Defining Your Double Bottom Line: Philanthropy and the Investment Landscape

Grantmaking traditionally has been at the heart of philanthropy, whereas impact was the exclusive expectation of any desired result. While there is still a place for this kind of pure push for change, many investors today expect more, leveraging the power of the markets to invest in a way that is both impactful and able to maximize their financial rewards. This is particularly true of foundations with an eye toward supporting the perpetuity of their missions and organizations. This approach also offers a range of innovative mission-based benefits, including extending the utility of philanthropic capital and generating more capital to reinvest into impact initiatives, potentially in partnership or in tandem with grantmaking. However, the focus of impact has also shifted in radical new ways, especially over the last few years, in response to social developments and generational shifts in value. These shifts call for greater intentionality in defining the nuance and complexities involved in any use of the term “impact.” This article argues the key importance of defining and crystalizing specific thresholds, metrics, and language around foundations’ missions to ensure demonstrable qualitative and quantitative measures of progress toward success (financially and impact-based); discusses how the long-term pursuit of values-based goals and financial performance are mutually inclusive and self-reinforcing, and can be combined to great effect with more traditional forms of philanthropy (i.e., grantmaking); and demonstrates how impact investing provides the opportunity for the engagement of additional stakeholders and members of the community. This article also addresses several key questions: How has the use of philanthropic capital evolved from an investment perspective? What does an effective impact definition include? In which ways do impact and financial priorities buoy each other? How does one find credible sources of ESG/impact data and what determines high-quality data? And, finally, how can organizations best articulate their missions in their investment policy statements to better define their double bottom line

Pregnancy in a noncommunicating rudimentary horn of a unicornuate uterus: a case report

Pregnancy in the rudimentary horn is rare and carries grave consequences for the mother and fetus. A case report is presented of a 26 year old single gravida 3 para 0+2 lady with rupture of a rudimentary horn pregnancy at a gestational age of 20 weeks. Laparotomy was done and the rudimentary horn excised. Post-operative recovery was uneventful. The need for a high index of suspicion and the role of ultrasonography in the accurate diagnosis is highlighted

MicroRNA (miRNA)-to-miRNA Regulation of programmed cell death 4 (PDCD4)

Copyright © 2019 Ajuyah et al. The regulation of tumor suppressor genes by microRNAs (miRNAs) is often demonstrated as a one-miRNA-to-one-target relationship. However, given the large number of miRNA sites within a 3= untranslated region (UTR), most targets likely undergo miRNA cooperation or combinatorial action. Programmed cell death 4 (PDCD4), an important tumor suppressor, prevents neoplastic events and is commonly downregulated in cancer. This study investigates the relationship between miRNA 21 (miR-21) and miR-499 in regulating PDCD4. This was explored using miRNA overexpression, mutational analysis of the PDCD4 3= UTR to assess regulation at each miRNA site, and 50% inhibitory concentration (IC50) calculations for combinatorial behavior. We demonstrate that the first miR-499 binding site within PDCD4 is inactive, but the two remaining sites are both required for PDCD4 suppression. Additionally, the binding of miR-21 to PDCD4 influenced miR-499 activity through an increase in its silencing potency and stabilization of its mature form. Furthermore, adjoining miRNA sites more than 35 nucleotides (nt) apart could potentially regulate thousands of 3= UTRs, similar to that observed between miR-21 and miR-499. The regulation of PDCD4 serves as a unique example of regulatory action by multiple miRNAs. This relationship was predicted to occur on thousands of targets and may represent a wider mode of miRNA regulation

Development of Rabbit Meat Products Fortified With n-3 Polyunsaturated Fatty Acids

Rabbit meat is a highly digestible, tasty, low-calorie food, often recommended by nutritionists over other meats. Currently research in the rabbit sector is interested in developing feeding strategies aiming to further increase the nutritional value of rabbit meat as a “functional food” by including n-3 polyunsaturated fatty acids (n-3 PUFA), conjugated linoleic acid (CLA), vitamins and antioxidants in rabbit diets and assessing their effects on both raw and stored/processed meat quality properties. Our recent studies indicate that the dietary inclusion from 3 to 6% of linseed might be considered as a way to achieve the enrichment of the meat with α-linolenic acid and to guarantee satisfactory product stability during further processing and storage. Considering that 6% dietary linseed corresponds to a n-3 PUFA content of 8.5% of the total fatty acids and a lipid content of 4.7 g/100 g of leg meat, a content of 396 mg n-3 PUFA/100g meat can be estimated, which represents about 19% of the recommended daily allowance (RDA) for n-3 PUFA

The role of miR-21 and miR-499 in head and neck cancer

University of Technology Sydney. Faculty of Science.Globally there are more than half a million new cases of head and neck cancer each year. More than 90% of head and neck tumours are head and neck squamous cell carcinomas (HNSCCs) which originate in the lip/oral cavity, nasopharynx, oropharynx, hypopharynx and the larynx. HNSCCs are inadequately diagnosed and as a result many head and neck cancer patients are diagnosed at the advanced stages of the disease. The lack of biomarkers for HNSCC has resulted in this poor diagnosis of the cancer. Furthermore, a limited understanding of the molecular biology of the cancer has led to few treatment options. The future of HNSCC diagnosis and treatment can lie in the small non-coding RNAs called miRNAs. miRNAs function as gene regulators and have been implicated in the development and progression of various cancers. In HNSCC, two miRNAs miR-21 and miR-499 have been found to be upregulated in tumours compared to normal tissues. Furthermore, these miRNAs both regulate the tumour suppressor gene Programmed Cell Death 4 (PDCD4). PDCD4 has been found to be involved in oncogenic pathways including apoptosis, proliferation, angiogenesis and invasion. PDCD4 is also downregulated in many HNSCC tumours. This thesis endeavoured to determine the role of miR-21 and miR-499 in HNSCC through their regulation of PDCD4. The first aim was to study the co-regulation of PDCD4 by miR-21 and miR-499. When genes are co-regulated by miRNAs this can lead to heavy regulation of the genes. This is essential for genes critical to cancer initiation and progression. Currently there are limited studies examining the various modes of regulation miRNAs can use to simultaneously regulate a single gene at its 3´ untranslated region (3´UTR). In this project, site mutants for miR-21 and miR-499 at the 3´UTR of PDCD4 were created and ligated to luciferase reporter vectors. Using luciferase assays it was revealed that miR-21 and miR-499 regulate the 3´UTR independently of each other. However, miR-21 does aid miR-499 interactions with the PDCD4 3´UTR. Furthermore, the last two miR-499 sites are regulated in a co-dependent manner and mutating either site completely abolishes regulation of PDCD4 by miR-499. This is the first study detailing the regulatory dynamics of PDCD4. The co-regulation of PDCD4 by miR-21 and miR-499 has an extra layer of complexity in that the miRNAs also have a regulatory relationship with each other. Overexpression of miR-21 was found to endogenously upregulate miR-499 expression in cells. There are few studies in the literature on miRNA mediated regulation of another miRNA. These studies show that miRNA mediated regulation usually occurs when a miRNA(s) has a binding site in the primary transcript of another miRNA or at the promoter region of the mature miRNA. Further research into miR-21’s upregulation of miR-499, found that the regulation was not reciprocal as overexpression of miR-499 did not affect miR-21 levels. A few models were designed and tested to investigate how miR-21 was able to regulate miR-499. Primary levels of miR-499 were unchanged by miR-21 overexpression. Thus regulation of miR-499 by miR-21 occurred post-transcription. The stability of miR-499 was measured when de novo synthesis of miRNAs was switched off. miR-499 was found like other miRNAs to degrade over 24 hours. However, if miR-21 was overexpressed in cells then miR-499 levels were stabilised. It was thought that perhaps miR-21 is able to stabilise miR-499 through target-mediated miRNA protection (TMMP). In this model the half-life of a miRNA can be increased by its interactions with a target mRNA. It is predicted that through a gene like PDCD4 miR-21 is able to encourage miR-499 interactions with the gene. Perhaps miR-21 binding removes obtrusive secondary structure at the miR-499 binding sites on the 3´UTR. This allows miR-499 to interact with the gene thus protecting it from degradation. A few studies have found that a single miRNA is able to alter the expression of multiple miRNAs. However, the mechanism behind this or even if this is a common occurrence with miRNAs in general is still yet to be understood. Therefore, the regulation of miR-499 by miR-21 was extended genome-wide to determine if other miRNAs were also affected by miR-21 overexpression. Affymetrix arrays revealed that not only were many miRNAs upregulated by miR-21 overexpression but also downregulated. Furthermore, miR-499 overexpression could also differentially regulate other miRNAs. The miRNAs that were most upregulated by miR-21 were found to have targets that could potentially be co-targeted by several of these miRNAs. miR-21 and miR-499 also had genes that they could potentially co-target together. Therefore, perhaps miRNAs that are regulated by other miRNAs are involved in regulating similar genes leading to an enhanced or differential regulation of these genes. Finally, the function of miR-21 and miR-499 in HNSCCs were examined. miR-21 is involved in certain oncogenic pathways in HNSCCs, but no studies have investigated miR-499’s role. Considering that miRNAs are at the forefront of gene dysregulation during cancer initiation and development, it is worth understanding how they are able to affect cancerous processes. This is useful for the identification of new biomarkers for HNSCC but also for the design of miRNA based therapeutics. Using live cell imaging and scratch assays, it was found that miR-21 and miR-499 were able to promote migration in HNSCCs. It is predicted that this promoted migration most likely occurs through the downregulation of the tumour suppressor genes PDCD4, SRY (Sex Determining Region Y) Box 6 and Forkhead Box Protein 04 (FOXO4). These genes have been shown in other cancers to be directly involved in migration. This thesis explores in depth the regulation of the tumour suppressor gene PDCD4 by miR-21 and miR-499 in a HNSCC context. It uncovers the type of regulation this gene undergoes, the relationship between the two miRNAs and other miRNAs and the function of these miRNAs in HNSCC. Studies such as these pave the way for designing new clinical therapeutics by understanding the molecular aberrations that lead to head and neck cancer development

Isolation of small noncoding RNAS from human serum

This protocol describes a method for extracting small RNAs from human serum. We have used this method to isolate microRNAs from cancer serum for use in DNA arrays and also singleplex quantitative PCR. The protocol utilizes phenol and guanidinium thiocyanate reagents with modifications to yield high quality RNA