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Key Points Phospholipase D (PLD) enzymes are one source of receptor-generated phosphatidic acid (PtdOH),which may subsequently be metabolized to diacylglycerol (DAG) and lysophosphatidic acid. There are other pathways that lead to PtdOH generation, but differences in pathways and in the acyl composition of the products seem to provide some specificity. Both direct and indirect inhibitors of PLD activity have been identified despite a long-held suspicion that this pathway was undruggable. The identification of raloxifene and halopemide as direct inhibitors was followed by the systematic development of isoenzyme-preferring compounds that have been used to further differentiate the functions of PLD1 and PLD2. PLD2 in host cells has been associated with viral entry processes and innate immune response pathways such that inhibition blocks efficient infection. This PLD2 pathway has been linked to autophagy via AKT kinases. As a potential target in antiretroviral therapy, PLD1 works through the CAD enzyme (which contains carbamoyl aspartate synthase, aspartate transcarbamylase and dihydro-orotase domains) to modulate pyrimidine biosynthesis. PLD activity and expression have been shown to be upregulated in several types of human cancers, in which PLD enzymes function downstream of a variety of known oncogenes. Inhibition of PtdOH production has a marked effect on tumorigenesis and malignant invasion. PLD1, PLD2 and PLD3 have each been suggested to have a role in Alzheimer disease and other neurodegenerative conditions, but a mechanism has not yet emerged to explain the roles of these proteins in central nervous system pathophysiology. Lipid second messengers such as phosphatidic acid (PtdOH) have a role in a wide range of pathological processes, and phospholipase D (PLD) enzymes are one of the major sources of signal-activated PtdOH generation. In this Review, Brown, Thomas and Lindsley discuss the development of PLD inhibitors, with a focus on isoform-specific inhibitors, and their potential applications in the treatment of cancer, neurodegeneration and infection. Lipid second messengers have essential roles in cellular function and contribute to the molecular mechanisms that underlie inflammation, malignant transformation, invasiveness, neurodegenerative disorders, and infectious and other pathophysiological processes. The phospholipase D (PLD) isoenzymes PLD1 and PLD2 are one of the major sources of signal-activated phosphatidic acid (PtdOH) generation downstream of a variety of cell-surface receptors, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins. Recent advances in the development of isoenzyme-selective PLD inhibitors and in molecular genetics have suggested that PLD isoenzymes in mammalian cells and pathogenic organisms may be valuable targets for the treatment of several human diseases. Isoenzyme-selective inhibitors have revealed complex inter-relationships between PtdOH biosynthetic pathways and the role of PtdOH in pathophysiology. PLD enzymes were once thought to be undruggable owing to the ubiquitous nature of PtdOH in cell signalling and concerns that inhibitors would be too toxic for use in humans. However, recent promising discoveries suggest that small-molecule isoenzyme-selective inhibitors may provide novel compounds for a unique approach to the treatment of cancers, neurodegenerative disorders and other afflictions of the central nervous system, and potentially serve as broad-spectrum antiviral and antimicrobial therapeutics.

I review the origins of gamma-decay isomers starting within a spherical shell-model basis. Some isomers can be directly connected to the attractive proton–neutron interaction that gives rise to low-lying aligned states with a large J min - J max gap. These two-particle isomers give rise multi-particle configurations with large J -gaps. The attractive T = 1 paring-type interactions between two protons or two neutron give rise to a close spacing between the high-lying states with J max and J max - 2 . The multi-particle configurations obtained with a pairing-type interaction can be classified by the seniority quantum number. Seniority selection rules for reduced matrix elements provide another source for isomers. Isomers can also be traced to the j -gaps in the single-particle energies obtained by realistic single-particle potentials.

Applications of configuration-mixing methods for nuclei near the proton and neutron drip lines are discussed. A short review of magic numbers is presented. Prospects for advances in the regions of four new “outposts” are highlighted: 28O, 42Si, 60Ca and 78Ni. Topics include shell gaps, single-particle properties, islands of inversion, collectivity, neutron decay, neutron halos, two-proton decay, effective charge, and quenching in knockout reactions.

BackgroundIn-utero hyperglycemia exposure influences later cardiometabolic risk, although few studies include women with pre-existing type 2 diabetes (T2D) or assess maternal body mass index (BMI) as a potential confounder.ObjectiveTo explore the association of maternal T2D and gestational diabetes mellitus (GDM) with childhood anthropometry, and the influence of maternal BMI on these associations.MethodsThe PANDORA cohort comprises women (n = 1138) and children (n = 1163). Women with GDM and T2D were recruited from a hyperglycemia in pregnancy register, and women with normoglycemia from the community. Wave 1 follow-up included 423 children, aged 1.5–5 years (median follow-up age 2.5 years). Multivariable linear regression assessed associations between maternal antenatal variables, including BMI and glycemic status, with offspring anthropometry (weight, height, BMI, skinfold thicknesses, waist, arm and head circumferences).ResultsGreater maternal antenatal BMI was associated with increased anthropometric measures in offspring independent of maternal glycemic status. After adjustment, including for maternal BMI, children exposed to maternal GDM had lower mean weight (−0.54 kg, 95% CI: −0.99, −0.11), BMI (−0.55 kg/m2, 95% CI: −0.91, −0.20), head (−0.52 cm, 95% CI: −0.88, −0.16) and mid-upper arm (−0.32 cm, 95% CI: −0.63, −0.01) circumferences, and greater mean suprailiac skinfold (0.78 mm, 95% CI: 0.13, 1.43), compared to children exposed to normoglycemia. Adjustment for maternal BMI strengthened the negative association between GDM and child weight, BMI and circumferences. Children exposed to maternal T2D had smaller mean head circumference (−0.82 cm, 95% CI: −1.33, −0.31) than children exposed to normoglycemia. Maternal T2D was no longer associated with greater child mean skinfolds (p = 0.14) or waist circumference (p = 0.18) after adjustment for maternal BMI.ConclusionsChildren exposed to GDM had greater suprailiac skinfold thickness than unexposed children, despite having lower mean weight, BMI and mid-upper arm circumference, and both GDM and T2D were associated with smaller mean head circumference. Future research should assess whether childhood anthropometric differences influence lifetime cardiometabolic and neurodevelopmental risk.

What individual differences in neural activity predict the future escalation of alcohol drinking from casual to compulsive? The neurobiological mechanisms that gate the transition from moderate to compulsive drinking remain poorly understood. We longitudinally tracked the development of compulsive drinking across a binge-drinking experience in male mice. Binge drinking unmasked individual differences, revealing latent traits in alcohol consumption and compulsive drinking despite equal prior exposure to alcohol. Distinct neural activity signatures of cortical neurons projecting to the brainstem before binge drinking predicted the ultimate emergence of compulsivity. Mimicry of activity patterns that predicted drinking phenotypes was sufficient to bidirectionally modulate drinking. Our results provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol drinking.

Rapid demographic, epidemiological, and nutritional transitons have brought a pressing need to track progress in adolescent health. Here, we present country-level estimates of 12 headline indicators from the Lancet Commission on adolescent health and wellbeing, from 1990 to 2016. Indicators included those of health outcomes (disability-adjusted life-years [DALYs] due to communicable, maternal, and nutritional diseases; injuries; and non-communicable diseases); health risks (tobacco smoking, binge drinking, overweight, and anaemia); and social determinants of health (adolescent fertility; completion of secondary education; not in education, employment, or training [NEET]; child marriage; and demand for contraception satisfied with modern methods). We drew data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016, International Labour Organisation, household surveys, and the Barro-Lee education dataset. From 1990 to 2016, remarkable shifts in adolescent health occurred. A decrease in disease burden in many countries has been offset by population growth in countries with the poorest adolescent health profiles. Compared with 1990, an additional 250 million adolescents were living in multi-burden countries in 2016, where they face a heavy and complex burden of disease. The rapidity of nutritional transition is evident from the 324·1 million (18%) of 1·8 billion adolescents globally who were overweight or obese in 2016, an increase of 176·9 million compared with 1990, and the 430·7 million (24%) who had anaemia in 2016, an increase of 74·2 million compared with 1990. Child marriage remains common, with an estimated 66 million women aged 20–24 years married before age 18 years. Although gender-parity in secondary school completion exists globally, prevalence of NEET remains high for young women in multi-burden countries, suggesting few opportunities to enter the workforce in these settings. Although disease burden has fallen in many settings, demographic shifts have heightened global inequalities. Global disease burden has changed little since 1990 and the prevalence of many adolescent health risks have increased. Health, education, and legal systems have not kept pace with shifting adolescent needs and demographic changes. Gender inequity remains a powerful driver of poor adolescent health in many countries. Australian National Health and Medical Research Council, and the Bill & Melinda Gates Foundation.

Low temperature ionic conducting materials such as OH − and H + ionic conductors are important electrolytes for electrochemical devices. Here we show the discovery of mixed OH − /H + conduction in ceramic materials. SrZr 0.8 Y 0.2 O 3- δ exhibits a high ionic conductivity of approximately 0.01 S cm −1 at 90 °C in both water and wet air, which has been demonstrated by direct ammonia fuel cells. Neutron diffraction confirms the presence of OD bonds in the lattice of deuterated SrZr 0.8 Y 0.2 O 3- δ . The OH − ionic conduction of CaZr 0.8 Y 0.2 O 3- δ in water was demonstrated by electrolysis of both H 2 18 O and D 2 O. The ionic conductivity of CaZr 0.8 Y 0.2 O 3- δ in 6 M KOH solution is around 0.1 S cm −1 at 90 °C, 100 times higher than that in pure water, indicating increased OH − ionic conductivity with a higher concentration of feed OH − ions. Density functional theory calculations suggest the diffusion of OH − ions relies on oxygen vacancies and temporarily formed hydrogen bonds. This opens a window to discovering new ceramic ionic conducting materials for near ambient temperature fuel cells, electrolysers and other electrochemical devices. Low temperature ionic conducting materials such as OH - and H + ionic conductors are important electrolyte materials. Here the authors report the discovery of fast mixed OH - /H + conductors in ceramic materials, SrZr0.8Y0.2O3-δ and CaZr0.8Y0.2O3-δ, for potential use as electrolytes in fuel cells.

Aims/hypothesisWomen with gestational diabetes mellitus (GDM) and obesity experience lower rates of breastfeeding. Little is known about breastfeeding among mothers with type 2 diabetes. Australian Indigenous women have a high prevalence of type 2 diabetes in pregnancy. We aimed to evaluate the association of hyperglycaemia, including type 2 diabetes, with breastfeeding outcomes.MethodsIndigenous (n = 495) and non-Indigenous (n = 555) participants of the Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) cohort included women without hyperglycaemia in pregnancy (n = 222), with GDM (n = 684) and with type 2 diabetes (n = 144). The associations of hyperglycaemia in pregnancy and breastfeeding at hospital discharge, 6 weeks and 6 months post-partum were evaluated with logistic regression, after adjustment for maternal obesity, ethnicity, maternal and neonatal characteristics.ResultsIndigenous women were more likely to predominantly breastfeed at 6 weeks across all levels of hyperglycaemia. Compared with women with no hyperglycaemia in pregnancy, women with type 2 diabetes had lower odds for exclusive breastfeeding at discharge (adjusted OR for exclusive breastfeeding 0.4 [95% CI 0.2, 0.8] p = 0.006). At 6 weeks and 6 months, the relationship between type 2 diabetes and predominant breastfeeding was not statistically significant (6 weeks 0.7 [0.3, 1.6] p = 0.40, 6 months 0.8 [0.4, 1.6] p = 0.60). Women with gestational diabetes were as likely to achieve predominant breastfeeding at 6 weeks and 6 months as women without hyperglycaemia in pregnancy.Conclusions/interpretationIndigenous women had high rates of breastfeeding. Women with type 2 diabetes had difficulty establishing exclusive breastfeeding at hospital discharge. Further research is needed to assess the impact on long-term breastfeeding outcomes.

Indigenous populations have high rates of disease and premature mortality. Most Indigenous communities are young, and adolescence (age 10–24 years) provides great opportunities for population health gain. However, the absence of a comprehensive account of Indigenous adolescents' health has been a barrier to effective policy. We aimed to report a national health profile for Indigenous adolescents in Australia. We undertook a systematic synthesis of population data to report the health and wellbeing of Indigenous adolescents in Australia. A reporting framework for Indigenous adolescent health in Australia was defined to measure health outcomes, health risks, and sociocultural determinants. Available data (primary data from national surveys and administrative datasets, and available published data) were mapped against the defined reporting framework, and the quality graded, with the highest quality data selected to report a health profile for Indigenous adolescents. Comparison with non-Indigenous adolescents was made where possible, and estimates (disaggregated by age, sex, and remoteness) were reported as relative risks. A national advisory group (six Indigenous young people, three Indigenous adult community members, three researchers, three policy makers, and two service providers, all aged ≥16 years) provided input about the reporting framework, interpretation of findings, and policy recommendations. Data were available for 184 (79%) of 234 elements of the reporting framework. All-cause mortality for Indigenous adolescents (70 per 100 000) was more than twice that of non-Indigenous adolescents, with about 60% of deaths due to intentional self-harm and road traffic injury. 80% of all deaths among Indigenous adolescents were considered as potentially avoidable in the current health system. Communicable diseases (particularly sexually transmitted infections) were leading contributors to morbidity. Almost a third of Indigenous adolescents aged 18–24 years reported high levels of psychological distress (twice the non-Indigenous rate). There was an excess burden of mental disorders and substance use, alongside emerging type 2 diabetes and ischaemic heart disease. Additionally, there were excess intentional and unintentional injuries. Many aspects of this health profile differed markedly from that of non-Indigenous adolescents: rates of acute rheumatic fever, pneumococcal infection, gonorrhoea, and type 2 diabetes resulting in admission to hospital were ten times higher; rates of assault and childbirth in those aged 15–19 years were five times higher; whereas rates of eating disorders, melanoma and other skin cancers, and anaphylaxis were significantly lower. Risks for future ill-health were common; 43% of 15–24 year olds were current tobacco smokers and about 45% had high body mass (overweight or obese). Disadvantage across sociocultural health determinants also emerged, particularly around education. Despite Australia's adolescents having one of the best health profiles globally, Indigenous adolescents have largely been left behind. Adequate responses will require intersectoral actions, including a health system responsive to the needs of Indigenous adolescents. Without a specific focus on adolescents, Australia will not redress Indigenous health inequalities. Australia's National Health and Medical Research Council, Sidney Myer Foundation, and the Murdoch Children's Research Institute.

Sacrificial anodes have been broadly deployed in electro-synthesis for the development of reductive electrosynthetic reactions. The metal cations released from sacrificial anodes during these processes are widely believed to not affect reaction outcomes. Here, we disclose an electrochemical deutero-(di)carboxylation of acetylenes and cinnamic acids that in fact relies on anodically generated Mg 2+ cations to achieve regioselective α -carboxylation to afford deuterated malonic acids with precise control over both the site and amount of deuteration. The unusual, beneficial role of Mg 2+ cations on product selectivity is supported by mechanistic studies and density functional theory [ZORA-B3LYP-D3BJ/def2-TZVP/DMF(SMD)] calculations, and is believed to mimic enzymatic α -carboxylation mechanisms. The deuteration patterns in the malonic acid products can be precisely controlled, providing a platform for the concise synthesis of high-value β - d₂ - and β - d₁ - α -amino acid analogs, as well as other precisely deuterated frameworks. The metal cations released from sacrificial anodes during reductive electrosynthetic reactions are widely believed to not affect reaction outcomes. Here, the authors disclose an electrochemical deutero-(di)carboxylation that relies on anodically generated Mg 2+ cations to achieve selectivity in both the site and amount of deuteration.