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Describes an approach that considers community quality of life. Discussion on urban quality and environment; Impact of community factors on health; Principles behind the community quality of life approach.

Maternal mRNAs are essential for protein synthesis during oogenesis and early embryogenesis. To adapt translation to specific needs during development, maternal mRNAs are translationally repressed by shortening the polyA tails. While mRNA deadenylation is associated with decapping and degradation in somatic cells, maternal mRNAs with short polyA tails are stable. Here we report that the germline-specific eIF4E paralog, eIF4E1b, is essential for zebrafish oogenesis. eIF4E1b localizes to P-bodies in zebrafish embryos and binds to mRNAs with reported short or no polyA tails, including histone mRNAs. Loss of eIF4E1b results in reduced histone mRNA levels in early gonads, consistent with a role in mRNA storage. Using mouse and human eIF4E1Bs (in vitro) and zebrafish eIF4E1b (in vivo), we show that unlike canonical eIF4Es, eIF4E1b does not interact with eIF4G to initiate translation. Instead, eIF4E1b interacts with the translational repressor eIF4ENIF1, which is required for eIF4E1b localization to P-bodies. Our study is consistent with an important role of eIF4E1b in regulating mRNA dormancy and provides new insights into fundamental post-transcriptional regulatory principles governing early vertebrate development., (© 2023. The Author(s).)

Proteins and RNAs are fundamental parts of biological systems, and their interactions affect many essential cellular processes. Therefore, it is crucial to understand at a molecular and at a systems level how proteins and RNAs form complexes and mutually affect their functions. In the present mini-review, we will first provide an overview of different mass spectrometry (MS)-based methods to study the RNA-binding proteome (RBPome), most of which are based on photochemical cross-linking. As we will show, some of these methods are also able to provide higher-resolution information about binding sites, which are important for the structural characterisation of protein-RNA interactions. In addition, classical structural biology techniques such as nuclear magnetic resonance (NMR) spectroscopy and biophysical methods such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence-based methods contribute to a detailed understanding of the interactions between these two classes of biomolecules. We will discuss the relevance of such interactions in the context of the formation of membrane-less organelles (MLOs) by liquid-liquid phase separation (LLPS) processes and their emerging importance as targets for drug discovery., (© 2023 The Author(s).)

Evolutionary processes take place in fluctuating environments, where carrying capacities and selective forces vary over time. The fate of a mutant type and the persistence time of polymorphic states were studied in some specific cases of varying environments, but a generic methodology is still lacking. Here, we present such a general analytic framework. We first identify a set of elementary building blocks, a few basic demographic processes like logistic or exponential growth, competition at equilibrium, sudden decline, and so on. For each of these elementary blocks, we evaluate the mean and the variance of the changes in the frequency of the mutant population. Finally, we show how to find the relevant terms of the diffusion equation for each arbitrary combination of these blocks. Armed with this technique one may calculate easily the quantities that govern the evolutionary dynamics, like the chance of ultimate fixation, the time to absorption, and the time to fixation., (© 2022 The Authors. Evolution published by Wiley Periodicals LLC on behalf of The Society for the Study of Evolution.)

Background: Necrotizing meningoencephalitis (NME) in the pug dogs is a fatal neuroinflammatory disease associated with rapid progression and poor response to conventional immunosuppressive therapy. Diagnosis is typically made after severe neurological abnormalities have manifested., Hypothesis/objective: Pug dogs at genetic risk for NME might manifest neurological abnormalities before developing pathognomonic clinical signs of NME., Animals: Thirty-six pug dogs less than 4 years of age asymptomatic for NME., Methods: Prospective observational cohort study with germline genome-wide genotyping. Neurological examinations were performed 4 weeks apart to document reproducible findings of central nervous system disease. Magnetic resonance imaging, cerebrospinal fluid analysis, and testing for infectious diseases were performed in all pugs with reproducible abnormalities detected on neurological examination., Results: The overall risk allele frequency in this cohort was 40%; 5 (14%) dogs were high risk, 19 (53%) dogs were medium risk, and 12 (33%) dogs were low genetic risk for NME. Reproducible abnormalities detected on neurological examination were identified in 8/24 (33%) genetically at-risk dogs and 0/12 (0%) low risk dogs. Clinical abnormalities included multifocal spinal pain in 8/8, reduced menace response in 5/8, and lateralizing postural reaction deficits in 5/8 pugs. There was a strong association between genotype risk and the presence of this clinical phenotype (P = .03)., Conclusions and Clinical Importance: Our findings suggest the presence of a novel early clinical phenotype of NME in apparently asymptomatic genetically at-risk pugs which might be used to plan early diagnostic and therapeutic clinical trials., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Temporal environmental variations affect diversity in communities of competing populations. In particular, the covariance between competition and environment is known to facilitate invasions of rare species via the storage effect. Here we present a quantitative study of the effects of temporal variations in two-species and in diverse communities. Four scenarios are compared: environmental variations may be either periodic (seasonal) or stochastic, and the dynamics may support the storage effect (global competition) or not (local competition). In two-species communities, coexistence is quantified via the mean time to absorption, and we show that stochastic variations yield shorter persistence time because they allow for rare sequences of bad years. In diverse communities, where the steady-state reflects a colonization-extinction equilibrium, the actual number of temporal niches is shown to play a crucial role. When this number is large, the same trends hold: storage effect and periodic variations increase both species richness and the evenness of the community. Surprisingly, when the number of temporal niches is small global competition acts to decrease species richness and evenness, as it focuses the competition to specific periods, thus increasing the effective fitness differences., Competing Interests: The authors have declared that no competing interests exist.

Species competition takes place in a fluctuating environment, so the selective forces on different populations vary through time. In many realistic situations the mean fitness and the amplitude of its temporal variations are abundance-dependent. Here we present a theory of two-species competition with abundance-dependent stochastic fitness variations and solve for the chance of ultimate fixation, the time to absorption and the time to fixation. We then examine the ability of this two-species system to serve as an effective model for high-diversity assemblages and to account for the presence of an intra-specific differential response to environmental variations. The effective model is shown to capture the main features of competition between composite populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Recent studies have found considerable trait variations within species. The effect of such intraspecific trait variability (ITV) on the stability, coexistence, and diversity of ecological communities received considerable attention and in many models it was shown to impede coexistence and decrease species diversity. Here we present a numerical study of the effect of genetically inherited ITV on species persistence and diversity in a temporally fluctuating environment. Two mechanisms are identified. First, ITV buffers populations against varying environmental conditions (portfolio effect) and reduces variation in abundances. Second, the interplay between ITV and environmental variations tends to increase the mean fitness of diverse populations. The first mechanism promotes persistence and tends to increase species richness, while the second reduces the chance of a rare species population (which is usually homogeneous) to invade, thus decreasing species richness. We show that for large communities the portfolio effect is dominant, leading to ITV promoting species persistence and richness., (© 2020 by the Ecological Society of America.)

To combat vitamin D deficiency, vitamin D 3 and vitamin D 2 are commonly used as a supplement or to fortify food sources. Human data show that the response of 25-hydroxyvitamin D (25(OH)D) to supplementation with vitamin D 3 is higher than to vitamin D 2 . To elucidate the metabolic route of both vitamers, we conducted a study with vitamin D-depleted mice, which were allotted into three groups (n = 12) and received equal doses of either deuterated vitamin D 3 , deuterated vitamin D 2 or both for 4 weeks. To further investigate the hepatic uptake and hydroxylation of both D-vitamers to 25(OH)D, we conducted cell culture experiments with murine and human hepatoma cells (Hepa1-6 and HepG2). The vitamin D metabolite concentrations in serum, tissues and cells were analyzed by LC-MS/MS or ELISA. In mice, vitamin D 2 resulted in lower serum and tissue concentrations of vitamin D (P < 0.001) than vitamin D 3 , while the group which received both D-vitamers showed values in between. Interestingly, vitamin D 2 fed mice had 1.9-times and 2.9-times higher serum concentrations of total and free 25(OH)D (P < 0.001) than mice fed vitamin D 3 , while the concentration of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) was 1.8-times lower (P < 0.001). The gene and protein expression of enzymes, involved in the hydroxylation and renal uptake of vitamin D remained largely unaffected by the D-vitamer. In contrast to the mice data, hepatoma cells preferred vitamin D 3 for 25-hydroxylation over vitamin D 2 (P < 0.001). In general, the formation of 25(OH)D was much more pronounced in human than in murine hepatoma cells (P < 0.001). To conclude, in contrast to humans, vitamin D 2 was more efficient in increasing 25(OH)D than vitamin D 3 in mice, although this difference was not caused by a preferential hydroxylation of vitamin D 2 in the liver. The metabolic routes of D 3 and D 2 in mice differ, showing lower circulating 1,25(OH) 2 D and tissue vitamin D concentrations in D 2 - than in D 3 -fed mice., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Population dynamics reflects an underlying birth-death process, where the rates associated with different events may depend on external environmental conditions and on the population density. A whole family of simple and popular deterministic models (such as logistic growth) supports a transcritical bifurcation point between an extinction phase and an active phase. Here we provide a comprehensive analysis of the phases of that system, taking into account both the endogenous demographic noise (random birth and death events) and the effect of environmental stochasticity that causes variations in birth and death rates. Three phases are identified: in the inactive phase the mean time to extinction T is independent of the carrying capacity N and scales logarithmically with the initial population size. In the power-law phase T∼N^{q}, and in the exponential phase T∼exp(αN). All three phases and the transitions between them are studied in detail. The breakdown of the continuum approximation is identified inside the power-law phase, and the accompanying changes in decline modes are analyzed. The applicability of the emerging picture to the analysis of ecological time series and to the management of conservation efforts is briefly discussed.

Background: The transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferation, differentiation, and apoptosis, and its overexpression contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells., Methods: U937T&#95;EVI1, a human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to gene expression profiling. qRT-PCR was used to confirm the regulation of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice., Results: Gene expression microarray analysis identified 27 unique genes that were up-regulated, and 29 unique genes that were down-regulated, in response to EVI1 induction in the human myeloid cell line U937T. The most strongly repressed gene was MS4A3, and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. MS4A3 mRNA levels were also negatively correlated with those of EVI1 in several published AML data sets. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model by increasing the rate of apoptosis., Conclusions: Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness.

The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARβ gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-β superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed.

Overexpression of ecotropic viral integration site 1 (EVI1) is associated with aggressive disease in acute myeloid leukemia (AML). Despite of its clinical importance, little is known about the mechanism through which EVI1 confers resistance to antileukemic drugs. Here, we show that a human myeloid cell line constitutively overexpressing EVI1 after infection with a retroviral vector (U937&#95;EVI1) was partially resistant to etoposide and daunorubicin as compared to empty vector infected control cells (U937&#95;vec). Similarly, inducible expression of EVI1 in HL-60 cells decreased their sensitivity to daunorubicin. Gene expression microarray analyses of U937&#95;EVI1 and U937&#95;vec cells cultured in the absence or presence of etoposide showed that 77 and 419 genes were regulated by EVI1 and etoposide, respectively. Notably, mRNA levels of 26 of these genes were altered by both stimuli, indicating that EVI1 regulated genes were strongly enriched among etoposide regulated genes and vice versa. One of the genes that were induced by both EVI1 and etoposide was CDKN1A/p21/WAF, which in addition to its function as a cell cycle regulator plays an important role in conferring chemotherapy resistance in various tumor types. Indeed, overexpression of CDKN1A in U937 cells mimicked the phenotype of EVI1 overexpression, similarly conferring partial resistance to antileukemic drugs.

Objectives: To determine the efficacy of amitriptyline (AMI) in treating irritable bowel syndrome (IBS) in adolescents., Study Design: Adolescents 12 to 18 years with newly diagnosed IBS were surveyed with a symptom checklist, pain rating scale, visual analog scale, and IBS quality of life (QOL) questionnaire. Subjects were randomized in a double-blinded fashion to receive AMI or placebo, and again completed surveys at 2, 6, 10, and 13 weeks., Results: Thirty-three patients (24 female) were enrolled. Patients receiving AMI were more likely to experience improvement from baseline in overall QOL at 6, 10, and 13 weeks (P = .019, .004, and .013). Patients receiving AMI were also more likely to experience a reduction in IBS-associated diarrhea at 6 and 10 weeks (P = .029 for both), a reduction in periumbilical pain at 10 weeks (P = .018), and a reduction in right lower quadrant pain at 6, 10, and 13 weeks (P = .014, .039, and .004)., Conclusion: AMI significantly improves overall QOL in adolescents with IBS and should be a therapeutic option for adolescents with this disorder.

A 4-year-old Latino boy with a history of malrotation, nonobstructing annular pancreas, and a Ladd procedure during infancy presented with recurrent severe gastrointestinal tract bleeding. Investigations revealed a large mass in the proximal small bowel. At laparotomy, the proximal jejunal segment containing the mass was resected. Pathological examinations revealed a large intraluminal polyp composed of ectopic gastric mucosa. The patient presented 10 months later with recurrent bleeding, and subsequent laparotomy demonstrated a newly acquired segment of jejunal polyposis not present at the first operation. The case is presented, along with a plan of patient surveillance and a review of the pertinent literature.