Preliminary Report of the AMS analysis of tsunami deposits in Tohoku – Japan – 18 th to the 21 st Century

Sedimentary records of tsunamis are a precious tool to assess the occurrence of past events, as attested by an abundant literature, which has seen a particular 'boom' in the aftermath of the 2004 Indian Ocean tsunami and the 2011 Tohoku tsunami. Despite an extensive literature, there is very little to no understanding of the role that the changing coastal environment is playing on the record of a tsunami, and for a given location, it is still unclear whether the largest tsunamis leave the largest amount of deposits. To research this question, the present study took place in Japan, in the Tohoku Region at Agawa-pond, because the pond act as a sediment trap. Using a sediment-slicer, a 1 m thick deposit was retrieved, from which 4 tsunami sequences were identified, including the latest 2011 tsunami. Using a series of sedimentary proxies: the AMS (Anisotropy of Magnetic Susceptibility), grain size analysis, quartz morphoscopy (morphology and surface characteristics) and the analysis of microfossils, disparities between the tsunami deposits were identified and most importantly a clear thinning of the tsunami deposit towards the top. Provided the present evidences, the authors discuss that the upward fining is due to at least two components that are seldom assessed in tsunami research (1) a modification of the depositional environment, with the progressive anthropization of the coast, providing less sediments to remobilize; and (2) a progressive filling of the Agawa pond, which progressively loses its ability to trap tsunami materials

Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach.

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program

Hard Habits to Break: Investigating Coastal Resource Utilisations and Management Systems in Sulawesi, Indonesia.

This research investigates the paradox that many coastal communities in developing countries are resource rich but income poor. Another aspect of this paradox is the belief that local communities possess traditional knowledge that respects nature. This belief contrasts the fact that major tropical coastal ecosystems, namely coral reefs and mangroves, are being destroyed at rapid and increasing rates, in many cases by the people whose livelihoods depend on them. These paradoxical circumstances lead to a central question: if the sustainability of coastal resources is vital for the livelihood of local communities, why are these resources being degraded, often to the point of complete destruction? This study explores the motives and consequences of destructive methods of coastal resource utilisation and examines the potential for sustainable livelihoods based on coastal resources currently under threat from destructive use patterns. The analysis is based on a field study conducted in 2006 and 2008 in eleven sites around the island of Sulawesi, Indonesia. This area is characterised by great biodiversity, including one of the highest marine biodiversities in the Asia-Pacific region. Coral and mangrove ecosystem resource use was found to be driven by different processes and activities; hence the destructive practices impacting both ecosystems were also different. Blast and poison fishing were the most widespread destructive resource use methods found for coral reefs whereas large-scale habitat conversion was responsible for mangrove ecosystem reduction. In the field both resources were found to be under enormous anthropogenic pressures, with published data suggesting that only 5.8% of Indonesian coral reefs are currently in excellent condition and only 38% of mangrove cover remaining in Sulawesi relative to that of 25 years ago. The dynamics of these coastal resources, and of their destruction, are classic examples of the ’tragedy of the commons’. Research findings further indicate that formal institutions tasked with managing these resources have not been able to promote their effective conservation. An array of competing demands and conflicting interests, coupled with inefficient institutional arrangements and under-investment, have rendered inadequate many resource management efforts, including the externally-imposed concepts, allowing destructive patterns of resource utilization to persist. Local communities are disempowered when confronted with (1) the intricate network of destructive-fishing actors targeting coral reefs, or (2) large company-government bureaucracy collusions allowing mangrove conversion. The existence of this collusive network must be considered in any effort to address problems of effective management. Empirical insights suggest that conservation at local level has to face the challenges of market-driven resource extraction at a global scale. Only when a coastal community manages to overcome the dilemma in managing common-pool resource, conservation measures can be implemented and a degree of sustainability attained. Findings from this research have important implications for the discourses on coastal resource policy and research. This research advances the discussions to the area where the core of conflict of interests among stakeholders took place, and yet has rarely been addressed previously. The synthesis from this study provides a strong basis to understand the nature of asymmetric relations amongst the resource stakeholders, and therefore will help in generating effective policies for a fairer coastal resource management regime

The 21 February 2005, catastrophic waste avalanche at Leuwigajah dumpsite, Bandung, Indonesia

International audienceOn 21 February 2005 the Leuwigajah dumpsite, Bandung (Java, Indonesia) was affected by a largeslide after heavy rainfalls. Second deadliest waste slide in history, it buried 71 houses and killed 143 people.Amongst the contemporary disastrous events of this type, only a few have been documented. We explored failurepreconditions, triggering mechanisms and local context that conducted to this disaster. We carried on four fieldinvestigations on the site. A series of aerial photographs were acquired and completed by topographical measureson the ground. The morphology of the slide and its trajectory were reconstructed. To constrain the movementcondition, we studied the internal structure of the source area and realized surveys among stakeholders of thedumpsite and citizen.Results: 2.7 10 6 m3 of waste materials spread 1000 m from the source in a rice field with an average thickness of10 m. The material displays a preferential fabric parallel to the previous topography. Numerous internal slip surfaces,underlined by plastic bags explain the low friction coefficient. The presence of methane within the waste dumpwas responsible for explosions prior to sliding and for the fire that affects whole sliding mass.Conclusions: Resulting of a combination of heavy rainfall and consecutive explosions due to biogas suddenrelease, this disaster was predictable in reason ofi) a front slope of the dump of about 100% before the failure;ii) a poor dumpsite management;iii) the extreme vulnerability of the marginalized scavengers living at risk at the foot of the instable dump

Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency

Background Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Methods and results Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Conclusions Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency

APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex

Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease

Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

Importance Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. Design, Setting, and Participants Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London, United Kingdom, between January 1, 2017, and January 30, 2019, because of onset of disease early in life, family history, and/or complex neuroinflammatory phenotypes. Main Outcomes and Measures The main outcome was the percentage of individuals with definitive molecular diagnoses, variant classification, and clinical phenotyping of patients with pathogenic variants identified using the NIP panel. The NIP panel was initially validated in 16 patients with known genetic diagnoses. Results The NIP was both sensitive (95%) and specific (100%) for detection of known mutations, including gene deletions, copy number variants, small insertions and deletions, and somatic mosaicism with allele fraction as low as 3%. Prospective testing of 60 patients (30 [50%] male; median [range] age, 9.8 [0.8-20] years) presenting with heterogeneous neuroinflammatory phenotypes revealed at least 1 class 5 (clearly pathogenic) variant in 9 of 60 patients (15%); 18 of 60 patients (30%) had at least 1 class 4 (likely pathogenic) variant. Overall, a definitive molecular diagnosis was established in 12 of 60 patients (20%). Conclusions and Relevance The NIP was associated with molecular diagnosis in this cohort and complemented routine laboratory and radiological workup of patients with neuroinflammation. Unexpected genotype-phenotype associations in patients with pathogenic variants deviating from the classic phenotype were identified. Obtaining an accurate molecular diagnosis in a timely fashion informed patient management, including successful targeted treatment in some instances and early institution of hematopoietic stem cell transplantation in other

A cell-permeable tool for analysing APP intracellular domain function and manipulation of PIKfyve activity

The mechanisms for regulating PIKfyve complex activity are currently emerging. The PIKfyve complex, consisting of the phosphoinositide kinase PIKfyve (also known as FAB1), VAC14 and FIG4, is required for the production of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). PIKfyve function is required for homeostasis of the endo/lysosomal system and is crucially implicated in neuronal function and integrity, as loss of function mutations in the PIKfyve complex lead to neurodegeneration in mouse models and human patients. Our recent work has shown that the intracellular domain of the Amyloid Precursor Protein (APP), a molecule central to the aetiology of Alzheimer's disease binds to VAC14 and enhances PIKfyve function. Here we utilise this recent advance to create an easy-to-use tool for increasing PIKfyve activity in cells. We fused APP's intracellular domain (AICD) to the HIV TAT domain, a cell permeable peptide allowing proteins to penetrate cells. The resultant TAT-AICD fusion protein is cell permeable and triggers an increase of PI(3,5)P2. Using the PI(3,5)P2 specific GFP-ML1Nx2 probe we show that cell-permeable AICD alters PI(3,5)P2 dynamics. TAT-AICD also provides partial protection from pharmacological inhibition of PIKfyve. All three lines of evidence show that the APP intracellular domain activates the PIKfyve complex in cells, a finding that is important for our understanding of the mechanism of neurodegeneration in Alzheimer's disease

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin B6-Dependent Epilepsy

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms which are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP; by compounds accumulating as a result of inborn errors of other pathways or by ingested small molecules. Whole exome sequencing of 2 children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial) (PROSC), a PLPbinding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified 4 additional children with biallelic PROSC mutations. Pretreatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant, lacking the PROSC homologue (ΔYggS) is pyridoxine-sensitive; complementation with human PROSC restored growth whilst hPROSC bearing p.Leu175Pro, p.Arg241Gln and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells - how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Whilst the mechanism involved is not fully understood our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions