High carbon dioxide emissions from Australian estuaries driven by geomorphology and climate.

Estuaries play an important role in connecting the global carbon cycle across the land-to-ocean continuum, but little is known about Australia's contribution to global CO2 emissions. Here we present an Australia-wide assessment, based on CO2 concentrations for 47 estuaries upscaled to 971 assessed Australian estuaries. We estimate total mean (±SE) estuary CO2 emissions of 8.67 ± 0.54 Tg CO2-C yr-1, with tidal systems, lagoons, and small deltas contributing 94.4%, 3.1%, and 2.5%, respectively. Although higher disturbance increased water-air CO2 fluxes, its effect on total Australian estuarine CO2 emissions was small due to the large surface areas of low and moderately disturbed tidal systems. Mean water-air CO2 fluxes from Australian small deltas and tidal systems were higher than from global estuaries because of the dominance of macrotidal subtropical and tropical systems in Australia, which have higher emissions due to lateral inputs. We suggest that global estuarine CO2 emissions should be upscaled based on geomorphology, but should also consider land-use disturbance, and climate.

Mitochondrial Phosphopantetheinylation is Required for Oxidative Function.

Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.

Sensitivity to change of the Systemic Therapy Inventory of Change (STIC) intersession scales.

Objective: The Systemic Therapy Inventory of Change (STIC) is a systemic measurement feedback system that provides therapists with feedback regarding the multidimensional clinical change in individual, couple, and family therapy. The STIC Intersession scales include Individual Problems and Strengths (IPS), Relationship with Partner (RWP), Family/Household (FH), and Child Problems and Strengths (CPS). They are administered to clients before each therapy session. The purpose of the current study is to investigate the STIC Intersession scales' sensitivity to change, the ability to detect reliable and valid changes that occur after an intervention. Method: Participants (N = 583) who voluntarily received individual, couple, or family therapy services in a randomized clinical trial attended the study. Results: By comparing the changes in pre-therapy and post-therapy scores of the STIC Intersession scales with those of the corresponding reference measures, the external sensitivity to change of the STIC Intersession scales was supported. The IPS Intersession scale showed greater change than the Beck Anxiety Inventory. However, no evidence supported the discriminant validity of CPS's change scores. Conclusion: Thus, the STIC Intersession IPS, RWP, and FH can be validly used to assess multi-systemic changes in both research and clinical work.

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

Discovery of Selective Tertiary Amide Inhibitors of Cyclin-Dependent Kinase 2 (CDK2).

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

Direct Cell Reprogramming and Phenotypic Conversion: An Analysis of Experimental Attempts to Transform Astrocytes into Neurons in Adult Animals.

Central nervous system (CNS) repair after injury or disease remains an unresolved problem in neurobiology research and an unmet medical need. Directly reprogramming or converting astrocytes to neurons (AtN) in adult animals has been investigated as a potential strategy to facilitate brain and spinal cord recovery and advance fundamental biology. Conceptually, AtN strategies rely on forced expression or repression of lineage-specific transcription factors to make endogenous astrocytes become "induced neurons" (iNs), presumably without re-entering any pluripotent or multipotent states. The AtN-derived cells have been reported to manifest certain neuronal functions in vivo. However, this approach has raised many new questions and alternative explanations regarding the biological features of the end products (e.g., iNs versus neuron-like cells, neural functional changes, etc.), developmental biology underpinnings, and neurobiological essentials. For this paper per se, we proposed to draw an unconventional distinction between direct cell conversion and direct cell reprogramming, relative to somatic nuclear transfer, based on the experimental methods utilized to initiate the transformation process, aiming to promote a more in-depth mechanistic exploration. Moreover, we have summarized the current tactics employed for AtN induction, comparisons between the bench endeavors concerning outcome tangibility, and discussion of the issues of published AtN protocols. Lastly, the urgency to clearly define/devise the theoretical frameworks, cell biological bases, and bench specifics to experimentally validate primary data of AtN studies was highlighted.

Universal logic with encoded spin qubits in silicon.

Quantum computation features known examples of hardware acceleration for certain problems, but is challenging to realize because of its susceptibility to small errors from noise or imperfect control. The principles of fault tolerance may enable computational acceleration with imperfect hardware, but they place strict requirements on the character and correlation of errors1. For many qubit technologies2-21, some challenges to achieving fault tolerance can be traced to correlated errors arising from the need to control qubits by injecting microwave energy matching qubit resonances. Here we demonstrate an alternative approach to quantum computation that uses energy-degenerate encoded qubit states controlled by nearest-neighbour contact interactions that partially swap the spin states of electrons with those of their neighbours. Calibrated sequences of such partial swaps, implemented using only voltage pulses, allow universal quantum control while bypassing microwave-associated correlated error sources1,22-28. We use an array of six 28Si/SiGe quantum dots, built using a platform that is capable of extending in two dimensions following processes used in conventional microelectronics29. We quantify the operational fidelity of universal control of two encoded qubits using interleaved randomized benchmarking30, finding a fidelity of 96.3% ± 0.7% for encoded controlled NOT operations and 99.3% ± 0.5% for encoded SWAP. The quantum coherence offered by enriched silicon5-9,16,18,20,22,27,29,31-37, the all-electrical and low-crosstalk-control of partial swap operations1,22-28 and the configurable insensitivity of our encoding to certain error sources28,33,34,38 all combine to offer a strong pathway towards scalable fault tolerance and computational advantage.

Radiographic changes in ribs following clipping of patent ductus arteriosus in preterm infants.

Objectives: There are no published reports on the rib abnormalities on the plain chest radiograph in preterm infants following surgical clipping of isolated patent ductus arteriosus. The purpose of this study was to describe changes in the ribs on the plain chest radiograph following surgical clipping of patent ductus arteriosus (surgery groups) in preterm infants compared to non-surgical closure of patent ductus arteriosus (control group). Methods: Data from preterm infants with patent ductus arteriosus clipping (surgery) via a left postero-lateral thoracotomy were compared with infants in whom the patent ductus arteriosus closed: spontaneously, with medications or use of an occlusive device (controls). Serial pre- and post-closure plain chest radiographs were randomly reviewed by a reader blinded to the route of closure and up to 1 year following the patent ductus arteriosus closure. Results: Of the total of 196 cases included in the study: 45 of the patent ductus arteriosus closed following treatment with medications, 8 cases closed with an occlusion device, 38 were closed surgically, and in 105 cases, the patent ductus arteriosus closed spontaneously. Compared to the pre-operative period, 36/38 (95%) infants in the surgery group had one or more of the following rib abnormalities: ipsilateral fourth and fifth rib fusion, narrowing of the ipsilateral fifth intercostal space, thinning of the ipsilateral fourth or fifth rib, or a combination of the above on the chest radiograph compared to 0% in the control group (p < 0.001). Conclusion: Radiographic rib abnormalities are common and appear in infancy following surgical clipping of patent ductus arteriosus in preterm infants. Further studies are needed to clarify the natural history of these abnormalities on thoracic cage and cardiopulmonary functions.

CCN2 participates in overload-induced skeletal muscle hypertrophy.

The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

Cardiac-derived TGF-ß1 confers resistance to diet-induced obesity through the regulation of adipocyte size and function.

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-ß1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-ß1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-ß1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-ß1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-ß1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-ß1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism.

Impact of surfactant selection and incorporation on in situ nanoparticle formation from amorphous solid dispersions.

Spray dried amorphous solid dispersions (ASDs) stand as one of the most effective formulation strategies to address issues of low aqueous solubility when developing new chemical entities.An emerging research topic focusing on the formation of amorphous nanoparticles or nanodroplets from ASD formulations has attracted attention recently. These ASD nanoparticlescan be highly beneficial and able to further increase oral bioavailability. The incorporation of surfactants in ASD formulations has been shown to facilitate the formation of these nanoparticles. Therefore, understanding the mechanism of surfactant-promoted nanoparticle formation becomes critical for the rational design of ASD formulations. This work demonstrated the importance of inclusion of the surfactant within the ASD composition for nanoparticle formation. In contrast, when a surfactant is added externally (e.g., by inclusion in the dosing vehicle), only a limited degree of nanoparticle formation was observed even at the optimized surfactant-to-drug ratios. A variety of different surfactants were also assessed for understanding their impact on ASD nanoparticle formation. The spray drying systems containing nonionic surfactants, Tween 80 and Vitamin E TPGS, produced higher amounts of in situ ASD nanoparticles when compared to an anionic surfactant, sodium lauryl sulfate (SLS). The ASD nanoparticles produced by the Genentech developmental compound, GDC-0334, were highly stable and retained their original particle size and amorphous feature for at least 18 h under biorelevant conditions. The high degree of nanoparticle formation from spray dried GDC-0334 containing Tween 80 combined with the superior physical stability of the nanoparticles also translated to enhanced in vivo performance in a rat pharmacokinetics study.

Field induced displacement reactions with proton bound dimers of organophosphorus compounds in a tandem differential mobility spectrometer.

Endothermic displacement reactions between proton bound dimers of organophosphorus compounds (OPCs) and isopropanol (IPA) were enabled in air at ambient pressure with tandem differential mobility spectrometry (DMS). Proton bound dimers (M2H+) were mobility isolated in purified air with a first DMS stage, mixed with IPA at ≥100 ppm in a middle reactive stage at 106 to 160 Td from a symmetrical 4 MHz waveform, and mobility analyzed in a second DMS stage. Although the enthalpy for displacement of M by IPA in M2H+ is unfavorable by +44 to 50 kJ mol-1, formation of the heterogenous proton bound dimer, MH+(IPA) arises from field induced dissociation of M2H+ to MH+ and addition of IPA. While peak dispersion for M2H+ of OPCs is limited to -2.25 to -0.5 V compensation voltage, peaks for MH+(IPA) were located at -10.5 to -8.25 V through a combination of ion transformation and mobility-based vapor modification. This inaugural use of ion reactions in air at ambient pressure demonstrates that multi-stage sequential processing of ions can improve significantly the analytical performance in a mobility spectrometer.

ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth.

Integration of cellular responses to extracellular cues is essential for cell survival and adaptation to stress. Extracellular signal-regulated kinase (ERK) 1 and 2 serve an evolutionarily conserved role for intracellular signal transduction that proved critical for cardiomyocyte homeostasis and cardiac stress responses. Considering the importance of ERK1/2 in the heart, understanding how these kinases operate in both normal and disease states is critical. Here, we review the complexity of upstream and downstream signals that govern ERK1/2-dependent regulation of cardiac structure and function. Particular emphasis is given to cardiomyocyte hypertrophy as an outcome of ERK1/2 activation regulation in the heart.

Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1.

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.

Epitranscriptomics in the Heart: a Focus on m6A.

PURPOSE OF REVIEW: Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (m6A), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of m6A's involvement in cardiac pathologies and processes. RECENT FINDINGS: Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the m6A modification. Results have revealed a multifaceted role for m6A in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of m6A in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by m6A is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.

Loneliness and Migraine Self-Management: A Cross-Sectional Assessment.

Background: Chronic illness is often comorbid with the psychological state of loneliness. Models of care for patients who experience chronic migraines may often lack an understanding of psychosocial influences of the illness. Addressing the effects of loneliness on the health behaviors of chronic migraine patients may further elucidate gaps in care that exist beyond the biomedical approach to migraine treatment. The primary aim of this study was to assess the relationship between loneliness and behavioral health decisions in chronic migraine patients, specifically patient ability to self-manage, and effectiveness of treatments. Methods: We conducted a cross-sectional survey among patients (n = 500) with migraine and assessed for the experience of loneliness by using the University of California, Los Angeles-Revised (UCLA-R) Three-item Loneliness Scale and the extent of migraine-related disability via the Migraine Disability Assessment (MIDAS). Furthermore, we evaluated patients for their ability to self-manage their migraines, and perceived effectiveness of treatment. Results: Nearly half of our population reported at least one measure of loneliness (230/500, 46.0%). Patients experiencing chronic migraine were statistically more likely to report feeling lonely when compared to patients with episodic migraines (P < .001). Patients who report loneliness had lower odds of feeling 'very satisfied" with their ability to self-manage their migraine symptoms (aOR = 0.34, 95% CI 0.14-0.81) and had lower odds of feeling "very satisfied" with their ability to avoid conditions that cause their headache (aOR = 0.39, 95% CI 0.16-0.91). Conclusions: Loneliness has significant effects on the illness experience of patients with chronic migraines, including their ability to self-manage or be satisfied with their current state of care. Psychosocial models of care that address loneliness among patients with chronic migraine may help improve health outcomes and management.

Understanding the Effect of Hydroxypropyl-ß-Cyclodextrin on Fenebrutinib Absorption in an Itraconazole-Fenebrutinib Drug-Drug Interaction Study.

Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug-drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug-drug interaction study. This observation was made in a drug-drug interaction study with the Bruton's tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (Cmax ) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (Tmax ) was observed in the itraconazole group. The in vitro binding constant between fenebrutinib and hydroxypropyl-ß-cyclodextrin was determined to be 2 × 105  M-1 , and the apparent permeability of fenebrutinib across a Madin-Darby canine kidney cell monolayer decreased in a cyclodextrin concentration-dependent manner. This observation was confirmed in vivo, in a pentagastrin-pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in Cmax , a prolonged Tmax , and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supported the hypothesis that complexation with cyclodextrin decreased rate and extent of fenebrutinib absorption. Physiologically-based pharmacokinetic modeling was used to translate the in vitro effect of cyclodextrin on fenebrutinib apparent permeability to the in vivo effect on absorption, which was then confirmed using the in vivo dog pharmacokinetic data.

Evaluating the Pharmacokinetics and Systemic Effects of a Permeability Enhancer Sodium N-[8-(2-hydroxybenzoyl)amino] Caprylate in Rats.

Oral administration is the preferred route for drug delivery and its success is highly dependent on a compound's ADME properties, of which, permeability plays a major role. Therefore, permeability enhancers are an attractive area of research in the pharmaceutical industry. Recent data suggest that sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) is an effective permeability enhancer, yet the pharmacokinetic (PK) and systemic effects of SNAC are poorly understood, specifically its oral bioavailability and systemic effects on distribution, which could influence the safety of certain drugs. To answer these questions, both in vitro and in vivo studies were conducted. Of 3 permeability enhancers (SNAC, 4-CNAB, and 5-CNAC), SNAC was found to have the greatest effect on the absorption of cyanocobalamin in rats. It was also found that SNAC is orally bioavailable (almost 40%) when dosed to rats. Based on these findings, tool compounds were co-dosed in rats to further evaluate the systemic effects of SNAC. Oral co-dosing of SNAC with an intravenous infusion of 2 poorly brain penetrant compounds, quinidine, and gabapentin, did not increase brain ISF: plasma ratio or total brain:plasma ratio for either of these compounds, implying that SNAC is effective only in the intestine at pharmacologically relevant concentrations.

Changes in Commitment and Sexual Satisfaction: Trajectories in Couple Therapy.

The purpose of this study was to examine the covarying relationship between commitment and sexual satisfaction in committed relationships throughout the course of couple therapy. A sample of 366 heterosexual couples completed questionnaires regarding sexual satisfaction and commitment at each of the first five sessions of couple therapy. Cross-lagged panel analyses revealed that, between the first and second therapy sessions, there was a bidirectional relationship between commitment and sexual satisfaction, with each variable at the first session predicting the other at the second session. In addition, sexual satisfaction at the second session predicted commitment at the third session.

Experimental and Computational Investigation of the Aerobic Oxidation of a Late Transition Metal-Hydride.

The rational development of homogeneous catalytic systems for selective aerobic oxidations of organics has been hampered by the limited available knowledge of how oxygen reacts with important organometallic intermediates. Recently, several mechanisms for oxygen insertion into late transition metal-hydride bonds have been described. Contributing to this nascent understanding of how oxygen reacts with metal-hydrides, a detailed mechanistic study of the reaction of oxygen with the IrIII hydride complex (dmPhebox)Ir(OAc)(H) (1) in the presence of acetic acid, which proceeds to form the IrIII complex (dmPhebox)Ir(OAc)2(OH2) (2), is described. The evidence supports a multifaceted mechanism wherein a small amount of an initially formed metal hydroperoxide proceeds to generate a metal-oxyl species that then initiates a radical chain reaction to rapidly convert the remaining IrIII-H. Insight into the initiation step was gained through kinetic and mechanistic studies of the radical chain inhibition by BHT (butylated hydroxytoluene). Computational studies were employed to contribute to a further understanding of initiation and propagation in this system.