The many-body electronic interactions of Fe(II)-porphyrin.

Fe(II)-porphyrin complexes exhibit a diverse range of electronic interactions between the metal and macrocycle. Herein, the incremental full configuration interaction method is applied to the entire space of valence orbitals of a Fe(II)-porphyrin model using a modest basis set. A novel visualization framework is proposed to analyze individual many-body contributions to the correlation energy, providing detailed maps of this complex's highly correlated electronic structure. This technique is used to parse the numerous interactions of two low-lying triplet states (3A2g and 3Eg) and to show that strong metal d-d and macrocycle π-π orbital interactions preferentially stabilize the 3A2g state. d-π interactions, on the other hand, preferentially stabilize the 3Eg state and primarily appear when correlating six electrons at a time. Ultimately, the Fe(II)-porphyrin model's full set of 88 valence electrons are correlated in 275 orbitals, showing the interactions up to the 4-body level, which covers the great majority of correlations in this system.

Stepwise basis set selection.

The computational cost of quantum chemical methods grows rapidly with increasing level of theory and basis set size. At increasing costs, higher accuracies can be reached, forcing a compromise between cost and accuracy for most molecular systems. Heats of reaction, however, are mostly determined by a subset of atoms that experience significant bonding and/or electronic changes. To exploit this fact, the Stepwise Basis Builder (SBB) algorithm selectively adds basis functions to reactive atoms and maintains small basis sets on spectator atoms. This article introduces the SBB algorithm and how it chooses a basis for each atom, predicts calculation errors, and uses these predicted errors to reach target levels of accuracy. Benchmarks show SBB heats of reaction and activation barriers converge to values consistent with higher-quality calculations using a greatly reduced number of basis functions. © 2018 Wiley Periodicals, Inc.

Association of Toll-like receptor polymorphisms with HIV status in North Americans.

Single-nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes TLR2-4 and TLR7-9, but not in TLR1 and TLR6, have been previously evaluated regarding human immunodeficiency virus (HIV) acquisition and disease progression in various populations, most of which were European. In this study, we examined associations between a total of 41 SNPs in 8 TLR genes (TLR1-4, TLR6-9) and HIV status in North American subjects (total n=276 (Caucasian, n=102; African American, n=150; other, n=24)). Stratification of the data by self-identified race revealed that a total of nine SNPs in TLR1, TLR4, TLR6 and TLR8 in Caucasians, and two other SNPs, one each in TLR4 and TLR8, in African Americans were significantly associated with HIV status at P<0.05. Concordant with the odds ratios of these SNPs, significant differences were observed in the SNP allele frequencies between HIV+ and HIV- subjects. Finally, in Caucasians, certain haplotypes of single (TLR1 and TLR4) and heterodimer (TLR2_TLR6) genes may be inferred as 'susceptible' or 'protective'. Our study provides in-depth insight into the associations between TLR variants, particularly TLR1 and TLR6, and HIV status in North Americans, and suggests that these associations may be race specific.

Variation in human ß-defensin genes: new insights from a multi-population study.

Human ß-defensin 2 (hBD-2) and hBD-3, encoded by DEFB4 and DEFB103A, respectively, have shown anti-HIV activity, and both genes exhibit copy number variation (CNV). Although the role of hBD-1, encoded by DEFB1, in HIV-1 infection is less clear, single nucleotide polymorphisms (SNPs) in DEFB1 may influence viral loads and disease progression. We examined the distribution of DEFB1 SNPs and DEFB4/103A CNV, and the relationship between DEFB1 SNPs and DEFB4/103A CNV using samples from two HIV/AIDS cohorts from the United States (n = 150) and five diverse populations from the Coriell Cell Repositories (n = 46). We determined the frequencies of 10 SNPs in DEFB1 using a post-PCR, oligonucleotide ligation detection reaction-fluorescent microsphere assay, and CNV in DEFB4/103A by real-time quantitative PCR. There were noticeable differences in the frequencies of DEFB1 SNP alleles and haplotypes among various racial/ethnic groups. The DEFB4/103A copy numbers varied from 2 to 8 (median, 4), and there was a significant difference between the copy numbers of self-identified whites and blacks in the US cohorts (Mann-Whitney U-test P = 0.04). A significant difference was observed in the distribution of DEFB4/103A CNV among DEFB1 -52G/A and -390T/A genotypes (Kruskal-Wallis P = 0.017 and 0.026, respectively), while not in the distribution of DEFB4/103A CNV among -52G/A_-44C/G_-20G/A diplotypes. These observations provide additional insights for further investigating the complex interplay between ß-defensin genetic polymorphisms and susceptibility to, or the progression or severity of, HIV infection/disease.

Queensland Lung Cancer Screening Study: rationale, design and methods.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.

Validation of the Roche AMPLICOR HIV DNA test version 1.5 for early infant diagnosis of HIV in Papua New Guinea.

Human immunodeficiency virus (HIV) is a significant public health issue in Papua New Guinea (PNG). After heterosexual transmission (90%), the second most common route of transmission is vertically from mother to child (3.5%). Before the introduction of molecular methods of HIV testing in PNG, diagnosing exposed infants was problematic because there were no reliable assays available for accurate early infant HIV detection. This study aimed to validate and assess a global gold standard for virological early infant HIV diagnosis in PNG: the AMPLICOR HIV DNA v1.5 assay (Roche) using dried blood spot (DBS) specimens. The assay was validated in three ways: by testing well-characterized DBS and kit controls and by blinded retesting of 42 patient specimens. The assay was further investigated by comparison with a serological assay. The results indicated that the assay was robust and highly reproducible using DBS and kit controls, with 100% sensitivity and specificity. Of the 42 infant DBS specimens that were retested blindly, 100% of the test results were concordant with diagnostic results. Among the 42 infant specimens tested with the Amplicor HIV DNA v1.5 assay we found that 33% of infants (n = 14) were HIV PCR positive and 67% (n = 28) negative. The earliest point of HIV detection established for this study was three months of age. This pilot study indicates that HIV-infected infants in PNG can be effectively diagnosed using virological testing and can thus be started earlier on treatment than was previously possible with serological testing.

Exploratory study of the 'weekend effect' for acute medical admissions to public hospitals in Queensland, Australia.

AIMS: To determine whether in-hospital deaths of patients admitted through emergency departments with acute exacerbations of chronic obstructive pulmonary disease (COPD), acute myocardial infarction, intracerebral haemorrhage and acute hip fracture are increased by weekend versus weekday admission (the 'weekend effect'). METHODS: We performed a retrospective analysis of statewide administrative data from public hospitals in Queensland, Australia, during the 2002/2003-2006/2007 financial years. The primary outcome was 30-day in-hospital mortality. The secondary outcome of 2-day in-hospital mortality helped determine whether increased mortality of weekend admissions was closely linked to weekend medical care. RESULTS: During the study period, there were 30 522 COPD, 17 910 acute myocardial infarction, 4183 acute hip fracture and 1781 intracerebral haemorrhage admissions. There was no significant weekend effect on 30-day in-hospital mortality for COPD (adjusted risk ratio = 0.92, 95% CI: 0.81-1.04, P= 0.222), intracerebral haemorrhage (adjusted risk ratio = 1.01, 95% CI: 0.86-1.16, P= 0.935) or acute hip fracture (adjusted risk ratio = 0.78, 95% CI: 0.54-1.03, P= 0.13). There was a significant weekend effect for acute myocardial infarction (adjusted risk ratio = 1.15, 95% CI: 1.03-1.26, P= 0.007). Two-day in-hospital mortality showed similar results. CONCLUSION: This is the first Australian study on the 'weekend effect' (in a cohort other than neonates), and the first study worldwide to assess specifically the weekend effect among COPD patients. Observed patterns were consistent with overseas research. There was a significant weekend effect for myocardial infarction. Further research is needed to determine whether location (e.g. rural), clinical (e.g. disease severity) and service provision factors (e.g. access to invasive procedures) influence the weekend effect for acute medical conditions in Australia.

Disruption of murine cardiac allograft acceptance by latent cytomegalovirus.

Cytomegalovirus (CMV) reactivation is a well-described complication of solid organ transplantation. These studies were performed to (1) determine if cardiac allograft transplantation of latently infected recipients results in reactivation of CMV and (2) determine what impact CMV might have on development of graft acceptance/tolerance. BALB/c cardiac allografts were transplanted into C57BL/6 mice with/without latent murine CMV (MCMV). Recipients were treated with gallium nitrate induction and monitored for graft survival, viral immunity and donor reactive DTH responses. Latently infected allograft recipients had approximately 80% graft loss by 100 days after transplant, compared with approximately 8% graft loss in naïve recipients. PCR evaluation demonstrated that MCMV was transmitted to cardiac grafts in all latently infected recipients, and 4/8 allografts had active viral transcription compared to 0/6 isografts. Latently infected allograft recipients showed intragraft IFN-alpha expression consistent with MCMV reactivation, but MCMV did not appear to negatively influence regulatory gene expression. Infected allograft recipients had disruption of splenocyte DTH regulation, but recipient splenocytes remained unresponsive to donor antigen even after allograft losses. These data suggest that transplantation in an environment of latent CMV infection may reactivate virus, and that intragraft responses disrupt development of allograft acceptance.

Asteroidal source of meteorites.

The evolution of asteroidal orbits initially near the Kirkwood Gap at the 1:2 commensurability with Jupiter's period provides a mechanism for the production of meteorites from the asteroid belt without excessive velocity change. The resulting yield ( approximately 10(9) grams per year) and the orbital elements of Earth-crossing objects are in agreement with observational data on meteorites.

Termites: a potentially large source of atmospheric methane, carbon dioxide, and molecular hydrogen.

Termites may emit large quantities of methane, carbon dioxide, and molecular hydrogen into the atmosphere. Global annual emissions calculated from laboratory measurements could reach 1.5 x 10(14) grams of methane and 5 x 10(16) grams of carbon dioxide. As much as 2 x 10(14) grams of molecular hydrogen may also be produced. Field measurements of methane emissions from two termite nests in Guatemala corroborated the laboratory results. The largest emissions should occur in tropical areas disturbed by human activities.

Atmosphere-surface exchange measurements.

The exchange of various trace species and energy at the earth's surface plays an important role in climate, ecology, and human health and welfare. Surface exchange measurements can be difficult to obtain yet are important to understand physical processes, assess environmental and global change impacts, and develop robust parameterizations of atmospheric processes. The physics and turbulent structure of the atmospheric boundary layer are reviewed as they contribute to dry surface exchange rates (fluxes). Micrometeorological, budget, and enclosure techniques used to measure or estimate surface fluxes are described, along with their respective advantages and limitations. Various measurement issues (such as site characteristics, sampling considerations, sensor attributes, and flow distortion) impact on the ability to obtain representative surface-based and airborne flux data.

Thunderstorms: an important mechanism in the transport of air pollutants.

Acid deposition and photochemical smog are urban air pollution problems, and they remain localized as long as the sulfur, nitrogen, and hydrocarbon pollutants are confined to the lower troposphere (below about 1-kilometer altitude) where they are short-lived. If, however, the contaminants are rapidly transported to the upper troposphere, then their atmospheric residence times grow and their range of influence expands dramatically. Although this vertical transport ameliorates some of the effects of acid rain by diluting atmospheric acids, it exacerbates global tropospheric ozone production by redistributing the necessary nitrogen catalysts. Results of recent computer simulations suggest that thunderstorms are one means of rapid vertical transport. To test this hypothesis, several research aircraft near a midwestern thunderstrom measured carbon monoxide, hydrocarbons, ozone, and reactive nitrogen compounds. Their concentrations were much greater in the outflow region of the storm, up to 11 kilometers in altitude, than in surrounding air. Trace gas measurements can thus be used to track the motion of air in and around a cloud. Thunderstorms may transform local air pollution problems into regional or global atmospheric chemistry problems.

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Glycophorin C delta(exon3) is not associated with protection against severe anaemia in Papua New Guinea.

The high frequencies of mutant haemoglobin and erythrocyte surface proteins in malaria-endemic regions have indicated that polymorphisms in human genes have been under selection pressure by severe malarial disease. Glycophorin C (GYPC) is a major surface erythrocyte protein and also a receptor for the Plasmodium falciparum erythrocyte-binding antigen 140 (EBA-140, also known as BAEBL). There is no binding to GYPC in Gerbich-negative (deletion of exon 3 in GYPC gene: GYPCC delta(exon3)) erythrocytes by EBA-140, hence limiting invasion of erythrocytes by certain P. falciparum lines. The GYPCC delta(exon3) allele reaches high frequencies in two areas of Papua New Guinea (PNG) where malaria is highly endemic. There is, however, no indication that Gerbich negativity protects against malaria-related illness. Using archival blood samples collected from children (<6 years of age) in the Wosera District, East Sepik Province, PNG, we investigated GYPC C delta(exon3) as a possible genetic component of protection against severe malarial anaemia (SMA). The frequency of this human genetic polymorphism was found to be in accordance with previous studies. However, our result showed no association between SMA and GYPC C delta(exon3). Until such an association is clearly shown with severe malaria outcomes, these results raise questions regarding the role of malaria as a selective force for Gerbich negativity.

120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A.

Pneumocystis carinii is the most common cause of life-threatening pneumonia in immunocompromised patients. In the current study, surfactant protein A (SP-A), the major nonserum protein constituent of pulmonary surfactant, is demonstrated to bind P. carinii in a specific and saturable manner. SP-A is surface bound and does not appear to be internalized or degraded by the P. carinii organism. Furthermore, SP-A binding to P. carinii is time- and calcium-dependent and is competitively inhibited by mannosyl albumin. In the absence of calcium or the presence of excess mannosyl albumin, SP-A binding to P. carinii is reduced by 95 and 71%, respectively. SP-A avidly binds P. carinii with a Kd of 8 x 10(-9) M and an estimated 8.4 x 10(6) SP-A binding sites per P. carinii organism, as determined from Scatchard plots. SP-A is shown to bind P. carinii in vivo, and a putative binding site for SP-A on P. carinii is demonstrated to be the mannoserich surface membrane glycoprotein gp120. These findings suggest that P. carinii can interact with the phospholipid-rich material in the alveolar spaces by specifically binding a major protein constituent of pulmonary surfactant.

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors.

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.

Microsatellite instability and other molecular abnormalities in non-small cell lung cancer.

Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple genetic loci may result from mismatch repair errors and occur in hereditary nonpolyposis colorectal carcinoma and certain sporadic cancers. In non-small cell lung cancer, we found that microsatellite instability was infrequent, affecting only 7 (6.5%) of 108 cases. Despite being observed in all histological subtypes and at different tumor stages, microsatellite instability most commonly affected only one of the six loci tested on five chromosomal arms. In addition, microsatellite instability was associated with extensive, concurrent molecular changes including K-ras and p53 mutations as well as frequent loss of heterozygosity at chromosomal regions 5q, 8p, 9p, 11p, and 17p.

Tumor progression and loss of heterozygosity at 5q and 18q in non-small cell lung cancer.

We investigated the frequency and clinical significance of loss of heterozygosity (LOH) at the APC, MCC, and DCC tumor suppressor gene loci in 108 cases of resected non-small cell lung cancer (NSCLC). LOH at the APC/MCC gene cluster at chromosome 5q21 occurred frequently; it affected 29% of informative NSCLC cases and correlated with a significantly worse survival (P < 0.01). Furthermore, in the subtype most frequently affected (SCC), LOH at 5q not only correlated with a worse survival but also tumor involvement of the mediastinal and/or hilar nodes. In contrast, LOH at the DCC locus at chromosome 18q was far less frequent, occurring in 14% of NSCLC cases, and it was not associated with advanced stage or prognosis. These data suggest that LOH at 5q has a role in determining tumor progression and survival in NSCLC, and may prove to be a clinically useful prognostic indicator.

Loss of heterozygosity frequently affects chromosome 17q in non-small cell lung cancer.

Although the short arm of chromosome 17, which contains the p53 gene, is frequently affected by loss of heterozygosity (LOH) in lung cancer, little is known about similar changes on the long arm. We found that LOH affected one or more of six loci along chromosome 17 in 59% of 102 informative non-small cell lung cancer (NSCLC) cases. Specifically, the frequency of LOH at 17q was 42%, approaching that at 17p (54%), and two distinct 17q regions were implicated. LOH at D17S4 on 17q was more frequent in adenocarcinomas than in squamous cell carcinomas, whereas squamous cell carcinomas had more LOH at 17p than at 17q, findings that indicate molecular genetic heterogeneity between the major NSCLC subtypes. In addition, LOH at 17q correlated with higher T stages and a significantly worse prognosis. In comparison, 25% of cases had mutations of p53 exons 5-8 but these were not associated with stage or survival. The data suggest that independent of p53, there are important tumor suppressor gene(s) on 17q that may influence NSCLC pathogenesis, progression, and survival.