Glutamate mediates photic entrainment of the central clock in the suprachiasmatic nucleus (SCN) by evoking intracellular Ca2+ signaling mechanisms. However, the detailed mechanisms of ...glutamate-evoked Ca2+ signals are not entirely clear. Here, we used a ratiometric Ca2+ and Na+ imaging technique to investigate glutamate-evoked Ca2+ responses. The comparison of Ca2+ responses to glutamate (100 μM) and high (20 mM) K+ solution indicated slower Ca2+ clearance, along with rebound Ca2+ suppression for glutamate-evoked Ca2+ transients. Increasing the length of exposure time in glutamate, but not in 20 mM K+, slowed Ca2+ clearance and increased rebound Ca2+ suppression, a result correlated with glutamate-induced Na+ loads. The rebound Ca2+ suppression was abolished by ouabain, monensin, Na+-free solution, or nimodipine, suggesting an origin of activated Na+/K+-ATPase (NKA) by glutamate-induced Na+ loads. Ouabain or Na+-free solution also slowed Ca2+ clearance, apparently by retarding Na+/Ca2+-exchanger (NCX)-mediated Ca2+ extrusion. Together, our results indicated the involvement of glutamate-induced Na+ loads, NKA, and NCX in shaping the Ca2+ response to glutamate. Nevertheless, in the absence of external Na+ (NMDG substituted), Ca2+ clearance was still slower for the Ca2+ response to glutamate than for 20 mM K+, suggesting participation of additional Ca2+ handlers to the slower Ca2+ clearance under this condition.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Glutamate mediates photic entrainment of the central clock in the suprachiasmatic nucleus (SCN) by evoking intracellular Casup.2+ signaling mechanisms. However, the detailed mechanisms of ...glutamate-evoked Casup.2+ signals are not entirely clear. Here, we used a ratiometric Casup.2+ and Nasup.+ imaging technique to investigate glutamate-evoked Casup.2+ responses. The comparison of Casup.2+ responses to glutamate (100 μM) and high (20 mM) Ksup.+ solution indicated slower Casup.2+ clearance, along with rebound Casup.2+ suppression for glutamate-evoked Casup.2+ transients. Increasing the length of exposure time in glutamate, but not in 20 mM Ksup.+, slowed Casup.2+ clearance and increased rebound Casup.2+ suppression, a result correlated with glutamate-induced Nasup.+ loads. The rebound Casup.2+ suppression was abolished by ouabain, monensin, Nasup.+-free solution, or nimodipine, suggesting an origin of activated Nasup.+/Ksup.+-ATPase (NKA) by glutamate-induced Nasup.+ loads. Ouabain or Nasup.+-free solution also slowed Casup.2+ clearance, apparently by retarding Nasup.+/Casup.2+-exchanger (NCX)-mediated Casup.2+ extrusion. Together, our results indicated the involvement of glutamate-induced Nasup.+ loads, NKA, and NCX in shaping the Casup.2+ response to glutamate. Nevertheless, in the absence of external Nasup.+ (NMDG substituted), Casup.2+ clearance was still slower for the Casup.2+ response to glutamate than for 20 mM Ksup.+, suggesting participation of additional Casup.2+ handlers to the slower Casup.2+ clearance under this condition.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pyrrolizidine alkaloids (PAs) are among the most significant groups of phytotoxins present in more than 6000 plants in the world. Hepatotoxic retronecine-type PAs and their corresponding
N
-oxides ...usually co-exist in plants. Although PA-induced hepatotoxicity is known for a long time and has been extensively studied, the toxicity of PA
N
-oxide is rarely investigated. Recently, we reported PA
N
-oxide-induced hepatotoxicity in humans and rodents and also suggested the association of such toxicity with metabolic conversion of PA
N
-oxides to the corresponding toxic PAs. However, the detailed biochemical mechanism of PA
N
-oxide-induced hepatotoxicity is largely unknown. The present study investigated biotransformation of four representative cyclic retronecine-type PA
N
-oxides to their corresponding PAs in both gastrointestinal tract and liver. The results demonstrated that biotransformation of PA
N
-oxides to PAs was mediated by both intestinal microbiota and hepatic cytochrome P450 monooxygenases (CYPs), in particular CYP1A2 and CYP2D6. Subsequently, the formed PAs were metabolically activated predominantly by hepatic CYPs to form reactive metabolites exerting hepatotoxicity. Our findings delineated, for the first time, that the metabolism-mediated mechanism of PA
N
-oxide intoxication involved metabolic reduction of PA
N
-oxides to their corresponding PAs in both intestine and liver followed by oxidative bioactivation of the resultant PAs in the liver to generate reactive metabolites which interact with cellular proteins leading to hepatotoxicity. In addition, our results raised a public concern and also encouraged further investigations on potentially remarkable variations in PA
N
-oxide-induced hepatotoxicity caused by significantly altered intestinal microbiota due to individual differences in diets, life styles, and medications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Transmembrane Ca
influx is essential to the proper functioning of the central clock in the suprachiasmatic nucleus (SCN). In the rat SCN neurons, the clearance of somatic Ca
following ...depolarization-induced Ca
transients involves Ca
extrusion via Na
/Ca
exchanger (NCX) and mitochondrial Ca
buffering. Here we show an important role of intracellular Na
in the regulation of Ca
in these neurons. The effect of Na
loading on Ca
was determined with the Na
ionophore monensin and the cardiac glycoside ouabain to block Na
/K
-ATPase (NKA). Ratiometric Na
and Ca
imaging was used to measure the change in Na
and Ca
, and cell-attached recordings to investigate the effects of monensin and ouabain on spontaneous firing. Our results show that in spite of opposite effects on spontaneous firing and basal Ca
, both monensin and ouabain induced Na
loading, and increased the peak amplitude, slowed the fast decay rate, and enhanced the slow decay phase of 20 mM K
-evoked Ca
transients. Furthermore, both ouabain and monensin preferentially enhanced nimodipine-insensitive Ca
transients. Together, our results indicate that in the SCN neurons the NKA plays an important role in regulating Ca
, in particular, associated with nimodipine-insensitive Ca
channels.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•A two-region physical input–output model is developed for water-energy nexus.•Sankey diagrams illustrate water-energy nexus between Hong Kong and South China.•Future nexus is modeled according to ...future demand and corresponding supply.•All types of water for energy and energy for water will increase by 7.8–9% in 2050.•Influences of new technologies and resource circulation are analyzed.
Most cities import energy and water from their hinterlands. Both the nexus in a city and that between the city and its hinterlands should be considered for comprehensive management of water and energy. To examine the water-energy nexus associated with the city embedded in the hinterland, a city-hinterland water-energy mixed-unit input–output methodology is proposed to model the effects of growth under different water and energy production and consumption scenarios based on the growth of the demands for water and energy resources from the city. This study presents a demonstration of the water-energy mixed-unit input–output approach by analyzing Hong Kong and its associated hinterland in mainland China. A Sankey diagram and several indicators have been presented to illustrate the water–energy nexus in 2015, as well as the nexus for future city growth and the nexus incorporating the water and energy infrastructures planned in Hong Kong. Several indicators in the results compare the interaction between water and energy systems and the dependence on hinterland for different scenarios in Hong Kong. The modeling outcomes show that the current water infrastructures might be able to meet the demand for water treatment in 2050. The indicators obtained from this study suggest that all types of water for energy and energy for water will increase by 7.8–9%.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The ability to distinguish malignant from indolent prostate cancer cells is critically important for identification of clinically significant prostate cancer to minimize unnecessary overtreatment and ...sufferings endured by patients who have indolent cancer. Recently, we discovered that loss of giantin function as the primary Golgi targeting site for endoplasmic reticulum-derived transport vesicles in aggressive prostate cancer cells caused a shift of the Golgi localization site of α-mannosidase 1A to 130 KDa Golgi matrix protein (GM130)-65 KDa Golgi reassembly-stacking protein (GRASP65) site resulting in emergence of high mannose N-glycans on trans-Golgi enzymes and cell surface glycoproteins. To extend this observation, we isolated two cell clones (Clone 1 and Clone 2) from high passage LNCaP cells, which exhibited androgen refractory property missing in low passage LNCaP cells, and characterized their malignant property. We have found that comparing to Clone 2, which does not have cell surface high mannose N-glycans and exhibits localization of α-mannosidase 1A at giantin site, Clone 1 displays cell surface high mannose N-glycans, exhibits localization of α-mannosidase 1A at GM130-GRASP65 site, and shows a faster rate of closing the wound in a wound healing assay. The results indicate that Golgi localization of α-mannosidase 1A at GM130-GRASP65 site and appearance of cell surface high mannose N-glycans may serve as markers of malignant prostate cancer cells.
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•High passage LNCaP cells contain indolent and malignant cells.•Indolent LNCaP cells exhibit Golgi localization of αmannosidase 1A at giantin.•Indolent LNCaP cells do not display high mannose N-glycans at cell surface.•Malignant LNCaP cells exhibit Golgi localization of αmannosidase1A at GM130-GRASP65.•Malignant LNCaP cells display high mannose N-glycans at cell surface.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The central clock in the suprachiasmatic nucleus (SCN) has higher metabolic activity than extra-SCN areas in the anterior hypothalamus. Here we investigated whether the Na
/H
exchanger (NHE) may ...regulate extracellular pH (pHe), intracellular pH (pHi) and Ca
in the SCN. In hypothalamic slices bathed in HEPES-buffered solution a standing acidification of ~0.3 pH units was recorded with pH-sensitive microelectrodes in the SCN but not extra-SCN areas. The NHE blocker amiloride alkalinised the pHe. RT-PCR revealed mRNA for plasmalemmal-type NHE1, NHE4, and NHE5 isoforms, whereas the NHE1-specific antagonist cariporide alkalinised the pHe. Real-time PCR and western blotting failed to detect day-night variation in NHE1 mRNA and protein levels. Cariporide induced intracellular acidosis, increased basal Ca
, and decreased depolarisation-induced Ca
rise, with the latter two effects being abolished with nimodipine blocking the L-type Ca
channels. Immunofluorescent staining revealed high levels of punctate colocalisation of NHE1 with serotonin transporter (SERT) or CaV1.2, as well as triple staining of NHE1, CaV1.2, and SERT or the presynaptic marker Bassoon. Our results indicate that NHE1 actively extrudes H
to regulate pHi and nimodipine-sensitive Ca
in the soma, and along with CaV1.2 may also regulate presynaptic Ca
levels and, perhaps at least serotonergic, neurotransmission in the SCN.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background and Aims
Mutational signature analyses are an effective tool in identifying cancer etiology. Humans are frequently exposed to pyrrolizidine alkaloids (PAs), the most common carcinogenic ...phytotoxins widely distributed in herbal remedies and foods. However, due to the lack of human epidemiological data, PAs are classified as group II hepatocarcinogens by the World Health Organization. This study identified a PA mutational signature as the biomarker to investigate the association of PA exposure with human liver cancer.
Approach and Results
Pyrrole‐protein adducts (PPAs), the PA exposure biomarker, were measured and found in 32% of surgically resected specimens from 34 patients with liver cancer in Hong Kong. Next, we delineated the mode of mutagenic and tumorigenic actions of retrorsine, a representative PA, in mice and human hepatocytes (HepaRG). Retrorsine induced DNA adduction, DNA damage, and activation of tumorigenic hepatic progenitor cells, which initiated hepatocarcinogenesis. PA mutational signature, as the unique molecular fingerprint of PA‐induced mutation, was derived from exome mutations in retrorsine‐exposed mice and HepaRG cells. Notably, PA mutational signature was validated in genomes of patients with PPA‐positive liver cancer but not patients with PPA‐negative liver cancer, confirming the specificity of this biomarker in revealing PA‐associated liver cancers. Furthermore, we examined the established PA mutational signature in 1,513 liver cancer genomes and found that PA‐associated liver cancers were potentially prevalent in Asia (Mainland China 48%, Hong Kong 44%, Japan 22%, South Korea 6%, Southeast Asia 25%) but minor in Western countries (North America 3% and Europe 5%).
Conclusions
This study provides a clinical indication of PA‐associated liver cancer. We discovered an unexpectedly extensive implication of PA exposure in patients with liver cancer, laying the scientific basis for precautionary approaches and prevention of PA‐associated human liver cancers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Self-powered intermittent systems typically adopt runtime checkpointing as a means to accumulate computation progress across power cycles and recover system status from power failures. However, ...existing approaches based on the checkpointing paradigm normally require system suspension and/or logging at runtime. This article presents a design which overcomes the drawbacks of checkpointing-based approaches, to enable failure-resilient intermittent systems. Our design allows accumulative execution and instant system recovery under frequent power failures while enforcing the serializability of concurrent task execution to improve computation progress and ensuring data consistency without system suspension during runtime, by leveraging the characteristics of data accessed in hybrid memory. We integrated the design into FreeRTOS running on a Texas Instruments device. The experimental results show that our design can still accumulate progress when the power source is too weak for checkpointing-based approaches to advance, and significantly improves the computation progress while reducing the recovery time.
The purpose of this study is to investigate the effects of laser spot size on the mechanical properties of AISI 420 stainless steel, fabricated by selective laser melting (SLM), process. Tensile ...specimens were built directly via the SLM process, using various laser spot diameters, namely 0.1, 0.2, 0.3, and 0.4 mm. The corresponding volumetric energy density (EV) is 80, 40, 26.7, and 20 J/mm3, respectively. Experimental results indicate that laser spot size is an important process parameter and has significant effects on the surface roughness, hardness, density, tensile strength, and microstructure of the SLM AISI 420 builds. A large laser spot with low volumetric energy density results in balling, un-overlapped defects, a large re-heated zone, and a large sub-grain size. As a result, SLM specimens fabricated by the largest laser spot diameter of 0.4 mm exhibit the roughest surface, lowest densification, and lowest ultimate tensile strength. To ensure complete melting of the powder and melt pool stability, EV of 80 J/mm3 proves to be a suitable laser energy density value for the given SLM processing and material system.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
![Glutamate-Evoked Ca[sup.2+]...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1422-0067/small "Glutamate-Evoked Ca[sup.2+] Responses in the Rat Suprachiasmatic Nucleus: Involvement of Na[sup.+]/K[sup.+]-ATPase and Na[sup.+]/Ca[sup.2+]-Exchanger")
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