Differential susceptibility of the embryo to inorganic lead during periimplantation in the mouse

The effect of intravenously administered inorganic lead on periimplantation period of embryonic development in the mouse was investigated with light microscopy. Three developmental stages were studied: the attachment of the blastocyst, the invasion of the trophoblast and the formation of the primitive streak. All three stages were affected, but the stage of invasion was found to be the most susceptible to lead as determined by decrease in frequency of animals with normal embryos.     

B cell selection and susceptibility to autoimmunity

Autoreactive B cells arise routinely as part of the naive B cell repertoire. The immune system employs several mechanisms in an attempt to silence these autoreactive cells before they achieve immunocompetence. The BCR plays a central role in B cell development, activation, survival, and apoptosis, and thus is a critical component of the regulation of both protective and autoreactive B cells. The strength of signal mediated by the BCR is determined by numerous factors, both B cell intrinsic and B cell extrinsic. Perturbations in the molecules that regulate the BCR signal strength or that activate pathways that engage in cross talk with the BCR-mediated signaling pathways can lead to the aberrant survival and activation of autoreactive B cells. In this review, we will discuss the some newly identified genetic loci and factors that modulate the BCR signal transduction pathway and, therefore, the regulation of autoreactive B cells. We will also provide evidence for a model of autoreactivity in which a reduction in the strength of the BCR signal allows the survival and the modulation of a naive B cell repertoire replete with autoreactivity.     

Differential metal content and gene expression in rat left ventricular hypertrophy due to hypertension and hyperactivity

The spontaneously hypertensive rat (SHR) has been studied extensively as a model of left ventricular hypertrophy (LVH) and associated cardiac dysfunction due to hypertension (HT). The SHR also possesses a hyperactive trait (HA). Crossbreeding SHR with Wistar–Kyoto (WKY) control rats, which are nonHT and nonHA, followed by selected inbreeding produced two additional homozygous strains: WKHT and WKHA, in which the traits of HT and HA, respectively, are expressed separately. WKHT, WKHA and SHR all display LVH, but only the SHR exhibits cardiac dysfunction. We hypothesized that cardiac dysfunction in the SHR is uniquely characterized by calcium overload. We measured total cardiac Ca, Cu, Fe, K, Mg and Zn in the four strains. We found elevated Ca and depressed Cu, Mg and Zn with HT, but not unique to SHR. We surmise that HT promotes aberrant regulation of cardiac Ca²⁺, Cu²⁺, Mg²⁺ and Zn²⁺, which does not necessarily result in cardiac dysfunction. Interestingly, Cu was elevated in HA strains compared to nonHA counterparts. We then analyzed gene expression as mRNA of Cu-containing proteins, most notably mitochondrial-Cox, Dbh, Lox, Loxl1, Loxl2, Sod1 and Tyr. The gene expression profiles of Lox, Loxl1, Loxl2 and Sod1 were found especially high in the WKHA, which if reflective of protein content could account for the high Cu content in the WKHA. The mRNA of other genes, notably Mb, Fxyd1, Maoa and Maob were also examined. We found that Maoa gene expression and monoamine oxidase-A (MAO-A) protein content were low in the SHR compared to the other strains. The finding that MAO-A protein is low in the SHR and normal in the WKHT and WKHA strains is most consistent with the idea that MAO-A protects against the development of cardiac dysfunction in LVH but not against LVH in these rats.     

Restriction of the T-cell receptor V delta gene repertoire is due to preferential rearrangement and is independent of antigen selection

To determine whether the limited V gene usage by the T-cell receptor delta (TCRD) chain is dictated by preferential rearrangement or by antigen selection, we characterized and compared the TCRDV gene repertoire of the productive with that of the unprotective allele in 80 human TCRG/TCRD clones. Six different V genes were found on the expressed allele; two of them, provisionally named DV7 and DV8, have not been described before on the surface of TCRG/TCRD T cells. Overall, six V genes and six non-V elements were isolated from the unproductive allele. Interestingly, the same set of genes was rearranged both in the productive and in the unproductive chromosome. These findings seem to suggest that antigen-independent mechanisms play a major role in the restriction of the TCRDV gene repertoire.The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide database and have been assigned the accession numbers Z46643 (DV7-E2), Z46644 (DV8-E6), Z46645 (DV8-M1), Z46641 (AV12-E4), Z46642 (AV29-E5), Z46652 (DREC-E13), Z46637 (TCR-d), Z46638 (TCR-n), Z46639 (TCR-r), Z46653 (PSI-DVu), and Z46640 (TCR-w)     

Differential selection for B-raf and Ha-ras mutated liver tumors in mice with high and low susceptibility to hepatocarcinogenesis

Activation of the Ras/Raf/MEK/ERK pathway is frequently observed in animal and human tumors. In our study, we analyzed B-raf codon 637 (formerly 624) and Ha-ras codon 61 mutations in liver tumors from C3H, B6C3F1 and C56BL mice which differ considerably with regard to their susceptibility to hepatocarcinogenesis. In total, 73% (102/140) of tumors induced by a single application of N-nitrosodiethylamine or 7,12-dimethylbenz[a]anthracene contained either B-raf or Ha-ras mutations and only <3% (4/140) were mutated in both genes. In addition, B-raf mutations were present in 76% (19/25) of early precancerous liver lesions. The prevalence of Ha-ras mutated tumors was significantly higher in the susceptible C3H and B6C3F1 mouse strains (39-50%) than in the comparatively resistant C57BL mouse (7%). B-raf mutated tumors, by contrast, were more frequent in C57BL mice (68%) than in the other two strains (17-45%). Taken together, our findings indicate that alterations affecting the Ras/Raf/MEK/ERK signalling pathway are a hallmark of carcinogen-induced liver tumors in mice. Moreover, our results show that mutational activation of B-raf in liver tumors of different mouse strains is, by contrast to Ha-ras, inversely related to their susceptibility to hepatocarcinogenesis. Although activated Ras and Raf proteins are assumed to have similar biological effects because they feed into the same signalling pathway, there seem to be subtle strain-specific differences in selection processes favouring the preferential outgrowth of either B-raf or Ha-ras mutated tumor populations in mouse liver.     

Diuretic response to acute hypertension is blunted during angiotensin II clamp

Acute hypertension inhibits proximal tubule (PT) fluid reabsorption. The resultant increase in end proximal flow rate provides the error signal to mediate tubuloglomerular feedback autoregulation of renal blood flow and glomerular filtration rate and suppresses renal renin secretion. To test whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after pretreatment with the bradykinin B(2) receptor blocker HOE-140 (100 microg/kg bolus). Because ACE also degrades bradykinin, HOE-140 was included to block effect of accumulating vasodilatory bradykinins during captopril infusion. HOE-140 increased the sensitivity of arterial blood pressure to ANG II: after captopril infusion without HOE-140, 20 ng x kg(-1) x min(-1) ANG II had no pressor effect, whereas with HOE-140, 20 ng x kg(-1) x min(-1) ANG II increased blood pressure from 104 +/- 4 to 140 +/- 6 mmHg. ANG II infused at 2 ng x kg(-1) x min(-1) had no pressor effect after captopril and HOE-140 infusion ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic response.     

Evidence that protein length expansion and contraction is partly due to mutational events in premeiotic cells

Studies on the rate of evolution of proteins typically concentrate on rates of change of orthologous amino acids rather than on changes in size (i.e., generation of nonorthologous domains). Recent work has focused attention on Ser/Thr-rich regions in yeast as these tend to undergo size changes rapidly, with size polymorphisms commonly being found, especially in proteins with cell-surface localization. The underlying mechanism generating the indels is presently unclear though, due to a lack of correlation with the location of meiotic double-strand breaks, it has, by exclusion, been conjectured to be replication slippage. Here we provide new evidence to support this possibility. Notably, we show that Ser/Thr-rich repeat regions are more generally associated with the location of Mre11p in premeiotic cells. This is to be expected if the repeats were produced by mutational events in mitotic cells possibly through replication slippage.     

Differential susceptibility of aeromonads and coliforms to cefsulodin

Volumn 62, no. 6, p. 1885, Abstract, line 3: "For 102 of 129 Aeromonas isolates" should read "For 102 of 130 Aeromonas isolates." Page 1887, column 1, lines 16 and 17: "and for 13 of 21 coliform isolates" should read "and for 13 of 94 coliform isolates." [This corrects the article on p. 1885 in vol. 62.].     

Differential susceptibility to human serum byAeromonas spp.

A total of 91 strains ofAeromonas (A. hydrophila, A. sobria, andA. caviae) of clinical origin were challenged in vitro against pooled human serum. A majority of the isolates ofA. hydrophila andA. sobria were resistant to the bactericidal activity of human serum, as opposed to the more serum-sensitiveA. caviae species. This difference in serum sensitivity may potentially explain the greater association of the former species with bacteremia and invasive disease.     

Kin selection is the key to altruism

Kin selection theory, also known as inclusive fitness theory, has been the subject of much debate and misunderstanding. Nevertheless, the idea that relatedness among individuals can drive the evolution of altruism has emerged as a central paradigm in evolutionary biology. Or has it? In two recent articles, E.O. Wilson argues that kin selection should no longer be considered the main explanation for the evolution of altruism in insect societies. Here, we discuss what these articles say about kin selection and how it relates to the theory. We conclude that kin selection remains the key explanation for the evolution of altruism in eusocial insects.     

Neotropical moth assemblages degrade due to oil palm expansion

Oil palm is one of the most rapidly expanding crops throughout the tropics, yet little is known about its impacts on Neotropical invertebrate biodiversity. Responses of insect assemblages to land conversion may substantially vary among taxa. We assessed geometrid and arctiine moth assemblages in a Costa Rican human dominated landscape, where oil palm plantations are now the second most common land cover. Moths were sampled during 6 months with automatic traps in the interior and margin of old-growth forests, young secondary forests and oil palm plantations in a 30 km² area. Our results show that richness and diversity of both taxa were severely reduced in oil palm compared to all other habitats. Geometrid abundance was highest in forest interiors and lowest in oil palm, while arctiine numbers did not differ between habitats. Dominance was highest in oil palm plantations, where one arctiine species and one geometrid species accounted for over 40% of total abundance in each of their respective taxa. Species composition was distinct in oil palm and forest interior sites, and depicted a gradient of habitat disturbance in ordination space that was strongly related to vegetation diversity and structure. This study demonstrates that oil palm plantations are not a suitable habitat for these moth taxa. Whilst some arctiine species seem adapted to disturbed habitats, geometrids were more dependent on old-growth forests, showing higher bioindicator potential. In the face of accelerated oil palm expansion, conservation strategies should focus on protecting old-growth forest remnants, as well as increasing species diversity and structural complexity of degraded habitats.     

Differential selection between the sexes and selection for sex

Anisogamy is known to generate an important cost for sexual reproduction (the famous "twofold cost of sex"). However, male-female differences may have other consequences on the evolution of sex, due to the fact that selective pressures may differ among the sexes. On the one hand, intralocus sexual conflict should favor asexual females, which can fix female-beneficial, male-detrimental alleles. On the other hand, it has been suggested repeatedly that sexual selection among males may help to purge the mutation load, providing an advantage to sexual females. However, no analytical model has computed the strength of selection acting on a modifier gene affecting the frequency of sexual reproduction when selection differs between the sexes. In this article, we analyze a two-locus model using two approaches: a quasi-linkage-equilibrium (QLE) analysis and a local stability analysis, whose predictions are verified using a multilocus simulation. We find that costly sex can be maintained when selection is stronger in males than in females, but acts in the same direction in both. Complete asexuality, however, evolves under any other form of selection. Finally, we discuss how experimental measurements of fitness variances and covariances between sexes could be used to determine the overall direction and strength on selection for sex arising from differences in selection between males and females.     

Increased severity of murine lupus in female mice is due to enhanced expansion of pathogenic T cells

A strong female predominance is a well-recognized feature of human lupus. The mechanism by which sex influences disease expression and severity is not fully understood. To address this question, we used the parent-into-F(1) (p-->F(1)) model of chronic graft-vs-host disease (cGVHD) in which lupus-like humoral autoimmunity and renal disease are induced in normal F(1) mice. An advantage of this model is that the pathogenic T cells driving disease (donor strain) can be studied separately from nonspecifically activated T cells (host strain). We observed that lupus-like disease using female donor and host mice (f-->F cGVHD) is characterized by more severe long-term disease (glomerulonephritis) than with male donor and host (m-->M cGVHD). Interestingly, differences in disease parameters could be seen at 2 wk after parental cell transfer, as evidenced by a 2- to 3-fold greater engraftment of donor CD4(+) T cells in f-->F cGVHD mice, which persisted throughout disease course. Enhanced engraftment of donor CD4(+) T cells in f-->F cGVHD mice was not due to differences in splenic homing, alloreactive precursor frequency, initial proliferation rates, or apoptotic rates, but rather to sustained high proliferation rates during wk 2 of disease compared with m-->M cGVHD mice. Crossover studies (m-->F, f-->M) demonstrated that enhanced donor CD4(+) T cell proliferation and engraftment segregate with the sex of the host. These results demonstrate that the sex of the recipient can influence the expansion of pathogenic T cells, thus increasing long-term the burden of autoreactive T cells and resulting in greater disease severity.     

PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning

We studied the extreme hemodilution to a hematocrit of 11% induced by three plasma expanders: polyethylene glycol (PEG)-conjugated albumin (PEG-Alb), 6% 70-kDa dextran, and 6% 500-kDa dextran. The experimental component of our study relied on microelectrodes and cardiac output to measure both the rheological properties of plasma-expander blood mixtures and nitric oxide (NO) bioavailability in vessel walls. The modeling component consisted of an analysis of the distribution of wall shear stress (WSS) in the microvessels. Our experiments demonstrated that plasma expansion with PEG-Alb caused a state of supraperfusion with cardiac output 40% above baseline, significantly increased NO vessel wall bioavailability, and lowered peripheral vascular resistance. We attributed this behavior to the shear thinning nature of blood and PEG-Alb mixtures. To substantiate this hypothesis, we developed a mathematical model of non-Newtonian blood flow in a vessel. Our model used the Quemada rheological constitutive relationship to express blood viscosity in terms of both hematocrit and shear rate. The model revealed that the net effect of the hemodilution induced by relatively low-viscosity shear thinning PEG-Alb plasma expanders is to reduce overall blood viscosity and to increase the WSS, thus intensifying endothelial NO production. These changes act synergistically, significantly increasing cardiac output and perfusion due to lowered overall peripheral vascular resistance.     

Glomerular sclerosis is prevented during urinary tract obstruction due to podocyte protection

Urine outflow obstruction activates a variety of profibrotic factors, including the intrarenal renin-angiotensin system. However, the obstruction also nullifies the transmural hydraulic pressure difference across the glomerular capillary wall, an established inducer of glomerulosclerosis. In the present study, we investigated whether, and by what mechanism, urine outflow obstruction affects the process of progressive glomerulosclerosis. For this purpose, we tested the effect of unilateral ureteral obstruction (UUO) of 7 days duration in two distinct mouse models of glomerulosclerosis. In the human immunodeficiency virus (HIV) nephropathy model, where HIV-1 genes are selectively expressed in podocytes and develop progressive podocyte damage and glomerulosclerosis, UUO protected against sclerosis with preservation of podocytes morphologically and immunohistochemically. In contrast, the nonobstructed contralateral kidneys of these mice, as well as sham-operated HIV-1 mouse kidneys, developed severe podocyte injury and glomerulosclerosis. The protection against glomerulosclerosis imparted by ureteral obstruction was also documented in the NEP25 model of podocyte injury, in which a single injection of immunotoxin, LMB2, triggers selective podocyte injury followed by glomerulosclerosis, both of which were protected by UUO. Notably, intervention with an angiotensin II type 1 receptor antagonist provided only a partial protective effect in each of the models. These results demonstrate that urine outflow obstruction protects the glomerulus from progressive sclerosis. The results further reveal that this protection occurs at a very early stage of the pathologic process, namely, damage of podocytes.     

Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension

Even if the importance of angiotensinogen (AGT) gene has been known in gene targeting animals and humans genetic studies, its precise mechanism and the interaction among AGT gene variants, plasma AGT concentration and risk for hypertension remain uncertain. We examined whether AGT gene variants predispose to hypertension via an increase of plasma AGT concentration. Plasma AGT concentration was estimated from plasma angiotensin I which was cleaved by an excess amount of human renin and measured by RIA. Using 9 AGT gene variants which included new polymorphisms (G-152A and T+31C), we examined the association with hypertension and with plasma concentration by a case-control study. Haplotype analysis revealed that G-6A, T+31C and M235T polymorphisms were in absolute linkage disequilibrium and were associated with hypertension but not with plasma AGT level. On the other hand, -1074t;T235 haplotype was associated with an increase of AGT level but not with hypertension. In the haplotype analysis, only H3 haplotype frequency, which contained G-6, T+31 and M235 alleles, was significantly increased in normotensive subjects, suggesting that this haplotype is associated with a hypotensive effect. According to combined haplotype analysis of diallele and microsatellite markers, it remains a possibility that M235T, T+31C, G-6A, A-20C and G-1074T polymorphisms may play an important role in increased risk for essential hypertension. Our results suggest that the positive association between AGT polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.