Understanding and Enhancing the Role of Business in International Development: A Conceptual Framework and Agenda for Research

It is now commonplace for development policy makers to refer to the contributions of businesses to the achievement of development goals and the importance of collaborations between businesses and development agencies. Many businesses give greater attention to the development impacts of their activities. There has been relatively little systematic and critical thinking about where and how businesses can contribute most effectively to the achievement of development objectives and, accordingly, how development agents should prioritise and focus their collaborations with businesses. This paper initiates such a systematic and critical approach, starting from the question ‘How can development policy work with and on businesses and the business environment so that the private goals of businesses contribute to most effectively to public development objectives?’ It identifies three basic categories of business and development initiatives: increasing the overall level of business activity, addressing sustainability challenges and promoting business activities that are particular benefit to the poor. The paper considers three major challenges for maximising the contributions businesses to the achievement of development goals. The first is increasing the alignments between business and objectives and development objectives, and the paper considers both the different ways this can be achieved and when such alignments are overly difficult to achieve. The second is to prioritise interventions. When resources are scarce, it is essential to pursue interventions that have the biggest development impact. This implies choosing interventions with goals and approaches that are most likely to be successful; in so doing, examining issues of feasibility, effectiveness and efficiency. So that scarce resources are focused on the areas of greatest benefit. The third is to achieve scaling up and systemic change. There are many examples of business activities that have positive development impacts but which are being pursued at small-scale and/or in quite specific geographical or sectoral contexts. How can such initiatives be up-scaled, translated and/or replicated in order to enhance impacts on the poor in ways that endure beyond the specific interventions applied

Characterizing viscoelastic materials via ensemble-based data assimilation of bubble collapse observations

Viscoelastic material properties at high strain rates are needed to model many biological and medical systems. Bubble cavitation can induce such strain rates, and the resulting bubble dynamics are sensitive to the material properties. Thus, in principle, these properties can be inferred via measurements of the bubble dynamics. Estrada et al. (2018) demonstrated such bubble-dynamic high-strain-rate rheometry by using least-squares shooting to minimize the difference between simulated and experimental bubble radius histories. We generalize their technique to account for additional uncertainties in the model, initial conditions, and material properties needed to uniquely simulate the bubble dynamics. Ensemble-based data assimilation minimizes the computational expense associated with the bubble cavitation model , providing a more efficient and scalable numerical framework for bubble-collapse rheometry. We test an ensemble Kalman filter (EnKF), an iterative ensemble Kalman smoother (IEnKS), and a hybrid ensemble-based 4D-Var method (En4D-Var) on synthetic data, assessing their estimations of the viscosity and shear modulus of a Kelvin–Voigt material. Results show that En4D-Var and IEnKS provide better moduli estimates than EnKF. Applying these methods to the experimental data of Estrada et al. (2018) yields similar material property estimates to those they obtained, but provides additional information about uncertainties. In particular, the En4D-Var yields lower viscosity estimates for some experiments, and the dynamic estimators reveal a potential mechanism that is unaccounted for in the model, whereby the apparent viscosity is reduced in some cases due to inelastic behavior, possibly in the form of material damage occurring at bubble collapse

Characterizing viscoelastic materials via ensemble-based data assimilation of bubble collapse observations

Viscoelastic material properties at high strain rates are needed to model many biological and medical systems. Bubble cavitation can induce such strain rates, and the resulting bubble dynamics are sensitive to the material properties. Thus, in principle, these properties can be inferred via measurements of the bubble dynamics. Estrada et al. (2018) demonstrated such bubble-dynamic high-strain-rate rheometry by using least-squares shooting to minimize the difference between simulated and experimental bubble radius histories. We generalize their technique to account for additional uncertainties in the model, initial conditions, and material properties needed to uniquely simulate the bubble dynamics. Ensemble-based data assimilation minimizes the computational expense associated with the bubble cavitation model. We test an ensemble Kalman filter (EnKF), an iterative ensemble Kalman smoother (IEnKS), and a hybrid ensemble-based 4D--Var method (En4D--Var) on synthetic data, assessing their estimations of the viscosity and shear modulus of a Kelvin--Voigt material. Results show that En4D--Var and IEnKS provide better moduli estimates than EnKF. Applying these methods to the experimental data of Estrada et al. (2018) yields similar material property estimates to those they obtained, but provides additional information about uncertainties. In particular, the En4D--Var yields lower viscosity estimates for some experiments, and the dynamic estimators reveal a potential mechanism that is unaccounted for in the model, whereby the viscosity is reduced in some cases due to material damage occurring at bubble collapse

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR

Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability

ONTOGENY AND PHYLOGENETIC SYSTEMATICS

Dedifferentiation, paedomorphosis, and the insertion and deletion of developmental stages make it impossible to deduce the genealogical hierarchy from only ontogenetic transformation series. Like the outgroup criterion, ontogenetic character precedence is not theory-neutral and to use it to deduce genealogy requires certain assumptions. If scientists are going to use logically unbeatable theories about the world, they might as well give up natural science and take up religion (Lewontin, 1972: 181).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73749/1/j.1096-0031.1985.tb00408.x.pd

Self-Mating in the Definitive Host Potentiates Clonal Outbreaks of the Apicomplexan Parasites Sarcocystis neurona and Toxoplasma gondii

Tissue-encysting coccidia, including Toxoplasma gondii and Sarcocystis neurona, are heterogamous parasites with sexual and asexual life stages in definitive and intermediate hosts, respectively. During its sexual life stage, T. gondii reproduces either by genetic out-crossing or via clonal amplification of a single strain through self-mating. Out-crossing has been experimentally verified as a potent mechanism capable of producing offspring possessing a range of adaptive and virulence potentials. In contrast, selfing and other life history traits, such as asexual expansion of tissue-cysts by oral transmission among intermediate hosts, have been proposed to explain the genetic basis for the clonal population structure of T. gondii. In this study, we investigated the contributing roles self-mating and sexual recombination play in nature to maintain clonal population structures and produce or expand parasite clones capable of causing disease epidemics for two tissue encysting parasites. We applied high-resolution genotyping against strains isolated from a T. gondii waterborne outbreak that caused symptomatic disease in 155 immune-competent people in Brazil and a S. neurona outbreak that resulted in a mass mortality event in Southern sea otters. In both cases, a single, genetically distinct clone was found infecting outbreak-exposed individuals. Furthermore, the T. gondii outbreak clone was one of several apparently recombinant progeny recovered from the local environment. Since oocysts or sporocysts were the infectious form implicated in each outbreak, the expansion of the epidemic clone can be explained by self-mating. The results also show that out-crossing preceded selfing to produce the virulent T. gondii clone. For the tissue encysting coccidia, self-mating exists as a key adaptation potentiating the epidemic expansion and transmission of newly emerged parasite clones that can profoundly shape parasite population genetic structures or cause devastating disease outbreaks

Pseudomonas aeruginosa Population Structure Revisited

At present there are strong indications that Pseudomonas aeruginosa exhibits an epidemic population structure; clinical isolates are indistinguishable from environmental isolates, and they do not exhibit a specific (disease) habitat selection. However, some important issues, such as the worldwide emergence of highly transmissible P. aeruginosa clones among cystic fibrosis (CF) patients and the spread and persistence of multidrug resistant (MDR) strains in hospital wards with high antibiotic pressure, remain contentious. To further investigate the population structure of P. aeruginosa, eight parameters were analyzed and combined for 328 unrelated isolates, collected over the last 125 years from 69 localities in 30 countries on five continents, from diverse clinical (human and animal) and environmental habitats. The analysed parameters were: i) O serotype, ii) Fluorescent Amplified-Fragment Length Polymorphism (FALFP) pattern, nucleotide sequences of outer membrane protein genes, iii) oprI, iv) oprL, v) oprD, vi) pyoverdine receptor gene profile (fpvA type and fpvB prevalence), and prevalence of vii) exoenzyme genes exoS and exoU and viii) group I pilin glycosyltransferase gene tfpO. These traits were combined and analysed using biological data analysis software and visualized in the form of a minimum spanning tree (MST). We revealed a network of relationships between all analyzed parameters and non-congruence between experiments. At the same time we observed several conserved clones, characterized by an almost identical data set. These observations confirm the nonclonal epidemic population structure of P. aeruginosa, a superficially clonal structure with frequent recombinations, in which occasionally highly successful epidemic clones arise. One of these clones is the renown and widespread MDR serotype O12 clone. On the other hand, we found no evidence for a widespread CF transmissible clone. All but one of the 43 analysed CF strains belonged to a ubiquitous P. aeruginosa “core lineage” and typically exhibited the exoS+/exoU− genotype and group B oprL and oprD alleles. This is to our knowledge the first report of an MST analysis conducted on a polyphasic data set

Virulence genes and previously unexplored gene clusters in four commensal 'Neisseria' spp. isolated from the human throat expands the neisserial gene repertoire

Commensal non-pathogenic spp. live within the human host alongside the pathogenic and and due to natural competence, horizontal gene transfer within the genus is possible and has been observed. Four distinct spp. isolates taken from the throats of two human volunteers have been assessed here using a combination of microbiological and bioinformatics techniques. Three of the isolates have been identified as biovar and one as . Specific gene clusters have been identified within these commensal isolate genome sequences that are believed to encode a Type VI Secretion System, a newly identified CRISPR system, a Type IV Secretion System unlike that in other spp., a hemin transporter, and a haem acquisition and utilization system. This investigation is the first to investigate these systems in either the non-pathogenic or pathogenic spp. In addition, the biovar possess previously unreported capsule loci and sequences have been identified in all four isolates that are similar to genes seen within the pathogens that are associated with virulence. These data from the four commensal isolates provide further evidence for a spp. gene pool and highlight the presence of systems within the commensals with functions still to be explored