Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation

ACKNOWLEDGMENTS We acknowledge Jennifer Lodge, Woei Lam, and Rajendra Upadhya for developing and sharing the chitin and chitosan MTBH assay. We thank Todd Brennan of Duke University for providing MyD88-deficient mice. We acknowledge Neil Gow for providing access to the Dionex HPAEC-PAD instrumentation. We also acknowledge Connie Nichols for critical reading of the manuscript. These experiments were supported by an NIH grant to J.A.A. and F.L.W., Jr. (R01 AI074677). C.M.L.W. was supported by a fellowship provided through the Army Research Office of the Department of Defense (no. W911NF-11-1-0136 f) (F.L.W., Jr.). J.W., L.W., and C.M. were supported by the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377) and the MRC, Centre for Medical Mycology (MR/N006364/1). FUNDING INFORMATION MRC Centre for Medical MycologyMR/N006364/1 Carol A. Munro HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) https://doi.org/10.13039/100000060R01 AI074677J. Andrew Alspaugh Wellcome https://doi.org/10.13039/100010269097377 Carol A. Munro DOD | United States Army | RDECOM | Army Research Office (ARO) https://doi.org/10.13039/100000183W911NF-11-1-0136 f Chrissy M. Leopold WagerPeer reviewe

A Cultural Comparison of the ''Dark Constellations'' in the Milky Way

Cultures around the world find meaning in the groupings of stars and features in the Milky Way. The striking appearance of our Galaxy in the night sky serves as a reference to traditional knowledge, encoding science and culture to a memory space, becoming part of their overarching cosmologies. This paper examines traditional views of the Milky Way from cultures around the world, primarily in the Southern Hemisphere. These views comprise dark constellations: familiar shapes made up of the dark dust lanes in the Milky Way, rather than the bright stars. Some of the better-known examples include the celestial emu from Aboriginal traditions of Australia, and the llama in Inca traditions of the Andes. We conduct a comparative analysis of cultural perceptions of ‘dark constellations’ in the Milky Way, examining common cultural themes and meanings at the crossroads of Indigenous Knowledge and Western science with applications to topics ranging from Indigenous Studies to psychology.Fil: Gullberg, Steven R.. Oklahoma State University; Estados UnidosFil: Hamacher, Duane. University of Melbourne; AustraliaFil: Lopez, Alejandro Martin. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas. Sección de Etnología y Etnografía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mejuto, Javier. Universidad Nacional Autónoma de Honduras; HondurasFil: Munro, Andrew M.. University of Oklahoma; Estados UnidosFil: Orchiston, Wayne. University of Southern Queensland; Australia. National Astronomical Research Institute of Thailand; Tailandi

Quantum optical microcombs

A key challenge for quantum science and technology is to realize large-scale, precisely controllable, practical systems for non-classical secured communications, metrology and, ultimately, meaningful quantum simulation and computation. Optical frequency combs represent a powerful approach towards this goal, as they provide a very high number of temporal and frequency modes that can result in large-scale quantum systems. The generation and control of quantum optical frequency combs will enable a unique, practical and scalable framework for quantum signal and information processing. Here, we review recent progress on the realization of energy–time entangled optical frequency combs and discuss how photonic integration and the use of fibre-optic telecommunications components can enable quantum state control with new functionalities, yielding unprecedented capability

Partial change in EphA4 knockout mouse phenotype: Loss of diminished GFAP upregulation following spinal cord injury

In a previous study we found that the EphA4 receptor inhibits regeneration following spinal cord injury by blocking regrowth of axons and regulation of astrocyte reactivity. In our original studies using EphA4 null mice [Goldshmit et al., J. Neurosci., 2004] we found attenuated astrocyte reactivity following spinal cord injury. Several other studies have now supported the role of EphA4 in regulating neural regeneration but a recent study [Herrmann et al., Exp. Neurol., 2010] did not find an effect of EphA4 on astrocyte reactivity. Re-examination of astrocytic gliosis following injury in our current cohort of EphA4 null mice revealed that they no longer showed attenuation of astrocyte reactivity, however other EphA4 null mouse phenotypes, such as decreased size of the dorsal funiculus were unaltered. We hypothesised that long-term breeding on the C57Bl/6 background may influence the EphA4-mediated astrocyte phenotype and compared astrocytic gliosis at 4 days following spinal cord injury in wildtype and EphA4 null mice on the C57Bl/6 background and backcrossed C57Bl/6×129Sv(F2) mice, as well as wildtype 129Sv mice. 129Sv mice had increased GFAP expression and increased numbers of reactive GFAP astrocytes compared to C57Bl/6 mice. There was no significant effect of EphA4 deletion on GFAP expression in C57Bl/6 mice or the F2 crosses other than a moderately decreased number of EphA4 null astrocytes in C57Bl/6 mice using one of two antibodies. Therefore, there has been an apparent change in EphA4-mediated astroglial phenotype associated with long term breeding of the EphA4 colony but it does not appear to be influenced by background mouse strain

A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in Pharmaceutical Metabolism

CYP102A1 (BM3) is a catalytically self-sufficient flavocytochrome fusion protein isolated from Bacillus megaterium, which displays similar metabolic capabilities to many drug-metabolizing human P450 isoforms. BM3′s high catalytic efficiency, ease of production and malleable active site makes the enzyme a desirable tool in the production of small molecule metabolites, especially for compounds that exhibit drug-like chemical properties. The engineering of select key residues within the BM3 active site vastly expands the catalytic repertoire, generating variants which can perform a range of modifications. This provides an attractive alternative route to the production of valuable compounds that are often laborious to synthesize via traditional organic means. Exten-sive studies have been conducted with the aim of engineering BM3 to expand metabolite pro-duction towards a comprehensive range of drug-like compounds, with many key examples found both in the literature and in the wider industrial bioproduction setting of desirable oxy-metabolite production by both wild-type BM3 and related variants. This review covers the past and current research on the engineering of BM3 to produce drug metabolites and highlights its crucial role in the future of biosynthetic pharmaceutical production

Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1

The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a C-C crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25 μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KD = 1.6 μM; tBu KD = 1.2 μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding

Are quasars accreting at super-Eddington rates?

In a previous paper, Collin & Hur\'e (2001), using a sample of Active Galactic Nuclei (AGN) where the mass has been determined by reverberation studies (Kaspi et al. 2000), have shown that if the optical luminosity is emitted by a steady accretion disc, about half of the objects are accreting close to or higher than the Eddington rate. We conclude here that this result is unavoidable, unless the masses are strongly underestimated by reverberation studies, which does not seem to be the case. There are three issues to the problem: 1. Accretion proceeds at Eddington or super-Eddington rates through thick discs. Several consequences follow: an anti-correlation between the line widths of the lines and the Eddington ratios, and a decrease of the Eddington ratio with an increasing black hole mass. Extrapolated to all quasars, these results imply that the amount of mass locked in massive black holes should be larger than presently thought. 2. The optical luminosity is not produced directly by the gravitational release of energy, and super-Eddington rates are not required. The optical luminosity has to be emitted by a dense and thick medium located at large distances from the center (10$^3$ to $10^4$ gravitational radii). It can be due to reprocessing of the X-ray photons from the central source in a geometrically thin warped disc, or in dense "blobs" forming a geometrically thick system, which can be a part of the accretion flow or the basis of an outflow. 3. Accretion discs are completely "non standard". Presently neither the predictions of models nor the observed spectral distributions are sufficient to help choosing between these solutions.Comment: 16 pages, 11 figures, accepted in A&

A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in Pharmaceutical Metabolism

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-12, pub-electronic 2021-10-21Publication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Grant(s): BB/M011208/1CYP102A1 (BM3) is a catalytically self-sufficient flavocytochrome fusion protein isolated from Bacillus megaterium, which displays similar metabolic capabilities to many drug-metabolizing human P450 isoforms. BM3′s high catalytic efficiency, ease of production and malleable active site makes the enzyme a desirable tool in the production of small molecule metabolites, especially for compounds that exhibit drug-like chemical properties. The engineering of select key residues within the BM3 active site vastly expands the catalytic repertoire, generating variants which can perform a range of modifications. This provides an attractive alternative route to the production of valuable compounds that are often laborious to synthesize via traditional organic means. Extensive studies have been conducted with the aim of engineering BM3 to expand metabolite production towards a comprehensive range of drug-like compounds, with many key examples found both in the literature and in the wider industrial bioproduction setting of desirable oxy-metabolite production by both wild-type BM3 and related variants. This review covers the past and current research on the engineering of BM3 to produce drug metabolites and highlights its crucial role in the future of biosynthetic pharmaceutical production