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Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months. Then, six-month-old diet-induced obese animals were allocated to sedentarism (DIO) or to a long-term treadmill training (DIOEX) up to 18 months of age. In exercised mice, iWAT depot revealed more adaptability, with an increase in the expression of fatty acid oxidation genes (Cpt1a, Acox1), and an amelioration of the inflammatory status, with a favorable modulation of pro/antiinflammatory genes and lower macrophage infiltration. Additionally, iWAT of trained animals showed an increment in the expression of mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenesis (Ucp1), and beige adipocytes genes (Cd137, Tbx1). In contrast, iBAT of aged obese mice was less responsive to exercise. Indeed, although an increase in functional brown adipocytes genes and proteins (Pgc1a, Prdm16 and UCP1) was observed, few changes were found on inflammation-related and fatty acid metabolism genes. The remodeling of iWAT and iBAT depots occurred along with an improvement in the HOMA index for insulin resistance and in glucose tolerance. In conclusion, long-term exercise effectively prevented the loss of iWAT and iBAT thermogenic properties during aging and obesity. In iWAT, the long-term exercise program also reduced the inflammatory status and stimulated a fat-oxidative gene profile. These exercise-induced adipose tissue adaptations could contribute to the beneficial effects on glucose homeostasis in aged obese mice., (© 2023. The Author(s).)

Background: Progress in the field of evolutionary forest ecology has been hampered by the huge challenge of phenotyping trees across their ranges in their natural environments, and the limitation in high-resolution environmental information., Findings: The GenTree Platform contains phenotypic and environmental data from 4,959 trees from 12 ecologically and economically important European forest tree species: Abies alba Mill. (silver fir), Betula pendula Roth. (silver birch), Fagus sylvatica L. (European beech), Picea abies (L.) H. Karst (Norway spruce), Pinus cembra L. (Swiss stone pine), Pinus halepensis Mill. (Aleppo pine), Pinus nigra Arnold (European black pine), Pinus pinaster Aiton (maritime pine), Pinus sylvestris L. (Scots pine), Populus nigra L. (European black poplar), Taxus baccata L. (English yew), and Quercus petraea (Matt.) Liebl. (sessile oak). Phenotypic (height, diameter at breast height, crown size, bark thickness, biomass, straightness, forking, branch angle, fructification), regeneration, environmental in situ measurements (soil depth, vegetation cover, competition indices), and environmental modeling data extracted by using bilinear interpolation accounting for surrounding conditions of each tree (precipitation, temperature, insolation, drought indices) were obtained from trees in 194 sites covering the species' geographic ranges and reflecting local environmental gradients., Conclusion: The GenTree Platform is a new resource for investigating ecological and evolutionary processes in forest trees. The coherent phenotyping and environmental characterization across 12 species in their European ranges allow for a wide range of analyses from forest ecologists, conservationists, and macro-ecologists. Also, the data here presented can be linked to the GenTree Dendroecological collection, the GenTree Leaf Trait collection, and the GenTree Genomic collection presented elsewhere, which together build the largest evolutionary forest ecology data collection available., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently found in different human cancers. While the tumor suppressor function of this complex is widely established in solid tumors, its role in hematologic malignancies is largely unknown. Recurrent point mutations in BCL7A gene, encoding a subunit of the SWI/SNF complex, have been reported in diffuse large B-cell lymphoma (DLBCL), but their functional impact remains to be elucidated. Here we show that BCL7A often undergoes biallelic inactivation, including a previously unnoticed mutational hotspot in the splice donor site of intron one. The splice site mutations render a truncated BCL7A protein, lacking a portion of the amino-terminal domain. Moreover, restoration of wild-type BCL7A expression elicits a tumor suppressor-like phenotype in vitro and in vivo. In contrast, splice site mutations block the tumor suppressor function of BCL7A by preventing its binding to the SWI/SNF complex. We also show that BCL7A restoration induces transcriptomic changes in genes involved in B-cell activation. In addition, we report that SWI/SNF complex subunits harbor mutations in more than half of patients with germinal center B-cell (GCB)-DLBCL. Overall, this work demonstrates the tumor suppressor function of BCL7A in DLBCL, and highlights that the SWI/SNF complex plays a relevant role in DLBCL pathogenesis.

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Background and Aims: Understanding inter-population variation in the allocation of resources to specific anatomical compartments and physiological processes is crucial to disentangle adaptive patterns in forest species. This work aims to evaluate phenotypic integration and trade-offs among functional traits as determinants of life history strategies in populations of a circum-Mediterranean pine that dwells in environments where water and other resources are in limited supply., Methods: Adult individuals of 51 populations of Pinus halepensis grown in a common garden were characterized for 11 phenotypic traits, including direct and indirect measures of water uptake at different depths, leaf area, stomatal conductance, chlorophyll content, non-structural carbohydrates, stem diameter and tree height, age at first reproduction and cone production. The population differentiation in these traits was tested through analysis of variance (ANOVA). The resulting populations' means were carried forward to a structural equation model evaluating phenotypic integration between six latent variables (summer water uptake depth, summer transpiration, spring photosynthetic capacity, growth, reserve accumulation and reproduction)., Key Results: Water uptake depth and transpiration covaried negatively among populations, as the likely result of a common selective pressure for drought resistance, while spring photosynthetic capacity was lower in populations originating from dry areas. Transpiration positively influenced growth, while growth was negatively related to reproduction and reserves among populations. Water uptake depth negatively influenced reproduction., Conclusions: The observed patterns indicate a differentiation in life cycle features between fast-growing and slow-growing populations, with the latter investing significantly more in reproduction and reserves. We speculate that such contrasting strategies result from different arrays of life history traits underlying the very different ecological conditions that the Aleppo pine must face across its distribution range. These comprise, principally, drought as the main stressor and fire as the main ecological disturbance of the Mediterranean basin., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The dataset presented here was collected by the GenTree project (EU-Horizon 2020), which aims to improve the use of forest genetic resources across Europe by better understanding how trees adapt to their local environment. This dataset of individual tree-core characteristics including ring-width series and whole-core wood density was collected for seven ecologically and economically important European tree species: silver birch (Betula pendula), European beech (Fagus sylvatica), Norway spruce (Picea abies), European black poplar (Populus nigra), maritime pine (Pinus pinaster), Scots pine (Pinus sylvestris), and sessile oak (Quercus petraea). Tree-ring width measurements were obtained from 3600 trees in 142 populations and whole-core wood density was measured for 3098 trees in 125 populations. This dataset covers most of the geographical and climatic range occupied by the selected species. The potential use of it will be highly valuable for assessing ecological and evolutionary responses to environmental conditions as well as for model development and parameterization, to predict adaptability under climate change scenarios.

Bark thickness is a key structural feature in woody plants in the protection against fire. We used 19 provenances of Pinus halepensis , an obligate-seeder species, in a replicated common garden at two environments contrasting in water availability to assess the interacting effects of site environment and population in the relative allocation to bark, expecting lower allocation at the drier site. Secondly, given the average fire frequency, we analyzed whether trees reached the critical absolute thickness soon enough for population persistence via aerial seed bank. Our analyses indicated that trees at the moister site allocated a rather fixed quantity of resources independent of tree size, and almost all populations reached critical absolute bark thickness to eventually survive fire. In contrast, at the drier site allocation to bark reduced with tree size, and most populations did not reach the critical bark thickness. Populations from areas with higher fire frequency had thicker basal bark, while those from areas with severe droughts and short vegetative periods, had thinner bark. In conclusion, drought-stressed trees have a higher risk to die from fires before achieving reproduction and building a sufficient aerial seed bank.

Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI 50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl - /HCO 3 - anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies., (Copyright © 2018 Ferrata Storti Foundation.)

Premise of the Study: Plants have developed mechanisms to withstand stressful environmental conditions, but the high energetic cost of these mechanisms may involve exchanges with other key functions. While trade-offs between cold hardiness and growth rates are a general assumption, we lack information regarding genetically based trade-offs between cold hardiness and other life-history traits. Such information has strong implications for tree conservation and breeding, especially in the context of ongoing climate change., Methods: We used a common garden progeny test to examine the relationships between seasonal cold hardiness and life-history traits of growth, reproduction, juvenile ontogeny, and phenology in 75 families of six maritime pine (Pinus pinaster Ait.) populations, three of continental and three of coastal origins., Key Results: We found a clear differentiation among populations with regard to cold hardiness and life-history traits. Two continental Iberian populations showed high cold tolerance and slower growth, but faster ontogenetic development in relation to both vegetative heteroblastic change in juveniles and the onset of female reproduction. The coastal populations displayed the opposite behavior, while the continental Moroccan population presented a unique combination of traits. We confirmed trade-offs between cold-hardiness and growth at the population level, but not within populations. There were no trade-offs with other life-history traits at either level., Conclusions: Relevant local adaptation syndromes were identified in the relationship between cold hardiness and life-history traits. These should be considered in developing tree management guidelines aimed at increasing productivity or adaptability under the expected conditions of climate change., (© 2016 Botanical Society of America.)

Despite the high prevalence of mental health problems among patients attending primary care, diagnosis and treatment of these disorders remain inadequate. Sound training of primary care physicians in how to manage mental health problems is needed to reduce the health, economic and social impact associated with these disorders. Among other elements, there is a need for cooperation between primary care physicians and mental health services. Distinct models are available for such collaboration. In 2006, our health department started a collaboration between these two levels of heath care, using a liaison model. Delays until the first specialist visit were reduced and satisfaction among health professionals increased, although these results should be interpreted with caution. Evidence has recently accumulated on the usefulness of the collaborative model, but evaluation of this model and extrapolation of its results are complex. We intend to evaluate our model more thoroughly, similar to other projects in our environment., (Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.)

A heteroblastic (or vegetative phase) change is an abrupt manifestation in the general heteroblastic development during the ontogeny of plants. The Canary Island pine undergoes an especially marked and delayed heteroblastic change, including both the formation of secondary needles on dwarf shoots and the onset of preformed growth. To assess genetic and environmental effects on the heteroblastic change in this species, we followed plants from 19 populations at a dry site and a wetter site. Comparing juvenile and adult needles from the same individuals, the adult had a significantly lower rate of water loss and higher leaf mass per area. Pooling data from all seed sources, the heteroblastic change took place when plants reached a critical height, on average, at 4 years of age at the dry site and 1 year earlier at the wet site. Within a subsample of individuals of equal size, mortality was significantly higher in juvenile plants than in mature plants. However, the juvenile phase was longer in plants from dry regions when compared to plants from highly productive, wet regions. This apparent contradiction might be explained through differential resource allocation and the cost of sclerophylly and resprouting ability. Considering the life strategy of the Canary Island pine, we interpret the prolonged juvenile phase as an unavoidable trade-off for the high tolerance of adults to harsh environments.

This study explores whether the presence of somatic mutations or a biased use of IgV(H) genes were associated with the clinical features in a series of 96 patients with mantle cell lymphoma (MCL). The cases were studied by seminested polymerase chain reaction using primers from the FR1 and J(H) regions. There was an unexpectedly high frequency of somatic mutations, with 29 of 103 sequences showing more than 2% of mutations. Biased usage of specific V(H) segments was also found; the most widely used genes in this series were V(H)3-21 (10 cases), V(H)3-23 (9 cases), V(H)4-34 (11 cases), and V(H)4-59 (9 cases). V(H) mutation frequency, taking into account different thresholds, did not distinguish different overall survival probabilities. Nevertheless, a more frequent use of V(H)3-21 or V(H)4-59 (8 of 18) was observed in the group of long-term survivors (18 cases > 5 years; P <.01). None of these long-term survivors presented the V(H)3-23 gene rearrangement. As in other lymphoproliferative disorders, the expression of CD38 or p53 or both was associated with a poorer survival probability. This nonrandom usage of IgV(H) segments suggests that specific antigens may play a pathogenically relevant role in the genesis or progression of subsets of MCL cases and may help in distinguishing a significant group of MCL long-term survivors.

Gymnastic technology had a decisive role in the configuration of a particular medical specialty, Physical Medicine and Rehabilitation. Its study is critical to understand the strong division of work roles that existed in this field, with a medical specialty and several professions linked to physiotherapy and rehabilitation. This process was developed in two well-defined phases: the assimilation of the knowledge and technological advances of gymnasts at the beginning of the 19th century, and the appropriation of the use of these appliances by doctors. Both factors favoured the emergence of the new professions.