Meeting expected surges in global biomass demand while protecting pristine ecosystems likely requires intensification of current croplands. Yet many uncertainties relate to the potentials for ...cropland intensification, mainly because conceptualizing and measuring land use intensity is intricate, particularly at the global scale. We present a spatially explicit analysis of global cropland use intensity, following an ecological energy flow perspective. We analyze (a) changes of net primary production (NPP) from the potential system (i.e. assuming undisturbed vegetation) to croplands around 2000 and relate these changes to (b) inputs of (N) fertilizer and irrigation and (c) to biomass outputs, allowing for a three dimensional focus on intensification. Globally the actual NPP of croplands, expressed as per cent of their potential NPP (NPPact%), amounts to 77%. A mix of socio-economic and natural factors explains the high spatial variation which ranges from 22.6% to 416.0% within the inner 95 percentiles. NPPact% is well below NPPpot in many developing, (Sub-) Tropical regions, while it massively surpasses NPPpot on irrigated drylands and in many industrialized temperate regions. The interrelations of NPP losses (i.e. the difference between NPPact and NPPpot), agricultural inputs and biomass harvest differ substantially between biogeographical regions. Maintaining NPPpot was particularly N-intensive in forest biomes, as compared to cropland in natural grassland biomes. However, much higher levels of biomass harvest occur in forest biomes. We show that fertilization loads correlate with NPPact% linearly, but the relation gets increasingly blurred beyond a level of 125 kgN ha−1. Thus, large potentials exist to improve N-efficiency at the global scale, as only 10% of global croplands are above this level. Reallocating surplus N could substantially reduce NPP losses by up to 80% below current levels and at the same time increase biomass harvest by almost 30%. However, we also show that eradicating NPP losses globally might not be feasible due to the high input costs and associated sustainability implications. Our analysis emphasizes the necessity to avoid mono-dimensional perspectives with respect to research on sustainable intensification pathways and the potential of integrated socio-ecological approaches for consistently contrasting environmental trade-offs and societal benefits of land use intensification.
Clinical efficacy of oxaliplatin is frequently limited by severe adverse effects and therapy resistance. Acquired insensitivity to oxaliplatin is, at least in part, associated with elevated levels of ...glutathione (GSH). In this study we report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase, the rate-limiting enzyme in GSH biosynthesis. Two complexes bearing either acetate (BSO-OxOAc) or an albumin-binding maleimide (BSO-OxMal) as second axial ligand were synthesized and characterized. The in vitro anticancer activity of BSO-OxOAc was massively reduced in comparison to oxaliplatin, proving its prodrug nature. Nevertheless, the markedly lower intracellular oxaliplatin uptake in resistant HCT116/OxR cells was widely overcome by BSO-OxOAc resulting in distinctly reduced resistance levels. Platinum accumulation in organs of a colorectal cancer mouse model revealed higher tumor selectivity of BSO-OxMal as compared to oxaliplatin. This corresponded with increased antitumor activity, resulting in significantly enhanced overall survival. BSO-OxMal-treated tumors exhibited reduced GSH levels, proliferative activity and enhanced DNA damage (pH2AX) compared to oxaliplatin. Conversely, pH2AX staining especially in kidney cells was distinctly increased by oxaliplatin but not by BSO-OxMal. Taken together, our data provide compelling evidence for enhanced tumor specificity of the oxaliplatin(IV)/BSO prodrug.
RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and ...phosphorylation events, as well as by caspase-8-mediated cleavage
. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis
. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1
mutant mouse strain. Whereas Ripk1
mice died postnatally from systemic inflammation, Ripk1
mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1
embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1
and Ripk1
cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1
mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.
WHAT WE ALREADY KNOW ABOUT THIS TOPIC
WHAT THIS ARTICLE TELLS US THAT IS NEW
BACKGROUND:Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. ...The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children’s hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children.
METHODS:This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy.
RESULTS:There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%).
CONCLUSIONS:The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.
Antiviral immunity requires early and late mechanisms in which IFN-alpha and IL-12 play major roles. However, the initial events leading to their production remain largely unclear. Given the crucial ...role of TLR in innate recognition, we investigated their role in antiviral immunity in vivo. Upon murine CMV (MCMV) infection, both MyD88-/- and TLR9-/- mice were more susceptible and presented increased viral loads compared with C57BL/6, TLR2-/-, TLR3-/-, or TLR4-/- mice. However, in terms of resistance to infection, IFN-alpha production and in many other parameters of early inflammatory responses, the MyD88-/- mice showed a more defective response than TLR9-/- mice. In the absence of the TLR9/MyD88 signaling pathway, cytokine production was dramatically impaired with a complete abolition of bioactive IL-12p70 serum release contrasting with a high flexibility for IFN-alpha release, which is initially (36 h) plasmacytoid dendritic cell- and MyD88-dependent, and subsequently (44 h) PDC-, MyD88-independent and, most likely, TLR-independent. NK cells from MCMV-infected MyD88-/- and TLR9-/- mice displayed a severely impaired IFN-gamma production, yet retained enhanced cytotoxic activity. In addition, dendritic cell activation and critical inflammatory cell trafficking toward the liver were still effective. In the long term, except for isotype switching to MCMV-specific IgG1, the establishment of Ab responses was not significantly altered. Thus, our results demonstrate a critical requirement of TLR9 in the process of MCMV sensing to assure rapid antiviral responses, coordinated with other TLR-dependent and -independent events that are sufficient to establish adaptive immunity.
Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific ...biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years interquartile range 3.9, 5.1, mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 95% CI, 1.15-4.52, MACE aHR, 1.88 95% CI, 1.07-3.28) and high NT-proBNP (all-cause death aHR, 1.61 95% CI, 1.14-2.26, MACE aHR, 1.38 95% CI, 1.07-1.80). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.
Objectives. The retinoblastoma (RB) pathway is crucial in the development and progression of many cancers. To better understand the biology of progressive breast cancer (BC), we examined protein ...expression of the RB pathway in primary BCs and matched axillary lymph node metastases (LM). Methods. Immunohistochemistry was used to evaluate cyclin D1, CDK4/6, RB, phosphorylated RB (pRB), and E2F1 expression in tissue arrays containing cores of 50 primary BCs and matched LM. The number of positive tumor cells and staining intensity were scored. Results. The proteins were localized in the nucleus, while CDK6 was detected in the cytoplasm and CDK4 was found in both. pRB and E2F1 showed higher expression in matched LM than in primary tumors. Expression of these proteins differed significantly by the percentage of positive tumor cells, while proteins in the proximal portion of the RB pathway showed no significant differences. The main path of alteration consisted of high pRB in primary BC, remaining pRB high in the majority of LM, variations occurring in fewer cases. All matched LM of the few primary tumors that had unaltered RB and pRB expression showed changes in RB or pRB expression. Conclusion. Expression of pRB and E2F1 was significantly higher in LM than in primary BC. A majority of cancers with LM showed altered RB or pRB expression, suggesting that proteins downstream in the RB pathway play a critical role in metastatic BC and disease progression. So looking at the RB pathway could be an option for chemotherapy decisions in patients with only few LM.
The COVID-19 pandemic led to rapid expansion of telemedicine services. We surveyed parent/guardians from March 10 to June 29, 2020, in an academic and community pediatric practice, and community ...pediatric providers from June 5 to July 13, 2020, to better understand their perceptions of telemedicine and compare parent/guardian satisfaction between in-person and telemedicine encounters. Overall patient satisfaction scores were high in both settings and did not differ between in-person and telemedicine visits (community setting: 93.36 ± 12.87 in-person vs. 88.04 ± 22.04 telemedicine; academic setting: 92.25 ± 11.2 vs. 95.37 ± 8.21). Most providers (82.5%) would be willing to use telemedicine in a nonpandemic situation. Telemedicine should remain available for primary care pediatrics during and after resolution of the pandemic.
Abstract
Aims
Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood ...during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients.
Methods and results
We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30 s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend).
Conclusion
The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF.
ClinicalTrials.gov Identifier
NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364
Graphical Abstract
Graphical Abstract
AF, atrial fibrillation; BMP10, bone morphogenetic protein 10; HR, hazard ratio
Plasmacytoid dendritic cells (pDCs) are specialized DCs that produce high levels of type I IFN upon viral infection. Despite their key immunoregulatory role, little is known about pDC ontogeny or how ...developmental events regulate their function. We show that mice expressing low levels of the transcription factor Ikaros (IkL/L) lack peripheral pDCs, but not other DC subsets. Loss of pDCs is associated with an inability to produce type I IFN after challenge with Toll-like receptor-7 and -9 ligands, or murine cytomegalovirus (MCMV) infection. In contrast, conventional DCs are present in normal numbers and exhibit normal responses in vivo after challenge with MCMV or inactivated toxoplasma antigen. Interestingly, IkL/L bone marrow (BM) cells contain a pDC population that appears blocked at the Ly-49Q– stage of differentiation and fails to terminally differentiate in response to Flt-3L, a cytokine required for pDC differentiation. This differentiation block is strictly dependent on a cell-intrinsic requirement for Ikaros in pDC-committed precursors. Global gene expression profiling of IkL/L BM pDCs reveals an up-regulation of genes not normally expressed, or expressed at low levels, in WT pDCs. These studies suggest that Ikaros controls pDC differentiation by silencing a large array of genes.
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