Estimating Discount Rates

Discount rates are essential to applied finance, especially in setting prices for regulated utilities and valuing the liabilities of insurance companies and defined benefit pension plans. This paper reviews the basic building blocks for estimating discount rates. It also examines market risk premiums, as well as what constitutes a benchmark fair or required rate of return, in the aftermath of the financial crisis and the U.S. Federal Reserve’s bond-buying program. Some of the results are disconcerting. In Canada, utilities and pension regulators responded to the crash in different ways. Utilities regulators haven’t passed on the full impact of low interest rates, so that consumers face higher prices than they should whereas pension regulators have done the opposite, and forced some contributors to pay more. In both cases this is opposite to the desired effect of monetary policy which is to stimulate aggregate demand. A comprehensive survey of global finance professionals carried out last year provides some clues as to where adjustments are needed. In the U.S., the average equity market required return was estimated at 8.0 per cent; Canada’s is 7.40 per cent, due to the lower market risk premium and the lower risk-free rate. This paper adds a wealth of historic and survey data to conclude that the ideal base long-term interest rate used in risk premium models should be 4.0 per cent, producing an overall expected market return of 9-10.0 per cent. The same data indicate that allowed returns to utilities are currently too high, while the use of current bond yields in solvency valuations of pension plans and life insurers is unhelpful unless there is a realistic expectation that the plans will soon be terminated

Financial constraints, R&D investment, and the value of cash

This paper investigates whether the relationship between financial constraints and the marginal value of corporate cash holdings varies across firms with and without R&D investment. We find that among firms with positive R&D investment the marginal value of cash is higher in financially constrained firms than unconstrained ones, whereas this difference is not significant among firms without R&D investment

Spatial and seasonal distribution patterns of the ragged-tooth shark Carcharias taurus along the coast of South Africa

Off South Africa, the ragged-tooth shark Carcharias Taurus has been occasionally reported from the West Coast, but it is more commonly found along the East and South coasts from Cape Town to northern KwaZulu-Natal (KZN) (Bass et al. 1975, Smale 2002). Mating is thought to occur off the south coast of KZN from October to late November (G Cliff, Natal Sharks Board, unpublished data). Pregnant females then move northward to spend the early part of their gestation in the warmer waters of northern KZN and possibly southern Moçambique. During July and August, the near-term pregnant females begin to move southwards towards the cooler waters of the Eastern Cape (Wallett 1973, Bass et al. 1975, G Cliff, unpublished data), where they give birth from September to November (Smale 2002). After parturition, many of the females migrate back to KZN. The whereabouts of mature males outside of the mating season is unclear. These broadscale distribution and migratory habits for C. taurus have been inferred from limited catch records obtained for only parts of its range along the South African coast

Shark fishing effort and catch of the ragged-tooth shark Carcharias taurus in the South African competitive shore-angling fishery

In South Africa, Carcharias taurus is commonly known as the ragged-tooth shark or raggie. The species is also referred to as the sand-tiger shark in North America and as the grey-nurse shark in Australia. It is a long-lived species with an estimated longevity of up to 40 years (Goldman 2002). Female sharks reach sexual maturity at approximately 10 years (Goldman 2002), and they exhibit a biennial reproductive cycle (Branstetter and Musick 1994, Lucifora et al. 2002, G Cliff, Natal Sharks Board, unpublished data). Intra-uterine cannibalisation results in a maximum fecundity of two pups per litter after a gestation period of approximately 9–12 months (Bass et al. 1975, Gilmore et al. 1983). These life-history characteristics make this species particularly susceptible to overexploitation

Neratinib as a Potential Therapeutic for Mutant RAS and Osimertinib-Resistant Tumours

Neratinib was developed as an irreversible catalytic inhibitor of ERBB2, which also acts to inhibit ERBB1 and ERBB4. Neratinib is U.S. Food and Drug Administration (FDA)-approved as a neo-adjuvant therapy for use in HER2+ breast cancer. More recently, chemical biology analyses and the authors’ own bench work have demonstrated that neratinib has additional targets, which open up the possibility of using the drug in cell types that either lack ERBB receptor family expression or who rely on survival signalling downstream of growth factor receptors. Neratinib rapidly disrupted mutant RAS nanoclustering, which was followed by mutant rat sarcoma virus proteins translocating via LC3-associated phagocytosis into the cytosol where they were degraded by macroautophagy. Neratinib catalytically inhibited the MAP4K mammalian STE20-like protein kinase 4 and also caused its degradation via macroautophagy. This resulted in ezrin dephosphorylation and the plasma membrane becoming flaccid. Neratinib disrupted the nanoclustering of RAC1, which was associated with dephosphorylation of PAK1 and Merlin, and with increased phosphorylation of the Merlin binding partners large tumour suppressor kinase 1/2, YAP, and TAZ. YAP and TAZ exited the nucleus. Neratinib retained its anti-tumour efficacy against NSCLC cells made resistant to either afatinib or to osimertinib. Collectively, these findings argue that the possibilities for the further development of neratinib as cancer therapeutic in malignancies that do not express or over-express members of the ERBB receptor family are potentially wide-ranging

[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling

In the completed phase I trial NCT01450384 combining the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib it was observed that 20 of 33 patients had prolonged stable disease or tumor regression, with one complete response and multiple partial responses. The pre-clinical studies in this manuscript were designed to determine whether [pemetrexed + sorafenib] –induced cell killing could be rationally enhanced by additional signaling modulators. Multiplex assays performed on tumor material that survived and re-grew after [pemetrexed + sorafenib] exposure showed increased phosphorylation of ERBB1 and of NFκB and IκB; with reduced IκB and elevated G-CSF and KC protein levels. Inhibition of JAK1/2 downstream of the G-CSF/KC receptors did not enhance [pemetrexed + sorafenib] lethality whereas inhibition of ERBB1/2/4 using kinase inhibitory agents or siRNA knock down of ERBB1/2/3 strongly promoted killing. Inhibition of ERBB1/2/4 blocked [pemetrexed + sorafenib] stimulated NFκB activation and SOD2 expression; and expression of IκB S32A S36A significantly enhanced [pemetrexed + sorafenib] lethality. Sorafenib inhibited HSP90 and HSP70 chaperone ATPase activities and reduced the interactions of chaperones with clients including c-MYC, CDC37 and MCL-1. In vivo, a 5 day transient exposure of established mammary tumors to lapatinib or vandetanib significantly enhanced the anti-tumor effect of [pemetrexed + sorafenib], without any apparent normal tissue toxicities. Identical data to that in breast cancer were obtained in NSCLC tumors using the ERBB1/2/4 inhibitor afatinib. Our data argue that the combination of pemetrexed, sorafenib and an ERBB1/2/4 inhibitor should be explored in a new phase I trial in solid tumor patients

2,6-Dide­oxy-2,6-imino-l-glycero-d-ido-heptitol

The title mol­ecule, C7H15NO5, the major product from selective enzymatic oxidation followed by hydrogeno­lysis of the corresponding azido­heptitol, was found by X-ray crystallography to exisit in a chair conformation with three axial hydroxyl groups. One of the hydroxymethyl groups is disordered over two sets of sites in a 0.590 (3):0.410 (3) ratio. In the crystal, O—H⋯O, O—H⋯(O,O), O—H⋯N and N—H⋯O hydrogen bonding occurs

Long-term SARS Coronavirus Excretion from Patient Cohort, China

This study investigated the long-term excretion of severe acute respiratory syndrome–associated coronavirus in sputum and stool specimens from 56 infected patients. The median (range) duration of virus excretion in sputa and stools was 21 (14–52) and 27 (16–126) days, respectively. Coexisting illness or conditions were associated with longer viral excretion in stools

Correlation between Cognition and Balance among Middle-Aged and Older Adults Observed through a Tai Chi Intervention program

Background: Age-associated decline in cognition and balance may cause severe ability loss for daily living activities among middle-aged and older adults. The relationship between cognition and balance in this aging population remains to be explored. Objective: The present study Is exploratory in nature and aimed to examine the relationship between balance (both static and dynamic components) and global cognitive function among middle-aged and older adults through Tai Chi (TC) practice as a research avenue. Methods: A short-term (12 weeks) intervention of TC was conducted among middle-aged and older adults in the community setting. Global cognitive function (using the Chinese version of the Montreal Cognitive Assessment score (MoCA) and balance (i.e., one leg standing test score; Timed Up and Go Test score, TUGT) of all participants were assessed before and after the intervention. Age, body mass index (BMI), sex, and physical fitness variables (Chair Stand Test, CST; the 6-Meter Walk Test, 6MWT) were also collected as confounding factors. Results: Significant moderator effects of baseline CST on the association between the dichotomized baseline MoCA score and the baseline left leg balance score (p = 0.0247), the baseline right leg balance score (p = 0.0140) and the baseline TUGT score (p = 0.0346) were found. Change score of left score balance (p = 0.0192) and change score of TUGT (p = 0.0162) were found to be significantly associated with change score of cognitive function. Conclusion: Cognitive function and balance are interrelated in middle-aged and older adults. The association between global cognitive function and balance Is moderated by strength of lower limbs. The change scores of cognitive function and balance introduced by TC training were found to be positively correlated. Future research Is warranted to further confirm the cause-effect relationship of cognitive function and balance and its influencing factors among middle-aged and older adults utilizing intervention studies with larger sample sizes

Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ