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Laelapine mites are one of the most common ectoparasites of cricetid rodents. The taxonomical status is unclear of mites reported as Laelaps manguinhosi-like mites, since morphological variation was reported within the species in association with taxonomically and ecologically distinct sigmodontine rodents. We analysed morphological (qualitative and metric variation) and molecular data of four morphotypes of L. manguinhosi-like mites collected from three sigmodontine rodents (Cricetidae) of the tribe Oryzomyini (Holochilus brasiliensis, Nectomys squamipes and Oligoryzomys flavescens) and one of the tribe Akodontini (Scapteromys aquaticus). For better understanding, we defined L. manguinhosi sensu lato as a species concept and limited in a narrower sense L. manguinhosi sensu stricto. The association known from the literature between L. manguinhosi sensu stricto and H. brasiliensis was confirmed and additional information of this mite was provided. Mites associated with the remaining rodent species appear to be new species within L. manguinhosi sensu lato species complex, here described as Laelaps galliarii sp. nov., Laelaps scapteromyos sp. nov., Laelaps odysseos sp. nov., parasitizing O. flavescens, S. aquaticus and N. squamipes, respectively. Morphological analysis showed clear separation between the four studied species, with the majority also supported by molecular data. These results reinforce previous observations that Laelaps species are specific at least to the level of the host genus. Phylogenetic analysis based on 18.S-ITS1-5.8S-ITS2 partial gene markers indicate an earlier host-switch scenario between an akodontine associate (L. scapteromyos sp. nov.) and an oryzomyine associate (L. manguinhosi sensu stricto) followed by cospeciation events. Studied morphotypes of Laelaps were resolved as three separated clades. The basal one included mite species associated exclusively with Murinae (Old World) rodents and the other two are specific to Sigmodontinae (New World). The clade of sigmodontine associates was further divided into a cluster of mites parasitizing semiaquatic rodents and another cluster comprising mites parasitizing scansorial rodents. The obtained topology indicates that both, the phylogeny of rodent hosts and their ecological traits may play an important role in the coevolutionary process of host-mite relationships.

SignificanceOur results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.

Summary The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD., Graphical Abstract, Highlights • Rapid generation of hippocampal spheroids (HSs) from hiPSCs using defined chemical agents • hiPSC-derived HSs can be utilized as a source of hippocampal neurons • hiPSC-derived HSs can be used to model Alzheimer disease • hiPSC-derived HSs can be used to develop innovative therapeutic solutions, In this article, Roybon and colleagues developed a protocol to efficiently and rapidly generate hippocampus neurons from human induced pluripotent stem cells, which they used to model Alzheimer disease and develop a gene therapy approach to modulate the expression of genes involved in synaptic transmission.

The use of aqueous solutions of ammonium nitrate and microorganisms in the proposed method will intensify the transition of radionuclides into soluble forms for assimilation by the root system of plants, obtaining maximum biomass of plants accumulating radionuclides, and significantly reducing the growing season. The process of obtaining biomass using the above technology makes it possible to repeat this method of purification many times, including within one seasonal period, until the content of radionuclides in the soil reaches acceptable values, after which the soil becomes suitable for agricultural use. The purpose of the study. Consider the transition of radionuclides into soluble forms for assimilation by the root system of plants. Material and Methods. To substantiate the possible directions of soil reclamation, we propose a conceptual model of radionuclide transport in the agrocenosis, on the basis of which a functional scheme for recultivation of soils contaminated with radionuclides has been developed. The collected biomass and the root system of plants must be disposed of. Due to the fact that large volumes of mass are subject to disposal, it is subjected to heat treatment - drying.

Savchenko & Lareschi (2019) and Lareschi (2020) described four new species of mites in the family Laelapidae. However, the papers were published in electronic form only and were not registered in ZooBank. They do not satisfy Article 8.5.3 of the International Code of Zoological Nomenclature (ICZN 2012), so the new names are not available from those papers. Therefore, the aim of the present note is to validate the names Laelaps schatzi, Androlaelaps azarae, Androlaelaps montensis and Androlaelaps cursor. Type specimens of the four new species are deposited in the Colección de Entomología, Museo de la Plata, Argentina.

Lipid peroxidation-initiated ferroptosis is an iron-dependent mechanism of programmed cell death taking place in neurological diseases. Here we show that a condensed benzo[b]thiazine derivative small molecule with an arylthiazine backbone (ADA-409-052) inhibits tert-Butyl hydroperoxide (TBHP)-induced lipid peroxidation (LP) and protects against ferroptotic cell death triggered by glutathione (GSH) depletion or glutathione peroxidase 4 (GPx4) inhibition in neuronal cell lines. In addition, ADA-409-052 suppresses pro-inflammatory activation of BV2 microglia and protects N2a neuronal cells from cell death induced by pro-inflammatory RAW 264.7 macrophages. Moreover, ADA-409-052 efficiently reduces infarct volume, edema and expression of pro-inflammatory genes in a mouse model of thromboembolic stroke. Targeting ferroptosis may be a promising therapeutic strategy in neurological diseases involving severe neuronal death and neuroinflammation.

The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes - including functional glutamate uptake - could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs - including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation., The Holger Crafoord Foundation, the Olav Thon Foundation, the Greta och Johan Kocks Foundation, the Bergvall Foundation, The Swedish Research Council, The Swedish Cancer Foundation (Cancerfonden), and the strategic Research Area at Lund University MultiPark

Por lo general, los roedores sigmodontinos (Cricetidae) están asociados con una variedad de ectoparásitos. Sin embargo, los estudios en el noreste argentino son escasos. Aquí analizamos las comunidades componentes de ectoparásitos asociados con sigmodontinos en el sur de la Provincia de Misiones. En total, se recolectaron 835 ectoparásitos de los 97 roedores examinados: 782 ácaros (Acari, Mesostigmata; S = 7; P = 78.35 %; MA = 8.06), 50 pulgas (Hexapoda, Siphonaptera; S = 2; P = 21.65 %; MA = 0.53), y dos garrapatas (Acari, Ixodida; S = 1; P = 2.06 %; MA = 0.02, P < 0.005). Las cinco especies siguientes se mencionan por primera vez para el noreste: Androlaelaps rotundus, Gigantolaelaps wolffsohni, Laelaps manguinhosi, L. paulistanensis y Polygenis (P.) tripus, y aumentan el conocimiento sobre la biodiversidad del área. Se observó una tendencia hacia la agregación para la mayoría de los ectoparásitos. De las 10 especies de ectoparásitos identificadas en el presente estudio, cinco se recolectaron de una especie hospedadora única, por lo que la riqueza específica varió entre tres y cuatro en cada comunidad componente. Dado que algunos de los ectoparásitos identificados pueden jugar un rol en la transmisión de patógenos, los resultados obtenidos contribuyen a una mejor comprensión de la relación ectoparásito-hospedador, que puede tener implicaciones epidemiológicas. Usually sigmodontine rodents (Cricetidae) are associated with a variety of ectoparasites. However, the studies in northeastern Argentina are scarce. Herein we analyze the ectoparasite component communities associated with four species of sigmodontines in the south of the Province of Misiones. In total, 835 ectoparasites were collected from the 97 rodents examined: 782 mites (Acari, Mesostigmata; S = 7; P = 78.35 %; MA = 8.06), 50 fleas (Hexapoda, Siphonaptera; S = 2; P = 21.65 %; MA = 0.53), and two ticks (Acari, Ixodida; S = 1; P = 2.06 %; MA = 0.02, P < 0.005). The following five species are mentioned for the first time for the northeastern: Androlaelaps rotundus, Gigantolaelaps wolffsohni, Laelaps manguinhosi, L. paulistanensis, and Polygenis (P.) tripus, increasing the biodiversity known for the area. A tendency toward host aggregation was observed for most of the ectoparasites. Out of 10 ectoparasite species identified in the present study, five were collected from a unique host species, and so, species richness varied between three and four in every component community. Since some of the ectoparasites identified may play a role as vectors of pathogens, the obtained results contribute to a better understanding of the ectoparasite-host relationship, which may have epidemiological implications. Fil: Lareschi, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; Argentina Fil: Savchenko, Ekaterina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; Argentina Fil: Urdapilleta, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Ministerio de Salud. Instituto Nacional de Medicina Tropical; Argentina

The Finnish-variant late infantile neuronal ceroid lipofuscinosis, also known as CLN5 disease, is caused by mutations in the CLN5 gene. Cln5 is strongly expressed in the developing brain and expression continues into adulthood. CLN5, a protein of unknown function, is implicated in neurodevelopment but detailed investigation is lacking. Using Cln5−/− embryos of various ages and cells harvested from Cln5−/− brains we investigated the hitherto unknown role of Cln5 in the developing brain. Loss of Cln5 results in neuronal differentiation deficits and delays in interneuron development during in utero period. Specifically, the radial thickness of dorsal telencephalon was significantly decreased in Cln5−/− mouse embryos at embryonic day 14.5 (E14.5), and expression of Tuj1, an important neuronal marker during development, was down-regulated. An interneuron marker calbindin and a mitosis marker p-H3 showed down-regulation in ganglionic eminences. Neurite outgrowth was compromised in primary cortical neuronal cultures derived from E16 Cln5−/− embryos compared with WT embryos. We show that the developmental deficits of interneurons may be linked to increased levels of the repressor element 1-silencing transcription factor, which we report to bind to glutamate decarboxylase (Gad1), which encodes GAD67, a rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA). Indeed, adult Cln5−/− mice presented deficits in hippocampal parvalbumin-positive interneurons. Furthermore, adult Cln5−/− mice presented deficits in hippocampal parvalbumin-positive interneurons and showed age-independent cortical hyper excitability as measured by electroencephalogram and auditory-evoked potentials. This study highlights the importance of Cln5 in neurodevelopment and suggests that in contrast to earlier reports, CLN5 disease is likely to develop during embryonic stages.

Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a male patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous variation p.A53T in the SNCA gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated iPSC line (CSC-32) preserved the mutation, displayed expression of common pluripotency markers, differentiated into derivatives of the three germ layers, and exhibited a normal karyotype. The clone CSC-32B is presented thereafter; it can be used to study the mechanisms underlying PD pathogenesis.

Mutations in the glucocerebrosidase (GBA) gene have been associated with the development of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line was generated from a 60-year old patient diagnosed with PD and carrying a new mutation variant p.R301C in GBA. Using non-integrating Sendai virus-based technology, we utilized OCT3/4, SOX2, c-MYC and KLF4 transcription factors to reprogram skin fibroblasts into iPSCs. The generated iPSC line retained the mutation, displayed expression of common pluripotency markers, differentiated into the three germ layers, and exhibited normal karyotype. The iPSC line can be further used for studying PD pathogenesis., We thank AnnaKarin Olden, Anna Hammarberg and Marianne Juhlin, for their technical support. We are also thankful to the 'Cell Line and DNA Biobank from Patients affected by Genetic Diseases' (Istituto G. Gaslini, Genova, Italy) and the 'Parkinson Institute Biobank, members of the Telethon Network of Genetic Biobanks (http://biobanknetwork.telethon.it; project no. GTB12001) funded by Telethon Italy, for providing fibroblast samples. This work was supported by the Strategic Research Environment MultiPark at Lund University, the Swedish Research Council (grant 2015-03684 to LR), Finnish Cultural Foundation (grant 00161167 to YP), Portuguese Foundation for Science and Technology for the doctoral fellowship - PDE/BDE/113598/2015 to AM and IF Starting and Development Grant to LP and AJS (IF/01079/2014 and IF/00111/2013).

Parkinson's disease (PD) is a neurodegenerative disease with unknown etiology. Here we show the generation of an induced pluripotent stem cell (iPSC) line, named CSC-40, from dermal fibroblasts obtained from a 59-year-old male patient with a homozygous p.Q456X mutation in the PTEN-induced putative kinase 1 (PINK/PARK6) gene and a confirmed diagnosis of PD, which could be used to model familial PD. A non-integrating Sendai virus-based delivery of the reprogramming factors OCT3/4, SOX2, c-MYC and KLF4 was employed. The CSC-40 cell line showed normal karyotyping and fingerprinting following transduction as well as sustained expression of several pluripotency markers and the ability to differentiate into all three germ layers., We thank AnnaKarin Olden and Marianne Juhlin, for their technical support. We are also thankful to the 'Cell Line and DNA Biobank from Patients affected by Genetic Diseases' (Istituto G. Gaslini, Genova, Italy) and the Parkinson Institute Biobank, members of the Telethon Network of Genetic Biobanks (http://biobanknetwork.telethon.it; project no. GTB12001) funded by Telethon Italy, for providing fibroblasts samples. This work was supported by the Strategic Research Environment MultiPark at Lund University, and the strong research environment BAGADILICO (grant 349-2007-8626), the Swedish Parkinson Foundation (Parkinsonoden; grant 889/16), the Swedish Research Council (grant 2015-03684 to LR), Finnish Cultural Foundation (grant 00161167 to YP) and the Portuguese Foundation for Science and Technology for the doctoral fellowship - PDE/BDE/113598/2015 to AM., info:eu-repo/semantics/publishedVersion

Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family and highly expressed in the naïve mouse brain and spinal cord. Despite the fact that IL-33 is known to be inducible by various inflammatory stimuli, its cellular localization in the central nervous system and role in pathological conditions is controversial. Administration of recombinant IL-33 has been shown to attenuate experimental autoimmune encephalomyelitis progression in one study, yet contradictory reports also exist. Here we investigated for the first time the pattern of IL-33 expression in the contused mouse spinal cord and demonstrated that after spinal cord injury (SCI) IL-33 was up-regulated and exhibited a nuclear localization predominantly in astrocytes. Importantly, we found that treatment with recombinant IL-33 alleviated secondary damage by significantly decreasing tissue loss, demyelination and astrogliosis in the contused mouse spinal cord, resulting in dramatically improved functional recovery. We identified both central and peripheral mechanisms of IL-33 action. In spinal cord, IL-33 treatment reduced the expression of pro-inflammatory tumor necrosis factor-alpha and promoted the activation of anti-inflammatory arginase-1 positive M2 microglia/macrophages, which chronically persisted in the injured spinal cord for up to at least 42 days after the treatment. In addition, IL-33 treatment showed a tendency towards reduced T-cell infiltration into the spinal cord. In the periphery, IL-33 treatment induced a shift towards the Th2 type cytokine profile and reduced the percentage and absolute number of cytotoxic, tumor necrosis factor-alpha expressing CD4+ cells in the spleen. Additionally, IL-33 treatment increased expression of T-regulatory cell marker FoxP3 and reduced expression of M1 marker iNOS in the spleen. Taken together, these results provide the first evidence that IL-33 administration is beneficial after CNS trauma. Treatment with IL33 may offer a novel therapeutic strategy for patients with acute contusion SCI.

Skin fibroblasts were collected from a 44-year-old patient with sporadic case of Parkinson's disease (PD). The non-integrating Sendai virus vector encoding OCT3/4, SOX2, c-MYC and KLF4 was used to reprogram fibroblasts into induced pluripotent stem cells (iPSCs). Generated iPSCs had normal karyotypes, expressed common stem cell markers, and were capable of differentiating into all three germ layers. Generated line could be used for PD modeling to understand the mechanisms that influence the disorder., We thank AnnaKarin Oldén and Marianne Juhlin, for their technical support. We are also thankful to the ‘Cell Line and DNA Biobank from Patients affected by Genetic Diseases’ (Istituto G. Gaslini, Genova, Italy) and the ‘Parkinson Institute Biobank, members of the Telethon Network of Genetic Biobanks (http://biobanknetwork.telethon.it; project no. GTB12001) funded by Telethon Italy, for providing fibroblasts samples. This work was supported by the Strategic Research Environment MultiPark at Lund University, the strong research environment BAGADILICO (349-2007-8626), the Swedish Parkinson Foundation (Parkinsonfonden; grant 899/16), the Swedish Research Council (grant 2015-03684 to LR), Finnish Cultural Foundation (grant 00161167 to YP) and the Portuguese Foundation for Science and Technology for the doctoral fellowship - PDE/BDE/113598/2015 to AM.

The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5 disease) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases. Vision loss is among the first clinical signs in childhood forms of NCLs. Mutations in CLN5 underlie CLN5 disease. The aim of this study was to characterize how the lack of normal functionality of the CLN5 protein affects the mouse retina. Scotopic electroretinography (ERG) showed a diminished c-wave amplitude in the CLN5 deficient mice already at 1 month of age, indicative of pathological events in the retinal pigmented epithelium. A- and b-waves showed progressive impairment later from 2 and 3 months of age onwards, respectively. Structural and immunohistochemical (IHC) analyses showed preferential damage of photoreceptors, accumulation of autofluorescent storage material, apoptosis of photoreceptors, and strong inflammation in the CLN5 deficient mice retinas. Increased levels of autophagy-associated proteins Beclin-1 and P62, and increased LC3b-II/LC3b-I ratio, were detected by Western blotting from whole retinal extracts. Photopic ERG, visual evoked potentials, IHC and cell counting indicated relatively long surviving cone photoreceptors compared to rods. In conclusion, CLN5 deficient mice develop early vision loss that reflects the condition reported in clinical childhood forms of NCLs. The vision loss in CLN5 deficient mice is primarily caused by photoreceptor degeneration., published version, peerReviewed

Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout an individual's lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5. Our findings demonstrate a newly identified crucial role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused by loss of Cln5. Our results demonstrate that, in Cln5 deficiency, proliferation of NPCs is increased, NPC migration is reduced and NPC differentiation towards the neuronal lineage is increased concomitantly with functional alterations in the NPCs. Moreover, the observed impairment in neurogenesis is correlated with increased expression of the pro-inflammatory cytokine IL-1β. A full understanding of the pathological mechanisms that lead to disease and the function of the NCL proteins are critical for designing effective therapeutic approaches for this devastating neurodegenerative disorder., published version, peerReviewed

Laelaps schatzi sp. nov. (Mesostigmata: Laelapidae) is described on the bases of mites collected from the sigmodontine Oligoryzomys flavescens Waterhouse, 1837 (Rodentia: Cricetidae) in Pereyra, Buenos Aires, Argentina, based on morphological, morphometric and molecular data. Two DNA fragments, mtDNA cytochrome oxidase subunit I (COI) and nuclear 18.S-ITS1-5.8S-ITS2 partial gene sequence were deposited in the public Genbank datebase. The DNA extraction was conducted nondestructively using Chelex®100 modified for this study, to prevent vouchers for further microscopically examination. Laelaps schatzi sp. nov. is similar in general appearance to Laelaps paulistanensis Fonseca, 1936 and Laelaps fonsecai Gettinger, 1992, but the new species is unique in presenting a reticulated surface pattern on the genital shield from level of Zv1 up to posterior margin, and in the presence of one or two additional impair seta/e between J4 setae of dorsal shield. Also, the phylogenetic analyses separate the new species from all other species available in the GenBank of Laelaps. Fil: Savchenko, Ekaterina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; Argentina Fil: Lareschi, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; Argentina

Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17α and tumor necrosis factor-α levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.

In this chapter we study the diffusion of automotive knowledge created in the Region of Stuttgart. Patents leave a paper trail in the form of citations that we analyze in order to show which regions learn from e-mobility and fuel cell knowledge created in the region of Stuttgart. We show that citations of the patents of both technologies tend to localize in Germany, Japan and the US. However, in case of e-mobility, while aggregating the countries by groups, the largest number of citations is made by European, more precisely Western European countries. The fact, that domestic knowledge flows in fuel cell technology are not the most intensive can be explained by the early stage of the technology and that there is no hard fundament, on which the new knowledge can be built.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) modulates gene expression in response to oxidative damage in neurodegenerative diseases, including spinal cord injury (SCI). We noticed that activation of Nrf2 pathway persists for an extended time after clinically relevant contusion model of SCI. Injured Nrf2(-/-) mice were impaired in hindlimb function, exhibited increased atrophy, demyelination, and astrogliosis of the SC concomitant with altered expression of genes controlling apoptosis, inflammation, and neurotrophic factors suggesting the importance of Nrf2 for recovery. We used lentiviral gene transfer to increase Nrf2 expression and improve functional recovery after SCI. Although the transferred Nrf2 was expressed in neurons and astrocytes, we noticed hindlimb function impairment and elevated expression of pro-inflammatory cytokines as an adverse effect. These toxic effects were not reduced by including Nrf2 in the lentiviral vector. Augmenting the amount of delivered Nrf2 gene diminished toxic effects of the lentivirus, yet was not sufficient to improve functional recovery. Results of this study lead to the hypothesis that Nrf2 plays a crucial and multifaceted role in recovery from SCI, but even high overexpression of Nrf2 in injured SC may not offer extra benefit, providing protection only against lentivirus-induced toxicity that is manifested in the SC.

Background Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia. Methods Aged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers. Results We show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6. Conclusions Our results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke.

Accumulation of amyloid β (Aβ) is a major hallmark in Alzheimer’s disease (AD). Bone marrow derived monocytic cells (BMM) have been shown to reduce Aβ burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficient phagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a method to obtain monocytic cells from BM-derived haematopoietic stem cells (HSC). Mouse or human HSC were isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory stimulus. The phagocytic capacity was determined with Aβ uptake assay in vitro and Aβ degradation assay of natively formed Aβ deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transduced with enhanced green fluorescent protein (eGFP) to determine the effect of gene modification on the potential of HSC-derived cells for therapeutic purposes. HSC-derived monocytic cells (HSCM) displayed inflammatory responses comparable to microglia and peripheral monocytes. We also show that HSCM contributed to Aβ reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood HSC, indicating a potential therapeutic relevance for AD.