FTY720 Reduces Post-Ischemic Brain Lymphocyte Influx but Does Not Improve Outcome in Permanent Murine Cerebral Ischemia

BACKGROUND: The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: FTY720 treatment resulted in substantial reduction of circulating lymphocytes while blood monocyte counts were significantly increased. The number of histologically and flow cytometrically analyzed brain invading T- and B lymphocytes was significantly reduced in FTY720 treated mice. However, despite testing a variety of treatment protocols, infarct volume and behavioural dysfunction were not reduced 7d after permanent occlusion of the distal middle cerebral artery (MCAO). Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment. Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO. Also, serum cytokine levels of IL-6 and TNF-α were increased in FTY720 treated animals compared to controls. CONCLUSIONS/SIGNIFICANCE: In the present study we were able to detect a reduction of lymphocyte brain invasion by FTY720 but could not achieve a significant reduction of infarct volumes and behavioural dysfunction. This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia

Working Anytime and Anywhere -Even When Feeling Ill? A Cross-sectional Study on Presenteeism in Remote Work

Background: Working despite feeling ill – presenteeism – is a widespread behavioral phenomenon. Previous research has shown that presenteeism is influenced by various work-related and personal factors. It's an illness behavior leading to a range of negative but also positive consequences. Due to coronavirus disease 2019 (COVID-19) pandemic, remote work has become the “new normal” for many employees. But so far, little is known about presenteeism in remote work. This study aims to investigate presenteeism in remote work by looking at the extent of remote presenteeism, differences to presenteeism in on-site work, and associated factors. Methods: A nationwide cross-sectional online survey was conducted in Germany with N = 233 participants. Data were analyzed using descriptive statistics, t-tests, and correlation analysis. Results: The results reveal that presenteeism is prevalent in remote work x̅ = 4.13 days (Md = 3; D = 2; s = 4.95). A low ability to detach from work (r = -.17; p = .005) and low supervisor support (r = -.14; p = .02) is associated with more remote presenteeism days. Remote working conditions seem to facilitate presenteeism. Conclusion: This study provides empirical insights into a subject area of great societal relevance. The results show that awareness should be raised for presenteeism in remote work. It should be regarded as a behavior that can be functional or dysfunctional, depending on the individual situation. Supervisor support and detachment should be fostered to help reduce dysfunctional presenteeism. Promotion of health literacy might help remote workers to decide on a health-oriented illness behavior. Further research is vital to analyze to what extent and under which circumstances presenteeism in remote work is (dys)functional and to derive clear recommendations

Conspecific and heterospecific grass litter effects on seedling emergence and growth in ragwort (Jacobaea vulgaris).

Jacobaea vulgaris Gaertn. or common ragwort is a widespread noxious grassland weed that is subject to different regulation measures worldwide. Seedling emergence and growth are the most crucial stages for most plants during their life cycle. Therefore, heterospecific grass or conspecific ragwort litter as well as soil-mediated effects may be of relevance for ragwort control. Our study examines the effects of conspecific and heterospecific litter as well as ragwort conditioned soil on seedling emergence and growth. We conducted pot experiments to estimate the influence of soil conditioning (with, without ragwort), litter type (grass, ragwort, grass-ragwort-mix) and amount (200 g/m², 400 g/m²) on J. vulgaris recruitment. As response parameters, we assessed seedling number, biomass, height and number of seedling leaves. We found that 200 g/m² grass litter led to higher seedling numbers, while litter composed of J. vulgaris reduced seedling emergence. Litter amounts of 400 g/m² had negative effects on the number of seedlings regardless of the litter type. Results for biomass, plant height and leaf number showed opposing patterns to seedling numbers. Seedlings in pots treated with high litter amounts and seedlings in ragwort litter became heavier, grew higher and had more leaves. Significant effects of the soil conditioned by ragwort on seedling emergence and growth were negligible. The study confirms that the amount and composition of litter strongly affect seedling emergence and growth of J. vulgaris. Moreover, while conspecific litter and high litter amounts negatively affected early seedling development in ragwort, those seedlings that survived accumulated more biomass and got taller than seedlings grown in heterospecific or less dense litter. Therefore, ragwort litter has negative effects in ragwort germination, but positive effects in ragwort growth. Thus, leaving ragwort litter on pastures will not reduce ragwort establishment and growth and cannot be used as management tool

Physical and functional interactions of the cytomegalovirus US6 glycoprotein with the transporter associated with antigen processing

The endoplasmic reticulum-resident human cytomegalovirus glycoprotein US6 (gpUS6) inhibits peptide translocation by the transporter associated with antigen processing (TAP) to prevent loading of major histocompatibility complex class I molecules and antigen presentation to CD8+ T cells. TAP is formed by two subunits, TAP1 and TAP2, each containing one multispanning transmembrane domain (TMD) and a cytosolic nucleotide binding domain. Here we reported that the blockade of TAP by gpUS6 is species-restricted, i.e. gpUS6 inhibits human TAP but not rat TAP. Co-expression of human and rat subunits of TAP demonstrates independent binding of gpUS6 to human TAP1 and TAP2, whereas gpUS6 does not bind to rat TAP subunits. gpUS6 associates with preformed TAP1/2 heterodimers but not with unassembled TAP subunits. To locate domains of TAP required for gpUS6 binding and function, we took advantage of reciprocal human/rat intrachain TAP chimeras. Each TAP subunit forms two contact sites within its TMD interacting with gpUS6. The dominant gpUS6-binding site on TAP2 maps to an N-terminal loop, whereas inhibition of peptide transport is mediated by a C-terminal loop of the TMD. For TAP1, two gpUS6 binding domains are formed by loops of the C-terminal TMD. The domain required for TAP inactivation is built by a distal loop of the C-terminal TMD, indicating a topology of TAP1 comprising 10 endoplasmic reticulum transmembrane segments. By forming multimeric complexes, gpUS6 reaches the distant target domains to arrest peptide transport. The data revealed a nonanalogous multipolar bridging of the TAP TMDs by gpUS6

Functional improvement after photothrombotic stroke in rats is associated with different patterns of dendritic plasticity after g-csf treatment and g-csf treatment combined with concomitant or sequential constraint-induced movement therapy

We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 μg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective

Time-related changes in hepatic and colonic mitochondrial oxygen consumption after abdominal infection in rats

Abstract Background Evidence suggests that early adaptive responses of hepatic mitochondria occur in experimentally induced sepsis. Little is known about both colonic mitochondrial function during abdominal infection and long-term changes in mitochondrial function under inflammatory conditions. We hypothesize that hepatic and colonic mitochondrial oxygen consumption changes time-dependently after sterile laparotomy and in the course of abdominal infection. The aim of the present study was to investigate the hepatic and colonic mitochondrial respiration after sterile laparotomy and abdominal infection over up to 96 h. Methods After approval of the local Animal Care and Use Committee, 95 Wistar rats were randomized into 8 groups (n = 11–12): 1–4 sham (laparotomy only) and 5–8 colon ascendens stent peritonitis (CASP). Healthy, unoperated animals served as controls (n = 9). The mitochondrial respiration in colon and liver homogenates was assessed 24, 48, 72, and 96 h after surgery. Mitochondrial oxygen consumption was determined using a Clark-type electrode. State 2 (oxygen consumption in the presence of the substrates for complexes I and II) and state 3 respiration (ADP dependent) were assessed. The respiratory control ratio (RCR state 3/state 2) and ADP/O ratio (ADP added/oxygen consumed) were calculated for both complexes. Data are presented as means ± SD, two-way ANOVA followed by Tukey’s post hoc test. Results Hepatic RCR was initially (after 24 h) elevated in both operated groups; after 48 h only, the septic group was elevated compared to controls. In CASP groups, the hepatic ADP/O ratio for complex I was elevated after 24 h (vs. controls) and after 48 h (vs. sham) but declined after 72 h (vs. controls). The ADP/O ratio for complex II stayed unchanged over the time period until 96 h. The colonic RCR and ADP/O did not change over time after sham or CASP operation. Conclusion Hepatic, but not colonic, mitochondrial respiration is increased in the initial phase (until 48 h) and normalizes in the longer course of time (until 96 h) of abdominal infection