Mesenchymal stem cells and management of COVID-19 pneumonia.

Human coronavirus, hCoV-19, is highly pathogenic with severe pneumonia associated with rapid virus replication. Arising in Wuhan China December 2019, the current COVID-19 epidemic has rapidly grown with person-to-person infection expanding to become a global health emergency now on pandemic scale. Governments will not be able to minimise both deaths from COVID-19 and the economic impact of viral spread in mitigation of this current COVID-19 pandemic, according to Anderson et al. 2020 [1], Keeping mortality as low as possible will be the highest priority for individuals; hence governments must put in place measures to ameliorate the inevitable economic downturn. The current global picture shows small chains of transmission in many countries and large chains resulting in extensive spread in a few countries, such as Italy, Iran, South Korea, and Japan. Most countries are likely to have spread of COVID-19, at least in the early stages, before any mitigation measures have an impact. The scale of the problem is massive. Here I consider new approaches to improve patient's biological resistance to COVID-19 using stem cells, and how benefit might be scaled and simplified using synthetic stem cells to meet logistical needs within a short time frame

LIF and the lung’s stem cell niche: is failure to use LIF to protect against COVID-19 a grave omission in managing the pandemic?

Tweetable abstract: What tips the SARS/COVID-19 balance into severe pneumonia, rather than recovery? Is it insufficient LIF – the lung’s own protective growth factor at the blood–air barrier

Post-main sequence evolution of A star debris discs

While the population of main sequence debris discs is well constrained, little is known about debris discs around evolved stars. This paper provides a theoretical framework considering the effects of stellar evolution on debris discs, particularly the production and loss of dust within them. Here we repeat a steady state model fit to disc evolution statistics for main sequence A stars, this time using realistic grain optical properties, then evolve that population to consider its detectability at later epochs. Our model predicts that debris discs around giant stars are harder to detect than on the main sequence because radiation pressure is more effective at removing small dust around higher luminosity stars. Just 12% of first ascent giants within 100pc are predicted to have discs detectable with Herschel at 160um. However this is subject to the uncertain effect of sublimation on the disc, which we propose can thus be constrained with such observations. Our model also finds that the rapid decline in stellar luminosity results in only very young white dwarfs having luminous discs. As such systems are on average at larger distances they are hard to detect, but we predict that the stellar parameters most likely to yield a disc detection are a white dwarf at 200pc with cooling age of 0.1Myr, in line with observations of the Helix Nebula. Our model does not predict close-in (<0.01AU) dust, as observed for some white dwarfs, however we find that stellar wind drag leaves significant mass (~10^{-2}Msolar), in bodies up to ~10m in diameter, inside the disc at the end of the AGB phase which may replenish these discs

Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic “LIF” Into the Brain: Preclinical Proof of Concept

Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life—and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood–brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB

Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF)

AbstractMultiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination.Impact statementNanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS

Institutions and the Diversity and Prevalence of Multinationals’ Knowledge-Augmenting Subsidiaries

Multinational corporations (MNCs) increasingly seek to gain access to, and exploit, locationally specific sources of advanced knowledge and technological capabilities, creating a need to explain (1) the diversity among these facilities and (2) how institutions influence MNCs’ abilities to invest in different subsidiary types. Extending debates on firms’ knowledge‐augmenting activities, the authors integrate institutions into their analytical framework to a greater extent than previous work has done. Moreover, existing contributions provide typologies of R&D subsidiaries. In contrast, the authors focus on a particular subset of subsidiaries, knowledge‐augmenting ones, and put forward a theory to explain their variety and their prevalence, enabling them to identify previously neglected subsidiary types that have important managerial and policy implications. By downplaying the diversity of these subsidiaries, existing work has not been able to capture the full range of managerial challenges as well as the costs and benefits of different subsidiary types to host countries. The authors, therefore, problematize firms’ abilities to gain access to foreign knowledge‐generating assets, highlight the importance of institutional environments, provide policy recommendations and identify areas for future research

Maintenance of phenotypic variation: repeatability, heritability and size-dependent processes in a wild brook trout population

Phenotypic variation in body size can result from within-cohort variation in birth dates, among-individual growth variation and size-selective processes. We explore the relative effects of these processes on the maintenance of wide observed body size variation in stream-dwelling brook trout (Salvelinus fontinalis). Based on the analyses of multiple recaptures of individual fish, it appears that size distributions are largely determined by the maintenance of early size variation. We found no evidence for size-dependent compensatory growth (which would reduce size variation) and found no indication that size-dependent survival substantially influenced body size distributions. Depensatory growth (faster growth by larger individuals) reinforced early size variation, but was relatively strong only during the first sampling interval (age-0, fall). Maternal decisions on the timing and location of spawning could have a major influence on early, and as our results suggest, later (>age-0) size distributions. If this is the case, our estimates of heritability of body size (body length = 0.25) will be dominated by processes that generate and maintain early size differences. As a result, evolutionary responses to environmental change that are mediated by body size may be largely expressed via changes in the timing and location of reproduction

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of s√=7TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV