Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Disentangling drivers of litter decomposition in a multi-continent network of tree diversity experiments.

Litter decomposition is a key ecosystem function in forests and varies in response to a range of climatic, edaphic, and local stand characteristics. Disentangling the relative contribution of these factors is challenging, especially along large environmental gradients. In particular, knowledge of the effect of management options, such as tree planting density and species composition, on litter decomposition would be highly valuable in forestry. In this study, we made use of 15 tree diversity experiments spread over eight countries and three continents within the global TreeDivNet network. We evaluated the effects of overstory composition (tree identity, species/mixture composition and species richness), plantation conditions (density and age), and climate (temperature and precipitation) on mass loss (after 3 months and 1 year) of two standardized litters: high-quality green tea and low-quality rooibos tea. Across continents, we found that early-stage decomposition of the low-quality rooibos tea was influenced locally by overstory tree identity. Mass loss of rooibos litter was higher under young gymnosperm overstories compared to angiosperm overstories, but this trend reversed with age of the experiment. Tree species richness did not influence decomposition and explained almost no variation in our multi-continent dataset. Hence, in the young plantations of our study, overstory composition effects on decomposition were mainly driven by tree species identity on decomposer communities and forest microclimates. After 12 months of incubation, mass loss of the high-quality green tea litter was mainly influenced by temperature whereas the low-quality rooibos tea litter decomposition showed stronger relationships with overstory composition and stand age. Our findings highlight that decomposition dynamics are not only affected by climate but also by management options, via litter quality of the identity of planted trees but also by overstory composition and structure.

Levodopa/dopa decarboxylase inhibitor associated microscopic colitis: An under-recognized drug reaction.

BACKGROUND: Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis. Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy. METHOD: A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis. RESULTS: All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication. Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological proven microscopic colitis. CONCLUSION: levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than previously suspected, with the potential to affect treatment compliance and therapeutic options.

Enhanced light interception and light use efficiency explain overyielding in young tree communities.

Diverse plant communities are often more productive than mono-specific ones. Several possible mechanisms underlie this phenomenon but their relative importance remains unknown. Here we investigated whether light interception alone or in combination with light use efficiency (LUE) of dominant and subordinate species explained greater productivity of mixtures relative to monocultures (i.e. overyielding) in 108 young experimental tree communities. We found mixed-species communities that intercepted more light than their corresponding monocultures had 84% probability of overyielding. Enhanced LUE, which arose via several pathways, also mattered: the probability of overyielding was 71% when, in a mixture, species with higher 'inherent' LUE (i.e. LUE in monoculture) intercepted more light than species with lower LUE; 94% when dominant species increased their LUE in mixture; and 79% when subordinate species increased their LUE. Our results suggest that greater light interception and greater LUE, generated by inter and intraspecific variation, together drive overyielding in mixed-species forests.

Remote spectral detection of biodiversity effects on forest biomass.

Quantifying how biodiversity affects ecosystem functions through time over large spatial extents is needed for meeting global biodiversity goals yet is infeasible with field-based approaches alone. Imaging spectroscopy is a tool with potential to help address this challenge. Here, we demonstrate a spectral approach to assess biodiversity effects in young forests that provides insight into its underlying drivers. Using airborne imaging of a tree-diversity experiment, spectral differences among stands enabled us to quantify net biodiversity effects on stem biomass and canopy nitrogen. By subsequently partitioning these effects, we reveal how distinct processes contribute to diversity-induced differences in stand-level spectra, chemistry and biomass. Across stands, biomass overyielding was best explained by species with greater leaf nitrogen dominating upper canopies in mixtures, rather than intraspecific shifts in canopy structure or chemistry. Remote imaging spectroscopy may help to detect the form and drivers of biodiversity-ecosystem function relationships across space and time, advancing the capacity to monitor and manage Earth's ecosystems.

Spatial complementarity in tree crowns explains overyielding in species mixtures.

Deciphering the mechanisms that link biodiversity with ecosystem functions is critical to understanding the consequences of changes in biodiversity. The hypothesis that complementarity and selection effects drive relationships between biodiversity and ecosystem functions is well accepted, and an approach to statistically untangle the relative importance of these effects has been widely applied. In contrast, empirical demonstrations of the biological mechanisms that underlie these relationships remain rare. Here, on the basis of a field experiment with young trees, we provide evidence that one form of complementarity in plant communities-complementarity among crowns in canopy space-is a mechanism, related to light interception and use, that links biodiversity with ecosystem productivity. Stem biomass overyielding increased sharply in mixtures with greater crown complementarity. Inherent differences among species in crown architecture led to greater crown complementarity in functionally diverse species mixtures. Intraspecific variation, specifically neighbourhood-driven plasticity in crowns, further modified spatial complementarity and strengthened the positive relationship with overyielding-crown plasticity and inherent interspecific differences contributed near equally in explaining patterns of overyielding. We posit that crown complementarity is an important mechanism that may contribute to diversity-enhanced productivity in forests.

Ectomycorrhizal fungal diversity and saprotrophic fungal diversity are linked to different tree community attributes in a field-based tree experiment.

Exploring the link between above- and belowground biodiversity has been a major theme of recent ecological research, due in large part to the increasingly well-recognized role that soil microorganisms play in driving plant community processes. In this study, we utilized a field-based tree experiment in Minnesota, USA, to assess the effect of changes in plant species richness and phylogenetic diversity on the richness and composition of both ectomycorrhizal and saprotrophic fungal communities. We found that ectomycorrhizal fungal species richness was significantly positively influenced by increasing plant phylogenetic diversity, while saprotrophic fungal species richness was significantly affected by plant leaf nitrogen content, specific root length and standing biomass. The increasing ectomycorrhizal fungal richness associated with increasing plant phylogenetic diversity was driven by the combined presence of ectomycorrhizal fungal specialists in plots with both gymnosperm and angiosperm hosts. Although the species composition of both the ectomycorrhizal and saprotrophic fungal communities changed significantly in response to changes in plant species composition, the effect was much greater for ectomycorrhizal fungi. In addition, ectomycorrhizal but not saprotrophic fungal species composition was significantly influenced by both plant phylum (angiosperm, gymnosperm, both) and origin (Europe, America, both). The phylum effect was caused by differences in ectomycorrhizal fungal community composition, while the origin effect was attributable to differences in community heterogeneity. Taken together, this study emphasizes that plant-associated effects on soil fungal communities are largely guild-specific and provides a mechanistic basis for the positive link between plant phylogenetic diversity and ectomycorrhizal fungal richness.

Functional identity is the main driver of diversity effects in young tree communities.

Two main effects are proposed to explain biodiversity-ecosystem functioning relationships: niche complementarity and selection effects. Both can be functionally defined using the functional diversity (FD) and functional identity (FI) of the community respectively. Herein, we present results from the first tree diversity experiment that separated the effect of selection from that of complementarity by varying community composition in high-density plots along a gradient of FD, independent of species richness and testing for the effects of FD and community weighted means of traits (a proxy for FI) on stem biomass increment (a proxy for productivity). After 4 years of growth, most mixtures did not differ in productivity from the averages of their respective monocultures, but some did overyield significantly. Those positive diversity effects resulted mostly from selection effects, primarily driven by fast-growing deciduous species and associated traits. Net diversity effect did not increase with time over 4 years.

The influence of support and particle size on the platinum catalysed oxygen reduction reaction.

A range of platinum deposits, equivalent thicknesses (delta) 0.2-2.5 nm, have been synthesised on carbon and reduced titania (TiO(x)) supports using physical vapour deposition on (10 x 10) arrays of electrodes. For delta < 1.0 nm, discrete platinum centres are formed and the TiO(x) supported platinum show two distinct characteristics: (a) a strong positive shift in the potential for the oxidation of monolayers of CO with decreasing loading of Pt leading to an inability to oxidise the CO on the lowest loadings and (b) a strong negative shift in the potential for the reduction of oxygen. Both observations can be understood in terms of an increase in the irreversibility of the Pt/PtO couple at such surfaces. The same trends, although significantly weaker, are seen with the carbon supported platinum, delta < 1.0 nm, and it is suggested that the Pt/PtO couple on carbon shows intermediate kinetics between Pt on TiO(x) and bulk Pt. These results have significant implications for understanding the mechanism of oxygen reduction on supported Pt catalysts and hence for the search for alternative supports to platinum for ORR electrocatalysts.

The influence of Pt particle size on the surface oxidation of titania supported platinum.

A range of reduced titania (TiO(x)) supported platinum electrocatalysts have been synthesised using physical vapour deposition on arrays of electrodes. Surfaces with equivalent thicknesses of platinum in the range 0.2-2.5 nm on a uniform layer of TiO(x) have been synthesised on 10 x 10 arrays. The arrays have been used to study the surface redox chemistry of the supported platinum as well as the oxidation of a monolayer of carbon monoxide on the platinum. It is shown that below an equivalent thickness of 0.8 nm, there is a positive shift in the potential for the oxidation of the platinum surface and a negative shift for the reduction of the oxide with decrease in the platinum loading. These shifts show that it is the kinetics of the platinum/platinum oxide couple that change with platinum loading; the couple becomes increasingly irreversible with decreasing loading. The peak potential for the oxidation of the monolayer of carbon monoxide also shifts positive and broadens with decreasing platinum loading; these trends are again particularly marked below an equivalent thickness of 0.8 nm while below 0.4 nm no CO oxidation peak is observed although it could be confirmed that CO is adsorbed on such surfaces. Again, these changes with platinum loading are associated with the irreversibility of the platinum/platinum oxide couple. At low equivalent thicknesses, it is impossible to form the oxidised platinum species within the carbon monoxide monolayer essential to the commencement of oxidation of the CO monolayer.

Deciduousness in a seasonal tropical forest in western Thailand: interannual and intraspecific variation in timing, duration and environmental cues.

Seasonal tropical forests exhibit a great diversity of leaf exchange patterns. Within these forests variation in the timing and intensity of leaf exchange may occur within and among individual trees and species, as well as from year to year. Understanding what generates this diversity of phenological behaviour requires a mechanistic model that incorporates rate-limiting physiological conditions, environmental cues, and their interactions. In this study we examined long-term patterns of leaf flushing for a large proportion of the hundreds of tree species that co-occur in a seasonal tropical forest community in western Thailand. We used the data to examine community-wide variation in deciduousness and tested competing hypotheses regarding the timing and triggers of leaf flushing in seasonal tropical forests. We developed metrics to quantify the nature of deciduousness (its magnitude, timing and duration) and its variability among survey years and across a range of taxonomic levels. Tree species varied widely in the magnitude, duration, and variability of leaf loss within species and across years. The magnitude of deciduousness ranged from complete crown loss to no crown loss. Among species that lost most of their crown, the duration of deciduousness ranged from 2 to 21 weeks. The duration of deciduousness in the majority of species was considerably shorter than in neotropical forests with similar rainfall periodicity. While the timing of leaf flushing varied among species, most ( approximately 70%) flushed during the dry season. Leaf flushing was associated with changes in photoperiod in some species and the timing of rainfall in other species. However, more than a third of species showed no clear association with either photoperiod or rainfall, despite the considerable length and depth of the dataset. Further progress in resolving the underlying internal and external mechanisms controlling leaf exchange will require targeting these species for detailed physiological and microclimatic studies.

Interpreting changes in the epidemiology of anencephaly and spina bifida following folic acid fortification of the U.S. grain supply in the setting of long-term trends, Atlanta, Georgia, 1968-2003.

BACKGROUND: The prevalence of anencephaly (AN) and spina bifida (SB) was declining long before fortification of enriched grains in the U.S. with folic acid. We examined whether changes in these defects surrounding fortification could be distinguished from preexisting trends. METHODS: We used data from the Metropolitan Atlanta Congenital Defects Program to identify three ascertainment periods: Period 1 (1968-1981), prenatal diagnoses rarely made; Period 2 (1981-1993), prenatal diagnoses made but not ascertained; Period 3 (1994-2003), prenatal diagnoses ascertained. We compared the annual percent change (APC) in AN and SB for each period using Poisson regression, then compared prevalences during each period for categories of pregnancy outcome, sex, race, gravidity, and maternal age. RESULTS: The prevalence of AN (N = 434) and SB (N = 663) declined during 1968-2003. The APCs in Periods 1, 2, and 3, respectively, were -6.9%, -2.9%, and -6.8% for AN, and -7.1%, -7.0%, and -6.2% for SB; 95% confidence intervals around the APCs for Periods 2 and 3 overlapped for both defects. Prevalence ratios (PRs) for females relative to males decreased for AN (2.3 in Period 1; 1.2 in Period 3); PRs for whites relative to blacks or African Americans decreased for both AN (2.7 in Period 1; 1.2 in Period 3) and SB (2.5 in Period 1; 1.1 in Period 3). CONCLUSIONS: Our analysis suggests that changes in AN and SB surrounding folic acid fortification (Period 3) could be part of preexisting trends. This must be considered when evaluating prevention efforts.

Combinatorial approach to the study of particle size effects in electrocatalysis: synthesis of supported gold nanoparticles.

A high-throughput method for physical vapor deposition has been applied to the synthesis of libraries of supported gold particles on amorphous substoichiometric TiO(x)() and carbon supports. The TiO(x)() substrate stoichiometry can be varied or kept constant across a supporting sample, and subsequent deposition of particle sizes on supports are controlled through the nucleation and growth process. TEM measurements indicate nucleation and growth of Au particles takes place, with the smallest particles initially observed at 1.4 nm with a maximum density of 5.5 x 10(12) cm(-2) on titania, and 2.6 nm with concomitantly lower density on carbon. The 1.4-nm particles on titania exhibit a binding energy shift in the Au(4f) core level of 0.3 eV from bulk gold, and the shift is approximately 0.1 eV by the time particles grow to a mean size of 2.5 nm. These shifts are associated with final state effects, and the supported gold particles are metallic and appear to be relatively stable in air. When combined with appropriate substrates and screening techniques, this method provides a highly controllable method for the high-throughput synthesis of model supported catalyst.

Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.

BACKGROUND: Observational studies and clinical trials have suggested that periconceptional use of folic acid can reduce the risk of birth defects other than neural tube defects (NTDs). Using data reported by states to the National Birth Defects Prevention Network, we examined whether folic acid fortification might have decreased the prevalence of other specific birth defects. METHODS: For each of 16 birth defect categories selected for study, birth prevalence for two time periods was calculated with data submitted from a number of states in 1995-1996 ("pre-fortification") and 1999-2000 ("post-fortification"). Changes in birth prevalence between the two time periods were assessed by calculating prevalence ratios and 95% confidence intervals for each defect, and compared by maternal race/ethnicity and availability of prenatally diagnosed cases. RESULTS: We confirmed previously reported reductions in the birth prevalence of NTDs. In addition, we found modest, yet statistically significant, decreases in the birth prevalence for transposition of the great arteries(12%), cleft palate only (12%), pyloric stenosis (5%), upper limb reduction defects (11%), and omphalocele (21%). More substantial subgroup decreases were observed for renal agenesis among programs that conduct prenatal surveillance (28%), for common truncus among Hispanics (45%), and for upper limb reduction defects among Hispanics (44%). There were modest yet significant increases in the prevalence of obstructive genitourinary defects (12%) and Down syndrome (7%), but not among programs conducting prenatal surveillance for these defects. CONCLUSIONS: These results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non-NTD birth defects.