Energetic Shift Research Articles

Integrated all-atom and coarse-grained simulations uncover structural, dynamics and energetic shifts in SARS-CoV-2 JN.1 and BA.2.86 variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, is an enveloped, positive-stranded RNA virus that enters human cells by using its spike protein to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Since its emergence, the virus has mutated, producing variants with increased transmissibility, immune evasion, and infectivity. The JN.1 variant, detected in January 2024, features a single substitution mutation (Leu455Ser) in the receptor-binding domain (RBD) of its spike protein, setting it apart from its parent lineage, BA.2.86. This variant has rapidly become globally predominant due to its enhanced transmission and significant epidemiological impact. To understand the causes behind the dominance of the JN.1 variant, we conducted a comprehensive study using all-atom molecular dynamics (MD) and coarse-grained MD simulations. This allowed us to examine the structural, dynamic, energetics and binding properties of the wild-type (Wuhan strain), BA.2.86, and JN.1 variants. Principal component and free energy landscape analyses revealed enhanced structural stability in the JN.1 variant. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) assessments indicated lower binding affinity for JN.1 as compared to BA.2.86. Intermolecular interaction analyses further confirmed BA.2.86′s superior binding affinity over JN.1 and wild-type. Additionally, we compared and validated our findings against experimentally determined cryo-electron microscopy (cryo-EM) structures of JN.1 and BA.2.86 variants, confirming the reliability of our simulation results. Overall, this study provides crucial insights into the structural-dynamics-energetics features and physicochemical properties that have contributed to the global prevalence of the JN.1 variant and sheds light on its potential to generate future subvariants.

Oral nicotinamide provides robust, dose-dependent structural and metabolic neuroprotection of retinal ganglion cells in experimental glaucoma

A compromised capacity to maintain NAD pools is recognized as a key underlying pathophysiological feature of neurodegenerative diseases. NAD acts as a substrate in major cell functions including mitochondrial homeostasis, cell signalling, axonal transport, axon/Wallerian degeneration, and neuronal energy supply. Dendritic degeneration is an early marker of neuronal stress and precedes cell loss. However, little is known about dendritic structural preservation in pathologic environments and remodelling in mature neurons. Retinal ganglion cell dendritic atrophy is an early pathological feature in animal models of the disease and has been demonstrated in port-mortem human glaucoma samples. Here we report that a nicotinamide (a precursor to NAD through the NAD salvage pathway) enriched diet provides robust retinal ganglion cell dendritic protection and preserves dendritic structure in a rat model of experimental glaucoma. Metabolomic analysis of optic nerve samples from the same animals demonstrates that nicotinamide provides robust metabolic neuroprotection in glaucoma. Advances in our understanding of retinal ganglion cell metabolic profiles shed light on the energetic shift that triggers early neuronal changes in neurodegenerative diseases. As nicotinamide can improve visual function short term in existing glaucoma patients, we hypothesize that a portion of this visual recovery may be due to dendritic preservation in stressed, but not yet fully degenerated, retinal ganglion cells.

Octupole moment driven free charge generation in partially chlorinated subphthalocyanine for planar heterojunction organic photodetectors

In this study, high-performance organic photodetectors are presented which utilize a pristine chlorinated subphthalocyanine photoactive layer. Optical and optoelectronic analyses indicate that the device photocurrent is primarily generated through direct charge generation within the chlorinated subphthalocyanine layer, rather than exciton separation at layer interfaces. Molecular modelling suggests that this direct charge generation is facilitated by chlorinated subphthalocyanine high octupole moment (−80 DÅ2), which generates a 200 meV shift in molecular energetics. Increasing the thickness of chlorinated subphthalocyanine leads to faster response time, correlated with a decrease in trap density. Notably, photodetectors with a 50 nm thick chlorinated subphthalocyanine photoactive layer exhibit detectivities approaching 1013 Jones, with a dark current below 10−7 A cm−2 up to −5 V. Based on these findings, we conclude that high octupole moment molecular semiconductors are promising materials for high-performance organic photodetectors employing single-component photoactive layer.

Metabolic Reprogramming By PRDM16 Drives Cytarabine Resistance in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) patients with high PRDM16 expression frequently experience induction failure and have a poor prognosis. However, the underlying molecular mechanisms are poorly understood. Here, we show that AML cells with high PRDM16 expression acquire resistance to cytarabine (AraC) through the activation of oxidative phosphorylation (OxPHOS) via regulation of c-MYC. Initially, we established a murine model of AML with high Prdm16 expression. We transduced c-Kit + bone marrow cells from wild-type mice with a retrovirus vector encoding MLL-AF9 (MF9) and the oncogenic short form of Prdm16 (sPrdm16). Using MF9/sPrdm16 cells, we next investigated whether AML cells with high Prdm16 expression exhibited resistance to AraC and/or daunorubicin (DNR), chemotherapeutic agents commonly used for induction chemotherapy. In the cell viability assay, MF9/sPrdm16 cells showed significantly higher IC 50 against AraC, but not against DNR, compared to MF9/control (control) cells, suggesting that high sPrdm16 expression confers relative resistance to AraC on AML cells. Colony-forming assay also confirmed resistant to AraC in MF9/sPrdm16 cells compared to control. Moreover, MF9/sPrdm16 cells were also resistant to AraC in vivo as demonstrated by the shortened survival of mice receiving MF9/sPrdm16 cells. To elucidate the mechanism of AraC resistance, we first examined cell cycle status of MF9/sPrdm16 cells since AraC exerts cytotoxicity in cell cycle dependent manner. To our surprise, MF9/sPrdm16 cells were cycling more rapidly than control cells as demonstrated by decreased G 0 phase and increased S/G 2/M phase. Intriguingly, RNA-sequencing analysis revealed that MF9/sPrdm16 cells displayed a signature of high OxPHOS by gene set enrichment analysis (GSEA). Indeed, oxygen consumption rate, superoxide production from mitochondria, and mitochondrial membrane potential were significantly elevated in MF9/sPrdm16 cells compared to control cells. The inhibition of mitochondrial respiration with metformin, the electron transport chain complex I inhibitor, or tigecycline, the mitochondrial protein synthesis inhibitor, abrogated AraC resistance in MF9/sPrdm16 cells by inducing an energetic shift towards a lower OxPHOS status. These results clearly indicated that sPrdm16 overexpression conferred MF9 cells with AraC resistance byincreasing OxPHOS in mitochondria. Next, we explored the mechanism how sPrdm16 regulates OxPHOS. In addition to elevated OxPHOS signature, RNA-sequencing data also showed strong enrichment of Myc target-signature in MF9/sPrdm16 cells. Western blot analysis showed that sPrdm16 overexpression induced up-regulation of c-Myc and its transcriptional target, Slc1a5, a glutamine transporter. We went on to analyze metabolic changes induced by sPrdm16 overexpression by capillary electrophoresis and mass spectrometry-based metabolome analysis. We found that sPrdm16 induced the accumulation of glutamine, glutamate, α-ketoglutaric acid, succinate, fumarate, and malate in MF9 cells, possibly by activating glutaminolysis via the regulation of c-Myc and Slc1a5 expression, leading to the activation of tricarboxylic acid (TCA) cycle and OxPHOS. We also confirmed the contribution of c-Myc to AraC resistance by overexpressing c-Myc in MF9 cells. As expected, MF9/c-Myc cells mimicked the phenotype of MF9/sPrdm16 cells such as resistance to AraC and high OxPHOS status. Furthermore, 10058-F4, a c-Myc inhibitor, abrogated AraC resistance in MF9/sPrdm16 cells. Next, we asked if the observation in MF9/sPrdm16 cells could be translated into human AML cells. Human AML cell lines, MOLM-13 and THP-1, with sPRDM16 overexpression also showed significantly higher IC 50 against AraC compared to Mock expressed cells. Moreover, RNA-seq data from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 clinical trial showed that AML blasts with high PRDM16 expression demonstrated a gene expression signature associated with “OxPHOS” and “Myc Targets”. In conclusion, our findings demonstrate that PRDM16 overexpression activates mitochondrial respiration through metabolic reprogramming via c-MYC, thereby conferres AraC resistance on AML cells. These results suggest that targeting mitochondrial respiration might be a novel treatment strategy to overcome chemoresistance in AML patients with high PRDM16 expression.

Investigating relationships among stress, reproduction, and immunity in three species of watersnake

Energy is a finite resource required for all physiological processes and must be allocated efficiently among essential activities to ensure fitness and survival. During the active season, adult organisms are expected to prioritize investment in reproduction over other energetically expensive processes, such as responding to immunological challenges. Furthermore, when encountering a stressor, the balance between reproduction and immunity might be disrupted in order to fuel the stress response. Because of the distinct differences in life histories across species, watersnakes provide a unique group of study in which to examine these tradeoffs. Over a two-year period, we captured three watersnake species throughout Northeast Arkansas. Animals were subjected to restraint stress and blood samples were collected throughout the acute stress response. Blood samples were used to assess innate immunity and steroid hormone concentrations. We found the peak in corticosterone concentration is season-specific, potentially because energetic reserves fluctuate with reproductive activities. We also found body condition was positively related to acute stress and negatively related to immunity. Watersnakes evidently prioritize reproduction over immunity, especially during the energetically intensive process of vitellogenesis. Energetic tradeoffs between reproduction, immunity, and the stress response are complex, and this study contributes to our understanding of energetic shifts in free-living organisms in the context of stress.

PO-01-172 METABOLIC SHIFT CONTRIBUTES TO SINOATRIAL NODE DYSFUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

Cardiometabolic alterations are frequent in patients with heart failure with preserved ejection fraction (HFpEF). We recently demonstrated sinoatrial node (SAN) dysfunction limits the chronotropic response in two distinct animal models of HFpEF; however, our new findings suggest a relationship between metabolism and SAN dysfunction. To identify metabolically-driven changes that facilitate SAN dysfunction in HFpEF. Male C57Bl6 mice fed with high fat (HFD) plus nitric oxide inhibitor (L-NAME) diet or regular chow served as HFpEF and controls, respectively. Transcriptomics, metabolomics, targeted quantitative proteomics of mitochondria, and optical mapping of SAN preparations from control and HFpEF-verified mice were performed. SAN from HFpEF-verified animals after 20 weeks of HFD+LNAME exhibited prolonged SAN recovery time (100%; P<0.05). A combination of multi-omics studies revealed changes in metabolic gene clusters suggesting a metabolic shift towards glycolysis as a source of energy. Supporting these findings, isolated mitochondria from HFpEF SANs showed depressed maximal mitochondrial respiration compared to controls (-42%; P<0.05). In addition, isolated pacemaker cells from HFpEF animals showed increased mitochondrial reactive oxygen species production compared to controls (+70%; P<0.05). Moreover, acute mitochondrial uncoupling induced by FCCP elicited a pronounced prolongation of SAN recovery time in HFpEF compared to controls (165%; P<0.05). Our results suggest that SAN dysfunction in HFpEF is closely associated with metabolic remodeling and energetic substrate shift. However, further studies are needed to establish the causality between metabolic changes and SAN dysfunction in HFpEF.

Molecular orientation-dependent energetic shifts in solution-processed non-fullerene acceptors and their impact on organic photovoltaic performance

The non-fullerene acceptors (NFAs) employed in state-of-art organic photovoltaics (OPVs) often exhibit strong quadrupole moments which can strongly impact on material energetics. Herein, we show that changing the orientation of Y6, a prototypical NFA, from face-on to more edge-on by using different processing solvents causes a significant energetic shift of up to 210 meV. The impact of this energetic shift on OPV performance is investigated in both bilayer and bulk-heterojunction (BHJ) devices with PM6 polymer donor. The device electronic bandgap and the rate of non-geminate recombination are found to depend on the Y6 orientation in both bilayer and BHJ devices, attributed to the quadrupole moment-induced band bending. Analogous energetic shifts are also observed in other common polymer/NFA blends, which correlates well with NFA quadrupole moments. This work demonstrates the key impact of NFA quadruple moments and molecular orientation on material energetics and thereby on the efficiency of high-performance OPVs.

Understanding the electronic pi-system of 2D covalent organic frameworks with Wannier functions

We investigate a family of hexagonal 2D covalent organic frameworks (COFs) with phenyl and biphenyl spacer units and different chemical linker species. Chemical trends are elucidated and attributed to microscopic properties of the pi-electron-system spanned by atomic p_z-orbitals. We systematically investigate the electronic structure, delocalization of electronic states, effects of disorder, bond torsion, and doping, and correlate these with variable pi-conjugation and nucleus-independent chemical shift (NICS) aromaticity. Molecular orbitals are obtained from maximally localized Wannier functions that have sigma- and pi-character, forming distinct sigma- and pi-bands for all valence states. The Wannier-orbital description goes beyond simple tight-binding models and enables a detailed understanding of the electronic topology, effective electronic coupling and delocalization. It is shown that a meaningful comparison between COFs with different chemical elements can only be made by examining the entire pi-electron system, while a comparison of individual bands (e.g., bands near the Fermi energy) can be a insufficient to derive general design rules for linker and spacer monomer selection. We further identify delocalized states that are spread across tens or hundreds of pores of the 2D COFs and analyze their robustness against structural and energetic disorders like out-of-plane rotations of molecular fragments, different strength of energetic disorder and energetic shifts due to chemical doping.

A novel two-dimensional superconducting Ti layer: density functional theory and electron-beam irradiation.

Since the discovery of graphene in an atomic thin layer format, many investigations have been conducted to search for two-dimensional (2D) layered materials, in which 3d-transition metals offer much new physics and great freedom of tunability. In this work, through electron-beam irradiation, we enable the manufacture of a new 2D Ti nanosheet from a suspension of Ti0.91O2 nanosheets. In state-of-the-art density functional theory (DFT), both empirical and linear response theory predicted that Hubbard Ueff values would be imposed, resulting in unstable phonon dispersion curves. In the end, the newly found Ti monolayer is confirmed to be a non-magnetic superconductor, with a medium level of electron-phonon coupling. The newly established Ti layer is quite robust under strain, and the evolution of local Dirac points in electronic bands is also analyzed in terms of linearity and energetic shift near the Fermi energy. As suggested by the Fermi surface, this metal monolayer experiences an electronic topological transition under strain. Our findings will encourage many more explorations of pure d metal-based isotopic monolayers with diverse structures and open a new playground for 2D superconductors and ultra-thin sensoring components.

Bandgap Engineering of Cesium Lead Halide Perovskite CsPbBr3 through Cu Doping

AbstractCu‐doped CsPbBr3 with strong blue emissions is a potentially ideal material for high‐quality light‐emitting diode (LED) devices. This study thoroughly analyzes the influence of a Cu dopant on CsPbBr3 materials through a series of theoretical investigations. Two artificial CsPbBr3 supercells are constructed, and their electronic properties are analyzed. Additionally, the antibonding nature of the conduction band minimum (CBM) and valance band maximum (VBM) of CsPbBr3 is elucidated. The results indicate that a Cu dopant can only alter the local lattice around it, not the entire lattice. Moreover, the CBM and VBM deformation potentials of CsPbBr3 behave differently. Therefore, the energetic shift of VBM is more sensitive to the shrinkage of lattice due to the smaller energy difference between the constituent orbitals, leading to a bandgap reduction with the lattice contraction. This study reveals that the two critical reasons for the increase of bandgap are the contribution of Cu‐3d orbitals to the VBM and the localized lattice distortion caused by Cu impurity. Therefore, this work clarifies how Cu impurities improve the blue light emitting performance of CsPbBr3 systems.

Site-Sensitive Selective CO2 Photoreduction to CO over Gold Nanoparticles.

We demonstrate a new case of materials-gene engineering to precisely design photocatalysts with the prescribed properties. Based on theoretical calculations, a phase-doping strategy was proposed to regulate the pathways of CO2 conversion over Au nanoparticles (NPs) loaded TiO2 photocatalysts. As a result, the thermodynamic bottleneck of CO2 -to-CO conversion is successfully unlocked by the incorporation of stable twinning crystal planes into face-centered cubic (fcc) phase Au NPs. Compared to bare pristine TiO2 , the activity results showed that the loading of regular fcc-Au NPs raised the CO production by 18-fold but suppressed the selectivity from 84 % to 75 %, whereas Au NPs with twinning (110) and (100) facets boosted the activity by nearly 40-fold and established near unity CO selectivity. This enhancement is shown to originate from a beneficial shift in the surface reactive site energetics arising at the twinned stacking fault, whereby both the CO reaction energy and desorption energy were significantly reduced.

Site‐Sensitive Selective CO2 Photoreduction to CO over Gold Nanoparticles

AbstractWe demonstrate a new case of materials–gene engineering to precisely design photocatalysts with the prescribed properties. Based on theoretical calculations, a phase‐doping strategy was proposed to regulate the pathways of CO2 conversion over Au nanoparticles (NPs) loaded TiO2 photocatalysts. As a result, the thermodynamic bottleneck of CO2‐to‐CO conversion is successfully unlocked by the incorporation of stable twinning crystal planes into face‐centered cubic (fcc) phase Au NPs. Compared to bare pristine TiO2, the activity results showed that the loading of regular fcc‐Au NPs raised the CO production by 18‐fold but suppressed the selectivity from 84 % to 75 %, whereas Au NPs with twinning (110) and (100) facets boosted the activity by nearly 40‐fold and established near unity CO selectivity. This enhancement is shown to originate from a beneficial shift in the surface reactive site energetics arising at the twinned stacking fault, whereby both the CO reaction energy and desorption energy were significantly reduced.

Osteoblasts induce glucose-derived ATP perturbations in chondrocytes through noncontact communication.

Cartilage and subchondral bone communicate with each other through material and signal exchanges. However, direct evidence provided by experimental studies on their interactions is insufficient. In the present study, we establish a noncontact co-culture model with a transwell chamber to explore the energetic perturbations in chondrocytes influenced by osteoblasts. Our results indicate that osteoblasts induce more ATP generation in chondrocytes through an energetic shift characterized by enhanced glycolysis and impaired mitochondrial tricarboxylic acid cycle. Enhanced glycolysis is shown by an increase of secreted lactate and the upregulation of glycolytic enzymes, including glucose-6-phosphate isomerase (Gpi), liver type ATP-dependent 6-phosphofructokinase (Pfkl), fructose-bisphosphate aldolase C (Aldoc), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), triosephosphate isomerase (Tpi1), and phosphoglycerate kinase 1 (Pgk1). Impaired mitochondrial tricarboxylic acid cycle is characterized by the downregulation of cytoplasmic aspartate aminotransferase (Got1) and mitochondrial citrate synthase (Cs). Osteoblasts induce the activation of Akt and P38 signaling to mediate ATP perturbations in chondrocytes. This study may deepen our understanding of the maintenance of metabolic homeostasis in the bone-cartilage unit.

Gate- versus defect-induced voltage drop and negative differential resistance in vertical graphene heterostructures

To enable the computer-aided design of vertically stacked two-dimensional (2D) van der Waals (vdW) heterostructure devices, we here introduce a non-equilibrium first-principles simulation method based on the multi-space constrained-search density functional formalism. Applying it to graphene/few-layer hBN/graphene field-effect transistors, we show that the negative differential resistance (NDR) characteristics can be produced not only from the gating-induced mismatch between two graphene Dirac cones in energy-momentum space but from the bias-dependent energetic shift of defect levels. Specifically, for a carbon atom substituted for a nitrogen atom (CN) within inner hBN layers, the increase of bias voltage is found to induce a self-consistent electron filling of in-gap CN states, which in turn changes voltage drop profiles and produces symmetric NDR characteristics. With the CN placed on outer hBN layers, however, the pinning of CN states to nearby graphene significantly modifies device characteristics, demonstrating the critical impact of atomic details for 2D vdW devices.

Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease.

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), mitochondrial reactive oxygen species (mtROS), biogenesis, fission and fusion, mitophagy and urinary mitochondrial biomarkers. Both glucose- and non-glucose-induced mitochondrial dysfunction will be discussed. In terms of glucose-induced mitochondrial dysfunction, the energetic shift from OXPHOS to aerobic glycolysis, called the Warburg effect, occurs and the resulting toxic intermediates of glucose metabolism contribute to DKD-induced injury. In terms of non-glucose-induced mitochondrial dysfunction, we will review the roles of lipotoxicity, hypoxia and vasoactive pathways, including endothelin-1 (Edn1)/Edn1 receptor type A signaling pathways. Although the relative contribution of each of these pathways to DKD remains unclear, the goal of this review is to highlight the complexity of mitochondrial dysfunction in DKD and to discuss how markers of mitochondrial dysfunction could help us stratify patients at risk for DKD.

Tropicalization unlocks novel trophic pathways and enhances secondary productivity in temperate reefs

Abstract The structure of ecological communities is rapidly changing across the globe due to climate‐mediated shifts in species distributions, with novel ecosystem states emerging as new species become dominant. While it is clear that such changes restructure habitat properties and their associated assemblages, how new nutritional resources and consumers may affect the ecosystem trophic structure and energetic dynamics remains poorly resolved. Here, we investigate how the reconfiguration of tropicalized reefs—that is, temperate ecosystems receiving an influx of tropical species—affects the availability of nutritional resources and energy flow through herbivore‐based trophic pathways. To do so, we quantified changes in algal and detrital resources along a tropicalization gradient in eastern Australia. We also estimated energy flow towards herbivorous fishes by quantifying their standing biomass (kg/ha), productivity (kg ha−1 day−1), and biomass turnover (% day−1), using an individual‐level modelling approach that combines estimates of fish growth rates and mortality. Along the gradient, tropicalized reefs had relatively higher amounts of palatable algal turfs and detrital particulates compared to non‐tropicalized sites. Feeding intensity by herbivorous fishes was also c. 400 times higher on tropicalized reefs, with tropical turf‐cropping surgeon fishes being responsible for &gt;98% of the feeding rates. Turf‐driven trophic pathways underpinned virtual all (&gt;99%) of the biomass produced by tropical fishes, which contributed up to 63% of the total herbivorous fish standing biomass and 86% of the productivity despite only representing 35% of the abundance. Turfs also fuelled most of the secondary productivity of tropical fishes on tropicalized reefs across Australia's western tropical–temperate transition zone, although their overall productivity was ~5 times lower. This is possibly due to turfs there containing elevated sediment loads, which dilute the nutritional quality of turf‐based resources, as well as other differences in the biogeographical context. We propose that algal turfs are central drivers of ecosystem energetic shifts on temperate reefs as they become tropicalized because they support novel algal and detrital trophic pathways that enhance secondary productivity and biomass turnover. Our results also suggest that turf characteristics such as organic content or sediment load may emerge as increasingly important drivers of energy flow in temperate locations where turfs dominate benthic cover. A free Plain Language Summary can be found within the Supporting Information of this article.

Some new competitive advantages in the field of energetic paradigm shift from coal and gas towards the blue hydrogen production

Abstract Achieving the 2030 and 2050 climate targets gears up several economic opportunities but also a package of threats for the EU Member States. The economic crisis caused by the COVID-19 pandemic will accelerate the energy transition, which is becoming an engine of post-coronavirus economic growth. In this landscape, new economic governance, speeding up innovation, cutting the red tape, and improving access to human and financial resources becomes essential for ensuring a sustainable and long-lasting economic development which is linked with reducing the carbon emissions. Basically, a race against the clock has begun, as the first significant climate targets are to be met in 2030, aiming to reduce GHG emissions by 55% from 1990 level. Several recent studies have sought to deepen the potential of hydrogen in achieving these climate goals explaining how it can be embedded into the European Union economy. It highlighted some important features and applications of hydrogen as a substitute for other polluting resources used today in energy production, transportation, or other economic and social domains. Using a regression model, the author identified a close correlation between the increase in the price of carbon certificates and the decline in coal production. An accelerated, three-fold increase in the price of carbon certificates could enable hydrogen to be used in the power sector, while ensuring post-2030 continuity for domestic natural gas production. The combination between blue hydrogen and natural gas might be the solution to eliminate two thirds of carbon emissions from energy production, while attracting European funds, as investments for the energy transition.

Ceramide Synthase 6 Knockout Reprograms Energy Metabolism in Mice

Abstract Objectives Ceramides, a group of bioactive lipids and important signaling molecules, have been implicated in the development of cardiometabolic disease, diabetes, and cancer. Recent studies have shown that targeting Ceramide Synthases (CerS), the enzymes producing ceramides, protected from glucose intolerance and diet induced obesity. We investigated metabolomic responses to high fat diet consumption in livers and plasma of wild type (WT) and CerS6 knockout (KO) mice to obtain mechanistic understanding of the protection provided by the enzyme knockout. Methods Upon weaning, male WT and CerS6 KO mice were placed on a high fat (HFD) or control (Ctrl) diet for 16 weeks. After 14 weeks on diet, mice were placed in calorimetry cages for 48 hours. Body composition was assessed before dietary intervention and before necropsy. Plasma and snap-frozen liver samples were subjected to untargeted metabolomic analysis at Metabolon®. Results CerS6 KO mice gained significantly less weight on HFD than WT mice. Calorimetry measurements revealed that over 24 hours CerS6 KO mice did not move more than WT in either x-, y- or z-planes. Interestingly, CerS6 KO mice on a HFD consumed significantly less food, and despite the higher caloric content of the diet, they also consumed fewer calories over the 24 hour period. No differences in fat excretion between WT and CerS6 KO mice were found, measured by fecal lipid content. Calorimetry data demonstrated that on HFD, regardless of genotype, animals oxidized fat for energy. On the Ctrl diet WT mice burned a mix of substrates while CerS6 KO mice preferentially oxidized glucose for energy during the light cycle. This indicates that during the active phase of the light cycle a switch in energy source occurred in KO but not WT mice. Untargeted metabolomics revealed significant differences in intermediates of glycolysis both in liver and plasma of the KO vs WT animals. Moreover, significant increases in multiple TCA cycle metabolites in KO vs WT plasma were seen in HFD fed mice. Conclusions We found a significant shift in tissue-level and whole-body energetics in CerS6 KO mice. This shift could be responsible for the beneficial metabolic effects of targeting CerS6 when HFD is consumed. Further studies will help determine how CerS6 and ceramides influence tissue and whole body metabolism. Funding Sources This work was funded by R01 CA193782 grant to NK.

Quantification of Cooperativity between Metal Sites in Dinuclear Transition Metal Complexes Containing the (2-Dimethylamino)-4-(2-pyrimidinyl)pyrimidine Ligand.

A concept for the quantification of cooperative effects in transition-metal complexes is presented. It is demonstrated for a series of novel N,N- (mononuclear) and C,N-coordinated homo- and heterometallic binuclear complexes based on the (2-dimethylamino)-4-(2-pyrimidinyl)pyrimidine ligand, which are accessible by applying roll-over cyclometallation. These iridium-, platinum-, and palladium-containing compounds are investigated with respect to their absorption and fluorescence spectra. The cooperative effects in the electronic absorptions, i. e., the energetic shifts between mononuclear and dinuclear complexes, and free ligands are analyzed on the basis of the lowest energy π-π* transitions and compared to calculated data, obtained from TD-DFT calculations. Furthermore the corresponding fluorescence spectra are presented and analyzed with respect to the concept of cooperativity.

Nicotinamide pathways as the root cause of sepsis - an evolutionary perspective on macrophage energetic shifts.

Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg‐like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3‐dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD+ supplies. We hypothesize that an insufficient cellular NAD+ supply is the root cause of metabolic shifts in macrophages. We assert that manipulation of nicotinamide pathways may correct deleterious immune responses. We propose evaluation of nicotinamide (Vitamin B3) and analogues, including isoniazid, nicotinamide mononucleotide and nicotinamide riboside, as potential therapy for infectious causes of sepsis, including COVID‐19.