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Sometimes unanticipated threats or opportunities create a situation in which work is required unexpectedly. On these occasions, such urgent and unexpected work demands an instant start, in contrast to the often lengthy processes of investigation, evaluation, development, selection and planning normal in businesses and public services before the start of a project. Managing the Urgent and Unexpected explores what is different managerially if work is unexpected, its implementation is urgent and an immediate start it is required. The authors draw on twelve cases ranging from the launch of the Freeview television system in the United Kingdom to the sifting and removal of the New York World Trade Center pile of debris following the 9/11 terrorist attack. They summarise how the response to each of these events was managed, demonstrate that opportunities may sometimes be created in the face of adversity and suggest how normal organizations can prepare to manage abnormal demands. Urgent and unexpected projects have to be rare in business or government to be economically and socially tolerable. And yet organizations can and should be prepared for the unexpected. The lessons offered here will help private and public organizations plan how to authorize and support future urgent work to take advantage of immediate new business opportunities or to protect or restore systems and services.

Sebaceous free fatty acids are metabolized by multiple skin microbes into bioactive lipid mediators termed oxylipins. This study investigated correlations between skin oxylipins and microbes on the superficial skin of pre-pubescent children ( N  = 36) and adults ( N  = 100), including pre- ( N  = 25) and post-menopausal females ( N  = 25). Lipidomics and metagenomics revealed that Malassezia restricta positively correlated with the oxylipin 9,10-DiHOME on adult skin and negatively correlated with its precursor, 9,10-EpOME, on pre-pubescent skin. Co-culturing Malassezia with keratinocytes demonstrated a link between 9,10-DiHOME and pro-inflammatory cytokines IL-1β and IL-6 production. We also observed strong correlations between other skin oxylipins and microbial taxa, highlighting life stage differences in sebum production and microbial community composition. Our findings imply a complex host-microbe communication system mediated by lipid metabolism occurring on human skin, warranting further research into its role in skin health and disease and paving the way towards novel therapeutic targets and treatments.

Diabetes is rapidly becoming a global epidemic, with the International Diabetes Federation noting that close to 9% of the global adult population suffers from the disorder. Over the past few decades, work has begun to combat this as many protocols have been developed to in vitro differentiate viable pancreatic cells for cell therapy. However, this process is currently not cost effective and other avenues for production may be optimal. Transdifferentiation is one such avenue, as overexpression of key transcription factors can shift an initial cell type toward that of a target cell type. Here transdifferentiation was employed to generate pancreatic progenitors, which could express markers from all key lineages of the pancreas. Specific transcription factors used for this process were determined by two powerful and pioneering bioinformatic analyses, Lineage-guided Principle Component Analysis (LgPCA) and Mogrify. LgPCA investigation was undertaken to deduce the most potent transcription factors from this novel genome-wide analysis of 19,362 genes. Mogrify complemented this data set with transdifferentiation specific factors. The combination of which provided a highly optimised cohort of genes to study. A comprehensive study of known regulatory networks in mouse and human pancreas development was combined with expression profiling during the in vitro differentiation of human embryonic stem cells (hESCs) to early pancreatic beta-cells. Having selected a prioritised cohort of 8 transcription factors an enhanced adeno-associated viruses (AAVs) generation protocol was developed for their delivery into cells in vitro. Transcription factors were applied to human fetal fibroblasts to assess their capacity to induce transdifferentiation toward pancreatic progenitors. This was evaluated by gene expression profiling, including the expression of the endogenous genes encoding the transduced factors. This approach identified the best trio of transcription factors for transdifferentiation toward the phenotype of pancreatic progenitor. While further optimisation is needed, including in vivo transplantation, the data indicates that cell phenotype can be reproducibly altered for at least 1-2 weeks by the transduction of a very limited set of transcription factors. The conclusion is that transdifferentiation could offer a viable route to the ultimate large-scale production of insulin-secreting beta-cells from fibroblasts.

Sometimes unanticipated threats or opportunities create a situation in which work is required unexpectedly. On these occasions, such urgent and unexpected work demands an instant start, in contrast to the often lengthy processes of investigation, evaluation, development, selection and planning normal in businesses and public services before the start of a project. Managing the Urgent and Unexpected explores what is different managerially if work is unexpected, its implementation is urgent and an immediate start it is required. The authors draw on twelve cases ranging from the launch of the Freeview television system in the United Kingdom to the sifting and removal of the New York World Trade Center pile of debris following the 9/11 terrorist attack. They summarise how the response to each of these events was managed, demonstrate that opportunities may sometimes be created in the face of adversity and suggest how normal organizations can prepare to manage abnormal demands. Urgent and unexpected projects have to be rare in business or government to be economically and socially tolerable. And yet organizations can and should be prepared for the unexpected. The lessons offered here will help private and public organizations plan how to authorize and support future urgent work to take advantage of immediate new business opportunities or to protect or restore systems and services

The skin microbiome plays an important role in immune homeostasis and skin health, and yet our understanding of in vivo microbial gene activity is hindered by the lack of a robust, non-invasive protocol for metatranscriptomics across skin sites. Circumventing the challenges of low microbial biomass, host contamination, and RNA stability, we developed a clinically tractable skin metatranscriptomics workflow that provides high technical reproducibility of profiles (Pearson r>0.95), uniform coverage across gene bodies, and strong enrichment of microbial mRNAs (2.5-40x;). Applying this protocol to a cohort of healthy adults (n=27) across five different skin sites (n=102, paired metatranscriptomes and metagenomes), identified a striking divergence between transcriptomic and genomic abundances, with Staphylococcus species and the skin fungi Malassezia having an outsized contribution to the metatranscriptomic landscape at most sites despite their modest representation in metagenomes. Species-level analysis showed skin site-specific enrichment of gene expression (e.g. increased levels of secreted fungal phospholipase C on cheeks relative to scalp), and revealed how key pathways were transcriptionally active in vivo (e.g. propionate and 4-aminobutyrate metabolism, potentially impacting skin barrier function). Gene-level analysis identified diverse antimicrobial genes transcribed by skin commensals in situ, including several uncharacterized bacteriocins, some of which are expressed at levels comparable to known antimicrobial genes. Correlation of microbial gene expression with organismal abundances uncovered >20 genes that putatively mediate interactions between microbes (e.g. a secreted Malassezia restricta protein with strongly negative in vivo association with Cutibacterium acnes; Spearman Rho>0.7). This work showcases the potential for leveraging skin metatranscriptomics to identify microbes whose activities play an outsized role in the community, and for uncovering pivotal microbial pathways and biomarkers linked to skin health and disease.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://figshare.com/projects/Skin_metatranscriptomics_manuscript_2024/202683