A transgenic mouse model for mammary carcinogenesis

Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and influence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172(R-H) construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the specific effects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent effect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNA flow analysis confirmed the presence of significant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies.     

A model for evolution and extinction

We present a model for evolution and extinction in large ecosystems. The model incorporates the effects of interactions between species and the influences of abiotic environmental factors. We study the properties of the model by approximate analytic solution and also by numerical simulation, and use it to make predictions about the distribution of extinctions and species lifetimes that we would expect to see in real ecosystems. It should be possible to test these predictions against the fossil record. The model indicates that a possible mechanism for mass extinction is the coincidence of a large coevolutionary avalanche in the ecosystem with a severe environmental disturbance.     

Organization of the human RH50A gene (RHAG) and evolution of base composition of the RH gene family

The alpha4 chain (CD49d), which constitutes one of the chains of alpha4beta1 (very late activating antigen-4 [VLA-4]) and alpha4beta7 integrins, mediates migration of T cells to extravascular spaces. The interaction between VLA-4 and vascular cell adhesion molecule-1 (VCAM-1) has been shown to be the critical pathway for the selective accumulation of eosinophils and basophils at sites of allergic inflammation. T lymphocytes are also specifically recruited into allergic sites, including the allergic asthmatic airway. Increased numbers of activated CD4+ cells expressing the DR antigen subset of the human leukocyte antigens (HLA-DR) appear in the allergic lung 48 h after allergen inhalation. The mechanisms by which these cells localize into the lung are still unknown. We report that stimulation of allergen-specific T cells with allergen in vitro resulted in enhanced expression of alpha4 chain (CD49d) as measured by receptor density on allergen-specific T-cell lines and T-cell clones. Kinetic studies showed that CD49d density was enhanced over a 24- to 48-h period in a time-dependent fashion, and was coordinately upregulated with HLA-DR expression. We also demonstrated that increased expression of CD49d on T-cell lines 24 h and 48 h after stimulation correlated with increased adhesion to the CS-1 fragment of fibronectin. In contrast, lymphocyte function-associated antigen-1b (LFA-1b) (CD11b), LFA-3 (CD58), and intercellular adhesion molecule-1 (ICAM-1) (CD54) expression did not change with allergen stimulation. We also showed that CD49d receptor density on T cells obtained by bronchoalveolar lavage (BAL) of allergic patients before and 48 h after allergen challenge was significantly higher than that on T cells taken from BAL of normal subjects and from controls with other inflammatory lung diseases. Taken together, these findings indicate that allergen stimulation activates allergen-specific T cells and coordinately induces increased CD49d receptor expression and binding to counterligands. We postulate that allergen-driven upregulation of CD49d, which together with the beta1 chain constitutes VLA-4 integrin, may be responsible for the selective accumulation of T cells in the allergic asthmatic lung.     

A note on Corballis (1997) and the genetics and evolution of handedness: Developing a unified distributional model from the sex-chromosomes gene hypothesis.

A unified, quantitative model for sex, twin, parent, and grandparent influences on handedness is presented. Recent research modeling the evolutionary development of genetic mechanisms for the transmission of handedness on the basis of genotype fitness has appeared to lead to the conclusion that a handedness gene cannot be located on the sex chromosomes. It is shown in this article, however, that this conclusion is not of general validity. The sex-chromosomes hypothesis is developed further, and it is demonstrated that a wide-ranging, detailed, and parsimonious account of the distribution of handedness is obtained when left-handedness is assumed to be associated recessively, and with low penetrance, with genetic variation located on the X chromosome. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome

HPC-1/syntaxin 1A is a membrane protein that plays an important role in exocytosis of neurotransmitters from neuronal cells. We previously mapped the human HPC-1/syntaxin 1A gene (STX1A) to chromosome 7q11.2, which is within the Williams syndrome (WS) region. Here, we performed FISH analysis on 46 patients with WS to examine the relationship between STX1A and WS. Our results showed a hemizygous deletion of the HPC-1/syntaxin 1A gene in each patient, suggesting that the neurological symptoms of WS may be related to the hemizygous deletion of STX1A.     

A process model for the microstructure evolution in ductile cast iron: Part I. the model

In the present investigation, the multiple phase changes occurring during solidification and subsequent cooling of near-eutectic ductile cast iron have been modeled using the internal state variable approach. According to this formalism, the microstructure evolution is captured mathematically in terms of differential variation of the primary state variables with time for each of the relevant mechanisms. Separate response equations have then been developed to convert the current values of the state variables into equivalent volume fractions of constituent phases utilizing the constraints provided by the phase diagram. The results may conveniently be represented in the form of C curves and process diagrams to illuminate how changes in alloy composition, graphite nucleation potential, and thermal program affect the microstructure evolution at various stages of the process. The model can readily be implemented in a dedicated numerical code for the thermal field in real castings and used as a guiding tool in design of new treatment alloys for ductile cast irons. An illustration of this is given in an accompanying article (Part II).     

Type I oculocutaneous albinism associated with a full-length deletion of the tyrosinase gene

Type I oculocutaneous albinism is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes because of deficient activity of tyrosinase (EC 1.14.18.1). Type I oculocutaneous albinism is caused by mutations in the tyrosinase structural gene, TYR; however, no large TYR gene deletions have been identified previously in humans. Here we report a patient with type IB oculocutaneous albinism who is a compound heterozygote for TYR allele containing a mutation that is likely to affect pre-RNA splicing and a paternally inherited allele in which the TYR gene is completely deleted, the first such allele described to date. Aside from the albinism in the proband, his phenotype and that of his normally pigmented father is otherwise normal, suggesting that this TYR deletion does not involve other functionally important contiguous genes.     

A trinucleotide deletion in the transthyretin gene (delta V 122) in a kindred with familial amyloidotic polyneuropathy

A 63-year-old white man of Ecuadorian origin had a subarachnoid hemorrhage at age 57 followed by numbness and paresthesia in his lower extremities. He subsequently developed sexual impotence, alternating constipation and diarrhea, urinary frequency, and difficulty in walking. Rectal biopsy revealed amyloid deposits immunohistochemically reactive with antitransthyretin antisera. Direct DNA sequencing of the transthyretin gene of the patient showed a trinucleotide deletion in exon 4. This deletion resulted in the loss of one of two valines at position 121 or 122. DNA analysis on 11 family members at risk revealed four mutant gene carriers. Plasma transthyretin levels in the mutant gene carriers measured by nephelometry were very low. Peptide sequence analysis revealed that most of plasma transthyretin was normal with only a small amount of variant protein. This is the first report of a DNA deletion in the transthyretin gene. We speculate that the loss of valine in the carboxyl terminal region of the transthyretin monomer alters stability of the tetrameric protein, which leads to rapid clearance from the plasma and amyloid deposition in the tissue.     

Chronic ultraviolet exposure-induced p53 gene alterations in Sencar mouse skin carcinogenesis model

Alterations of the tumor suppresser gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10/37 (27%) of SCCs and 12/24 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C-->A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C-->T, two C-->A, one C-->G, and one A-->T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin.     

Viral carcinogenesis of brain (author''s transl)

To test the hypothesis that intarpartum acidosis has a role in the etiology of hyaline membrane disease (HMD), blood was collected from the umbilical artery (UA) at birth from 110 premature infants and analyzed for hydrogen ion concentration ([H+]), PCO2, standard bicarbonate, and lactic acid. The infants were followed until a definite diagnosis was made of HMD (33 infants), type II respiratory distress syndrome (16 infants) or the absence of respiratory distress (61 infants). In general, infants with HMD were more premature and had lower Apgar scores than nondistressed infants; however, there were no significant differences between the two groups in any acid-base measurement. Only in those patients of 32 to 37 weeks' gestational age was it possible to detect a significant increase in UA [H+] in infants with HMD compared to those without respiratory distress. There was evidence that the reduced Apgar score of infants with HMD may be due to immaturity and abnormal pulmonary function secondary to lung disease. It is concluded that acidosis at birth is not a factor in the development of HMD except possibly in more mature infants.     

A process model for the heat-affected zone microstructure evolution in duplex stainless steel weldments: Part I. the model

The present investigation is concerned with modeling of the microstructure evolution in duplex stainless steels under thermal conditions applicable to welding. The important reactions that have been modeled are the dissolution of austenite during heating, subsequent grain growth in the delta ferrite regime, and finally, the decomposition of the delta ferrite to austenite during cooling. As a starting point, a differential formulation of the underlying diffusion problem is presented, based on the internal-state variable approach. These solutions are later manipulated and expressed in terms of the Scheil integral in the cases where the evolution equation is separable or can be made separable by a simple change of variables. The models have then been applied to describe the heat-affected zone microstructure evolution during both thick-plate and thin-plate welding of three commercial duplex stainless steel grades: 2205, 2304, and 2507. The results may conveniently be presented in the form of novel process diagrams, which display contours of constant delta ferrite grain size along with information about dissolution and reprecipitation of austenite for different combinations of weld input energy and peak temperature. These diagrams are well suited for quantitative readings and illustrate, in a condensed manner, the competition between the different variables that lead to structural changes during welding of duplex stainless steels.     

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM

Angiotensin 1 converting enzyme (ACE) catalyses the step which generates angiotensin II, and also inactivates bradykinin, peptides which play a key role in modulating vascular tone. Plasma ACE levels are under genetic control and up to 50% of the variation is due to an insertion/deletion (I/D) polymorphism of ACE gene with highest levels found in DD homozygotes. Studies have shown an association of diabetic nephropathy and ischaemic heart disease with angiotensin converting enzyme gene polymorphism in subjects with diabetes. We examined the association between diabetic retinopathy and ACE gene insertion/deletion polymorphism in 363 subjects with NIDDM (aged 68.3 +/- 10.7 years; 201 male, 162 female), 186 subjects with IDDM (aged 42.4 +/- 15.0 years; 100 male, 86 female) and 98 controls. These subjects were characterized for ACE I/D polymorphism employing standard primers. Diabetic retinopathy was diagnosed by ophthalmoscopy through dilated pupils by an ophthalmologist and classified as non-proliferative or proliferative retinopathy. As expected, diabetic retinopathy was strongly associated with duration of diabetes (p < 0.001) in both IDDM and NIDDM. Any retinopathy was present in 51% subjects with IDDM and 49% of subjects with NIDDM, while 22% of IDDM subjects and 5% of subjects with NIDDM had proliferative retinopathy. The frequency of I allele was 0.477 vs 0.482 vs 0.510 and D allele was 0.523 vs 0.518 vs 0.490, among subjects with IDDM, NIDDM and controls, respectively. The frequency of ACE I/D genotype was similar in subjects with IDDM, NIDDM, and controls (chi 2 = 0.46, df = 4, p = ns). Presence or absence of retinopathy was not significantly associated with ACE genotype in subjects with IDDM (chi 2 = 3.42, df = 2, p = ns) or NIDDM (chi 2 = 0.51, df = 2, p = ns). Among subjects with retinopathy, there was no significant association between ACE genotype and type of retinopathy. Controlled for duration of diabetes, the frequency of I/D genotype was not significantly different in 271 subjects with retinopathy (IDDM and NIDDM combined) when compared with 86 subjects without retinopathy at 15 years or more after diagnosis of diabetes (chi 2 = 1.29, df = 2, p = ns). These findings indicate that I/D polymorphism of ACE gene is not a useful marker and is unlikely to play a major role in determining genetic susceptibility to diabetic retinopathy or the severity of diabetic retinopathy.     

Molecular evolution of a duplication: the sex-peptide (Acp70A) gene region of Drosophila subobscura and Drosophila madeirensis

In Drosophila melanogaster, the Acp70A gene, which is involved in the postmating reactions of the female, is a single-copy gene. However, in Drosophila subobscura, the gene is duplicated and both copies are transcribed. To study the molecular evolution of the duplication, a 2.1-kb fragment encompassing both copies of the duplication was sequenced for 10 lines of D. subobscura and one line of Drosophila madeirensis. Estimates of the divergence between the two copies of the duplicated region and between the two species studied, D. subobscura and D. madeirensis, revealed that both copies of the Acp70a gene had evolved independently since their duplication. The ratio of nonsynonymous to silent divergence between copies was generally higher than one. The McDonald and Kreitman test revealed an excess of nonsynonymous changes fixed since the duplication and before the split of the D. subobscura and D. madeirensis lineages. These results point to natural selection driving protein evolution after the duplication. Specifically, adaptive evolution appears to have caused the initial differentiation between copies of the N-terminal parts of the proteins, while purifying selection could be responsible for the high conservation of the C-terminal parts.     

HLA class I (A, B) and II (DR, DQ) gene and haplotype frequencies in blood donors from Wales

Recent studies have disclosed several oscillations occurring during resting sleep within the frequency range of the classical delta band (0.5-4 Hz). There are at least 3 oscillations with distinct mechanisms and sites of origin: a slow (<1 Hz) cortically-generated oscillation, a clock-like thalamic oscillation (1-4 Hz), and a cortical oscillation (1-4 Hz). The present paper reviews data on these oscillations and the possible mechanisms which coalesce them into the polymorphic waves of slow wave sleep. Data stem from intracellular (over 500 single cell and 50 double impalements) and field potentials recorded from the cortex and thalamus of cats (120 animals) under ketamine and xylazine anesthesia. Other experiments were based on whole night EEG recordings from humans (5 subjects). The frequency of the slow oscillation both in anesthetized animals and in naturally sleeping humans ranged between 0.1 and 1 Hz (89% of the cases being between 0.5 and 0.9 Hz). The slow (<1 Hz) oscillation is reflected in the EEG as rhythmic sequences of surface-negative waves (associated with hyperpolarizations of deeply-lying neurons) and surface-positive K-complexes (representing excitation in large pools of cortical neurons). Through its long-range synchronization, the slow oscillation has the ability to trigger and to group thalamically-generated spindles and two delta (1-4 Hz) oscillations. Finally, it is argued that the analysis of the electroencephalogram should transcend the spectral analyses, by taking into account the shape of the waves and, when possible, the basic mechanisms that generate those waves.     

A de nevo complex t(7;13;8) translocation with a deletion in the TRPS gene region

Molecular cytogenetic analyses have resolved the pathogenetic aberration of an 8-year-old girl with tricho-rhino-phalangeal syndrome type I (TRPS I), normal intelligence, and a karyotype originally described as 46,XX,t(8;13)(q24;q21). R- and Q-banding and high resolution R-banding analyses have also disclosed a seemingly mosaic abnormality of the distal short arm of chromosome 7 but have not fully characterized this abnormality. Combined primed in situ labelling and chromosome painting, and three-colour chromosome painting have revealed a complex, apparently balanced translocation t(7;13;8). Fluorescence in situ hybridization with yeast artificial chromosome and cosmid clones from 8q24.1 has shown an interstitial deletion of at least 3 Mb covering most of the TRPS I critical region.     

A carcinogenesis model describing mutational events at the DNA adduct level

A stochastic carcinogenesis model is proposed to describe a sequence of component mutational changes that constitute the G:C-->A:T base substitution. This paper provides the biological basis and mathematical formulation underlying the proposed model. In addition, the paper elaborates on a numerical approach for studying the cumulant functions, survival functions, and hazard functions of the model. Several numerical examples are given of potential applications of the model.