Energy Metabolism and the Induction of the Unfolded Protein Response: A Dissertation

White adipose plays a major role in the regulation of whole body metabolism through the storage and hydrolysis of triglycerides and by secretion of adipokines. The function of endocrine cells is highly dependent on the unfolded protein response (UPR), a homeostatic signaling mechanism that balances the protein folding capacity of the endoplasmic reticulum (ER) with the cell\u27s secretory protein load. Here we demonstrate that the adipocyte UPR pathway is necessary for its secretory functions, and can thus play a crucial role in the control of whole body energy homeostasis. ER protein folding capacity is dependent both on the number of available chaperones as well as on their activity, which requires a sufficient ATP supply. In 3T3-L1 adipocytes, mitochondrial biogenesis occurred in parallel with induction of the UPR; therefore, we tested whether it was necessary for efficient ER function. Inhibition of mitochondrial ATP synthesis through depletion of Tfam, a mitochondrial transcription factor, or treatment with inhibitors of oxidative phosphorylation, demonstrate that ER function is sensitive to acute changes in adenine nucleotide levels. In addition, adenylate kinase 2 (AK2), which regulates mitochondrial adenine nucleotide interconversion, is markedly induced during adipocyte and B cell differentiation. AK2 depletion impairs induction of the UPR and secretion in both cell types. Interestingly, cytosolic adenylate kinase 1 (AK1) does not have the same effect upon UPR induction. We show that adenine nucleotides promote proper ER function and alterations in specific aspects of ATP synthesis can impair UPR signaling. Understanding the complex energetic regulation of the UPR may provide insight into the relationship between UPR and disease

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function

Association between malaria and household air pollution interventions in a predominantly rural area of Ghana.

BACKGROUND: Though anecdotal evidence suggests that smoke from HAP has a repellent effect on mosquitoes, very little work has been done to assess the effect of biomass smoke on malaria infection. The study, therefore, sought to investigate the hypothesis that interventions to reduce household biomass smoke may have an unintended consequence of increasing placental malaria or increase malaria infection in the first year of life. METHODS: This provides evidence from a randomized controlled trial among 1414 maternal-infant pairs in the Kintampo North and Kintampo South administrative areas of Ghana. Logistic regression was used to assess the association between study intervention assignment (LPG, Biolite or control) and placental malaria. Finally, an extended Cox model was used to assess the association between study interventions and all episodes of malaria parasitaemia in the first year of infant's life. RESULTS: The prevalence of placental malaria was 24.6%. Out of this, 20.8% were acute infections, 18.7% chronic infections and 60.5% past infections. The study found no statistical significant association between the study interventions and all types of placental malaria (OR = 0.88; 95% CI 0.59-1.30). Of the 1165 infants, 44.6% experienced at least one episode of malaria parasitaemia in the first year of life. The incidence of first and/or only episode of malaria parasitaemia was however found to be similar among the study arms. CONCLUSION: The findings suggest that cookstove interventions for pregnant women and infants, when combined with additional malaria prevention strategies, do not lead to an increased risk of malaria among pregnant women and infants

Prenatal Household Air Pollution Alters Cord Blood Mononuclear Cell Mitochondrial DNA Copy Number: Sex-Specific Associations.

BACKGROUND: Associations between prenatal household air pollution (HAP) exposure or cookstove intervention to reduce HAP and cord blood mononuclear cell (CBMC) mitochondrial deoxyribonucleic acid copy number (mtDNAcn), an oxidative stress biomarker, are unknown. MATERIALS AND METHODS: Pregnant women were recruited and randomized to one of two cookstove interventions, including a clean-burning liquefied petroleum gas (LPG) stove, or control. Prenatal HAP exposure was determined by serial, personal carbon monoxide (CO) measurements. CBMC mtDNAcn was measured by quantitative polymerase chain reaction. Multivariable linear regression determined associations between prenatal CO and cookstove arm on mtDNAcn. Associations between mtDNAcn and birth outcomes and effect modification by infant sex were explored. RESULTS: LPG users had the lowest CO exposures (p = 0.02 by ANOVA). In boys only, average prenatal CO was inversely associated with mtDNAcn (β = -14.84, SE = 6.41, p = 0.03, per 1ppm increase in CO). When examined by study arm, LPG cookstove had the opposite effect in all children (LPG β = 19.34, SE = 9.72, p = 0.049), but especially boys (β = 30.65, SE = 14.46, p = 0.04), as compared to Control. Increased mtDNAcn was associated with improved birth outcomes. CONCLUSIONS: Increased prenatal HAP exposure reduces CBMC mtDNAcn, suggesting cumulative prenatal oxidative stress injury. An LPG stove intervention may reverse this effect. Boys appear most susceptible

Prenatal household air pollutant exposure is associated with reduced size and gestational age at birth among a cohort of Ghanaian infants.

BACKGROUND: Low birth weight and prematurity are important risk factors for death and disability, and may be affected by prenatal exposure to household air pollution (HAP). METHODS: We investigate associations between maternal exposure to carbon monoxide (CO) during pregnancy and birth outcomes (birth weight, birth length, head circumference, gestational age, low birth weight, small for gestational age, and preterm birth) among 1288 live-born infants in the Ghana Randomized Air Pollution and Health Study (GRAPHS). We evaluate whether evidence of malaria during pregnancy, as determined by placental histopathology, modifies these associations. RESULTS: We observed effects of CO on birth weight, birth length, and gestational age that were modified by placental malarial status. Among infants from pregnancies without evidence of placental malaria, each 1 ppm increase in CO was associated with reduced birth weight (-53.4 g [95% CI: -84.8, -21.9 g]), birth length (-0.3 cm [-0.6, -0.1 cm]), gestational age (-1.0 days [-1.8, -0.2 days]), and weight-for-age Z score (-0.08 standard deviations [-0.16, -0.01 standard deviations]). These associations were not observed in pregnancies with evidence of placental malaria. Each 1 ppm increase in maternal exposure to CO was associated with elevated odds of low birth weight (LBW, OR 1.14 [0.97, 1.33]) and small for gestational age (SGA, OR 1.14 [0.98, 1.32]) among all infants. CONCLUSIONS: Even modest reductions in exposure to HAP among pregnant women could yield substantial public health benefits, underscoring a need for interventions to effectively reduce exposure. Adverse associations with HAP were discernible only among those without evidence of placental malaria, a key driver of impaired fetal growth in this malaria-endemic area

Corrigendum to "Prenatal household air pollutant exposure is associated with reduced size and gestational age at birth among a cohort of Ghanaian infants" [Environ. Int. 155 (2021) 106659].

[This corrects the article PMC8628363.]

Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for invisible decays of the Higgs boson produced via vector boson fusion (VBF) has been performed with 101  fb$^{-1}$ of proton-proton collisions delivered by the LHC at $\sqrt{s}$ =13  TeV and collected by the CMS detector in 2017 and 2018. The sensitivity to the VBF production mechanism is enhanced by constructing two analysis categories, one based on missing transverse momentum and a second based on the properties of jets. In addition to control regions with Z and W boson candidate events, a highly populated control region, based on the production of a photon in association with jets, is used to constrain the dominant irreducible background from the invisible decay of a Z boson produced in association with jets. The results of this search are combined with all previous measurements in the VBF topology, based on data collected in 2012 (at $\sqrt{s}$ =8  TeV), 2015, and 2016, corresponding to integrated luminosities of 19.7, 2.3, and 36.3  fb$^{-1}$, respectively. The observed (expected) upper limit on the invisible branching fraction of the Higgs boson is found to be 0.18 (0.10) at the 95% confidence level, assuming the standard model production cross section. The results are also interpreted in the context of Higgs-portal models

Search for top squarks in the four-body decay mode with single lepton final states in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the pair production of the lightest supersymmetric partner of the top quark, the top squark (t∼1), is presented. The search targets the four-body decay of the t∼1, which is preferred when the mass difference between the top squark and the lightest supersymmetric particle is smaller than the mass of the W boson. This decay mode consists of a bottom quark, two other fermions, and the lightest neutralino (χ∼01), which is assumed to be the lightest supersymmetric particle. The data correspond to an integrated luminosity of 138 fb−1 of proton-proton collisions at a center-of-mass energy of 13 TeV collected by the CMS experiment at the CERN LHC. Events are selected using the presence of a high-momentum jet, an electron or muon with low transverse momentum, and a significant missing transverse momentum. The signal is selected based on a multivariate approach that is optimized for the difference between m(t∼1) and m(χ∼01). The contribution from leading background processes is estimated from data. No significant excess is observed above the expectation from standard model processes. The results of this search exclude top squarks at 95% confidence level for masses up to 480 and 700 GeV for m(t∼1) − m(χ∼01) = 10 and 80 GeV, respectively