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.

Development of a composite drought indicator for operational drought monitoring in the MENA region.

This paper presents the composite drought indicator (CDI) that Jordanian, Lebanese, Moroccan, and Tunisian government agencies now produce monthly to support operational drought management decision making, and it describes their iterative co-development processes. The CDI is primarily intended to monitor agricultural and ecological drought on a seasonal time scale. It uses remote sensing and modelled data inputs, and it reflects anomalies in precipitation, vegetation, soil moisture, and evapotranspiration. Following quantitative and qualitative validation assessments, engagements with policymakers, and consideration of agencies' technical and institutional capabilities and constraints, we made changes to CDI input data, modelling procedures, and integration to tailor the system for each national context. We summarize validation results, drought modelling challenges and how we overcame them through CDI improvements, and we describe the monthly CDI production process and outputs. Finally, we synthesize procedural and technical aspects of CDI development and reflect on the constraints we faced as well as trade-offs made to optimize the CDI for operational monitoring to support policy decision-making-including aspects of salience, credibility, and legitimacy-within each national context.

RIP-Seq analysis of non-PPR chloroplast editing factors reveals broad RNA interactions and enrichment of less efficiently translated RNAs by OZ1 and ORRM1 complexes.

C-to-U RNA editing in angiosperm chloroplasts requires a large suite of proteins bound together in the editosome. The editosome is comprised of PPR proteins, RIP/MORFs, OZ proteins, and ORRM proteins that physically interact in high molecular weight complexes. The specific functions of non-PPR editing factors in the editosome are unclear, however, specific subsets of editing sites are affected by absence of non-PPR editing factors. Unlike the PPR components of editosomes that have predictable nucleotide specificities, domains present in non-PPR editing factors make RNA associations difficult to predict. In this study, chloroplast extracts were isolated from juvenile maize seedlings. RNAs were immunoprecipitated using polyclonal antibodies targeting non-PPR editing factors RIP9, OZ1, and ORRM1. RNA libraries from duplicate experiments were compared. RIP9 was associated with most of the non-ribosomal RNA content of chloroplasts, consistent with a general binding function to PPR L-motifs and tethering of large ribonucleoprotein complexes. The breadth of RNA associations was greater than predicted and include mRNAs without predicted editing sites, tRNA sequences, and introns. OZ1 and ORRM1 were associated with a highly similar pool of RNAs that have a bias toward lower translational efficiency values in mature chloroplasts. Lower translational efficiency was also associated with the pool of edited RNAs compared to RNAs without editing sites. The unexpected breadth of interactions by non-PPR editing factors suggests the editosome is large, diverse, and associated with RNAs with lower relative translational efficiency in mature chloroplasts.

What Drove Program Participants to Initially Attend Congregate Meals? Socialization, Health, and Other Reasons.

The Congregate Nutrition Services support efforts to keep older Americans independent and engaged in their communities. We examined participants' self-reported reasons for initially attending the congregate meals program and whether reasons differed by participant characteristics. Descriptive statistics and tests of differences were used to compare participants (n = 1,072). Individuals attended congregate meals for several reasons, with the top two being socialization (36.3%) and age- or health-related reasons (18.7%). Those attending for socialization were less likely to be lower income, have food insecurity, or live with 3+ ADL limitations while participants who first attended due to age or health-related reasons were more likely to be low income, food insecure, and from historically marginalized populations. Health and social service professionals and community organizations could expand data collection on older adults in their communities and partner with congregate meal providers to encourage participation for individuals with unmet nutritional, health, and socialization needs.

Electrode-Skin Impedance Model Parameter Estimation in the Frequency-Domain.

This paper presents a method for identifying parameter values for a double parallel resistor/constant-phase-element model of the electrode-skin interface for individual silver and silver/silver chloride electrodes. The impedance of each electrode was measured in five from 1 Hz-10 kHz. Phase features of these data were used to guide initial estimates for parameter values which were refined using a least squares algorithm. Resultant model impedances were compared with experimental data across a typical biosignal bandwidth (1 Hz-500 Hz). The method was effective in estimating component values in most datasets, and resulted in a mean relative RMS error of 7 % (σ = 8.3%) across the biosignal bandwidth.Clinical relevance- This work establishes a feature-based method for finding component parameter estimates for an electrode contact impedance model.

Short tandem repeats bind transcription factors to tune eukaryotic gene expression.

Short tandem repeats (STRs) are enriched in eukaryotic cis-regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate transcription factor (TF)-DNA affinities and apparent on-rates by about 70-fold by directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density, with impacts well predicted by statistical mechanics. Confirming that STRs also affect TF binding in cells, neural networks trained only on in vivo occupancies predicted effects identical to those observed in vitro. Approximately 90% of TFs preferentially bound STRs that need not resemble known motifs, providing a cis-regulatory mechanism to target TFs to genomic sites.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

A ribonuclease activity linked to DYW1 in vitro is inhibited by RIP/MORF proteins.

Organellar C-to-U RNA editing in plants occurs in complexes composed of various classes of nuclear-encoded proteins. DYW-deaminases are zinc metalloenzymes that catalyze hydrolytic deamination required for C-to-U modification editing. Solved crystal structures for DYW-deaminase domains display all structural features consistent with a canonical cytidine deamination mechanism. However, some recombinant DYW-deaminases from plants have been associated with ribonuclease activity in vitro. Direct ribonuclease activity by an editing factor is confounding since it is not required for deamination of cytosine, theoretically would be inimical for mRNA editing, and does not have a clear physiological function in vivo. His-tagged recombinant DYW1 from Arabidopsis thaliana (rAtDYW1) was expressed and purified using immobilized metal affinity chromatography (IMAC). Fluorescently labeled RNA oligonucleotides were incubated with recombinant AtDYW1 under different conditions. Percent relative cleavage of RNA probes was recorded at multiple time points from triplicate reactions. The effects of treatment with zinc chelators EDTA and 1, 10-phenanthroline were examined for rAtDYW1. Recombinant His-tagged RNA editing factors AtRIP2, ZmRIP9, AtRIP9, AtOZ1, AtCRR4, and AtORRM1 were expressed in E. coli and purified. Ribonuclease activity was assayed for rAtDYW1 in the presence of different editing factors. Lastly, the effects on nuclease activity in the presence of nucleotides and modified nucleosides were investigated. RNA cleavage observed in this study was linked to the recombinant editing factor rAtDYW1 in vitro. The cleavage reaction is sensitive to high concentrations of zinc chelators, indicating a role for zinc ions for activity. The addition of equal molar concentrations of recombinant RIP/MORF proteins reduced cleavage activity associated with rAtDYW1. However, addition of equal molar concentrations of purified recombinant editing complex proteins AtCRR4, AtORRM1, and AtOZ1 did not strongly inhibit ribonuclease activity on RNAs lacking an AtCRR4 cis-element. Though AtCRR4 inhibited AtDYW1 activity for oligonucleotides with a cognate cis-element. The observation that editing factors limit ribonuclease activity of rAtDYW1 in vitro, suggests that nuclease activities are limited to RNAs in absence of native editing complex partners. Purified rAtDYW1 was associated with the hydrolysis of RNA in vitro, and activity was specifically inhibited by RNA editing factors.

Ocular Amyloid, Condensates, and Aggregates - Higher-Order Protein Assemblies Participate in Both Retinal Degeneration and Function.

The formation of higher-order protein assemblies (commonly called protein aggregates) has long been associated with disease states, particularly in neurodegenerative disorders. Within the eye, protein aggregation has also been implicated in various retinal degenerative diseases ranging from retinitis pigmentosa (RP) to Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD) to age-related macular degeneration (AMD). Yet, many essential cellular processes including transcription, translation, and the formation of non-membrane bound organelles require the formation of functional, non-pathologic protein aggregates to maintain cellular homeostasis. Thus, functional protein aggregates, also called condensates, likely play essential roles in maintaining normal retina function. However, currently, there is a critical gap in our knowledge: What proteins form higher-order assemblies under normal conditions within the retina and what function do these structures serve? Herein, we present data suggesting that protein aggregation is identifiable in multiple retinal layers of normal, healthy murine retina, and briefly discuss the potential contributions of aggregated proteins to normal retinal function, with a focus on the photoreceptor inner and outer segment.

Explainable machine learning for the prediction and assessment of complex drought impacts.

Drought is a common and costly natural disaster with broad social, economic, and environmental impacts. Machine learning (ML) has been widely applied in scientific research because of its outstanding performance on predictive tasks. However, for practical applications like disaster monitoring and assessment, the cost of the models failure, especially false negative predictions, might significantly affect society. Stakeholders are not satisfied with or do not "trust" the predictions from a so-called black box. The explainability of ML models becomes progressively crucial in studying drought and its impacts. In this work, we propose an explainable ML pipeline using the XGBoost model and SHAP model based on a comprehensive database of drought impacts in the U.S. The XGBoost models significantly outperformed the baseline models in predicting the occurrence of multi-dimensional drought impacts derived from the text-based Drought Impact Reporter, attaining an average F2 score of 0.883 at the national level and 0.942 at the state level. The interpretation of the models at the state scale indicates that the Standardized Precipitation Index (SPI) and Standardized Temperature Index (STI) contribute significantly to predicting multi-dimensional drought impacts. The time scalar, importance, and relationships of the SPI and STI vary depending on the types of drought impacts and locations. The patterns between the SPI variables and drought impacts indicated by the SHAP values reveal an expected relationship in which negative SPI values positively contribute to complex drought impacts. The explainability based on the SPI variables improves the trustworthiness of the XGBoost models. Overall, this study reveals promising results in accurately predicting complex drought impacts and rendering the relationships between the impacts and indicators more interpretable. This study also reveals the potential of utilizing explainable ML for the general social good to help stakeholders better understand the multi-dimensional drought impacts at the regional level and motivate appropriate responses.

Panarchy theory for convergence.

Coping with surprise and uncertainty resulting from the emergence of undesired and unexpected novelty or the sudden reorganization of systems at multiple spatiotemporal scales requires both a scientific process that can incorporate diverse expertise and viewpoints, and a scientific framework that can account for the structure and dynamics of interacting social-ecological systems (SES) and the inherent uncertainty of what might emerge in the future. We argue that combining a convergence scientific process with a panarchy framework provides a pathway for improving our understanding of, and response to, emergence. Emergent phenomena are often unexpected (e.g., pandemics, regime shifts) and can be highly disruptive, so can pose a significant challenge to the development of sustainable and resilient SES. Convergence science is a new approach promoted by the U.S. National Science Foundation for tackling complex problems confronting humanity through the integration of multiple perspectives, expertise, methods, tools, and analytical approaches. Panarchy theory is a framework useful for studying emergence, because it characterizes complex systems of people and nature as dynamically organized and structured within and across scales of space and time. It accounts for the fundamental tenets of complex systems and explicitly grapples with emergence, including the emergence of novelty, and the emergent property of social-ecological resilience. We provide an overview of panarchy, convergence science, and emergence. We discuss the significant data and methodological challenges of using panarchy in a convergence approach to address emergent phenomena, as well as state-of-the-art methods for overcoming them. We present two examples that would benefit from such an approach: climate change and its impacts on social-ecological systems, and the relationships between infectious disease and social-ecological systems.

Compositional changes in the humin fraction resulting from the long-term cultivation of an Irish grassland soil: Evidence from FTIR and multi-NMR spectroscopies.

Soil humin (HN), a major long-term sink for carbon in the pedosphere, plays a key role in the global carbon cycle, and has been less extensively studied than the humic and fulvic acids components. There are increasing concerns about the depletions of soil organic matter (SOM) arising from modern soil cultivation practices but there has been little focus on how HN can be altered as the result. This study has compared the HN components in a soil under cultivation for wheat for >30 years with those from an adjacent contiguous soil that had been under long-term grass for all that time. A urea-fortified basic solution isolated additional humic fractions from soils that had been exhaustively extracted in basic media. Then further exhaustive extractions of the residual soil material with dimethyl sulfoxide, amended with sulphuric acid isolated what may be called the "true" HN fraction. The long-term cultivation resulted in a loss of 53 % soil organic carbon in the surface soil. Infrared and multi-NMR spectroscopies showed the "true" HN to be dominated by aliphatic hydrocarbons and carboxylated structures, but with clear evidence for lesser amounts of carbohydrate and peptide materials, and with weaker evidence for lignin-derived substances. These lesser-amount structures can be sorbed on the soil mineral colloid surfaces and/or covered by the hydrophobic HN component or entrained within these which have strong affinities for the mineral colloids. HN from the cultivated site contained less carbohydrate and more carboxyl groups suggesting slow transformations took place resulting from the cultivation, but these were much slower than for the other components of SOM. It is recommended that a study be made of the HN in a soil under long-term cultivation for which the SOM content has reached a steady state and where HN will be expected to dominate the components of SOM.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results.

OBJECTIVE: The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS: Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS: Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS: Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov).

Health phenome of Parkinson's patients reveals prominent mood-sleep cluster.

Background: Associations between phenotypic traits, environmental exposures, and Parkinson's disease have largely been evaluated one-by-one, piecemeal, and pre-selections. A comprehensive picture of comorbidities, phenotypes, exposures, and polypharmacy characterizing the complexity and heterogeneity of real-world patients presenting to academic movement disorders clinics in the US is missing. Objectives: To portrait the complexity of features associated with patients with Parkinson's disease in a study of 933 cases and 291 controls enrolled in the Harvard Biomarkers Study. Methods: The primary analysis evaluated 64 health features for associations with Parkinson's using logistic regression adjusting for age and sex. We adjusted for multiple testing using the false discovery rate (FDR) with £ 0.05 indicating statistical significance. Exploratory analyses examined feature correlation clusters and feature combinations. Results: Depression (OR = 3.11, 95% CI 2.1 to 4.71), anxiety (OR = 3.31, 95% CI 2.01-5.75), sleep apnea (OR 2.58, 95% CI 1.47-4.92), and restless leg syndrome (RLS; OR 4.12, 95% CI 1.81-12.1) were significantly more common in patients with Parkinson's than in controls adjusting for age and sex with FDR £ 0.05. The prevalence of depression, anxiety, sleep apnea, and RLS were correlated, and these diseases formed part of a larger cluster of mood traits and sleep traits linked to PD. Exposures to pesticides (OR 1.87, 95% CI 1.37-2.6), head trauma (OR 2.33, 95% CI 1.51-3.73), and smoking (OR 0.57, 95% CI 0.43-0.75) were significantly associated with the disease consistent with previous studies. Vitamin supplementation with cholecalciferol (OR 2.18, 95% CI 1.4-3.45) and coenzyme Q10 (OR 2.98, 95% CI 1.89-4.92) was more commonly used by patients than controls. Cumulatively, 43% (398 of 933) of Parkinson's patients had at least one psychiatric or sleep disorder, compared to 21% (60 of 291) of healthy controls. Conclusions: 43% of Parkinson's patients seen at Harvard-affiliated teaching hospitals have depression, anxiety, and disordered sleep. This syndromic cluster of mood and sleep traits may be pathophysiologically linked and clinically important.

DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal.

Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression during cardiogenesis. Embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific transcriptional networks at two critical cardiogenic junctures: embryonic cardiogenesis, where it was particularly important for left ventricle-specific genes, and postnatal cardiomyocyte cell cycle withdrawal, with Dot1L mutants having more mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, H3K79me2 in specific regulatory elements also contributed to silencing genes usually not expressed in cardiomyocytes. These results reveal mechanisms by which DOT1L successively regulates left ventricle specification and cardiomyocyte cell cycle withdrawal.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.