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Understanding Maple
\"Maple is a powerful symbolic computation system that is widely used in universities around the world. This short introduction gives readers an insight into the rules that control how the system works, and how to understand, fix, and avoid common problems. Topics covered include algebra, calculus, linear algebra, graphics, programming, and procedures. Each chapter contains numerous illustrative examples, using mathematics that does not extend beyond first-year undergraduate material. Maple worksheets containing these examples are available for download from the author's personal website. The book is suitable for new users, but where advanced topics are central to understanding Maple they are tackled head-on. Many concepts which are absent from introductory books and manuals are described in detail. With this book, students, teachers, and researchers will gain a solid understanding of Maple and how to use it to solve complex mathematical problems in a simple and efficient way.\"-- Provided by publisher.
Book
Opportunities and challenges in the diagnostic utility of dermal interstitial fluid
The volume of interstitial fluid (ISF) in the human body is three times that of blood. Yet, collecting diagnostically useful ISF is more challenging than collecting blood because the extraction of dermal ISF disrupts the delicate balance of pressure between ISF, blood and lymph, and because the triggered local inflammation further skews the concentrations of many analytes in the extracted fluid. In this Perspective, we overview the most meaningful differences in the make-up of ISF and blood, and discuss why ISF cannot be viewed generally as a diagnostically useful proxy for blood. We also argue that continuous sensing of small-molecule analytes in dermal ISF via rapid assays compatible with nanolitre sample volumes or via miniaturized sensors inserted into the dermis can offer clinically advantageous utility, particularly for the monitoring of therapeutic drugs and of the status of the immune system.
This Perspective argues that dermal interstitial fluid cannot be generally considered a diagnostically useful proxy for blood, yet that it can offer advantageous utility for the monitoring of therapeutic drugs and of the status of the immune system.
Journal Article
The cinema of Oliver Stone : art, authorship and activism
This book analyses the work of Oliver Stone - arguably one of the foremost political filmmakers in Hollywood during the last thirty years. From early productions like Platoon (1986) and Wall Street (1987) to contemporary dramas and documentaries such as World Trade Center (2006), Wall Street: Money Never Sleeps (2010) and The Untold History of the United States (2012) Stone has re-defined political filmmaking in an era when Hollywood and the United States in general has been experiencing rapid and radical change. Drawing on previously unseen production files as well as hours of interviews with the director and his associates within the industry, this book is a thematic exploration of Stone's life and work, charting the development of political and aesthetic changes in his filmmaking. Those changes are mapped onto academic debates about the relationship between film and history as well as wider critiques about Hollywood and the film industry.
BOOK
Rational design of aptamer switches with programmable pH response
Aptamer switches that respond sensitively to pH could enhance control over molecular devices, improving their diagnostic and therapeutic efficacy. Previous designs have inserted pH-sensitive DNA motifs into aptamer sequences. Unfortunately, their performance was limited by the motifs’ intrinsic pH-responses and could not be tuned to operate across arbitrary pH ranges. Here, we present a methodology for converting virtually any aptamer into a molecular switch with pH-selective binding properties — in acidic, neutral, or alkaline conditions. Our design inserts two orthogonal motifs that can be manipulated in parallel to tune pH-sensitivity without altering the aptamer sequence itself. From a single ATP aptamer, we engineer pH-controlled target binding under diverse conditions, achieving pH-induced selectivity in affinity of up to 1,000-fold. Importantly, we demonstrate the design of tightly regulated aptamers with strong target affinity over only a narrow pH range. Our approach offers a highly generalizable strategy for integrating pH-responsiveness into molecular devices.
Previous design strategies for pH sensitive aptamers were not readily tunable across pH ranges. Here the authors present a general method to convert aptamers into pH-responsive switches using two orthogonal motifs.
Journal Article
A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial
MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.
We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.
Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.
Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.
National Institutes of Health and National Cancer Institute.
Journal Article
Independent control of the thermodynamic and kinetic properties of aptamer switches
Molecular switches that change their conformation upon target binding offer powerful capabilities for biotechnology and synthetic biology. Aptamers are useful as molecular switches because they offer excellent binding properties, undergo reversible folding, and can be engineered into many nanostructures. Unfortunately, the thermodynamic and kinetic properties of the aptamer switches developed to date are intrinsically coupled, such that high temporal resolution can only be achieved at the cost of lower sensitivity or high background. Here, we describe a design strategy that decouples and enables independent control over the thermodynamics and kinetics of aptamer switches. Starting from a single aptamer, we create an array of aptamer switches with effective dissociation constants ranging from 10 μM to 40 mM and binding kinetics ranging from 170 ms to 3 s. Our strategy is broadly applicable to other aptamers, enabling the development of switches suitable for a diverse range of biotechnology applications.
Aptamer switches are promising biotechnological tools but coupling of their affinity and temporal response limits their versatility. Here, the authors developed an intramolecular strand-displacement strategy that allows for independent fine-tuning of thermodynamics and kinetics of aptamer switches.
Journal Article
Ecological countermeasures to prevent pathogen spillover and subsequent pandemics
Substantial global attention is focused on how to reduce the risk of future pandemics. Reducing this risk requires investment in prevention, preparedness, and response. Although preparedness and response have received significant focus, prevention, especially the prevention of zoonotic spillover, remains largely absent from global conversations. This oversight is due in part to the lack of a clear definition of prevention and lack of guidance on how to achieve it. To address this gap, we elucidate the mechanisms linking environmental change and zoonotic spillover using spillover of viruses from bats as a case study. We identify ecological interventions that can disrupt these spillover mechanisms and propose policy frameworks for their implementation. Recognizing that pandemics originate in ecological systems, we advocate for integrating ecological approaches alongside biomedical approaches in a comprehensive and balanced pandemic prevention strategy.
In this Perspective, the authors discuss the importance of preventing zoonotic spillover to prevent pandemics. They highlight mechanisms by which environmental changes can enable spillover, identify ecological interventions for spillover prevention and suggest policy frameworks through which interventions can be implemented.
Journal Article
Engineering artificial photosynthesis based on rhodopsin for CO2 fixation
Microbial rhodopsin, a significant contributor to sustaining life through light harvesting, holds untapped potential for carbon fixation. Here, we construct an artificial photosynthesis system which combines the proton-pumping ability of rhodopsin with an extracellular electron uptake mechanism, establishing a pathway to drive photoelectrosynthetic CO
2
fixation by
Ralstonia eutropha
(also known as
Cupriavidus necator
) H16, a facultatively chemolithoautotrophic soil bacterium.
R. eutropha
is engineered to heterologously express an extracellular electron transfer pathway of
Shewanella oneidensis
MR-1 and
Gloeobacter
rhodopsin (GR). Employing GR and the outer-membrane conduit MtrCAB from
S. oneidensis
, extracellular electrons and GR-driven proton motive force are integrated into
R. eutropha
’s native electron transport chain (ETC). Inspired by natural photosynthesis, the photoelectrochemical system splits water to supply electrons to
R. eutropha
via the Mtr outer-membrane route. The light-activated proton pump - GR, supported by canthaxanthin as an antenna, powers ATP synthesis and reverses the ETC to regenerate NADH/NADPH, facilitating
R. eutropha
’s biomass synthesis from CO
2
. Overexpression of a carbonic anhydrase further enhances CO
2
fixation. This artificial photosynthesis system has the potential to advance the development of efficient photosynthesis, redefining our understanding of the ecological role of microbial rhodopsins in nature.
Microbial rhodopsins are major contributors to global light harvesting on Earth, but their role in carbon fixation is unclear. Here, the authors construct an artificial photosynthesis system by combining rhodopsin with an extracellular electron uptake mechanism for photoelectrosynthetic CO
2
fixation in
Ralstonia eutropha
.
Journal Article
Optical coherence tomography angiography characteristics in diabetic patients without clinical diabetic retinopathy
PurposeThe purpose of this study is to measure optical coherence tomography angiography (OCTA)-defined retinal vascular and choriocapillaris parameters in diabetic patients without clinically evident diabetic retinopathy.MethodsRetrospective case series of eyes in patients with a documented history of either type 1 or type 2 diabetes mellitus without any clinical signs of diabetic retinopathy seen at the Vanderbilt Eye Institute. All eyes underwent dilated funduscopic examination along with OCTA. OCTA analytics were performed to calculate vessel density, flow area, and foveal avascular zone size.ResultsThirty-seven eyes of 20 patients were included in the analysis. The mean glycated hemoglobin A1c of the 20 patients was 7.2%. All patients underwent dilated funduscopic examination by a fellowship-trained retina specialist. No patients had any overt retinopathy on clinical examination. Fifteen eyes had vascular abnormalities (microaneurysms) present on OCTA. Patients with microaneurysms and patients without microaneurysms were compared. Vessel density of the 6 × 6 mm macular cube images was significantly increased in patients with microaneurysms compared with patients without microaneurysms. There were no other significant differences in OCTA characteristics.ConclusionOCTA can detect microvascular changes not otherwise noted on dilated clinical examination. These pre-clinical findings may facilitate earlier intervention for improved glycemic control and prevention of the onset of clinical retinopathy.
Journal Article