The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity

The entrepreneurial marketing management and commercialization arrangements of born-global bio-enterprises: the case of UK companies

Born global bio-enterprises are a unique “breed” of relatively small biotechnology enterprises operating in multiple countries. The companies are nimble and seemingly well-prepared for challenges that ephemeral markets such as the internationalised biotechnology sector brings. The international marketing management challenges they encounter appear to stimulate their entrepreneurial marketing and commercialisation instincts. Surprisingly, there is a dearth of studies that examine their entrepreneurial predispositions. As such, this study is an attempt to explain their entrepreneurial tendencies by investigating the marketing and commercialisation strategies adopted by born global bio-enterprises in the UK’s biotechnology industry. The study assumes a multi-case approach examining five archetypical born global bio-enterprises currently active in the UK. It contributes to the international entrepreneurship and marketing management literature. Specifically, it provides international business managers with new knowledge about various marketing manoeuvres they can apply in international networks for their marketing mileage. In doing so, the study proposes a theoretical framework mapping out entrepreneurial marketing and commercialisation arrangements in internationalised biotechnology markets. Its findings are useful to various stakeholders including: policy makers, managers of technology-based companies and business management researchers

A population of naive-like CD4(+) T cells stably polarized to the T(H)1 lineage

T-bet is the lineage-specifying transcription factor for CD4+ TH1 cells. T-bet has also been found in other CD4+ T cell subsets, including TH17 cells and Treg, where it modulates their functional characteristics. However, we lack information on when and where T-bet is expressed during T cell differentiation and how this impacts T cell differentiation and function. To address this, we traced the ontogeny of T-bet-expressing cells using a fluorescent fate-mapping mouse line. We demonstrate that T-bet is expressed in a subset of CD4+ T cells that have naïve cell surface markers and transcriptional profile and that this novel cell population is phenotypically and functionally distinct from previously described populations of naïve and memory CD4+ T cells. Naïve-like T-bet-experienced cells are polarized to the TH1 lineage, predisposed to produce IFN-γ upon cell activation, and resist repolarization to other lineages in vitro and in vivo. These results demonstrate that lineage-specifying factors can polarize T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T-helper response

Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022

HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting

Continuous Glucose Monitoring and Exercise in Type 1 Diabetes: Past, Present and Future

Prior to the widespread use of continuous glucose monitoring (CGM), knowledge of the effects of exercise in type 1 diabetes (T1D) was limited to the exercise period, with few studies having the budget or capacity to monitor participants overnight. Recently, CGM has become a staple of many exercise studies, allowing researchers to observe the otherwise elusive late post-exercise period. We performed a strategic search using PubMed and Academic Search Complete. Studies were included if they involved adults with T1D performing exercise or physical activity, had a sample size greater than 5, and involved the use of CGM. Upon completion of the search protocol, 26 articles were reviewed for inclusion. While outcomes have been variable, CGM use in exercise studies has allowed the assessment of post-exercise (especially nocturnal) trends for different exercise modalities in individuals with T1D. Sensor accuracy is currently considered adequate for exercise, which has been crucial to developing closed-loop and artificial pancreas systems. Until these systems are perfected, CGM continues to provide information about late post-exercise responses, to assist T1D patients in managing their glucose, and to be useful as a tool for teaching individuals with T1D about exercise

Reducing misinformation effects in older adults with cognitive interview mnemonics

We examined the effect of a prior Modified Cognitive Interview on young and older adults’ recall of a short film of a staged crime and subsequent reporting of misinformation. Participants viewed the film followed the next day by misinformation presented in a postevent summary. They were then interviewed with either a Modified Cognitive Interview or a control interview followed by a recognition memory test. A Modified Cognitive Interview elicited more correct details and improved overall accuracy compared to a control interview in both age groups, although the young adults recollected three times more correct information in a Modified Cognitive Interview than the older adults. In both age groups, correct recollections of person and action details were higher in a Modified Cognitive Interview than a control interview. Importantly, older adults who were interviewed with a Modified Cognitive Interview were not susceptible to misinformation effects