Safety Evaluation of Red Light Running Camera Intersections in Illinois

As a part of this research, the safety performance of red light running (RLR) camera systems was evaluated for a sample of 41 intersections and 60 RLR camera approaches located on state routes under IDOT’s jurisdiction in the Chicago suburbs. Comprehensive traffic crash analyses based on 3 years of before-installation crash data and 3 years of after-installation crash data were conducted in order to evaluate the safety effects of the RLR cameras. Two methods were used to evaluate the crash experience at the RLR camera locations: the naïve before and after, and the empirical Bayes. The observed crash reductions were tested for statistical significance using the Poisson test at a 95% level of confidence. Using the empirical Bayes method for those crash types where safety performance factors (SPFs) were available, crash modification factors were developed for statistically significant crash reductions based on the unbiased index of effectiveness metric. The results of the naïve before and after and the empirical Bayes methods indicated statistically significant reductions in total intersection crashes of 36% to 34% and in angle RLR intersection crashes of 53% to 67%, respectively. Other findings of the installation of the RLR camera system based on the naïve before and after method indicated significant reductions in intersection injury crashes of 18% and a non-significant change in rear-end RLR crashes. The resulting crash modification factors are 0.656 for total intersection crashes and 0.331 for angle RLR intersection crashes. Overall, the safety evaluation provides evidence that the installation of RLR camera systems on state routes reduces angle RLR crashes, which are associated with severe injury; has a nominal impact on rear-end RLR crashes; and has a positive impact on reducing total intersection crashes, as studied in Chicago suburbs. It is recommended that IDOT continue to promote the installation of RLR cameras at locations where justified, thereby improving intersection safety for Illinois motorists.IDOT-R27-SP32Ope

Author Correction: Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles (Scientific Reports, (2019), 9, 1, (11632), 10.1038/s41598-019-48064-w)

Triple negative breast cancer (TNBC) has poor survival, exhibits rapid metastases, lacks targeted therapies and reliable prognostic markers. Here, we examined metastasis promoting role of cancer testis antigen SPANXB1 in TNBC and its utility as a therapeutic target and prognostic biomarker. Expression pattern of SPANXB1 was determined using matched primary cancer, lymph node metastatic tissues and circulating small extracellular vesicles (sEVs). cDNA microarray analysis of TNBC cells stably integrated with a metastasis suppressor SH3GL2 identified SPANXB1 as a potential target gene. TNBC cells overexpressing SH3GL2 exhibited decreased levels of both SPANXB1 mRNA and protein. Silencing of SPANXB1 reduced migration, invasion and reactive oxygen species production of TNBC cells. SPANXB1 depletion augmented SH3GL2 expression and decreased RAC-1, FAK, A-Actinin and Vinculin expression. Phenotypic and molecular changes were reversed upon SPANXB1 re-expression. SPANXB1 overexpressing breast cancer cells with an enhanced SPANXB1:SH3GL2 ratio achieved pulmonary metastasis within 5 weeks, whereas controls cells failed to do so. Altered expression of SPANXB1 was detected in the sEVs of SPANXB1 transduced cells. Exclusive expression of SPANXB1 was traceable in circulating sEVs, which was associated with TNBC progression. SPANXB1 represents a novel and ideal therapeutic target for blocking TNBC metastases due to its unique expression pattern and may function as an EV based prognostic marker to improve TNBC survival. Uniquely restricted expression of SPANXB1 in TNBCs, makes it an ideal candidate for targeted therapeutics and prognostication

Allele-Specific Transcriptional Activity at Type 2 Diabetes-Associated Single Nucleotide Polymorphisms in Regions of Pancreatic Islet Open Chromatin at the JAZF1 Locus

Translation of noncoding common variant association signals into meaningful molecular and biological mechanisms explaining disease susceptibility remains challenging. For the type 2 diabetes association signal in JAZF1 intron 1, we hypothesized that the underlying risk variants have cis-regulatory effects in islets or other type 2 diabetes–relevant cell types. We used maps of experimentally predicted open chromatin regions to prioritize variants for functional follow-up studies of transcriptional activity. Twelve regions containing type 2 diabetes–associated variants were tested for enhancer activity in 832/13 and MIN6 insulinoma cells. Three regions exhibited enhancer activity and only rs1635852 displayed allelic differences in enhancer activity; the type 2 diabetes risk allele T showed lower transcriptional activity than the nonrisk allele C. This risk allele showed increased binding to protein complexes, suggesting that it functions as part of a transcriptional repressor complex. We applied DNA affinity capture to identify factors in the complex and determined that the risk allele preferentially binds the pancreatic master regulator PDX1. These data suggest that the rs1635852 region in JAZF1 intron 1 is part of a cis-regulatory complex and that maps of open chromatin are useful to guide identification of variants with allelic differences in regulatory activity at type 2 diabetes loci

Strategies to fine-map genetic associations with lipid levels by combining epigenomic annotations and liver-specific transcription profiles

Characterization of the epigenome promises to yield the functional elements buried in the human genome sequence, thus helping to annotate non-coding DNA polymorphisms with regulatory functions. Here, we develop two novel strategies to combine epigenomic data with transcriptomic profiles in humans or mice to prioritize potential candidate SNPs associated with lipid levels by genome-wide association study (GWAS). First, after confirming that lipid-associated loci that are also expression quantitative trait loci (eQTL) in human livers are enriched for ENCODE regulatory marks in the human hepatocellular HepG2 cell line, we prioritize candidate SNPs based on the number of these marks that overlap the variant position. This method recognized the known SORT1 rs12740374 regulatory SNP associated with LDL-cholesterol, and highlighted candidate functional SNPs at 15 additional lipid loci. In the second strategy, we combine ENCODE chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) data and liver expression datasets from knockout mice lacking specific transcription factors. This approach identified SNPs in specific transcription factor binding sites that are located near target genes of these transcription factors. We show that FOXA2 transcription factor binding sites are enriched at lipid-associated loci and experimentally validate that alleles of one such proxy SNP located near the FOXA2 target gene BIRC5 show allelic differences in FOXA2-DNA binding and enhancer activity. These methods can be used to generate testable hypotheses for many non-coding SNPs associated with complex diseases or traits

Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the CDC123/CAMK1D Type 2 Diabetes GWAS Locus

Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3′UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus

Repeated long separations from pups produce depression-like behavior in rat mothers

Long (LMS) versus brief (BMS) daily separations of rat pups from their mothers have contrasting effects on their adult stress responses and maternal behavior by respectively decreasing and increasing licking received from their mothers. We hypothesized that LMS decreases pup licking in mothers by inducing learned helplessness, creating a depression-like state. We subjected postpartum rats to LMS (3 h), BMS (15 min) or no separation (NMS) on postpartum days 2–14. After weaning, mothers were given a forced swim test (FST). LMS mothers exhibited more immobility and fewer escape attempts than BMS or NMS mothers. These results suggest that LMS induces a depression-like state, which may account for the reductions in maternal behavior seen in LMS mothers. Immobility in the FST is recognized as an animal model of depression. Therefore, LMS may be a model of maternal depression

Characterization of a pathogenic variant in the ABCD1 gene through protein molecular modeling

Background. The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. Methods. A newly characterized and suspected pathogenic variant in ABCD1 was analyzed using our protein informatics platform (PIP). Personalized protein-level molecular studies were completed on genetic testing data, complementing the analysis and clinical study. Results. A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 variant are presented. The unique ABCD1 protein is discussed, and the proband’s case is compared to existing reports of AMN. Conclusions. Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient’s disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity

High expression of focal adhesion kinase (p125(FAK)) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

INTRODUCTION: Focal adhesion kinase (FAK) regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. In breast carcinoma, FAK overexpression has been linked to cancer progression but the prognostic relevance remains unknown. In particular, with regard to lymph node-negative breast cancer it is important to identify high-risk patients who would benefit from further adjuvant therapy. METHODS: We analyzed 162 node-negative breast cancer cases to determine the prognostic relevance of FAK expression, and we investigated the relationship of FAK with major associated signaling pathways (HER2, Src, Akt and extracellular regulated kinases) by immunohistochemistry and western blot analysis. RESULTS: Elevated FAK expression did not predict patient outcome, in contrast to tumor grading (P = 0.005), Akt activation (P = 0.0383) and estrogen receptor status (P = 0.0033). Significant positive correlations were observed between elevated FAK expression and HER2 overexpression (P = 0.001), as well as phospho-Src Tyr-215 (P = 0.021) and phospho-Akt (P < 0.001), but not with phospho-ERK1/2 (P = 0.108). Western blot analysis showed a significant correlation of FAK Tyr-861 activation and HER2 overexpression (P = 0.01). CONCLUSIONS: Immunohistochemical detection of FAK expression is of no prognostic significance in node-negative breast cancer but provides evidence that HER2 is involved in tumor malignancy and metastatic ability of breast cancer through a novel signaling pathway participating FAK and Src

Assessing Terrorist Motivations for Attacking Critical Infrastructure

Certain types of infrastructure--critical infrastructure (CI)--play vital roles in underpinning our economy, security and way of life. These complex and often interconnected systems have become so ubiquitous and essential to day-to-day life that they are easily taken for granted. Often it is only when the important services provided by such infrastructure are interrupted--when we lose easy access to electricity, health care, telecommunications, transportation or water, for example--that we are conscious of our great dependence on these networks and of the vulnerabilities that stem from such dependence. Unfortunately, it must be assumed that many terrorists are all too aware that CI facilities pose high-value targets that, if successfully attacked, have the potential to dramatically disrupt the normal rhythm of society, cause public fear and intimidation, and generate significant publicity. Indeed, revelations emerging at the time of this writing about Al Qaida's efforts to prepare for possible attacks on major financial facilities in New York, New Jersey, and the District of Columbia remind us just how real and immediate such threats to CI may be. Simply being aware that our nation's critical infrastructure presents terrorists with a plethora of targets, however, does little to mitigate the dangers of CI attacks. In order to prevent and preempt such terrorist acts, better understanding of the threats and vulnerabilities relating to critical infrastructure is required. The Center for Nonproliferation Studies (CNS) presents this document as both a contribution to the understanding of such threats and an initial effort at ''operationalizing'' its findings for use by analysts who work on issues of critical infrastructure protection. Specifically, this study focuses on a subsidiary aspect of CI threat assessment that has thus far remained largely unaddressed by contemporary terrorism research: the motivations and related factors that determine whether a terrorist organization will attack critical infrastructure. In other words, this research investigates: (1) why terrorists choose to attack critical infrastructure rather than other targets; (2) how groups make such decisions; (3) what, if any, types of groups are most inclined to attack critical infrastructure targets; and (4) which types of critical infrastructure terrorists prefer to attack and why. In an effort to address the above questions as comprehensively as possible, the project team employed four discrete investigative approaches in its research design. These include: (1) a review of existing terrorism and threat assessment literature to glean expert consensus regarding terrorist target selection, as well as to identify theoretical approaches that might be valuable to analysts and decision-makers who are seeking to understand such terrorist group decision-making processes; (2) the preparation of several concise case studies to help identify internal group factors and contextual influences that have played significant roles in leading some terrorist groups to attack critical infrastructure; (3) the creation of a new database--the Critical Infrastructure Terrorist Incident Catalog (CrITC)--to capture a large sample of empirical CI attack data that might be used to illuminate the nature of such attacks to date; and (4) the development of a new analytical framework--the Determinants Effecting Critical Infrastructure Decisions (DECIDe) Framework--designed to make the factors and dynamics identified by the study more ''usable'' in any future efforts to assess terrorist intentions to target critical infrastructure. Although each is addressed separately in the following chapters, none of the four aspects of this study were developed in isolation. Rather, all the constituent elements of the project informed--and were informed by--the others. For example, the review of the available literature on terrorist target selection made possible the identification of several target selection factors that were both important in the development of the analytical framework and subsequently validated by the case studies. Similarly, statistical analysis of the CrITIC data yielded measurable evidence that supported hypotheses derived from the framework, the case studies, and the writings of various experts. Besides providing an important mechanism of self-reinforcement and validation, the project's multifaceted nature made it possible to discern aspects of CI attack motivations that would likely have been missed if any single approach had been adopted

Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

The majority of genetic variants associated with type 2 diabetes (T2D) are located outside of genes in noncoding regions that may regulate gene expression in disease-relevant tissues, like pancreatic islets. Here, we present the largest integrated analysis to date of high-resolution, high-throughput human islet molecular profiling data to characterize the genome (DNA), epigenome (DNA packaging), and transcriptome (gene expression). We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner. Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk