Neutrophils are the main defense cells of the innate immune system. Upon stimulation, neutrophils release their chromosomal DNA to trap and kill microorganisms and inhibit their dissemination. These ...chromatin traps are termed neutrophil extracellular traps (NETs) and are decorated with granular and cytoplasm proteins. NET release can be induced by several microorganism membrane components, phorbol 12-myristate 13-acetate as well as by amyloid fibrils, insoluble proteinaceous molecules associated with more than 40 different pathologies among other stimuli. The intracellular signaling involved in NET formation is complex and remains unclear for most tested stimuli. Herein we demonstrate that a metabolic shift toward the pentose phosphate pathway (PPP) is necessary for NET release because glucose-6-phosphate dehydrogenase (G6PD), an important enzyme from PPP, fuels NADPH oxidase with NADPH to produce superoxide and thus induce NETs. In addition, we observed that mitochondrial reactive oxygen species, which are NADPH-independent, are not effective in producing NETs. These data shed new light on how the PPP and glucose metabolism contributes to NET formation.
Background: Neutrophil extracellular traps (NETs) are DNA meshes that snare and kill microorganisms, impeding their dissemination.
Results: Glucose but not fructose supports NET formation through a metabolic shift toward pentose phosphate pathway (PPP).
Conclusion: PPP impairment leads to decreased NET production.
Significance: This study provides novel knowledge about the mechanisms of NET induction, opening new avenues of study and intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human activity and land‐use change are dramatically altering the sizes, geographical distributions and functioning of biological populations worldwide, with tremendous consequences for human ...well‐being. Yet our ability to measure, monitor and forecast biodiversity change – crucial to addressing it – remains limited. Biodiversity monitoring systems are being developed to improve this capacity by deriving metrics of change from an array of in situ data (e.g. field plots or species occurrence records) and Earth observations (EO; e.g. satellite or airborne imagery). However, there are few ecologically based frameworks for integrating these data into meaningful metrics of biodiversity change. Here, I describe how concepts of pattern and scale in ecology could be used to design such a framework. I review three core topics: the role of scale in measuring and modelling biodiversity patterns with EO, scale‐dependent challenges linking in situ and EO data and opportunities to apply concepts of pattern and scale to EO to improve biodiversity mapping. From this analysis emerges an actionable approach for measuring, monitoring and forecasting biodiversity change, highlighting key opportunities to establish EO as the backbone of global‐scale, science‐driven conservation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Race/ethnicity and socioeconomic status (SES) are social categories that capture differential exposure to conditions of life that have health consequences. Race/ethnicity and SES are linked to each ...other, but race matters for health even after SES is considered. This commentary considers the complex ways in which race combines with SES to affect health. There is a need for greater attention to understanding how risks and resources in the social environment are systematically patterned by race, ethnicity and SES, and how they combine to influence cardiovascular disease and other health outcomes. Future research needs to examine how the levels, timing and accumulation of institutional and interpersonal racism combine with other toxic exposures, over the life-course, to influence the onset and course of illness. There is also an urgent need for research that seeks to build the science base that will identify the multilevel interventions that are likely to enhance the health of all, even while they improve the health of disadvantaged groups more rapidly than the rest of the population so that inequities in health can be reduced and ultimately eliminated. We also need sustained research attention to identifying how to build the political support to reduce the large shortfalls in health.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Wind-driven upwelling in the ocean around Antarctica helps regulate the exchange of carbon dioxide (CO2) between the deep sea and the atmosphere, as well as the supply of dissolved silicon to the ...euphotic zone of the Southern Ocean. Diatom productivity south of the Antarctic Polar Front and the subsequent burial of biogenic opal in underlying sediments are limited by this silicon supply. We show that opal burial rates, and thus upwelling, were enhanced during the termination of the last ice age in each sector of the Southern Ocean. In the record with the greatest temporal resolution, we find evidence for two intervals of enhanced upwelling concurrent with the two intervals of rising atmospheric CO2 during deglaciation. These results directly link increased ventilation of deep water to the deglacial rise in atmospheric CO2.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of ...patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
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•Efficient generation of a biobank of patient-derived bladder cancer organoids•Organoids recapitulate the histological and molecular spectrum of human bladder cancer•Bladder tumor organoids display clonal evolution in culture and as xenografts•Drug response of organoids can be validated in xenografts
A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We propose new M-algorithm BCJR (M-BCJR) algorithms for low-complexity turbo equalization and apply them to severe intersymbol interference (ISI) introduced by faster than Nyquist signaling. These ...reduced-search detectors are evaluated in simple detection over the ISI channel and in iterative decoding of coded FTN transmissions. In the second case, accurate log likelihood ratios are essential and we introduce a 3-recursion M-BCJR that provides this. Focusing signal energy by a minimum phase conversion before the M-BCJR is also essential; we propose an improvement to this older idea. The new M-BCJRs are compared to reduced-trellis VA and BCJR benchmarks. The FTN signals carry 4-8 bits/Hz-s in a fixed spectrum, with severe ISI models as long as 32 taps. The combination of coded FTN and the reduced-complexity BCJR is an attractive narrowband coding method.
Neutrophils are short-lived leukocytes that die by apoptosis, necrosis, and NETosis. Upon death by NETosis, neutrophils release fibrous traps of DNA, histones, and granule proteins named neutrophil ...extracellular traps (NETs), which can kill bacteria and fungi. Inoculation of the protozoan Leishmania into the mammalian skin causes local inflammation with neutrophil recruitment. Here, we investigated the release of NETs by human neutrophils upon their interaction with Leishmania parasites and NETs' ability to kill this protozoan. The NET constituents DNA, elastase, and histones were detected in traps associated to promastigotes by immunofluorescence. Electron microscopy revealed that Leishmania was ensnared by NETs released by neutrophils. Moreover, Leishmania and its surface lipophosphoglycan induced NET release by neutrophils in a parasite number- and dose-dependent manner. Disruption of NETs by DNase treatment during Leishmania-neutrophil interaction increased parasite survival, evidencing NETs' leishmanicidal effect. Leishmania killing was also elicited by NET-rich supernatants from phorbol 12-myristate 13-acetate-activated neutrophils. Immunoneutralization of histone during Leishmania-neutrophil interaction partially reverted Leishmania killing, and purified histone killed the parasites. Meshes composed of DNA and elastase were evidenced in biopsies of human cutaneous leishmaniasis. NET is an innate response that might contribute to diminish parasite burden in the Leishmania inoculation site.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Fibrations in CICY threefolds Anderson, Lara B.; Gao, Xin; Gray, James ...
The journal of high energy physics,
10/2017, Volume:
2017, Issue:
10
Journal Article
Peer reviewed
Open access
A
bstract
In this work we systematically enumerate genus one fibrations in the class of 7, 890 Calabi-Yau manifolds defined as complete intersections in products of projective spaces, the so-called ...CICY threefolds. This survey is independent of the description of the manifolds and improves upon past approaches that probed only a particular algebraic form of the threefolds (i.e. searches for “obvious” genus one fibrations as in
1
,
2
). We also study K3-fibrations and nested fibration structures. That is, K3 fibrations with potentially many distinct elliptic fibrations. To accomplish this survey a number of new geometric tools are developed including a determination of the full topology of all CICY threefolds, including triple intersection numbers. In 2, 946 cases this involves finding a new “favorable” description of the manifold in which all divisors descend from a simple ambient space. Our results consist of a survey of obvious fibrations for all CICY threefolds and a complete classification of all genus one fibrations for 4, 957 “Kähler favorable” CICYs whose Kähler cones descend from a simple ambient space. Within the CICY dataset, we find 139, 597 obvious genus one fibrations, 30, 974 obvious K3 fibrations and 208, 987 nested combinations. For the Kähler favorable geometries we find a complete classification of 377, 559 genus one fibrations. For one manifold with Hodge numbers (19, 19) we find an explicit description of an infinite number of distinct genus-one fibrations extending previous results for this particular geometry that have appeared in the literature. The data associated to this scan is available here
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