Systems capable of residing for prolonged periods of time in the gastric cavity have transformed our ability to diagnose and treat patients. Gastric resident systems for drug delivery, ideally need ...to be: ingestible, be able to change shape or swell to ensure prolonged gastric residence, have the mechanical integrity to withstand the forces associated with gastrointestinal motility, be triggerable to address any side effects, and be drug loadable and release drug over a prolonged period of time. Materials that have been primarily utilized for these applications have been largely restricted to thermoplastics and thermosets. Here we describe a novel set of materials, triggerable tough hydrogels, meeting all these requirement, supported by evaluation in a large animal model and ultimately demonstrate the potential of triggerable tough hydrogels to serve as prolonged gastric resident drug depots. Triggerable tough hydrogels may be applied in myriad of applications, including bariatric interventions, drug delivery, and tissue engineering.The use of drug delivery systems for the gastrointestinal tract has been faced with a number of drawbacks related to their prolonged use. Here, the authors develop a drug-loaded hydrogel with high strength to withstand long-term gastrointestinal motility and can be triggered to dissolve on demand.
The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
The first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we present ...crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures reveal that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutations at the KRAS-CRD interface result in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.
Consumption of globally traded agricultural commodities like soy and palm oil is one of the primary causes of deforestation and biodiversity loss in some of the world’s most species-rich ecosystems. ...However, the complexity of global supply chains has confounded efforts to reduce impacts. Companies and governments with sustainability commitments struggle to understand their own sourcing patterns,while the activities of more unscrupulous actors are conveniently masked by the opacity of global trade. We combine state-of-the-art material flow, economic trade, and biodiversity impact models to produce an innovative approach for understanding the impacts of trade on biodiversity loss and the roles of remote markets and actors.We do this for the production of soy in the Brazilian Cerrado, home to more than 5% of the worlds species. Distinct sourcing patterns of consumer countries and trading companies result in substantially different impacts on endemic species. Connections between individual buyers and specific hot spots explain the disproportionate impacts of some actors on endemic species and individual threatened species, such as the particular impact of European Union consumers on the recent habitat losses for the iconic giant anteater (Myrmecophaga tridactyla). In making these linkages explicit, our approach enables commodity buyers and investors to target their efforts much more closely to improve the sustainability of their supply chains in their sourcing regions while also transforming our ability to monitor the impact of such commitments over time.
About the Authors: Shruthi Krishnamurthy Affiliation: Department of Pathology, Microbiology and Immunology, University of California Davis, Davis, California, United States of America ORCID ...http://orcid.org/0000-0003-4540-6613 Eleni K. Konstantinou Affiliation: Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America ORCID http://orcid.org/0000-0002-7155-5770 Lucy H. Young Affiliation: Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America ORCID http://orcid.org/0000-0001-8634-7512 Daniel A. Gold Affiliation: Department of Pathology, Microbiology and Immunology, University of California Davis, Davis, California, United States of America Jeroen P. J. Saeij * E-mail: jsaeij@ucdavis.edu Affiliation: Department of Pathology, Microbiology and Immunology, University of California Davis, Davis, California, United States of America ORCID http://orcid.org/0000-0003-0289-7109Citation: Krishnamurthy S, Konstantinou EK, Young LH, Gold DA, Saeij JPJ (2017) The human immune response to Toxoplasma: Autophagy versus cell death. Humans also lack the multitude of murine immunity-related GTPases (IRGs) that are induced upon IFNgamma stimulation and play a crucial role in the destruction of the membrane surrounding the parasitophorous vacuole (PV) in which Toxoplasma resides in the host cytoplasm. ...the mechanisms involved in the production of IFNgamma in humans (Fig 1) differ from those in mice and the pathways that mediate parasite clearance are less well understood (reviewed in 1). See the main text for explanations. https://doi.org/10.1371/journal.ppat.1006176.g001 IFNgamma-dependent, noncanonical autophagy-mediated clearance of Toxoplasma in humans Autophagy is a degradation process that clears cytoplasmic material such as misfolded proteins and damaged organelles. During autophagy, cytosolic microtubule-associated protein light chain 3 (LC3), a ubiquitin-like protein, is processed and conjugated to the lipid phosphatidylethanolamine (PE)...
The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. ...Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.
This paper describes polymeric nanostructures with dynamically tunable wetting properties. Centimeter‐scale areas of monolithic nanoridges can be generated by strain relief of thermoplastic ...polyolefin films with fluoropolymer skin layers. Changing the amount of strain results in polyolefin ridges with aspect ratios greater than four with controlled feature densities. Surface chemistry and topography are demonstrated to be able to be tailored by SF6‐plasma etching to access multiple wetting states: Wenzel, Cassie–Baxter, and Cassie‐impregnating states. Reversible transitions among the wetting states can be realized in a programmable manner by cyclic stretching and reshrinking the patterned substrates without delamination and cracking.
Centimeter‐scale areas of monolithic nanoridges are generated by strain relief of polyolefin films with fluoropolymer skin layers. SF6‐plasma treatment can tailor the surface chemistry and topography of the nanostructures to access multiple wetting states, including Wenzel, Cassie–Baxter, and Cassie‐impregnating states. Reversible transitions between wetting states can be realized in a programmable manner by stretching and reshrinking the patterned substrate.
Despite their limited spatial extent, freshwater ecosystems host remarkable biodiversity, including one-third of all vertebrate species. This biodiversity is declining dramatically: Globally, ...wetlands are vanishing three times faster than forests, and freshwater vertebrate populations have fallen more than twice as steeply as terrestrial or marine populations. Threats to freshwater biodiversity are well documented but coordinated action to reverse the decline is lacking. We present an Emergency Recovery Plan to bend the curve of freshwater biodiversity loss. Priority actions include accelerating implementation of environmental flows; improving water quality; protecting and restoring critical habitats; managing the exploitation of freshwater ecosystem resources, especially species and riverine aggregates; preventing and controlling nonnative species invasions; and safeguarding and restoring river connectivity. We recommend adjustments to targets and indicators for the Convention on Biological Diversity and the Sustainable Development Goals and roles for national and international state and nonstate actors.
SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein ...and as an effector of MRAS. Here we show that SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.
•SCRIB interacts with SHOC2 and MRAS and links the ERK pathway with cell polarity•MRAS-SHOC2-SCRIB complex provides a paradigm for crosstalk between PP1 holoenzymes•MRAS-SHOC2-SCRIB complex allows for regulation of ERK pathway spatiotemporal dynamics•MRAS-SHOC2-SCRIB complex plays selective role in tumorigenic growth
MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a ...phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and transformation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings. Activating mutations in MRAS (as well as SHOC2 and PP1) do occur in the RASopathy Noonan syndrome, underscoring a key role for MRAS within the RAS-ERK pathway. MRAS also has unique roles in cell migration and differentiation and has properties consistent with a key role in the regulation of cell polarity. Further investigations should shed light on what remains a relatively understudied RAS family member.
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