Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications

NGL-1/LRRC4C Deletion Moderately Suppresses Hippocampal Excitatory Synapse Development and Function in an Input-Independent Manner

Netrin-G ligand-1 (NGL-1), also known as LRRC4C, is a postsynaptic densities (PSDs)-95-interacting postsynaptic adhesion molecule that interacts trans-synaptically with presynaptic netrin-G1. NGL-1 and its family member protein NGL-2 are thought to promote excitatory synapse development through largely non-overlapping neuronal pathways. While NGL-2 is critical for excitatory synapse development in specific dendritic segments of neurons in an input-specific manner, whether NGL-1 has similar functions is unclear. Here, we show that Lrrc4c deletion in male mice moderately suppresses excitatory synapse development and function, but surprisingly, does so in an input-independent manner. While NGL-1 is mainly detected in the stratum lacunosum moleculare (SLM) layer of the hippocampus relative to the stratum radiatum (SR) layer, NGL-1 deletion leads to decreases in the number of PSDs in both SLM and SR layers in the ventral hippocampus. In addition, both SLM and SR excitatory synapses display suppressed short-term synaptic plasticity in the ventral hippocampus. These morphological and functional changes are either absent or modest in the dorsal hippocampus. The input-independent synaptic changes induced by Lrrc4c deletion involve abnormal translocation of NGL-2 from the SR to SLM layer. These results suggest that Lrrc4c deletion moderately suppresses hippocampal excitatory synapse development and function in an input-independent manner

Limitations in representation of physical processes preven successful simulation of PM2.5 during KORUS-AQ

High levels of fine particulate matter (PM2.5) pollution in East Asia often exceed local air quality standards. Observations from the Korea United States-Air Quality (KORUS-AQ) field campaign in May and June 2016 showed that development of extreme pollution (haze) occurred through a combination of long-range transport and favorable meteorological conditions that enhanced local production of PM2.5. Atmospheric models often have difficulty simulating PM2.5 chemical composition during haze, which is of concern for the development of successful control measures. We use observations from KORUS-AQ to examine the ability of the GEOS-Chem chemical transport model to simulate PM2.5 composition throughout the campaign and identify the mechanisms driving the pollution event. In the surface level, the model underestimates campaign average sulfate aerosol by −64 % but overestimates nitrate aerosol by 36 %. The largest underestimate in sulfate occurs during the pollution event in conditions of high relative humidity, where models typically struggle to generate the high concentrations due to missing heterogeneous chemistry in aerosol liquid water in the polluted boundary layer. Hourly surface observations show that the model nitrate bias is driven by an overestimation of the nighttime peak. In the model, nitrate formation is limited by the supply of nitric acid, which is biased by +100 % against aircraft observations. We hypothesize that this is due to a missing sink, which we implement here as a factor of five increase in dry deposition. We show that the resulting increased deposition velocity is consistent with observations of total nitrate as a function of photochemical age. The model does not account for factors such as the urban heat island effect or the heterogeneity of the built-up urban landscape resulting in insufficient model turbulence and surface area over the study area that likely results in insufficient dry deposition. Other species such as NH3 could be similarly affected but were not measured during the campaign. Nighttime production of nitrate is driven by NO2 hydrolysis in the model, while observations show that unexpectedly elevated nighttime ozone (not present in the model) should result in N2O5 hydrolysis as the primary pathway. The model is unable to represent nighttime ozone due to an overly rapid collapse of the afternoon mixed layer and excessive titration by NO. We attribute this to missing nighttime heating driving deeper nocturnal mixing that would be expected to occur in a city like Seoul. This urban heating is not considered in air quality models run at large enough scales to treat both local chemistry and long-range transport. Key model failures in simulating nitrate, mainly overestimated daytime nitric acid, incorrect representation of nighttime chemistry, and an overly shallow and insufficiently turbulent nighttime mixed layer, exacerbate the model’s inability to simulate the buildup of PM2.5 during haze pollution. To address the underestimate in sulfate most evident during the haze event, heterogeneous aerosol uptake of SO2 is added to the model which previously only considered aqueous production of sulfate from SO2 in cloud water. Implementing a simple parameterization of this chemistry improves the model abundance of sulfate but degrades the SO2 simulation implying that emissions are underestimated. We find that improving model simulations of sulfate has direct relevance to determining local vs. transboundary contributions to PM2.5. During the haze pollution event, the inclusion of heterogeneous aerosol uptake of SO2 decreases the fraction of PM2.5 attributable to long-range transport from 66 % to 54 %. Locally-produced sulfate increased from 1 % to 46 % of locally-produced PM2.5, implying that local emissions controls would have a larger effect than previously thought. However, this additional uptake of SO2 is coupled to the model nitrate prediction which affects the aerosol liquid water abundance and chemistry driving sulfate-nitrate-ammonium partitioning. An additional simulation of the haze pollution with heterogeneous uptake of SO2 to aerosol and simple improvements to the model nitrate simulation results in 30 % less sulfate due to 40 % less nitrate and aerosol water, and results in an underestimate of sulfate during the haze event. Future studies need to better consider the impact of model physical processes such as dry deposition and boundary layer mixing on the simulation of nitrate and the effect of improved nitrate simulations on the overall simulation of secondary inorganic aerosol (sulfate+nitrate+ammonium) in East Asia. Foreign emissions are rapidly changing, increasing the need to understand the impact of local emissions on PM2.5 in South Korea to ensure continued air quality improvements

An Intelligent Planner of Processing Equipment for CSCW-based Shop Floor Control in Agile Manufacturing

A common control model used to implement computer integrated manufacturing(CIM) is based on the hierarchical decomposition of the shop floor activities, in which supervisory controllers are responsible for all the interactions among subordinates. Although the hierarchical control philosophy provides for easy understanding of complex systems, an emerging manufacturing paradigm, agile manufacturing, requires a new control structure necessary to accommodate the rapid development of a shop floor controller. This is what is called CSCW(computer supported cooperative work)-based control or component-based heterarchical control. As computing resources and communication network on the shop floor become increasingly intelligent and powerful, the new control architecture is about to come true in a modern CIM system. In this paper, CSCW-based control is adopted and investigated, in which a controller for a unit of device performs 3 main functions - planning, scheduling and execution. In this paper, attention is paid to a planning function and all the detailed planning activities for CSCW-based shop floor control are identified. Interactions with other functions are also addressed. Generally speaking, planning determines tasks to be scheduled in the future. In other words, planning analyzes process plans and transforms process plans into detailed plans adequate for shop floor control. Planning is also responsible for updating the process plan and identifying/resolving replanning activities whether they come from scheduling or execution

Development of a planner of processing equipments for heterarchical SFCS

A common control model used to implement computer integrated manufacturing(CIM) is based on the hierarchical decomposition of the shop floor activities, in which supervisory controllers are responsible for all the interactions among subordinates. Although the hierarchical control philosophy provides for easy understanding of complex systems, an emerging manufacturing paradigm, agile manufacturing, requires a new control structure necessary to accommodate the rapid development of a shop floor controller. This is what is called autonomous agent-based heterarchical control. As computing resources and communication network on the shop floor become increasingly intelligent and powerful, the new control architecture is about to come true in a modern CIM system. In this paper, heterarchical control is adopted and investigated, in which a controller for a unit of device performs three main functions - planning, scheduling and execution. Attention is paid to the planning function and all the detailed planning activities for heterarchical shop floor control are identified. Interactions with other functions are also addressed. In general, planning determines tasks to be scheduled in the future. In other words, planning analyzes process plans and transforms process plans into detailed plans adequate for shop floor control. Planning is also responsible for updating a process plan and identifying/resolving replanning activities whether they come from scheduling or execution.clos

Architectural Requirements for Rapid Development of Agile Manufacturing Systems

As product life cycle becomes shortened, high product quality becomes necessary for survival, and continuous and unexpected change becomes key obstacles in success, the need for a method of rapidly and cost-effectively developing products, production facilities and supporting software including design, process planning, shop floor control systems becomes urgent. The essence of this concept of manufacturing would be characterized by adopting a new term "agility". Agile manufacturing can be successfully accomplished using various well-defined system architecture. This paper provides a primary sketch of architectural requirements for rapid development of agile manufacturing systems. There are several aspects of system architecture : control, function, process, information, communication, distribution, development, and implementation. In the past, the confusion of those architectures prohibited the successful construction of the automated CIM systems

Rise of Work from Home & Post-pandemic Urban Form in Global Cities

COVID-19 pandemic has unprecedented impact on the lives of urban residents in global cities. Due to the changing lifestyle facing the pandemic, global cities have experienced the structural shift in urban form. This paper aims to study the changing patterns of commuting (resulted from increasing work from home options), population (re)distribution, demand in office space at urban cores among the four global cities facing the COVID-19 pandemic. The four global cities included in this study are New York, London, Tokyo, and Los Angeles. Through meta-analysis among these four global cities, this paper compares the pandemic experience shapes the evolution of structural shifts in urban form. For all four cast study cities, the share of WfH (Work from Home) among workers has significantly increased during the pandemic and this pattern is expected to last in post-pandemic era. Population (re)distribution pattern differs slightly. In the global cities like New York, London, and Tokyo, intra-metro residential relocation was the main type of population redistribution. However, in Los Angeles, the inter-metro migration (mainly out-migration) to nearby metros with rapidly growing economy and more affordable housing options was the dominant type of population (re)distribution in pandemic. With the high WfH pattern in post-pandemic era, the observed population (re)distribution pattern is expected continue. Accordingly, demand for office space at urban core declines with higher vacancy rate and lower rental prices compared to that during the pre-pandemic period

Gene Dosage- and Age-Dependent Differential Transcriptomic Changes in the Prefrontal Cortex of Shank2-Mutant Mice

Shank2 is an abundant postsynaptic scaffolding protein that is known to regulate excitatory synapse assembly and synaptic transmission and has been implicated in various neurodevelopmental disorders, including autism spectrum disorders (ASD). Previous studies on Shank2-mutant mice provided mechanistic insights into their autistic-like phenotypes, but it remains unclear how transcriptomic patterns are changed in brain regions of the mutant mice in age- and gene dosage-dependent manners. To this end, we performed RNA-Seq analyses of the transcripts from the prefrontal cortex (PFC) of heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile (week 3) and adult (week 12) stages. Juvenile heterozygous Shank2-mutant mice showed upregulation of glutamate synapse-related genes, downregulation of ribosomal and mitochondrial genes, and transcriptomic changes that are opposite to those observed in ASD (anti-ASD) such as upregulation of ASD_down (downregulated in ASD), GABA neuron-related, and oligodendrocyte-related genes. Juvenile homozygous Shank2 mice showed upregulation of chromatin-related genes and transcriptomic changes that are in line with those occurring in ASD (pro-ASD) such as downregulation of ASD_down, GABA neuron-related, and oligodendrocyte-related genes. Adult heterozygous and homozygous Shank2-mutant mice both exhibited downregulation of ribosomal and mitochondrial genes and pro-ASD transcriptomic changes. Therefore, the gene dosage- and age-dependent effects of Shank2 deletions in mice include differential transcriptomic changes across distinct functional contexts, including synapses, chromatin, ribosomes, mitochondria, GABA neurons, and oligodendrocytes.11Nsciescopu

Ethyl Pyruvate Directly Attenuates Active Secretion of HMGB1 in Proximal Tubular Cells via Induction of Heme Oxygenase-1

Renal ischemia reperfusion (IR) is a main cause of acute kidney injury leading to high morbidity and mortality during postoperative periods. This study investigated whether ethyl pyruvate (EP) protects the kidney against renal IR injury. Male C57BL/6 mice were treated with vehicle or EP (40 mg/kg) 1 h before ischemia and the plasma creatinine (Cr) levels and tubular damage were evaluated after reperfusion. EP attenuated the IR-induced plasma Cr levels, renal inflammation and apoptotic cell death, but the effect of EP was abolished by pretreating Zinc protoporphyrin (ZnPP), a heme oxygenase (HO)-1 inhibitor. HO-1 is a stress-induced protein and protects the kidney against IR injury. EP increased significantly HO-1 expression in the proximal tubular cells in vivo and HK-2 cells in vitro. Inhibition of PI3K/Akt pathway and knockdown of Nrf2 blocked HO-1 induction by EP. High mobility group box 1 (HMGB1) secretion was assessed as an early mediator of IR injury; plasma HMGB1 were significantly elevated as early as 2 h to 24 h after reperfusion and these were attenuated by EP, but the effect of EP was abolished by ZnPP. EP also reduced HMGB1 secretion stimulated by TNF-α in HK-2 cells, and the inhibition of PI3K/Akt and knockdown of HO-1 blocked the effect of EP. Conclusively, EP inhibits the active secretion of HMGB1 from proximal tubular cells during IR injury by inducing HO-1 via activation of PI3K/Akt and Nrf2 pathway

Mineralocorticoid Receptor Antagonism Attenuates Multiple Organ Failure after Renal Ischemia and Reperfusion in Mice

Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR