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The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

The sludge in this study was obtained from refinery crude oil storage tanks. It contained a high proportion of hydrocarbon composition and harmful substances (such as polycyclic aromatic hydrocarbons and benzene). Through the microwave irradiation treatment process, the harmful substances were removed from the sludge which was then recycled and combined with agricultural waste mushroom substrates to produce refuse derived fuel (RDF). The results showed that the calorific value of RDF was 7279 cal/g when the blending ratio (wt/wt) of oil sludge and mushroom substrates was 5:5. On the other hand, when the portion of the mushroom substrates was increased, the sludge became easier to ignite with better combustion reaction. When the blending ratio (wt/wt) was changed from 8:2 to 5:5, the ignition index and comprehensive performance index were increased by 51.9 and 50.2%. Therefore, mixing the sludge with agricultural waste mushroom substrates is in line with the concept of waste recycling and circular economy.

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing translating ribosome affinity purification with RNA-sequencing (TRAP-seq) data with single-nucleus RNA-sequencing (snRNA-seq) data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of six major genetically and anatomically differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

While Cre-dependent viral systems permit the manipulation of many neuron types, some cell populations cannot be targeted by a single DNA recombinase. Although the combined use of Flp and Cre recombinases can overcome this limitation, insufficient recombinase activity can reduce the efficacy of existing Cre+Flp-dependent viral systems. We developed a sensitive dual recombinase-activated viral approach: tTA-driven Recombinase-Guided Intersectional Targeting (tTARGIT) adeno-associated viruses (AAVs). tTARGIT AAVs utilize a Flp-dependent tetracycline transactivator (tTA) ‘Driver’ AAV and a tetracycline response element-driven, Cre-dependent ‘Payload’ AAV to express the transgene of interest. We employed this system in Slc17a6FlpO;LeprCre mice to manipulate LepRb neurons of the ventromedial hypothalamus (VMH; LepRbVMH neurons) while omitting neighboring LepRb populations. We defined the circuitry of LepRbVMH neurons and roles for these cells in the control of food intake and energy expenditure. Thus, the tTARGIT system mediates robust recombinase-sensitive transgene expression, permitting the precise manipulation of previously intractable neural populations.

Abstract Hepatic glucose production (HGP) is required to maintain normoglycemia during fasting. Glucagon is the primary hormone responsible for increasing HGP; however, there are many additional hormone and metabolic factors that influence glucagon sensitivity. In this study we report that the bioactive lipid lysophosphatidic acid (LPA) regulates hepatocyte glucose production by antagonizing glucagon-induced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Treatment of primary hepatocytes with exogenous LPA blunted glucagon-induced PEPCK expression and glucose production. Similarly, knockout mice lacking the LPA-degrading enzyme phospholipid phosphate phosphatase type 1 (PLPP1) had a 2-fold increase in endogenous LPA levels, reduced PEPCK levels during fasting, and decreased hepatic gluconeogenesis in response to a pyruvate challenge. Mechanistically, LPA antagonized glucagon-mediated inhibition of STAT3, a transcriptional repressor of PEPCK. Importantly, LPA did not blunt glucagon-stimulated glucose production or PEPCK expression in hepatocytes lacking STAT3. These data identify a novel role for PLPP1 activity and hepatocyte LPA levels in glucagon sensitivity via a mechanism involving STAT3.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

The authors describe Taiwan's successful strategy in achieving control of coronavirus disease (COVID-19) without economic shutdown, despite the prediction that millions of infections would be imported from travelers returning from Chinese New Year celebrations in Mainland China in early 2020. As of September 2, 2020, Taiwan reports 489 cases, 7 deaths, and no locally acquired COVID-19 cases for the last 135 days (greater than 4 months) in its population of over 23.8 million people. Taiwan created quasi population immunity through the application of established public health principles. These non-pharmaceutical interventions, including public masking and social distancing, coupled with early and aggressive identification, isolation, and contact tracing to inhibit local transmission, represent a model for optimal public health management of COVID-19 and future emerging infectious diseases.

Abstract Background The rate of cesarean delivery was 35% in 2007 in Taiwan. It is unclear how many of the cesarean deliveries were without medical indications. Women's preference for cesarean delivery during their course of pregnancy has rarely been studied and therefore our objectives were to examine rate of cesarean deliveries without medical indications, to explore women's preference for cesarean delivery as their gestation advances, and to compare background and perinatal factors among women who underwent different modes of delivery in Taiwan. Methods This prospective study applied a longitudinal design. The study participants were 473 women who received prenatal care at four hospitals in Taipei and answered structured questionnaires at 20 to 24 weeks of pregnancy, 34 to 36 weeks of pregnancy, and 5 to 7 weeks after delivery. Results Of the 151 women (31.9%) who had cesarean deliveries, 19.9% were without medical indication. Three indications: malpresentation, prior cesarean section, and dysfunctional labor together accounted for 82.6% of cesarean section with medical indications. The prevalence of maternal preference for cesarean delivery was found to be 12.5% and 17.5% during the second and third trimester, respectively. Of the women who preferred cesarean delivery during the second trimester, 93.2% eventually had a cesarean delivery. Women who were older, with older spouses, and who had health problems before or during pregnancy were more likely to have cesarean deliveries. Conclusions About 20% of cesarean deliveries were without medical indications. Women's preference for cesarean delivery during the second trimester predicts subsequent cesarean delivery. Counseling regarding mode of delivery should be offered early in pregnancy, especially for women who are older or with older spouses, have health problems, or had a prior cesarean section.

Abstract Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy.

Abstract Background Traditional Chinese medicine (TCM) has remained an integral part of Chinese culture and society for thousands of years. In Taiwan TCM is a recognized element of its National Health Insurance Scheme. However, there is no knowledge about how TCM is accessed by foreign workers from a non-Asian cultural background. The objectives of this study were to investigate the prevalence and patterns of TCM use among non-Asian white-collar workers living in Taiwan, and examine factors likely to influence their use of TCM. Methods This study applied a cross-sectional survey design. A total of 207 white-collar foreign workers of a non-Asian background currently holding National Health Insurance cards who had lived in Taiwan for 4 months or more participated in this study. Results The prevalence of TCM use was 45%. The most frequently used therapies were traditional Chinese herbs/medicine and acupuncture. Factors indicating the likelihood of TCM usage were age 31–40 years, visit to an allopathic medical doctor in the last year, ability to read Chinese, having a friend or family member available to assist in the use of TCM, and access to information about TCM services available in Taiwan. Conclusion Utilization of TCM by people of a non-Asian background living in Taiwan appears to be most influenced by enabling factors including language ability, access to information, and informal reference persons.

Abstract Background Although the previous study demonstrated the envelope protein of dengue viruses is under purifying selection pressure, little is known about the genetic differences of full-length viral genomes of DENV-3. In our study, complete genomic sequencing of DENV-3 strains collected from different geographical locations and isolation years were determined and the sequence diversity as well as selection pressure sites in the DENV genome other than within the E gene were also analyzed. Results Using maximum likelihood and Bayesian approaches, our phylogenetic analysis revealed that the Taiwan's indigenous DENV-3 isolated from 1994 and 1998 dengue/DHF epidemics and one 1999 sporadic case were of the three different genotypes – I, II, and III, each associated with DENV-3 circulating in Indonesia, Thailand and Sri Lanka, respectively. Sequence diversity and selection pressure of different genomic regions among DENV-3 different genotypes was further examined to understand the global DENV-3 evolution. The highest nucleotide sequence diversity among the fully sequenced DENV-3 strains was found in the nonstructural protein 2A (mean ± SD: 5.84 ± 0.54) and envelope protein gene regions (mean ± SD: 5.04 ± 0.32). Further analysis found that positive selection pressure of DENV-3 may occur in the non-structural protein 1 gene region and the positive selection site was detected at position 178 of the NS1 gene. Conclusion Our study confirmed that the envelope protein is under purifying selection pressure although it presented higher sequence diversity. The detection of positive selection pressure in the non-structural protein along genotype II indicated that DENV-3 originated from Southeast Asia needs to monitor the emergence of DENV strains with epidemic potential for better epidemic prevention and vaccine development.

The authors describe Taiwan's successful strategy in achieving control of coronavirus disease (COVID-19) without economic shutdown, despite the prediction that millions of infections would be imported from travelers returning from Chinese New Year celebrations in Mainland China in early 2020. As of September 2, 2020, Taiwan reports 489 cases, 7 deaths, and no locally acquired COVID-19 cases for the last 135 days (greater than 4 months) in its population of over 23.8 million people. Taiwan created quasi population immunity through the application of established public health principles. These non-pharmaceutical interventions, including public masking and social distancing, coupled with early and aggressive identification, isolation, and contact tracing to inhibit local transmission, represent a model for optimal public health management of COVID-19 and future emerging infectious diseases.

The COVID-19 pandemic has strained health care system resources and reduced the availability of life-sustaining and medical-grade personal protective equipment (PPE) though the combination of increased demand and disrupted manufacturing supply chains. As a result of these shortages, many health care providers have temporarily used largely untested, improvised PPE (iPPE). Lack of quality control for makeshift PPE and frequent repurposing of used items to conserve supplies increase both the risk of provider infection and nosocomial spread to uninfected patients. One strategy to reduce risk of infection and preserve existing equipment is the implementation of secondary barrier devices placed directly over patients or providers. The authors describe an inexpensive, disposable, positive-pressure head isolation unit that can be rapidly constructed from materials readily available in nearly all health care settings for under five US dollars. The unit was successfully deployed in Taiwan during the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, and again during the COVID-19 pandemic. The iPPE worn directly by the health care workers (HCWs) can be donned prior to patient contact in the presence of an air source. This strategy may be more protective than a covering placed over the patient in an aerosol-generating environment, which requires the HCW to be in close contact with the patient prior to securing the protective device.

Obesity is primarily due to excessive energy intake and lipid accumulation, leading to type 2 diabetes. Studies showed radish seed extract (RSE) can impede weight gain in mice, but the mechanism was unclear. We hypothesized that RSE inhibits obesity by stimulating adipocyte browning. Radish seeds were water-extracted, yielding a sulforaphene (SE) concentration of 1.381 ± 0.005 mg/g RSE. In 3T3-L1 adipocyte differentiation experiments, RSE and SE increased the expression of beige adipocyte markers uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α). In C57BL/6 mice, RSE and SE mitigated weight increase, averted fatty liver, and diminished fat accumulation. In the adipose tissue, we also noted the enhanced browning of white adipocytes through elevated expression of UCP1 and PGC1α. Increased mitochondrial numbers in treated adipocytes supported this effect. Additionally, RSE and SE improved glucose homeostasis and insulin sensitivity in high-fat diet-fed mice, indicating RSE's potential to prevent obesity and diabetes by enhancing adipocyte thermogenesis. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) surface antigen (HBsAg) seroprevalence was high before the national vaccine policy was introduced in Taiwan, indicating significant HBV infection rates. The success of the HBV immunization program and other preventive measures likely led to decreased HBsAg prevalence among pregnant women. This study reports on the HBV seroprevalence among pregnant women in Taiwan from 2016 to 2021, including those potentially affected by the universal hepatitis B vaccination at birth. Methods: This claim-based cohort study included pregnant women with hospital-based prenatal HBV screening data: 162,662 for HBsAg and 161,729 for HBeAg, from 2016 to 2021. Patient medical records were reviewed to collect information on demographic characteristics and other health conditions. Logistic regression models were used to identify risk factors associated with HBsAg and HBV e antigen (HBeAg) positivity. Results: The seroprevalence for HBsAg and HBeAg during the study period was 4.0% and 0.6%, respectively. HBsAg positivity was highest among women born before July 1984 (pre-vaccination period; 8.6%), decreasing to 2.2% among those born between July 1986 and 1988 (national vaccination implementation) and further declining to 1.1% for those born after 1997. These data underscore the crucial role of large-scale immunization strategies in controlling HBV infections. Similarly, HBeAg positivity was highest among pregnant women born before the vaccination program (~ 1.0%), decreasing significantly to 0.4% for those born after 1989. The results showed geographic variations, potentially reflecting factors such as the mother's age and foreign nationality. However, the birth year was the most crucial factor associated with HBV marker positivity. Conclusions: The implementation of national vaccination programs has demonstrated significant success in reducing HBV seroprevalence among pregnant women, which is particularly evident in the substantial decrease in HBsAg seroprevalence in Taiwan post-July 1986. These findings emphasize the importance of continued and consistent vaccination efforts, supporting the need for ongoing public health strategies to combat HBV infections effectively. [ABSTRACT FROM AUTHOR]