The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. ...However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A century-old tenet in physics and engineering asserts that any type of system, having bandwidth Δω, can interact with a wave over only a constrained time period Δt inversely proportional to the ...bandwidth (Δt·Δω ~ 2π). This law severely limits the generic capabilities of all types of resonant and wave-guiding systems in photonics, cavity quantum electrodynamics and optomechanics, acoustics, continuum mechanics, and atomic and optical physics but is thought to be completely fundamental, arising from basic Fourier reciprocity. We propose that this “fundamental” limit can be overcome in systems where Lorentz reciprocity is broken. As a system becomes more asymmetric in its transport properties, the degree to which the limit can be surpassed becomes greater. By way of example, we theoretically demonstrate how, in an astutely designed magnetized semiconductor heterostructure, the above limit can be exceeded by orders of magnitude by using realistic material parameters. Our findings revise prevailing paradigms for linear, time-invariant resonant systems, challenging the doctrine that high-quality resonances must invariably be narrowband and providing the possibility of developing devices with unprecedentedly high time-bandwidth performance.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We develop a statistical model using extreme value theory to estimate the 2000–2050 changes in ozone episodes across the United States. We model the relationships between daily maximum temperature ...(Tmax) and maximum daily 8 h average (MDA8) ozone in May–September over 2003–2012 using a Point Process (PP) model. At ~20% of the sites, a marked decrease in the ozone‐temperature slope occurs at high temperatures, defined as ozone suppression. The PP model sometimes fails to capture ozone‐Tmax relationships, so we refit the ozone‐Tmax slope using logistic regression and a generalized Pareto distribution model. We then apply the resulting hybrid‐extreme value theory model to projections of Tmax from an ensemble of downscaled climate models. Assuming constant anthropogenic emissions at the present level, we find an average increase of 2.3 d a−1 in ozone episodes (>75 ppbv) across the United States by the 2050s, with a change of +3–9 d a−1 at many sites.
Key Points
We use observed ozone‐temperature relationships and extreme value theory to predict future ozone
An unexpected 20% of U.S. sites show ozone suppression at extremely high temperatures
Results from CMIP5 imply increases in U.S. ozone episodes by as much as 3–9 days by the 2050s
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Liver resection is effective for hepatocellular carcinoma (HCC) exceeding the Milan criteria in selected patients. However, the benefit of anatomical resection (AR) versus non‐anatomical ...resection (NAR) has not been clarified in this patient subgroup. This study aimed to compare outcomes between AR and NAR for HCC exceeding the Milan criteria.
Methods
Data on consecutive patients with HCC exceeding the Milan criteria who underwent liver resection with curative intent over a recent 6‐year interval were extracted from a prospective single‐centre HCC database and examined retrospectively. The postoperative outcomes of patients were compared before and after propensity score matching.
Results
Some 546 patients were included: 264 in the AR and 282 in the NAR group. In the original cohort, the AR group contained more patients with larger tumours, multiple tumours, macroscopic portal vein tumour thrombi, incomplete tumour capsules and microscopic vascular invasion. After propensity score matching, 177 pairs of patients were selected. The baseline data, including liver function and tumour burden, were similar in the matched groups. The 3‐year recurrence‐free survival rate was comparable between the matched NAR and AR groups (36·5 versus 28·5 per cent; P = 0·448). Similar results were observed for 3‐year overall survival (57·5 versus 50·3 per cent; P = 0·385), recurrence patterns and early recurrence rates (57·6 per cent versus 59·9 per cent; P = 0·712).
Conclusion
AR and NAR achieved favourable and similar outcomes for HCC exceeding the Milan criteria in selected patients.
No difference
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Avoidance of noxious ambient heat is crucial for survival. A well-known phenomenon is that animals are sensitive to the rate of temperature change. However, the cellular and molecular underpinnings ...through which animals sense and respond much more vigorously to fast temperature changes are unknown. Using Drosophila larvae, we found that nociceptive rolling behavior was triggered at lower temperatures and at higher frequencies when the temperature increased rapidly. We identified neurons in the brain that were sensitive to the speed of the temperature increase rather than just to the absolute temperature. These cellular and behavioral responses depended on the TRPA1 channel, whose activity responded to the rate of temperature increase. We propose that larvae use low-threshold sensors in the brain to monitor rapid temperature increases as a protective alert signal to trigger rolling behaviors, allowing fast escape before the temperature of the brain rises to dangerous levels.
Soil acidification is a major problem in soils of intensive Chinese agricultural systems. We used two nationwide surveys, paired comparisons in numerous individual sites, and several long-term ...monitoring-field data sets to evaluate changes in soil acidity. Soil pH declined significantly (P < 0.001) from the 1980s to the 2000s in the major Chinese crop-production areas. Processes related to nitrogen cycling released 20 to 221 kilomoles of hydrogen ion (H⁺) per hectare per year, and base cations uptake contributed a further 15 to 20 kilomoles of H⁺ per hectare per year to soil acidification in four widespread cropping systems. In comparison, acid deposition (0.4 to 2.0 kilomoles of H⁺ per hectare per year) made a small contribution to the acidification of agricultural soils across China.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
RNA transcripts are bound and regulated by RNA-binding proteins (RBPs). Current methods for identifying in vivo targets of an RBP are imperfect and not amenable to examining small numbers of cells. ...To address these issues, we developed TRIBE (targets of RNA-binding proteins identified by editing), a technique that couples an RBP to the catalytic domain of the Drosophila RNA-editing enzyme ADAR and expresses the fusion protein in vivo. RBP targets are marked with novel RNA editing events and identified by sequencing RNA. We have used TRIBE to identify the targets of three RBPs (Hrp48, dFMR1, and NonA). TRIBE compares favorably to other methods, including CLIP, and we have identified RBP targets from as little as 150 specific fly neurons. TRIBE can be performed without an antibody and in small numbers of specific cells.
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•TRIBE is a genetic tool that identifies in vivo targets of RNA-binding proteins (RBPs)•An RBP of interest is fused to the catalytic domain of an RNA-editing enzyme•RBP targets are marked by novel RNA-editing events•Cell-specific targets can be identified from tiny amounts of RNA
A technique called TRIBE identifies cell-specific targets of RNA-binding proteins, even in small cell populations, via the detection of RNA-editing events conferred by a genetically encoded enzymatic fusion to the RNA-binding protein of interest.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but ...acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims
To explore the role of anaerobic ammonium oxidation (anammox) in nitrogen removal in freshwater marshes.
Methods and Results
The 16S rRNA gene sequences of Candidatus Kuenenia and Candidatus ...Brocadia were simultaneously detected in the sediment of freshwater marshes of Green Bay Wetland that is located in Eastern China by using Illumina‐based sequencing of the total bacterial 16S rRNA genes, and Candidatus Brocadia comprised more than 80% of the total anammox‐related sequences. The abundance of anammox bacteria was determined by quantitative PCR on their hydrazine synthase (hzs) genes, which ranged from 3·13 × 104 to 1·58 × 105 copies per g sediment with little temporal variation. The potential anammox rates measured by 15N‐stable isotope pairing technique were 0·78–5·37 nmol N g−1 sediment per h, accounting for 4·3–38·5% of total sediment dinitrogen gas (N2) production. Both the anammox activity and its contribution to N2 production were sensitive to temporal variation and correlated well with the sediment NO3− content. To further examine the nitrogen removal potential via anammox, batch culture was set‐up to enrich anammox bacteria from the marsh sediments. Both the activity and abundance of anammox bacteria increased significantly after 6 months of incubation, varying from 61·6 to 95·8 nmol N g−1 sediment per h and 2·86 × 105 to 6·58 × 105 copies per g sediment respectively.
Conclusions
Our results revealed the great potential of anammox in nitrogen removal in freshwater marshes.
Significance and Impact of the Study
This is the first study to show the anammox activity and its temporal variation in freshwater marsh sediments, which improved our understanding of nitrogen removal mechanisms in freshwater marshes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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