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NAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are incompletely understood. Yeast (Saccharomyces cerevisiae) cells lacking the N-terminal (Nt) protein acetyltransferase complex NatB exhibit an approximate 50% reduction in NAD+ levels and aberrant metabolism of NAD+ precursors, changes that are associated with a decrease in nicotinamide mononucleotide adenylyltransferase (Nmnat) protein levels. Here, we show that this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins and not of other NatB substrates. Nt-acetylation critically regulates protein degradation by the N-end rule pathways, suggesting that the absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t½) of non-Nt-acetylated Nmnats did not significantly differ from those of Nt-acetylated Nmnats. Accordingly, deletion or depletion of the N-end rule pathway ubiquitin E3 ligases in NatB mutants did not restore NAD+ levels. Next, we examined whether the status of Nt-acetylation would affect the translation of Nmnats, finding that the absence of Nt-acetylation does not significantly alter the polysome formation rate on Nmnat mRNAs. However, we observed that NatB mutants have significantly reduced Nmnat protein maturation. Our findings indicate that the reduced Nmnat levels in NatB mutants are mainly due to inefficient protein maturation. Nmnat activities are essential for all NAD+ biosynthesis routes, and understanding the regulation of Nmnat protein homeostasis may improve our understanding of the molecular basis and regulation of NAD+ metabolism.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite involved in various cellular processes. The cellular NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD+ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD+ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD+ metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD+ homeostasis factors. These findings help provide a molecular basis for how may NAD+ and NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD+ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD+ homeostasis, and regulation of NAD+ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD+ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD+ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD+ homeostasis. These studies may also contribute to the development of effective NAD+-based therapeutic strategies specific for different types of NAD+ deficiency related disorders.

NADH (NAD+) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD+ metabolism is incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established an NAD+ intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD+ biosynthesis. We found that a mutant strain (mac1Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD+ levels. Similar phenotypes were also observed in the hst1Δ strain, deficient in the NAD+-dependent histone deacetylase Hst1, which inhibits de novo NAD+ synthesis by repressing BNA gene expression when NAD+ is abundant. Interestingly, the mac1Δ and hst1Δ mutants shared a similar NAD+ metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD+ synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD+ synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novo NAD+ synthesis. In summary, we have identified and characterized novel NAD+ homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD+ metabolism.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD+ metabolism is not yet fully understood. To investigate this, we established a NAD+-intermediate specific reporter system to identify factors required for salvage of metabolically linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an Nα-terminal acetyltransferase responsible for acetylation of the N terminus of specific Met-retained peptides. In NatB mutants, increased NA/NAM levels were concomitant with decreased NAD+ We identified the vacuolar pool of nicotinamide riboside (NR) as the source of this increased NA/NAM. This NR pool is increased by nitrogen starvation, suggesting NAD+ and related metabolites may be trafficked to the vacuole for recycling. Supporting this, increased NA/NAM release in NatB mutants was abolished by deleting the autophagy protein ATG14 We next examined Tpm1 (tropomyosin), whose function is regulated by NatB-mediated acetylation, and Tpm1 overexpression (TPM1-oe) was shown to restore some NatB mutant defects. Interestingly, although TPM1-oe largely suppressed NA/NAM release in NatB mutants, it did not restore NAD+ levels. We showed that decreased nicotinamide mononucleotide adenylyltransferase (Nma1/Nma2) levels probably caused the NAD+ defects, and NMA1-oe was sufficient to restore NAD+ NatB-mediated N-terminal acetylation of Nma1 and Nma2 appears essential for maintaining NAD+ levels. In summary, our results support a connection between NatB-mediated protein acetylation and NAD+ homeostasis. Our findings may contribute to understanding the molecular basis and regulation of NAD+ metabolism.

NAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are incompletely understood. Yeast (Saccharomyces cerevisiae) cells lacking the N-terminal (Nt) protein acetyltransferase complex NatB exhibit an approximate 50% reduction in NAD+ levels and aberrant metabolism of NAD+ precursors, changes that are associated with a decrease in nicotinamide mononucleotide adenylyltransferase (Nmnat) protein levels. Here, we show that this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins and not of other NatB substrates. Nt-acetylation critically regulates protein degradation by the N-end rule pathways, suggesting that the absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats did not significantly differ from those of Nt-acetylated Nmnats. Accordingly, deletion or depletion of the N-end rule pathway ubiquitin E3 ligases in NatB mutants did not restore NAD+ levels. Next, we examined whether the status of Nt-acetylation would affect the translation of Nmnats, finding that the absence of Nt-acetylation does not significantly alter the polysome formation rate on Nmnat mRNAs. However, we observed that NatB mutants have significantly reduced Nmnat protein maturation. Our findings indicate that the reduced Nmnat levels in NatB mutants are mainly due to inefficient protein maturation. Nmnat activities are essential for all NAD+ biosynthesis routes, and understanding the regulation of Nmnat protein homeostasis may improve our understanding of the molecular basis and regulation of NAD+ metabolism. [ABSTRACT FROM AUTHOR]

A reporter has refused to allow the construction of a driveway and parking area in front of a house in an Aberdeenshire conservation area after finding that it would set [...]

NADH (NAD+) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD+ metabolism is incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established an NAD+ intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD+ biosynthesis. We found that a mutant strain (mac1Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD+ levels. Similar phenotypes were also observed in the hst1Δ strain, deficient in the NAD+-dependent histone deacetylase Hst1, which inhibits de novo NAD+ synthesis by repressing BNA gene expression when NAD+ is abundant. Interestingly, the mac1Δ and hst1Δ mutants shared a similar NAD+ metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD+ synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD+ synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novoNAD+ synthesis. In summary, we have identified and characterized novel NAD+ homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD+ metabolism. [ABSTRACT FROM AUTHOR]

Objective: Prevalence ranges to classify levels of wasting and stunting have been used since the 1990s for global monitoring of malnutrition. Recent developments prompted a re-examination of existing ranges and development of new ones for childhood overweight. The present paper reports from the WHO-UNICEF Technical Expert Advisory Group on Nutrition Monitoring.Design: Thresholds were developed in relation to sd of the normative WHO Child Growth Standards. The international definition of 'normal' (2 sd below/above the WHO standards median) defines the first threshold, which includes 2·3 % of the area under the normalized distribution. Multipliers of this 'very low' level (rounded to 2·5 %) set the basis to establish subsequent thresholds. Country groupings using the thresholds were produced using the most recent set of national surveys.Setting: One hundred and thirty-four countries.Subjects: Children under 5 years.Results: For wasting and overweight, thresholds are: 'very low' (≈6 times 2·5 %). For stunting, thresholds are: 'very low' (≈12 times 2·5 %).Conclusions: The proposed thresholds minimize changes and keep coherence across anthropometric indicators. They can be used for descriptive purposes to map countries according to severity levels; by donors and global actors to identify priority countries for action; and by governments to trigger action and target programmes aimed at achieving 'low' or 'very low' levels. Harmonized terminology will help avoid confusion and promote appropriate interventions. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD+ metabolism is not yet fully understood. To investigate this, we established a NAD+- intermediate specific reporter system to identify factors required for salvage of metabolically linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an N-terminal acetyltransferase responsible for acetylation of the N terminus of specific Met-retained peptides. In NatB mutants, increasedNA/NAMlevels were concomitant with decreased NAD+. We identified the vacuolar pool of nicotinamide riboside (NR) as the source of this increased NA/NAM. This NR pool is increased by nitrogen starvation, suggesting NAD+ and related metabolites may be trafficked to the vacuole for recycling. Supporting this, increased NA/NAMrelease in NatB mutants was abolished by deleting the autophagy protein ATG14. We next examined Tpm1 (tropomyosin), whose function is regulated by NatB-mediated acetylation, and Tpm1 overexpression (TPM1-oe) was shown to restore some NatB mutant defects. Interestingly, although TPM1-oe largely suppressed NA/NAM release in NatB mutants, it did not restore NAD+ levels. We showed that decreased nicotinamide mononucleotide adenylyltransferase (Nma1/Nma2) levels probably caused theNAD+ defects, and NMA1-oe was sufficient to restore NAD+. NatB-mediated N-terminal acetylation of Nma1 and Nma2 appears essential for maintaining NAD+ levels. In summary, our results support a connection between NatB-mediated protein acetylation and NAD+ homeostasis. Our findings may contribute to understanding the molecular basis and regulation of NAD+ metabolism. [ABSTRACT FROM AUTHOR]

The increased attention to tracking progress towards the Millennium Development Goals (MDG), including Goal 4 of reducing child mortality, has drawn attention to a number of interrelated technical, operational and political challenges and to the underlying weaknesses of country health information systems upon which reliable monitoring depends. Assessments of child mortality published in 2005, for almost all low-income countries, are based on an extrapolation of the trends observed during the 1990s, rather than on the empirical data for more recent years. The validity of the extrapolation depends on the quality and quantity of the data used, and many countries lack suitable data. In the long run, it is hoped that vital registration or sample registration systems will be established to monitor vital events in a sustainable way. However, in the short run, tracking child mortality in high-mortality countries will continue to rely on household surveys and extrapolations of historical trends. This will require more collaborative efforts both to collect data through initiatives to strengthen health information systems at the country level, and to harmonize the estimation process. The latter objective requires the continued activity of a coordinating group of international agencies and academics that aims to produce transparent estimates — through the consistent application of an agreed-upon methodology — for monitoring at the international level. [ABSTRACT FROM AUTHOR]

NAD + is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD + biosynthesis pathways are incompletely understood. Yeast ( Saccharomyces cerevisiae ) cells lacking the N-terminal (Nt) protein acetyltransferase complex NatB exhibit an approximate 50% reduction in NAD + levels and aberrant metabolism of NAD + precursors, changes that are associated with a decrease in nicotinamide mononucleotide adenylyltransferase (Nmnat) protein levels. Here, we show that this decrease in NAD + and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins and not of other NatB substrates. Nt-acetylation critically regulates protein degradation by the N-end rule pathways, suggesting that the absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover ( t ½ ) of non-Nt-acetylated Nmnats did not significantly differ from those of Nt-acetylated Nmnats. Accordingly, deletion or depletion of the N-end rule pathway ubiquitin E3 ligases in NatB mutants did not restore NAD + levels. Next, we examined whether the status of Nt-acetylation would affect the translation of Nmnats, finding that the absence of Nt-acetylation does not significantly alter the polysome formation rate on Nmnat mRNAs. However, we observed that NatB mutants have significantly reduced Nmnat protein maturation. Our findings indicate that the reduced Nmnat levels in NatB mutants are mainly due to inefficient protein maturation. Nmnat activities are essential for all NAD + biosynthesis routes, and understanding the regulation of Nmnat protein homeostasis may improve our understanding of the molecular basis and regulation of NAD + metabolism., (© 2020 Croft et al.)

Nicotinamide adenine dinucleotide (NAD + ) is an essential metabolite involved in various cellular processes. The cellular NAD + pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD + metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD + homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD + metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD + homeostasis factors. These findings help provide a molecular basis for how may NAD + and NAD + homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD + biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD + homeostasis, and regulation of NAD + metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD + homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD + precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD + homeostasis. These studies may also contribute to the development of effective NAD + -based therapeutic strategies specific for different types of NAD + deficiency related disorders.

NADH (NAD + ) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD + metabolism is incompletely understood. Here, using budding yeast ( Saccharomyces cerevisiae ), we established an NAD + intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD + biosynthesis. We found that a mutant strain ( mac1 Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD + levels. Similar phenotypes were also observed in the hst1 Δ strain, deficient in the NAD + -dependent histone deacetylase Hst1, which inhibits de novo NAD + synthesis by repressing BNA gene expression when NAD + is abundant. Interestingly, the mac1 Δ and hst1 Δ mutants shared a similar NAD + metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD + synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD + synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novo NAD + synthesis. In summary, we have identified and characterized novel NAD + homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD + metabolism., (© 2019 James Theoga Raj et al.)

Nicotinamide adenine dinucleotide (NAD + ) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD + metabolism is not yet fully understood. To investigate this, we established a NAD + -intermediate specific reporter system to identify factors required for salvage of metabolically linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an N α -terminal acetyltransferase responsible for acetylation of the N terminus of specific Met-retained peptides. In NatB mutants, increased NA/NAM levels were concomitant with decreased NAD + We identified the vacuolar pool of nicotinamide riboside (NR) as the source of this increased NA/NAM. This NR pool is increased by nitrogen starvation, suggesting NAD + and related metabolites may be trafficked to the vacuole for recycling. Supporting this, increased NA/NAM release in NatB mutants was abolished by deleting the autophagy protein ATG14 We next examined Tpm1 (tropomyosin), whose function is regulated by NatB-mediated acetylation, and Tpm1 overexpression ( TPM1-oe ) was shown to restore some NatB mutant defects. Interestingly, although TPM1-oe largely suppressed NA/NAM release in NatB mutants, it did not restore NAD + levels. We showed that decreased nicotinamide mononucleotide adenylyltransferase (Nma1/Nma2) levels probably caused the NAD + defects, and NMA1-oe was sufficient to restore NAD + NatB-mediated N-terminal acetylation of Nma1 and Nma2 appears essential for maintaining NAD + levels. In summary, our results support a connection between NatB-mediated protein acetylation and NAD + homeostasis. Our findings may contribute to understanding the molecular basis and regulation of NAD + metabolism., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Skilled attendance at delivery is one of the key indicators to reflect progress toward the Millennium Development Goal of improving maternal health. This paper assesses global progress in the use of skilled attendants at delivery and identifies factors that could assist in achieving Millennium Development Goals for maternal health. National data covering a substantial proportion of all developing country births were used for the estimation of trends and key differentials in skilled assistance at delivery. Between 1990 and 2000, the percentage of births with a skilled attendant increased from 45% to 54% in developing countries, primarily as a result of an increasing use of doctors. A substantial proportion of antenatal care users do not deliver with a skilled attendant. Delivery care use among antenatal care users is highly correlated with wealth. Women aged 35 and above, who are at greatest risk of maternal death, are the least likely to receive professional delivery care. Births in mid-level facilities appear to be a strategy that has been overlooked. More effective strategies are needed to promote skilled attendance at birth during antenatal care, particularly among poor women. Specific interventions are also needed to encourage older and high parity mothers to seek professional care at delivery.