SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.

Barriers and future improvements of workplace-based learning in Korean medicine clinical clerkship: perspectives of graduates.

BACKGROUND: Workplace-based learning (WPBL) has emerged as an essential practice in healthcare education. However, WPBL is rarely implemented in Korean medicine (KM) due to the passive attitude of teachers and possible violation of medical laws that limit the participation of trainees in medical treatment. In this study, we implemented WPBL in the clinical clerkship of Acupuncture and Moxibustion Medicine at a single College of KM and explored the barriers and future improvements of WPBL. METHODS: The WPBL was implemented from January to July 2019. During the clerkship, each senior student was assigned an inpatient at the university hospital. WPBL was conducted as follows: patient presentation by the supervisor, interaction with the patient at the bedside, preparation of medical records, oral case presentation, and discussion with feedback. The student performed a physical examination and review of systems as a clinical task. In addition, six doctors of KM who are currently practicing after three years of WPBL were interviewed in September 2022 to investigate the real-world effects and unmet needs of WPBL in their workplaces. RESULTS: Two major themes identified from the interview were: "the experience of novice doctors of KM with KM practice" and "Current state of KM clinical education." The five subcategories were: "Clinical competency priorities vary according to the KM workplace," "Difficulties faced by doctors of KM immediately after graduation," "WPBL experience of the interviewees," "Necessary but difficult to implement real patient learning," and "Unmet needs for clinical clerkship in KM." CONCLUSION: It is essential to consider the unique characteristics of KM practice and the duties required in various workplaces for successful WPBL. We anticipate our study to be a starting point for improving the WPBL and addressing the unmet needs in KM clinical education.

Phase-dependent gas sensitivity of MoS2 chemical sensors investigated with phase-locked MoS2.

In the present study, phase-dependent gas sensitivities of MoS2 chemical sensors were examined. While 1T-phase MoS2 (1T-MoS2) has shown better chemical sensitivity than has 2H-phase MoS2 (2H-MoS2), the instability of the 1T phase has been hindering applications of 1T-MoS2 as chemical sensors. Here, the chemical sensitivity of MoS2 locked in its 1T phase by using a ZnO phase lock was investigated. To develop MoS2 chemical sensors locked in the 1T phase, we synthesized a multi-dimensional nanomaterial by growing ZnO nanorods onto MoS2 nanosheets (ZnO@1T-MoS2). Raman spectroscopy and x-ray photoelectron spectroscopy analyses of such phase-locked 1T-MoS2 subjected to flash light irradiation 100 times confirmed its robustness. ZnO nanomaterials hybridized on MoS2 nanosheets not only froze the MoS2 at its 1T phase, but also increased the active surface area for chemical sensing. The resulting hybridized material showed better response, namely better sensitivity, to NO2 gas exposure at room temperature than did 1T-MoS2 and 2H-MoS2. This result indicated that increased surface area and heterojunction formation between MoS2 and ZnO constitute a more promising route for improving sensitivity than using the 1T phase itself.

Development of New Stringency Indices for Nonpharmacological Social Distancing Policies Implemented in Korea During the COVID-19 Pandemic: Random Forest Approach.

BACKGROUND: In the absence of an effective treatment method or vaccine, the outbreak of the COVID-19 pandemic elicited a wide range of unprecedented restriction policies aimed at mitigating and suppressing the spread of the SARS-CoV-2 virus. These policies and their Stringency Index (SI) of more than 160 countries were systematically recorded in the Oxford COVID-19 Government Response Tracker (OxCGRT) data set. The SI is a summary measure of the overall strictness of these policies. However, the OxCGRT SI may not fully reflect the stringency levels of the restriction policies implemented in Korea. Korea implemented 33 COVID-19 restriction policies targeting 4 areas: public facilities, public events, social gatherings, and religious gatherings. OBJECTIVE: This study aims to develop new Korea Stringency Indices (KSIs) that reflect the stringency levels of Korea's restriction policies better and to determine which government-implemented policies were most effective in managing the COVID-19 pandemic in Korea. METHODS: The random forest method was used to calculate the new KSIs using feature importance values and determine their effectiveness in managing daily COVID-19 confirmed cases. Five analysis periods were considered, including November 01, 2020, to January 20, 2021 (Period 1), January 20, 2021, to June 27, 2021 (Period 2), November 01, 2020, to June 27, 2021 (Period 3), June 27, 2021, to November 01, 2021 (Period 4), and November 01, 2021, to April 24, 2022 (Period 5). RESULTS: Among the KSIs, public facilities in period 4, public events in period 2, religious gatherings in periods 1 and 3, and social gatherings in period 5 had the highest importance. Among the public facilities, policies associated with operation hour restrictions in cinemas, restaurants, PC rooms, indoor sports facilities, karaoke, coffee shops, night entertainment facilities, and baths or saunas had the highest importance across all analysis periods. Strong positive correlations were observed between daily confirmed cases and public facilities, religious gatherings, and public events in period 1 of the pandemic. From then, weaker and negative correlations were observed in the remaining analysis periods. The comparison with the OxCGRT SI showed that the SI had a relatively lower feature importance and correlation with daily confirmed cases than the proposed KSIs, making KSIs more effective than SI. CONCLUSIONS: Restriction policies targeting public facilities were the most effective among the policies analyzed. In addition, different periods call for the enforcement of different policies given their effectiveness varies during the pandemic.

Forecasting the spread of COVID-19 based on policy, vaccination, and Omicron data.

The COVID-19 pandemic caused by the novel SARS-COV-2 virus poses a great risk to the world. During the COVID-19 pandemic, observing and forecasting several important indicators of the epidemic (like new confirmed cases, new cases in intensive care unit, and new deaths for each day) helped prepare the appropriate response (e.g., creating additional intensive care unit beds, and implementing strict interventions). Various predictive models and predictor variables have been used to forecast these indicators. However, the impact of prediction models and predictor variables on forecasting performance has not been systematically well analyzed. Here, we compared the forecasting performance using a linear mixed model in terms of prediction models (mathematical, statistical, and AI/machine learning models) and predictor variables (vaccination rate, stringency index, and Omicron variant rate) for seven selected countries with the highest vaccination rates. We decided on our best models based on the Bayesian Information Criterion (BIC) and analyzed the significance of each predictor. Simple models were preferred. The selection of the best prediction models and the use of Omicron variant rate were considered essential in improving prediction accuracies. For the test data period before Omicron variant emergence, the selection of the best models was the most significant factor in improving prediction accuracy. For the test period after Omicron emergence, Omicron variant rate use was considered essential in deciding forecasting accuracy. For prediction models, ARIMA, lightGBM, and TSGLM generally performed well in both test periods. Linear mixed models with country as a random effect has proven that the choice of prediction models and the use of Omicron data was significant in determining forecasting accuracies for the highly vaccinated countries. Relatively simple models, fit with either prediction model or Omicron data, produced best results in enhancing forecasting accuracies with test data.

Mothers' Experiences of Childbirth and Perspectives on Korean Medicine-Based Postpartum Care in Korea: A Qualitative Study.

This study aimed to record the experiences of childbirth and postpartum care of postpartum women and gain an in-depth understanding of their experiences of Korean medicine-based postpartum healthcare. The investigator conducted a 60-90-min interview with the 8 participants (mean age 34 years), and the comments were analyzed using the thematic analysis method. The two major themes emerging from the participants' comments were: "experience and awareness of childbirth and postpartum care" and "experiences of the Korean medicine-based postpartum program". The first theme was analyzed in four primary categories: (1) experiences of breakdown of the body and mind; (2) impossibility of postpartum care without help; (3) experiences of relentless effort for recovery; and (4) experiences of body and mind recovery. The second theme was analyzed in four primary categories: (1) participation with vague expectations; (2) experiences of the effects of managing postpartum symptoms; (3) the need for a comprehensive Korean medicine management for postpartum women; and (4) suggested improvements for the Korean medicine-based postpartum program. Mothers recognized the importance of Korean medicine treatment during the postpartum period for the management of Sanhupung symptoms and postpartum care and reported the benefits of body warming, Sanhupung prevention, pain reduction, and sense of psychological stability.

A case study on the application evaluation of integrative medical service model for the improvement of quality of life for dementia patients and caregivers.

BACKGROUND: Since 4 major diseases and geriatric diseases require consistent management, individuals with any of these diseases cannot live alone and need caregivers' assistance. Given these characteristics, an integrative medical service model for 4 major diseases and geriatric diseases was developed in Korea, currently. Dementia, one of the typical geriatric diseases, requires caregivers' assistance from the beginning because of its enormous burden. Thus, it is necessary to provide an integrative medical service that can improve the quality of life (QoL) for both patients and caregivers. Therefore, this study aims to collect various feedback by applying an integrative medical service, which was developed to improve the QoL in patients with dementia and their caregivers, to a single case, and to modify and improve the integrative medical service model based on the results. METHOD/DESIGN: The integrative medical service program, which was developed to improve the QoL in patients with dementia and their caregivers in Korea, will be used for a patient-caregiver pair. This is an observational study with quantitative and qualitative feedback from various viewpoints. The program will be conducted in 8 sessions (twice a week, within 120 minutes). The patient will receive both Western and Korean medicine, and an integrative service will be provided to improve cognitive rehabilitation and QoL. Feedback collected at each session will be reflected on the program of the subsequent session. RESULTS: This study will then modify and improve the program with feedback and provide integrative medical services to a patient with dementia and caregiver. DISCUSSION: Patients with dementia need a program that would help them maintain cognitive function, and caregivers need a program that would improve their QoL by reducing the caregiving burden. This study is unique because the developed program is performed after modification based on feedback from the previous session. Accordingly, the patient and caregiver can check which program is the most satisfactory and helpful in improving their QoL. We expect that this study can modify the integrative medical service model to the optimized patient-based model. This study can also be used as basic data for a clinical pathway development study that applies the modified model to medical institutes.

Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals.

Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination. Recent studies have identified PSD-95 and cofilin as substrates for neddylation in the brain and have shown that neddylation modulates the maturation and stability of dendritic spines in developing neurons. However, the precise substrates and functional consequences of neddylation at presynaptic terminals remain elusive. Here, we provide evidence that the mGlu7 receptor is a target of neddylation in heterologous cells and rat primary cultured neurons. We found that mGlu7 neddylation is reduced by agonist treatment and is required for the clustering of mGlu7 in the presynaptic active zone. In addition, we observed that neddylation is not required for the endocytosis of mGlu7, but it facilitates the ubiquitination of mGlu7 and stabilizes mGlu7 protein expression. Finally, we demonstrate that neddylation is necessary for the maturation of excitatory presynaptic terminals, providing a key role for neddylation in synaptic function.

Forecasting of the COVID-19 pandemic situation of Korea.

For the novel coronavirus disease 2019 (COVID-19), predictive modeling, in the literature, uses broadly susceptible exposed infected recoverd (SEIR)/SIR, agent-based, curve-fitting models. Governments and legislative bodies rely on insights from prediction models to suggest new policies and to assess the effectiveness of enforced policies. Therefore, access to accurate outbreak prediction models is essential to obtain insights into the likely spread and consequences of infectious diseases. The objective of this study is to predict the future COVID-19 situation of Korea. Here, we employed 5 models for this analysis; SEIR, local linear regression (LLR), negative binomial (NB) regression, segment Poisson, deep-learning based long short-term memory models (LSTM) and tree based gradient boosting machine (GBM). After prediction, model performance comparison was evelauated using relative mean squared errors (RMSE) for two sets of train (January 20, 2020‒December 31, 2020 and January 20, 2020‒January 31, 2021) and testing data (January 1, 2021‒February 28, 2021 and February 1, 2021‒February 28, 2021) . Except for segmented Poisson model, the other models predicted a decline in the daily confirmed cases in the country for the coming future. RMSE values' comparison showed that LLR, GBM, SEIR, NB, and LSTM respectively, performed well in the forecasting of the pandemic situation of the country. A good understanding of the epidemic dynamics would greatly enhance the control and prevention of COVID-19 and other infectious diseases. Therefore, with increasing daily confirmed cases since this year, these results could help in the pandemic response by informing decisions about planning, resource allocation, and decision concerning social distancing policies.

Statistical Estimation of Effects of Implemented Government Policies on COVID-19 Situation in South Korea.

Since the outbreak of novel SARS-COV-2, each country has implemented diverse policies to mitigate and suppress the spread of the virus. However, no systematic evaluation of these policies in their alleviation of the pandemic has been done. We investigate the impact of five indices derived from 12 policies in the Oxford COVID-19 Government Response Tracker dataset and the Korean government's index, which is the social distancing level implemented by the Korean government in response to the changing pandemic situation. We employed segmented Poisson model for this analysis. In conclusion, health and the Korean government indices are most consistently effective (with negative coefficients), while the restriction and stringency indexes are mainly effective with lagging (1~10 days), as intuitively daily confirmed cases of a given day is affected by the policies implemented days before, which shows that a period of time is required before the impact of some policies can be observed. The health index demonstrates the importance of public information campaign, testing policy and contact tracing, while the government index shows the importance of social distancing guidelines in mitigating the spread of the virus. These results imply the important roles of these polices in mitigation of the spread of COVID-19 disease.

Which National Factors Are Most Influential in the Spread of COVID-19?

The outbreak of the novel COVID-19, declared a global pandemic by WHO, is the most serious public health threat seen in terms of respiratory viruses since the 1918 H1N1 influenza pandemic. It is surprising that the total number of COVID-19 confirmed cases and the number of deaths has varied greatly across countries. Such great variations are caused by age population, health conditions, travel, economy, and environmental factors. Here, we investigated which national factors (life expectancy, aging index, human development index, percentage of malnourished people in the population, extreme poverty, economic ability, health policy, population, age distributions, etc.) influenced the spread of COVID-19 through systematic statistical analysis. First, we employed segmented growth curve models (GCMs) to model the cumulative confirmed cases for 134 countries from 1 January to 31 August 2020 (logistic and Gompertz). Thus, each country's COVID-19 spread pattern was summarized into three growth-curve model parameters. Secondly, we investigated the relationship of selected 31 national factors (from KOSIS and Our World in Data) to these GCM parameters. Our analysis showed that with time, the parameters were influenced by different factors; for example, the parameter related to the maximum number of predicted cumulative confirmed cases was greatly influenced by the total population size, as expected. The other parameter related to the rate of spread of COVID-19 was influenced by aging index, cardiovascular death rate, extreme poverty, median age, percentage of population aged 65 or 70 and older, and so forth. We hope that with their consideration of a country's resources and population dynamics that our results will help in making informed decisions with the most impact against similar infectious diseases.

Effects of government policies on the spread of COVID-19 worldwide.

The outbreak of novel COVID-19 disease elicited a wide range of anti-contagion and economic policies like school closure, income support, contact tracing, and so forth, in the mitigation and suppression of the spread of the SARS-CoV-2 virus. However, a systematic evaluation of these policies has not been made. Here, 17 implemented policies from the Oxford COVID-19 Government Response Tracker dataset employed in 90 countries from December 31, 2019, to August 31, 2020, were analyzed. A Poisson regression model was applied to analyze the relationship between policies and daily confirmed cases using a generalized estimating equations approach. A lag is a fixed time displacement in time series data. With that, lagging (0, 3, 7, 10, and 14 days) was also considered during the analysis since the effects of policies implemented on a given day may affect the number of confirmed cases several days after implementation. The countries were divided into three groups depending on the number of waves of the pandemic observed in each country. Through subgroup analysis, we showed that with and without lagging, contact tracing and containment policies were significant for countries with two waves, while closing, economic, and health policies were significant for countries with three waves. Wave-specific analysis for each wave showed that significant health, economic, and containment policies varied across waves of the pandemic. Emergency investment in healthcare was consistently significant among the three groups of countries, while the Stringency index was significant among all waves of the pandemic. These findings may help in making informed decisions regarding whether, which, or when these policies should be intensified or lifted.

Suicidal Ideation of the Elderly According to Their Involvement in Grandchild Care.

The purpose of the present study was to examine the severity of suicidal ideation of the older adults according to the amount of involvement in grandchild care. Data for this research were drawn from a cross-sectional study conducted on community-dwelling adults aged 65 years or older. The 922 participants were divided into three groups according to their involvement in grandchild care: 18.5% had provided daily care, 12.4% had provided occasional care, and 69.1% had never cared for their grandchildren. ANCOVA analysis showed that the scores for depression was significantly lower in the group which took care of their grandchildren occasionally compared to the other two groups. The scores for suicidal ideation was significantly higher in the group which had never taken care of their grandchildren compared to the other two groups. Current study suggests that grandparenting may have a positive effect on suicidal ideation of the older adults.

Time-dependent effects of free fatty acids on glucose effectiveness in type 2 diabetes.

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.

The rice FON1 gene controls vegetative and reproductive development by regulating shoot apical meristem size.

Most plant organs develop from meristems. Rice FON1, which is an ortholog of Clv1, regulates stem cell proliferation and organ initiation. The point muta-tions, fon1-1 and fon1-2, disrupt meristem balance, resulting in alteration of floral organ numbers and the architecture of primary rachis branches. In this study, we identified two knockout alleles, fon1-3 and fon1-4, generated by T-DNA and Tos17 insertion, respectively. Unlike the previously isolated point mutants, the null mutants have alterations not only of the reproductive organs but also of vegetative tissues, producing fewer tillers and secondary rachis branches. The mutant plants are semi-dwarfs due to delayed leaf emergence, and leaf senescence is delayed. SEM analysis showed that the shoot apical meristems of fon1-3 mutants are enlarged. These results indicate that FON1 controls vegetative as well as reproductive development by regulating meristem size.

Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans.

Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans.

Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants.

BACKGROUND: Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs). METHODS: Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers. RESULTS: We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index-matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants. CONCLUSIONS: These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases.

Adipocyte-derived factors potentiate nutrient-induced production of plasminogen activator inhibitor-1 by macrophages.

Macrophages are more abundant in adipose tissue from obese individuals than from those of normal weight and may contribute to the metabolic consequences of obesity by producing various circulating factors. One of these factors is plasminogen activator inhibitor-1 (PAI-1), which contributes to both atherosclerosis and insulin resistance. Because nutritional factors appear to regulate PAI-1 expression, we hypothesized that exposure to fatty acids and adipocyte secretory products could stimulate production of PAI-1 by adipose macrophages. Increased free fatty acid (FFA) concentrations in blood for 5 hours in nondiabetic, overweight subjects markedly suppressed insulin-stimulated glucose uptake and raised circulating PAI-1 concentrations, with a concomitant increase in the expression of the PAI-1 gene in adipose tissue. FFAs also rapidly increased PAI-1 gene expression in adipose macrophages and PAI-1 protein immunofluorescence surrounding these cells. By contrast, PAI-1 expression in circulating monocytes was very low and was not affected by raising the concentration of FFAs. Medium from cultured adipocytes stimulated PAI-1 expression in cultured macrophages and potentiated the increase in PAI-1 messenger RNA expression in response to FFAs. Together, our data suggest that adipocyte-derived factors prime adipose macrophages so that they respond to nutritional signals (FFAs) by releasing a key inflammatory adipokine, PAI-1.

Getting the message across: mechanisms of physiological cross talk by adipose tissue.

Obesity is associated with resistance of skeletal muscle to insulin-mediated glucose uptake, as well as resistance of different organs and tissues to other metabolic and vascular actions of insulin. In addition, the body is exquisitely sensitive to nutrient imbalance, with energy excess or a high-fat diet rapidly increasing insulin resistance, even before noticeable changes occur in fat mass. There is a growing acceptance of the fact that, as well as acting as a storage site for surplus energy, adipose tissue is an important source of signals relevant to, inter alia, energy homeostasis, fertility, and bone turnover. It has also been widely recognized that obesity is a state of low-grade inflammation, with adipose tissue generating substantial quantities of proinflammatory molecules. At a cellular level, the understanding of the signaling pathways responsible for such alterations has been intensively investigated. What is less clear, however, is how alterations of physiology, and of signaling, within one cell or one tissue are communicated to other parts of the body. The concepts of cell signals being disseminated systemically through a circulating "endocrine" signal have been complemented by the view that local signaling may similarly occur through autocrine or paracrine mechanisms. Yet, while much elegant work has focused on the alterations in signaling that are found in obesity or energy excess, there has been less attention paid to ways in which such signals may propagate to remote organs. This review of the integrative physiology of obesity critically appraises the data and outlines a series of hypotheses as to how interorgan cross talk takes place. The hypotheses presented include the "fatty acid hypothesis,", the "portal hypothesis,", the "endocrine hypothesis,", the "inflammatory hypothesis,", the "overflow hypothesis,", a novel "vasocrine hypothesis," and a "neural hypothesis," and the strengths and weaknesses of each hypothesis are discussed.

Identification of active transposon dTok, a member of the hAT family, in rice.

Recent completion of the sequencing of the rice genome has revealed that it contains >40% repetitive sequences, most of which are related to inactive transposable elements. During the molecular analysis of the floral organ number 1/multiple pistil 2 (fon1/mp2) mutant, we identified an active transposable element dTok0 that was inserted at the kinase domain of FON1, a homolog of CLAVATA1. Insertion of the element into FON1 generated an 8 bp duplication of its target sites, which is one of the major characteristics of the hAT family of transposons. The dTok0 element was actively transposed out of the FON1 gene, leaving 5-8 bp footprints. Reinsertion into a new location was observed at a low frequency. Analysis of the genome sequence showed that the rice cultivar 'Nipponbare' contains 25 copies of dTok elements; similar numbers were present in all the Oryza species examined. Because dTok0 does not encode a transposase, enzyme activity should be provided in trans. We identified a putative autonomous transposon, Tok1 that contains an intact open reading frame of the Ac-like transposase.