Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.

Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.

Inbreeding and thermal adaptation in Drosophila subobscura

Using a well-adapted Drosophila subobscura population (Avala, Serbia), a drastic experiment of inbreeding was carried out to assess whether the expected level of homozygosity could be reached or if other evolutionary forces affected the process. In general, no significant changes of inversion (or arrangement) frequencies were detected after 12 brother sister mating generations. Furthermore, no significant differences were obtained between observed and expected (under the inbreeding model) karyotypic frequencies. Thus, these results seemed to indicate that the main evolutionary factor in the experiment was inbreeding. However, in the G12 generation, complete chromosomal fixation was reached only in two out of the eight final inbred lines. In these lines, the chromosomal compositions were difficult to interpret, but they could be likely a consequence of adaptation to particular laboratory conditions (constant 18 °C, food, light period, etc.). Finally, in a second experiment, the inbred lines presented higher fertility at 18 °C than at 13 °C. Also, there was a significant line effect on fertility: inbred line number 6 (A1, J1, U1+2; U1+2+6, E8, and O3+4+7) presented the highest values, which maybe the result of an adaptation to laboratory conditions. Thus, the results obtained in our experiments reflect the adaptive potential of D. subobscura inversions.

Enhancing the efficiency of freight transport by using simulation

The role of transport in the economy is twofold. As a sector of economic activity it contributes to a share of national income. On the other hand, improvements in transport infrastructure create room for accelerated economic growth. As a means to support railways as a safe and environmentally friendly transportation mode, the EU legislation has required the opening of domestic railway freight for competition from beginning of year 2007. The importance of railways as a mode of transport has been great in Finland, as a larger share of freight has been carried on rails than in Europe on average. In this thesis it is claimed that the efficiency of goods transport can be enhanced by service specific investments. Furthermore, it is stressed that simulation can and should be used to evaluate the cost-efficiency of transport systems on operational level, as well as to assess transportation infrastructure investments. In all the studied cases notable efficiency improvements were found. For example in distribution, home delivery of groceries can be almost twice as cost efficient as the current practice of visiting the store. The majority of the cases concentrated on railway freight. In timber transportation, the item with the largest annual transport volume in domestic railway freight in Finland, the transportation cost could be reduced most substantially. Also in international timber procurement, the utilization of railway wagons could be improved by combining complementary flows. The efficiency improvements also have positive environmental effects; a large part of road transit could be moved to rails annually. If impacts of freight transport are included in cost-benefit analysis of railway investments, up to 50 % increase in the net benefits of the evaluated alternatives can be experienced, avoiding a possible inbuilt bias in the assessment framework, and thus increasing the efficiency of national investments in transportation infrastructure. Transportation systems are a typical example of complex real world systems that cannot be analysed realistically by analytical methods, whereas simulation allows inclusion of dynamics and the level of detail required. Regarding simulation as a viable tool for assessing the efficiency of transportation systems finds support also in the international survey conducted for railway freight operators; operators use operations research methods widely for planning purposes, while simulation is applied only by the larger operators.

Comparative performance of the stable isotope signatures of carbon, nitrogen and oxygen in assessing early vigour and grain yield in durum wheat

The present paper studied the performance of the stable isotope signatures of carbon (δ13C), nitrogen (δ15N) and oxygen (δ18O) in plants when used to assess early vigour and grain yield (GY) in durum wheat growing under mild and moderate Mediterranean stress conditions. A collection of 114 recombinant inbred lines was grown under rainfed (RF) and supplementary irrigation (IR) conditions. Broad sense heritabilities (H2) for GY and harvest index (HI) were higher under RF conditions than under IR. Broad sense heritabilities for δ13C were always above 0·60, regardless of the plant part studied, with similar values for IR and RF trials. Some of the largest genetic correlations with GY were those shown by the δ13C content of the flag leaf blade and mature grains. Under both water treatments, mature grains showed the highest negative correlations between δ13C and GY across genotypes. Flag leaf δ13C was negatively correlated with GY only under RF conditions. The δ13C in seedlings was negatively correlated, under IR conditions only, with GY but also with early vigour. The sources of variation in early vigour were studied by stepwise analysis using the stable isotope signatures measured in seedlings. The δ13C was able to explain almost 0·20 of this variation under RF, but up to 0·30 under IR. In addition, nitrogen concentration in seedlings accounted for another 0·05 of variation, increasing the amount explained to 0·35. The sources of variation in GY were also studied through stable isotope signatures and biomass of different plant parts: δ13C was always the first parameter to appear in the models for both water conditions, explaining c. 0·20 of the variation. The second parameter (δ15N or N concentration of grain, or biomass at maturity) depended on the water conditions and the plant tissue being analysed. Oxygen isotope composition (δ18O) was only able to explain a small amount of the variation in GY. In this regard, despite the known and previously described value of δ13C as a tool in breeding, δ15N is confirmed as an additional tool in the present study. Oxygen isotope composition does not seem to offer any potential, at least under the conditions of the present study.

Terveyskorttiprojektin kustannusvaikuttavuuden arviointi

Tämän kandidaatintyön lähtökohtana oli selvittää Helsingin kaupungin Terveysasemaosaston Terveyskorttiprojektin aikana toteutetun pilotin taloudellisuutta ja vaikuttavuutta rinnakkaispalveluna. Kirjallisuuskatsauksen tavoitteena oli selvittää millaisilla metodeilla kustannusvaikuttavuutta voidaan analysoida terveydenhuollossa. Lisäksi tavoitteena oli selvittää kyseisen projektin kustannusten suhdetta palvelun vaikuttavuuteen, eli muutoksiin asiakkaiden terveystottumuksissa. Keskeisimpiä kustannusvaikuttavuuden arviointimenetelmiä terveydenhuollossa ovat kustannusten minimointianalyysi (KMA), kustannus-hyötyanalyysi (KHA), kustannus-vaikuttavuusanalyysi (KVA) ja kustannus-utiliteettianalyysi (KUA). Käytännön päätöksenteon analyyttinen mallintaminen empirian- ja näyttöön perustuvan tiedon pohjalta osoittautui kirjallisuuskatsauksessa myös päteväksi tavaksi arvioida palveluiden vaikuttavuutta. Terveyskorttiprojektin suurimmat kustannussäästöt, verrattuna perinteiseen vastaanotto-malliin, muodostuivat verkkopalvelun seulontavaiheessa. Terveyden edistämisen osa-alueisiin painonhallinta, liikunta ja ravitsemus palvelu soveltui hyvin. Palvelun käytettävyyden kehittämishaasteiksi muodostuivat tulosten perusteella tekniset ongelmat, vuoro-vaikutuksen puute ja asiakkaan oman motivaation löytyminen.

Photosynthetic characteristics of hybrid and conventional rice plants as a function of plant competition

The objective of this work was to evaluate the characteristics related to the photosynthetic ability of hybrid and inbred rice varieties, as a way to assess which of the two presented higher potential to stand out under conditions of competition. The trial was set in a greenhouse in completely randomized block design and 2 x 6 factorial scheme with four replications. Factor A consisted of rice varieties (hybrid or inbred) and factor B by competition levels. Treatments consisted in maintaining one plant of either BRS Pelota (inbred) or Inov (hybrid) variety at the center of the plot, under competition with 0, 1, 2, 3, 4 or 5 plants of the variety BRS Pelota at the periphery of the experimental unit, according to the treatment. Fifty days after emergence (DAE), sub-stomatal CO2 concentration (Ci - mmol mol-1), photosynthetic rate (A - mmol m-2 s-1) and CO2 consumed (DC - mmol mol-1) were quantified, as well as shoot dry mass(SDM).Hybrid plants present higher photosynthesis capacity than inbred plants, when competing with up to 3 times its own density. When under the same competitive intensity, hybrid plants surpass the inbred. However, it should be emphasized that, when in farm condition, the lower competitive capacity with weeds often attributed to the hybrid varieties, probably is due to their lower planting density, but if weed competition is kept at low levels, hybrid rice plants may perform in the same way or usually better than inbred plants.

Microsatellite-dense genetic map: towards genome coverage in a tropical maize (Zea mays L.) population

Dense molecular genetic maps are used for an efficient quantitative trait loci (QTL) mapping and in the marker-assisted selection programs. A dense genetic map was generated with 139 microsatellite markers using 256 F2 plants generated by the crossing of two tropical maize inbred lines (L-02-03D and L-20-01F). This map presented 1,858.61 cM in length, where 10 linkage groups were found spanned, with an average interval of 13.47 cM between adjacent markers. Seventy seven percent of the maize genetic mapping bins were covered, which means an increase of 14% coverage in relation to the previous tropical maize maps. The results provide a more detailed and informative genetic map in a tropical maize population representing the first step to make possible the studies of genetic architecture to identify and map QTL and estimate their effects on the variation of quantitative traits, thus allowing the manipulation and use in tropical maize breeding programs.