention, followed by post hoc t-tests. Results: Increased effects of intervention were obtained for both knowledge and social emotional learning in both UAE and India. Specifically, there was a significant increase in awareness of migration and refugees in both India (P < 0.001) and UAE (P < 0.001). Interesting effects of gender were seen in which females in both countries showed increases in compassion from others (P < 0.05). Conclusion: This study opens a new window in game-based learning. The design of a structured course with learning outcomes that are centered around a digital game establishes its potential to create engaging and accessible solutions to simultaneously build domain knowledge and social-emotional competencies in adolescents.

Development and standardization of the DALI-DAB (dyslexia assessment for languages of India - dyslexia assessment battery).

A majority of Indian schoolchildren are biliterate in that they acquire literacy in at least two language systems, necessitating dyslexia assessment in both. The DALI-DAB assesses risk for dyslexia by evaluating reading ability and literacy-learning potential through a battery including literacy tests (letter and word reading, spelling, nonword reading, reading comprehension), and mediator skills (phonological awareness, processing automaticity and executive fluency, oral language) in multiple languages. DALI-DAB was developed in three languages - English, Hindi, and Marathi - and standardized on a sample of 1013 children. Reliability analyses revealed high internal consistency (α > 0.8) in most tests in all three languages. Low standard error of measurement values supported DALI-DAB score stability over repeated testing. Construct validity was variously reinforced through, (i) selection of culture-referenced, research-based tests, (ii) approval of test materials by schoolteachers (face validity) and (iii) grade-correlated performance increases on all DALI-DAB tests, besides robust correlations between (iv) literacy and mediator skill test scores (p < .001, concurrent validity), (v) equivalent tests across languages (p < .01, convergent validity), and (vi) DALI-DAB and WJ III ACH literacy scores (p < .01, criterion validity), in contrast to (vii) low correlation between DALI-DAB and WJ III ACH math scores (p > .05, discriminant validity). Overall, the DALI-DAB represents the first standardized dyslexia assessment tool for bilingual-biliterate children.

Periodontally accelerated osteogenic orthodontics: A perio-ortho ambidextrous perspective.

The interdisciplinary collaboration of periodontics and orthodontics has allowed teeth to be moved 2-3 times faster, reducing the time required for traditional orthodontic therapy considerably. Periodontally accelerated osteogenic orthodontics (PAOO), also known as Wilckodontics, is a combination of a selective decortication facilitated orthodontics and alveolar augmentation. With this technique, there is no dependence on the pre-existing alveolar volume. This case report describes the treatment of permanent mandibular molar protraction in a 14-year-old patient undergoing orthodontic therapy using PAOO with piezosurgery.

Perceived Closeness and Autistic Traits Modulate Interpersonal Vocal Communication.

Vocal modulation is a critical component of interpersonal communication. It not only serves as a dynamic and flexible tool for self-expression and linguistic information but also plays a key role in social behavior. Variation in vocal modulation can be driven by individual traits of interlocutors as well as factors relating to the dyad, such as the perceived closeness between interlocutors. In this study we examine both of these sources of variation. At an individual level, we examine the impact of autistic traits, since lack of appropriate vocal modulation has often been associated with Autism Spectrum Disorders. At a dyadic level, we examine the role of perceived closeness between interlocutors on vocal modulation. The study was conducted in three separate samples from India, Italy, and the UK. Articulatory features were extracted from recorded conversations between a total of 85 same-sex pairs of participants, and the articulation space calculated. A larger articulation space corresponds to greater number of spectro-temporal modulations (articulatory variations) sampled by the speaker. Articulation space showed a positive association with interpersonal closeness and a weak negative association with autistic traits. This study thus provides novel insights into individual and dyadic variation that can influence interpersonal vocal communication.