Regional and local patterns of genetic variation and structure in yellow‐necked mice ‐ the roles of geographic distance,population abundance,and winter severity

The goal of this study, conducted in seven large woodlands and three areas with small woodlots in northeastern Poland in 2004–2008, was to infer genetic structure in yellow‐necked mouse Apodemus flavicollis population and to evaluate the roles of environmental and population ecology variables in shaping the spatial pattern of genetic variation using 768 samples genotyped at 13 microsatellite loci. Genetic variation was very high in all studied regions. The primal genetic subdivision was observed between the northern and the southern parts of the study area, which harbored two major clusters and the intermediate area of highly admixed individuals. The probability of assignment of individual mice to the northern cluster increased significantly with lower temperatures of January and July and declined in regions with higher proportion of deciduous and mixed forests. Despite the detected structure, genetic differentiation among regions was very low. Fine‐scale structure was shaped by the population density, whereas higher level structure was mainly shaped by geographic distance. Genetic similarity indices were highly influenced by mouse abundance (which positively correlated with the share of deciduous forests in the studied regions) and exhibited the greatest change between 0 and 1 km in the forests, 0 and 5 km in small woodlots. Isolation by distance pattern, calculated among regions, was highly significant but such relationship between genetic and geographic distance was much weaker, and held the linearity at very fine scale (~1.5 km), when analyses were conducted at individual level.     

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

An efficient synthetic strategy to 3‐methylidene‐2,3‐dihydroquinolin‐4(1H)‐ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2‐(tosylamino)benzoate, condensation of thus formed diethyl 2‐oxo‐2‐(2‐N‐tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3‐(diethoxyphosphoryl)‐1,2‐dihydroquinolin‐4‐ols as Horner–Wadsworth–Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3‐dimenthoxyphosphoryl group as a chiral auxiliary. Single X‐ray crystal analysis of (2S)‐3‐(dimenthoxyphosphoryl)‐2‐phenyl‐1‐tosyldihydroquinolin‐4‐ol revealed the presence of strong resonance‐assisted hydrogen bond (RAHB). The obtained 3‐methylidene‐2,3‐dihydroquinolin‐4(1H)‐ones were then tested for their cytotoxic activity against two leukemia cell lines NALM‐6 and HL‐60 and a breast cancer MCF‐7 cell line. All compounds showed very high cytotoxic activity with the IC₅₀ values mostly below 1 μm in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells (HUVEC) and on human mammary gland/breast cells (MCF‐10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF‐7 cells treated with two selected analogs. Both compounds were strong ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.     

Size extensivity of elastic properties of alkane fragments

Using MP2, CCSD, and B3LYP methods of computational chemistry, we show length dependence in the intrinsic elastic properties of short alkane fragments. For isolated alkane fragments of finite length in the gas phase and zero temperature, the intrinsic elasticity constants are found to vary with the number of carbon atoms and its parity. From extrapolation of the elasticity constants calculations to infinite chain length, and by comparing with in-situ elasticity constant of single poly(ethylene) molecule obtained with atomic force microscopy, we estimate the softening effect of environment on the extension response of the polymer.     

Association between single nucleotide polymorphisms of TPH1 and TPH2 genes,and depressive disorders

Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804‐7C>A (rs10488682), c.‐1668T>A (rs623580), c.803+221C>A (rs1800532), c.‐173A>T (rs1799913)—TPH1, c.‐1449C>A (rs7963803), and c.‐844G>T (rs4570625)—TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes. Among the studied polymoorphisms, the G/G genotype and G allele of c.804‐7C>A—TPH1, the T/T homozygote of c.803+221C>A—TPH1, the A/A genotype and A allele of c.1668T>A—TPH1, the G/G homozygote and G allele of c.‐844G>T—TPH2, and the C/A heterozygote and A allele of c.‐1449C>A—TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.‐1668T>A—TPH1, the G/T heterozygote and T allele of c.‐844G>T—TPH2, and the C/C homozygote and C allele of c.‐1449C>A—TPH2 decreased the risk of development of depressive disorders . Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.     

Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration

Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.     

Habitual physical activity and peak anaerobic power in elderly women

The aim of this study was to investigate the relationship between maximal anaerobic power (P _max) and corresponding optimal velocity (V _opt) and habitual physical activity (PA) on the one hand and with maximal oxygen consumption (V˙O_2max) on the other hand, in elderly women. Twenty-nine community dwelling, healthy women aged 66–82 years participated in the study. PA was evaluated using the Questionnaire d'Activite Physique Saint-Etienne (QAPSE) and expressed using two QAPSE activity indices: mean habitual daily energy expenditure (MHDEE) and daily energy expenditure corresponding to leisure time sports activities (sports activity). The subjects' P _max and V _opt were measured while they cycled on a friction-loaded non-isokinetic cycle ergometer. P _max was expressed relative to body mass [P _max/kg(W · kg⁻¹)], and relative to the mass of two quadriceps muscles [P _{max /Quadr}(W·kg_Quadr ⁻¹)]. A negative relationship between P _max/kg (Spearman's r = −0.56; P < 0.01), P _max/Quadr (r = −0.53; P < 0.01) and V _opt (r = −0.45; P < 0.05) and age was found. P _max/kg was positively associated with MHDEE (r = 0.51; P < 0.01) and sports activity (r = 0.58; P < 0.01), as were P _max/Quadr and V _opt (r = 0.55; P < 0.01 and r = 0.54; P < 0.01, respectively). P _max/kg, P _max/Quadr and V _opt correlated positively with V˙O_2max. The positive relationship between ergometer measurements and PA indices was similar to that between V˙O_2max and PA. P _max/kg was, moreover, closely related to V _opt (r = 0.77; P < 0.001). When a multiple stepwise regression analysis was used to select the variables influencing ergometer measurements, MHDEE contributed significantly to P _max/kg variance, whereas sports activity contributed to P _max/Quadr and V _opt variances. In conclusion, the data from this cross-sectional study suggest that in healthy elderly women habitual PA, and especially leisure time PA, alleviates the decline of the P _max of the quadriceps muscles. Accepted: 30 January 1997     

Localization of TGF-beta signaling intermediates Smad2, 3, 4, and 7 in developing and mature human and mouse kidney.

Smad proteins are signaling intermediates of the TGF-beta superfamily and are involved in a range of biological activities including development and immune responses. We studied the expression of TGF-beta-receptor activated Smads (Smad2 and Smad3), the common partner Smad (Smad4), an inhibitory Smad (Smad7), and the activated (phosphorylated) Smad2 (pSmad2) in developing and adult kidneys of humans and mice. These studies demonstrate associated expression of these Smads in multiple renal cell types in all developmental stages and in mature non-diseased kidneys. Smad expression is in general most widespread at the earliest stages of nephron development and diminishes as components of the nephrons become more differentiated. Paucity of Smad expression in mesangial cells in contrast to widespread expression of these Smads in glomerular visceral epithelial cells in both developing and mature kidneys was remarkable. Divergent and less extensive expression of Smad4, compared with other Smad proteins, was also demonstrated in tubules of human kidneys. Based on the observed expression patterns, these findings demonstrate, for the first time, expression of the TGF-beta-receptor-activated Smad2 and Smad3, the common mediator Smad4, and the inhibitory Smad7 in the developing human fetal kidney, extending observations previously made in rodent systems to humans.     

Model for the mechanism controlling the expression of competent state in Pneumococcus cultures

Tomasz, Alexander (The Rockefeller University, New York, N.Y.). Model for the mechanism controlling the expression of competent state in pneumococcus cultures. J. Bacteriol. 91:1050-1061. 1966.-The phenotypic expression of competence allowing the cells to absorb genetically active deoxyribonucleic acid molecules from their environment was examined in pneumococcal cultures growing under a variety of environmental conditions. The most important single parameter affecting the time course of this expression process was found to be the cell concentration. Constant high levels of competence could be maintained in cultures growing in a continuous-dilution device. The expression of competence seems to occur through a specific induction process "catalyzed" by a macromolecular cell product-the activator substance. Under most growth conditions, the availability of endogenous activator seems to limit the expression of competence. An "autocatalytic" production of activator ensues during the activation of cells to the competent state. Evidence is presented for physiological influences affecting the cell's capacity to react with the activator. A physiological model is proposed for the control of the competent state in pneumococcus.