MULTI-ACTION NITRIC OXIDE-RELEASE SYSTEMS FOR BIOMEDICAL APPLICATIONS

Antibiotic-resistant bacterial infections pose a significant threat to global health. Limitations in treating resistant, biofilm-based, and polymicrobial infections necessitate the development of novel antimicrobial agents that limit the potential for resistance. Nitric oxide (NO), an endogenous signaling molecule, is involved in a host of physiological properties, including the eradication of foreign pathogens. As NO also possesses roles in modulating inflammation, angiogenesis, and thrombosis, it represents an attractive molecule for the multimodal treatment of chronic wound and catheter-based infections. Hyaluronic acid (HA), a biopolymer involved in endogenous wound healing, was modified with a series of alkylamines to store and release NO, with release kinetics dependent upon the alkylamine structure. The NO-releasing HA derivatives exhibited broad-spectrum antibacterial efficacy against a range of wound pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus. The biopolymers also exhibited antibiofilm action against P. aeruginosa biofilms. Nitric oxide-releasing HA was evaluated using an infected murine model and proved beneficial in accelerating wound healing and reducing bacterial burden. Two glycosaminoglycans, HA and chondroitin sulfate (CS), were derivatized with alkylamines to form NO donors and compared regarding their wound healing properties. Both NO- releasing glycosaminoglycans exhibited bactericidal activity against antibiotic-susceptible and multi-drug resistant strains of P. aeruginosa and S. aureus. The alkylamine identity, glycosaminoglycan identity, and NO-release capability were all found to influence skin cell proliferation and adhesion to the extracellular matrix. Owing to NO’s anti-inflammatory properties, the NO-releasing glycosaminoglycans were found to mitigate activation of inflammatory pathways via Toll-like receptor 4. Comparison in an infected murine model demonstrated that NO-releasing CS outperformed HA in accelerating wound closure, with success attributed to both NO and the CS backbone. Nitric oxide-releasing hemodialysis catheter lock solutions were prepared using low molecular weight NO donors with different NO-release profiles. Slow, sustained release of NO from the catheter surface was found to be superior to high NO flux in preventing bacterial and protein adhesion as well as removing pre-adhered bacteria from the surface, indicating the potential for this system to act as both a preventative and treatment strategy. Minimal toxicity of the catheter lock solutions was discovered toward mammalian cells.Doctor of Philosoph

Production of low-density and high-strength paperboards by controlled micro-nano fibrillation of fibers

One of the critical challenges in the fber-based packaging industry is to produce low-density paperboards with high functionality and atractive cost structure. In this study, we examine how control of the hierarchical fber swelling can be used to enhance bonding and generate a low-density fber network with excellent strength properties. Here, the osmotic pressure inside the cell wall is increased by adding phosphate groups with a deep eutectic solvent (DES) functional drying method. Together with mechanical refning, this process causes the fbril aggregates to split and swell up massively. This efect was measured by a novel thermoporosimetry analysis method. The treated fbers have enhanced external fbrillation, fbrillar fnes and bonding potential. When mixed with relatively stif, unrefned fbers, a well-bonded sheet with lower density than a conventionally refned reference sheet was achieved. The results suggest that pulp fbers can be “nanoengineered” to enhance performance without the complications of producing and adding nanocellulose

Late Quaternary Faulting History of the Carrizal and Related Faults, La Paz Region, Baja California Sur, Mexico

The southwest margin of the Gulf of California has an array of active normal faults despite this being an oblique-divergent plate boundary with spreading centers that localized deformation along the plate boundary 2–3 million years ago. The Carrizal and Centenario faults form the western border fault of the Gulf of California marginal fault system within and south of La Paz Bay, and ∼20–30 km west of the capital city of La Paz, Baja California Sur, Mexico. Geologic and geomorphic mapping, optically stimulated luminescence (OSL) geochronology, and paleoseismic investigations onshore, compressed high-intensity radar pulse (CHIRP) profiling offshore, and analysis of uplifted marine terraces in the footwall of the offshore Carrizal fault provide some of the first numerical and geometrical constraints on late Pleistocene–Holocene faulting along the Carrizal fault. The onshore Carrizal fault has ruptured with up to ∼1–2 m of vertical displacement per event, likely producing ∼M 6.3–6.9 earthquakes, and at least two to three surface rupturing earthquakes have occurred since 22 ka. Onshore paleoseismic excavations and uplifted marine terraces on the western side of La Paz Bay both suggest offset rates of 0.1–0.2 mm/yr, with a footwall uplift rate of 0.13 mm/yr since 128 ka, and an approximately constant rate since marine oxygen-isotope stage (MIS) 11 terraces (420 ka). A CHIRP survey identified underwater fault scarps with heights ranging from 21 to 86 m on the Carrizal fault in La Paz Bay and from 3 to 5 m along the Centenario fault. The offshore Carrizal fault lies 8–10 km east of the western edge of La Paz Bay, forming a right step from the onshore Carrizal fault. The offshore Carrizal fault is the oldest fault of the fault system, and the fault likely grew in the latest Miocene to Pliocene in a complex way to the south toward the onshore Centenario and Carrizal faults. When the Alarcon spreading center started its modern rates at 2.4 Ma, the Carrizal fault likely slowed to the 0.1–0.2 mm/yr rates of the late Quaternary determined in this study

Editorial: Submarine Active Faults: From Regional Observations to Seismic Hazard Characterization

Since the beginning of the XXI Century, our society has witnessed a number of catastrophic earthquakes with devastating consequences (e.g., Sumatra 2004, Haiti 2010, Japan 2010, Nepal 2015, Italy 2009 and 2016). Localizing the active faults and understanding their earthquake history is key to improve modern probabilistic seismic hazard assessment (PSHA) and, thus, to mitigate the consequences of future events. Seismicity models to characterize the earthquake frequency in a region in PSHA studies have been traditionally based on archaeological, historical and instrumental earthquake records. However, the rapid advance of active tectonics and paleoseismological studies has resulted in the development of seismicity models for faults, since they allow characterizing the active faults, reconstructing their 3D geometry at depth, and determining their past earthquake history and seismic potential based on the interpretation of the geological record. Traditionally, active tectonics and paleoseismological research had been mainly conducted to study onshore active faults. However, the occurrence of the offshore Sumatra (2004) and Japan (2010) earthquakes and consequent tsunamis, which caused tens of thousands of casualties and extensive and severe damage and economic losses, have brought into sharp focus the need to better understand the geohazards related to submarine active faults. In the last few years, the availability of offshore geological and geophysical data at various scales (e.g., deep and shallow borehole, wide angle seismic profiles, tomography, 3D and 2D seismic reflection surveys, high resolution bathymetry or seafloor imaging) has allowed for a better definition of offshore fault systems. These studies focused on accurately constraining the kinematic, architecture and linkage of active faults, and, in some cases, identify recent earthquake ruptures or recognize and date individual events. In addition, underwater active tectonics and paleoseismological studies benefit from: (1) low erosional rates that preserve fault morphology and segmentation; (2) continuous sedimentation in time and space that allows for local and/or regional stratigraphic and chronostratigraphic correlations; (3) multiscale seafloor mapping and sub-seafloor seismic imaging; and 4) absence–or lowest amount–of human modification. This Research Topic includes fourteen published articles focused in the study of underwater active tectonic regions or active fault systems around the world (Figure 1). They use different datasets (i.e., bathymetry, seismicity from a local seismic network, sub-bottom profiling, reflection seismic profiles or sedimentary cores) to identify and characterize the seismic cycle of active faults using multidisciplinary approaches and innovative methodologies. The main goal of this Research Topic has been to show the present advance in underwater active tectonics and paleoseismology in order to improve our understanding about the seismic and tsunami hazard. Here we provide a short review of the contributions grouped by the main topics

Mechanisms of Taxane Resistance

The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome

In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders

Adenomatous Polyposis Coli loss controls cell cycle regulators and response to paclitaxel in MDA-MB-157 metaplastic breast cancer cells

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in both PTX-treated APC shRNA1 and parental cells, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased baseline CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio

Thrombospondin-1 Contributes to Mortality in Murine Sepsis through Effects on Innate Immunity

BACKGROUND:Thrombospondin-1 (TSP-1) is involved in many biological processes, including immune and tissue injury response, but its role in sepsis is unknown. Cell surface expression of TSP-1 on platelets is increased in sepsis and could activate the anti-inflammatory cytokine transforming growth factor beta (TGFβ1) affecting outcome. Because of these observations we sought to determine the importance of TSP-1 in sepsis. METHODOLOGY/PRINCIPAL FINDINGS:We performed studies on TSP-1 null and wild type (WT) C57BL/6J mice to determine the importance of TSP-1 in sepsis. We utilized the cecal ligation puncture (CLP) and intraperitoneal E. coli injection (i.p. E. coli) models of peritoneal sepsis. Additionally, bone-marrow-derived macrophages (BMMs) were used to determine phagocytic activity. TSP-1-/- animals experienced lower mortality than WT mice after CLP. Tissue and peritoneal lavage TGFβ1 levels were unchanged between animals of each genotype. In addition, there is no difference between the levels of major innate cytokines between the two groups of animals. PLF from WT mice contained a greater bacterial load than TSP-1-/- mice after CLP. The survival advantage for TSP-1-/- animals persisted when i.p. E. coli injections were performed. TSP-1-/- BMMs had increased phagocytic capacity compared to WT. CONCLUSIONS:TSP-1 deficiency was protective in two murine models of peritoneal sepsis, independent of TGFβ1 activation. Our studies suggest TSP-1 expression is associated with decreased phagocytosis and possibly bacterial clearance, leading to increased peritoneal inflammation and mortality in WT mice. These data support the contention that TSP-1 should be more fully explored in the human condition

A multicentre evaluation and expert recommendations of use of the newly developed BioFire Joint Infection polymerase chain reaction panel

Septic arthritis is a serious condition with significant morbidity and mortality, routinely diagnosed using culture. The FDA has recently approved the rapid molecular BioFire® Joint Infection Panel (BJIP) for synovial fluid. We aimed to evaluate the BJIP compared to culture and its potential use in patient management. A multicentre retrospective evaluation of BJIP was conducted in the UK and Ireland. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated between the BJIP and routine culture. A multidisciplinary team (MDT) discussion addressing the optimal or potential case use of the assay practice was facilitated. Three hundred ninety-nine surplus synovial fluid samples (~ 70% from native joints) from eight centres were processed using BJIP in addition to routine culture. An increased yield of positive results was detected using BJIP compared to routine culture (98 vs 83), giving an overall PPA of 91.6% and overall NPA of 93% for the BJIP compared to culture results. The BJIP detected resistant markers and additional organisms that could influence antibiotic choices including Neisseria gonorrhoeae and Kingella kingae. The MDT agreed that the assay could be used, in addition to standard methods, in adult and children patients with specialist advice use based on local needs. Rapid results from BJIP were assessed as having potential clinical impact on patient management. Organisms not included in the panel may be clinically significant and may limit the value of this test for PJI