The water planetary boundary (PB) has attracted wide academic attention, but empirical water footprint research that accommodates local biophysical boundaries remains scarce. Here we develop two ...novel quantitative footprint indicators, the water exceedance footprint and the surplus water footprint. The first measures the amount of excessive water withdrawal (exceeded amount of water withdrawn against local water PBs) and the latter evaluates the potential of surplus water that can be sustainably utilised (amount of surplus water available within local water PBs). We quantify the extent to which demand for goods and services in Chinese provinces and cities are driving excessive withdrawal of local and global water resources. We investigate both territorial and consumption-based water withdrawal deficit and surplus against local water withdrawal PBs. We also trace how PB-exceeded water and surplus water are appropriated for producing certain commodities. In 2015, China’s domestic water exceedance reaches 101 km3 while the total water exceedance footprint is 92 km3. We find that 47% of domestic excessive water withdrawal is associated with interprovincial trade. Exceeded water transfers were dominated by agricultural trade from the drier North to the wetter South. A revised virtual water trade network informed by exceedance and surplus water footprint metrics could help address sustainability concerns that arise from the trade of water-intensive commodities. Our findings highlight that policy targets need to accommodate PB exceedance of both direct and virtual water use.
Display omitted
•We develop two novel quantitative footprints to measure absolute water withdrawal sustainability.•Water exceedance footprints reveal regions’ transgression of local planetary boundaries elsewhere.•Water surplus footprints assess whether regions can sustainably supply and consume water.•47% of the Chinese territorial water exceedance is embedded in interprovincial trade.•Consumption-based PB water footprint indicators inform water resources management.
Hydrogel adhesives are attractive for applications in intelligent soft materials and tissue engineering, but conventional hydrogels usually have poor adhesion. In this study, we designed a strategy ...to synthesize a novel adhesive with a thin hydrogel adhesive layer integrated on a tough substrate hydrogel. The adhesive layer with positive charges of ammonium groups on the polymer backbones strongly bonds to a wide range of nonporous materials’ surfaces. The substrate layer with a dual hydrogen bond system consists of (i) weak hydrogen bonds between N,N-dimethyl acrylamide (DMAA) and acrylic acid (AAc) units and (ii) strong multiple hydrogen bonds between 2-ureido-41H-pyrimidinone (UPy) units. The dual hydrogen-bond network endowed the hydrogel adhesives with unique mechanical properties, e.g., toughness, highly stretchability, and insensitivity to notches. The hydrogel adhesion to four types of materials like glass, 316L stainless steel, aluminum, Al2O3 ceramic, and two biological tissues including pig skin and pig kidney was investigated. The hydrogel bonds strongly to dry solid surfaces and wet tissue, which is promising for biomedical applications.
Intracranial primary central nervous system lymphoma (PCNSL) is a rare aggressive malignant tumor with poor prognosis. The effect of surgical resection on intracranial PCNSL is still controversial. ...This study investigates the efficacy and safety of surgical resection, as well as to analyze the clinical characteristics and prognostic factors of intracranial PCNSL.
The clinical materials of 89 consecutive patients with intracranial PCNSL were analyzed retrospectively. Outcome in survival was assessed by progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were performed for various potential prognostic factors to identify independent prognostic factors of intracranial PCNSL.
Among the 89 patients, gross total resection (GTR) was achieved in 57 patients (64.0%), subtotal resection (STR) in 14 patients (15.8%), and biopsy in 18 patients (20.2%).The PFS and OS at 2 years were estimated at 32.3% and 74.1%, respectively. The median PFS was 20 months (95% confidence interval, 16–23) and the median OS was 32 months (95% confidence interval, 25–38). Patients with surgical resection (GTR and STR) had better PFS than those with biopsy, and the difference of PFS was statistically significant (P = 0.007). However, the difference of OS was not statistically significant (P = 0.062). Multivariate analysis showed that invasion of deep structure was the only independent risk factor for intracranial PCNSL. Eleven patients (12.4%) had surgical complications, mainly including limb weakness and visual field defect.
For intracranial PCNSL, surgical excision can improve PFS but not OS. Invasion of deep structure was the only independent risk factor for intracranial PCNSL.
Excessive glutamate in cerebrospinal fluid after subarachnoid hemorrhage (SAH) causes excitotoxic damage through calcium overloading and a subsequent apoptotic cascade. GluN1/GluN2B containing ...N-methyl-Daspartate (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) can play a leading role in glutamate-mediated excitotoxicity. Here we report that Ifenprodil (100μM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10μM), a NAM of mGluR1, have an additive efficacy against glutamate (100μM)-induced Ca2+ release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons. Compared with intraperitoneal injection of Ifenprodil (10mg/kg) and JNJ16259685 (1mg/kg) separately, the combination therapy of Ifenprodil plus JNJ16259685 significantly improves the neurological deficit at 24h and 72h after experimental SAH. It reduces the number of TUNEL/DAPI-positive and activated caspase-3/NeuN-positive cells in cortical and hippocampal CA1 regions at 72h, decreases levels of glutamate in cerebrospinal fluid at 72h, and reduces the mitochondrial Ca2+ concentration. Meanwhile, the combination therapy attenuates apoptosis as shown by an increased Bcl-2 expression, decreased Bax expression and release of cytochrome c, and reduction of cleaved caspase-9 and caspase-3 at 24h after SAH. These findings indicate that targeting both the intracellular Ca2+ overloading and neuronal apoptosis using the Ifenprodil and JNJ16259685 is a promising new therapy for SAH.
Excessive glutamate causes over-stimulation of GluN1/GluN2B NMDA receptors and mGluR1, which in turn contributes to the calcium overload and cell death. Blockage of GluN1/GluN2B NMDA receptors and mGluR1 using combination therapy of Ifenprodil and JNJ16259685 has additive efficacy against SAH-induced neurological deficit and neuronal apoptosis. Display omitted
•Ifenprodil and JNJ16259685 have additive effect against glutamate-mediated Ca2+ overloading and cell apoptosis.•Ifenprodil and JNJ16259685 have enhanced neuroprotection against early brain injury after SAH.•A dual-target inhibition of Ca2+ overloading and apoptosis using the Ifenprodil and JNJ16259685
GPCRs play critical roles in cell communication. Although GPCRs can form heteromers, their role in signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical ...dimers to study the functional interaction between each subunit. mGluRs can form both constitutive homo- and heterodimers. Whereas both mGlu2 and mGlu4 couple to G proteins, G protein activation is mediated by mGlu4 heptahelical domain (HD) exclusively in mGlu2-4 heterodimers. Such asymmetric transduction results from the action of both the dimeric extracellular domain, and an allosteric activation by the partially-activated non-functional mGlu2 HD. G proteins activation by mGlu2 HD occurs if either the mGlu2 HD is occupied by a positive allosteric modulator or if mGlu4 HD is inhibited by a negative modulator. These data revealed an oriented asymmetry in mGlu heterodimers that can be controlled with allosteric modulators. They provide new insight on the allosteric interaction between subunits in a GPCR dimer.
China is confronted with an unprecedented water crisis regarding its quantity and quality. In this study, we quantified the dynamics of China's embodied water use and chemical oxygen demand (COD) ...discharge from 2010 to 2015. The analysis was conducted with the latest available water use data across sectors in primary, secondary and tertiary industries and input-output models. The results showed that (1) China's water crisis was alleviated under urbanisation. Urban consumption occupied the largest percentages (over 30%) of embodied water use and COD discharge, but embodied water intensities in urban consumption were far lower than those in rural consumption. (2) The 'new normal' phase witnessed the optimisation of China's water use structures. Embodied water use in light-manufacturing and tertiary sectors increased while those in heavy-manufacturing sectors (except chemicals and transport equipment) dropped. (3) Transformation of China's international market brought positive effects on its domestic water use. China's water use (116-80 billion tonnes (Bts))9 and COD discharge (3.95-2.22 million tonnes (Mts)) embodied in export tremendously decreased while its total export values (11-25 trillion CNY) soared. Furthermore, embodied water use and COD discharge in relatively low-end sectors, such as textile, started to transfer from international to domestic markets when a part of China's production activities had been relocated to other developing countries.
Edaravone dexborneol is a novel neuroprotective drug that comprises edaravone and (+)-borneol in a 4:1 ratio. Phase II and III studies have demonstrated that Chinese patients treated with edaravone ...dexborneol within 48 h of AIS onset have better functional outcomes than those treated with edaravone alone. However, the effect of edaravone dexborneol on subarachnoid hemorrhage (SAH) has not yet been elucidated. This study aimed to investigate the therapeutic effects of edaravone dexborneol on SAH-induced brain injury and long-term behavioral deficits and to explore the possible mechanisms. The experimental rat SAH model was induced by an intraluminal puncture of the left middle cerebral artery (MCA). Edaravone dexborneol or edaravone at a clinical dose was infused into the tail vein for 3 days post-SAH surgery. Behavioral outcomes were assessed by a modified Garcia scoring system and rotarod, foot-fault, and corner tests. Immunofluorescence, Western blot, and ELISA methods were used to evaluate neuronal damage and oxidative stress. Our results showed that a post-SAH therapeutic regimen with edaravone dexborneol helped improve neurological function up to 21 days after SAH surgery and demonstrated a greater beneficial effect than edaravone alone, accompanied by an obvious inhibition of neuronal apoptosis in the CA1 hippocampus and basal cortex regions. Mechanistically, edaravone dexborneol not only suppressed the lipid peroxidation product malondialdehyde (MDA) but also improved the total antioxidant capability (TAC) 3 days after SAH. Notably, edaravone dexborneol treatment significantly inhibited the expression of another lipid peroxidation product, 4-hydroxynonenal (4-HNE), in the CA1 hippocampus and basal cortex, which are vital participants in the process of neuronal oxidative damage and death after SAH because of their acute cytotoxicity. Together, our results demonstrate that edaravone dexborneol confers neuroprotection and stabilizes long-term behavioral ability after SAH injury, possibly by suppressing 4-HNE-associated oxidative stress. These results may help develop new clinical strategies for SAH treatment.
Lysosomal-associated transmembrane protein 5 (LAPTM5) has been demonstrated to be involved in regulating immunity, inflammation, cell death, and autophagy in the pathophysiological processes of many ...diseases. However, the function of LAPTM5 in cerebral ischemia-reperfusion (I/R) injury has not yet been reported. In this study, we found that LAPTM5 expression was dramatically decreased during cerebral I/R injury both
in vivo
and
in vitro
. LAPTM5 knockout (KO) mice were compared with a control, and they showed a larger infarct size and more serious neurological dysfunction after transient middle cerebral artery occlusion (tMCAO) treatment. In addition, inflammatory response and apoptosis were exacerbated in these processes. Furthermore, gain- and loss-of-function investigations in an
in vitro
model revealed that neuronal inflammation and apoptosis were aggravated by LAPTM5 knockdown but mitigated by its overexpression. Mechanistically, combined RNA sequencing and experimental verification showed that the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway was mainly involved in the detrimental effects of LAPTM5 deficiency following I/R injury. Specifically, LAPTM5 directly interacts with ASK1, leading to decreased ASK1 N-terminal dimerization and the subsequent reduced activation of downstream JNK/p38 signaling. In conclusion, LAPTM5 was demonstrated to be a novel modulator in the pathophysiology of brain I/R injury, and targeting LAPTM5 may be feasible as a stroke treatment.
Inflammation is one major cause of poor outcomes of subarachnoid hemorrhage (SAH). The recent evidence suggested that adoptive regulatory T-cell (Treg) therapy conferred potential neuroprotection by ...suppressing cerebral inflammation against cerebral ischemia. Therefore, we proposed that Treg transfer might protect the brain against SAH by decreasing cerebral inflammation. In this study, we injected the autologous blood into cisterna magna twice to make the SAH model and administrated Tregs by vein to SAH rats. Intriguingly, adoptive transfer of Tregs significantly ameliorated SAH-induced brain edema and increased cerebral blood flow. Moreover, Treg-afforded cerebral protection was accompanied by suppressing SAH-induced cerebral inflammation. Concurrently, administration of Tregs attenuated the activation of the toll-like receptor 4 and nuclear factor-kappa B (TLR4/NF-κB) signaling pathway, which should be involved in the suppression of SAH-induced cerebral inflammation. Altogether, our study suggested that Treg adoptive transfer could attenuate SAH-induced cerebral inflammation by suppressing the activation of the TLR4/NF-κB signaling pathway, and thus provided new insights into the potent Treg cells-based therapy specifically targeting on post-SAH inflammatory dysregulation.
PDF
