Urban climate and cardiovascular health: Focused on seasonal variation of urban temperature, relative humidity, and PM2.5 air pollution.

Seasonal effects on subclinical cardiovascular functions (CVFs) are an important emerging health issue for people living in urban environment. The objectives of this study were to demonstrate the effects of seasonal variations of temperature, relative humidity, and PM2.5 air pollution on CVFs. A total of 86 office workers in Taipei City were recruited, their arterial pressure waveform was recorded by cuff sphygmomanometer using an oscillometric blood pressure (BP) device for CVFs assessment. Results of paried t-test with Bonferroni correction showed significantly increased systolic and diastolic BP (SBP, DBP), central end-systolic and diastolic BP (cSBP, cDBP) and systemic vascular resistance, but decreased heart rate (HR), stroke volume (SV), cardio output (CO), and cardiac index in winter compared with other seasons. After controlling for related confounding factors, SBP, DBP, cSBP, cDBP, LV dp/dt max, and brachial-ankle pulse wave velocity (baPWV) were negatively associated with, and SV was positively associated with seasonal temperature changes. Seasonal changes of air pollution in terms of PM2.5 were significantly positively associated with DBP and cDBP, as well as negatively associated with HR and CO. Seasonal changes of relative humidity were significantly negatively associated with DBP, and cDBP, as well as positively associated with HR, CO, and baPWV. This study provides evidence of greater susceptibility to cardiovascular events in winter compared with other seasons, with ambient temperature, relative humidity, and PM2.5 as the major factors of seasonal variation of CVFs.

Forest Bathing Is Better than Walking in Urban Park: Comparison of Cardiac and Vascular Function between Urban and Forest Parks.

Forest bathing is beneficial for human health. To investigate whether walking in forest or urban parks affects cardiovascular functions (CVFs), the present study was conducted in five forest trails in the Xitou Experimental Forest and in five urban parks in Taipei city. We recruited 25 adult volunteers for an observational pilot study in forest parks (n = 14) and urban parks (n = 11). CVFs were assessed by measuring the arterial pressure waveform using an oscillometric blood pressure (BP) device. The baseline and paired differences of systolic BP (SBP), central end SBP, heart rate, left ventricle (LV) dP/dt max and cardiac output in participants were lower before and after walking in a forest park than those in an urban park. In addition, the systemic vascular compliance and brachial artery compliance of those who walked in a forest park were significantly higher compared with those in an urban park. Linear mixed models demonstrated lower levels of SBP by 5.22 mmHg, heart rate by 2.46 beats/min, and cardiac output by 0.52 L/min, and LV dP/dt max by 146.91 mmHg/s among those who walked in forest compared to those in an urban park after controlling covariates. This study provides evidence of the potential beneficial effects of walking exercise in forest parks on CVFs.

Area-population control of fungus-growing termite, Odontotermes formosanus, using hexaflumuron durable baits.

BACKGROUND: Fungus-growing termites (Termitidae: Macrotermitinae) are common forest and agriculture pests. To evaluate the efficacy of termite baiting in suppressing field population of fungus-growing termites, a durable termite bait with hexaflumuron was evenly installed in a one-hectare forest area dominated by a fungus-growing termite, Odontotermes formosanus (Shiraki). Monthly monitoring of termite foraging activity on baits and wood stakes was conducted for 4 years to quantify efficacy of baits. To examine whether the hexaflumuron led to colony death, pesticides in fungus gardens of active and deceased nests were quantified using a LC-QTOF/MS. RESULTS: After baiting, 50% and 90% of baits were fed upon 10 and 24 months, respectively. After 2 years of baiting, the monthly number of wood stakes occupied by termites was reduced from 34.7 ± 1.8 to 17.6 ± 2.5 (-49.1%), and the number of wood stakes consumed was reduced from 17.7 ± 0.8 to 13.3 ± 1.2 (-25.7%). Hexaflumuron was detected in deceased colonies, including five of six fungus gardens and the fungal tissue of Xyleria grown on fungus gardens, with a concentration of 0.31-20.11 mg kg-1 dry weight. CONCLUSION: This study demonstrated that durable hexaflumuron baits consumed by fungus-growing termites were further incorporated into fungus gardens, resulted in colony elimination and negative area-population effects, supporting that durable hexaflumuron baits are effective in suppressing field populations of fungus-growing termites. © 2021 Society of Chemical Industry.

The Role of Social Context in Physiological and Psychological Restoration in a Forest: Case Study of a Guided Forest Therapy Program in Taiwan.

Existing studies have demonstrated the restorative benefits of being in forests. However, most studies have designed participants to engage individually in forest walking and viewing, which neglects the social aspect of conversation. Researchers suggested that social context should be studied in order to have a better understanding how forests foster human health. To this end, we examined the role of social context using three types of forest therapy programs: a guided program, a self-guided program, and a walk alone program. A between-subject, pretest-posttest field experimental design was employed to evaluate restorative effects by measuring the physiological responses and mood states incurred in different forest therapy programs. Our findings showed, that the walk alone group exhibited a significant systolic blood pressure decrease and a significant increase in sympathetic nervous activity; the self-guided group showed a significant increase in heart rate values and significant decreases in systolic blood pressure and diastolic blood pressure; and the guided group revealed a significant decrease in systolic blood pressure. Further, the three forest therapy programs had positive effects on improving mood states, except a nonsignificant vigor-activity increase in the walk alone group. The three programs did not exhibit significant differences in changes of restorative benefits in physiological and psychological measures except for a significant difference in changes in sympathetic nervous activity between the walk alone group and guided group. The results showed the restorative benefits of forest therapy are apparent regardless of the program type. The management team should continue promoting forest therapy for public health by providing different types of forest therapy programs and experiences.

Seasonal Effects of High-Altitude Forest Travel on Cardiovascular Function: An Overlooked Cardiovascular Risk of Forest Activity.

Cardiovascular physiological responses involving hypoxemia in low temperature environments at high altitude have yet to be adequately investigated. This study aims to demonstrate the health effects of hypoxemia and temperature changes in cardiovascular functions (CVFs) by comparing intra-individual differences as participants ascend from low (298 m, 21.9 °C) to high altitude (2729 m, 9.5 °C). CVFs were assessed by measuring the arterial pressure waveform according to cuff sphygmomanometer of an oscillometric blood pressure (BP) device. The mean ages of participants in winter and summer were 43.6 and 41.2 years, respectively. The intra-individual brachial systolic, diastolic BP, heart rate, and cardiac output of participants significantly increased, as participants climbed uphill from low to high altitude forest. Following the altitude increase from 298 m to 2729 m, with the atmosphere gradually reducing by 0.24 atm, the measured average SpO2 of participants showed a significant reduction from 98.1% to 81.2%. Using mixed effects model, it is evident that in winter, the differences in altitude affects CVFs by significantly increases the systolic BP, heart rate, left ventricular dP/dt max and cardiac output. This study provides evidence that cardiovascular workload increased significantly among acute high-altitude travelers as they ascend from low to high altitude, particularly in winter.

ERK Regulates NeuroD1-mediated Neurite Outgrowth via Proteasomal Degradation.

Neurogenic differentiation 1 (NeuroD1) is a class B basic helix-loop-helix (bHLH) transcription factor and regulates differentiation and survival of neuronal and endocrine cells by means of several protein kinases, including extracellular signal-regulated kinase (ERK). However, the effect of phosphorylation on the functions of NeuroD1 by ERK has sparked controversy based on context-dependent differences across diverse species and cell types. Here, we evidenced that ERK-dependent phosphorylation controlled the stability of NeuroD1 and consequently, regulated proneural activity in neuronal cells. A null mutation at the ERK-dependent phosphorylation site, S274A, increased the half-life of NeuroD1 by blocking its ubiquitin-dependent proteasomal degradation. The S274A mutation did not interfere with either the nuclear translocation of NeuroD1 or its heterodimerization with E47, its ubiquitous partner and class A bHLH transcription factor. However, the S274A mutant increased transactivation of the E-box-mediated gene and neurite outgrowth in F11 neuroblastoma cells, compared to the wild-type NeuroD1. Transcriptome and Gene Ontology enrichment analyses indicated that genes involved in axonogenesis and dendrite development were downregulated in NeuroD1 knockout (KO) mice. Overexpression of the S274A mutant salvaged neurite outgrowth in NeuroD1-deficient mice, whereas neurite outgrowth was minimal with S274D, a phosphomimicking mutant. Our data indicated that a longer protein half-life enhanced the overall activity of NeuroD1 in stimulating downstream genes and neuronal differentiation. We propose that blocking ubiquitin-dependent proteasomal degradation may serve as a strategy to promote neuronal activity by stimulating the expression of neuron-specific genes in differentiating neurons.

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment.

The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII's oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.

Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction.

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.

Opposing Functions of BRD4 Isoforms in Breast Cancer.

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1.

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

Dysregulation of hypothalamic-pituitary estrogen receptor α-mediated signaling causes episodic LH secretion and cystic ovary.

Polycystic ovary syndrome (PCOS) is a hypothalamic-pituitary-gonadal (HPG) axis disorder. PCOS symptoms most likely result from a disturbance in the complex feedback regulation system of the HPG axis, which involves gonadotrophic hormones and ovarian steroid hormones. However, the nature of this complex and interconnecting feedback regulation makes it difficult to dissect the molecular mechanisms responsible for PCOS phenotypes. Global estrogen receptor α (ERα) knockout (KO) mice exhibit a disruption of the HPG axis, resulting in hormonal dysregulation in which female ERα KO mice have elevated levels of serum estradiol (E2), testosterone, and LH. The ERα KO females are anovulatory and develop cystic hemorrhagic ovaries that are thought to be due to persistently high circulating levels of LH from the pituitary. However, the role of ERα in the pituitary is still controversial because of the varied phenotypes reported in pituitary-specific ERα KO mouse models. Therefore, we developed a mouse model where ERα is reintroduced to be exclusively expressed in the pituitary on the background of a global ERα-null (PitERtgKO) mouse. Serum E2 and LH levels were normalized in PitERtgKO females and were comparable to wild-type serum levels. However, the ovaries of PitERtgKO adult mice displayed a more overt cystic and hemorrhagic phenotype when compared with ERα KO littermates. We determined that anomalous sporadic LH secretion caused the severe ovarian phenotype of PitERtgKO females. Our observations suggest that pituitary ERα is involved in the estrogen negative feedback regulation, whereas hypothalamic ERα is necessary for the precise control of LH secretion. Uncontrolled, irregular LH secretion may be the root cause of the cystic ovarian phenotype with similarities to PCOS.-Arao, Y., Hamilton, K. J., Wu, S.-P., Tsai, M.-J., DeMayo, F. J., Korach, K. S. Dysregulation of hypothalamic-pituitary estrogen receptor α-mediated signaling causes episodic LH secretion and cystic ovary.

Health effects of seasonal variation in cardiovascular hemodynamics among workers in forest environments.

Seasonal variation in cardiovascular functions (CVFs) associated with climatic changes is an important emerging public health issue. The objectives of this study were to demonstrate seasonal variation in CVFs by comparing intra-individual differences between winter and summer among people working in a forest environment and to discuss the possible mechanisms accounting for the health effects of seasonal variation in cardiovascular hemodynamics. A total of 72 staff members of the Experimental Forest of National Taiwan University were recruited for continuous health monitoring during two seasons to investigate the intra-individual seasonal variation in CVFs, complete blood counts, and biochemical examinations. CVFs were assessed by measuring the arterial pressure waveform by a cuff sphygmomanometer using an oscillometric blood pressure device, and aortic stiffness was measured by brachial-ankle pulse wave velocity (baPWV). The results showed that cholesterol levels, white and red blood cell counts, and platelet counts were higher in winter than in summer. Subjects showed not only higher vascular stress, as indicated by higher levels of brachial systolic and diastolic blood pressure (SBP and DBP), central end-SBP and DBP, systemic vascular resistance (SVR), and baPWV, but also lower cardiac activities, including lower levels of heart rate, left ventricular contractility, and cardiac output in winter than in summer. The central and brachial BP, cardiac output, SVR, and baPWV were significantly associated with temperature changes in seasonal variation after controlling related confounding factors. This study provides evidence of higher vascular stress and susceptibility to atherothrombosis during winter compared with summer.

Tuber elevatireticulatum sp. nov., a new species of whitish truffle from Taiwan.

BACKGROUND: There are estimated 180-220 species of Tuber described in the world, but the diversity of the genus in Taiwan is poorly known, with only two species recorded, i.e., Tuber formosanum and T. furfuraceum. During our survey of hypogenous fungi in Taiwan, a whitish truffle belongs to Puberulum clade was collected from roots of Keteleeria fortunei var. cyclolepis in central Taiwan and appeared to differ from the two recorded species. RESULTS: The whitish truffle is herein described as a new species Tuber elevatireticulatum, which is distinguished from closely resembled Asian whitish truffles species like Tuber thailandicum, T. panzhihuanense, T. latisporum and T. sinopuberulum by the association with Keteleeria host, small light brown ascocarps with a dark brown gleba, dark brownish and elliptical ascospores ornamented with a prominently raised alveolate reticulum. Molecular phylogenetic analyses of both ITS and LSU loci clearly supports T. elevatireticulatum as a new species without any significant incongruence. CONCLUSIONS: The whitish truffle is herein described as a new species T. elevatireticulatum based on the evidence from morphology and DNA sequences. T. elevatireticulatum is the first scientific record of whitish truffle in Taiwan.

Foraging Phenology of the Fungus-Growing Termite Odontotermes formosanus (Blattodea: Termitidae).

Fungus-growing termites are major contributors to litter decomposition and an agriculture pest in tropical and subtropical Africa and Asia. The foraging behavior of fungus-growing termites was hypothesized to be seasonal and may associate with climatic factors and the occurrence of natural enemies. In this study, we tested the effects of climatic factors and the presence of ants on the foraging activity of the fungus-growing termite Odontotermes formosanus (Shiraki) (Blattodea: Termitidae). Termite-foraging activities were quantified monthly based on the number of wood stakes occupied, amount of wood consumed, and foraging population size. The rate of wood-stake decomposition was measured by monitoring 484 wood stakes in a tropical forest over the course of nearly 6 yr. The results revealed that temperature and rainfall are the major climatic factors influencing the foraging seasonality of O. formosanus. Termites occupied fewer wood stakes during hot-wet seasons when fewer ants were present. The results of a path analysis supported that termite-foraging seasonality correlated mainly with climatic factors rather than the presence of ants. A new foraging hypothesis, the eat-and-run strategy, is proposed to explain the inconsistent seasonal foraging behaviors observed in fungus-growing termites.

Stitch guide technique for bicanalicular nasal intubation in single canalicular laceration reconstruction.

Various surgical techniques for canalicular laceration reconstruction have been described in previous study. But there are still two difficult points which may take time in the operation even with the assistance of magnification. We present a simple and effective way to achieve the bicanalicular nasal intubation for the single canalicular laceration. From Jan 2005 to Dec 2015, 20 patients (21 eyes) with upper or lower canalicular laceration were treated with the Crawford lacrimal intubation set by this stitch guide method. We used the eye pigtail probe and the steel probe of the intubation set to dispose a 4-0 Nylon suture as a guide to pull down the silicone tube to the nostril. The functional and anatomic success rates in the 20 eyes are 90% (18/20) and 85% (17/20) respectively. The average time for bicanalicular nasal intubation by this method is 6.87 ± 1.83 min. The result of stitch guide technique to achieve bicanalicular nasal intubation in single canalicular laceration reconstruction is almost the same as the traditional method. Our anatomic and functional success rates are 85% and 90% respectively which are comparable to the previous studies. But this new method takes less time to complete the intubation with little variation. The magnification with microscopy could be omitted and no new instrument is needed. The stitch guide technique for bicanalicular nasal intubation with Crawford intubation system is a reliable and easy way to perform in single canalicular laceration reconstruction.

SRC-3 Coactivator Governs Dynamic Estrogen-Induced Chromatin Looping Interactions during Transcription.

Enhancers are thought to activate transcription by physically contacting promoters via looping. However, direct assays demonstrating these contacts are required to mechanistically verify such cellular determinants of enhancer function. Here, we present versatile cell-free assays to further determine the role of enhancer-promoter contacts (EPCs). We demonstrate that EPC is linked to mutually stimulatory transcription at the enhancer and promoter in vitro. SRC-3 was identified as a critical looping determinant for the estradiol-(E2)-regulated GREB1 locus. Surprisingly, the GREB1 enhancer and promoter contact two internal gene body SRC-3 binding sites, GBS1 and GBS2, which stimulate their transcription. Utilizing time-course 3C assays, we uncovered SRC-3-dependent dynamic chromatin interactions involving the enhancer, promoter, GBS1, and GBS2. Collectively, these data suggest that the enhancer and promoter remain "poised" for transcription via their contacts with GBS1 and GBS2. Upon E2 induction, GBS1 and GBS2 disengage from the enhancer, allowing direct EPC for active transcription.

Health effects of a forest environment on natural killer cells in humans: an observational pilot study.

Health effect assessments based on natural killer (NK) cells are an important emerging area of human health. We recruited 90 forest staff members in Xitou, Taiwan and 110 urban staff members in Taipei to investigate the health effects of forest environment exposure on NK cells (CD3-/CD56+) and activating NK cells (CD3-/CD56+/CD69+) in humans. We also invited 11 middle-aged volunteers in a pilot study to participate in a five-day/four-night forest trip to Xitou forest to investigate the health effects of a forest trip on NK cells and activating NK cells. Results showed that NK cells were higher in the forest group (19.5 ± 9.1%) than in the urban group (16.4 ± 8.4%). In particular, the percentage of NK cells was significantly higher in the forest group than in the urban group among the subgroups of male, a higher body mass index (≥ 25 kg/m2), without hypertension, lower high-sensitivity C-reactive protein, hyperglycemia, without smoking habit, and with tea drinking habit. After the five-day trip in Xitou forest, the percentage of activating NK cells of the invited participants from Taipei increased significantly after the trip to Xitou forest (0.83 ± 0.39% vs. 1.72 ± 0.1%). The percentage of activating NK cells was 1.13 ± 0.43%, which was higher than the baseline value of 0.77 ± 0.38% before the forest trip among the seven subjects who participated in the follow-up study four days after returning to Taipei. This study suggests that exposure to forest environments might enhance the immune response of NK cells and activating NK cells in humans.

Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer.

Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis 1 . However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis 2 , is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours.

Agricultural waste derived fuel from oil meal and waste cooking oil.

Oil meal is a by-product of the oil industry (peanut meal, sesame meal, and camellia meal). Oil is extracted from seeds, and the leftover meal is then pelletized, and this process generates a large amount of waste oil meal in Taiwan. In this study, peanut meal, sesame meal, and camellia meal derived fuels were prepared from the waste oil meal with waste cooking oil. The combustion behaviors of the oil meal derived fuels were also investigated. The characteristics of the derived fuel made from oil meal with waste cooking oil showed that the ash content is less than 10% and its calorific value reached 5000 kcal/kg. Additionally, the activation energy of the oil meal and waste cooking oil was analyzed by the Kissinger method. The results show that the fuel prepared in this work from the oil meal mixed with waste cooking oil is suitable for use as an alternative fuel and also avoids food safety issues.