Proteasomes degrade most proteins in mammalian cells and are established targets of anti-cancer drugs. All eukaryotic proteasomes have three types of active sites: chymotrypsin-like, trypsin-like, and caspase-like. Chymotrypsin-like sites are the most important in protein degradation and are the primary target of most proteasome inhibitors. The biological roles of trypsin-like and caspase-like sites and their potential as co-targets of anti-neoplastic agents are not well defined. Here we describe the development of novel, site-specific inhibitors and active-site probes of chymotrypsin-like and caspase-like sites. Using these compounds, we show that cytotoxicity of proteasome inhibitors does not correlate with inhibition of chymotrypsin-like sites and that co-inhibition of either trypsin-like and/or caspase-like sites is needed to achieve maximal cytotoxicity. Thus, caspase-like and trypsin-like sites must be considered as co-targets of anti-cancer drugs.

The conservation of humpback dolphins, distributed in coastal waters of the Indo-West Pacific and eastern Atlantic Oceans, has been hindered by a lack of understanding about the number of species in the genus (Sousa) and their population structure. To address this issue, we present a combined analysis of genetic and morphologic data collected from beach-cast, remote-biopsied and museum specimens from throughout the known Sousa range. We extracted genetic sequence data from 235 samples from extant populations and explored the mitochondrial control region and four nuclear introns through phylogenetic, population-level and population aggregation frameworks. In addition, 180 cranial specimens from the same geographical regions allowed comparisons of 24 morphological characters through multivariate analyses. The genetic and morphological data showed significant and concordant patterns of geographical segregation, which are typical for the kind of demographic isolation displayed by species units, across the Sousa genus distribution range. Based on our combined genetic and morphological analyses, there is convincing evidence for at least four species within the genus (S. teuszii in the Atlantic off West Africa, S. plumbea in the central and western Indian Ocean, S. chinensis in the eastern Indian and West Pacific Oceans, and a new as-yet-unnamed species off northern Australia).

Patients with Chronic Obstructive Pulmonary Disease (COPD) and tracheostomy are at high risk for exacerbations and hospitalizations. Macrolide treatment has shown to reduce exacerbations in moderate-to-severe COPD. To evaluate the safety and the efficacy of long-term azithromycin use in outpatients with severe COPD and tracheostomy. A multicenter, randomized, uncontrolled, pilot trial evaluating the safety and the efficacy of azithromycin 500 mg three day-a-week for 6 months (AZI) vs. standard of care (SC) in severe COPD outpatients with tracheostomy. Patients were monitored for six months of treatment plus six months of follow up. The primary outcome was the reduction in the number of exacerbations and hospitalizations. A total of 22 patients was randomized (11 to SC and 11 to AZI). Patients in AZI had a significant lower cumulative number of exacerbations after the first 3 months of treatment when compared to patients in SC (p = 0.001), as well as hospitalizations (p = 0.02). Kaplan-Meier survival curves for time to first exacerbation showed a significant reduction in AZI of the rates of first exacerbation when compared to SC (log rank test = 12.14, p < 0.001), as well as to first hospitalization (log-rank = 4.09, p = 0.04). Azithromycin significantly improved the quality of life in comparison to SC. No serious adverse events in the AZI group were reported. Long-term azithromycin treatment seems to be safe and effective in severe COPD outpatients with tracheostomy in reducing exacerbations, hospitalizations, as well as in improving quality of life.

In developing regions, coastal communities are particularly dependent on small-scale fisheries for food security and income. However, information on the scale and impacts of small-scale fisheries on coastal marine ecosystems are frequently lacking. Large marine vertebrates (marine mammals, sea turtles and chondrichthyans) are often among the first species to experience declines due to fisheries. This paper reviews the interactions between small-scale fisheries and vulnerable marine megafauna in the southwestern Indian Ocean. We highlight an urgent need for proper documentation, monitoring and assessment at the regional level of small-scale fisheries and the megafauna affected by them to inform evidence-based fisheries management. Catch and landings data are generally of poor quality and resolution with compositional data, where available, mostly anecdotal or heavily biased towards easily identifiable species. There is also limited understanding of fisheries effort, most of which relies on metrics unsuitable for proper assessment. Management strategies (where they exist) are often created without strong evidence bases or understanding of the reliance of fishers on resources. Consequently, it is not possible to effectively assess the current status and ensure the sustainability of these species groups; with indications 123Rev Fish Biol Fisheries (2018Fisheries ( ) 28:89-115 https://doi.org/10.1007 of overexploitation in several areas. To address these issues, a regionally collaborative approach between government and non-governmental organisations, independent researchers and institutions, and smallscale fisheries stakeholders is required. In combination with good governance practices, appropriate and effective, evidence-based management can be formulated to sustain these resources, the marine ecosystems they are intrinsically linked to and the livelihoods of coastal communities that are tied to them.

No abstract

Asymmetric cross-coupling of aryl iodides (ArI) with secondary arylphosphines (PHMe(Ar'), Ar' = (2,4,6)-R3C6H2; R = i-Pr (Is), Me (Mes), Ph (Phes)) in the presence of the base NaOSiMe3 and a chiral Pd catalyst precursor, such as Pd((R,R)-Me-Duphos)(trans-stilbene), gave the tertiary phosphines PMe(Ar')(Ar) in enantioenriched form. Sterically demanding secondary phosphine substituents (Ar') and aryl iodides with electron-donating para substituents resulted in the highest enantiomeric excess, up to 88%. Phosphination of ortho-substituted aryl iodides required a Pd(Et-FerroTANE) catalyst but gave low enantioselectivity. Observations during catalysis and stoichiometric studies of the individual steps suggested a mechanism for the cross-coupling of PhI and PHMe(Is) (1) initiated by oxidative addition to Pd(0) yielding Pd((R,R)-Me-Duphos)(Ph)(I) (3). Reversible displacement of iodide by PHMe(Is) gave the cation [Pd((R,R)-Me-Duphos)(Ph)(PHMe(Is))][I] (4), which was isolated as the triflate salt and crystallographically characterized. Deprotonation of 4-OTf with NaOSiMe3 gave the phosphido complex Pd((R,R)-Me-Duphos)(Ph)(PMeIs) (5); an equilibrium between its diastereomers was observed by low-temperature NMR spectroscopy. Reductive elimination of 5 yielded different products depending on the conditions. In the absence of a trap, the unstable three-coordinate phosphine complex Pd((R,R)-Me-Duphos)(PMeIs(Ph)) (6) was formed. Decomposition of 5 in the presence of PhI gave PMeIs(Ph) (2) and regenerated 3, while trapping with phosphine 1 during catalysis gave Pd((R,R)-Me-Duphos)(PHMe(Is))2 (7), which reacted with PhI to give 3. Deprotonation of 1:1 or 1.4:1 mixtures of cations 4-OTf gave the same 6:1 ratio of enantiomers of PMeIs(Ph) (2), suggesting that the rate of P inversion in 5 was greater than or equal to the rate of reductive elimination. Kinetic studies of the first-order reductive elimination of 5 were consistent with a Curtin-Hammett-Winstein-Holness (CHWH) scheme, in which pyramidal inversion at the phosphido ligand was much faster than P-C bond formation. The absolute configuration of the phosphine (SP)-PMeIs(p-MeOC6H4) was determined crystallographically; NMR studies and comparison to the stable complex 5-Pt were consistent with an RP-phosphido ligand in the major diastereomer of the intermediate Pd((R,R)-Me-Duphos)(Ph)(PMeIs) (5). Therefore, the favored enantiomer of phosphine 2 appeared to be formed from the major diastereomer of phosphido intermediate 5, although the minor intermediate diastereomer underwent P-C bond formation about three times more rapidly. The effects of the diphosphine ligand, the phosphido substituents, and the aryl group on the ratio of diastereomers of the phosphido intermediates Pd(diphos*)(Ar)(PMeAr'), their rates of reductive elimination, and the formation of three-coordinate complexes were probed by low-temperature 31P NMR spectroscopy; the results were also consistent with the CHWH scheme.

No abstract

The present study assesses socio-demographic and health service determinants of termination of breastfeeding within the first 2 years of life in India by analysing data from the nationally representative National Family Health Survey-2 using Cox regression modelling techniques. While the likelihood of stopping breastfeeding increased with increasing household wealth status, it declined with increasing maternal age at childbirth. The likelihood of stopping breastfeeding was significantly higher among female children compared with male children, and the gender differential was attenuated by increasing maternal educational status. Overall, findings of the present study suggest that breastfeeding promotion programmes in India should focus on certain high-risk motherchild pairs such as female infants, first-born babies, babies born in the private sector and in urban areas, as well as mothers who are literate, have a higher wealth status, are aged less than 20 years and belong to Sikh or Christian communities. Qualitative studies to understand cultural factors or norms and causal pathways responsible for the association of identified factors and early termination of breastfeeding, especially household wealth status and maternal education, are also called for.