In natural populations, quantitative traits seldom show short‐term evolution at the rate predicted by evolutionary models. Resolving this “paradox of stasis” is a key goal in evolutionary biology, as ...it directly challenges our capacity to predict evolutionary change. One particularly promising hypothesis to explain the lack of evolutionary responses in a key offspring trait, body weight, is that positive selection on juveniles is counterbalanced by selection against maternal investment in offspring growth, given that reproduction is costly for the mothers. Here, we used data from one of the longest individual‐based studies of a wild mammal population to test this hypothesis. We first showed that despite positive directional selection on birth weight, and heritable variation for this trait, no genetic change has been observed for birth weight over the past 47 years in the study population. Contrarily to our expectation, we found no evidence of selection against maternal investment in birth weight—if anything, selection favors mothers that produce large calves. Accordingly, we show that genetic change in birth weight over the study period is actually lower than that predicted from models including selection on maternal performance; ultimately our analysis here only deepens rather than resolves the paradox of stasis.
Maternal effects, either environmental or genetic in origin, are an underappreciated source of phenotypic variance in natural populations. Maternal genetic effects have the potential to constrain or ...enhance the evolution of offspring traits depending on their magnitude and their genetic correlation with direct genetic effects. We estimated the maternal effect variance and its genetic component for 12 traits expressed over the life history in a pedigreed population of wild red deer (morphology, survival/longevity, breeding success). We only found support for maternal genetic effect variance in the two neonatal morphological traits: birth weight (
h
M
g
2
=
0.31
) and birth leg length (
h
M
g
2
=
0.17
). For these two traits, the genetic correlation between maternal and direct additive effects was not significantly different from zero, indicating no constraint to evolution from genetic architecture. In contrast, variance in maternal genetic effects enhanced the additive genetic variance available to respond to natural selection. Maternal effect variance was negligible for late-life traits. We found no evidence for sex differences in either the direct or maternal genetic architecture of offspring traits. Our results suggest that maternal genetic effect variance declines over the lifetime, but also that this additional heritable genetic variation may facilitate evolutionary responses of early-life traits.
Maternal effects are ubiquitous. Yet, the pathways through which maternal effects occur in wild mammals remain largely unknown. We hypothesise that maternal immune transfer is a key mechanism by ...which mothers can affect their offspring fitness, and that individual variation in maternally derived antibodies mainly depends on a mother's characteristics and the environmental conditions she experiences. To test this, we assayed six colostrum‐derived antibodies in the plasma of 1447 neonates in a wild red deer population. Neonatal antibody levels were mainly affected by maternal genes, environmental variation and costs of prior reproductive investment. We found consistent heterogeneity in maternal performance across traits, with mothers producing the heaviest calves also having calves with more antibodies. Unexpectedly, antibody levels were not associated with calf survival. We provide a unique example of how evolutionary theory on maternal effects can be used to gain insight into the causes of maternal effects in wild populations.
Maternal immune transfer is a key mechanism by which mothers can affect their offspring. We used a long‐term individual‐based study to investigate the causes and consequences of variation in maternally transferred antibodies in a red deer population. For the first time in a wild mammal, we report that past reproductive effort negatively affected maternal immune transfer. However, neonatal antibody levels were not associated with calf survival.
T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete ...motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin αVβ3 expression: Th2 cell differentiation led to high αVβ3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of αVβ3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of αVβ3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.
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•Differential dependency on chemokines for Th1 and Th2 cell interstitial migration•Th differentiation programs elevated αVβ3 integrin expression on Th2 cells•Increased αVβ3 integrin is sufficient to facilitate chemokine-independent migration•Th1 and Th2 programming for distinct modes of migration optimizes effector function
Immune responses are functionally tailored to best contain a specific pathogen challenge. T cells differentiate into functionally distinct subsets (Th1, Th2, Th17) defined by discrete cytokine production. Gaylo-Moynihan et al. find that functional specialization also extends to the navigation system used by T cell subsets to efficiently migrate within infected tissues.
Social structure, limited dispersal, and spatial heterogeneity in resources are ubiquitous in wild vertebrate populations. As a result, relatives share environments as well as genes, and ...environmental and genetic sources of similarity between individuals are potentially confounded. Quantitative genetic studies in the wild therefore typically account for easily captured shared environmental effects (e.g., parent, nest, or region). Fine-scale spatial effects are likely to be just as important in wild vertebrates, but have been largely ignored. We used data from wild red deer to build "animal models" to estimate additive genetic variance and heritability in four female traits (spring and rut home range size, offspring birth weight, and lifetime breeding success). We then, separately, incorporated spatial autocorrelation and a matrix of home range overlap into these models to estimate the effect of location or shared habitat on phenotypic variation. These terms explained a substantial amount of variation in all traits and their inclusion resulted in reductions in heritability estimates, up to an order of magnitude up for home range size. Our results highlight the potential of multiple covariance matrices to dissect environmental, social, and genetic contributions to phenotypic variation, and the importance of considering fine-scale spatial processes in quantitative genetic studies.
T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here we have shown Th cell differentiation also imposes discrete ...motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G-protein coupled receptor (GPCR) and chemokine-dependent fashion while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription factor-dependent programming of integrin α
V
β
3
expression: Th2 cell differentiation led to high α
V
β
3
expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of α
V
β
3
on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of α
V
β
3
tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.
Immune responses are functionally tailored to best contain a specific pathogen challenge. T cells differentiate into functionally distinct subsets (Th1, Th2, Th17) defined by discrete cytokine production. Gaylo-Moynihan et al find functional specialization also extends to the navigation system used by T cell subsets to efficiently migrate within infected tissues.
Background: While reduced intensity conditioning has allowed older patients to undergo allogeneic hematopoietic stem cell transplantation (HSCT) for a variety of hematologic malignancies, age is ...still viewed as a relative contraindication. In particular, only limited and conflicting data are available on outcomes of patients ≥ 70 years old.
Methods: To determine outcomes and utility or futility of transplant for "older" patients, we conducted a retrospective study of all patients 65 and older who underwent allogeneic SCT at our institution between March 2002 and March 2015. 33 patients age 70-75 (median 71 years) were compared to 95 concurrent allogeneic HSCT recipients age 65-69 (median 67).
Results: The two groups (70-75 and 65-69) were similar in terms of donor type (70% URD 30% MRD vs. 67% URD 27% MRD 3% cord blood, p=0.86), conditioning regimen (75% flu/bu vs. 65% flu/bu, p =0.26), HCT-CI scores (mean 2.7 vs 2.9, p=0.29), disease phase (9% vs. 15% with primary refractory/active disease, p=0.651) and disease distribution (AML/MDS in 76% and 80%, p=0.7).
The OS for all patients was 51% at 1 year and 38% at 2 years, with a median follow up of 13.1 mo and no differences between age groups (fig 1, p=0.70). The median survival was 12.5 months in the 70-75 group vs. 13.7 months in the 65-69 group. As seen in Table 1, transplant was well tolerated and outcomes similar between both age groups with minimal 30 day mortality. Comparing patients age 70-75 to those 65-69, there was no difference in OS at 100d, 1 year or 2 years. There was no difference in grade II-IV acute GVHD (p=0.50). The cause of death was similar in both groups; of the patients who died, death was treatment-related in 45% and 40% of 70+ versus younger patients respectively, largely due to GVHD and infection. Relapse accounted for death in 55% and 57% of older versus younger patients who died.
Conclusions: These data suggest that at least selected patients ≥70 years old can tolerate allogeneic HSCT similar to patients ages 65-69. Outcomes in both age groups remain limited by a high risk of relapse highlighting that better methods for tumor control are needed such as post-transplant maintenance or novel disease-specific strategies that minimize GVHD but allow for enhanced GVL induction. However age ≥70 should not be an absolute contraindication for transplant.
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Shaw:Vitality Institute: Research Funding; Novartis: Research Funding. Frey:Servier: Consultancy; Amgen: Consultancy; Novartis: Research Funding. Gill:Novartis: Patents & Royalties, Research Funding. Luger:Astellas: Honoraria; Dava Oncology: Honoraria; Pfizer: Consultancy; Onconova: Other: Clinical Trial –Institutional PI; Seattle Genetics: Other: Clinical Trial–Institutional PI; Ariad: Other: Clinical Trial–Institutional PI; Celgene: Other: Clinical Trial–Institutional PI; Cyclacel: Other: Clinical Trial, Institutional PI. . Mangan:Novartis: Research Funding; Incyte: Other: Advisory Board. Stadtmauer:Celgene: Consultancy; Takeda: Consultancy; Teva: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Porter:Genentech: Other: Spouse Employment; Novartis: Patents & Royalties, Research Funding.
To compare the prevalences of childhood and adult physical and sexual abuse in women with chronic pelvic pain to those in women with chronic nonpelvic pain (headache) and pain-free women.
Using a ...structured interview, we assessed the prevalence rates of both sexual abuse and physical abuse in 64 women with chronic pelvic pain, 42 women with chronic headache, and 46 pain-free women. Abuse histories were stratified by age at occurrence and severity. Demographic characteristics of the three groups were also assessed.
Women with chronic pelvic pain were found to have a higher lifetime prevalence of sexual abuse, involving penetration or other contact with the unclothed genitals or anus (ie, major sexual abuse), than either comparison group. Further, more women in the chronic pelvic pain group had experienced major sexual abuse in both childhood and adulthood than women in the headache group, but there was no difference with the pain-free group. With respect to physical abuse, women in the chronic pelvic pain group had a higher lifetime prevalence than pain-free women, but not compared to those with chronic headache. In addition, more women with chronic pelvic pain reported physical abuse in both childhood and adulthood and both major sexual abuse and physical abuse at some time in their lives than did either comparison group.
These results support a specific association between major sexual abuse and chronic pelvic pain and a more general association between physical abuse and chronic pain. Moreover, the global nature of the abuse histories of the women in the chronic pelvic pain group suggests that more rigorous studies of the relation between abuse history and chronic pelvic pain are needed.
To assess the potential role of childhood and adulthood physical and sexual abuse and complaints of chronic pain in accounting for psychiatric symptomatology in adult women.
We assessed sexual abuse, ...physical abuse, depression, anxiety, and somatization in 64 women with chronic pelvic pain, 42 women with chronic headache, and 46 women without chronic pain complaints. Using multiple regression analyses, we tested a model comprising sociodemographic, chronic pain, childhood sexual abuse and physical abuse, and adulthood sexual abuse and physical abuse variables in the prediction of depression, anxiety and somatization.
This model significantly predicted all three outcomes. However, childhood sexual abuse was not significant in the prediction of any of the outcome variables, whereas childhood physical abuse was significant in the prediction of all three. Further, the adulthood abuse variable set contributed significantly to the prediction of somatization, and the individual variable of adulthood sexual abuse was predictive of anxiety.
The relation observed between childhood sexual abuse and the outcomes of depression, anxiety, and somatization in women may be a function of its association with other forms of abuse, particularly childhood physical abuse. Further investigation is clearly needed of the nature of the relations between the various categories of abuse and psychological morbidity.
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