β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase,UCH-L1

We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.     

Adaptive developmental plasticity: what is it,how can we recognize it and when can it evolve?

Developmental plasticity describes situations where a specific input during an individual''s development produces a lasting alteration in phenotype. Some instances of developmental plasticity may be adaptive, meaning that the tendency to produce the phenotype conditional on having experienced the developmental input has been under positive selection. We discuss the necessary assumptions and predictions of hypotheses concerning adaptive developmental plasticity (ADP) and develop guidelines for how to test empirically whether a particular example is adaptive. Central to our analysis is the distinction between two kinds of ADP: informational, where the developmental input provides information about the future environment, and somatic state-based, where the developmental input enduringly alters some aspect of the individual''s somatic state. Both types are likely to exist in nature, but evolve under different conditions. In all cases of ADP, the expected fitness of individuals who experience the input and develop the phenotype should be higher than that of those who experience the input and do not develop the phenotype, while the expected fitness of those who do not experience the input and do not develop the phenotype should be higher than those who do not experience the input and do develop the phenotype. We describe ancillary predictions that are specific to just one of the two types of ADP and thus distinguish between them.     

Glycans from Fasciola hepatica Modulate the Host Immune Response and TLR-Induced Maturation of Dendritic Cells

Helminths express various carbohydrate-containing glycoconjugates on their surface, and they release glycan-rich excretion/secretion products that can be very important in their life cycles, infection and pathology. Recent evidence suggests that parasite glycoconjugates could play a role in the evasion of the immune response, leading to a modified Th2-polarized immune response that favors parasite survival in the host. Nevertheless, there is limited information about the nature or function of glycans produced by the trematode Fasciola hepatica, the causative agent of fasciolosis. In this paper, we investigate whether glycosylated molecules from F. hepatica participate in the modulation of host immunity. We also focus on dendritic cells, since they are an important target of immune-modulation by helminths, affecting their activity or function. Our results indicate that glycans from F. hepatica promote the production of IL-4 and IL-10, suppressing IFNγ production. During infection, this parasite is able to induce a semi-mature phenotype of DCs expressing low levels of MHCII and secrete IL-10. Furthermore, we show that parasite glycoconjugates mediate the modulation of LPS-induced maturation of DCs since their oxidation restores the capacity of LPS-treated DCs to secrete high levels of the pro-inflammatory cytokines IL-6 and IL-12/23p40 and low levels of the anti-inflammatory cytokine IL-10. Inhibition assays using carbohydrates suggest that the immune-modulation is mediated, at least in part, by the recognition of a mannose specific-CLR that signals by recruiting the phosphatase Php2. The results presented here contribute to the understanding of the role of parasite glycosylated molecules in the modulation of the host immunity and might be useful in the design of vaccines against fasciolosis.     

Liver Accumulation of Plasmodium chabaudi-Infected Red Blood Cells and Modulation of Regulatory T Cell and Dendritic Cell Responses

It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (Pc-iRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.     

How costly is clutch formation in the Audouin's Gull Larus audouinii?

During the Audouin's Gull's breeding season at the Ebro Delta in 1993, 24 fresh eggs from eight three-egg clutches (modal clutch-size) were collected at the peak of the laying period. Eggs were processed to obtain formalin-fixed yolks, which were halved and stained using the potassium dichromate method. Digitized images of the yolks were examined to assess the daily rates of yolk deposition. We used these data in combination with egg compositional analysis to build a model of energy demands during the formation of an average clutch in Audouin's Gull. To show how the different parameters of clutch formation affect the daily energy investment peak, we performed a simulation analysis in which the rapid yolk development (RYD) period, the follicle triggering interval (FTI), the laying interval (LI) and the albumen synthesis period (ASP) were allowed to vary simultaneously. In our sample, the mean RYD period was seven days with a range from six to eight days. There were no significant differences in yolk volume among eggs in a clutch, but albumen volume was significantly smaller in third eggs. According to our model the albumen synthesis of the a-egg coincides with the energy demand peak for clutch formation. This peak represents an increase by ca. 42% in female energy requirements. Values obtained from the simulation analysis showed that only the ASP of the a-egg and the RYD durations of the second and third follicles produced noticeable reductions in peak energy investment. We predict that in gulls, whose laying intervals seem to be kept constant, significant increases of the durations of the RYD periods of second and third eggs, or even significant reductions of yolk size of these eggs, may operate simultaneously to match the energy demands during clutch formation to the prevailing food conditions.     

Isolation and characterization of a type II restriction endonuclease from Streptococcus thermophilus

The alpha-toxin (phospholipase C) of Clostridium perfringens has been reported to contain catalytically essential zinc ions. We report here that histidine residues are essential for the co-ordination of these ion(s). Incubation of alpha toxin with diethylpyrocarbonate, a histidine modifying reagent, did not result in the loss of phospholipase C activity unless the protein was first incubated with EDTA, suggesting that zinc ions normally protect the susceptible histidine residues. When the amino acid sequences of three phospholipase C's were aligned, essential zinc binding histidine residues in the non-toxic B. cereus phospholipase C were found in similar positions in the toxic C. perfringens enzyme and the weakly toxic C. bifermentans phospholipase C.     

Production of entomopathogenic nematodes in submerged monoxenic culture: A review

Monoxenic liquid culture is the most suitable technology for scaling up to industrial production of entomopathogenic nematodes (EPNs); however, the variability of the yield production remains a current problem in the process. The aim of this study was to analyze the parameters and criteria for EPN production in liquid culture based on scientific and technological knowledge from the last two decades. While experimental research has permitted the yield production of Heterorhabditis bacteriophora (362 × 10³ infective juveniles [IJs]/ml) and Steinernema carpocapsae (252 × 10³ IJs/ml), simultaneously, theoretical approaches have contributed to the understanding of the culture process, based on biological parameters of the bacterium–nematode complex and hydrodynamic and rheological parameters of the complex gas–liquid–solid system. Under this interdisciplinary research approach, bioprocess and biosystem engineering can contribute to design the various control strategies of the process variables, increase the productivity, and reduce the variability that until now distinguishes the in vitro production of EPNs by the liquid culture.     

Striking difference in response to expanding brood parasites by birds in western and eastern Beringia

Two species of obligate brood‐parasitic Cuculus cuckoos are expanding their ranges in Beringia. Both now breed on the Asian side, close to the Bering Strait, and are found in Alaska during the breeding season. From May to July 2017, we used painted 3D‐printed model eggs of two cuckoo host‐races breeding in northeastern Siberia to test behavioral responses of native songbirds on both sides of the Bering Strait, with particular attention to species that are known cuckoo hosts in their Siberian range. Each host nest was tested after the second egg was laid and, if possible, again 4 days later with a model of a different type. Although our Siberian study site was also outside the known breeding ranges of the cuckoos, we found that Siberian birds had strong anti‐parasite responses, with 14 of 22 models rejected. In contrast, birds in Alaska had virtually no detectable anti‐parasite behaviors, with only one of 96 models rejected; the rejecters were Red‐throated Pipits (Anthus cervinus). Such differences suggest that the cuckoos might successfully parasitize naïve hosts and become established in North America whether or not their historic host species are widely available.