Pancreatic Polypeptide Controls Energy Homeostasis via Npy6r Signaling in the Suprachiasmatic Nucleus in Mice

SummaryY-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r−/−) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r−/− mice have low lean mass with increased adiposity. Npy6r−/− mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r−/−, mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r−/−, mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition

Doing Biopolitics Differently? Radical Potential in the Post-2015 MDG and SDG Debates

Post print On institutional repository or subject-based repository after a 18 months embargo, withdraw

Dynamic cervical lung lobe herniation in a Shih Tzu dog

An 8-year-old spayed female Shih Tzu was referred to University Veterinary Hospital (UVH) with history of chronic coughing for more than a year duration. Dry, hacking cough was heard and bilateral wheezing lung sound was noted upon physical examination. Auscultation of heart revealed left apical systolic heart murmur Grade III/VI. A soft, intermittent swelling was observed at ventral neck, cranial to thoracic inlet (protruded upon expiration and collapsed upon inspiration). Thoracic radiography taken showed presence of apical radiolucency at cervical region and bronchial pattern at caudodorsal lungs with left atrium enlargement and right-sided heart enlargement. Echocardiographic examination revealed myxomatous mitral valve disease (MMVD) with mild regurgitation. Based on diagnostic imaging, this case was diagnosed as dynamic lung lobe herniation secondary to chronic coughing concurrent with myxomatous mitral valve disease. Other differential diagnosis that may lead to chronic cough such as of tracheal collapsed and bronchiectasis was not rule out

Coronary artery calcification – distribution, extent and 1-year outcomes in patients with low to intermediate pre-test probability of coronary artery disease.

Background: Coronary artery calcium (CAC) is an established marker to predict major cardiovascular events (MACE), and has incremental value over traditional risk factors (CVRF). CAC is widely available, easily reproducible, and used in nearly all coronary computed tomography angiography (CCTA) assessment protocols for coronary artery disease (CAD). The distribution and extent of CAC, and its prognostic implications in local Malaysian patients with low to intermediate pre-test probability (LI-PTP) of CAD had not been established. Objectives: We aimed to establish the distribution, extent and prognostic implications of CAC in patients without known CAD, but with LI-PTP of CAD, undergoing CCTA for chest pain evaluation. Methods: Clinical information was obtained from consecutive patients who underwent CAC and CCTA examination from January 2020 to January 2021 at a single public access tertiary referral centre. The primary outcomes were the distribution and extent of CAC, and its relationship with MACE at 1 year. Results: Of 499 consecutive patients, 7 were excluded due to high PTP. CAC was present in 172/492 (35%). Within this group, 74/172 (41.3%) had CAC score of 1-100 (mild), 75/172 (42.4%) had a CAC of 101- 400 (moderate), 23/172 (13.4%) had CAC of >400 (high). 136 had suspected significant CAD and was offered conventional coronary angiography (CCA). 91/492 underwent CCA, and 38 were found to have significant CAD. Of those found to have significant CAD, 7/38 (18.4%) had CAC of zero, 8/38 (21.1%) had mild CAC, 12/38 (31.6%) moderate, and 11/38 (30%) high CAC. Severe CAC was associated with a higher rate of revascularization 11/23 (47.8%), compared to those with zero 7/320 (2.2%), mild 8/74 (10.8%) and moderate 12/75 (16%) CAC. Predictors of high CAC were age, male gender, and presence of cardiovascular disease risk factors. Of the 492 patients, 230 patients completed 1 year follow-up, and from this, 1 patient had a MACE. Conclusion In patients with LI-PTP risk of CAD, CAC was seen in approximately one third of our cohort. In the group with high CAC, a higher proportion required coronary revascularization, but MACE remained low at 1 year

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

Coronary Computed Tomography Angiography as part of initial strategy, in assessment of patients with chest pain – clinical experience and 1 year prognosis.

Background: Coronary computed tomography angiography (CCTA) has been showed to have high specificity and sensitivity for detecting coronary artery disease (CAD). In Malaysia, national guidelines state that CCTA may be used in low- to intermediate pre-test probability (LI-PTP) of CAD, who have an equivocal functional test result, and who are asymptomatic or mildly symptomatic with good exercise capacity. Recent evidence suggested a ‘CCTA-first’ strategy in the evaluation of a patient with chest pain could provide prognostic benefits. Prognostic benefits of adopting this strategy in Malaysia has not been well studied. Objectives: We aimed to evaluate 12-month clinical outcomes of patients with LI-PTP, using the CCTA as an initial strategy, or as part of the work-up for, chest pain assessment. Methods: Consecutive patients who underwent CCTA examination from January 2020 to January 2021 were enrolled. Clinical information was then extracted. Primary outcome was defined as presence of stenosis of >50% in a major epicardial coronary artery; and secondary outcome defined as a composite of all-cause mortality, non-fatal myocardial infarction (MI) and coronary revascularisation. Results: Among the initial 499 patients, 7 were excluded as they were high in PTP. The mean PTP was 47.1±26.3. Baseline characteristics were available in 300 patients. The mean age was 53.5±11.4 years, 59.3% were male, 18.6% were diabetic, 71.2% had hypertension, and 50.8% had hypercholestrolaemia. 1.9% had an equivocal functional test for ischaemia. Of the 492 LI-PTP patients who underwent CCTA, 136 patients were suspected to have significant CAD, and recommended conventional coronary angiography (CCA). Of these, 91 patients underwent CCA. From this group 38 were found to have significant CAD which warranted revascularisation – 32 by percutaneous coronary intervention (PCI) and 6 referred for coronary artery bypass surgery (CABG). Therefore, utilising this strategy, 7.7% (38/492) of patients met the primary outcome. Of the original cohort of 492 LI-PTP patients, only 230 completed 1 year follow up, and from this, one patient met the secondary outcome. Conclusion Incorporation of CCTA into contemporary chest pain evaluation identified significant number of patients with significant CAD and was also associated with a low cardiac event rate at 1 year follow-up

Prevalence of Acid alpha-Glucosidase (GAA) Pseudodefiency Allele and It’s Clinical Significance Among Patients with Cardiomyopathy

Background: Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of lysosomal acid alpha-glucosidase (GAA) activity, leading to the progressive accumulation of glycogen in lysosomes of the skeletal and cardiac muscles. An alpha-glucosidase (GAA) pseudodeficiency allele is a change in the GAA gene sequence that results in GAA enzyme activity reduction, but does not cause Pompe disease. In Japan and Taiwan, there is high prevalence of pseudodeficiency allele (c.1725G>A and c.2065G>A) detected from their newborn screening. We observed similar prevalence of pseudodeficiency allele among our patients who had genetic test performed for suspected hereditary cardiomyopathy. Objectives: To report the prevalence of GAA pseudodeficiency allele, and to ascertain its clinical significance among patients with cardiomyopathy. Methods: The clinical data of the patients with GAA mutations were retrieved. Patients were called back for neurological examination, lung function test, measurement of creatine kinase (CK) level and dried-blood-spot for GAA enzymatic activity. Results: From January to December 2021, 33 patients underwent genetic testing. 23 out of the 33 genetic analyses included GAA mutation. 9 (39.13%) out of 23 were tested positive for pseudodeficiency allele. Their median age was 53 years (range 29-82), 44.4% were males with equal ethnic distribution (33.3% Malay, 33.3% Chinese, 33.3% Dayaks). All were heterozygous for the pseudodeficiency allele: 5 (55.6%) with c.[1726A; 2065A] allele, the other 4 (44.4%) c.2065G>A. The underlying cardiomyopathy phenotypes were hypertrophic (44.4%), transthyretin amyloid (22.2%), hypertensive (22.2%) and Fabry (11.1%). 1 patient (11.1%) with transthyretin amyloid cardiomyopathy died of advanced heart failure at age 79 years. 1 patient had mild motor weakness of the limbs attributable to thyrotoxicosis, while the other 7 patients had normal skeletal motor function. Their median predicted forced vital capacity was 87.5% (range 76-103), median CK level was 103 U/L (range 39-297) and median GAA activity was 4.8 micromol/l/h (range 3.2-9.2) [normal > 2.0]. Conclusion: The prevalence of GAA pseudodeficiency allele among patients with cardiomyopathy is 39.13%. None of the patients exhibit significant muscle weakness or respiratory insufficiency despite low normal enzymatic activity. Whether the presence of pseudodeficiency allele affects the prognosis of the underlying cardiomyopathy remains uncertain

Water Network Optimization with Wastewater Regeneration Models

The conventional water network synthesis approach greatly simplifies wastewater treatment units by using fixed recoveries, creating a gap for their applicability to industrial processes. This work describes a unifying approach combining various technologies capable of removing all the major types of contaminants through the use of more realistic models. The following improvements are made over the typical superstructure-based water network models. First, unit-specific shortcut models are developed in place of the fixed contaminant removal model to describe contaminant mass transfer in wastewater treatment units. Shortcut wastewater treatment cost functions are also incorporated into the model. In addition, uncertainty in mass load of contaminants is considered to account for the range of operating conditions. Furthermore, the superstructure is modified to accommodate realistic potential structures. We present a modified Lagrangean-based decomposition algorithm in order to solve the resulting nonconvex mixed-integer nonlinear programming (MINLP) problem efficiently. Several examples are presented to illustrate the effectiveness and limitations of the algorithm for obtaining the global optimal solutions.The authors would like to acknowledge financial support from the National Science Foundation for financial support under grant CBET-1437668, the program “Estancias de movilidad en el extranjero “Jose Castillejo” para jóvenes doctores” (JC2011-0051) of the Spanish Ministerio de Educación, and from the University of Alicante (GRE11-19)

Mechanism of Chemical Activation of Nrf2

NF-E2 related factor-2 (Nrf2) promotes the transcription of many cytoprotective genes and is a major drug target for prevention of cancer and other diseases. Indeed, the cancer-preventive activities of several well-known chemical agents were shown to depend on Nrf2 activation. It is well known that chemopreventive Nrf2 activators stabilize Nrf2 by blocking its ubiquitination, but previous studies have indicated that this process occurs exclusively in the cytoplasm. Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2 and orchestrates Nrf2 ubiquitination, and it has been a widely-held view that inhibition of Nrf2 ubiquitination by chemopreventive agents results from the dissociation of Nrf2 from its repressor Keap1. Here, we show that while the activation of Nrf2 by prototypical chemical activators, including 5,6-dihydrocyclopenta-1,2-dithiole-3-thione (CPDT) and sulforaphane (SF), results solely from inhibition of its ubiquitination, such inhibition occurs predominantly in the nucleus. Moreover, the Nrf2 activators promote Nrf2 association with Keap1, rather than disassociation, which appears to result from inhibition of Nrf2 phosphorylation at Ser40. Available evidence suggests the Nrf2 activators may block Nrf2 ubiquitination by altering Keap1 conformation via reaction with the thiols of specific Keap1 cysteines. We further show that while the inhibitory effects of CPDT and SF on Nrf2 ubiquitination depend entirely on Keap1, Nrf2 is also degraded by a Keap1-independent mechanism. These findings provide significant new insight about Nrf2 activation and suggest that exogenous chemical activators of Nrf2 enter the nucleus to exert most of their inhibitory impact on Nrf2 ubiquitination and degradation

Static and dynamic characteristics of protein contact networks

The principles underlying protein folding remains one of Nature's puzzles with important practical consequences for Life. An approach that has gathered momentum since the late 1990's, looks at protein hetero-polymers and their folding process through the lens of complex network analysis. Consequently, there is now a body of empirical studies describing topological characteristics of protein macro-molecules through their contact networks and linking these topological characteristics to protein folding. The present paper is primarily a review of this rich area. But it delves deeper into certain aspects by emphasizing short-range and long-range links, and suggests unconventional places where "power-laws" may be lurking within protein contact networks. Further, it considers the dynamical view of protein contact networks. This closer scrutiny of protein contact networks raises new questions for further research, and identifies new regularities which may be useful to parameterize a network approach to protein folding. Preliminary experiments with such a model confirm that the regularities we identified cannot be easily reproduced through random effects. Indeed, the grand challenge of protein folding is to elucidate the process(es) which not only generates the specific and diverse linkage patterns of protein contact networks, but also reproduces the dynamic behavior of proteins as they fold. Keywords: network analysis, protein contact networks, protein foldingComment: Added Appendix