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"Willis, Christine"
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Piper Reed, rodeo star
After bidding goodbye to her friends Michael and Nicole, who are moving away, Piper and her sisters spend winter break with their two sets of grandparents in Piney Woods, Louisiana, where Piper learns that the best adventures are the unexpected ones.
Book
ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease
Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer’s disease (AD). The classical renin–angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13–14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ
42
and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9–10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12–13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.
Journal Article
Piper Reed, clubhouse queen
While her father, a Navy Chief, is on ship duty for six months, nine-year-old Piper stays busy with new neighbors, Christmas at a spaceship beach house, a trip to New Orleans, and especially the upcoming Gypsy Club pet show.
Book
Strobilurin biosynthesis in Basidiomycete fungi
Strobilurins from fungi are the inspiration for the creation of the β-methoxyacrylate class of agricultural fungicides. However, molecular details of the biosynthesis of strobilurins have remained cryptic. Here we report the sequence of genomes of two fungi that produce strobilurins and show that each contains a biosynthetic gene cluster, which encodes a highly reducing polyketide synthase with very unusual C-terminal hydrolase and methyltransferase domains. Expression of
stpks1
in
Aspergillus oryzae
leads to the production of prestrobilurin A when the fermentation is supplemented with a benzoyl coenzyme A (CoA) analogue. This enables the discovery of a previously unobserved route to benzoyl CoA. Reconstruction of the gene cluster in
A. oryzae
leads to the formation of prestrobilurin A, and addition of the gene
str9
encoding an FAD-dependent oxygenase leads to the key oxidative rearrangement responsible for the creation of the β-methoxyacrylate toxophore. Finally, two methyltransferases are required to complete the synthesis.
Strobilurins are fungal metabolites that inspired the creation of β-methoxyacrylate agricultural fungicides. Here, Nofiani et al. identify the strobilurin biosynthesis gene cluster, encoding a polyketide synthase as well as an FAD-dependent oxygenase for an oxidative rearrangement leading to β-methoxyacrylate formation.
Journal Article
Piper Reed, forever friend
Ten-year-old Piper moves yet again when her father, who is a Chief Petty Officer in the Navy, gets assigned to Norfolk, Virginia, and although the move takes a bit of adjustment, she soon makes friends with the girl next door and catches up with old friends too.
Book
Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives
The rise in antibiotic resistance is a major threat for human health. Basidiomycete fungi represent an untapped source of underexploited antimicrobials, with pleuromutilin—a diterpene produced by
Clitopilus passeckerianus
—being the only antibiotic from these fungi leading to commercial derivatives. Here we report genetic characterisation of the steps involved in pleuromutilin biosynthesis, through rational heterologous expression in
Aspergillus oryzae
coupled with isolation and detailed structural elucidation of the pathway intermediates by spectroscopic methods and comparison with synthetic standards.
A. oryzae
was further established as a platform for bio-conversion of chemically modified analogues of pleuromutilin intermediates, and was employed to generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity. These studies pave the way for future characterisation of biosynthetic pathways of other basidiomycete natural products in ascomycete heterologous hosts, and open up new possibilities of further chemical modification for the growing class of potent pleuromutilin antibiotics.
Pleuromutilin derivatives are potent antibacterial drugs obtained from Basidiomycete fungi. Here, the authors report the genetic characterisation of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity.
Journal Article
Piper Reed, Navy brat
Piper's sad about leaving her home and friends behind when her father, a Navy aircraft mechanic, is transferred again, but with help from her often-annoying sisters and a surprise from their parents, she finds happiness in their new home in Pensacola, Florida.
Book
Genetic engineering of Sorangium cellulosum reveals hidden enzymology in myxobacterial natural product biosynthesis
Sorangium cellulosum
is a cellulolytic myxobacterium that produces a vast array of complex natural products with diverse chemical scaffolds and biological activities. However, biosynthetic investigations of these metabolites have been hindered by the scarcity of genetic manipulation tools available for their producing microorganisms. Here, we develop an efficient electroporation method for transforming foreign DNA into various
Sorangium
strains, enabling effective genetic engineering via homologous recombination. This facilitates delineation of the biosynthetic pathway to ambruticin, unveiling several previously undisclosed steps. Notably, AmbK is identified as the elusive epoxide hydrolase responsible for the formation of the tetrahydropyran ring during post-polyketide synthase (PKS) modification, while the terminal PKS module AmbH is shown to catalyse dual rounds of chain elongation during polyketide assembly. Our findings provide significant insights into the intricate molecular machinery governing myxobacterial natural product biosynthesis and greatly enhance our ability to further engineer
Sorangium
strains to unlock their biosynthetic potentials.
Myxobacteria, particularly Sorangium strains, are rich sources of bioactive natural products but are challenging to genetically engineer. Here, the authors present an efficient electroporation method for multiple Sorangium strains and reveal a revised model of ambruticin biosynthesis.
Journal Article
Piper Reed, party planner
When she discovers the price of the clubhouse she covets, ten-year-old Piper and her fellow Gypsy Club members try to earn the money by creating a birthday-party-planning business.
Book
Resistance to and synthesis of the antibiotic mupirocin
Key Points
The spread of methicillin-resistant
Staphylococcus aureus
(MRSA) necessitates the development of new antibiotics.
The control of mupirocin production in soil bacteria is in proportion to bacterial cell density.
Mupirocin inhibits isoleucyl-tRNA synthetase, and spontaneous mupirocin-resistant mutants are generally less fit than wild-type bacteria.
Mupirocin can be used topically but not systemically owing to its rapid hydrolysis.
Mupirocin is made by a complex polyketide biosynthetic pathway.
Engineering mupirocin production
in vivo
or producing it by chemical synthesis could enable the production of new derivatives, the biological activity of which could then be explored.
Mupirocin is a polyketide antibiotic produced by
Pseudomonas fluorescens
that is used to control the carriage of methicillin-resistant
Staphylococcus aureus
. Here, Thomas and colleagues describe the mechanisms underlying the mode of action and biosynthesis of mupirocin and discuss how this understanding could lead to the development of novel antibiotics.
Mupirocin, a polyketide antibiotic produced by
Pseudomonas fluorescens
, is used to control the carriage of methicillin-resistant
Staphylococcus aureus
on skin and in nasal passages as well as for various skin infections. Low-level resistance to the antibiotic arises by mutation of the mupirocin target, isoleucyl-tRNA synthetase, whereas high-level resistance is due to the presence of an isoleucyl-tRNA synthetase with many similarities to eukaryotic enzymes. Mupirocin biosynthesis is carried out by a combination of type I multifunctional polyketide synthases and tailoring enzymes encoded in a 75 kb gene cluster. Chemical synthesis has also been achieved. This knowledge should allow the synthesis of new and modified antibiotics for the future.
Journal Article