Lafora Disease (LD), a type of progressive myoclonus epilepsy, is a fatal autosomal recessive disorder. The hallmark of LD is the accumulation of insoluble polyglucosan deposits known as Lafora bodies in nerve, heart, liver, skin and skeletal muscle cells. Half of all LD cases are caused by mutations in the gene that encodes the dual specificity phosphatase, laforin. Laforin contains two domains: a carbohydrate-binding module (CBM) and a phosphatase domain. Together, they allow laforin to bind and dephosphorylate complex carbohydrates, an activity conserved from humans to plants. However, laforin has yet to be crystallized successfully, and the dynamic behavior of the two domains remains unknown. Due to the unavailability of laforin for study, we probed solvent accessibility of the plant functional equivalent of laforin, starch-excess 4 (SEX4), utilizing enhanced peptide amide hydrogen/deuterium (H/D) exchange mass spectrometry (DXMS) in order to elucidate the structural dynamics of these proteins. We also explored changes in H/ D exchange of the SEX4 protein upon the binding of amylopectin, a glucose polymer and known substrate of both laforin and SEX4. Employing DXMS, we observed substrate- induced exchange decrease in regions of the CBM with conserved binding residues and in the phosphatase active site pocket. Exchange decrease was also observed in a loop of the CBM not implicated in carbohydrate binding, indicating a site undergoing substrate-induced allosteric changes or yet unidentified carbohydrate-binding residues. The lack of exchange rate changes in all other regions of SEX4 indicates that the phosphatase domain of SEX4 undergoes little conformational changes upon substrate binding, and likely retains an open and active conformation. The functional homology of SEX4 with laforin makes it highly likely our results hold true for laforin

Studies on associations between biomarkers of vitamin D metabolism and fracture risk have focused predominantly on White or elderly populations and may not be generalizable to relatively healthy multiethnic populations. We tested associations of total 25-hydroxyvitamin D (25[OH]D), the ratio of 24,25-dihydroxyvitamin D₃ to 25-hydroxyvitamin D₃ (vitamin D metabolite ratio, VDMR), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations measured in serum with risk of hip and vertebral fractures in the Multi-Ethnic Study of Atherosclerosis (MESA). Serum 25-hydroxyvitamin D₂ and D₃ and 24,25-dihydroxyvitamin D₃ were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study cohort of 6466 participants was without clinically apparent cardiovascular disease and was 39% White, 27% Black, 22% Hispanic, and 12% Chinese. The mean age was 62 years, and 53% were female. There were 128 hip and vertebral fractures over a mean follow-up of 14.2 years. 25(OH)D, the VDMR, PTH, and FGF-23 were not significantly associated with fracture risk after adjustment for demographics, diabetes, smoking, systolic blood pressure, body mass index, medication use, albuminuria, and estimated glomerular filtration rate. Principal component analysis did not suggest differences in linear combinations of 25(OH)D, the VDMR, PTH, and FGF-23 between participants who experienced fractures and those who did not. We did not observe significant interaction between race and ethnicity and any biomarker of vitamin D metabolism on fracture risk. In conclusion, none of the four serum biomarkers of vitamin D metabolism investigated showed a significant association with fracture risk in relatively healthy multiethnic populations. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Background

Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown.

Methods

We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m² (binary) were evaluated as outcomes.

Results

Mean age was 70 ± 10 years, mean eGFR was 78 ± 17 mL/min/1.73 m², and 156 (15%) individuals had eGFR <60 mL/min/1.73 m²; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m² lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m² (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors.

Conclusions

Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D₃ supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; n_control = 13; n_AD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

Background

Different 25-hydroxyvitamin D [25(OH)D] thresholds for treatment with vitamin D supplementation have been suggested and are derived almost exclusively from observational studies. Whether other characteristics, including race/ethnicity, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown.

Objectives

The aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation.

Methods

A total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk of oral vitamin D3 (2000 IU/d; n = 499) or placebo (n = 167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations from baseline to 16 wk.

Results

Among 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear fashion. With baseline 25(OH)D ≥30 ng/mL as the reference, 25(OH)D <20 ng/mL was associated with a larger decline in PTH with vitamin D3 supplementation (-10; 95% CI: -15, -6 pg/mL), whereas 25(OH)D of 20-30 ng/mL was not (-2; 95% CI: -6, 1 pg/mL). A segmented threshold model identified a baseline 25(OH)D concentration of 21 (95% CI: 13, 31) ng/mL as an inflection point for difference in change in PTH. Race/ethnicity, BMI, and eGFR did not modify vitamin D treatment response. There was no significant change in 1,25(OH)2D in either treatment group.

Conclusions

Of characteristics most commonly associated with vitamin D metabolism, only baseline 25(OH)D <20 ng/mL modified the PTH response to vitamin D supplementation, providing support from a clinical trial to use this threshold to define insufficiency. This trial was registered at clinicaltrials.gov as NCT02925195.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5' ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains.