A distinct epigenetic signature at targets of a leukemia protein

BACKGROUND: Human myelogenous leukemia characterized by either the non random t(8; 21)(q22; q22) or t(16; 21)(q24; q22) chromosome translocations differ for both their biological and clinical features. Some of these features could be consequent to differential epigenetic transcriptional deregulation at AML1 targets imposed by AML1-MTG8 and AML1-MTG16, the fusion proteins deriving from the two translocations. Preliminary findings showing that these fusion proteins lead to transcriptional downregulation of AML1 targets, marked by repressive chromatin changes, would support this hypothesis. Here we show that combining conventional global gene expression arrays with the power of bioinformatic genomic survey of AML1-consensus sequences is an effective strategy to identify AML1 targets whose transcription is epigenetically downregulated by the leukemia-associated AML1-MTG16 protein. RESULTS: We interrogated mouse gene expression microarrays with probes generated either from 32D cells infected with a retroviral vector carrying AML1-MTG16 and unable of granulocyte differentiation and proliferation in response to the granulocyte colony stimulating factor (G-CSF), or from 32D cells infected with the cognate empty vector. From the analysis of differential gene expression alone (using as criteria a p value < 0.01 and an absolute fold change > 3), we were unable to conclude which of the 37 genes downregulated by AML1-MTG16 were, or not, direct AML1 targets. However, when we applied a bioinformatic approach to search for AML1-consensus sequences in the 10 Kb around the gene transcription start sites, we closed on 17 potential direct AML1 targets. By focusing on the most significantly downregulated genes, we found that both the AML1-consensus and the transcription start site chromatin regions were significantly marked by aberrant repressive histone tail changes. Further, the promoter of one of these genes, containing a CpG island, was aberrantly methylated. CONCLUSION: This study shows that a leukemia-associated fusion protein can impose a distinct epigenetic repressive signature at specific sites in the genome. These findings strengthen the conclusion that leukemia-specific oncoproteins can induce non-random epigenetic changes

Prevalence of Malnutrition in Orally and Tube-Fed Elderly Nursing Home Residents in Germany and Its Relation to Health Complaints and Dietary Intake

Objective. To investigate the prevalence of malnutrition in orally and tube-fed nursing home (NH) residents in Germany and its relation to common health complaints and dietary intake. Methods. In 350 NH residents, subjects' characteristics, Mini Nutritional Assessment (MNA), and several health problems were inquired with the nursing staff using standardised interviews. In a subset of 122 residents, dietary intake was assessed by 3-day weighing records. Results. 7.7% of the participants were tube fed. 24.1% of orally nourished and 57.7% of tube-fed residents were malnourished (MNA < 17 p.). Malnutrition was significantly related to nausea/vomiting, constipation, pressure ulcers, dehydration, infections, antibiotic use, and hospitalisation. Mean daily energy intake was 1535 ± 413 kcal and mean protein intake was 54.2 ± 0.9 g/d irrespective of the nutritional state. Conclusion. In Germany, malnutrition is widespread among NH residents and is related to common health problems. The MNA rather reflects health condition than currently reduced dietary intake

Environmental influences on Aedes aegypti catches in Biogents Sentinel traps during a Californian "rear and release" program: implications for designing surveillance programs

As Aedes aegypti continues to expand its global distribution, the diseases it vectors (dengue, Zika, chikungunya and yellow fever) are of increasing concern. Modern efforts to control this species include "rear and release" strategies where lab-reared mosquitoes are distributed throughout the landscape to replace or suppress invasive populations. These programs require intensive surveillance efforts to monitor their success, and the Biogents Sentinel (BGS) trap is one of the most effective tools for sampling adult Ae. aegypti. BGS trap catches can be highly variable throughout landscapes, so we investigated the potential impacts of environmental factors on adult Ae. aegypti capture rates during a "rear and release" program in California to better understand the relative contributions of true variability in population density across a landscape and trap context. We recorded male and female Ae. aegypti catches from BGS traps, with and without CO2, throughout control sites where no mosquitoes were released and in treatment sites where males infected with Wolbachia were released. BGS trap catches were positively influenced by higher proportions of shade or bushes in the front yard of the premises as well as the presence of potential larval habitats such as subterranean vaults. In contrast, an increase in residential habitat within a 100 m radius of trap locations negatively influenced BGS trap catches. For male Ae. aegypti, increased visual complexity of the trap location positively influenced capture rates, and the presence of yard drains negatively affected catch rates in control sites. Lastly, for BGS traps using CO2, higher catch rates were noted from traps placed greater than one meter from walls or fences for both male and female mosquitoes. These results have important implications for surveillance programs of Ae. aegypti throughout the Californian urban environment including adult monitoring during "rear and release" programs

Управление дебиторской задолженностью и организация ее учета (на примере АО «Алмалыкский горно-металлургический комбинат»)

Объект исследования: АО «Алмалыкский горно-металлургический комбинат». Цель работы: изучить и сравнить систему бухгалтерского учета дебиторской задолженности в России и Узбекистане; рассмотреть особенности учета и управления дебиторской задолженностью на АО «Алмалыкский ГМК». Экономическая значимость работы обусловлена тем, что вопросы эффективного учета и управления дебиторской задолженностью, направленные на увеличение объема реализации за счет расширения продажи продукции в кредит надежным клиентам и обеспечение своевременного возврата долга. Правильное раскрытие и классификация дебиторской задолженности, необходимы для точной оценки финансового состояния предприятия.The object of study: JSC "Almalyk Mining and Metallurgical Complex ". Objective: To study and compare the system of accounting of receivables in Russia and Uzbekistan; consider the characteristics of accounting and management of accounts receivable at the JSC "Almalyk MMC". The economic significance of the work due to the fact that the issues of effective accounting and receivables management aimed at increasing the volume of sales by expanding sales of products on credit to customers reliable and ensuring timely repayment of debt. Proper disclosure and classification of receivables necessary to accurately assess the financial condition of the company. This requires timely and accurate reflection of the accounts receivable in the accounts the enterprise

Multiple hydrothermal sources along the south Tonga arc and Valu Fa Ridge

Quantifying hydrothermal venting at the boundaries of tectonic plates is an outstanding geoscience problem. Considerable progress has been made by detailed surveys along mid-ocean ridges (MORs), but until recently little was known about fluid venting along volcanic arcs. We present the first systematic survey for hydrothermal venting along the 425-km-long south Tonga arc and new chemistry data for particle and thermal plumes previously reported along an adjacent 88-km-long section of the back-arc Valu Fa Ridge (VFR). Eleven hydrothermal plumes, recognized by their anomalous light backscattering, Eh, temperature, pH, dissolved 3He, CH4, and total dissolvable Fe and Mn, were identified arising from seven volcanic centers along the arc. Five plumes on the VFR were characterized chemically. Vent field density for the south Tonga arc was 2.6 sites/100 km of arc front, comparable to that found by surveys of the Kermadec arc (1.9 to 3.8 sites/100 km) and to MORs in the eastern Pacific (average value for 2280 km of surveyed ridgecrest: 3.2 sites/100 km). A "vent gap" occurs along a 190 km section of the arc closest to the VFR, and a site density twice the average for MORs on the eastern edge of the Pacific plate was found on this part of the VFR (6.6 sites/100 km). We suggest magmas ascending under the adjacent south Tonga arc have been captured by the VFR. While chemical enrichments of plumes on the south Tonga arc were, in general, slightly less than those on the Kermadec arc, several instances of excessive anomalies in pH suggest a similar presence of fluids enriched in magmatic volatiles (CO2-SO2-H2S). Locally, venting on the VFR has contributed to accumulations of 3He, Fe, and Mn within the southern Lau basin. On a broader scale, our results provide considerable support for the notion that venting from intraoceanic arcs on the convergent margin of the Pacific plate adds significantly to the total hydrothermal input into the Pacific Ocean

Morphological and Molecular Characterization Using Genitalia and CoxI Barcode Sequence Analysis of Afrotropical Mosquitoes with Arbovirus Vector Potential

Funding Information: Eddyson Montalvo-Sabino was recipient of a grant from “Programa Nacional de Becas y Crédito Educativo” (PRONABEC), 2019—Beca Generacion del Bicentenario, from the “Ministerio de Educación” of Peru. A.P. Abilio was a recipient of a grant from Wellcome Trust (Grant WT087546MA) through SACIDS RVF and NPHI-Phase-II from the National Institute for Health of Mozambique through a cooperative agreement number [5NU14GH001237-03-00]. Marietjie Venter was a recipient of a sub-award from the Global Disease Detection Program, US-CDC award 5U19GH000571-02 with the NICD and University of Pretoria that funded vector surveillance in South Africa (2012–2015) and by the Cooperative Agreement Number (5 NU2GGH001874-02-00) with the University of Pretoria (2014–2017). Milehna M. Guarido received a studentship through this grant. A.P.G. Almeida has been a recipient of the Visiting Professor Programme by the University of Pretoria for the work in South Africa. This work received financial support from the Global Health and Tropical Medicine Center (GHTM|IHMT|NOVA), which is funded through FCT contract UID/Multi/04413/2013, Portugal. The findings and conclusions expressed in this manuscript are those of the author(s) and do not necessarily represent the official position of the funding agencies. Publisher Copyright: © 2022 by the authors.Potential arboviral Afrotropical mosquito vectors are underrepresented in public databases of CoxI barcode sequences. Furthermore, available CoxI sequences for many species are often not associated with voucher specimens to match the corresponding fine morphological characterization of specimens. Hence, this study focused on the characterization of Culicine mosquitoes from South Africa, Mozambique, and Angola and their classification using a complementary approach including a morphological analysis of specimens’ genitalia and phylogenetic study based on the analysis of CoxI barcode sequences using maximum likelihood and Bayesian phylogenetic inference methods, alongside Median-Joining Network and PCOORD analyses. Overall, 800 mosquitoes (652 males and 148 females) from 67 species, were analyzed. Genitalia from 663 specimens allowed the identification of 55 species of 10 genera. A total of 247 CoxI partial gene sequences corresponding to 65 species were obtained, 11 of which (Aedes capensis, Ae. mucidus, Culex andersoni, Cx. telesilla, Cx. inconspicuosus, Eretmapodites subsimplicipes, Er. quinquevittatus, Ficalbia uniformis, Mimomyia hispida, Uranotaenia alboabdominalis, and Ur. mashonaensis) are, to the best of our knowledge, provided here for the first time. The presence of Cx. pipiens ecotypes molestus and pipiens and their hybrids, as well as Cx. infula, is newly reported in the Afrotropical region. The rates of correct sequence identification using BOLD and BLASTn (≥95% identity) were 64% and 53%, respectively. Phylogenetic analysis revealed that, except for subgenus Eumelanomyia of Culex, there was support for tribes Aedini, Culicini, Ficalbiini, and Mansoniini. A divergence >2% was observed in conspecific sequences, e.g., Aedeomyia africana, Ae. cumminsii, Ae. unilineatus, Ae. metallicus, Ae. furcifer, Ae. caballus, and Mansonia uniformis. Conversely, sequences from groups and species complexes, namely, Ae. simpsoni, Ae. mcintoshi, Cx. bitaeniorhynchus, Cx. simpsoni, and Cx. pipiens were insufficiently separated. A contribution has been made to the barcode library of Afrotropical mosquitoes with associated genitalia morphological identifications.publishersversionpublishe

Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

<p>Abstract</p> <p>Background</p> <p>The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only.</p> <p>Methods/Design</p> <p>This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis.</p> <p>Discussion</p> <p>This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions.</p

Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial

IntroductionDespite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM).MethodsThe LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model.ResultsA total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15–2.01, p &lt; 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61–1.25) in participants with T2DM and 0.64 (0.51–0.80) in participants without diabetes (pinteraction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10).DiscussionIn conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results