Critiquing Construct Validity in World City Network Research: Moving from Office Location Networks to Inter-Organizational Projects in the Modeling of Intercity Business Flows.

The interlocking world city network model and other office location approaches (OLAs) have become the most widely used empirical models of the world city network (WCN). Despite numerous methodological improvements, they continue to rely on a legacy of using data on office locations of firms to indirectly estimate intercity business flows. To advance the dialogue about how to improve on existing empirical models of the WCN, we examine the content, construct and structural validity of OLAs. We analyze the link between the theoretical construct of intercity business flows and network projections obtained from office location data and uncover evidence that calls into question the validity of OLAs as empirical models of the WCN. In the spirit of no deconstruction without reconstruction, we then develop an alternative empirical model of the WCN, based on directly observable relational ties among APS firms, which are formed through co-production of complex services. We call this the inter-organizational project approach (IOPA). We argue for IOPA's construct validity as an empirical model of the WCN and offer empirical evidence for its structural validity. We demonstrate it using a global sample of 161,114 investment bank syndicates in the 2000-2015 period.

Effects of Statins on Renal Outcome in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: HMG CoA reductase inhibitors (statins) are known to prevent cardiovascular disease and improve lipid profiles. However, the effects of statins on renal outcomes, including decline in estimated glomerular filtration rate (eGFR) and proteinuria in patients with chronic kidney disease (CKD), are controversial. This meta-analysis evaluated the impact of statins on renal outcomes in patients with CKD. MATERIALS AND METHODS: We comprehensively searched the databases of MEDLINE, EMBASE, and Cochrane Databases. The inclusion criteria were published RCT and cohort studies comparing statin therapy to placebo or active controls in patients with CKD (eGFR <60 ml/min/1.73 m(2)) not requiring dialysis. The primary outcome was the differences in the change of eGFR. We also examined change of protein concentration in urine as a secondary outcome. A meta-analysis comparing statin and its control groups and a subgroup analysis examining intensity of statin were performed. RESULTS: From 142 full-text articles, 10 studies were included in the meta-analysis. Overall, there was a significant difference in rate of eGFR change per year favoring statin group (mean difference (MD) = 0.10 ml/min/1.73 m(2), 95% CI: 0.09 to 0.12). In our subgroup analysis, those who received high-intensity statins had a significant difference in eGFR with a MD of 3.35 (95% CI: 0.91 to 5.79) ml/min/1.73 m(2) compared to control. No significant change in eGFR was found with moderate- and low-intensity statin therapy. Compared with the control group, the statin group did not have a difference in reduction of proteinuria with MD in change of proteinuria of 0.19 gm/day (95% CI: -0.02 to 0.40). CONCLUSION: Overall, there was a difference in change of eGFR between the statin and control group. High-intensity statins were found to improve a decline in eGFR in population with CKD not requiring dialysis compared with control, but moderate- and low-intensity statins were not. Statins were not found to decrease proteinuria in patients with CKD.

Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to integrate and examine the association between NSAID use and venous thromboembolism (VTE). METHODS: We conducted a systematic review and meta-analysis of studies that reported odds ratios, relative risks, hazard ratios or standardized incidence ratios for VTE among NSAID users compared with non-users. Pooled risk ratios and 95% CIs were calculated using a random effects generic inverse variance model. RESULTS: Six studies with 21 401 VTE events were identified and included in the data analysis. The pooled risk ratio of VTE in NSAID users was 1.80 (95% CI 1.28, 2.52). CONCLUSION: Our study demonstrated a statistically significant increased risk of VTE among NSAID users. This finding has important public health implications given the prevalence of NSAID use in the general population.

Is the incidence of malignancy increased in patients with sarcoidosis? A systematic review and meta-analysis.

A possible causal relationship between sarcoidosis and malignancy has been the subject of debates for decades. To better understand this association, we conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio or standardized incidence ratio with 95% confidence interval (CI) comparing the incidence of malignancy in patients with sarcoidosis versus non-sarcoidosis participants. Pooled risk ratios (RR) and 95% CI were calculated using a random-effect, generic inverse variance methodology. Five studies were identified and included in our data analyses. The pooled RR of malignancy in patients with sarcoidosis was 1.21 (95% CI: 1.04-1.40). However, when we performed a sensitivity analysis that included only studies that compared the incidence of malignancy after the first year of the diagnosis of sarcoidosis with the incidence of malignancy after the first year of index date for non-sarcoidosis controls, the pooled risk ratio decreased and did not reach statistical significance (RR 1.13, 95% CI: 0.97-1.32). Furthermore, analysis for publication bias has suggested that publication bias in favour of positive studies may be present. In conclusion, after accounting for possible detection bias and publication bias, there does not appear be a significant association between sarcoidosis and malignancy.

Risk of malignancy in patients with giant cell arteritis and polymyalgia rheumatica: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between giant cell arteritis (GCA)/polymyalgia rheumatica (PMR) and malignancy risk. METHODS: We conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio, or standardized incidence ratio (SIRs) with 95% confidence comparing malignancy risk in patients with GCA/PMR versus non-GCA/PMR participants. Pooled risk ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance method. RESULT: A total of six studies were identified and included in our data analysis. The pooled risk ratio of malignancy in patients with GCA/PMR was 1.14 (95% CI: 1.05-1.22). The risk was higher in the first 6-12 months after diagnosis with the pooled risk ratio of 2.16 (95% CI: 1.85-2.53). However, when we performed a sensitivity analysis that excluded one study with a potential selection bias, the pooled risk ratio decreased and did not achieve statistical significance. CONCLUSION: Our study demonstrated a low but statistically significant increased malignancy risk among patients with GCA/PMR. However, when we excluded one study with potential selection bias, the new pooled risk ratio did not achieve statistical significance.

Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies.

BACKGROUND: The association between membranous nephropathy (MN) and cancer has been well documented. However, the true prevalence and characteristics of cancer associated with MN have not been well described. METHODS: A systematic review and meta-analysis of cohort studies was conducted to summarize the prevalence of cancer-associated MN as well as patient characteristics and types of cancer in this population. We used a random-effects meta-analysis model to estimate the prevalence of cancer. RESULTS: We included 6 studies (n = 785). The estimated prevalence of cancer was 10.0% (95% CI, 6.1-14.6). The mean age of MN patients with cancer was 67 ± 7 years. The diagnosis of cancer preceded the diagnosis of MN in 20 ± 6.8%. Lung cancer was the most common type of tumor, accounting for 22 cases (26%), followed by prostate cancer (13 cases, 15%), hematologic malignancies (12 cases, 14%), colorectal cancer (9 cases, 11%), breast cancer (6 cases, 7%), and stomach and esophageal cancer (5 cases, 6%). CONCLUSION: The estimated prevalence of cancer in patients with MN is 10% (95% CI, 6.1-14.6). The vast majority of tumors associated with MN are lung and prostate cancer. Hematologic malignancies should also be considered as one of the potential cancers associated with MN. Our study was based on a largely Caucasian population; therefore, the findings might not be applicable to other populations.

Protease inhibitors and avascular necrosis: a systematic review and meta-analysis.

Avascular necrosis (AVN) is a pathological process associated with many medical conditions, including human immunodeficiency virus (HIV) infection. Whether or not the use of protease inhibitors (PIs) confers additional risk for AVN to HIV-infected patients is controversial. Previous epidemiological studies showed an increased risk of AVN among PI users, but these studies did not have enough power to achieve statistical significance. A meta-analysis of case-control studies reporting the odds ratios (ORs) of AVN among HIV-infected patients who were exposed to PIs compared with non-exposed patients was conducted. Pooled ORs and 95% confidence intervals (CIs) were calculated using a fixed-effect Mantel-Haenszel analysis. Four case-control studies were identified and included for data analysis. The meta-analysis demonstrated an increased odds of AVN in participants exposed to PIs, with an OR of 2.09 (95% CI 1.01-4.31; P=0.05). The statistical heterogeneity of this meta-analysis was determined not to be important, with an I(2) of 0%. The meta-analysis revealed a statistically significant increased odds of AVN among PI-exposed, HIV-infected patients. Physician should be aware of this association as it may help guide potential therapeutic options, particularly for patients with other classic risk factors for AVN.

Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta-analysis.

We performed this meta-analysis to assess venous thromboembolism risk in patients with rheumatoid arthritis. A comprehensive search was performed in MEDLINE, EMBASE, and the Cochrane databases. Nine observational studies met our inclusion criteria and were included in the data analysis. The pooled risk ratios of deep venous thrombosis, pulmonary embolism, and venous thromboembolism in patients with rheumatoid arthritis (RA) compared with non-RA participants were 2.08 (95% CI 1.75-2.47), 2.17 (95% CI 2.05-2.31), and 1.96 (95% CI 1.81-2.11), respectively. Subgroup analysis demonstrated a consistent increased risk in every study design (cohort, case-control, and cross-sectional). Our results indicate a significant increased risk of venous thromboembolism among patients with rheumatoid arthritis.

Genome-scale reconstruction of the sigma factor network in Escherichia coli: topology and functional states.

BACKGROUND: At the beginning of the transcription process, the RNA polymerase (RNAP) core enzyme requires a σ-factor to recognize the genomic location at which the process initiates. Although the crucial role of σ-factors has long been appreciated and characterized for many individual promoters, we do not yet have a genome-scale assessment of their function. RESULTS: Using multiple genome-scale measurements, we elucidated the network of σ-factor and promoter interactions in Escherichia coli. The reconstructed network includes 4,724 σ-factor-specific promoters corresponding to transcription units (TUs), representing an increase of more than 300% over what has been previously reported. The reconstructed network was used to investigate competition between alternative σ-factors (the σ70 and σ38 regulons), confirming the competition model of σ substitution and negative regulation by alternative σ-factors. Comparison with σ-factor binding in Klebsiella pneumoniae showed that transcriptional regulation of conserved genes in closely related species is unexpectedly divergent. CONCLUSIONS: The reconstructed network reveals the regulatory complexity of the promoter architecture in prokaryotic genomes, and opens a path to the direct determination of the systems biology of their transcriptional regulatory networks.

Detailing the optimality of photosynthesis in cyanobacteria through systems biology analysis.

Photosynthesis has recently gained considerable attention for its potential role in the development of renewable energy sources. Optimizing photosynthetic organisms for biomass or biofuel production will therefore require a systems understanding of photosynthetic processes. We reconstructed a high-quality genome-scale metabolic network for Synechocystis sp. PCC6803 that describes key photosynthetic processes in mechanistic detail. We performed an exhaustive in silico analysis of the reconstructed photosynthetic process under different light and inorganic carbon (Ci) conditions as well as under genetic perturbations. Our key results include the following. (i) We identified two main states of the photosynthetic apparatus: a Ci-limited state and a light-limited state. (ii) We discovered nine alternative electron flow pathways that assist the photosynthetic linear electron flow in optimizing the photosynthesis performance. (iii) A high degree of cooperativity between alternative pathways was found to be critical for optimal autotrophic metabolism. Although pathways with high photosynthetic yield exist for optimizing growth under suboptimal light conditions, pathways with low photosynthetic yield guarantee optimal growth under excessive light or Ci limitation. (iv) Photorespiration was found to be essential for the optimal photosynthetic process, clarifying its role in high-light acclimation. Finally, (v) an extremely high photosynthetic robustness drives the optimal autotrophic metabolism at the expense of metabolic versatility and robustness. The results and modeling approach presented here may promote a better understanding of the photosynthetic process. They can also guide bioengineering projects toward optimal biofuel production in photosynthetic organisms.

Genetic basis of growth adaptation of Escherichia coli after deletion of pgi, a major metabolic gene.

Bacterial survival requires adaptation to different environmental perturbations such as exposure to antibiotics, changes in temperature or oxygen levels, DNA damage, and alternative nutrient sources. During adaptation, bacteria often develop beneficial mutations that confer increased fitness in the new environment. Adaptation to the loss of a major non-essential gene product that cripples growth, however, has not been studied at the whole-genome level. We investigated the ability of Escherichia coli K-12 MG1655 to overcome the loss of phosphoglucose isomerase (pgi) by adaptively evolving ten replicates of E. coli lacking pgi for 50 days in glucose M9 minimal medium and by characterizing endpoint clones through whole-genome re-sequencing and phenotype profiling. We found that 1) the growth rates for all ten endpoint clones increased approximately 3-fold over the 50-day period; 2) two to five mutations arose during adaptation, most frequently in the NADH/NADPH transhydrogenases udhA and pntAB and in the stress-associated sigma factor rpoS; and 3) despite similar growth rates, at least three distinct endpoint phenotypes developed as defined by different rates of acetate and formate secretion. These results demonstrate that E. coli can adapt to the loss of a major metabolic gene product with only a handful of mutations and that adaptation can result in multiple, alternative phenotypes.

RNA polymerase mutants found through adaptive evolution reprogram Escherichia coli for optimal growth in minimal media.

Specific small deletions within the rpoC gene encoding the ß'-subunit of RNA polymerase (RNAP) are found repeatedly after adaptation of Escherichia coli K-12 MG1655 to growth in minimal media. Here we present a multiscale analysis of these mutations. At the physiological level, the mutants grow 60% faster than the parent strain and convert the carbon source 15-35% more efficiently to biomass, but grow about 30% slower than the parent strain in rich medium. At the molecular level, the kinetic parameters of the mutated RNAP were found to be altered, resulting in a 4- to 30-fold decrease in open complex longevity at an rRNA promoter and a ∼10-fold decrease in transcriptional pausing, with consequent increase in transcript elongation rate. At a genome-scale, systems biology level, gene expression changes between the parent strain and adapted RNAP mutants reveal large-scale systematic transcriptional changes that influence specific cellular processes, including strong down-regulation of motility, acid resistance, fimbria, and curlin genes. RNAP genome-binding maps reveal redistribution of RNAP that may facilitate relief of a metabolic bottleneck to growth. These findings suggest that reprogramming the kinetic parameters of RNAP through specific mutations allows regulatory adaptation for optimal growth in new environments.

The transcription unit architecture of the Escherichia coli genome.

Bacterial genomes are organized by structural and functional elements, including promoters, transcription start and termination sites, open reading frames, regulatory noncoding regions, untranslated regions and transcription units. Here, we iteratively integrate high-throughput, genome-wide measurements of RNA polymerase binding locations and mRNA transcript abundance, 5' sequences and translation into proteins to determine the organizational structure of the Escherichia coli K-12 MG1655 genome. Integration of the organizational elements provides an experimentally annotated transcription unit architecture, including alternative transcription start sites, 5' untranslated region, boundaries and open reading frames of each transcription unit. A total of 4,661 transcription units were identified, representing an increase of >530% over current knowledge. This comprehensive transcription unit architecture allows for the elucidation of condition-specific uses of alternative sigma factors at the genome scale. Furthermore, the transcription unit architecture provides a foundation on which to construct genome-scale transcriptional and translational regulatory networks.

Genome-scale reconstruction of the Lrp regulatory network in Escherichia coli.

Broad-acting transcription factors (TFs) in bacteria form regulons. Here, we present a 4-step method to fully reconstruct the leucine-responsive protein (Lrp) regulon in Escherichia coli K-12 MG 1655 that regulates nitrogen metabolism. Step 1 is composed of obtaining high-resolution ChIP-chip data for Lrp, the RNA polymerase and expression profiles under multiple environmental conditions. We identified 138 unique and reproducible Lrp-binding regions and classified their binding state under different conditions. In the second step, the analysis of these data revealed 6 distinct regulatory modes for individual ORFs. In the third step, we used the functional assignment of the regulated ORFs to reconstruct 4 types of regulatory network motifs around the metabolites that are affected by the corresponding gene products. In the fourth step, we determined how leucine, as a signaling molecule, shifts the regulatory motifs for particular metabolites. The physiological structure that emerges shows the regulatory motifs for different amino acid fall into the traditional classification of amino acid families, thus elucidating the structure and physiological functions of the Lrp-regulon. The same procedure can be applied to other broad-acting TFs, opening the way to full bottom-up reconstruction of the transcriptional regulatory network in bacterial cells.

Genome-wide analysis of Fis binding in Escherichia coli indicates a causative role for A-/AT-tracts.

We determined the genome-wide distribution of the nucleoid-associated protein Fis in Escherichia coli using chromatin immunoprecipitation coupled with high-resolution whole genome-tiling microarrays. We identified 894 Fis-associated regions across the E. coli genome. A significant number of these binding sites were found within open reading frames (33%) and between divergently transcribed transcripts (5%). Analysis indicates that A-tracts and AT-tracts are an important signal for preferred Fis-binding sites, and that A(6)-tracts in particular constitute a high-affinity signal that dictates Fis phasing in stretches of DNA containing multiple and variably spaced A-tracts and AT-tracts. Furthermore, we find evidence for an average of two Fis-binding regions per supercoiling domain in the chromosome of exponentially growing cells. Transcriptome analysis shows that approximately 21% of genes are affected by the deletion of fis; however, the changes in magnitude are small. To address the differential Fis bindings under growth environment perturbation, ChIP-chip analysis was performed using cells grown under aerobic and anaerobic growth conditions. Interestingly, the Fis-binding regions are almost identical in aerobic and anaerobic growth conditions-indicating that the E. coli genome topology mediated by Fis is superficially identical in the two conditions. These novel results provide new insight into how Fis modulates DNA topology at a genome scale and thus advance our understanding of the architectural bases of the E. coli nucleoid.

Genomewide identification of protein binding locations using chromatin immunoprecipitation coupled with microarray.

Interactions between cis-acting elements and proteins play a key role in transcriptional regulation of all known organisms. To better understand these interactions, researchers developed a method that couples chromatin immunoprecipitation with microarrays (also known as ChIP-chip), which is capable of providing a whole-genome map of protein-DNA interactions. This versatile and high-throughput strategy is initiated by formaldehyde-mediated cross-linking of DNA and proteins, followed by cell lysis, DNA fragmentation, and immunopurification. The immunoprecipitated DNA fragments are then purified from the proteins by reverse-cross-linking followed by amplification, labeling, and hybridization to a whole-genome tiling microarray against a reference sample. The enriched signals obtained from the microarray then are normalized by the reference sample and used to generate the whole-genome map of protein-DNA interactions. The protocol described here has been used for discovering the genomewide distribution of RNA polymerase and several transcription factors of Escherichia coli.