Preferential expression of the transcription coactivator HTIF1alpha gene in acute myeloid leukemia and MDS-related AML

HTIF1α, a transcription coactivator which is able to mediate RARα activity and functionally interact with PML, is encoded by a gene on chromosome 7q32–34, which is a critical region in acute myeloid leukemias (AML). With the assumption that this gene may be related to AML, we investigated the HTIF1α DNA structure and RNA expression in leukemic cells from 36 M1–M5 AML patients (28 ‘de novo’ and eight ‘secondary’ to myelodysplastic syndrome (MDS)). Abnormal HTIF1α DNA fragments were never found, whereas loss of HTIF1α DNA was observed in the patients with chromosome 7q32 deletion and translocation, and in one case without detectable chromosome 7 abnormality. HTIF1α RNA was found in acute myelocytic leukemic blasts, and was almost undetectable in normal mononuclear cells. The expression varied among the patients: higher in M1 to M3 subtypes, with the highest values in M1; low levels were constantly observed in M4 and M5 AML. In addition, HTIF1α was significantly overexpressed in MDS-related AML (MDR-AML), but not in MDS. We also found that HTIF1α expression was high in myeloid cell lines. In myeloblastic HL60 and promyelocytic NB4 cells, induced to differentiate along the monocytic–macrophage pathway by TPA or vitamin D3, HTIF1α expression decreased, whereas it was maintained at high levels on induction to granulocytic differentiation by RA or DMSO. In K562 cells, HTIF1α RNA levels did not change after hemin-induced erythroid differentiation. These results suggest that HTIF1α could play a role in myeloid differentiation, being distinctly regulated in hematopoietic lineages

Dendritic Cell Differentiation

Dauer et al. ([1][1]) presented a method to differentiate CD14+ cells into mature dendritic cells (DC) within 48 h (FastDC). FastDC displayed a DC-like morphology, down-regulated CD14, and induced proliferation of autologous T cells against soluble Ags as efficiently as standard monocyte-derived D

Rhinocerotidae (Mammalia, Perissodactyla) from the middle Pleistocene levels of Grotta Romanelli (Lecce, southern Italy)

The rhinoceros remains collected during the past century in the lower levels XII (= K) and XI (= I) of the famous Pleistocene locality of Grotta Romanelli (Lecce, southern Italy) are described and compared in detail for the first time. Some remains are referred to Stephanorhinus sp. and others are assigned here to the late early-middle Pleistocene European species Stephanorhinus hundsheimensis based on several morphological characters. Based on its olivine-bearing texture, the volcanoclastic ash sampled from some rhinoceros bones can be referred to the first phase of the Monte Vulture activity (around 630 ka). The results of the stable isotope analyses suggest that the climate in the lowest levels of Grotta Romanelli could have been more arid than it was at the time of the upper level IX, which is generally referred to the late Pleistocene. In addition, both recent day δ18Opptvalues and MAT are very similar to values calculated for levels X and XII, suggesting that the climate at those times may have been close to the Present one, whereas climate in level IX may have been somewhat cooler. The presence of Stephanorhinus hundsheimensis suggests a middle Pleistocene age for the lower levels of Grotta Romanelli, in agreement with the results obtained from the volcanoclastic material

The association of proBNPage with manifestations of age-related cardiovascular, physical, and psychological impairment in community-dwelling older adults

NT-proB-type natriuretic peptide (NT-proBNP) serum concentration can be transformed by simple formulas into proBNPage, a surrogate of biological age strongly associated with chronological age, all-cause mortality, and disease count. This cross-sectional study aimed to assess whether proBNPage is also associated with other manifestations of the aging process in comparison with other variables. The study included 1117 noninstitutionalized older adults (73.1 +/- 5.6 years, 537 men). Baseline measurements of serum NT-proBNP, erythrocyte sedimentation rate, hemoglobin, lymphocytes, and creatinine, which have previously been shown to be highly associated with both age and all-cause mortality, were performed. These variables were compared between subjects with and without manifestations of cardiovascular impairment (myocardial infarction (MI), stroke, peripheral artery disease (PAD), arterial revascularizations (AR)), physical impairment (long step test duration (LSTD), walking problems, falls, deficit in one or more activities of daily living), and psychological impairment (poor self-rating of health (PSRH), anxiety/depression, Mini Mental State Examination (MMSE) score < 24). ProBNPage (years) was independently associated (OR, 95% CI) with MI (1.08, 1.07-1.10), stroke (1.02, 1.00-1.05), PAD (1.04, 1.01-1.06), AR (1.06, 1.04-1.08), LSTD (1.03, 1.02-1.04), walking problems (1.02, 1.01-1.03), and PSRH (1.02, 1.01-1.02). For 5 of these 7 associations, the relationship was stronger than that of chronological age. In addition, proBNPage was univariately associated with MMSE score < 24, anxiety/depression, and falls. None of the other variables provided comparable performances. Thus, in addition to the known associations with mortality and disease count, proBNPage is also associated with cardiovascular manifestations as well as noncardiovascular manifestations of the aging process

Evidence for a disaggregation of the universe.

Combining the kinematical definitions of the two dimensionless parameters, the deceleration q(x) and the Hubble t 0 H(x), we get a differential equation (where x=t/t 0 is the age of the universe relative to its present value t 0). First integration gives the function H(x). The present values of the Hubble parameter H(1) [approximately t 0 H(1)≈1], and the deceleration parameter [approximately q(1)≈−0.5], determine the function H(x). A second integration gives the cosmological scale factor a(x). Differentiation of a(x) gives the speed of expansion of the universe. The evolution of the universe that results from our approach is: an initial extremely fast exponential expansion (inflation), followed by an almost linear expansion (first decelerated, and later accelerated). For the future, at approximately t≈3t 0 there is a final exponential expansion, a second inflation that produces a disaggregation of the universe to infinity. We find the necessary and sufficient conditions for this disaggregation to occur. The precise value of the final age is given only with one parameter: the present value of the deceleration parameter [q(1)≈−0.5]. This emerging picture of the history of the universe represents an important challenge, an opportunity for the immediate research on the Universe. These conclusions have been elaborated without the use of any particular cosmological model of the univers

Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF

Current Options for Visualization of Local Deformation in Modern Shape Analysis Applied to Paleobiological Case Studies

In modern shape analysis, deformation is quantified in different ways depending on the algorithms used and on the scale at which it is evaluated. While global affine and non-affine deformation components can be decoupled and computed using a variety of methods, the very local deformation can be considered, infinitesimally, as an affine deformation. The deformation gradient tensor F can be computed locally using a direct calculation by exploiting triangulation or tetrahedralization structures or by locally evaluating the first derivative of an appropriate interpolation function mapping the global deformation from the undeformed to the deformed state. A suitable function is represented by the thin plate spline (TPS) that separates affine from non-affine deformation components. F, also known as Jacobian matrix, encodes both the locally affine deformation and local rotation. This implies that it should be used for visualizing primary strain directions (PSDs) and deformation ellipses and ellipsoids on the target configuration. Using C = FTF allows, instead, one to compute PSD and to visualize them on the source configuration. Moreover, C allows the computation of the strain energy that can be evaluated and mapped locally at any point of a body using an interpolation function. In addition, it is possible, by exploiting the second-order Jacobian, to calculate the amount of the non-affine deformation in the neighborhood of the evaluation point by computing the body bending energy density encoded in the deformation. In this contribution, we present (i) the main computational methods for evaluating local deformation metrics, (ii) a number of different strategies to visualize them on both undeformed and deformed configurations, and (iii) the potential pitfalls in ignoring the actual three-dimensional nature of F when it is evaluated along a surface identified by a triangulation in three dimensions

Role of Dok-1 and Dok-2 in Leukemia Suppression

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis

Exploiting the Reducing Properties of Lignin for the Development of an Effective Lignin@Cu2O Pesticide

Lignin is a natural polymer produced in huge amounts by the paper industry. Innovative applications of lignin, especially in agriculture, represent a valuable way to develop a more sustainable economy. Its antioxidant and antimicrobial properties, combined with its biodegradability, make it particularly attractive for the development of plant protection products. Copper is an element that has long been used as a pesticide in agriculture. Despite its recognized antimicrobial activity, the concerns derived from its negative environmental impact is forcing research to move toward the development of more effective and sustainable copper-based pesticides. Here a simple and sustainable way of synthesizing a new hybrid material composed of Cu2O nanocrystals embedded into lignin, named Lignin@Cu2O is presented. The formation of cuprite nanocrystals leaves the biopolymer intact, as evidenced by infrared spectroscopy, gel permeation chromatography, and Pyrolysis-GC analysis. The combined activity of lignin and cuprite make Lignin@Cu2O effective against Listeria monocytogenes and Rhizoctonia solani at low copper dosage, as evidenced by in vitro and in vivo tests conducted on tomato plants

Increase on environmental seasonality through the European Early Pleistocene inferred from dental enamel hypoplasia

An in-depth study of the Early Pleistocene European remains of Hippopotamus has allowed the first detailed description of the incidence and types of dental alterations related to palaeopathologies and potentially linked to climatic and environmental factors. The results of a long-term qualitative and quantitative assessment highlight the importance of nutrient deficiencies on the development of dental enamel hypoplasia in Hippopotamus. Glacial cyclicity and the resulting changes in humidity and plant community structure conditioned the local environments critical for the survival of this taxon. Two main intervals of putative constrained nutritionally restrictions were detected at ca. 1.8 Ma and ca. 0.86 Ma (i.e., MIS63 and MIS21, respectively). Statistical comparisons show an increase in the frequency of dental hypoplasia between these two chronological periods, thus reinforcing the idea of increased seasonality in the circum-Mediterranean environments during the Early Pleistocene