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DNA computing is a highly interdisciplinary field which combines molecular operations with theoretical algorithm design. A number of algorithms have been demonstrated in DNA computing, but to date network flow problems have not been studied. We aim to provide an approach to calculate the value of the maximum flow in networks by encoding the mathematical problem in DNA molecules and by using molecular biology techniques to manipulate the DNA. We present results which demonstrate that the algorithm works for an example network problem.

Alpha-1-antitrypsin (AAT) is a protease inhibitor (PI), deficiency of which is associated with emphysema and liver disease. The most common deficiency alleles are the S (p.Glu288Val) and Z (p.Glu366Lys) alleles. The Z allele predisposes the AAT protein to polymerization with accumulation in hepatocytes leading to liver disease in PIZ individuals. Most AAT variants have a characteristic pattern of isoforms by isoelectric focusing (IEF). A novel AAT variant called PIZbristol (p.Thr109Met) with an unusual pattern on IEF was described in 1997. We report a patient with the PIZZbristol phenotype that has not been previously described. A 43-year-old man was referred by his GP to a respiratory clinic for breathlessness. His AAT concentration was 0.50 g/L (reference range 1.0–2.0 g/L). An unusual pattern on IEF was seen and sequencing revealed the presence of the rare variant Zbristol in combination with the Z mutation. This is the second reported case of Zbristol and the first in combination with the Z mutation. The patient maintained plasma AAT concentrations around 0.50–0.70 g/L which suggested that the Zbristol protein contributed to the low plasma concentration of AAT. The clinical symptoms associated with PIZ are usually attributed to the plasma deficiency, but his only respiratory complaint was that of breathlessness. This suggests that the PIZZbristol phenotype may confer an effect on respiratory function but is not involved in liver disease. [ABSTRACT FROM AUTHOR]

We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17). [ABSTRACT FROM AUTHOR]

A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies. [ABSTRACT FROM AUTHOR]

Study Objectives: To determine whether the adenine (A)-guanine (G) substitution polymorphism at position - 308 on the tumor necrosis factor-alpha gene confers susceptibility to COPD or to the development of a more severe form of disease.Design: A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a control population (n = 99). Patients were followed up prospectively for a period of 2 years.Participants and Setting: Participants included 106 COPD patients recruited from a respiratory outpatient clinic and 99 control subjects recruited from patients admitted for cardiac catheterization.Measurements and Results: DNA was extracted from venous blood, and each subject was genotyped for the polymorphism by polymerase chain reaction amplification and restriction digestion using Nco1. There was no increased frequency of the A allele in patients compared to control subjects. AA homozygous patients had less reversible airflow obstruction (p<0.05) and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up (p<0.001), despite a shorter cigarette smoking history.Conclusions: This study suggests that homozygosity for this A allele predisposes to more severe airflow obstruction and a worse prognosis in COPD. [ABSTRACT FROM AUTHOR]

The proteinase inhibitor null (Pi-) allele is a rare cause of alpha 1 antitrypsin (AAT) deficiency. In three families, all the subjects with AAT deficiency due to PiZ- presented in early childhood with recurrent chest infections and wheezing presumably related to passive smoking. In Pi- the AAT gene is present and there is no evidence for a gene deletion. In one family a restriction fragment length polymorphism (RFLP) detected with the enzyme XbaI segregates with the Pi- allele. In a family where a consanguineous marriage occurred, the XbaI polymorphism segregates with the normal M1 allele rather than Pi-, suggesting that Pi- may have originated from M1. In contrast, a third family and 20 normal unrelated subjects do not show the RFLP. [ABSTRACT FROM PUBLISHER]

Alpha 1 antitrypsin deficiency predisposes subjects to developing pulmonary emphysema and childhood liver cirrhosis. We have studied restriction fragment length polymorphisms (RFLPs) of the alpha 1 antitrypsin gene in a normal population and a group of patients with pulmonary emphysema. We have identified five RFLPs with eight restriction enzymes. The most frequent polymorphisms have been detected with the enzymes MspI, PstI, and TaqI at frequencies of 46.8%, 6.4%, and 5.0% respectively in the group of normal subjects. [ABSTRACT FROM PUBLISHER]

alpha 1 antitrypsin deficiency is associated with predisposition to the development of pulmonary emphysema and childhood cirrhosis. There are two common deficiency alleles in the European population, proteinase inhibitor (Pi) Z and S. In addition, there are rare Pinull or QO variants which can be difficult to diagnose. A family assigned as having the PiQO allele by AAT protein quantification and isoelectric focusing was shown by DNA sequencing to have the PiMheerlen mutation (Pro369-Leu). This highlights the difficulties of diagnosis of PiQO. [ABSTRACT FROM PUBLISHER]

Abstract Background Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates including IREB2. A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility. Methods We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in the IREB2 gene, and for four SNPs in the TGFbeta1 gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre. Results Our data replicate the association of IREB2 SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified for TGFbeta1. Conclusions These studies have therefore confirmed that the IREB2 locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis.

Abstract Background Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. Methods To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. Results Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. Conclusions Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Introduction: Maternal EGF up-regulates invasion of the decidua by the extra-villous cytotrophoblast, a process that is central to placentation, which is impaired in pre-eclampsia (PE). The EGF G61A polymorphism results in reduced EGF expression. EGF A61G is in strong partial linkage disequilibrium with the EGF G67149A polymorphism that results in the substitution of methionine by isoleucine in the EGF protein. We examined whether these polymorphisms were associated with PE in white Caucasians in Nottingham, UK and in Sinhalese in Colombo, Sri Lanka (SL). Methods: 261 normotensive pregnant women (UK: 81, SL: 180) and 253 pre-eclamptic women (UK: 74, SL: 179) were genotyped using PCR/RFLP (EGF G61A) and MS-PCR (EGF G67149) methods. Allele frequencies and haplotypes were analysed using the Chi-Squared test and the maximum likelihood method respectively. Results: The 67149G allele was associated with PE in the SL population (p=0.021), but not in the UK population (p=0.157). Proportions of 61G/67149G, 61G/67149A, 61A/67149G, and 61A/67149A haplotypes were: UK-Cases 0.20,0.22,0.42,0.16; UK-Controls 0.20,0.13,0.49,0.18; SL-Cases 0.28,0.26,0.25,0.20; SL-Controls 0.23,0.33,0.21,0.23. Haplotype distributions differed between UK and SL populations (p<0.001) but were not significantly associated with PE (p>0.1). Conclusions: There are significant population differences in the frequencies of EGF haplotypes. Further studies are required to test the association of 67149G with PE. [ABSTRACT FROM AUTHOR]

This chapter explores the methods used for the analysis of alpha1-antitrypsin gene expression. This includes the use of the polymerase chain reaction (PCR), reverse transcriptase-PCR (RT-PCR), and whole transcriptome analysis combined with parallel DNA sequencing to understand the processes involved in AAT expression., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)