Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant

Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae. During mitosis, the common TAO3 allele interacts with CBK1-a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2-a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait

Using Motor Tempi to Understand Rhythm and Grammatical Skills in Developmental Language Disorder and Typical Language Development

Children with developmental language disorder (DLD) show relative weaknesses on rhythm tasks beyond their characteristic linguistic impairments. The current study compares preferred tempo and the width of an entrainment region for 5- to 7-year-old typically developing (TD) children and children with DLD and considers the associations with rhythm aptitude and expressive grammar skills in the two populations. Preferred tempo was measured with a spontaneous motor tempo task (tapping tempo at a comfortable speed), and the width (range) of an entrainment region was measured by the difference between the upper (slow) and lower (fast) limits of tapping a rhythm normalized by an individual’s spontaneous motor tempo. Data from N = 16 children with DLD and N = 114 TD children showed that whereas entrainment-region width did not differ across the two groups, slowest motor tempo, the determinant of the upper (slow) limit of the entrainment region, was at a faster tempo in children with DLD vs. TD. In other words, the DLD group could not pace their slow tapping as slowly as the TD group. Entrainment-region width was positively associated with rhythm aptitude and receptive grammar even after taking into account potential confounding factors, whereas expressive grammar did not show an association with any of the tapping measures. Preferred tempo was not associated with any study variables after including covariates in the analyses. These results motivate future neuroscientific studies of low-frequency neural oscillatory mechanisms as the potential neural correlates of entrainment-region width and their associations with musical rhythm and spoken language processing in children with typical and atypical language development

Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant

Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae. During mitosis, the common TAO3 allele interacts with CBK1—a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2—a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait

A diagnostic randomised controlled trial to study the impact of rapid diagnostic tests in patients with Acute febrile illness when compared to conventional diagnostics (DRACO study)

[Extract] Dear editor In the paper by Feagins et al., the authors discuss the utility and limitations of rapid diagnostic tests (RDTs) in patients with meningitis.1 To explore the clinical utility of RDTs in patients with Acute febrile illness (AFI), we designed this study. The clinical presentation of AFIs are often overlapping; therefore, arriving at an etiological diagnosis requires serological tests. Conventionally, serological tests like Enzyme-linked immunosorbent assay (ELISA) are used, but they have a long turnaround time. We postulated that the use of RDTs with a short turnaround time might result in a reduced hospital stay and reduced antibiotic consumption

Musical rhythm perception relates to typical and atypical language development: a multi-method approach

Introduction: There is growing evidence that individual dif erences in music aptitude explain significant variance in speech-language task performance. In particular, children\u2019s musical rhythm skills are correlated with their early literacy and spoken language (Politimou et al., 2019). Rhythm and grammar are both organized hierarchically with rule-based structure that unfolds over time. Rhythm deficits are emerging in recent studies (Ladanyi et al., in revision) as a potential feature of developmental language disorder (DLD), a prevalent communication impairment characterized by dif iculties in grammar and vocabulary. The goal of this study was to test neural and cognitive mechanisms underlying the relationship between rhythm and language ability in children across a wide range of language development. Methods: We conducted a series of experiments in children ages 5-8, in which expressive grammar, working memory, and rhythm (musical rhythm, speech rhythm, neural rhythms) were assessed. Children had non-verbal IQ in the normal range (>78) and normal hearing; language characterization was conducted under the supervision of a Speech-Language Pathologist. In Experiment 1, we examined the respective contributions of sensitivity to speech rhythm (a prosody-matching task) and auditory working memory (number recall) as mediators between musical rhythm perception and expressive grammar in typically developing (TD) children. In Experiment 2 (EEG) we tested the relationship between neural entrainment to musical rhythms and language ability in children with developmental language disorder (DLD) and TD peers. Results: Experiment 1 used a path model in TD children (N=110) to test whether speech rhythm and/or working memory mediate the association between musical rhythm and expressive grammar. Interestingly, musical rhythm had a direct ef ect on grammar (direct ef ect; \u3b2=.24), but neither speech rhythm nor working memory mediated this association (indirect ef ect; \u3b2=-.01). In Experiment 2, individual dif erences in musical rhythm processing (measured with EEG time-frequency analysis) predicted grammar (evoked beta: p=.025; evoked gamma: p =.024) in a pooled group of N=66 TD and N=16 with DLD. Moreover, within DLD, evoked gamma EEG predicted complex syntax items (p=.022), while in TD, evoked beta predicted complex syntax (p=.028), suggesting rhythm processing is linked to hierarchical language use. Discussion:These studies converged with earlier work (in smaller samples) showing musical rhythm perception skills as a predictor of individual dif erences in expressive grammar (e.g., Gordon et al., 2015) and more broadly, with a growing number of studies linking language development to musical abilities. Experiment 1 showed that most of the variance is unique to musical rhythm and not explained by sensitivity to prosodic cues or auditory working memory. Experiment 2 pointed to neural entrainment to rhythm as a potential mechanism contributing to grammatical skill in school-aged children, with EEG evoked beta and gamma as predictors of complex syntax. These findings suggest an emerging role of neural oscillatory networks linked to expressive language skills within typical and atypical development

The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) Framework for Understanding Musicality-Language Links Across the Lifespan

Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality. In support of the MAPLE framework, we review and discuss findings from over seventy behavioral and neural studies, highlighting that musicality is robustly associated with individual differences in a range of speech-language skills required for communication and development. These include speech perception-in-noise, prosodic perception, morphosyntactic skills, phonological skills, reading skills, and aspects of second/foreign language learning. Overall, the current work provides a clear agenda and framework for studying musicality-language links using individual differences approaches, with an emphasis on leveraging advances in the genomics of complex musicality and language traits

Safe Delivery application with facilitation increases knowledge and confidence of obstetric and neonatal care among frontline health workers in India

Background: Digital learning tools have proliferated among healthcare workers in India. Evidence of their effectiveness is however minimal. We sought to examine the impact of the Safe Delivery App (SDA) on knowledge and confidence among frontline health workers (HW) in India. We also studied whether facilitation to address technical challenges enhanced self-learning. Methods: Staff nurses and nurse-midwives from 30 facilities in two states were divided into control and intervention groups through randomization. Knowledge and confidence were assessed at baseline and after 6 months. Three rounds of facilitation addressing technical challenges in downloading and usage along with reminders about the next phase of learning were conducted in the intervention group. A user satisfaction scale along with qualitative interviews was conducted in the intervention group at the endline along with qualitative interviews on facilitation. Results: The knowledge and confidence of the healthcare workers significantly increased from the baseline to endline by 4 percentage points (P < 0.001). The participants who received facilitation had a higher mean score difference in knowledge and confidence compared to those who did not receive facilitation (P < 0.001). The participants were highly satisfied with the app and video was the most-watched feature. They reported a positive experience of the facilitation process. Conclusion: The effectiveness and acceptability of the SDA indicate the applicability of mHealth learning tools at the primary healthcare level. In a time of rapid digitalization of training, facilitation or supportive supervision needs further focus while on-ground digital training could be invested in to overcome digital illiteracy among healthcare workers