Jesper Dahlgaard

A systematic review of mechanisms of change in mindfulness-based cognitive therapy in the treatment of recurrent major depressive disorder.

BACKGROUND The investigation of treatment mechanisms in randomized controlled trials has considerable clinical and theoretical relevance. Despite the empirical support for the effect of mindfulness-based cognitive therapy (MBCT) in the treatment of recurrent major depressive disorder (MDD), the specific mechanisms by which MBCT leads to therapeutic change remain unclear. OBJECTIVE By means of a systematic review we evaluate how the field is progressing in its empirical investigation of mechanisms of change in MBCT for recurrent MDD. METHOD To identify relevant studies, a systematic search was conducted. Studies were coded and ranked for quality. RESULTS The search produced 476 articles, of which 23 were included. In line with the theoretical premise, 12 studies found that alterations in mindfulness, rumination, worry, compassion, or meta-awareness were associated with, predicted or mediated MBCTs effect on treatment outcome. In addition, preliminary studies indicated that alterations in attention, memory specificity, self-discrepancy, emotional reactivity and momentary positive and negative affect might play a role in how MBCT exerts its clinical effects. CONCLUSION The results suggest that MBCT could work through some of the MBCT models theoretically predicted mechanisms. However, there is a need for more rigorous designs that can assess greater levels of causal specificity.

dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors

dlk1/FA1 (delta-like 1/fetal antigen-1) is a member of the epidermal growth factor-like homeotic protein family whose expression is known to modulate the differentiation signals of mesenchymal and hematopoietic stem cells in bone marrow. We have demonstrated previously that Dlk1 can maintain the human bone marrow mesenchymal stem cells (hMSC) in an undifferentiated state. To identify the molecular mechanisms underlying these effects, we compared the basal gene expression pattern in Dlk1-overexpressing hMSC cells (hMSC-dlk1) versus control hMSC (negative for Dlk1 expression) by using Affymetrix HG-U133A microarrays. In response to Dlk1 expression, 128 genes were significantly up-regulated (with >2-fold; p < 0.001), and 24% of these genes were annotated as immune response-related factors, including pro-inflammatory cytokines, in addition to factors involved in the complement system, apoptosis, and cell adhesion. Also, addition of purified FA1 to hMSC up-regulated the same factors in a dose-dependent manner. As biological consequences of up-regulating these immune response-related factors, we showed that the inhibitory effects of dlk1 on osteoblast and adipocyte differentiation of hMSC are associated with Dlk1-induced cytokine expression. Furthermore, Dlk1 promoted B cell proliferation, synergized the immune response effects of the bacterial endotoxin lipopolysaccharide on hMSC, and led to marked transactivation of the NF-κB. Our data suggest a new role for Dlk1 in regulating the multiple biological functions of hMSC by influencing the composition of their microenvironment “niche.” Our findings also demonstrate a role for Dlk1 in mediating the immune response.

BEHAVIORAL DIFFERENTIATION IN OVIPOSITION ACTIVITY IN DROSOPHILA BUZZATII FROM HIGHLAND AND LOWLAND POPULATIONS IN ARGENTINA: PLASTICITY OR THERMAL ADAPTATION?

Abstract Highland populations of several Drosophila species in Argentina were active early in the afternoon in the field as opposed to populations from a much warmer lowland site, where flies were mainly active in the early evening prior to sunset. For one of these species, Drosophila buzzatii, we tested for a genetic component of activity differences by carrying out crosses within and between populations and measuring oviposition activity of the progeny in the laboratory. We found that activity in the highland population exceeded that in the lowland one during the midafternoon, whereas activity in the lowland population exceeded that in the highland one prior to the beginning of the dark period. Oviposition activity for the period corresponding to the field observations was regressed on the proportion of the genome derived from the highland population. This variable significantly predicted oviposition activity between 1400 and 1600 and between 2000 and 2200 h. Activity of both reciprocal crosses was intermediate and not significantly different from each other, suggesting that nuclear genetic, rather than cytoplasmic factors contribute to differences in oviposition activity between the populations. Two morphological, one genetic, and one stress resistance trait were also scored to examine whether temperature differences between environments were associated with other differences between populations. Wing length of wild‐caught and laboratory‐reared flies from the highland population significantly exceeded that in the lowland. Thorax length of laboratory‐reared flies from the highland population also significantly exceeded that from the lowland. Chromosomal inversion frequencies differed significantly between the two populations with a fivefold reduction in the frequency of arrangement 2st in the highland as compared to the lowland population. This arrangement is known for its negative dose effect on size, and thus, the highland population has experienced a genetic change, perhaps as a result of adaptation to the colder environment, where body size and the frequency of arrangement 2st have changed in concert. Finally, a heat knockdown test revealed that the lowland population was significantly more resistant to high temperature than the highland one. In conclusion, we suggest that temperature has been an important selective agent causing adaptive differentiation between these two populations. We also suggest that the activity rhythms of the two populations have diverged as a consequence of behavioral evolution, that is, through avoidance of stressful temperatures as a mean of thermal adaptation.

Effects of inbreeding and environmental stress on fitness – using Drosophila buzzatii as a model organism

Wild endangered populations can suffer fromadverse effects on fitness due to inbreedingand environmental stress. Often, both geneticand environmental stress factors may be presentin populations at the same time. Thereforeknowledge on the potential interactions betweenthese factors is important for the conservationof wild populations. When measuring fitness(e.g. survival and reproductive potential) ofindividuals in the laboratory, and in nature,inbreeding by environment interactions are nowbeing reported more often. The increased focuson environmental dependency of inbreedingdepression will therefore enable conservationbiologists to include this knowledge in themanagement of endangered populations in thewild. In this study, the effects ofenvironmental stress and inbreeding on fitnessare estimated in a laboratory population ofDrosophila buzzatii. Random- or full-sibmating were used to generate independentreplicate lines of four different inbreedinglevels (F = 0, F = 0.25, F = 0.50, F = 0.672)in four different environments. Theenvironments were thermal and dimethoate stressseparately and in combination, as well as anon-stressful control environment. Twoexperiments were carried out to measureproductivity (a multiplicative measure offecundity and viability) using a full factorialdesign. In the first experiment, productivitywas estimated for all lines and inbreedinglevels in the environment in which flies wereinbred and reared for several generations. Inthe second experiment, productivity of thelines reared in the control environment wastested in all four environments and for allinbreeding levels. Our results show asignificant effect of inbreeding andenvironmental stress on productivity in bothexperiments and the effect increased when flieswere exposed to novel environmental conditions.Productivity was not affected by theinteraction between inbreeding andenvironmental stress when flies were tested inthe environments in which they were reared,whereas there was a tendency towards a stressby inbreeding interaction when flies wereexposed to novel environments. The variance andthe coefficient of variation in productivitywere each affected by environmental stress andinbreeding, indicating that environmentalconditions as well as genetic background areimportant for variation in productivity.However, the two measures of variation oftenshowed opposite trends. The results obtained inthis study indicate that the environmentalconditions under which inbreeding occurs areimportant. This is relevant for the maintenanceand management of populations in captivity andin relation to reintroduction of endangeredspecies in nature.

Quantitative trait loci affecting knockdown resistance to high temperature in Drosophila melanogaster

Knockdown resistance to high temperature is an ecologically important trait in small insects. A composite interval mapping was performed on the two major autosomes of Drosophila melanogaster to search for quantitative trait loci (QTL) affecting knockdown resistance to high temperature (KRHT). Two dramatically divergent lines from geographically different thermal environments were artificially selected on KRHT. These lines were crossed to produce two backcross (BC) populations. Each BC was analysed for 200 males with 18 marker loci on chromosomes 2 and 3. Three X‐linked markers were used to test for X‐linked QTL in an exploratory way. The largest estimate of autosome additive effects was found in the pericentromeric region of chromosome 2, accounting for 19.26% (BC to the low line) and 29.15% (BC to the high line) of the phenotypic variance in BC populations, but it could represent multiple closely linked QTL. Complete dominance was apparent for three QTL on chromosome 3, where heat‐shock genes are concentrated. Exploratory analysis of chromosome X indicated a substantial contribution of this chromosome to KRHT. The results show that a large‐effect QTL with dominant gene action maps on the right arm of chromosome 3. Further, the results confirm that QTL for heat resistance are not limited to chromosome 3.

Effects of inbreeding in three life stages of Drosophila buzzatii after embryos were exposed to a high temperature stress

The interaction between inbreeding and high-temperature stress was examined in the cactophilic fruit fly, Drosophila buzzatii. Embryos of four inbreeding levels (F = 0, F = 0.25, F = 0.375, F = 0.5) were either maintained at 25°C throughout egg-to-adult development or were exposed to 41.5°C for 110 min at an age of 20 h. Hatching, larva-to-pupa survival, pupa-to-adult survival, and egg-to-adult survival were estimated. Heat shock reduced hatching rates, but survival to adulthood for individuals that hatched was unaffected by the heat shock. Inbreeding reduced the proportion of eggs hatching in the 25°C control group only. For larva-to-pupa and pupa-to-adult survival there was no interaction between inbreeding and stress. The effect of inbreeding on egg-to-adult survival was stronger in the 25°C control group compared with the group exposed to heat shock. The results imply environmental dependency of inbreeding depression and suggest that stress tolerance may not always be reduced by inbreeding. The thermal microenvironment of cactus rots in the field was assessed by measuring temperatures inside 17 rots. Internal rot temperatures varied with a maximum temperature of 48°C during the day. Selection for temperature tolerance in nature may have depleted genetic variation for this trait limiting the effect of inbreeding on thermal resistance.

Heat and cold-induced male sterility in Drosophila buzzatii: genetic variation among populations for the duration of sterility

Here we studied three phenotypic traits in Drosophila buzzatii that are strongly effected by temperature, and are expected to be closely associated with fitness in nature. The traits measured were thermal threshold of male sterility, time for males to gain fertility when reared at a sterility-inducing temperature and transferred to 25°C on eclosion and survival after development. The last two traits were measured under four temperature regimes, constant 12°C, 25°C, 31°C, and fluctuating 25°C (18 h) and 38°C (6 h). We looked for genetic variation in these traits and relations among them in four lines of D. buzzatii originating from Argentina and Tenerife. The thermal threshold of heat-induced male sterility was found to lie within the range of 30.0–31.0°C. When measuring the time for males to gain fertility, males reared at a nonstressful temperature (25°C) were fertile 58–67 h after emergence with only minor differences among lines. When reared constant 31°C, males were fertile 174–225 h after hatching. The Argentinean lines were significantly faster in recovering from sterility than were the lines from Tenerife. When reared in a fluctuating temperature regime, differences among lines increased, dividing the lines into three significantly different groups, with a sterility period of 135–215 h. When reared at 12°C from the pupal stage, males were fertile after 106–130 h with significant difference in the variance but not in the mean duration of sterility. Significant differences in viability were found among development temperatures, but not among lines, and viability and the duration of sterility seem to be genetically independent.

Genetic variation in original and colonizing Drosophila buzzatii populations analysed by microsatellite loci isolated with a new PCR screening method

A new polymerase chain reaction‐based screening method for microsatellites is presented. Using this method, we isolated 12 microsatellite loci from Drosophila buzzatii, two of which were X‐linked. We applied the other 10 microsatellite loci to the analysis of genetic variation in five natural populations of D. buzzatii. Two populations were from the species’ original distribution in Argentina, whereas the other three were from Europe (two) and Australia that were colonized 200 and 65 years ago, respectively. Allelic variation was much larger in the original populations than in the colonizing ones and there was a tendency to decreased heterozygosity in the colonizing populations. We used three different statistical procedures for detecting population bottlenecks. All procedures suggested that the low variability in the populations in the Old World was not the result of the recent population decline, but was due to a founder effect followed by a population expansion. In fact, one procedure which detects population expansions and declines based on the genealogical history of microsatellite data suggested that an expansion had taken place in all the colonized populations.

Heat-shock tolerance and inbreeding in Drosophila buzzatii

The effect of inbreeding on survival after a short-term heat shock was tested for two age groups of the cactophilic fruit fly, Drosophila buzzatii, reared under nonstress conditions. Four inbreeding levels (F = 0, F = 0.25, F = 0.375, F = 0.5) were generated by outcrossing or full-sib mating. All flies were conditioned at 36.5°C for 75 min prior to exposure to stress, to activate the synthesis of heat-shock proteins. These proteins are known to protect cells against stress damage. The younger group of flies were exposed to a thermal stress of 40.7°C for 88 min, 103 min, or 118 min and the older flies to the same temperature only for 88 min or 103 min, as the survival of older flies after heat stress was much lower than that of the younger flies. Survival after heat shock declined with increased inbreeding in both age groups. For the younger flies, the slope of the regression line, F, on survival was lower at higher stress levels. For the older flies, inbreeding effects were similar at both stress levels. Mortality without stress also differed significantly among inbreeding groups, mainly because of a large difference between the F = 0.5 group and all others.

A 71-Gene Signature of TRAIL Sensitivity in Cancer Cells

TNF-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent because of its ability to selectively induce apoptosis in cancer cells but not in most normal cells. However, some cancer cells are resistant to TRAIL cytotoxicity thereby limiting its therapeutic efficacy. Using genome-wide mRNA expression profiles from the NCI60 panel and their differential sensitivities to TRAIL-induced apoptosis, we have identified 71 genes whose expression levels are systemically higher in TRAIL-sensitive cell lines than resistant lines. The elevated expression of the 71 genes was able to accurately predict TRAIL sensitivity in the NCI60 training set and two test sets consisting of a total of 95 human cancer cell lines. Interestingly, the 71-gene signature is dominated by two functionally related gene families—interferon (IFN)-induced genes and the MHC genes. Consistent with this result, treatment with IFN-γ augmented TRAIL-induced apoptosis. The 71-gene signature could be evaluated clinically for predicting tumor response to TRAIL-related therapies. Mol Cancer Ther; 11(1); 34–44. ©2011 AACR.