Organizational Agility through Project Portfolio Management

In dynamic environments, organizational agility is essential for survival; organizations must be able to adapt to change in order to succeed. In project-based organizations, a dynamic project portfolio management (PPM) capability can enhance organizational agility. PPM is an important organizational capability that enables organizations to manage and balance the portfolio holistically, to align projects with strategy, and to ensure adequate resourcing for projects in order to maximize the benefits from project investments. A dynamic PPM capability enables organizations to be agile and flexible by facilitating adjustments to the project portfolio and reallocating resources in response to the changes in the environment. In order for the PPM capability to remain relevant, it must evolve to reflect changes in the environment. Examples of aspects of PPM that enhance organizational agility are outlined in this paper to provide guidance for practitioners

Cellular iron governs the host response to malaria

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria

First report of mitochondrial COI in foraminifera and implications for DNA barcoding

Foraminifera are a species-rich phylum of rhizarian protists that are highly abundant in many marine environments and play a major role in global carbon cycling. Species recognition in Foraminifera is mainly based on morphological characters and nuclear 18S ribosomal RNA barcoding. The 18S rRNA contains variable sequence regions that allow for the identification of most foraminiferal species. Still, some species show limited variability, while others contain high levels of intragenomic polymorphisms, thereby complicating species identification. The use of additional, easily obtainable molecular markers other than 18S rRNA will enable more detailed investigation of evolutionary history, population genetics and speciation in Foraminifera. Here we present the first mitochondrial cytochrome c oxidase subunit 1 (COI) gene sequences ("barcodes") of Foraminifera. We applied shotgun sequencing to single foraminiferal specimens, assembled COI, and developed primers that allow amplification of COI in a wide range of foraminiferal species. We obtained COI sequences of 49 specimens from 17 species from the orders Rotaliida and Miliolida. Phylogenetic analysis showed that the COI tree is largely congruent with previously published 18S rRNA phylogenies. Furthermore, species delimitation with ASAP and ABGD algorithms showed that foraminiferal species can be identified based on COI barcodes.Microbial BiotechnologyNaturali

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

High-quality Extragalactic Legacy-field Monitoring (HELM) with DECam : project overview and first data release

Funding: This work is supported by NSF grants AST-2206499 and AST-2308077. R.J.A. was supported by FONDECYT grant No. 1231718 and by the ANID BASAL project FB210003. F.E.B. acknowledges support from ANID—Millennium Science Initiative Program —ICN12_009, CATA-BASAL—FB210003, and FONDECYT Regular—1200495. Y.Q.X. acknowledges support from the National Key R&D Program of China (2023YFA1608100), NSFC grants (12025303, 12393814), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0550300).High-quality Extragalactic Legacy-field Monitoring (HELM) is a long-term observing program that photometrically monitors several well-studied extragalactic legacy fields with the Dark Energy Camera (DECam) imager on the CTIO 4 m Blanco telescope. Since 2019 February, HELM has been monitoring regions within COSMOS, XMM-LSS, CDF-S, S-CVZ, ELAIS-S1, and SDSS Stripe 82 with few-day cadences in the (u)gri(z) bands, over a collective sky area of ∼38 deg2. The main science goal of HELM is to provide high-quality optical light curves for a large sample of active galactic nuclei (AGNs), and to build decades-long time baselines when combining past and future optical light curves in these legacy fields. These optical images and light curves will facilitate the measurements of AGN reverberation mapping lags, as well as studies of AGN variability and its dependencies on accretion properties. In addition, the time-resolved and coadded DECam photometry will enable a broad range of science applications from galaxy evolution to time-domain science. We describe the design and implementation of the program and present the first data release that includes source catalogs and the first ∼3.5 yr of light curves during 2019A–2022A.Peer reviewe

Online Stakeholder Interactions in the Early Stage of a Megaproject

The purpose of this paper is to examine the network structure of online stakeholder discussions in the planning stage of a UK public mega project, High Speed Rail. By providing new rail connections between London, Birmingham and Manchester, this project is highly complex as it is embedded in a network of stakeholder relationships that may support or oppose the project. Data drawn from Twitter was analyzed using Social Network Analysis and inductive analysis of user profiles and content. Findings indicate that the majority of online stakeholders oppose the project and form stable clusters. Larger clusters within this network may attempt to deploy power directly in the form of a manipulation strategy while smaller clusters may seek to ally themselves with more powerful groups, a pathway strategy. Overall, the methodology is a useful complement to existing methods and may provide real time insights into the complex, evolving discussions around mega projects

Dopaminergic D1 receptor signalling is necessary, but not sufficient for cued fear memory destabilisation

Rationale. Pharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation. Objectives. Here, we aimed to determine the functional involvement of dopamine D1 receptors in cued fear memory destabilisation, using systemic drug administration. Results. We observed that direct D1 receptor agonism was not sufficient to stimulate tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Instead, administration of the nootropic nefiracetam did facilitate mifepristone-induced amnesia, in a manner that was dependent upon dopamine D1 receptor activation, although. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters. Conclusions. The use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear

An interactome-centered protein discovery approach reveals novel components involved in mitosome function and homeostasis in giardia lamblia

Protozoan parasites of the genus Giardia are highly prevalent globally, and infect a wide range of vertebrate hosts including humans, with proliferation and pathology restricted to the small intestine. This narrow ecological specialization entailed extensive structural and functional adaptations during host-parasite co-evolution. An example is the streamlined mitosomal proteome with iron-sulphur protein maturation as the only biochemical pathway clearly associated with this organelle. Here, we applied techniques in microscopy and protein biochemistry to investigate the mitosomal membrane proteome in association to mitosome homeostasis. Live cell imaging revealed a highly immobilized array of 30–40 physically distinct mitosome organelles in trophozoites. We provide direct evidence for the single giardial dynamin-related protein as a contributor to mitosomal morphogenesis and homeostasis. To overcome inherent limitations that have hitherto severely hampered the characterization of these unique organelles we applied a novel interaction-based proteome discovery strategy using forward and reverse protein co-immunoprecipitation. This allowed generation of organelle proteome data strictly in a protein-protein interaction context. We built an initial Tom40-centered outer membrane interactome by co-immunoprecipitation experiments, identifying small GTPases, factors with dual mitosome and endoplasmic reticulum (ER) distribution, as well as novel matrix proteins. Through iterative expansion of this protein-protein interaction network, we were able to i) significantly extend this interaction-based mitosomal proteome to include other membrane-associated proteins with possible roles in mitosome morphogenesis and connection to other subcellular compartments, and ii) identify novel matrix proteins which may shed light on mitosome-associated metabolic functions other than Fe-S cluster biogenesis. Functional analysis also revealed conceptual conservation of protein translocation despite the massive divergence and reduction of protein import machinery in Giardia mitosomes