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Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD.

Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in the or genes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption of or in mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues. and mice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carrying significantly improved pathology in mice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the human gene in mice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between - and -based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targeting mutations in Lafora disease.

This paper presents field investigations and numerical analyses of the landslide, affecting Malin village of Pune district in Maharashtra, India. The Malin village was wiped out due to Malin landslide, occurred on July 30, 2014; however, only a primary school and few houses remained safe during the event, and mass of the people buried in debris of slide. To study the causes of the event, field study has been carried out. Representative samples of slope-forming geomaterials (soil/rock) have been collected at three locations of the hill viz. L1 (bottom of the hill), L2 (middle of the hill) and L3 (top of the hill) along with massive and vesicular basalt for the determination of the geotechnical properties in the laboratory. The estimated geotechnical properties have been used for numerical modeling of the hill slope that has been performed to calculate factor of safety, maximum displacement, displacement direction and accumulated maximum shear strain with the help of numerical programs based on limit equilibrium method and finite element method approaches, respectively. This study shows that the hill slope was unstable with FoS < 1 and prone to failure. It was triggered by various man-made and natural factors like heavy rainfall, unscientific construction activities at the top of the hill and along the hill, unplanned cultivations and lack of drainage system. Also, the results of the numerical analysis can be successfully implemented to minimize/reduce impact and frequency of landslide in the area of similar morphology.

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malin KO ) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase‐inactive laforin rescues the laforin‐deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin‐ or malin‐deficient mouse lines expressing phosphatase‐inactive laforin. We find that: (i) in laforin‐deficient mice, phosphatase‐inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin‐deficient mice, phosphatase‐inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin‐dependent fashion, and that loss of this control underlies LD. Synopsis Abnormal glycogen chain length distribution strictly correlates with glycogen accumulation and Lafora body (LB) formation in Lafora disease (LD). Against current hypotheses, neither glycogen hyperphosphorylation nor deficient general autophagy are prerequisites of the disease. By methodological advances chain length distribution (CLD) and phosphorylation of glycogen were determined in brain tissue confirming that overexpressed wild‐type laforin corrects the molecular phenotype in an LD mouse model. Phosphatase‐inactive laforin does not correct glycogen hyperphosphorylation in malin‐ and laforin‐deficient mice and prevents abnormal CLD and accumulation of glycogen as well as LB formation. Prevention of abnormal chain length distribution and accumulation of brain glycogen as well as LB formation by phosphatase‐inactive laforin is malin‐dependent as no rescue occurs in malin‐deficient mice. General impairment of autophagy is not necessary in LD as markers of autophagic flux are not changed in any of our LD mouse models. Laforin controls glycogen chain length distribution in a malin‐dependent fashion, and lack of this control leads to abnormal glycogen structure, glycogen accumulation, LB formation, hence to LD. Graphical Abstract Abnormal glycogen chain length distribution strictly correlates with glycogen accumulation and Lafora body (LB) formation in Lafora disease (LD). Against current hypotheses, neither glycogen hyperphosphorylation nor deficient general autophagy are prerequisites of the disease.

High biological productivity and the efficient export of carbon-enriched subsurface waters to the open ocean via the continental shelf pump mechanism make mid-latitude continental shelves like the northwest European shelf (NWES) significant sinks for atmospheric CO 2 . Tidal forcing, as one of the regionally dominant physical forcing mechanisms, regulates the mixing-stratification status of the water column that acts as a major control for biological productivity on the NWES. Because of the complexity of the shelf system and the spatial heterogeneity of tidal impacts, there still are large knowledge gaps on the role of tides for the magnitude and variability of biological carbon fixation on the NWES. In our study, we utilize the flexible cross-scale modeling capabilities of the novel coupled hydrodynamic–biogeochemical modeling system SCHISM–ECOSMO to quantify the tidal impacts on primary production on the NWES. We assess the impact of both the barotropic tide and the kilometrical-scale internal tide field explicitly resolved in this study by comparing simulated hindcasts with and without tidal forcing. Our results suggest that tidal forcing increases biological productivity on the NWES and that around 16% (14.47 Mt C) of annual mean primary production on the shelf is related to tidal forcing. Vertical mixing of nutrients by the barotropic tide particularly invigorates primary production in tidal frontal regions, whereas resuspension and mixing of particulate organic matter by tides locally hinders primary production in shallow permanently mixed regions. The tidal impact on primary production is generally low in deep central and outer shelf areas except for the southwestern Celtic Sea, where tidal forcing substantially increases annual mean primary production by 25% (1.53 Mt C). Tide-generated vertical mixing of nutrients across the pycnocline, largely attributed to the internal tide field, explains one-fifth of the tidal response of summer NPP in the southwestern Celtic Sea. Our results therefore suggest that the tidal NPP response in the southwestern Celtic Sea is caused by a combination of processes likely including tide-induced lateral on-shelf transport of nutrients. The tidally enhanced turbulent mixing of nutrients fuels new production in the seasonally stratified parts of the NWES, which may impact the air–sea CO 2 exchange on the shelf.

The H component of the magnetic field measured at the terrestrial surface presents several periodic signals caused by changes in the ring current that flows within the terrestrial magnetosphere. One of the most important of them is associated to the phenomenon known as the Semiannual Anomaly which produces two significant minima during the equinoxes. This phenomenon is global, i.e., every observatory registers a similar effect independently of the hemisphere where it is located. A second important signal is due to the phenomenon known as the Annual Anomaly that produces significant different values for solstices, with a particular feature: the effect depends on the hemisphere where the observatory is located, with maximum during local summer. In spite of the time since their discoveries (more than a hundred years ago) the physical processes behind them are still open to discussion. In this work we present a new physical interpretation for the combined effects of both anomalies. The main concept developed is that along the year the shape of the magnetospheric cavities within which the ring current flows is deformed according to the geometric configuration between the solar wind and the magnetosphere. Key Points This article contains an interpretation of the annual and semiannual anomalies It extends a previous idea for solar wind‐magnetosphere coupling mechanism It is based on long term data series from more than 100 geomag. observatories

A poem is presented.

Lafora disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b−/−m ice, we observed an increase in a modified form of peroxiredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD.