Energetic Changes Research Articles

COMPUTATIONAL STUDY OF NICOTINAMIDE WITH PARENT URACIL AND ANTICANCER URACIL DERIVATIVES

The density functional theory calculations have been applied to investigate hydrogen-bonded complexes of nicotinamide with parent uracil and its anticancer derivatives namely 5 fluorouracil and 2 thiouracil. The optimized complexes are analyzed in terms of structural, electronic, and energetic changes, binding free energy and enthalpy changes, dipole moments, atomic charge variation, electron delocalizations, topological parameters, chemical reactivity descriptors, etc. The study suggests that the most stable complexes are formed by nicotinamide with fluorouracil and the least stable with thiouracil. The uracil and its derivatives act as far better hydrogen bond donors than nicotinamide in the optimized complexes. Significant charge transfer between nicotinamide and parent uracil and its derivatives is suggested by Frontier Molecular Orbital (FMO) analysis and E(2) from Natural Bond Orbital analysis. The present computational study shows that uracil drugs form stable intercalation sites with nicotinamide. The results may prove useful in the molecular designing of new anticancer agents.

Dynamic phase transition theory

Thermodynamic conventions suffer from describing dynamical distinctions, especially when the structural and energetic changes induced by rare events are insignificant. By using the ensemble theory in the trajectory space, we present a statistical approach to address this problem. Rather than spatial particle-particle interaction which dominates thermodynamics, the temporal correlation of events dominates the dynamics. The zeros of dynamic partition function mark phase transitions in the space-time, i.e., dynamic phase transition (DPT), as Yang and Lee formulate traditional phase transitions, and hence determine dynamic phases on both sides of the zeros. Analogous to the role of temperature (pressure) as thermal (mechanical) potential, we interpret the controlling variable of DPT, i.e., dynamic field, as the dynamical potential. These findings offer possibility towards a unified picture of phase and phase transition.

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients’ muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin‐deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin‐deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products.

The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.

Effects of hindgut acidosis on metabolism, inflammation, and production in dairy cows consuming a standard lactation diet

Postruminal intestinal barrier dysfunction caused by excessive hindgut fermentation may be a source of peripheral inflammation in dairy cattle. Therefore, the study objectives were to evaluate the effects of isolated hindgut acidosis on metabolism, inflammation, and production in lactating dairy cows. Five rumen-cannulated lactating Holstein cows (32.6 ± 7.2 kg/d of milk yield, 242 ± 108 d in milk; 642 ± 99 kg of body weight; 1.8 ± 1.0 parity) were enrolled in a study with 2 experimental periods (P). During P1 (4 d), cows were fed ad libitum a standard lactating cow diet (26% starch dry matter) and baseline data were collected. During P2 (7 d), all cows were fed the same diet ad libitum and abomasally infused with 4 kg/d of pure corn starch (1 kg of corn starch + 1.25 L of H2O/infusion at 0600, 1200, 1800, and 0000 h). Effects of time (hour relative to the first infusion or day) relative to P1 were evaluated using PROC MIXED in SAS (version 9.4; SAS Institute Inc.). Infusing starch markedly reduced fecal pH (5.84 vs. 6.76) and increased fecal starch (2.2 to 9.6% of dry matter) relative to baseline. During P2, milk yield, milk components, energy-corrected milk yield, and voluntary dry matter intake remained unchanged. At 14 h, plasma insulin and β-hydroxybutyrate increased (2.4-fold and 53%, respectively), whereas circulating glucose concentrations remained unaltered. Furthermore, blood urea nitrogen increased at 2 h (23%) before promptly decreasing below baseline at 14 h (13%). Nonesterified fatty acids tended to decrease from 2 to 26 h (40%). Circulating white blood cells and neutrophils increased on d 4 (36 and 73%, respectively) and somatic cell count increased on d 5 (4.8-fold). However, circulating serum amyloid A and lipopolysaccharide-binding protein concentrations were unaffected by starch infusions. Despite minor changes in postabsorptive energetics and leukocyte dynamics, abomasal starch infusions and the subsequent hindgut acidosis had little or no meaningful effects on biomarkers of immune activation or production variables.

Energetic competition in the complexation affinity of paracetamol with water and oxalic acid

The intermolecular interactions of active pharmaceutical ingredients (APIs) are the driving forces of API molecular activity and stability, in vivo receptor binding, environmental transport, and persistence. In manufacturing, API complexation with another molecule to create stable crystalline structures is pursued, but the formation of more energetically stable complexes can lead to undesired consequences. Density functional theory (DFT) was used to describe the role played by hydrogen bonding in the formation of paracetamol and oxalic acid (PCA-OXA) complexes. PCA-OXA hydrogen bonding sites were investigated to determine strength and overall contribution/competition during the initial stages of the nucleation process. Structural and energetic changes were evaluated for 1:1 PCA-OXA, PCA-Water, and OXA-Water complexes both in vacuum and in water environments via explicit and implicit solvation. Results show significant shortening of the hydrogen bonds within the PCA-OXA complex with large changes in energy in the PCA-OXA complexation mechanism. Two out of the four complexation sites play the largest roles in the initial steps of the nucleation process. In an aqueous environment, little to no energetic competition for PCA hydrogen bonds formation with other molecules is observed. Post Hartree–Fock methods (MP2 and CCSD) were used to calibrate and verify the DFT results.

Muscle endurance: Is bipedalism the cause?

One may ask if the transition to bipedalism from the condition of quadrupedalism, which occurred about 7 million years ago, has been the cause or consequence of a series of fundamental physiological muscular aspects including the cost of locomotion, a crucial determinant of endurance, which has been found to be significantly lower in humans than in apes. This issue strictly links to unsolved issues regarding the significance of several muscular structural and functional adaptations, classically attributed to bipedalism and its associated locomotions, which we cannot simply attribute to the acquisition of the upright position and which may directly or indirectly contribute to the observed changes in muscle energetics that make the modern human an exceptional endurance walker and runner compared to quadrupedals.

Abstract 13652: A Randomised Double-Blind Placebo-Controlled Study of Fenofibrate as a Metabolic Modulator to Augment Cardiac Physiology in Moderate-Severe Aortic Stenosis

Background: Pressure overload in aortic stenosis (AS) is associated with reduced cardiac fatty acid oxidation (FAO) and evidence of myocardial steatosis and impaired myocardial energetics. Here, we investigated whether modulating myocardial metabolism to increase FAO with a PPARα agonist, Fenofibrate in moderate-severe AS had effects on cardiac metabolism and physiology. Methods: 67 participants with asymptomatic moderate-severe AS were prospectively randomised (double-blinded) to receive either Fenofibrate 200mg once daily (N= 54) or placebo (N=13) for 6 months (180 ± 7 days duration). Follow-up data is available in 42 patients. Primary endpoint was reduction in myocardial triglyceride content (MTG) measured using proton magnetic resonance spectroscopy (MRS). Secondary endpoints included cardiac PCr/ATP measured by 31P-MRS and LV strain assessed using MR tagging. Results: There was significant reduction in MTG content (-0.40%, CI -0.74 to -0.06, p= 0.022), with a no significant reduction seen in placebo. (-0.46%, CI -1.1 to 0.17, p= 0.13). A significant increase in venous butyrate levels was seen in the fibrate group (+0.09 mmol/l, CI 0.006 to 0.17, p= 0.036) in line with increased fatty acid oxidation. No change in cardiac energetics was seen in either group. No change in cardiac function was seen in either group, global longitudinal strain (-0.07%, p 0.89 Fibrate vs -0.31%, p 0.67 Placebo), circumferential strain ( -0.15 %, p 0.80 Fibrate vs 1.71%, p 0.07 Placebo). Conclusions: Fenofibrate can potentially upregulate fatty acid oxidation in hypertrophied AS hearts reducing myocardial lipid content, but this did not have any measurable beneficial physiological effect in moderate-severe AS.

Glucose and fatty acids catabolism during in vitro decidualization of human endometrial stromal cells

The differentiation of endometrial stromal cells, named decidualization, is essential for the proper formation of the materno-fetal interphase. One important feature of decidualization is the increased glucose consumption and its utilization by endometrial cells to produce energy. Besides glucose, fatty acids are another important energy source for living cells and it has been described that endometrial stromal cells rely on the proper function of the oxidation of fatty acids for the correct decidualization. It is, however, unknown whether the turn-over of fatty acid degradation is modified during decidualization. Furthermore, it is also unknown how the final products of glucose and fatty acid catabolism are related to the function of the tricarboxylic acid cycle for the efficient ATP production. In this study, we evaluated the content levels of different intermediate metabolites and the expression of the key enzymes related to the degradation of glucose and fatty acids during the in vitro decidualization of human endometrial stromal cells. Our results suggest that human endometrial stromal cells undergo energetic metabolic changes during decidualization and that decidualizing and non-decidualizing cells differ in the level of activation of different metabolic pathways and, probably, in the use of intermediate metabolites.

Structural and thermodynamic evolution of an amorphous SiOC ceramic after swift heavy ion irradiation

Radiation induced structural and energetic changes have been widely studied in crystalline materials, but studied to a much lesser extent in amorphous solids. Using a combination of neutron pair distribution function (PDF) analysis and high temperature oxide melt solution calorimetry, we obtained critical insights into the structural and energetic evolution in a swift heavy ion irradiated amorphous SiOC polymer-derived ceramic. The radiation modified SiOC structure becomes energetically less stable by 24.0±1.6 kJ/mol compared to the unirradiated structure. This destabilization is related to decreased connectivity of the Si-O-C network and destruction of free carbon. In comparison with unirradiated SiOC, the irradiated structure is more likely to become phase separated during subsequent thermal annealing. Our study has important implications for evaluating amorphous SiOC ceramic as a possible radiation resistant structure for nuclear applications.

Gestational diabetes, preeclampsia and the maternal heart

Abstract Background Gestational diabetes mellitus (GDM) and preeclampsia (pE) are both associated with an increased risk of cardiovascular mortality and morbidity, including an increased risk of developing heart failure in later life. Both conditions are increasing in prevalence; GDM affects up to 12% and pE affects 3–5% of pregnancies worldwide. Compromised cardiac energy production is an important contributor to most forms of heart disease. The changes in myocardial energetics in GDM and pE have not been characterised previously. Purpose We sought to assess if women with GDM and women with pE in the third trimester of pregnancy exhibit adverse cardiac alterations in myocardial energetics, function or tissue characteristics. Methods Thirty-eight healthy pregnant (HP) women, thirty women with GDM and fifteen women with pE were recruited, matched for age and ethnicity. Participants underwent phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for assessment of myocardial energetics (phosphocreatine to ATP ratio (PCr/ATP)), tissue characteristics, biventricular volumes and ejection fractions, left ventricular (LV) mass, global longitudinal strain (GLS) and mitral in-flow E/A ratio. Results The biochemical characteristics and multiparametric MR results are given in Table 1. The women in the GDM and the pE groups had higher body-mass index. There was a stepwise increase in the systolic and diastolic BP from the HP to the GDM to the pE group. There was no difference in NTproBNP concentrations between the groups. The gestational weight gain was higher in women with GDM and pE compared to the HP group. The women in the GDM and the pE groups showed similar reductions in myocardial PCr/ATP ratios compared to HP group (Figure 1a), accompanied by lower LV end-diastolic volumes and higher LV mass (Figure 1b) and enhanced LV concentricity in both groups (Figure 1c). While LV ejection fractions were similar across the groups, the GLS was reduced in women with GDM and in women with pE (Figure 1d). Conclusions We show here for the first time that despite no prior diagnosis of diabetes or hypertension, women with GDM or pE manifest impaired myocardial contractility and higher LV mass, associated with reductions in myocardial energetics. These findings may aid our understanding of the long-term cardiovascular risks associated with these conditions. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Wellcome Trust

A phase 2a trial investigating ninerafaxstat – a novel cardiac mitotrope for the treatment of diabetic cardiomyopathy (IMPROVE-DiCE)

Abstract Background Type 2 diabetes (T2D) is a significant, independent contributor to the development of heart failure (HF), driven by energetic, metabolic, structural and functional myocardial changes. The T2D heart is characterised by over-reliance on fatty acid utilisation, shows reduced glucose oxidation and inhibition of pyruvate dehydrogenase (PDH). This results in a diminished myocardial energy reserve and blunted adenosine triphosphate (ATP) generation as well as cardiac steatosis, contributing to lipotoxicity, and diastolic dysfunction. Purpose We assessed the effects of ninerafaxstat – a novel cardiac mitotrope designed to shift myocardial substrate utilisation in favour of glucose and thus, restore myocardial energy homeostasis – on cardiac metabolism & diastolic function in patients with T2D and obesity. Methods In this open-label, mechanistic phase 2a trial, we enrolled 21 patients with T2D & obesity (HbA1c median 7.0% (IQR 6.6, 7.8), weight 97kg (90, 102)) and subsequently treated them with 200mg ninerafaxstat twice daily for 4 or 8 weeks; (Fig. 1). Cardiac metabolism and function were assessed pre- & post-treatment using magnetic resonance imaging (MRI), 31P-, 1H- and, in a subset of n=9, hyperpolarized [1-13C]pyruvate MR spectroscopy. Results T2D patients at baseline presented with impaired myocardial energetics with a markedly reduced PCr/ATP (1.6 [1.4, 2.1]), myocardial steatosis (myocardial triglycerides 2.2% [1.5, 3.2]) left ventricular (LV) hypertrophy (LV mass 130g [98, 152]), and diastolic dysfunction (peak diastolic strain rate 0.86 1/s [0.82, 1.06]). Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p<0.01), reduced myocardial triglyceride content (by 34%, p=0.03) and improved LV diastolic function (peak circumferential diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05) (Fig. 2). PDH flux was increased in 7/9 subjects (mean 45%, p=0.08), consistent with improved glucose utilisation. Left ventricular volumes and mass, heart rate and blood pressure remained unchanged. Conclusions Treatment with ninerafaxstat significantly improves myocardial energetics, reduces myocardial steatosis and improves diastolic function in patients with T2D and obesity. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Imbria Pharmaaceuticals

Biophysical Impact of 5-Week Training Cessation on Sprint Swimming Performance.

To assess changes in swimming performance, anthropometrics, kinematics, energetics, and strength after 5-week training cessation. Twenty-one trained and highly trained swimmers (13 males: 17.4 [3.1]y; 50-m front crawl 463 [77] FINA points; 8 females: 16.7 [1.7]y; 50-m front crawl 535 [48] FINA points) performed a 50-m front-crawl all-out swim test, dryland and pool-based strength tests, and 10-, 15-, 20-, and 25-m front-crawl all-out efforts for anaerobic critical velocity assessment before and after a 5-week training cessation. Heart rate and oxygen uptake (V˙O2) were continuously measured before and after the 50-m swim test (off-kinetics). Performance was impaired 1.9% (0.54s) for males (P = .007, d = 0.91) and 2.9% (0.89s) for females (P = .033, d = 0.93). Neither the anthropometrical changes (males: r2 = .516, P = .077; females: r2 = .096, P = .930) nor the physical activities that each participant performed during the off-season (males: r2 = .060, P = .900; females: r2 = .250, P = .734) attenuated performance impairments. Stroke rate and clean swimming speed decreased (P < .05), despite similar stroke length and stroke index (P > .05). Blood lactate concentrations remained similar (P > .05), but V˙O2 peak decreased in females (P = .04, d = 0.85). Both sexes showed higher heart rate before and after the 50-m swim test after 5 weeks (P < .05). Anaerobic metabolic power deterioration was only observed in males (P = .035, d = 0.65). Lower in-water force during tethered swimming at zero speed was observed in males (P = .033, d = 0.69). Regarding dryland strength, lower-body impairments were observed for males, while females showed upper-body impairments (P < .05). A 5-week training cessation yielded higher heart rate in the 50-m front crawl, anaerobic pathways, and dryland strength impairments. Coaches should find alternatives to minimize detraining effects during the off-season.

Surface energetics mediated charge transfer and exciton transfer in cation-adsorbed rubrene/PbS nanocrystal hybrids

Organic molecule and inorganic nanocrystal (NC) hybrids have become a promising platform for photon energy conversion. Although surface energetics modification has proven effective in promoting triplet energy transfer, singlet energy transfer and charge transfer have been barely investigated. Here, we systematically clarify the photophysical dynamics of charge, singlet exciton, and triplet exciton within the energy conversion process based on hybrids of rubrene and Cd2+-adsorbed PbS NCs. It is found that a considerable number of charges in rubrene molecules can be transferred to cation-induced surface states in the ∼2 ps time scale with high efficiency to trigger a delayed biexciton effect, which provides a novel approach to uncover the intermediate role of NC surface states. For the triplet exciton, strong interaction with surface states is investigated with a recycling energy transfer of around 14% efficiency, which is found to be insensitive to changes in NC surface energetics. As a result, the maximum photoluminescence lifetime of PbS NCs was enhanced by about 38%. This work reveals the neglected photo-physical dynamics in the transfer process between organic molecules/inorganic NCs and validates the capability of the surface state in sensitization of organic charges and excitons.

P.03 Myosin dysregulation in nemaline myopathy

Nemaline myopathy (NM) is one of the most common congenital myopathies. NM is often related to pathogenic variants in the <i>NEB, ACTA1, TPM2</i> and <i>TPM3</i> genes. Even though the exact disease mechanisms remain to be elucidated, histological analyses of NM patients' muscle biopsies may reveal unexplained accumulation of glycogen and abnormal mitochondria. Thus, the aim of the present work was to identify what could cause such change in muscle energetics. For that, we applied mant-ATP chase experiments on skeletal muscle fibres from patients diagnosed with NM. We observed that the myosin-stabilising conformational state, known as the super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting patient muscle fibres expressing NEB and ACTA1 mutations. Such alteration was linked to hyper-phosphorylation of myosin-binding protein C, a protein linking myosin molecules to the thin filaments. Hence, our results may indicate a contribution of myosin to some of the histopathological aberrations related to NM.

Annual and spatial variation in the condition and lipid storage of juvenile Chukchi Sea gadids during a recent period of environmental warming (2012 to 2019).

The Arctic is undergoing dramatic environmental change with decreasing sea-ice extent and increasing summer temperatures. The late summers of 2017 and 2019 on the eastern Chukchi Sea were anomalously warm, nearly 4 °C warmer than the previous 30-year average. Increased ocean temperatures can affect the energetics of North Pacific fish by increasing their metabolic demands and via shifting fish prey assemblages. Here we describe the total lipids as well as fatty acid (FA) trophic markers in juveniles of two Arctic gadids (polar cod, Boreogadus saida and saffron cod, Eleginus gracilis) as well as two sub-Arctic gadids (walleye pollock, Gadus chalcogrammus and Pacific cod, Gadus macrocephalus) collected on recent ecosystem surveys spanning the north Bering and Chukchi seas. Fifty percent of the variance in the lipid composition of gadids was accounted for by species-specific differences, while ecosystem measurements such as bottom temperature, large > C3 stage Calanus abundance, and surface temperature were found to independently account for 25%, 12% and 10%, respectively. Allometric relationships in lipid storage revealed that polar cod have a different lipid profile than other gadids, suggesting a species-specific life-history strategy for high lipid storage that is an adaptation to Arctic environments. Both polar cod and saffron cod had reduced lipid storage in 2017 compared to fish collected in earlier years. Polar cod in 2017 were significantly lower in total lipid, triacylglycerols (TAG), diatom- (16:1n-7/16:0) and Calanus-sourced (∑C20+ C22) FAs over the Chukchi Shelf. Juvenile gadids showed interspecific differences in the spatial distribution of high lipid individuals, with polar cod having the highest lipids in the northern ice-associated regions of the Chukchi Sea and walleye pollock in the southern Chukchi Sea. In 2019, polar cod's distribution had shifted north such that they were only abundant in the northern Chukchi Sea, where they maintained higher region-specific lipid storage than in 2017. It is concerning that reduced lipid content in polar cod was associated with elevated water temperatures, given predicted continued warming in the Chukchi Sea. Energetic changes in juvenile gadids may be associated with future increased natural mortality rates for regional populations (e.g. overwintering) and unstable foraging value for birds and mammals in the Arctic.

Energetics and electronics of polar Diels–Alder reactions at the atomic level: QTAIM and IQA analyses of complete IRC paths

The mechanism of Diels–Alder reactions between cyclopentadiene and several cyanoethylenes was studied by means of Density Functional Theory calculations using QTAIM and IQA (Interacting Quantum Atoms) analyses along complete IRC paths. Each geometry from the IRC had its wavefunction computed and the topology of the electronic density for it was then evaluated. By means of IQA, the global energetic profile was partitioned among the various atoms in the molecule, providing insight into what atoms are the main ones responsible for the magnitude of the energy barriers. The (a)synchronicity of the reaction mechanisms featuring non-symmetrically substituted dienophiles was characterized, from QTAIM, by the electron densities and Laplacians over the LCP’s as well as by the different atomic energy barriers obtained from IQA. The magnitude of the atomic barrier nicely explains the (a)synchronicity of the reaction mechanisms, and the degree of (a)synchronicity is nicely revealed by the difference between the earlier and later bond breaking and bond formations. The main conclusion is that important energetic and electronic changes are occurring before and after the position of the transition state structure, mainly for those asynchronous mechanisms, and although these provide essential insight into the reaction mechanism, most studies cannot assess this kind of information because they are focusing solely on reactants, transition states, and products. We advocate that the additional computational effort required for such analyses is more than compensated by the great amount of useful information it provides.

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis.

Multiple parallels exist between placentation and cancer dissemination at molecular, cellular, and anatomical levels, presenting placentation as a unique model to mechanistically understand the onset of cancer metastasis. In humans, interaction of placenta and the endometrium results eventually in deep invasion of placental extravillous trophoblasts (EVTs) into the maternal stroma, a process similar to stromal trespass by disseminating carcinoma cells. In anticipation of implantation, endometrial fibroblasts (ESFs) undergo a process called decidualization during the secretory phase of the menstrual cycle. Decidualization, among other substantial changes associated with ESF differentiation, also involves a component of fibroblast activation, and myofibroblast transformation. Here, using traction force microscopy, we show that increased cellular contractility in decidualized ESFs is reversed after interaction with EVTs. We also report here the large changes in energetic state of ESFs upon decidualization, showing increased oxidative phosphorylation, mitochondrial competency and ATP generation, as well as enhanced aerobic glycolysis, presenting mechanical contractility and energetic state as new functional hallmarks for decidualization. These energetic changes accompanying the marked increase in contractile force generation in decidualization were reduced in the presence of EVTs. We also show that increase in decidual contractility and mechanical resistance to invasion is achieved by SRF-MRTF transcriptional activation, achieved via increased phosphorylation of fibroblast-specific myosin light chain 9 (MYL9). EVT induced paracrine secretion of Heparin Binding Epidermal Growth Factor (HBEGF), a potent MAPK activator, which shifts the balance of SRF association away from MRTF based transcription, reducing decidual ESF contractility and mechanical resistance to placental invasion. Our results identify a new axis of intercellular communication in the placental bed modulating stromal force generation and resistance to invasion with concurrent downregulation of cellular energetics. These findings have important implications for implantation related disorders, as well as stromal control of cancer dissemination.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease

BackgroundNeurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). MethodsWe measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. ResultsMost regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. ConclusionsPhosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

The roles of charge transfer and polarization in non-covalent interactions: a perspective from ab initio valence bond methods.

Noncovalent interactions are ubiquitous and have been well recognized in chemistry, biology and material science. Yet, there are still recurring controversies over their natures, due to the wide range of noncovalent interaction terms. In this Essay, we employed the Valence Bond (VB) methods to address two types of interactions which recently have drawn intensive attention, i.e., the halogen bonding and the CH‧‧‧HC dihydrogen bonding. The VB methods have the advantage of interpreting molecular structures and properties in the term of electron-localized Lewis (resonance) states (structures), which thereby shed specific light on the alteration of the bonding patterns. Due to the electron localization nature of Lewis states, it is possible to define individually and measure both polarization and charge transfer effects which have different physical origins. We demonstrated that both the ab initio VB method and the block-localized wavefunction (BLW) method can provide consistent pictures for halogen bonding systems, where strong Lewis bases NH3, H2O and NMe3 partake as the halogen bond acceptors, and the halogen bond donors include dihalogen molecules and XNO2 (X = Cl, Br, I). Based on the structural, spectral, and energetic changes, we confirm the remarkable roles of charge transfer in these halogen bonding complexes. Although the weak C-H∙∙∙H-C interactions in alkane dimers and graphene sheets are thought to involve dispersion only, we show that this term embeds delicate yet important charge transfer, bond reorganization and polarization interactions.