Improved detection of amnestic MCI by means of discriminative vector quantization of single-trial cognitive ERP responses

Cognitive event-related potentials (ERPs) are widely employed in the study of dementive disorders. The morphology of averaged response is known to be under the influence of neurodegenerative processes and exploited for diagnostic purposes. This work is built over the idea that there is additional information in the dynamics of single-trial responses. We introduce a novel way to detect mild cognitive impairment (MCI) from the recordings of auditory ERP responses. Using single trial responses from a cohort of 25 amnestic MCI patients and a group of age-matched controls, we suggest a descriptor capable of encapsulating single-trial (ST) response dynamics for the benefit of early diagnosis. A customized vector quantization (VQ) scheme is first employed to summarize the overall set of ST-responses by means of a small-sized codebook of brain waves that is semantically organized. Each ST-response is then treated as a trajectory that can be encoded as a sequence of code vectors. A subject's set of responses is consequently represented as a histogram of activated code vectors. Discriminating MCI patients from healthy controls is based on the deduced response profiles and carried out by means of a standard machine learning procedure. The novel response representation was found to improve significantly MCI detection with respect to the standard alternative representation obtained via ensemble averaging (13% in terms of sensitivity and 6% in terms of specificity). Hence, the role of cognitive ERPs as biomarker for MCI can be enhanced by adopting the delicate description of our VQ scheme.

On the comparison of VR-responses, as performance measures in prospective memory, with auditory P300 responses in MCI detection

Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general spatial navigation task or an executive function (EF) virtual action planning. There has been only one previous work with virtual reality and the use of a virtual action planning supermarket for the diagnosis of mild cognitive impairment. The authors of that study examined the feasibility and the validity of the virtual action planning supermarket (VAP-S) for the diagnosis of patients with mild cognitive impairment (MCI) and found that the VAP-S is a viable tool to assess EF deficits. In our study we employed the in-house platform of virtual action planning museum (VAP-M) and a sample of 25 MCI and 25 controls, in order to investigate deficits in spatial navigation, prospective memory and executive function. In addition, we used the morphology of late components in event-related potential (ERP) responses, as a marker for cognitive dysfunction. The related measurements were fed to a common classification scheme facilitating the direct comparison of both approaches. Our results indicate that both the VAP-M and ERP averages were able to differentiate between healthy elders and patients with amnestic mild cognitive impairment and agree with the findings of the virtual action planning supermarket (VAP-S). The sensitivity (specificity) was 100% (98%) for the VAP-M data and 87%(90%) for the ERP responses. Considering that ERPs have proven to advance the early detection and diagnosis of "presymptomatic AD", the suggested VAP-M platform appears as an appealing alternative.

The Immune System of Spiders

Spiders, as all other arthropods, have an open circulatory system, and their body fluid, the hemolymph, freely moves between lymphatic vessels and the body cavities (see Wirkner and Huckstorf 2013). The hemolymph can be considered as a multifunctional organ, central for locomotion (Kropf 2013), respiration (Burmester 2013) and nutrition, and it amounts to approximately 20 % of a spider’s body weight. Any injury includes not only immediate hemolymph loss but also pathogen attacks and subsequent infections. Therefore spiders have to react to injuries in a combined manner to stop fluid loss and to defend against microbial invaders. This is achieved by an innate immune system which involves several host defence systems such as hemolymph coagulation and the production of a variety of defensive substances (Fukuzawa et al.2008). In spiders, the immune system is localised in hemocytes which are derived from the myocardium cells of the heart wall where they are produced as prohemocytes and from where they are released as different cell types into the hemolymph (Seitz 1972). They contribute to the defence against pathogens by phagocytosis, nodulation and encapsulation of invaders. The humoral response includes mechanisms which induce melanin production to destroy pathogens, a clotting cascade to stop hemolymph loss and the constitutive production of several types of antimicrobial peptides, which are stored in hemocyte granules and released into the hemolymph (Fukuzawa et al.2008) (Fig.7.1). The immune system of spiders is an innate immune system. It is hemolymph-based and characterised by a broad but not very particular specificity. Its advantage is a fast response within minutes to a few hours. This is in contrast to the adaptive immune system of vertebrates which can react to very specific pathogens, thus resulting in much more specific responses. Moreover, it creates an immunological memory during the lifetime of the species. The disadvantage is that it needs more time to react with antibody production, usually many hours to a few days, and needs to be built up during early ontogenesis.

The development and characterization of two types of chronic responses in irradiated mouse colon

The hypothesis to be tested is that there are two distinct types of chronic responses in irradiated normal tissues, each resulting from damage to different cell populations in the tissue. The first is a sequala of chronic epithelial depletion in which the tissue's integrity cannot be maintained, i.e. a "consequential" chronic response. The other response is due to cell loss in the connective tissue and/or vascular stroma, i.e. a "primary" chronic response. The purpose of this study was to test the hypothesis in the murine colon by first, establishing a model of each chronic response and then, by determining whether the responses differed in timing of expression, histology, and expression of specific collagen types. The model of late damage used was colonic obstructions/strictures induced by a single dose of 27 Gy ("consequential" response) and two equal doses of 14.75 Gy (t = 10 days) ("primary" response). "Consequential" lesions appeared as early as 5 weeks after 27 Gy and were characterized by a deep mucosal ulceration and a thickened fibrotic serosa containing excessive accumulations of collagen types I and III. Both types were commingled in the scar at the base of the ulcer. Fibroblasts were synthesizing pro-collagen types I and III mRNA 10 weeks prior to measurable increases in collagen. A significant decrease in the ratio of collagen types I:III was associated with the "consequential" response at 4-5 months post-irradiation. The "primary" response, on the other hand, did not appear until 40 weeks after the split dose even though the total dose delivered was approximately the same as that for the "consequential" response. The "primary" response was characterized with an intact mucosa and a thickened fibrotic submucosa which contained excessive amounts of only collagen type I. An increased number of fibroblasts were synthesizing pro-collagen type I mRNA nearly 25 weeks before collagen type I levels were increased. The "primary" response lesion had a significantly elevated collagen type I:III ratio at 10-13 months post-irradiation. These data show a clear difference between the two chronic response and suggest that not all chronic responses share a common pathogenesis, but depend on the cell population in the tissue that is damaged. ^

Religion and the Senses in Early Modern Europe

Sensation is the subject of a burgeoning field in the humanities. This volume examines its role in the religious changes and transformations of early modern Europe. Sensation was not only central to the doctrinal disputes of the Reformation, but also critical in shaping new or reformed devotional practices. From this vantage point the book explores the intersections between the world of religion and the spheres of art, music, and literature; food and smell; sacred things and spaces; ritual and community; science and medicine. Deployed in varying, often contested ways, the senses were essential pathways to the sacred. They permitted knowledge of the divine and the universe, triggered affective responses, shaped holy environments, and served to heal, guide, or discipline body and soul.

Highly pathogenic adapted HIV-1 strains limit host immunity and dictate rapid disease progression.

OBJECTIVE: The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome. DESIGN: We carried out comparative functional analyses in rapid progressors (n = 46) and standard progressors (n = 46) early after HIV-1 seroconversion (≤1 year). The viral traits tested were viral replicative capacity, co-receptor usage, and genomic variation. Host CD8 T-cell responses, humoral activity, and HLA immunogenetic markers were also determined. RESULTS: Our data demonstrate an unusual convergence of highly pathogenic HIV-1 strains in rapid progressors. Compared with standard progressors, rapid progressor viral strains show higher in-vitro replicative capacity (81.5 vs. 67.9%; P = 0.025) and greater X4/DM co-receptor usage (26.3 vs. 2.8%; P = 0.006) in early infection. Limited or absent functional HIV-1 CD8 T-cell responses and neutralizing activity were measured in rapid progressors. Moreover, the increase in common HLA allele-restricted CD8 T-cell escape mutations in rapid progressors acts as a signature of uncontrolled HIV-1 replication and early impairment of adaptive cellular responses. CONCLUSION: Our data support a dominant role for viral factors in rapid progressors. Robust HIV-1 replication and intrinsic viral properties limit host adaptive immune responses, thus driving rapid disease progression.

Adaptive Algorithms for Personalized Diabetes Treatment

Dynamic systems, especially in real-life applications, are often determined by inter-/intra-variability, uncertainties and time-varying components. Physiological systems are probably the most representative example in which population variability, vital signal measurement noise and uncertain dynamics render their explicit representation and optimization a rather difficult task. Systems characterized by such challenges often require the use of adaptive algorithmic solutions able to perform an iterative structural and/or parametrical update process towards optimized behavior. Adaptive optimization presents the advantages of (i) individualization through learning of basic system characteristics, (ii) ability to follow time-varying dynamics and (iii) low computational cost. In this chapter, the use of online adaptive algorithms is investigated in two basic research areas related to diabetes management: (i) real-time glucose regulation and (ii) real-time prediction of hypo-/hyperglycemia. The applicability of these methods is illustrated through the design and development of an adaptive glucose control algorithm based on reinforcement learning and optimal control and an adaptive, personalized early-warning system for the recognition and alarm generation against hypo- and hyperglycemic events.

The Early Activation Marker CD69 Regulates the Expression of Chemokines and CD4 T Cell Accumulation in Intestine

Migration of naïve and activated lymphocytes is regulated by the expression of various molecules such as chemokine receptors and ligands. CD69, the early activation marker of C-type lectin domain family, is also shown to regulate the lymphocyte migration by affecting their egress from the thymus and secondary lymphoid organs. Here, we aimed to investigate the role of CD69 in accumulation of CD4 T cells in intestine using murine models of inflammatory bowel disease. We found that genetic deletion of CD69 in mice increases the expression of the chemokines CCL-1, CXCL-10 and CCL-19 in CD4(+) T cells and/or CD4(-) cells. Efficient in vitro migration of CD69-deficient CD4 T cells toward the chemokine stimuli was the result of increased expression and/or affinity of chemokine receptors. In vivo CD69(-/-) CD4 T cells accumulate in the intestine in higher numbers than B6 CD4 T cells as observed in competitive homing assay, dextran sodium sulphate (DSS)-induced colitis and antigen-specific transfer colitis. In DSS colitis CD69(-/-) CD4 T cell accumulation in colonic lamina propria (cLP) was associated with increased expression of CCL-1, CXCL-10 and CCL-19 genes. Furthermore, treatment of DSS-administrated CD69(-/-) mice with the mixture of CCL-1, CXCL-10 and CCL-19 neutralizing Abs significantly decreased the histopathological signs of colitis. Transfer of OT-II×CD69(-/-) CD45RB(high) CD4 T cells into RAG(-/-) hosts induced CD4 T cell accumulation in cLP. This study showed CD69 as negative regulator of inflammatory responses in intestine as it decreases the expression of chemotactic receptors and ligands and reduces the accumulation of CD4 T cells in cLP during colitis.

Influences of porcine circo-, arteriviruses and cathelicidins in plasmacytoid dendritic cell-derived interferon-alpha responses

Type I interferons (IFNs), mainly IFN-α/β play a crucial role in innate defense against viruses. In addition to their direct antiviral activity, type I IFNs have antitumoral and immunomodulatory effects. Although all cells are virtually able to induce IFN-α, the plasmacytoid dendritic cell (pDC) subset represents the ultimate producers of IFN-α as well as other proinflammatory cytokines. Due to the specific expression of TLR7 and TLR9 recognizing single-stranded (ss) RNA and unmethylated CpG motifs respectively, pDCs can secrete up to 1000 times more IFN-α than any cellular types. Additionally, it is well known that several cytokines including type I and II IFNs, Flt3-L, IL-4 and GM-CSF favor pDC-derived IFN-α responses to unmethylated CpG motifs. In a first step, we aimed to characterize and clarify the interactions of two porcine viruses with pDCs. The double-stranded DNA replicative forms of porcine circovirus type 2 (PCV2) were demonstrated to inhibit CpG-induced IFN- α by pDCs. Our study showed that none of the cytokines known to enhance pDC responsiveness can counter-regulate the PCV2-mediated inhibition of IFN-α induced by CpG, albeit IFN-γ significantly reduced the level of inhibition. Interestingly, the presence of IFN-γ enabled pDCs to induce IFN-α to low doses of PCV2. We also noted that after DNase treatment, PCV2 preparations were still able to stimulate pDCs. These data suggest that encapsulated viral ssDNA promotes the induction of IFN-α in pDCs treated with IFN-γ whereas free DNA, presumably as double-stranded forms, was responsible for inhibiting pDC responses. Regarding PRRSV, it has been reported that North American isolates did not induce and even inhibited IFN-α response in pDCs. However, PRRSV infection was also shown to lead to an induction of IFN-α in the serum and in the lungs suggesting that certain cells are responsive to the virus. Contrasting to previous reports we found that numerous PRRSV isolates directly induced IFN-α in pDCs. This response was still observed after UV-inactivation of viruses and required TLR7 signaling. The inhibition of CpG-induced IFN-α was weak and strain dependent, again contrasting with a previous report. We also observed that IFN-γ and IL-4 enhanced IFN-α response to two prototype strains, VR-2332 and LVP23. In summary, we demonstrated that both PCV2 and PRRSV promote IFN-α secretion in pDCs in vitro suggesting that IFN-α detected in PCV2- or PRRSV-infected animal might originate from pDCs. On the other hand, PRRSV replication is restricted to the macrophage (MΦ) lineage. These innate immune cells represent a heterogeneous population which can be induce to “classical” (M1) and “alternative” (M2) activated MΦ acquiring inflammatory or “wound-healing” functional properties, respectively. Nonetheless, little is known about the effect of polarization into M1 or M2 and the susceptibility of these cells to PRRSV. Thus, we examined the impact of cytokine on MΦ polarization into M1 or M2. Infections of these cells by several PRRSV isolates enabled the discrimination of PRRSV isolate in a genotype- and irulencedependent manner in M1 and IFN-β-activated MΦ. In contrast, the expression of PRRSV nucleocapsid in M2 or inactivated MΦ was indistinguishable among the PRRSV isolates tested. In the last part of my Thesis, we investigated the influence of three synthetic porcine cathelicidin peptides for their ability to deliver nucleic acid to pDCs. We reported that all cathelicidins tested can complex and quickly deliver nucleic acids resulting in IFN-α induction. Moreover, we show that the typical α- helical amphipathic conformation is required to mediate killing of bacteria but not for inducing IFN-α secretion by pDCs. Furthermore, we found that E.coli treated with one of these cathelicidins is able to induce significantly higher levels of IFN-α compared to a non-sense version of the peptide. These data suggest that cathelicidins could influence the immune response in a two-step process. First, these peptides target bacteria leading to cell lysis. In turn, cathelicidins form complexes and deliver extracellular microbial nucleic acids released into pDCs. These pDC-derived IFN-α responses could be of particular relevance in driving the adaptive immune responses against microbial infections.

Comparison of hepatic adaptation in extreme metabolic phenotypes observed in early lactation dairy cows on-farm

The aim was to study the variation in metabolic responses in early-lactating dairy cows (n = 232) on-farm that were pre-selected for a high milk fat content (>45 g/l) and a high fat/protein ratio in milk (>1.5) in their previous lactation. Blood was assayed for concentrations of metabolites and hormones. Liver was measured for mRNA abundance of 25 candidate genes encoding enzymes and receptors involved in gluconeogenesis (6), fatty acid β-oxidation (6), fatty acid and triglyceride synthesis (5), cholesterol synthesis (4), ketogenesis (2) and the urea cycle (2). Two groups of cows were formed based on the plasma concentrations of glucose, non-esterified fatty acids (NEFA) and β-hydroxybutyric acid (BHBA) (GRP+, high metabolic load; glucose <3.0 mm, NEFA >300 μm and BHBA >1.0 mm, n = 30; GRP-, low metabolic load; glucose >3.0 mm, NEFA <300 μm and BHBA <1.0 mm, n = 30). No differences were found between GRP+ and GRP- for the milk yield at 3 weeks post-partum, but milk fat content was higher (p < 0.01) for GRP+ than for GRP-. In week 8 post-partum, milk yield was higher in GRP+ in relation to GRP- (37.5 vs. 32.5 kg/d; p < 0.01). GRP+ in relation to GRP- had higher (p < 0.001) NEFA and BHBA and lower glucose, insulin, IGF-I, T3 , T4 concentrations (p < 0.01). The mRNA abundance of genes related to gluconeogenesis, fatty acid β-oxidation, fatty acid and triglyceride synthesis, cholesterol synthesis and the urea cycle was different in GRP+ compared to GRP- (p < 0.05), although gene transcripts related to ketogenesis were similar between GRP+ and GRP-. In conclusion, high metabolic load post-partum in dairy cows on-farm corresponds to differences in the liver in relation to dairy cows with low metabolic load, even though all cows were pre-selected for a high milk fat content and fat/protein ratio in milk in their previous lactation.

Parameterization of temperature sensitivity of spring phenology and its application in explaining diverse phenological responses to temperature change

Existing evidence of plant phenological change to temperature increase demonstrates that the phenological responsiveness is greater at warmer locations and in early-season plant species. Explanations of these findings are scarce and not settled. Some studies suggest considering phenology as one functional trait within a plant's life history strategy. In this study, we adapt an existing phenological model to derive a generalized sensitivity in space (SpaceSens) model for calculating temperature sensitivity of spring plant phenophases across species and locations. The SpaceSens model have three parameters, including the temperature at the onset date of phenophases (Tp), base temperature threshold (Tb) and the length of period (L) used to calculate the mean temperature when performing regression analysis between phenology and temperature. A case study on first leaf date of 20 plant species from eastern China shows that the change of Tp and Tb among different species accounts for interspecific difference in temperature sensitivity. Moreover, lower Tp at lower latitude is the main reason why spring phenological responsiveness is greater there. These results suggest that spring phenophases of more responsive, early-season plants (especially in low latitude) will probably continue to diverge from the other late-season plants with temperatures warming in the future.

Porcine cathelicidins efficiently complex and deliver nucleic acids to plasmacytoid dendritic cells and can thereby mediate bacteria-induced IFN-α responses.

Cathelicidins constitute potent antimicrobial peptides characterized by a high cationic charge that enables strong interactions with nucleic acids. In fact, the only human cathelicidin LL-37 triggers rapid sensing of nucleic acids by plasmacytoid dendritic cells (pDC). Among the porcine cathelicidins, phylogenetic analysis of the C-terminal mature peptide showed that porcine myeloid antimicrobial peptide (PMAP)-36 was the most closely related of the 11 porcine cathelicidins to human LL-37. Despite several investigations evaluating potent antimicrobial functions of porcine cathelicidins, nothing is known about their ability to promote pDC activation. We therefore investigated the capacity of the proline-arginine-rich 39-aa peptide, PMAP-23, PMAP-36, and protegrin-1 to complex with bacterial DNA or synthetic RNA molecules and facilitate pDC activation. We demonstrate that these peptides mediate a rapid and efficient uptake of nucleic acids within minutes, followed by robust IFN-α responses. The highest positively charged cathelicidin, PMAP-36, was found to be the most potent peptide tested for this effect. The peptide-DNA complexes were internalized and also found to associate with the cell membranes of pDC. The amphipathic conformation typical of PMAP-36 was not required for IFN-α induction in pDC. We also demonstrate that PMAP-36 can mediate IFN-α induction in pDC stimulated by Escherichia coli, which alone fail to activate pDC. This response was weaker with a scrambled PMAP-36, relating to its lower antimicrobial activity. Collectively, our data suggest that the antimicrobial and nucleic acid-complexing properties of cathelicidins can mediate pDC activation-promoting adaptive immune responses against microbial infections.

Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses.

Segmented filamentous bacterium (SFB) is a symbiont that drives postnatal maturation of gut adaptive immune responses. In contrast to nonpathogenic E. coli, SFB stimulated vigorous development of Peyer's patches germinal centers but paradoxically induced only a low frequency of specific immunoglobulin A (IgA)-secreting cells with delayed accumulation of somatic mutations. Moreover, blocking Peyer's patch development abolished IgA responses to E. coli, but not to SFB. Indeed, SFB stimulated the postnatal development of isolated lymphoid follicles and tertiary lymphoid tissue, which substituted for Peyer's patches as inductive sites for intestinal IgA and SFB-specific T helper 17 (Th17) cell responses. Strikingly, in mice depleted of gut organized lymphoid tissue, SFB still induced a substantial but nonspecific intestinal Th17 cell response. These results demonstrate that SFB has the remarkable capacity to induce and stimulate multiple types of intestinal lymphoid tissues that cooperate to generate potent IgA and Th17 cell responses displaying only limited target specificity.

On the comparison of a novel serious game and electroencephalography biomarkers for early dementia screening

Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general spatial navigation task or an executive function (EF) virtual action planning. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. In our study we employed the in-house platform of virtual action planning museum (VAP-M) and a sample of 25 MCI and 25 controls, in order to investigate deficits in spatial navigation, prospective memory, and executive function. In addition, we used the morphology of late components in event-related potential (ERP) responses, as a marker for cognitive dysfunction. The related measurements were fed to a common classification scheme facilitating the direct comparison of both approaches. Our results indicate that both the VAP-M and ERP averages were able to differentiate between healthy elders and patients with amnestic mild cognitive impairment and agree with the findings of the virtual action planning supermarket (VAP-S). The sensitivity (specificity) was 100% (98%) for the VAP-M data and 87% (90%) for the ERP responses. Considering that ERPs have proven to advance the early detection and diagnosis of "presymptomatic AD," the suggested VAP-M platform appears as an appealing alternative.

Antipredator defences of young are independently determined by genetic inheritance, maternal effects and own early experience in mouthbrooding cichlids.

1. Predation is a prime force of natural selection. Vulnerability to predation is typically highest early in life, hence effective antipredator defences should work already shortly after birth. Such early defences may be innate, transmitted through non-genetic parental effects or acquired by own early experience. 2. To understand potential joint effects of these sources of antipredator defences on pheno- typic expression, they should be manipulated within the same experiment. We investigated innate, parental and individual experience effects within a single experiment. Females of the African cichlid Simochromis pleurospilus were exposed to the offspring predator Ctenochromis horei or a benign species until spawning. Eggs and larvae were hand-reared, and larvae were then exposed to odour cues signalling the presence or absence of predators in a split-brood design. 3. Shortly after independence of maternal care, S. pleurospilus undergo a habitat shift from a deeper, adult habitat to a shallow juvenile habitat, a phase where young are thought to be par- ticularly exposed to predation risk. Thus, maternal effects induced by offspring predators pres- ent in the adult habitat should take effect mainly shortly after independence, whereas own experience and innate antipredator responses should shape behaviour and life history of S. pleurospilus during the later juvenile period. 4. We found that the manipulated environmental components independently affected different offspring traits. (i) Offspring of predator-exposed mothers grew faster during the first month of life and were thus larger at termination of maternal care, when the young migrate from the adult to the juvenile habitat. (ii) The offspring’s own experience shortly after hatching exerted lasting effects on predator avoidance behaviour. (iii) Finally, our results suggest that S. pleuro- spilus possess a genetically inherited ability to distinguish dangerous from benign species. 5. In S. pleurospilus, maternal effects were limited to a short but critical time window, when young undergo a niche shift. Instead, own environmental sampling of predation risk combined with an innate predisposition to correctly identify predators appears to prepare the young best for the environment, in which they grow up as juveniles.