Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

Solutions of 1,3-diketones and 1,3-ketoester derivatives react with fluorine to give the corresponding 2,2-difluoro-1,3-dicarbonyl derivatives in the presence of quinuclidine. Quinuclidine reacts with fluorine in situ to generate a fluoride ion that facilitates limiting enolization processes, and an electrophilic N-F fluorinating agent that is reactive towards neutral enol species

HspB5 Activates a Neuroprotective Glial Cell Response in Experimental Tauopathy

Progressive neuronal death during tauopathies is associated with aggregation of modified, truncated or mutant forms of tau protein. Such aggregates are neurotoxic, promote spreading of tau aggregation, and trigger release of pro-inflammatory factors by glial cells. Counteracting such pathogenic effects of tau by simultaneously inhibiting protein aggregation as well as pro-inflammatory glial cell responses would be of significant therapeutic interest. Here, we examined the use of the small heat-shock protein HspB5 for this purpose. As a molecular chaperone, HspB5 counteracts aggregation of a wide range of abnormal proteins. As a TLR2 agonist, it selectively activates protective responses by CD14-expressing myeloid cells including microglia. We show that intracerebral infusion of HspB5 in transgenic mice with selective neuronal expression of mutant human P301S tau has significant neuroprotective effects in the superficial, frontal cortical layers. Underlying these effects at least in part, HspB5 induces several potent neuroprotective mediators in both astrocytes and microglia including neurotrophic factors and increased potential for removal of glutamate. Together, these findings highlight the potentially broad therapeutic potential of HspB5 in neurodegenerative proteinopathies

Assessing the efficacy of medetomidine and tiletamine-zolazepam for remote immobilisation of feral horses (Equus caballus)

Context The study of any wild animal's home range requires the collection of spatiotemporal data, obtained independently of climatic conditions or time of day. This can be achieved by the attachment of global positioning system (GPS) data loggers, which, in large species, is best achieved by remote immobilisation. Feral horses (Equus caballus) usually occupy remote areas of Australia; however, a considerable population increase has been observed in a close proximity to metropolitan areas of the Australian east coast, creating increasing conflict with human interests. Aim The aim of the present study was to investigate the efficacy of remote chemical immobilisation of feral horses with medetomidine combined with tiletamine-zolazepam to facilitate placement of satellite GPS collars. Methods Nine feral horses were darted from the ground with 60mg (i.m.) medetomidine and 1500mg (i.m.) tiletamine-zolazepam. The effects of medetomidine were reversed with 50-100mg (i.m. or i.v.) atipamezole 30-40min after induction (IV/IM). Physiological variables monitored during anaesthesia were heart rate, respiratory rate, temperature and oxygen haemoglobin saturation (Spo2). Key results All horses were successfully immobilised with between one and three darts (n≤9). The mean (± s.e.m.) dose of medetomidine was 0.15±0.01mg kg-1, whereas that of tiletamine-zolazepam was 3.61±0.16mg kg-1. Mean time from darting to lateral recumbency was 13.3±2.7min and mean recumbency time was 54±13min. Vital signs for all anaesthetised animals remained within the normal range during anaesthesia, with the exception of one animal exhibiting a transient drop in Spo2. There were no deaths. Key conclusions The combination of medetomidine and tiletamine-zolazepam provided adequate anaesthesia in feral horses in the field for application of GPS collars. Implications Although a limited number of horses was immobilised, the present study shows that the combination of medetomidine and tiletamine-zolazepam provides effective short-term anaesthesia for feral horses, affording a practical and field-accessible capture technique. This method could also be applied to other management actions requiring the safe and humane capture of feral horses

Identification of unique reciprocal and non reciprocal cross packaging relationships between HIV-1, HIV-2 and SIV reveals an efficient SIV/HIV-2 lentiviral vector system with highly favourable features for in vivo testing and clinical usage.

BACKGROUND: Lentiviral vectors have shown immense promise as vehicles for gene delivery to non-dividing cells particularly to cells of the central nervous system (CNS). Improvements in the biosafety of viral vectors are paramount as lentiviral vectors move into human clinical trials. This study investigates the packaging relationship between gene transfer (vector) and Gag-Pol expression constructs of HIV-1, HIV-2 and SIV. Cross-packaged vectors expressing GFP were assessed for RNA packaging, viral vector titre and their ability to transduce rat primary glial cell cultures and human neural stem cells. RESULTS: HIV-1 Gag-Pol demonstrated the ability to cross package both HIV-2 and SIV gene transfer vectors. However both HIV-2 and SIV Gag-Pol showed a reduced ability to package HIV-1 vector RNA with no significant gene transfer to target cells. An unexpected packaging relationship was found to exist between HIV-2 and SIV with SIV Gag-Pol able to package HIV-2 vector RNA and transduce dividing SV2T cells and CNS cell cultures with an efficiency equivalent to the homologous HIV-1 vector however HIV-2 was unable to deliver SIV based vectors. CONCLUSION: This new non-reciprocal cross packaging relationship between SIV and HIV-2 provides a novel way of significantly increasing bio-safety with a reduced sequence homology between the HIV-2 gene transfer vector and the SIV Gag-Pol construct thus ensuring that vector RNA packaging is unidirectional.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

iPSC-derived myelinoids to study myelin biology of humans

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (“myelinoids”) and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination—both at the level of individual oligodendrocytes and globally across whole myelinoids—and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination

A water cycle for the Anthropocene

International audienceHumor us for a minute and do an online image search of the water cycle. How many diagrams do you have to scroll through before seeing any sign of humans? What about water pollution or climate change—two of the main drivers of the global water crisis? In a recent analysis of more than 450 water cycle diagrams, we found that 85% showed no human interaction with the water cycle and 98% omitted any sign of climate change or waterpollution (Abbott et al., 2019). Additionally, 92% of diagrams depicted verdant, temperate ecosystems with abundant freshwater and 95% showed only a single river basin. It did not matter if the diagrams came from textbooks, scientific articles, or the internet, nor if they were old or new; most showed an undisturbed water cycle, free from human interference. These depictions contrast starkly with the state of the water cycle in the Anthropocene, when land conversion, human water use, and climate change affect nearly every water pool and flux (Wurtsbaugh et al., 2017; Falkenmark et al., 2019; Wine and Davison, 2019). The dimensions and scale of human interference with water are manifest in failing fossil aquifersin the world’s great agricultural regions (Famiglietti, 2014), accelerating ice discharge from the Arctic (Box et al., 2018), and instability in atmospheric rivers that support continental rainfall (Paul et al., 2016).We believe that incorrect water cycle diagrams are a symptom of a much deeper and widespread problem about how humanity relates to water on Earth. Society does not understand how the water cycle works nor how humans fit into it (Attari, 2014; Linton, 2014; Abbott et al., 2019). In response to this crisis of understanding, we call on researchers, educators, journalists, lawyers, and policy makers to change how we conceptualize and present the global water cycle. Specifically, we must teach where water comes from, what determines its availability, and how many individuals and ecosystems are in crisis because of water mismanagement, climate change, and land conversion. Because the drivers of the global water crisis are truly global, ensuring adequate water for humans and ecosystems will require coordinated efforts that extend beyond geopolitical borders and outlast the tenure of individual administrations (Keys et al., 2017; Adler, 2019). This level of coordination and holistic thinking requires widespread understanding of the water cycle and the global water crisis. Making the causes and consequences of the water crisis visible in our diagrams is atractable and important step towards the goal of a sustainable relationship with water that includes ecosystems and society

Human domination of the global water cycle absent from depictions and perceptions

International audienceHuman water use, climate change and land conversion have created a water crisis for billions of individuals and many ecosystems worldwide. Global water stocks and fluxes are estimated empirically and with computer models, but this information is conveyed to policymakers and researchers through water cycle diagrams. Here we compiled a synthesis of the global water cycle, which we compared with 464 water cycle diagrams from around the world. Although human freshwater appropriation now equals half of global river discharge, only 15% of the water cycle diagrams depicted human interaction with water. Only 2% of the diagrams showed climate change or water pollution—two of the central causes of the global water crisis—which effectively conveys a false sense of water security. A single catchment was depicted in 95% of the diagrams, which precludes the representation of teleconnections such as ocean–land interactions and continental moisture recycling. These inaccuracies correspond with specific dimensions of water mismanagement, which suggest that flaws in water diagrams reflect and reinforce the misunderstanding of global hydrology by policymakers, researchers and the public. Correct depictions of the water cycle will not solve the global water crisis, but reconceiving this symbol is an important step towards equitable water governance, sustainable development and planetary thinking in the Anthropocene

Multi-modality machine learning predicting Parkinson's disease

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available