Climate Allocation Compass, a Framework for Real-World Decarbonization (Compass-FRWD)

Climate finance currently falls far short of what\u27s required to achieve net-zero targets. In a collaboration with the Man Group, we offer a framework setting out how investors can help to close this gap. Key takeaways: To address the global climate finance gap,CCSI and Man Group have developed the Climate Allocation Compass, a Framework for Real-World Decarbonization (‘Compass-FRWD’). Compass-FRWD is a six-step asset allocation framework designed to guide strategic capital investment across multiple portfolios. It does so by setting financing targets relative to real-world emission gaps, thereby prioritizing sectors and geographies according to decarbonization needs. Compass-FRWD provides a cyclical, investor-level framework, taking a multi-asset class approach to achieving optimal capital allocation through continuous adaptation and learning. Overcoming investment barriers also requires collaboration across financial services, with asset owners, policymakers and multilateral development banks. It requires bolstering issuers’ corporate transition strategies, addressing data reliability issues, and enlarging the universe of investable opportunities

A randomized, placebo-controlled, double-blinded pilot study of angiotensin 1–7 (TXA-127) for the treatment of severe COVID-19

Coronavirus disease 2019 (COVID-19) is associated with acute respiratory distress syndrome and multi-organ failure. SARS-CoV-2 enters cells through angiotensin-converting enzyme 2 (ACE-2), resulting in endocytosis and translocation. During this process, ACE-2 is phagocytosed and rendered non-functional [1]. ACE-2 mediates the conversion of angiotensin II to angiotensin 1–7, a vasodilator that opposes the effect of angiotensin [2, 3]. Reduction of ACE-2 likely causes a decrease in conversion of angiotensin I and II with excess angiotensin II causing vasoconstriction, oxidative stress, inflammation, apoptosis, fibrosis and water and solute retention. The hyperinflammatory state and acute kidney injury in COVID-19 could be in part explained by a reduction of ACE-2 and angiotensin 1–7

Climate Allocation Compass, a Framework for Real-World Decarbonization (Compass-FRWD)

Climate finance currently falls far short of what's required to achieve net-zero targets. In a collaboration with the Man Group, we offer a framework setting out how investors can help to close this gap. Key takeaways: (1) To address the global climate finance gap, CCSI and Man Group have developed the Climate Allocation Compass, a Framework for Real-World Decarbonization (‘Compass-FRWD’). (2) Compass-FRWD is a six-step asset allocation framework designed to guide strategic capital investment across multiple portfolios. It does so by setting financing targets relative to real-world emission gaps, thereby prioritizing sectors and geographies according to decarbonization needs. (3) Compass-FRWD provides a cyclical, investor-level framework, taking a multi-asset class approach to achieving optimal capital allocation through continuous adaptation and learning. (4) Overcoming investment barriers also requires collaboration across financial services, with asset owners, policymakers and multilateral development banks. It requires bolstering issuers’ corporate transition strategies, addressing data reliability issues, and enlarging the universe of investable opportunities

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD

Genetics ignite focus on microglial inflammation in Alzheimer’s disease

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer’s disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD

Knockdown of Alpha-1 Antitrypsin with antisense oligonucleotide does not exacerbate smoke induced lung injury.

Alpha-1 Antitrypsin (AAT) is a serum protease inhibitor that regulates increased lung protease production induced by cigarette smoking. Mutations in the Serpina1 gene cause AAT to form hepatoxic polymers, which can lead to reduced availability for the protein's primary function and severe liver disease. An AAT antisense oligonucleotide (ASO) was previously identified to be beneficial for the AATD liver disease by blocking the mutated AAT transcripts. Here we hypothesized that knockdown of AAT aggravates murine lung injury during smoke exposure and acute exacerbations of chronic obstructive pulmonary disease (COPD). C57BL/6J mice were randomly divided into 4 groups each for the smoking and smoke-flu injury models. The ASO and control (No-ASO) were injected subcutaneously starting with smoking or four days prior to influenza infection and then injected weekly at 50 mg/kg body weight. ASO treatment during a 3-month smoke exposure significantly decreased the serum and lung AAT expression, resulting in increased Cela1 expression and elastase activity. However, despite the decrease in AAT, neither the inflammatory cell counts in the bronchoalveolar lavage fluid (BALF) nor the lung structural changes were significantly worsened by ASO treatment. We observed significant differences in inflammation and emphysema due to smoke exposure, but did not observe an ASO treatment effect. Similarly, with the smoke-flu model, differences were only observed between smoke-flu and room air controls, but not as a result of ASO treatment. Off-target effects or compensatory mechanisms may account for this finding. Alternatively, the reduction of AAT with ASO treatment, while sufficient to protect from liver injury, may not be robust enough to lead to lung injury. The results also suggest that previously described AAT ASO treatment for AAT mutation related liver disease may attenuate hepatic injury without being detrimental to the lungs. These potential mechanisms need to be further investigated in order to fully understand the impact of AAT inhibition on protease-antiprotease imbalance in the murine smoke exposure model