Lentiviral Vector Delivery of Human Interleukin-7 (hIL-7) to Human Immune System (HIS) Mice Expands T Lymphocyte Populations

Genetically modified mice carrying engrafted human tissues provide useful models to study human cell biology in physiologically relevant contexts. However, there remain several obstacles limiting the compatibility of human cells within their mouse hosts. Among these is inadequate cross-reactvitiy between certain mouse cytokines and human cellular receptors, depriving the graft of important survival and growth signals. To circumvent this problem, we utilized a lentivirus-based delivery system to express physiologically relevant levels of human interleukin-7 (hIL-7) in Rag2-/-γc-/- mice following a single intravenous injection. hIL-7 promoted homeostatic proliferation of both adoptively transferred and endogenously generated T-cells in Rag2-/-γc-/- Human Immune System (HIS) mice. Interestingly, we found that hIL-7 increased T lymphocyte numbers in the spleens of HIV infected HIS mice without affecting viral load. Taken together, our study unveils a versatile approach to deliver human cytokines to HIS mice, to both improve engraftment and determine the impact of cytokines on human diseases

Entrepreneurs' exit and paths to retirement : theoretical and empirical considerations

The number of ageing entrepreneurs in micro- and small-sized companies is rapidly increasing in Finland and other European Union countries. Over half a million jobs, in over one hundred thousand companies within the EU, are lost annually due to unsuccessful, predominantly retirement-related transfers of businesses. This challenge coincides with EU Grand Challenges and has been highlighted in the Entrepreneurship 2020 Action Plan (European Commission 2013). It has been estimated that in Finland, some 8000 jobs are lost yearly due to the ageing of entrepreneurs. Therefore, entrepreneur ageing has implications not only for the ageing individual but also for the company and the society at large. As entrepreneurs age it becomes more essential for them to start planning when and how they transition into retirement. While they may experience several exits and subsequent re-entries into working life via buying or starting new companies, exiting ones entrepreneurial career due to old age retirement differs from exits that occur earlier during the career. In this chapter, we provide a short overview of the entrepreneur retirement and exit literature from an age perspective. Furthermore, we present a theoretical conceptualization which combines entrepreneur retirement process with exit theories. This will enable scholars to better understand the retirement process, including decision-making, transitioning, and adjustment to retirement. We also provide empirical evidence using data collected among Finnish entrepreneurs in 2012 and 2015, where we outline the types of exits and assess several factors, including age, in association with exit intentions.fi=vertaisarvioitu|en=peerReviewed

A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development

Aptamers for pharmaceuticals and their application in environmental analytics

Aptamers are single-stranded DNA or RNA oligonucleotides, which are able to bind with high affinity and specificity to their target. This property is used for a multitude of applications, for instance as molecular recognition elements in biosensors and other assays. Biosensor application of aptamers offers the possibility for fast and easy detection of environmental relevant substances. Pharmaceutical residues, deriving from human or animal medical treatment, are found in surface, ground, and drinking water. At least the whole range of frequently administered drugs can be detected in noticeable concentrations. Biosensors and assays based on aptamers as specific recognition elements are very convenient for this application because aptamer development is possible for toxic targets. Commonly used biological receptors for biosensors like enzymes or antibodies are mostly unavailable for the detection of pharmaceuticals. This review describes the research activities of aptamer and sensor developments for pharmaceutical detection, with focus on environmental applications

Finite-Step Algorithms for Single-Controller and Perfect Information Stochastic Games

Abstract. After a brief survey of iterative algorithms for general stochas-tic games, we concentrate on finite-step algorithms for two special classes of stochastic games. They are Single-Controller Stochastic Games and Per-fect Information Stochastic Games. In the case of single-controller games, the transition probabilities depend on the actions of the same player in all states. In perfect information stochastic games, one of the players has exactly one action in each state. Single-controller zero-sum games are effi-ciently solved by linear programming. Non-zero-sum single-controller stochastic games are reducible to linear complementary problems (LCP). In the discounted case they can be modified to fit into the so-called LCPs of Eave’s class L. In the undiscounted case the LCP’s are reducible to Lemke’s copositive plus class. In either case Lemke’s algorithm can be used to find a Nash equilibrium. In the case of discounted zero-sum perfect informa-tion stochastic games, a policy improvement algorithm is presented. Many other classes of stochastic games with orderfield property still await efficient finite-step algorithms. 1