The ANTARES deep-sea neutrino telescope comprises a three-dimensional array of photomultipliers to detect the Cherenkov light induced by upgoing relativistic charged particles originating from ...neutrino interactions in the vicinity of the detector. The large scattering length of light in the deep sea facilitates an angular resolution of a few tenths of a degree for neutrino energies exceeding 10
TeV. In order to achieve this optimal performance, the time calibration procedures should ensure a relative time calibration between the photomultipliers at the level of ∼1
ns. The methods developed to attain this level of precision are described.
Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the USA and other developed countries worldwide. Following the initial mechanical insult, the brain's primary innate ...immune effector, microglia, initiate inflammatory signaling cascades and pathophysiological responses that can lead to chronic neuroinflammation and neurodegenerative sequelae. The p38alpha MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions. Therefore, we tested here whether microglia p38alpha contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38alpha in microglia using a CX3CR1 Cre-lox system, subjected the p38alpha knockout and wild-type mice to a controlled cortical impact TBI, and measured inflammatory responses at acute (1-day) and subacute (7-day) post-injury time points. We found that deletion of p38alpha in microglia only was sufficient to attenuate multiple pro-inflammatory responses following TBI, notably reducing pro-inflammatory cytokine/chemokine production and recruitment of inflammatory monocytes into the brain and preventing the persistent microglial morphological activation. These data provide strong evidence supporting a role for microglial p38alpha in propagation of a chronic and potentially neurotoxic pro-inflammatory environment in the brain following TBI. Keywords: TBI, p38alpha, Kinase, Microglia, Monocytes, Cytokines, Chemokines, Neuroinflammation, Knockout
Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated ...induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature. Epigenetic reprogramming was therefore not sufficient to eliminate leukemic behavior. This approach also allowed us to study the properties of distinct AML subclones, including differential drug susceptibilities of KRAS mutant and wild-type cells, and predict relapse based on increased cytarabine resistance of a KRAS wild-type subclone. Overall, our findings illustrate the value of AML-iPSCs for investigating the mechanistic basis and clonal properties of human AML.
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•Human AML cells can be reprogrammed into induced pluripotent stem cells (AML-iPSCs)•Reprogramming resets epigenetic status but retains cytogenetic and mutational abnormalities•Leukemic behavior and methylation are reacquired upon hematopoietic differentiation•AML iPSCs enable investigation of genetic subclones and clonal relapse patterns
Chao et al. show that MLL-rearranged AML patient cells can be reprogrammed into induced pluripotent stem cells (iPSCs). These cells reacquire leukemic properties and associated methylation/gene expression patterns after hematopoietic differentiation and provide a means to study the differential properties of specific disease subclones.
Background
Genome wide association studies have identified single nucleotide polymorphisms (SNPs) within INPP5D (Phosphatidylinositol‐3,4,5‐trisphosphate 5‐phosphatase 1), the gene encoding SHIP1, ...that are strongly associated with Alzheimer’s Disease (AD) risk. INPP5D is expressed in the brain, mostly in microglia and can include up to 27 exons. In the brain, INPP5D encodes several isoforms. The full‐length 27 exon isoform encodes an amino‐terminal SH2 domain followed by the phosphatase domain. Truncated isoforms lacking the SH2 domain begin from internal transcription start sites. Whether these isoforms are relevant to the SNP’s actions in AD is unclear.
Method
RNA from AD and non‐AD anterior cingulate human brain samples was analyzed via quantitative polymerase chain reaction for the copy number of each isoform relative to INPP5D standard curves. The AD‐associated SNPs were identified using TaqMan (ABI). Isoform expression results were analyzed as a function of microglial gene expression (ITGAM and AIF1), total INPP5D expression, AD status, and SNP status. We also evaluated INPP5D expression as a function of SNPs by using data from GTEX. Single cell RNAseq was performed on APP/PS1 mice to understand the relationship between INPP5D expression and microglial activation. Lastly, we performed SHIP1 immunocytochemistry on AD and non‐AD human brain slices.
Result
Expression of each INPP5D isoform was strongly correlated with microglial gene expression and showed an increase with AD neuropathology. None of the isoforms showed a significant association with AD‐associated SNPs. In contrast, GTEX analysis suggested a modest but significant association between rs35349669 and INPP5D expression; the minor T allele, which is associated with increased AD risk, was associated with decreased INPP5D expression in spleen and blood. INPP5D was expressed at equivalent levels in microglia, regardless of homeostatic versus disease‐associated microglial status. Immunocytochemistry supported that SHIP1 expression was restricted to microglia in the human brain.
Conclusion
INPP5D is expressed as multiple isoforms, and expression of these isoforms is increased with AD neuropathology. INPP5D expression does not change in disease‐associated microglia. The mechanisms whereby AD genetics influence INPP5D expression is not clear, but the rs35349669 allele that increases AD risk may be associated with a decrease in INPP5D expression.
We conducted a retrospective study in a general hospital in Buenos Aires, Argentina (2009-2015) aimed at evaluating outcomes in HIV-infected pregnant women (HIPW), who were prescribed raltegravir ...(RAL)- containing antiretroviral therapy (ART). A total of 239 HIPW were enrolled in our study; among them 31 received RAL (12.9%) at different clinical stages: i) intensification (INS): addition of RAL to current ART because of detectable antepartum viral load, 13 (41.9%); ii) late presenter (LP): standard ART + RAL as fourth drug, 15 (48.4%); iii) treatment of resistant-HIV: 3 (9.7%). Median gestational age at RAL initiation was 34 weeks and median exposure was 30 days. In INS-group, median viral load (VL) decrease was 1.48 log10. In LPgroup, median VL decline was 2.15 log10. No clinical adverse events or maternal intolerance attributable to RAL were observed. Elective cesarean section was done in 51.7%; mild elevation of transaminases was observed in 35% of neonates. No vertical transmission was documented.
Passive wind dispersal is one of the major mechanisms through which organisms disperse and colonise new areas. The detailed understanding of which factors affect this process may help to preserve its ...efficiency for the future. Despite its interest, the analysis of factors affecting the aeroplankton dispersal in urban environments is rare in literature. We sampled the aeroplankton community uninterruptedly every 4 hours from 17 May to 19 September 2011 in the urban garden of Parco d'Orléans, within the campus of the University of Palermo (Sicily). Sampling was performed by means of a Johnson-Taylor suction trap with automatised sample storing. Weather variables were recorded at a local meteorological station. Overall, 11,739 insects were caught during the present study, about 60% of which belonged to the order Hymenoptera, with particular presence of families Agaonidae and Formicidae. The suction trap also captured specimens of very small size, and in some cases, species caught resulted in new records for Italy. Composition and abundance of the aeroplankton community was influenced by alternation of day/night, as well as by daily fluctuations of climatic variables, for example fluctuating temperature. The taxonomic diversity of the samples was also studied, and was higher when the wind blew from the nearby green area. Our findings confirm that passive transport of arthropods strictly depends on weather conditions, and that the presence of natural areas within the urban environment significantly contributes to raising aeroplankton diversity, eventually fuelling overall biodiversity at a local scale.
In 2016, the research ice-breaker Polarstern surveyed the submerged peaks of the permanently ice-covered Langseth Ridge, a tectonic feature comprising the Karasik seamount and two deeper seamount ...peaks, abutting the Gakkel ultra-slow spreading ridge (87°N 62°E to 85.5°N 57.4°E)1. A towed marine camera sled and a hybrid remotely operated vehicle revealed these peaks to be covered by a dense demosponge community, at first glance reminiscent of North Atlantic Geodia grounds (sensu2). Sponges were observed on top of a thick layer of spicule mat (Figure 1 and Video S1), intermixed with underlying layers of empty siboglinid tubes and bivalve shells, a substrate covering almost the entire seafloor. We observed trails of densely interwoven spicules connected directly to the underside or lower flanks of sponge individuals (Figure 1), suggesting these trails are traces of motile sponges. This is the first time abundant sponge trails have been observed in situ and attributed to sponge mobility. Given the low primary production in this permanently ice-covered region, these trails may relate to feeding behavior and/or a strategy for dispersal of juveniles. Such trails may remain visible for long periods given the regionally low sedimentation rates.
In 2016 the icebreaker RV Polarstern investigated the ice-covered Langseth Ridge seamounts at 86.5°N with towed cameras and robots. Here, Morganti et al. describe the discovery of one of the densest sponge communities known to date in a highly oligotrophic region.
Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development ...of dementia after TBI. Age is a significant factor in both the risk of and the incidence of acquired brain injury. TBI-induced inflammatory response is associated with activation of brain resident microglia and accumulation of infiltrating monocytes, which plays a pivotal role in chronic neurodegeneration and loss of neurological function after TBI. Despite the extensive clinical evidence implicating neuroinflammation with the TBI-related sequelae, the specific role of these different myeloid cells and the influence of age on TBI-initiated innate immune response remain unknown and poorly studied.
We used gene profiling and pathway analysis to define the effect of age on inflammatory response at the time of injury. The recruitment of peripheral CCR2(+) macrophages was delineated using the CX3CR1 (GFP/+) CCR2 (RFP/+) reporter mouse. These responses were examined in the context of CCR2/5 antagonism using cenicriviroc.
Unsupervised gene clustering and pathway analysis revealed that age predisposes exacerbated inflammatory response related to the recruitment and activation of peripheral monocytes to the injured brain. Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2(+) macrophages after TBI compared to young animals. Exaggerated recruitment of this population of cells was associated with an augmented inflammatory response in the aged TBI animals. Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals.
Importantly, these findings demonstrate that peripheral monocytes play a non-redundant and contributing role to the etiology of trauma-induced inflammatory sequelae in the aged brain.
The chemokine CX3CL1/fractalkine is expressed by neurons as a transmembrane-anchored protein that can be cleaved to yield a soluble isoform. However, the roles for these two types of endogenous ...CX3CL1 in neurodegenerative pathophysiology remain elusive. As such, it has been difficult to delineate the function of the two isoforms of CX3CL1, as both are natively present in the brain. In this study we examined each isoform's ability to regulate neuroinflammation in a mouse model of Parkinson's disease initiated by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We were able to delineate the function of both CX3CL1 isoforms by using adeno-associated virus-mediated gene therapy to selectively express synthetic variants of CX3CL1 that remain either permanently soluble or membrane bound. In the present study we injected each CX3CL1 variant or a GFP-expressing vector directly into the substantia nigra of CX3CL1(-/-) mice. Our results show that only the soluble isoform of CX3CL1 is sufficient for neuroprotection after exposure to MPTP. Specifically, we show that the soluble CX3CL1 isoform reduces impairment of motor coordination, decreases dopaminergic neuron loss, and ameliorates microglial activation and proinflammatory cytokine release resulting from MPTP exposure. Furthermore, we show that the membrane-bound isoform provides no neuroprotective capability to MPTP-induced pathologies, exhibiting similar motor coordination impairment, dopaminergic neuron loss, and inflammatory phenotypes as MPTP-treated CX3CL1(-/-) mice, which received the GFP-expressing control vector. Our results reveal that the neuroprotective capacity of CX3CL1 resides solely upon the soluble isoform in an MPTP-induced model of Parkinson's disease.
Cytokines are important mediators of intracranial inflammation following traumatic brain injury (TBI). In the present study, the neurological impairment and mortality, blood-brain barrier (BBB) ...function, intracranial polymorphonuclear leukocyte (PMN) accumulation, and posttraumatic neuronal cell death were monitored in mice lacking the genes for tumor necrosis factor (TNF)/lymphotoxin-α (LT-α) (TNF/LT-α−/−) and interleukin-6 (IL-6) and in wild-type (WT) littermates subjected to experimental closed head injury (total n = 107). The posttraumatic mortality was significantly increased in TNF/LT-α−/− mice (40%; P < 0.02) compared with WT animals (10%). The IL-6−/− mice also showed a higher mortality (17%) than their WT littermates (5.6%), but the difference was not statistically significant (P > 0.05). The neurological severity score was similar among all groups from 1 to 72 hours after trauma, whereas at 7 days, the TNF/LT-α−/− mice showed a tendency toward better neurological recovery than their WT littermates. Interestingly, neither the degree of BBB dysfunction nor the number of infiltrating PMNs in the injured hemisphere was different between WT and cytokine-deficient mice. Furthermore, the analysis of brain sections by in situ DNA nick end labeling (TUNEL histochemistry) at 24 hours and 7 days after head injury revealed a similar extent of posttraumatic intracranial cell death in all animals. These results show that the pathophysiological sequelae of TBI are not significantly altered in mice lacking the genes for the proinflammatory cytokines TNF, LT-α, and IL-6. Nevertheless, the increased posttraumatic mortality in TNF/LT-α-deficient mice suggests a protective effect of these cytokines by mechanisms that have not been elucidated yet.
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