Macrophage transplantation rescues RNASET2-deficientleukodystrophy by replacing deficient microglia in a zebrafish model

RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replace- ment through transplantation of adult whole kidney marrow–derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue— restoring rnaset2 mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy

A Dual (Brachial and Contralateral Femoral) Approach for Subintimal Angioplasty of Long Ilio-Femoral Occlusive Disease Including the Iliac Ostium

As techniques and device technology have improved, the success rates and long patency of ilio-femoral occlusive disease have also improved. In the case of extensive iliac occlusive disease, however, wire passage and handling remain a challenge due to the relatively weak guiding catheter backup support with the contralateral femoral approach. There has been no report on methods to overcome this problem. We performed a successful percutaneous translunimal angioplasty for long ilio-femoral occlusive disease including the iliac ostium by a dual approach including simultaneous brachial and contralateral femoral arteries for subintimal angioplasty

Modularity and Intrinsic Evolvability of Hsp90-Buffered Change

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an ‘evolutionary capacitor’, allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects—abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the ‘Hsp90 capacitor hypothesis’ and standard quantitative genetic models of threshold traits

Computational fluid dynamics modelling of residence times in vegetated stormwater ponds

Experimental data characterising dispersion within Typha latifolia were previously collected in a laboratory setting. This mixing characterisation was combined with previously proposed computational fluid dynamics modelling approaches to predict residence time distributions for vegetated stormwater treatment pond layouts (including a wetland) derived from Highways England design guidance. The results showed that the presence of vegetation resulted in residence times closer to plug flow, indicating significant improvements in stormwater treatment capability. The new modelling approach reflects changes in residence time due to mixing within the vegetation, but it also suggests that it is more important to include vegetation within the model in the correct location than it is to accurately characterise it. Estimates of hydraulic efficiency suggest that fully vegetated stormwater ponds such as wetlands should function well as a treatment device, but more typical ponds with clear water need to be designed to be between 50% and 100% larger than their nominal residence times would suggest when designed against treatment criteria

Paroxysmal Atrial Fibrillation Presenting as Acute Lower Limb Ischemia

An ischemic foot can be developed by acute arterial occlusion. Given proper treatment within critical time, the patient can avoid foot amputation and death. Early proper diagnosis and treatment by family physician at the initial clinical interviewing is important in saving the affected leg and the life. Thrombosis and embolism are the common causes of acute arterial occlusion. Thrombosis mostly arises from underlying cardiac disease such as arrhythmia, coronary artery disease and valvular heart disease while arterial occlusion by embolism can be shown on a narrowed artery related with systemic atherosclerosis. Because the treatment options depend on the underlying cause of the acute ischemic foot, it is important to identify the cause of acute ischemic foot. At this paper, we reported a case that the cause of acute ischemic foot of the patient proved paroxysmal atrial fibrillation after some diagnostic tests

Impaired Competence for Pretense in Children with Autism: Exploring Potential Cognitive Predictors.

Lack of pretense in children with autism has been explained by a number of theoretical explanations, including impaired mentalising, impaired response inhibition, and weak central coherence. This study aimed to empirically test each of these theories. Children with autism (n=60) were significantly impaired relative to controls (n=65) when interpreting pretense, thereby supporting a competence deficit hypothesis. They also showed impaired mentalising and response inhibition, but superior local processing indicating weak central coherence. Regression analyses revealed that mentalising significantly and independently predicted pretense. The results are interpreted as supporting the impaired mentalising theory and evidence against competing theories invoking impaired response inhibition or a local processing bias. The results of this study have important implications for treatment and intervention

Modeling the dynamics of glacial cycles

This article is concerned with the dynamics of glacial cycles observed in the geological record of the Pleistocene Epoch. It focuses on a conceptual model proposed by Maasch and Saltzman [J. Geophys. Res.,95, D2 (1990), pp. 1955-1963], which is based on physical arguments and emphasizes the role of atmospheric CO2 in the generation and persistence of periodic orbits (limit cycles). The model consists of three ordinary differential equations with four parameters for the anomalies of the total global ice mass, the atmospheric CO2 concentration, and the volume of the North Atlantic Deep Water (NADW). In this article, it is shown that a simplified two-dimensional symmetric version displays many of the essential features of the full model, including equilibrium states, limit cycles, their basic bifurcations, and a Bogdanov-Takens point that serves as an organizing center for the local and global dynamics. Also, symmetry breaking splits the Bogdanov-Takens point into two, with different local dynamics in their neighborhoods

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure

Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems

A generic mechanism - networked buffering - is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems. \ud \u

Metagenomic Comparison of Two Thiomicrospira Lineages Inhabiting Contrasting Deep-Sea Hydrothermal Environments

Background: The most widespread bacteria in oxic zones of carbonate chimneys at the serpentinite-hosted Lost City hydrothermal field, Mid-Atlantic Ridge, belong to the Thiomicrospira group of sulfur-oxidizing chemolithoautotrophs. It is unclear why Thiomicrospira-like organisms thrive in these chimneys considering that Lost City hydrothermal fluids are notably lacking in hydrogen sulfide and carbon dioxide. Methodology/Principal Findings: Here we describe metagenomic sequences obtained from a Lost City carbonate chimney that are highly similar to the genome of Thiomicrospira crunogena XCL-2, an isolate from a basalt-hosted hydrothermal vent in the Pacific Ocean. Even though T. crunogena and Lost City Thiomicrospira inhabit different types of hydrothermal systems in different oceans, their genomic contents are highly similar. For example, sequences encoding the sulfur oxidation and carbon fixation pathways (including a carbon concentration mechanism) of T. crunogena are also present in the Lost City metagenome. Comparative genomic analyses also revealed substantial genomic changes that must have occurred since the divergence of the two lineages, including large genomic rearrangements, gene fusion events, a prophage insertion, and transposase activity. Conclusions/Significance: Our results show significant genomic similarity between Thiomicrospira organisms inhabiting different kinds of hydrothermal systems in different oceans, suggesting that these organisms are widespread and highl