Therapeutic targeting of leukocyte trafficking across the blood-brain barrier

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS not to disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses are mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly regulating immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier control immune cell entry into the CNS, which is rare under physiological conditions. During a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis (MS), immunocompetent cells readily traverse the BBB and subsequently enter the CNS parenchyma. Most of our current knowledge on the molecular mechanisms involved in immune cell entry into the CNS has been derived from studies performed in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Thus, a large part of our current knowledge on immune cell entry across the BBBs is based on the results obtained in this animal model. Similarly, knowledge on the benefits and potential risks associated with therapeutic targeting of immune cell recruitment across the BBB in human diseases are mostly derived from such treatment regimen in MS. Other mechanisms of immune cell entry into the CNS might therefore apply under different pathological conditions such as bacterial meningitis or stroke and need to be considered.

Role of protein translocation pathways across the endoplasmic reticulum in Trypanosoma brucei

The translocation of secretory and membrane proteins across the endoplasmic reticulum (ER) membrane is mediated by co-translational (via the signal recognition particle (SRP)) and post-translational mechanisms. In this study, we investigated the relative contributions of these two pathways in trypanosomes. A homologue of SEC71, which functions in the post-translocation chaperone pathway in yeast, was identified and silenced by RNA interference. This factor is essential for parasite viability. In SEC71-silenced cells, signal peptide (SP)-containing proteins traversed the ER, but several were mislocalized, whereas polytopic membrane protein biogenesis was unaffected. Surprisingly trypanosomes can interchangeably utilize two of the pathways to translocate SP-containing proteins except for glycosylphosphatidylinositol-anchored proteins, whose level was reduced in SEC71-silenced cells but not in cells depleted for SRP68, an SRP-binding protein. Entry of SP-containing proteins to the ER was significantly blocked only in cells co-silenced for the two translocation pathways (SEC71 and SRP68). SEC63, a factor essential for both translocation pathways in yeast, was identified and silenced by RNA interference. SEC63 silencing affected entry to the ER of both SP-containing proteins and polytopic membrane proteins, suggesting that, as in yeast, this factor is essential for both translocation pathways in vivo. This study suggests that, unlike bacteria or other eukaryotes, trypanosomes are generally promiscuous in their choice of mechanism for translocating SP-containing proteins to the ER, although the SRP-independent pathway is favored for glycosylphosphatidylinositol-anchored proteins, which are the most abundant surface proteins in these parasites.

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4(+) T cells of a T helper 1, T helper 2, or interleukin-10-producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G(i)-protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. CONCLUSION: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation.

Solid organ transplantation across the ABO histo-blood group barrier: a case report

The ABO blood group system until recently constituted an insuperable barrier for solid organ transplantation, but cases of heart transplantation in infants and kidney transplantation in adults have been reported, wherein ABO-incompatible grafts have been successful. In 1990, the molecular genetic basis of three major alleles at the ABO locus was elucidated; A and B glycosyltransferases are specified by a variety of functional alleles at this locus. The antibody response to ABH antigens, namely, naturally occurring anti-A/B IgM and IgG isotype agglutinins, are controlled preoperatively by recipient conditioning using plasma exchange, immunoadsorption, and immunosuppressive regimens. We report an O-type patient who accidentally received a B-type cardiac allograft in 1997 who survived for 5 years, dying for an unrelated reason. Over a period of 45 months semiquantitatively we monitored the expression of ABO-type antigens in graft heart vessels using monoclonal antibodies on sections of formalin-fixed, paraffin-embedded biopsies. We observed a progressive change in the antigenic profile of graft endothelial cells from B- to O-type, which was first detected at 1 year posttransplant and most prominent 3 years later, the end of the observation period. No temporal relationship was observed between the transition from B to O expression, the anti-B antibody levels or the immunosuppressive regimen.

The adaptive power of the present: Perceptions of past, present, and future life satisfaction across the life span

Despite remarkable stability of life satisfaction across the life span, it may be adaptive to perceive change in life satisfaction. We shed new light on this topic with data from 766 individuals from three age groups and past, present, and future life satisfaction perceptions across the life span. On average, participants were most satisfied with their current life. When looking back, satisfaction increased from past to present, and when looking ahead, satisfaction decreased into the future. Trajectories were best fitted with a curvilinear growth model. Neuroticism and extraversion predicted the level of trajectories, but none of the Big Five predicted the slope. We conclude that humans have an adaptive capacity to perceive the present life as being the best possible.

Recognition memory across the lifespan: the impact of word frequency and study-test interval on estimates of familiarity and recollection

The goal of this study was to investigate recognition memory performance across the lifespan and to determine how estimates of recollection and familiarity contribute to performance. In each of three experiments, participants from five groups from 14 up to 85 years of age (children, young adults, middle-aged adults, young-old adults, and old-old adults) were presented with high- and low-frequency words in a study phase and were tested immediately afterwards and/or after a one day retention interval. The results showed that word frequency and retention interval affected recognition memory performance as well as estimates of recollection and familiarity. Across the lifespan, the trajectory of recognition memory followed an inverse u-shape function that was neither affected by word frequency nor by retention interval. The trajectory of estimates of recollection also followed an inverse u-shape function, and was especially pronounced for low-frequency words. In contrast, estimates of familiarity did not differ across the lifespan. The results indicate that age differences in recognition memory are mainly due to differences in processes related to recollection while the contribution of familiarity-based processes seems to be age-invariant.

Holocene flood frequency across the Central Alps – solar forcing and evidence for variations in North Atlantic atmospheric circulation

The frequency of large-scale heavy precipitation events in the European Alps is expected to undergo substantial changes with current climate change. Hence, knowledge about the past natural variability of floods caused by heavy precipitation constitutes important input for climate projections. We present a comprehensive Holocene (10,000 years) reconstruction of the flood frequency in the Central European Alps combining 15 lacustrine sediment records. These records provide an extensive catalog of flood deposits, which were generated by flood-induced underflows delivering terrestrial material to the lake floors. The multi-archive approach allows suppressing local weather patterns, such as thunderstorms, from the obtained climate signal. We reconstructed mainly late spring to fall events since ice cover and precipitation in form of snow in winter at high-altitude study sites do inhibit the generation of flood layers. We found that flood frequency was higher during cool periods, coinciding with lows in solar activity. In addition, flood occurrence shows periodicities that are also observed in reconstructions of solar activity from C-14 and Be-10 records (2500-3000, 900-1200, as well as of about 710, 500, 350, 208 (Suess cycle), 150, 104 and 87 (Gleissberg cycle) years). As atmospheric mechanism, we propose an expansion/shrinking of the Hadley cell with increasing/decreasing air temperature, causing dry/wet conditions in Central Europe during phases of high/low solar activity. Furthermore, differences between the flood patterns from the Northern Alps and the Southern Alps indicate changes in North Atlantic circulation. Enhanced flood occurrence in the South compared to the North suggests a pronounced southward position of the Westerlies and/or blocking over the northern North Atlantic, hence resembling a negative NAO state (most distinct from 4.2 to 2.4 kyr BP and during the Little Ice Age). South-Alpine flood activity therefore provides a qualitative record of variations in a paleo-NAO pattern during the Holocene. Additionally, increased South Alpine flood activity contrasts to low precipitation in tropical Central America (Cariaco Basin) on the Holocene and centennial time scale. This observation is consistent with a Holocene southward migration of the Atlantic circulation system, and hence of the ITCZ, driven by decreasing summer insolation in the Northern hemisphere, as well as with shorter-term fluctuations probably driven by solar activity. (C) 2013 Elsevier Ltd. All rights reserved.

Developmental aspects of synaesthesia across the adult lifespan

In synaesthesia, stimuli such as sounds, words or letters trigger experiences of colors, shapes or tastes and the consistency of these experiences is a hallmark of this condition. In this study we investigate for the first time whether there are age-related changes in the consistency of synaesthetic experiences. We tested a sample of more than 400 grapheme-color synaesthetes who have color experiences when they see letters and/or digits with a well-established test of consistency. Our results showed a decline in the number of consistent grapheme-color associations across the adult lifespan. We also assessed age-related changes in the breadth of the color spectrum. The results showed that the appearance of primary colors (i.e., red, blue, and green) was mainly age-invariant. However, there was a decline in the occurrence of lurid colors while brown and achromatic tones occurred more often as concurrents in older age. These shifts in the color spectrum suggest that synaesthesia does not simply fade, but rather undergoes more comprehensive changes. We propose that these changes are the result of a combination of both age-related perceptual and memory processing shifts.

Gender-fair language in the context of leadership: Preventing the lack of fit for women

Women are still underrepresented in leadership due to a perceived a ‘lack of fit’. Thus, women are hired less likely, evaluated unfavorably or are less willing to take over a leadership role than their male counterparts. Because gender-fair language (e.g., feminine-masculine word pairs, German: ‘Geschäftsführerin/Geschäftsführer’, CEO, fem./CEO, masc.) leads to a higher mental inclusion of women compared to generic masculine forms (German: ‘Geschäftsführer’, CEO,masc.), we argue that masculine forms endorse the ‘lack of fit’ for women in leadership, whereas gender-fair language reduces it. Three studies support our assumption. Masculine forms led to a ‘lack of fit’ for women in leader selection: they were hired less likely (Study 1) and evaluated less favorably (Study 2) than their male counterparts. Moreover, women showed less willingness to apply when masculine forms were used in the advertisement for a leadership position. Contrary, no such gender-bias was obtained in case of gender-fair language.

Gender-fair Language Changes the Social Perception of Professional Groups: The Case of German and Italian.

Gender-fair language, including women and men, such as word pairs has a substantial impact on the mental representation, as a large body of studies have shown. When using exclusively the masculine form as a generic, women are mentally significantly less represented than men. Word pairs, however, lead to a higher cognitive inclusion of women. Surprisingly little research has been conducted to understand how the perception of professional groups is affected by gender-fair language. Providing evidence from an Italian-Austrian cross-cultural study with over 400 participants, we argue that gender-fair language impacts the perception of professional groups, in terms of perceived gender-typicality, number of women and men assumed for a profession, social status and average income. Results hint at a pervasive pay-off: on the one hand, gender-fair language seems to boost the mental representations in favor of women and professions are perceived as being rather gender-neutral. On the other hand professional groups are assigned lower salary and social status with word pairs. Implications of results are discussed.