Sleep Timing and Neurocognitive Networks in Youth

Sleep timing, particularly later midpoint of sleep, has been linked to emotion dysregulation and psychopathology. Prior adult studies link poor sleep (e.g., shorter duration, later midpoint), to altered resting-state functional connectivity (rs-FC) within and between key neurocognitive networks, particularly the default mode network (DMN), which is involved in internal thought and rumination. Importantly, many psychiatric disorders begin during adolescence, a period of shifted sleep schedules. We explored associations between midpoint of sleep and rs-FC of the DMN and other core neurocognitive networks in youth. Sleep timing was measured in 3,798 youth (11.9±0.6 years, 47.5% female) from the Adolescent Brain Cognitive Development study using Fitbit watches (over 13.1±6.5 days). Internalizing symptoms were measured using self-report and rs-FC was measured between the DMN and three neurocognitive networks: dorsal attention network (DAN), frontoparietal network (FPN), and salience network (SN). Associations between sleep timing and rs-FC were measured using linear regressions adjusting for age, sex, race, parental education, family income, puberty, and head motion. Average midpoint of sleep was 3:35 AM (range: 12:34 AM-11:27 PM). Later midpoint of sleep was associated with increased self-reported depressive symptoms. Later midpoint of sleep was associated with lower DMN-DAN rs-FC. There were no associations between midpoint of sleep and DMN-DMN, DMN-FPN, or DMN-SN network rs-FC. These results add to and extend prior studies in youth by incorporating objective measures of sleep timing (Fitbit data), and in a large national sample. Additionally, our findings may have implications for the consideration of sleep timing when designing behavioral-health interventions in youth

Cargo of Birds to Arkansas, the Hurricanes in 2008 and the Swept Clean Hypothesis

Three hurricanes in the hurricane season of 2008 brought to Arkansas several unusual marine and other birds from southerly locations. There were 10 species noted, totaling 44 individual birds. Sooty Terns, numbering 15, were the most numerous. Laughing Gulls were next in abundance. In the mix of birds there was only 1 new species for the state, a Least Grebe. The hurricanes brought vastly different cargos of birds, and two hypotheses relating to how hurricanes transport birds are proposed. The findings supported the swept clean hypothesis over the blown through hypothesis

Integrating Fiber Optic Strain Sensors into Metal Using Ultrasonic Additive Manufacturing

Ultrasonic additive manufacturing, a rather new three-dimensional (3D) printing technology, uses ultrasonic energy to produce metallurgical bonds between layers of metal foils near room temperature. This low temperature attribute of the process enables integration of temperature sensitive components, such as fiber optic strain sensors, directly into metal structures. This may be an enabling technology for Digital Twin applications, i.e., virtual model interaction and feedback with live load data. This study evaluates the consolidation quality, interface robustness, and load sensing limits of commercially available fiber optic strain sensors embedded into aluminum alloy 6061. Lastly, an outlook on the technology and its applications is described

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog

Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of nonchromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective: To characterise genetic and clinical findings in individuals with SHH mutations. Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p¼0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p¼0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive

Influence of Cu(СH[3]COO)[2] promoting additive on bituminous coal oxidation process

The process of coal oxidation with applied Cu(СH[3]COO)[2] additive was studied by the capillary incipient wetness impregnation method with 5% mass concentration. The experiment was conducted by thermogravimetric analysis at a heating rate of 2.5°C/min to a maximum temperature of 600°C in atmospheric air. It was established that application of the initiation additive leads to a significant reduction in the initial temperature of sublimation and active oxidation of volatile compounds ([tau]Ti=78°C) and the oxidation end temperature ([tau]T[f]=64°C). It was established that in the presence of copper acetate the nature of coal oxidation reaction significantly changes (DTG data). The parameters of the coals oxidation process in the presence of copper acetate were determined, and an assumption was made about the presence of a composite catalytic effect

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo