We present an unprecedented set of high-resolution climate simulations, consisting of a 500-year pre-industrial control simulation and a 250-year historical and future climate simulation from 1850 to 2100. A high-resolution configuration of the Community Earth System Model version 1.3 (CESM1.3) is used for the simulations with a nominal horizontal resolution of 0.25°for the atmosphere and land models and 0.1°for the ocean and sea-ice models. At these resolutions, the model permits tropical cyclones and ocean mesoscale eddies, allowing interactions between these synoptic and mesoscale phenomena with large-scale circulations. An overview of the results from these simulations is provided with a focus on model drift, mean climate, internal modes of variability, representation of the historical and future climates, and extreme events. Comparisons are made to solutions from an identical set of simulations using the standard resolution (nominal 1°) CESM1.3 and to available observations for the historical period to address some key scientific questions concerning the impact and benefit of increasing model horizontal resolution in climate simulations. An emerging prominent feature of the high-resolution pre-industrial simulation is the intermittent occurrence of polynyas in the Weddell Sea and its interaction with an Interdecadal Pacific Oscillation. Overall, high-resolution simulations show significant improvements in representing global mean temperature changes, seasonal cycle of sea-surface temperature and mixed layer depth, extreme events and in relationships between extreme events and climate modes. Plain Language Summary Although the current generation of climate models has demonstrated high fidelity in simulating and projecting global temperature change, these models show large uncertainties when it comes to questions concerning how rising global temperatures will impact local weather conditions. This is because the resolution (~100 km) at which the majority of climate models simulate the climate is not fine enough to resolve these small-scale regional features. Conducting long-term (multi-centuries) high-resolution (~10 km) climate simulations has been a great challenge for the research community due to the extremely high computational demands. Through international

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

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