Transcription Factor AP-2 Regulatory Signatures in Breast Cancer

PhDAP-2 transcription factors are highly conserved basic helix-span-helix proteins whose members ((x, ß, y, S and c) are crucial regulators of bryonic development. They also play an important role in human neoplasia. uohis ochemical studies have detected high levels of AP-2y expression in primary tumo of breast cancer patients. This high expression has been correlated with reduced survival in all patients and reduced survival in an ERa positive subset treated with hormone therapy. In breast cancer cell lines, AP- 2 factors have been implicated in the regulation of the ERBB2 proto-oncogene and ERa. In an effort to further understand the role of AP-2y in breast carcinoma, this study has sought to identify additional AP-2 activated cellular pathways and ultimately novel transcriptional targets for AP-2 through the use of gene expression profiling. RNAi using three independent AP-2y targeting sequences, has been used to deplete AP- 2y levels in the ERa positive MCF-7 breast carcinoma cell line, chosen as it exclusively expresses the AP-2y family member. Microarrays were then utilised to create an AP-2y dependent transcription profile. Statistical comparisons between non-silencing control siRNA and AP-2y targeting siRNA groups identified a total of 162 gene expression changes (p<0.01). These changes implicate AP-2y in the control of cell cycle progression and developmental signalling. Indeed a role for AP-2y in the control of cell cycle, in particular at the GUS transition, has been verified using flow cytometry. Several of these gene expression changes, including IGFBP3, Transgelin and KIAA1324, have been confirmed using qPCR and immunoblotting. Finally, elevated levels of p21 mRNA and protein have been observed following AP-2y silencing in MCF-7 cells. Additionally, the activity of a p21 promoter reporter is repressed following transfection with an AP-2y expression construct in HepG2 cells. These results coupled with ChIP experiments showing AP-2y occupancy at the proximal promoter region of p21 in cycling MCF-7 cells, implicate AP-2y in the repression of p21 transcription and suggest a role for AP2y in- the, control of cell cycle in breast carcinoma in part through the transcriptional repression of p21

High fidelity estimates of paratransit energy consumption from per-second GPS tracking data

Paratransit, in particular the minibus taxi, is the mainstay of public transport in sub-Saharan Africa. These vehicles are often second-hand, ageing, fuel inefficient, and expensive to operate - issues that electrification can ameliorate. However, modeling and planning large-scale transitions to electric paratransit require reliable estimates of vehicle energy consumption. This paper provides such estimates by applying a vehicle kinetic model to per-second GPS data gathered on minibus taxis. Data include 62 trips across three routes with different driving conditions near Stellenbosch, South Africa. We find a range of energy consumption from 0.29 to 0.51 kWh/km (mean = 0.39 kWh/km). Past estimates in literature relied on per-minute GPS data, which we show leads to inaccurate energy consumption estimates. We recommend new kWh/km values for modeling vehicle operations and grid impact, and discuss how future work can utilize our analysis to advance the transition to electric paratransit sub-Saharan Africa

Temporal dynamics of aquatic communities and implications for pond conservation

Conservation through the protection of particular habitats is predicated on the assumption that the conservation value of those habitats is stable. We test this assumption for ponds by investigating temporal variation in macroinvertebrate and macrophyte communities over a 10-year period in northwest England. We surveyed 51 ponds in northern England in 1995/6 and again in 2006, identifying all macrophytes (167 species) and all macroinvertebrates (221 species, excluding Diptera) to species. The alpha-diversity, beta-diversity and conservation value of these ponds were compared between surveys. We find that invertebrate species richness increased from an average of 29. 5 species to 39. 8 species between surveys. Invertebrate gamma-diversity also increased between the two surveys from 181 species to 201 species. However, this increase in diversity was accompanied by a decrease in beta-diversity. Plant alpha-, beta and gamma-diversity remained approximately constant between the two periods. However, increased proportions of grass species and a complete loss of charophytes suggests that the communities are undergoing succession. Conservation value was not correlated between sampling periods in either plants or invertebrates. This was confirmed by comparing ponds that had been disturbed with those that had no history of disturbance to demonstrate that levels of correlation between surveys were approximately equal in each group of ponds. This study has three important conservation implications: (i) a pond with high diversity or high conservation value may not remain that way and so it is unwise to base pond conservation measures upon protecting currently-speciose habitats; (ii) maximising pond gamma-diversity requires a combination of late and early succession ponds, especially for invertebrates; and (iii) invertebrate and plant communities in ponds may require different management strategies if succession occurs at varying rates in the two groups

Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Background Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer. Methods All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed. Results The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes. Conclusions Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months’ duration. (Current Controlled Trials number, ISRCTN98278138.

Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function.

Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets

Submission to the Toronto Police Services Board’s Use of New Artificial Intelligence Technologies Policy- LEAF and the Citizen Lab

We write as a group of experts in the legal regulation of artificial intelligence (AI), technology-facilitated violence, equality, and the use of AI systems by law enforcement in Canada. We have experience working within academia and legal practice, and are affiliated with LEAF and the Citizen Lab who support this letter.We reviewed the Toronto Police Services Board Use of New Artificial Intelligence Technologies Policy and provide comments and recommendations focused on the following key observations:1. Police use of AI technologies must not be seen as inevitable2. A commitment to protecting equality and human rights must be integrated more thoroughly throughout the TPSB policy and its AI analysis procedures3. Inequality is embedded in AI as a system in ways that cannot be mitigated through a policy only dealing with use4. Having more accurate AI systems does not mitigate inequality5. The TPS must not engage in unnecessary or disproportionate mass collection and analysis of data6. TPSB’s AI policy should provide concrete guidance on the proactive identification and classification of risk7. TPSB’s AI policy must ensure expertise in independent vetting, risk analysis, and human rights impact analysis8. The TPSB should be aware of assessment challenges that can arise when an AI system is developed by a private enterprise9. The TPSB must apply the draft policy to all existing AI technologies that are used by, or presently accessible to, the Toronto Police ServiceIn light of these key observations, we have made 33 specific recommendations for amendments to the draft policy

Honey bee foraging distance depends on month and forage type

To investigate the distances at which honey bee foragers collect nectar and pollen, we analysed 5,484 decoded waggle dances made to natural forage sites to determine monthly foraging distance for each forage type. Firstly, we found significantly fewer overall dances made for pollen (16.8 %) than for non-pollen, presumably nectar (83.2 %; P < 2.2 × 10−23). When we analysed distance against month and forage type, there was a significant interaction between the two factors, which demonstrates that in some months, one forage type is collected at farther distances, but this would reverse in other months. Overall, these data suggest that distance, as a proxy for forage availability, is not significantly and consistently driven by need for one type of forage over the other