Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

The changing global distribution and prevalence of canine transmissible venereal tumour.

BACKGROUND: The canine transmissible venereal tumour (CTVT) is a contagious cancer that is naturally transmitted between dogs by the allogeneic transfer of living cancer cells during coitus. CTVT first arose several thousand years ago and has been reported in dog populations worldwide; however, its precise distribution patterns and prevalence remain unclear. RESULTS: We analysed historical literature and obtained CTVT prevalence information from 645 veterinarians and animal health workers in 109 countries in order to estimate CTVT's former and current global distribution and prevalence. This analysis confirmed that CTVT is endemic in at least 90 countries worldwide across all inhabited continents. CTVT is estimated to be present at a prevalence of one percent or more in dogs in at least 13 countries in South and Central America as well as in at least 11 countries in Africa and 8 countries in Asia. In the United States and Australia, CTVT was reported to be endemic only in remote indigenous communities. Comparison of current and historical reports of CTVT indicated that its prevalence has declined in Northern Europe, possibly due to changes in dog control laws during the nineteenth and twentieth centuries. Analysis of factors influencing CTVT prevalence showed that presence of free-roaming dogs was associated with increased CTVT prevalence, while dog spaying and neutering were associated with reduced CTVT prevalence. Our analysis indicated no gender bias for CTVT and we found no evidence that animals with CTVT frequently harbour concurrent infectious diseases. Vincristine was widely reported to be the most effective therapy for CTVT. CONCLUSIONS: Our results provide a survey of the current global distribution of CTVT, confirming that CTVT is endemic in at least 90 countries worldwide. Additionally, our analysis highlights factors that continue to modify CTVT's prevalence around the world and implicates free-roaming dogs as a reservoir for the disease. Our analysis also documents the disappearance of the disease from the United Kingdom during the twentieth century, which appears to have been an unintentional result of the introduction of dog control policies.This is the author's accepted manuscript. The final version of this article has been published by BioMed Central: http://www.biomedcentral.com/1746-6148/10/168

Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination

The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer(-/-) Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism

Localization and Broadband Follow-Up of the Gravitational-Wave Transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser InterferometerGravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimatesof the time, significance, and sky location of the event were shared with 63 teams of observers covering radio,optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter wedescribe the low-latency analysis of the GW data and present the sky localization of the first observed compactbinary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-rayCoordinates Network circulars, giving an overview of the participating facilities, the GW sky localizationcoverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger,there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadbandcampaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broadcapabilities of the transient astronomy community and the observing strategies that have been developed to pursueneutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-upcampaign are being disseminated in papers by the individual teams

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The Development of Inclusive Learning Relationships in Mainstream Settings: A Multimodal Perspective

The debate regarding the inclusion of children with Special Educational Needs and Disabilities (SEND) in mainstream education in the UK partly revolves around what makes the classroom environment inclusive. Through the potential offered by the specific qualitative methodologies employed, this study aimed to explore the development of teachers’ pedagogical practices and learning relationships upon the inclusive education of children with special educational needs and disabilities in two primary school classes. The study considered the views and behaviours of primary school pupils with and without special educational needs, primary school teachers and teaching assistants (TAs) in one mainstream school. Drawing on a multimodal approach to discourse analysis to account for the complex relationships between symbolic and non-verbal modes of classroom signification, the study explored how meaning is produced in classrooms and children’s modes of communication, as well as in teachers’ practices. The two classes are compared on the basis of teaching observations, interviews, transcripts of dialogues, and analyses of classroom organisation and decoration. This paper suggests that the greatest influence on the educational and social outcomes of students with special educational needs is the behaviour and practices of the classroom teacher

Automated detection of cerebral microbleeds on MR images using knowledge distillation framework

Introduction: Cerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate automated detection of CMBs would help to determine quantitative imaging biomarkers (e.g., CMB count) on large datasets. In this work, we propose a fully automated, deep learning-based, 3-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g., GRE/SWI/QSM) for their accurate detections. Methods: In our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. Results: On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of <2 false positives per subject. The knowledge distillation framework improves the cluster-wise TPR of the student model by 15%. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and better cluster-wise precision compared to existing state-of-the-art methods. When evaluating across different datasets, our method showed good generalizability with a cluster-wise TPR >80 % with different modalities. The python implementation of the proposed method is openly available