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This is the second part of a three-part paper on North American climate in phase 5 of the Coupled Model Intercomparison Project (CMIP5) that evaluates the twentieth-century simulations of intraseasonal to multidecadal variability and teleconnections with North American climate. Overall, the multimodel ensemble does reasonably well at reproducing observed variability in several aspects, but it does less well at capturing observed teleconnections, with implications for future projections examined in part three of this paper. In terms of intraseasonal variability, almost half of the models examined can reproduce observed variability in the eastern Pacific and most models capture the midsummer drought over Central America. The multimodel mean replicates the density of traveling tropical synoptic-scale disturbances but with large spread among the models. On the other hand, the coarse resolution of the models means that tropical cyclone frequencies are underpredicted in the Atlantic and eastern North Pacific. The frequency and mean amplitude of ENSO are generally well reproduced, although teleconnections with North American climate are widely varying among models and only a few models can reproduce the east and central Pacific types of ENSO and connections with U.S. winter temperatures. The models capture the spatial pattern of Pacific decadal oscillation (PDO) variability and its influence on continental temperature and West Coast precipitation but less well for the wintertime precipitation. The spatial representation of the Atlantic multidecadal oscillation (AMO) is reasonable, but the magnitude of SST anomalies and teleconnections are poorly reproduced. Multidecadal trends such as the warming hole over the central-southeastern United States and precipitation increases are not replicated by the models, suggesting that observed changes are linked to natural variability. © 2013 American Meteorological Society.

This study examines the possible relationship between predictions of weekly and biweekly averages of 10-m winds at 3-week lead time and interannual variability over the western Pacific and Indian Ocean (WP-IO) using Climate Forecast System version 2 (CFSv2) reforecasts for period 1979–2008. There is a large temporal correlation between forecasts and reanalyses for zonal, meridional, and total wind magnitudes at 10 m over most of WP-IO for the average of weeks 1 and 2 (W1 and W2) in reforecasts initialized in January (JIR) and May (MIR). The model has some correlations that exceed 95% confidence in some portions of WP-IO in week 3 (W3) but no skill in week 4 (W4) over most of the region. The model depicts prediction skill in the 14-day average of weeks 3–4 (W3–4) over portions of WP-IO, similar to the level of skill in W3. The amplitude of interannual variability (IAV) for 10-m winds in W1 of JIR and MIR is close to that in reanalyses. As lead time increases, the amplitude of IAV of 10-m winds gradually decreases over WP-IO in reforecasts, in contrast to behavior in reanalyses. The amplitude of IAV of predicted 10-m winds in W3–4 over WP-IO is equivalent to that in W3 and W4 in reforecasts. In contrast, the amplitude of IAV in W3–4 in January and May of the reanalysis is much smaller than IAV of W3 and W4. Therefore, one of the possible causes for prediction skill in W3–4 over subregions of WP-IO is due to a reduction of IAV bias in W3–4 in comparison to IAV bias in W3 and W4. [ABSTRACT FROM AUTHOR]

Background: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown., Methods: We compared changes in NMJs and activity-dependent signalling pathways in HSA LR and Mbnl1 ΔE3/ΔE3 mice, two established mouse models of DM1., Results: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1 ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation., Conclusions: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients., (© 2024. The Author(s).)

Curbing the worst impacts of global climate change will require rapidly transitioning away from fossil fuel across all sectors of the economy. This transition will also yield substantial co-benefits, as fossil fuel combustion releases harmful pollutants into the air. In this article, we present an analysis of the co-benefits to health and health-care costs related from decarbonization of the power sector, using the Virginia Clean Economy Act (VCEA) as a case study. Using a model that combines a source-response matrix approach to pollutant concentration modelling tied to health impact functions, our analysis shows that, by 2045, the VCEA will save up to 32 lives per year across the state, and avoid up to $355 million per year in health-related costs. Fossil-fuel free generation will also help the most disadvantaged communities, as counties in the highest poverty rate quintile also avoid the most pollutant-related deaths., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3' UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Mouse models of dysferlinopathies are valuable tools with which to investigate the pathomechanisms underlying these diseases and to test novel therapeutic strategies. One such mouse model is the Dysf (tm1Kcam) strain, which was generated using a targeting vector to replace a 12-kb region of the dysferlin gene and which features a progressive muscular dystrophy. A prerequisite for successful animal studies using genetic mouse models is an accurate genotyping protocol. Unfortunately, the lack of robustness of currently available genotyping protocols for the Dysf (tm1Kcam) mouse has prevented efficient colony management. Initial attempts to improve the genotyping protocol based on the published genomic structure failed. These difficulties led us to analyze the targeted locus of the dysferlin gene of the Dysf (tm1Kcam) mouse in greater detail., Methods: In this study we resequenced and analyzed the targeted locus of the Dysf (tm1Kcam) mouse and developed a novel PCR protocol for genotyping., Results: We found that instead of a deletion, the dysferlin locus in the Dysf (tm1Kcam) mouse carries a targeted insertion. This genetic characterization enabled us to establish a reliable method for genotyping of the Dysf (tm1Kcam) mouse, and thus has made efficient colony management possible., Conclusion: Our work will make the Dysf (tm1Kcam) mouse model more attractive for animal studies of dysferlinopathies.

Muscular dystrophies are classically subdivided according to their clinical phenotype, and were historically defined as progressive myopathies in which muscle biopsies demonstrate muscle fibre necrosis and regeneration, as well as replacement of muscle fibres by adipose and connective tissue. In recent years, great progress has been made in identifying the genetic basis of many myopathies, thereby presenting opportunities to develop therapeutic strategies that act on specific molecular pathomechanisms. The different therapeutic strategies and their molecular targets will be reviewed.

Dysferlin is a transmembrane protein implicated in surface membrane repair of muscle cells. Mutations in dysferlin cause the progressive muscular dystrophies Miyoshi myopathy, limb girdle muscular dystrophy 2B, and distal anterior compartment myopathy. Dysferlinopathies are inherited in an autosomal recessive manner, and many patients with this disease harbor mis-sense mutations in at least one of their two pathogenic DYSF alleles. These patients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degraded by the cellular quality control system. We reasoned that mis-sense mutated dysferlin, if salvaged from degradation, might be biologically functional. We used a dysferlin-deficient human myoblast culture harboring the common R555W mis-sense allele and a DYSF-null allele, as well as control human myoblast cultures harboring either two wild-type or two null alleles. We measured dysferlin protein and mRNA levels, resealing kinetics of laser-induced plasmalemmal wounds, myotube formation, and cellular viability after treatment of the human myoblast cultures with the proteasome inhibitors lactacystin or bortezomib (Velcade). We show that endogenous R555W mis-sense mutated dysferlin is degraded by the proteasomal system. Inhibition of the proteasome by lactacystin or Velcade increases the levels of R555W mis-sense mutated dysferlin. This salvaged protein is functional as it restores plasma membrane resealing in patient-derived myoblasts and reverses their deficit in myotube formation. Bortezomib and lactacystin did not cause cellular toxicity at the regimen used. Our results raise the possibility that inhibition of the degradation pathway of mis-sense mutated dysferlin could be used as a therapeutic strategy for patients harboring certain dysferlin mis-sense mutations.

Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson's disease, tauopathies, Huntington's disease, and familial encephalopathy with neuroserpin inclusion bodies. The latter is an autosomal dominant disorder caused by point mutations in neuroserpin resulting in its destabilization. Mutant neuroserpin polymerizes and forms intracellular aggregates that eventually lead to neurodegeneration. We generated genetically modified mice expressing the late-onset S49P-Syracuse or the early-onset S52R-Portland mutation of neuroserpin in central nervous system neurons. Mice exhibited morphological, biochemical, and clinical features resembling those found in the human disease. Analysis of brains revealed large intraneuronal inclusions composed exclusively of mutant neuroserpin, accumulating long before the development of clinical symptoms in a time-dependent manner. Clinical symptoms and amount of neuroserpin inclusions correlated with the predicted instability of the protein. The presence of inclusion bodies in subclinical mice indicates that in humans the prevalence of the disease could be higher than anticipated. In addition to shedding light on the pathophysiology of the human disorder, these mice provide an excellent model to study mechanisms of neurodegeneration or establish novel therapies for familial encephalopathy with neuroserpin inclusion bodies and other neurodegenerative diseases with intracellular protein deposition.

We identified a direct interaction between the neuronal transmembrane protein calsyntenin-1 and the light chain of Kinesin-1 (KLC1). GST pulldowns demonstrated that two highly conserved segments in the cytoplasmic domain of calsyntenin-1 mediate binding to the tetratricopeptide repeats of KLC1. A complex containing calsyntenin-1 and the Kinesin-1 motor was isolated from developing mouse brain and immunoelectron microscopy located calsyntenin-1 in association with tubulovesicular organelles in axonal fiber tracts. In primary neuronal cultures, calsyntenin-1-containing organelles were aligned along microtubules and partially colocalized with Kinesin-1. Using live imaging, we showed that these organelles are transported along axons with a velocity and processivity typical for fast axonal transport. Point mutations in the two kinesin-binding segments of calsyntenin-1 significantly reduced binding to KLC1 in vitro, and vesicles bearing mutated calsyntenin-1 exhibited a markedly altered anterograde axonal transport. In summary, our results indicate that calsyntenin-1 links a certain type of vesicular and tubulovesicular organelles to the Kinesin-1 motor.

Neuroserpin is an axonally secreted serine protease inhibitor expressed in the nervous system that protects neurons from ischemia-induced apoptosis. Mutant neuroserpin forms have been found polymerized in inclusion bodies in a familial autosomal encephalopathy causing dementia, or associated with epilepsy. Regulation of neuroserpin expression is mostly unknown. Here we demonstrate that neuroserpin mRNA and the RNA-binding protein HuD are co-expressed in the rat central nervous system, and that HuD binds neuroserpin mRNA in vitro with high affinity. Gel-shift, supershift and T1 RNase assays revealed three HuD-binding sequences in the 3'-untranslated region (3'-UTR) of neuroserpin mRNA. They are AU-rich and 20, 51 and 19 nt in length. HuD binding to neuroserpin mRNA was also demonstrated in extracts of PC12 pheochromocytoma cells. Additionally, ectopic expression of increasing amounts of HuD in these cells results in the accumulation of neuroserpin 3'-UTR mRNA. Furthermore, stably transfected PC12 cells over-expressing HuD contain increased levels of both neuroserpin mRNAs (3.0 and 1.6 kb) and protein. Our results indicate that HuD stabilizes neuroserpin mRNA by binding to specific AU-rich sequences in its 3'-UTR, which prolongs the mRNA lifetime and increases protein level.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.